of patients 150 832 596 153 CV mortality 12.0% 17.1% 23.3% 26.1% Annual CV mortality 2.2% 3.1% 4.2% 4.7%

60-79 60-79

Fig. 1. Differences in cardiovascular mortality between patients without PVCs (black) and those with PVCs (gray) are shown. Within each heart rate group, there is a significant increase in mortality when PVCs are present (p<0.001). Mortality also increases as heart rate increases in both patients with and without PVCs (p<0.001). PVC = premature ventricular

pvc

**Heart Rate (bpm)**

80-99 80-99

pvc

>100 >100

pvc

Without PVCs

**Heart Rate 80-99**

**Heart Rate >99**

**Heart Rate <60**

CV = cardiovascular; PVC = premature ventricular contraction Table IV. Cardiovascular mortality by heart rate group.

<60 <60

pvc

With PVCs

cardiovascular mortality.

0%

10%

**Cardiovascular** 

contraction

**Mortality**

20%

30%

Multiple PVCs (≥2 PVC per ECG) were present in 47% patients with PVCs. Of these 10% were couplets or salvos, 21% had multiform morphologies, and 15% had ventricular bigeminal or trigeminal patterns. The demographics and prevalence of ECG abnormalities for these patients are shown in Table II. Patients with multiple PVCs were older than those with only single PVCs present on the ECG. Those with complex forms were older than those with non-complex morphologies. There were no statistically significant differences in the prevalence of Q waves, LVH, right or left bundle branch block between those patients with or without multiple PVCs. Patients with complex PVCs had statistically significantly more Q waves on their ECGs than those without complex PVCs (p=0.007).

The average annual all-cause mortality in the total population was 3.9% with mortality in those with PVCs (6.7%) significantly higher than for those without PVCs (3.8%) (Table III). The average annual CV mortality in the total population was 1.5% (39% of the deaths) with CV mortality in those with PVCs (3.5%) significantly higher than for those without PVCs (1.4%). Those with complex PVCs had an annual CV mortality rate of 5.1%. The hazard ratios for patients with all types of PVCs were significantly increased when compared to patients having no PVCs on an ECG. The age-adjusted hazard ratios in patients with any PVCs versus those with no PVCs was 1.39 (95% CI 1.29 - 1.50) for all cause mortality and 1.81 (95% CI 1.62 - 2.01) for cardiovascular mortality. There was no statistically significant difference in mortality between patients who had multiple (≥2) PVCs per ECG and those with only single PVCs. The age-adjusted hazard ratio for complex PVCs (versus no PVCs) for all-cause and cardiovascular mortality in all patients was 1.6 (95% CI 1.3-1.9) and 2.1 (95% CI 1.6-2.8), respectively. Patients with complex PVCs appeared to have increased allcause and CV mortality as compared to those with non-complex PVCs but the difference in survival did not achieve statistical significance. Similar findings resulted when the analysis was limited to patients with normal resting ECGs. After considering age, BMI, and ECG findings in a Cox hazard model, the presence of any resting PVCs were found to be independent predictors of mortality with a hazard ratio of 2.0 (95% CI 1.1-2.8)


CV = cardiovascular; PVC = premature ventricular contraction.

Table III. Mortality in patients with and without PVCs.

When patients were divided into groups by heart rate (<60, 60-79, 80-99 and >100 bpm) and by the presence or absence of PVCs, mortality increased progressively with heart rate and doubled with the presence of PVCs (Table IV, Figure 1). Cardiovascular mortality ranged from a low of 6.3% in those with heart rates less than 60 bpm and no PVCs to a high of 26.1% in those with a heart rate > 100 bpm and PVCs. Within each heart rate group, there was a significant increase in mortality when PVCs were present (p<0.001). The differences in

Multiple PVCs (≥2 PVC per ECG) were present in 47% patients with PVCs. Of these 10% were couplets or salvos, 21% had multiform morphologies, and 15% had ventricular bigeminal or trigeminal patterns. The demographics and prevalence of ECG abnormalities for these patients are shown in Table II. Patients with multiple PVCs were older than those with only single PVCs present on the ECG. Those with complex forms were older than those with non-complex morphologies. There were no statistically significant differences in the prevalence of Q waves, LVH, right or left bundle branch block between those patients with or without multiple PVCs. Patients with complex PVCs had statistically significantly more Q

The average annual all-cause mortality in the total population was 3.9% with mortality in those with PVCs (6.7%) significantly higher than for those without PVCs (3.8%) (Table III). The average annual CV mortality in the total population was 1.5% (39% of the deaths) with CV mortality in those with PVCs (3.5%) significantly higher than for those without PVCs (1.4%). Those with complex PVCs had an annual CV mortality rate of 5.1%. The hazard ratios for patients with all types of PVCs were significantly increased when compared to patients having no PVCs on an ECG. The age-adjusted hazard ratios in patients with any PVCs versus those with no PVCs was 1.39 (95% CI 1.29 - 1.50) for all cause mortality and 1.81 (95% CI 1.62 - 2.01) for cardiovascular mortality. There was no statistically significant difference in mortality between patients who had multiple (≥2) PVCs per ECG and those with only single PVCs. The age-adjusted hazard ratio for complex PVCs (versus no PVCs) for all-cause and cardiovascular mortality in all patients was 1.6 (95% CI 1.3-1.9) and 2.1 (95% CI 1.6-2.8), respectively. Patients with complex PVCs appeared to have increased allcause and CV mortality as compared to those with non-complex PVCs but the difference in survival did not achieve statistical significance. Similar findings resulted when the analysis was limited to patients with normal resting ECGs. After considering age, BMI, and ECG findings in a Cox hazard model, the presence of any resting PVCs were found to be

waves on their ECGs than those without complex PVCs (p=0.007).

independent predictors of mortality with a hazard ratio of 2.0 (95% CI 1.1-2.8)

**No PVCs N=43,671**

All-cause mortality 23% 22% 39% <0.001

mortality 3.9% 3.8% 6.7% <0.001

CV mortality 8.3% 7.9% 19.6% <0.001

When patients were divided into groups by heart rate (<60, 60-79, 80-99 and >100 bpm) and by the presence or absence of PVCs, mortality increased progressively with heart rate and doubled with the presence of PVCs (Table IV, Figure 1). Cardiovascular mortality ranged from a low of 6.3% in those with heart rates less than 60 bpm and no PVCs to a high of 26.1% in those with a heart rate > 100 bpm and PVCs. Within each heart rate group, there was a significant increase in mortality when PVCs were present (p<0.001). The differences in

Annual CV mortality 1.5% 1.4% 3.5% <0.001

**PVCs**

**N=1,731 P-value**

**Total N=45,402**

CV = cardiovascular; PVC = premature ventricular contraction. Table III. Mortality in patients with and without PVCs.

Annual all-cause

event free survival between groups is also clearly demonstrated with Kaplan-Meier cumulative survival curve (Figure 2). The PVC and heart rate stratifications performed similarly when patients were divided into those with normal and abnormal ECGs. Cox regression analysis (controlled for age, gender, outpatient vs. inpatient status and normal vs. abnormal ECG) demonstrates that PVCs (RR 1.61, 95% CI 1.44-1.80, p<0.001) and heart rate (RR 1.02 for each 1 bpm increase, 95% CI 1.01-1.02, p<0.001) are independent predictors of cardiovascular mortality.


CV = cardiovascular; PVC = premature ventricular contraction

Table IV. Cardiovascular mortality by heart rate group.

Fig. 1. Differences in cardiovascular mortality between patients without PVCs (black) and those with PVCs (gray) are shown. Within each heart rate group, there is a significant increase in mortality when PVCs are present (p<0.001). Mortality also increases as heart rate increases in both patients with and without PVCs (p<0.001). PVC = premature ventricular contraction

The Prevalence and Prognostic Value of Rest Premature Ventricular Contractions 35

mechanisms cannot replace the evidence based approach. Partly due to these results, PVCs are generally ignored on a routine ECG. But, PVCs may still have an important role in risk

A higher prevalence of PVCs has been seen in patients with coronary artery disease (Bikkina, Larson, & Levy, 1992), hypertension (Vogt et al., 1990), accompanying ECG abnormalities (Fisher & Tyroler, 1973), and nearly every form of structural heart disease. PVCs also increase with age (Flegg, 1988; Kostis et al., 1982). In the acute phase of myocardial infarction, PVCs are seen in 80-90% of patients and have been related to residual ischemia (Mukharji et al., 1984), degree of coronary narrowing (Minisi et al., 1988), degree of left ventricular involvement (Bigger et al., 1984; Tracy et al., 1987), and age of infarction

In patients without established cardiovascular disease, there have been conflicting findings with some authors concluding that PVCs are benign in this population (Fleg & Kennedy, 1992; Rodstein, Wolloch, & Gubner, 1971) and others reporting increased mortality (Abdalla et al., 1987; Bikkina, Larson, & Levy, 1992; Rabkin, Mathewson & Tate, 1981) although the methods used to determine true absence of coronary artery disease varied greatly between studies. Our results are consistent with the Framingham Heart Study of 6,033 men and women who underwent one hour ambulatory electrocardiography (Bikkina, Larson, & Levy, 1992). After adjusting for age and traditional risk factors for coronary artery disease, there was a significant and independent association between asymptomatic ectopy in men without clinically apparent coronary heart disease and the risk for all-cause mortality (RR 2.3) as well as death from coronary heart disease (RR 2.1). Such an association was not seen

The idea that looking at the frequency and morphology of PVCs might provide additional predictive power has been investigated. Ismaile et al. reported findings from a prospective study of 15,637 apparently healthy white men who underwent screening for the Multiple Risk Factor Intervention Trial (MRFIT) (Abdalla et al., 1987). They used 2 minute resting rhythm strips and concluded that the presence of frequent or complex PVCs is associated with a significant and independent risk for sudden cardiac death (RR 4.2; RR 3.0 for the presence of any PVCs). Our study confirms the risk predicted by any PVC but only shows a non-significant trend towards worse outcome with complex or multiple PVCs. This may be because we looked at all-cause and cardiovascular mortality but did not limit our outcome

Gillman et al. evaluated 4,530 untreated hypertensives using 36-year follow-up data from the Framingham Study (Gillman et al., 1993). Regression analysis, after adjustment for age and systolic blood pressure, showed that there was a two-fold increase in cardiovascular mortality for each heart rate increment of 40 beats/min. In a French study of 19,386 subjects undergoing routine health examinations, resting tachycardia was demonstrated to be a predictor of non-cardiovascular mortality in both genders, and of cardiovascular mortality in men, independent of age and blood pressure (Benetos et al., 1999). Heart rate on the initial ECG after acute myocardial infarction has also been shown to be an independent predictor of prognosis (Hathaway et al., 1998). Our results add to the evidence that heart rate is an

in women or in men with known coronary artery disease.

stratification even if treatment with antiarrhythmic medications is not appropriate.

(Kostis et al., 1987).

to sudden death.

**5.2 Heart rate** 

important prognostic variable.

Logisitic regression controlled for age, gender and normal vs. abnormal ECG was performed to confirm that heart rate was a significant and independent predictor of the presence of PVCs (OR 1.40 for each 20 bpm, 95% CI 1.33 to 1.48, p<0.001).

Although patients with PVCs were older than those without PVCs (univariate analysis above), age alone cannot explain the different heart rates because regression analysis showed that resting heart rate did not change significantly with age (slope of less than 1 bpm per decade). When multiple regression analysis was performed to evaluate predictors of heart rate, age did not demonstrate a statistically significant contribution.

Fig. 2. Kaplan-Meier cumulative survival curves demonstrate decreasing survival with increasing heart rate among patients without PVCs and more significant declines in survival in those with PVCs. The curves followed a consistent order with increasing mortality with increasing rate and with the matching color coded line with PVCs exhibiting an increased mortality. PVC = premature ventricular contraction

### **5. Discussion**

### **5.1 PVCs**

The "PVC hypothesis" that PVC suppression would prevent sudden death was popularized by Lown and others in the 1960's and 1970's and was accepted as dogma well into the late 1980's. It was based on seemingly sound logic that that sudden death in myocardial infarction survivors is due to ventricular fibrillation (Nikolic & Bishop 1982; Pratt, Francis & Luck, 1983) and that PVCs precede and therefore identify those patients who are susceptible to these episodes (Lown, 1971). It was assumed that the suppression of PVCs with antiarrhythmic drugs would be beneficial but the disappointing results of the CAST trials (CAST Investigators, 1989, 1992) negated the causal role theory of PVCs. In fact, the negating of the "PVC hypothesis" by the CAST results is a classic example of why hypothetical mechanisms cannot replace the evidence based approach. Partly due to these results, PVCs are generally ignored on a routine ECG. But, PVCs may still have an important role in risk stratification even if treatment with antiarrhythmic medications is not appropriate.

A higher prevalence of PVCs has been seen in patients with coronary artery disease (Bikkina, Larson, & Levy, 1992), hypertension (Vogt et al., 1990), accompanying ECG abnormalities (Fisher & Tyroler, 1973), and nearly every form of structural heart disease. PVCs also increase with age (Flegg, 1988; Kostis et al., 1982). In the acute phase of myocardial infarction, PVCs are seen in 80-90% of patients and have been related to residual ischemia (Mukharji et al., 1984), degree of coronary narrowing (Minisi et al., 1988), degree of left ventricular involvement (Bigger et al., 1984; Tracy et al., 1987), and age of infarction (Kostis et al., 1987).

In patients without established cardiovascular disease, there have been conflicting findings with some authors concluding that PVCs are benign in this population (Fleg & Kennedy, 1992; Rodstein, Wolloch, & Gubner, 1971) and others reporting increased mortality (Abdalla et al., 1987; Bikkina, Larson, & Levy, 1992; Rabkin, Mathewson & Tate, 1981) although the methods used to determine true absence of coronary artery disease varied greatly between studies. Our results are consistent with the Framingham Heart Study of 6,033 men and women who underwent one hour ambulatory electrocardiography (Bikkina, Larson, & Levy, 1992). After adjusting for age and traditional risk factors for coronary artery disease, there was a significant and independent association between asymptomatic ectopy in men without clinically apparent coronary heart disease and the risk for all-cause mortality (RR 2.3) as well as death from coronary heart disease (RR 2.1). Such an association was not seen in women or in men with known coronary artery disease.

The idea that looking at the frequency and morphology of PVCs might provide additional predictive power has been investigated. Ismaile et al. reported findings from a prospective study of 15,637 apparently healthy white men who underwent screening for the Multiple Risk Factor Intervention Trial (MRFIT) (Abdalla et al., 1987). They used 2 minute resting rhythm strips and concluded that the presence of frequent or complex PVCs is associated with a significant and independent risk for sudden cardiac death (RR 4.2; RR 3.0 for the presence of any PVCs). Our study confirms the risk predicted by any PVC but only shows a non-significant trend towards worse outcome with complex or multiple PVCs. This may be because we looked at all-cause and cardiovascular mortality but did not limit our outcome to sudden death.

#### **5.2 Heart rate**

34 Advances in Electrocardiograms – Clinical Applications

Logisitic regression controlled for age, gender and normal vs. abnormal ECG was performed to confirm that heart rate was a significant and independent predictor of the

Although patients with PVCs were older than those without PVCs (univariate analysis above), age alone cannot explain the different heart rates because regression analysis showed that resting heart rate did not change significantly with age (slope of less than 1 bpm per decade). When multiple regression analysis was performed to evaluate predictors

Heart Rate Group

 <60 li 60-79 80-99 >100

HRg

12.0

Fig. 2. Kaplan-Meier cumulative survival curves demonstrate decreasing survival with increasing heart rate among patients without PVCs and more significant declines in survival in those with PVCs. The curves followed a consistent order with increasing mortality with increasing rate and with the matching color coded line with PVCs exhibiting an increased

0.0 3.0 6.0 9.0 12.0 Years

The "PVC hypothesis" that PVC suppression would prevent sudden death was popularized by Lown and others in the 1960's and 1970's and was accepted as dogma well into the late 1980's. It was based on seemingly sound logic that that sudden death in myocardial infarction survivors is due to ventricular fibrillation (Nikolic & Bishop 1982; Pratt, Francis & Luck, 1983) and that PVCs precede and therefore identify those patients who are susceptible to these episodes (Lown, 1971). It was assumed that the suppression of PVCs with antiarrhythmic drugs would be beneficial but the disappointing results of the CAST trials (CAST Investigators, 1989, 1992) negated the causal role theory of PVCs. In fact, the negating of the "PVC hypothesis" by the CAST results is a classic example of why hypothetical

mortality. PVC = premature ventricular contraction

0.500

0.625

0.750

Survival

Survival

0.875

1.000

**5. Discussion** 

**5.1 PVCs** 

presence of PVCs (OR 1.40 for each 20 bpm, 95% CI 1.33 to 1.48, p<0.001).

of heart rate, age did not demonstrate a statistically significant contribution.

Gillman et al. evaluated 4,530 untreated hypertensives using 36-year follow-up data from the Framingham Study (Gillman et al., 1993). Regression analysis, after adjustment for age and systolic blood pressure, showed that there was a two-fold increase in cardiovascular mortality for each heart rate increment of 40 beats/min. In a French study of 19,386 subjects undergoing routine health examinations, resting tachycardia was demonstrated to be a predictor of non-cardiovascular mortality in both genders, and of cardiovascular mortality in men, independent of age and blood pressure (Benetos et al., 1999). Heart rate on the initial ECG after acute myocardial infarction has also been shown to be an independent predictor of prognosis (Hathaway et al., 1998). Our results add to the evidence that heart rate is an important prognostic variable.

The Prevalence and Prognostic Value of Rest Premature Ventricular Contractions 37

Some investigators have proposed the nerve sprouting hypothesis of ventricular arrhythmia to explain arrhythmic events seen in patients with a history of myocardial infarction (Chen et al, 2001). The theory is that myocardial damage results in nerve injury which is followed by sympathetic nerve sprouting and regionally increased sympathetic tone. The increased SNS activity in the local area of remodeled myocardium results in PVCs, ventricular tachycardia/fibrillation and sudden death. Support for this hypothesis was provided by an evaluation of cardiac nerves in explanted native hearts of human transplant recipients (Cao et al., 2000). Infusion of nerve growth factor into the left stellate ganglion of dogs was also shown to result in increased development of ventricular arrhythmias (Cao et al., 2000). The recurring theme of research in this area is that the response to injury results in heterogeneous sympathetic innervation which is highly arrhythmogenic (Verrier &

The population in our study included a relatively diverse group of all consecutive inpatients and outpatients who had a 12-lead ECG for any reason; the only exclusion criteria were the presence of atrial fibrillation or a paced rhythm. This differs from many previous studies of either more narrowly defined high-risk populations of patients referred to electrophysiologists or more broadly defined low-risk community epidemiological cohorts. These differences may be an advantage as our study is clinically based and includes all patients at our facility referred for an ECG. Base-line clinical data, laboratory studies and diagnostic tests such as echocardiograms or cardiac catheterizations were not available. Information on medications, especially beta-blockers, would have been very useful. The ECGs were obtained over the span of more than a decade during which time there were changes in practice patterns and beta-blocker usage. However, there is no reason to think that beta-blocker usage would be less in those with PVCs (such that this would explain their higher heart rate). We also lack other markers of sympathetic activity to confirm our hypothesis. An important limitation of the study is that PVCs are identified on a single 10 second ECG recording. This 'snapshot' might not be expected to provide as much clinically meaningful information as longer term ambulatory ECG monitoring but, the extremely large number of patients available for analysis allows significant results to be obtained. The 4% prevalence of PVCs found in our study compares favorably with a rate of 2-7% in previous epidemiologic studies including those using 2-min rhythm strips. (Crow et al.,

Overall, this is a retrospective analysis and, as such, should be considered hypothesis generating rather than conclusive evidence of a cause and effect relationship. The predictive models generated here should be validated using other electrocardiographic databases and

Our study suggests that the simple 12-lead ECG provides valuable information and can complement more advanced strategies for arrhythmic risk stratification. The presence of any PVC on a single ECG is a powerful predictor of all-cause and cardiovascular mortality. The presence of multiple or complex PVCs was not a significantly better predictor although there was a trend towards worse prognosis in patients with complex forms. These observations are true even in those patients with otherwise normal baseline ECGs.

1975; Fisher & Tyroler, 1973; Kostis et al., 1987; Simpson et al., 200).

Antzelevitch, 2004).

**5.5 Study limitations** 

in prospective evaluations.

**6. Conclusions** 

Several large studies confirm our finding of heart rate not being related to age (Gillum, 1988; Morcet et al., 1999; Simpson et al., 2002; Spodick et al., 1992). There are conflicting reports in the literature as to the association of gender and heart rate. Some studies suggest that heart rate is higher in women (Gillum, 1988; Morcet et al., 1999) while others confirm our finding of heart rate being lower in women (Simpson et al., 2002).

### **5.3 PVCs and heart rate**

Few studies have evaluated the relationship of resting PVCs with increased heart rate on an ECG. The Atherosclerosis Risk In Communities (ARIC) study reported the prevalence of PVCs in 15,792 individuals aged 45-65 years on a longer than normal ECG recording of 2 minutes (Simpson et al., 2002). PVCs were present in 6% of these middle-aged adults and faster sinus rates were directly related to PVC prevalence.

The relationship of PVCs to heart rate has been described in a series of studies using Holter monitoring. The relationship between the frequency of PVCs and underlying heart rate was reported in patients with frequent PVCs; the most frequent relationship was an increase in PVCs with increasing heart rate (Acanfora et al., 1993; Winkle, 1982) It has also been shown that there are three reproducible trends characterizing the dynamic behavior of PVCs: a tachycardia-enhanced pattern (28%), a bradycardia-enhanced pattern (24%), and an indifferent pattern in the remainder of patients (48%) (Pitzalis et al. 1997). Another study suggested that beta-blockers were most effective in reducing PVC frequency in the tachycardia and indifferent groups (Pitzalis et al., 1996). Propafenone has also been shown to be most effective in tachycardia-enhanced patients (Saikawa et al., 2001).

### **5.4 Sympathetic nervous system**

Several lines of evidence suggest that activation of the sympathetic nervous system (SNS) plays a primary role in the generation of PVCs, ventricular arrhythmias and sudden cardiac death (Grassi et al., 2003; Podrid, Fuchs & Candinas, 1990). Circulating catecholamines and increased heart rate are known to interact with all three major mechanisms involved in the generation of arrhythmias: enhanced automaticity, triggered automaticity, and reentry (Stein et al., 1998). Substantial experimental data from animal studies shows that activation of the SNS is a strong stimulus for the development of ventricular tachyarrhythmias. It is well established that medications with beta-blocking properties help to decrease the frequency of PVCs (Krittayaphong et al, 2002) and prevent sudden death (JAMA, 1982; Pederson, 1985). Decreased sympathetic tone and improvement of cardiac autonomic regulation appear to play a major role in the ability of beta-blockers to reduce PVCs (Acanfora et al., 2000).

Studies of genetic disorders, animal models, and spontaneous human arrhythmias have helped to create a better understanding of this relationship.1 Infusion of nerve growth factor into animal models, designed to mimic long-term elevations of sympathetic activity and signaling, resulted in apoptosis, hypertrophy, and fibrosis. In human studies, changes in heart rate have been shown to occur prior to the onset of PVCs and ventricular arrhythmias (Anderson et al., 1999; Nemec, Hammill & Shen, 1999; Pitzalis et al, 1997; Sapoznikov, Luria & Gotsman, 1999). The propensity for PVCs and ventricular arrhythmias is highest when there are superimposed effects of short-, intermediate, and long-term changes. Parasympathetic inhibition of SNS activity may be part of a normal regulatory process that is lost in patients with severe heart failure and other disorders.

Some investigators have proposed the nerve sprouting hypothesis of ventricular arrhythmia to explain arrhythmic events seen in patients with a history of myocardial infarction (Chen et al, 2001). The theory is that myocardial damage results in nerve injury which is followed by sympathetic nerve sprouting and regionally increased sympathetic tone. The increased SNS activity in the local area of remodeled myocardium results in PVCs, ventricular tachycardia/fibrillation and sudden death. Support for this hypothesis was provided by an evaluation of cardiac nerves in explanted native hearts of human transplant recipients (Cao et al., 2000). Infusion of nerve growth factor into the left stellate ganglion of dogs was also shown to result in increased development of ventricular arrhythmias (Cao et al., 2000). The recurring theme of research in this area is that the response to injury results in heterogeneous sympathetic innervation which is highly arrhythmogenic (Verrier & Antzelevitch, 2004).

### **5.5 Study limitations**

36 Advances in Electrocardiograms – Clinical Applications

Several large studies confirm our finding of heart rate not being related to age (Gillum, 1988; Morcet et al., 1999; Simpson et al., 2002; Spodick et al., 1992). There are conflicting reports in the literature as to the association of gender and heart rate. Some studies suggest that heart rate is higher in women (Gillum, 1988; Morcet et al., 1999) while others confirm our finding

Few studies have evaluated the relationship of resting PVCs with increased heart rate on an ECG. The Atherosclerosis Risk In Communities (ARIC) study reported the prevalence of PVCs in 15,792 individuals aged 45-65 years on a longer than normal ECG recording of 2 minutes (Simpson et al., 2002). PVCs were present in 6% of these middle-aged adults and

The relationship of PVCs to heart rate has been described in a series of studies using Holter monitoring. The relationship between the frequency of PVCs and underlying heart rate was reported in patients with frequent PVCs; the most frequent relationship was an increase in PVCs with increasing heart rate (Acanfora et al., 1993; Winkle, 1982) It has also been shown that there are three reproducible trends characterizing the dynamic behavior of PVCs: a tachycardia-enhanced pattern (28%), a bradycardia-enhanced pattern (24%), and an indifferent pattern in the remainder of patients (48%) (Pitzalis et al. 1997). Another study suggested that beta-blockers were most effective in reducing PVC frequency in the tachycardia and indifferent groups (Pitzalis et al., 1996). Propafenone has also been shown

Several lines of evidence suggest that activation of the sympathetic nervous system (SNS) plays a primary role in the generation of PVCs, ventricular arrhythmias and sudden cardiac death (Grassi et al., 2003; Podrid, Fuchs & Candinas, 1990). Circulating catecholamines and increased heart rate are known to interact with all three major mechanisms involved in the generation of arrhythmias: enhanced automaticity, triggered automaticity, and reentry (Stein et al., 1998). Substantial experimental data from animal studies shows that activation of the SNS is a strong stimulus for the development of ventricular tachyarrhythmias. It is well established that medications with beta-blocking properties help to decrease the frequency of PVCs (Krittayaphong et al, 2002) and prevent sudden death (JAMA, 1982; Pederson, 1985). Decreased sympathetic tone and improvement of cardiac autonomic regulation appear to play a major role in the ability of beta-blockers to reduce PVCs

Studies of genetic disorders, animal models, and spontaneous human arrhythmias have helped to create a better understanding of this relationship.1 Infusion of nerve growth factor into animal models, designed to mimic long-term elevations of sympathetic activity and signaling, resulted in apoptosis, hypertrophy, and fibrosis. In human studies, changes in heart rate have been shown to occur prior to the onset of PVCs and ventricular arrhythmias (Anderson et al., 1999; Nemec, Hammill & Shen, 1999; Pitzalis et al, 1997; Sapoznikov, Luria & Gotsman, 1999). The propensity for PVCs and ventricular arrhythmias is highest when there are superimposed effects of short-, intermediate, and long-term changes. Parasympathetic inhibition of SNS activity may be part of a normal regulatory process that

is lost in patients with severe heart failure and other disorders.

to be most effective in tachycardia-enhanced patients (Saikawa et al., 2001).

of heart rate being lower in women (Simpson et al., 2002).

faster sinus rates were directly related to PVC prevalence.

**5.3 PVCs and heart rate** 

**5.4 Sympathetic nervous system** 

(Acanfora et al., 2000).

The population in our study included a relatively diverse group of all consecutive inpatients and outpatients who had a 12-lead ECG for any reason; the only exclusion criteria were the presence of atrial fibrillation or a paced rhythm. This differs from many previous studies of either more narrowly defined high-risk populations of patients referred to electrophysiologists or more broadly defined low-risk community epidemiological cohorts. These differences may be an advantage as our study is clinically based and includes all patients at our facility referred for an ECG. Base-line clinical data, laboratory studies and diagnostic tests such as echocardiograms or cardiac catheterizations were not available. Information on medications, especially beta-blockers, would have been very useful. The ECGs were obtained over the span of more than a decade during which time there were changes in practice patterns and beta-blocker usage. However, there is no reason to think that beta-blocker usage would be less in those with PVCs (such that this would explain their higher heart rate). We also lack other markers of sympathetic activity to confirm our hypothesis. An important limitation of the study is that PVCs are identified on a single 10 second ECG recording. This 'snapshot' might not be expected to provide as much clinically meaningful information as longer term ambulatory ECG monitoring but, the extremely large number of patients available for analysis allows significant results to be obtained. The 4% prevalence of PVCs found in our study compares favorably with a rate of 2-7% in previous epidemiologic studies including those using 2-min rhythm strips. (Crow et al., 1975; Fisher & Tyroler, 1973; Kostis et al., 1987; Simpson et al., 200).

Overall, this is a retrospective analysis and, as such, should be considered hypothesis generating rather than conclusive evidence of a cause and effect relationship. The predictive models generated here should be validated using other electrocardiographic databases and in prospective evaluations.

### **6. Conclusions**

Our study suggests that the simple 12-lead ECG provides valuable information and can complement more advanced strategies for arrhythmic risk stratification. The presence of any PVC on a single ECG is a powerful predictor of all-cause and cardiovascular mortality. The presence of multiple or complex PVCs was not a significantly better predictor although there was a trend towards worse prognosis in patients with complex forms. These observations are true even in those patients with otherwise normal baseline ECGs.

The Prevalence and Prognostic Value of Rest Premature Ventricular Contractions 39

Fisher FD, Tyroler HA. Relationship between ventricular premature contractions on routine

Fleg JL. Ventricular arrhythmias in the elderly: prevalence, mechanisms, and therapeutic

Fleg JL, Kennedy HL. Long-term prognostic significance of ambulatory electrocardiographic

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Grassi G, Seravalle G, Bertinieri G, et al. Behaviour of the adrenergic cardiovascular drive in atrial fibrillation and cardiac arrhythmias. Acta Physiol Scand 2003;177:399-404. Hathaway WR, Peterson ED, Wagner GS, et al. Prognostic significance of the initial

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Kostis JB, McCrone K, Moreyra AE, et al. The effect of age, blood pressure and gender on the incidence of premature ventricular contractions. Angiology 1982;33:464-73. Krittayaphong R, Bhuripanyo K, Punlee K, et al. Effect of atenolol on symptomatic

Lown B, Wolf M. Approaches to sudden death from coronary heart disease. Circulation

Minisi AJ, Mukharji J, Rehr RB, et al. Association between extent of coronary artery disease

Morcet JF, Safar M, Thomas F, et al. Associations between heart rate and other risk factors in

Mukharji J, Rude RE, Poole WK, et al. Risk factors for sudden death after acute myocardial

Nemec J, Hammill SC, Shen WK. Increase in heart rate precedes episodes of ventricular

Nikolic G, Bishop RL, Singh JB. Sudden death recorded during Holter monitoring.

Pedersen TR. Six-year follow-up of the Norwegian Multicenter Study on Timolol after Acute

Pitzalis MV, Mastropasqua F, Massari F, et al. Dependency of premature ventricular

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Regression analysis demonstrates that heart rate is a significant and independent predictor of the presence of PVCs. Our findings support the hypothesis that activation of the sympathetic nervous system is an important factor in the genesis of PVCs and ventricular arrhythmias. The presence of elevated heart rate is a significant prognostic factor and the combination of increased heart rate and PVCs dramatically increases mortality.

### **7. References**


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33.


**4** 

*USA* 

Harinder R. Singh

**Arrhythmias in Children and Young Adults** 

*Assistant Professor, Pediatrics, Pediatric Electrophysiologist and Associate, Cardiology, The Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan,* 

One of the challenges that physicians taking care of children face is the interpretation of an electrocardiogram (ECG). The findings on ECG should be seen in the light of a patient's clinical presentation. In this evidence-based chapter, we will explore the most common pediatric arrhythmias, including sinus arrhythmia, premature beats, brady-arrhythmias, escape rhythms and tachy-arrhythmias including different types of atrial, junctional and ventricular tachycardias. The objective of this chapter is to familiarize the reader with ECG

**2.1** *Definition*: Sinus arrhythmia is the normal variation in the rate of the sino-atrial (SA)

**2.2** *Incidence*: It is common in children and the incidence decreases with age(Kaushal and

**2.3** *Mechanism*: It occurs due to change in sinus node function related to changes in the autonomic tone. Inspiration and expiration are associated with increased and decreased heart rate due to decreased and increased parasympathetic tone, respectively(Coker et al. 1984). Sinus arrhythmia disappears with conditions associated with elevated sympathetic

**2.4** *Clinical presentation*: Auscultation reveals irregular heart rhythm which varies with

**2.5** *ECG*: ECG reveals sinus rhythm with variation in P-P interval preceding the change in R-

**2.6** *Management*: No work-up is needed because sinus arrhythmia is a normal variant with

**3.1.1** *Definition*: Premature atrial contraction (PAC), or atrial premature beat, is a premature

**3.1.2** *Incidence*: PACs were reported in 14% of full-term infants on 24-hour ECGs (Southall et al. 1980). Among 10-13 year old boys with healthy hearts, 13% had singlet PACs (Scott et al.

interpretation of common pediatric arrhythmias in children and young adults.

node that is mainly associated with the respiratory phases.

R intervals without any significant change in P-R interval (Figure 1).

discharge arising from an atrial focus other than the sino-atrial (SA) node.

**1. Introduction** 

**2. Sinus arrhythmia** 

tone causing increased heart rate.

**3.1 Premature atrial contractions** 

**3. Ectopic complexes (premature beats)** 

Taylor 2002).

respiration.

excellent prognosis.


## **Arrhythmias in Children and Young Adults**

### Harinder R. Singh

*Assistant Professor, Pediatrics, Pediatric Electrophysiologist and Associate, Cardiology, The Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, USA* 

### **1. Introduction**

40 Advances in Electrocardiograms – Clinical Applications

Pitzalis MV, Mastropasqua F, Massari F, et al. Holter-guided identification of premature

Podrid PJ, Fuchs T, Candinas R. Role of the sympathetic nervous system in the genesis of

Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of

Rabkin SW, Mathewson FA, Tate RB. Relationship of ventricular ectopy in men without

Rodstein M, Wolloch L, Gubner RS. Mortality study of the significance of extrasystoles in an

Saikawa T, Niwa H, Ito M, et al. The effect of propafenone on premature ventricular

Sapoznikov D, Luria MH, Gotsman MS. Changes in sinus RR interval patterns preceding

Simpson RJ, Jr, Cascio WE, Schreiner PJ, et al. Prevalence of premature ventricular

Tracy CM, Winkler J, Brittain E, et al. Determinants of ventricular arrhythmias in mildly

Vogt M, Motz W, Scheler S, et al. Disorders of coronary microcirculation and arrhythmias in

Verrier RL, Antzelevitch C. Autonomic aspects of arrhythmogenesis: the enduring and the

Winkle RA. The relationship between ventricular ectopic beat frequency and heart rate.

activity, and automaticity. Am Heart J 1998;136:425-34.

systemic arterial hypertension. Am J Cardiol 1990;65:45G-50G.

Suppression Trial (CAST) Investigators. N Engl J Med 1989;321:406-12. Pratt CM, Francis MJ, Luck JC, et al. Analysis of ambulatory electrocardiograms in 15

preceding arrhythmic events. J Am Coll Cardiol 1983;2:789-97.

ventricular arrhythmia. Circulation 1990;82:I103-13.

insured population. Circulation 1971;44:617-25.

rate trends. Int J Cardiol 1999;69:217-24.

new. Curr Opin Cardiol 2004;19:2-11.

Circulation 1982;66:439-46.

1996;131:508-15.

Am Heart J 1981;101:135-42.

J 2001;42:701-11.

J Cardiol 1992;69:1245-6.

ventricular contractions susceptible to suppression by beta-blockers. Am Heart J

arrhythmia suppression after myocardial infarction. The Cardiac Arrhythmia

patients during spontaneous ventricular fibrillation with special reference to

apparent heart disease to occurrence of ischemic heart disease and sudden death.

contractions (PVC): an analysis based on heart rate dependency of PVCs. Jpn Heart

ventricular ectopic beats: assessment with rate enhancement and dynamic heart

contractions in a population of African American and white men and women: the Atherosclerosis Risk in Communities (ARIC) study. Am Heart J 2002;143:535-40. Spodick DH, Raju P, Bishop RL, et al. Operational definition of normal sinus heart rate. Am

symptomatic patients with coronary artery disease and influence of inducible left ventricular dysfunction on arrhythmia frequency. J Am Coll Cardiol 1987;9:483-8. Stein KM, Karagounis LA, Markowitz SM, et al. Heart rate changes preceding ventricular

ectopy in patients with ventricular tachycardia caused by reentry, triggered

One of the challenges that physicians taking care of children face is the interpretation of an electrocardiogram (ECG). The findings on ECG should be seen in the light of a patient's clinical presentation. In this evidence-based chapter, we will explore the most common pediatric arrhythmias, including sinus arrhythmia, premature beats, brady-arrhythmias, escape rhythms and tachy-arrhythmias including different types of atrial, junctional and ventricular tachycardias. The objective of this chapter is to familiarize the reader with ECG interpretation of common pediatric arrhythmias in children and young adults.

### **2. Sinus arrhythmia**

**2.1** *Definition*: Sinus arrhythmia is the normal variation in the rate of the sino-atrial (SA) node that is mainly associated with the respiratory phases.

**2.2** *Incidence*: It is common in children and the incidence decreases with age(Kaushal and Taylor 2002).

**2.3** *Mechanism*: It occurs due to change in sinus node function related to changes in the autonomic tone. Inspiration and expiration are associated with increased and decreased heart rate due to decreased and increased parasympathetic tone, respectively(Coker et al. 1984). Sinus arrhythmia disappears with conditions associated with elevated sympathetic tone causing increased heart rate.

**2.4** *Clinical presentation*: Auscultation reveals irregular heart rhythm which varies with respiration.

**2.5** *ECG*: ECG reveals sinus rhythm with variation in P-P interval preceding the change in R-R intervals without any significant change in P-R interval (Figure 1).

**2.6** *Management*: No work-up is needed because sinus arrhythmia is a normal variant with excellent prognosis.

### **3. Ectopic complexes (premature beats)**

### **3.1 Premature atrial contractions**

**3.1.1** *Definition*: Premature atrial contraction (PAC), or atrial premature beat, is a premature discharge arising from an atrial focus other than the sino-atrial (SA) node.

**3.1.2** *Incidence*: PACs were reported in 14% of full-term infants on 24-hour ECGs (Southall et al. 1980). Among 10-13 year old boys with healthy hearts, 13% had singlet PACs (Scott et al.

Arrhythmias in Children and Young Adults 43

**3.2.1** *Definition*: A premature ventricular contraction (PVC) or ventricular premature beat (VPB) is an early ventricular beat that originates below the bifurcation of the bundle of His. It is characterized by a premature wide QRS complex that is morphologically different compared to the baseline QRS complexes (Sherron et al. 1985; Olgin and Zipes 2005b). **3.2.2** *Incidence*: PVCs follow a bi-modal distribution and are seen in 18% of neonates, 20% of toddlers, 16% of school children, 20-30% of adolescents and subsequent increases in late adulthood (Southall et al. 1980). On 24-hour ECG monitoring of subjects without heart disease, 54% of young women (Sobotka et al. 1981) and 50% of young males had PVCs (Brodsky et al. 1977). Surgically-corrected Tetralogy of Fallot patients have an incidence of 6-

**3.2.3** *Mechanism*: Three mechanisms inducing PVCs include: automaticity, re-entry, and triggered activity. PVCs can result from mechanical, electrical, and chemical stimulation leading to ventricular depolarization. Abnormalities in metabolism, electrolytes, or iatrogenic causes can initiate PVCs in children. Both slow and fast heart rates are associated

**3.2.4** *Natural history*: PVCs increase with age and are more common in males (Silka and Garson 1999). In the absence of heart disease, PVCs are inconsequential under the age of 30 years but influence risk of sudden death in those over 30 years (Chiang et al. 1969). PVCs may be present in those with increased vagal tone such as athletes or in those with increased stimulation such as intake of caffeine, alcohol, and/or nicotine. In adults without structural heart disease, PVCs induced during exercise and recovery phases were associated with increased risk of mortality (Frolkis et al. 2003). PVCs also occur in those with surgicallycorrected congenital heart disease, myocarditis, right-ventricular dysfunction, congestive heart failure, cardiomyopathy, ventricular hypertrophy, myocardial infarction, ventricular non-compaction and iatrogenic causes (Chandar et al. 1990; Vaksmann et al. 1990; Espinola-

Fig. 2.b Premature atrial complex that is normally conducted

Fig. 2.c Premature atrial complex that is conducted with aberrancy

**3.2 Premature ventricular contractions** 

48% (Vaksmann et al. 1990),(Chandar et al. 1990).

with PVCs (Sherron et al. 1985).

Zavaleta et al. 2006; Sestito et al. 2007).

Fig. 1. Sinus arrhythmia

1980). On 24-hour ECG monitoring, 64% of young women (Sobotka et al. 1981) and 56% of male adolescents had PACs (Brodsky et al. 1977). Frequent causes of PACs include intake of caffeine, nicotine, alcohol, and other stimulants. PACs can be associated with atrial enlargement, electrolyte abnormalities, mechanical trauma, chronic pulmonary disease, and heart failure.

**3.1.3** *Mechanism*: PACs can occur either due to a re-entry mechanism, (Wallace and Daggett 1964) automaticity outside of the SA node, or triggered activity (Wit and Cranefield 1977).

**3.1.4** *Natural history*: PACs can give rise to atrial fibrillation and flutter, especially in older post-operative patients(Jideus et al. 2006). They may subside with removal or correction of the inciting stimuli. Control of congestive heart failure, ischemic heart disease, pulmonary disease, and electrolyte abnormalities may decrease the incidence of PACs.

**3.1.5** *Clinical presentation*: Patients with PACs may be asymptomatic or perceive them as palpitations. They may be incidentally detected as irregular heart rhythm on auscultation.

**3.1.6** *ECG*: A PAC presents as a P-wave that appears earlier than expected on an ECG. The P-wave morphology may appear different. The PR interval in a PAC is often different than the previous PR interval. PACs can have three possible outcomes: 1) block at the AV node due to AV nodal refractoriness (Figure 2a), 2) conduct normally through the AV node (Figure 2b), or 3) conduct with aberrancy due to His-bundle refractoriness (Figure 2c). There is no compensatory ventricular pause.

**3.1.7** *Work-up*: A 12-lead ECG is usually adequate for evaluation; however, Holter monitoring may be performed.

**3.1.8** *Management and Prognosis*: Control of exogenous factors will decrease the incidence of PACs. No physical restrictions need to be imposed on children without heart and/or lung disease, or electrolyte abnormalities. Beta blocker like bisoprolol decreased PACs by 50%, although 25% of these patients had adverse reactions associated with beta blockade (Sugimoto et al. 1986). Prognosis is excellent for patients with PACs with normal hearts and needs no treatment.

Fig. 2.a Premature atrial complex that is blocked

1980). On 24-hour ECG monitoring, 64% of young women (Sobotka et al. 1981) and 56% of male adolescents had PACs (Brodsky et al. 1977). Frequent causes of PACs include intake of caffeine, nicotine, alcohol, and other stimulants. PACs can be associated with atrial enlargement, electrolyte abnormalities, mechanical trauma, chronic pulmonary disease, and

**3.1.3** *Mechanism*: PACs can occur either due to a re-entry mechanism, (Wallace and Daggett 1964) automaticity outside of the SA node, or triggered activity (Wit and Cranefield 1977). **3.1.4** *Natural history*: PACs can give rise to atrial fibrillation and flutter, especially in older post-operative patients(Jideus et al. 2006). They may subside with removal or correction of the inciting stimuli. Control of congestive heart failure, ischemic heart disease, pulmonary

**3.1.5** *Clinical presentation*: Patients with PACs may be asymptomatic or perceive them as palpitations. They may be incidentally detected as irregular heart rhythm on auscultation. **3.1.6** *ECG*: A PAC presents as a P-wave that appears earlier than expected on an ECG. The P-wave morphology may appear different. The PR interval in a PAC is often different than the previous PR interval. PACs can have three possible outcomes: 1) block at the AV node due to AV nodal refractoriness (Figure 2a), 2) conduct normally through the AV node (Figure 2b), or 3) conduct with aberrancy due to His-bundle refractoriness (Figure 2c). There

**3.1.7** *Work-up*: A 12-lead ECG is usually adequate for evaluation; however, Holter

**3.1.8** *Management and Prognosis*: Control of exogenous factors will decrease the incidence of PACs. No physical restrictions need to be imposed on children without heart and/or lung disease, or electrolyte abnormalities. Beta blocker like bisoprolol decreased PACs by 50%, although 25% of these patients had adverse reactions associated with beta blockade (Sugimoto et al. 1986). Prognosis is excellent for patients with PACs with normal hearts and

disease, and electrolyte abnormalities may decrease the incidence of PACs.

Fig. 1. Sinus arrhythmia

is no compensatory ventricular pause.

Fig. 2.a Premature atrial complex that is blocked

monitoring may be performed.

needs no treatment.

heart failure.

Fig. 2.b Premature atrial complex that is normally conducted

Fig. 2.c Premature atrial complex that is conducted with aberrancy

### **3.2 Premature ventricular contractions**

**3.2.1** *Definition*: A premature ventricular contraction (PVC) or ventricular premature beat (VPB) is an early ventricular beat that originates below the bifurcation of the bundle of His. It is characterized by a premature wide QRS complex that is morphologically different compared to the baseline QRS complexes (Sherron et al. 1985; Olgin and Zipes 2005b).

**3.2.2** *Incidence*: PVCs follow a bi-modal distribution and are seen in 18% of neonates, 20% of toddlers, 16% of school children, 20-30% of adolescents and subsequent increases in late adulthood (Southall et al. 1980). On 24-hour ECG monitoring of subjects without heart disease, 54% of young women (Sobotka et al. 1981) and 50% of young males had PVCs (Brodsky et al. 1977). Surgically-corrected Tetralogy of Fallot patients have an incidence of 6- 48% (Vaksmann et al. 1990),(Chandar et al. 1990).

**3.2.3** *Mechanism*: Three mechanisms inducing PVCs include: automaticity, re-entry, and triggered activity. PVCs can result from mechanical, electrical, and chemical stimulation leading to ventricular depolarization. Abnormalities in metabolism, electrolytes, or iatrogenic causes can initiate PVCs in children. Both slow and fast heart rates are associated with PVCs (Sherron et al. 1985).

**3.2.4** *Natural history*: PVCs increase with age and are more common in males (Silka and Garson 1999). In the absence of heart disease, PVCs are inconsequential under the age of 30 years but influence risk of sudden death in those over 30 years (Chiang et al. 1969). PVCs may be present in those with increased vagal tone such as athletes or in those with increased stimulation such as intake of caffeine, alcohol, and/or nicotine. In adults without structural heart disease, PVCs induced during exercise and recovery phases were associated with increased risk of mortality (Frolkis et al. 2003). PVCs also occur in those with surgicallycorrected congenital heart disease, myocarditis, right-ventricular dysfunction, congestive heart failure, cardiomyopathy, ventricular hypertrophy, myocardial infarction, ventricular non-compaction and iatrogenic causes (Chandar et al. 1990; Vaksmann et al. 1990; Espinola-Zavaleta et al. 2006; Sestito et al. 2007).

Arrhythmias in Children and Young Adults 45

metabolic heart disease. PVCs inducible during exercise can be ominous in patients with structural heart disease and are of higher significance (Silka and Garson 1999). Athletes with structural heart disease in high-risk groups with PVCs should be restricted to low-intensity

**3.3.1** *Definition*: A premature junctional complex (PJC) or beat (PJB) is a premature discharge that originates in the AV junction either at the level of the AV node or the bundle of His, in

**3.3.2** *Incidence*: PJCs can occur in structurally normal or abnormal hearts and in all age groups. The incidence and prevalence are not well known. Among 16-19 year old males, 0.21% had premature junctional complexes on 12-lead ECG and similar in other age groups

**3.3.3** *Mechanism*: PJCs arise due to increased automaticity or triggered activity due to after depolarizations within the AV junction (Hoffman and Cranefield 1964; Rosen et al. 1980). PJCs may predispose the patient to ventricular tachycardia. Potential causes include normal variants, use of stimulants or alcohol, hypokalemia, hypoxemia, ischemia, and digitalis

**3.3.4** *Clinical presentation*: It may be incidentally detected or may produce symptoms like

**3.3.5** *ECG*: ECG shows QRS complex morphology similar to sinus node originated activation, without preceding P-wave. A PJC conducting to the ventricle with aberrancy has a QRS complex comparable to PVC. A retrograde P-wave may appear before, during, or

**3.3.6** *Work-up*: Depending on the frequency of the PJCs, an ECG can identify the premature complexes. If unsuccessful, a 24-hour Holter monitor may be used. An electrophysiology study maybe needed to identify the location of the origin of the PJCs; origin distal to the AV

**3.3.7** *Management and Prognosis*: Patients with PJCs are usually left untreated. The management of underlying causes is essential to decrease symptomatic PJCs. If symptoms are severe, medical management and pacing may be warranted to increase the heart rate.

**4.1.1** *Definition*: The inability of the sino-atrial (SA) node to discharge/activate (sinus pause/arrest) or inappropriately activate (tachycardia-bradycardia syndrome) the atrial tissue.

sports (Zipes and Garson 1994).

(Hiss and Lamb 1962).

toxicity (Sherron et al. 1985).

palpitations, syncope, or dizziness.

Fig. 4. Premature junctional complex

**4.1 Sinus node dysfunction (SND)** 

**4. Bradyarrhythmias** 

after the QRS complex (Sherron et al. 1985) (Figure 4).

node can initiate ventricular tachycardia (Sherron et al. 1985).

**3.3 Premature junctional complexes** 

the absence of a preceding atrial discharge.

**3.2.5** *Clinical presentation*: PVCs are the most common cause of irregular heart beats in children. They are usually detected incidentally and occasionally produce symptoms. Single PVCs are generally well-tolerated by children. Symptoms secondary to PVCs include palpitations, lightheadedness, fatigue, chest pain, and shortness of breath.

**3.2.6** *ECG*: To be classified as PVC, four criteria should be met: 1) premature QRS without a premature P wave, 2) difference in QRS morphology between PVC and regular QRS complex, 3) prolonged QRS duration for age, and 4) different QRS and T wave vectors. Unifocal PVCs have a fixed morphology, as opposed to PACs with aberrant conduction. Multifocal PVCs have different morphologies due to the different locations of onset and electrical instability of the ventricle (Silka and Garson 1999). There is a compensatory pause after PVC, i.e., R-R interval produced by SA node initiated QRS complexes on either side of the PVC is equal to twice the normal R-R interval (figure 3). PVCs may present as isolated, couplets, bigeminy or trigeminy pattern. If the PVC originates in the right ventricle, the QRS morphology appears as a left bundle branch block pattern and if the PVC originates in the left ventricle, the QRS morphology appears as a right bundle branch block pattern.

**3.2.7** *Differential diagnoses*: 1) Premature atrial complex with aberrant conduction, 2) premature junctional complex with aberrant conduction, and 3) anterograde conduction over an accessory pathway with pre-excitation.

Fig. 3. Premature ventricular complex with a compensatory pause

**3.2.8** *Work-up*: A detailed history of episodes is necessary. A history of congenital heart disease with subsequent surgical correction should be obtained. In addition to an ECG and 24-hour Holter monitoring, an exercise test is important in determining whether the frequency of PVCs or symptoms worsen with activity (Paridon 2006; Zipes 2006). Multifocal PVCs in structural heart disease require further workup. Echocardiography and electrophysiology studies may be warranted in surgically corrected patients or those with structural heart disease if there are PVCs and malignant ventricular arrhythmias (Case 1999).

**3.2.9** *Management and Prognosis*: Management of PVCs depends on two factors: 1) a history of structural heart disease or surgically corrected congenital heart disease, and 2) the symptoms experienced by the patient. In children, PVCs are considered to be benign if they disappear with exercise (Attina et al. 1987). The majority of children with normal hearts presenting with asymptomatic single PVC, bigeminy, or trigeminy do not require treatment. Given that surgically-corrected congenital heart disease is associated with increased predisposition to non-sustained ventricular tachycardia and sudden cardiac death, children may require treatment with anti-arrhythmics under the supervision of a pediatric cardiologist. Beta-blockers can assist in suppressing PVCs in symptomatic patients (Alexander 2001a). If symptoms are not medically controlled, catheter ablation is an option (Zhu et al. 1995). Prognosis depends on whether there is underlying structural and

**3.2.5** *Clinical presentation*: PVCs are the most common cause of irregular heart beats in children. They are usually detected incidentally and occasionally produce symptoms. Single PVCs are generally well-tolerated by children. Symptoms secondary to PVCs include

**3.2.6** *ECG*: To be classified as PVC, four criteria should be met: 1) premature QRS without a premature P wave, 2) difference in QRS morphology between PVC and regular QRS complex, 3) prolonged QRS duration for age, and 4) different QRS and T wave vectors. Unifocal PVCs have a fixed morphology, as opposed to PACs with aberrant conduction. Multifocal PVCs have different morphologies due to the different locations of onset and electrical instability of the ventricle (Silka and Garson 1999). There is a compensatory pause after PVC, i.e., R-R interval produced by SA node initiated QRS complexes on either side of the PVC is equal to twice the normal R-R interval (figure 3). PVCs may present as isolated, couplets, bigeminy or trigeminy pattern. If the PVC originates in the right ventricle, the QRS morphology appears as a left bundle branch block pattern and if the PVC originates in the

palpitations, lightheadedness, fatigue, chest pain, and shortness of breath.

left ventricle, the QRS morphology appears as a right bundle branch block pattern.

over an accessory pathway with pre-excitation.

Fig. 3. Premature ventricular complex with a compensatory pause

PVCs and malignant ventricular arrhythmias (Case 1999).

**3.2.7** *Differential diagnoses*: 1) Premature atrial complex with aberrant conduction, 2) premature junctional complex with aberrant conduction, and 3) anterograde conduction

**3.2.8** *Work-up*: A detailed history of episodes is necessary. A history of congenital heart disease with subsequent surgical correction should be obtained. In addition to an ECG and 24-hour Holter monitoring, an exercise test is important in determining whether the frequency of PVCs or symptoms worsen with activity (Paridon 2006; Zipes 2006). Multifocal PVCs in structural heart disease require further workup. Echocardiography and electrophysiology studies may be warranted in surgically corrected patients or those with structural heart disease if there are

**3.2.9** *Management and Prognosis*: Management of PVCs depends on two factors: 1) a history of structural heart disease or surgically corrected congenital heart disease, and 2) the symptoms experienced by the patient. In children, PVCs are considered to be benign if they disappear with exercise (Attina et al. 1987). The majority of children with normal hearts presenting with asymptomatic single PVC, bigeminy, or trigeminy do not require treatment. Given that surgically-corrected congenital heart disease is associated with increased predisposition to non-sustained ventricular tachycardia and sudden cardiac death, children may require treatment with anti-arrhythmics under the supervision of a pediatric cardiologist. Beta-blockers can assist in suppressing PVCs in symptomatic patients (Alexander 2001a). If symptoms are not medically controlled, catheter ablation is an option (Zhu et al. 1995). Prognosis depends on whether there is underlying structural and metabolic heart disease. PVCs inducible during exercise can be ominous in patients with structural heart disease and are of higher significance (Silka and Garson 1999). Athletes with structural heart disease in high-risk groups with PVCs should be restricted to low-intensity sports (Zipes and Garson 1994).

### **3.3 Premature junctional complexes**

**3.3.1** *Definition*: A premature junctional complex (PJC) or beat (PJB) is a premature discharge that originates in the AV junction either at the level of the AV node or the bundle of His, in the absence of a preceding atrial discharge.

**3.3.2** *Incidence*: PJCs can occur in structurally normal or abnormal hearts and in all age groups. The incidence and prevalence are not well known. Among 16-19 year old males, 0.21% had premature junctional complexes on 12-lead ECG and similar in other age groups (Hiss and Lamb 1962).

**3.3.3** *Mechanism*: PJCs arise due to increased automaticity or triggered activity due to after depolarizations within the AV junction (Hoffman and Cranefield 1964; Rosen et al. 1980). PJCs may predispose the patient to ventricular tachycardia. Potential causes include normal variants, use of stimulants or alcohol, hypokalemia, hypoxemia, ischemia, and digitalis toxicity (Sherron et al. 1985).

**3.3.4** *Clinical presentation*: It may be incidentally detected or may produce symptoms like palpitations, syncope, or dizziness.

**3.3.5** *ECG*: ECG shows QRS complex morphology similar to sinus node originated activation, without preceding P-wave. A PJC conducting to the ventricle with aberrancy has a QRS complex comparable to PVC. A retrograde P-wave may appear before, during, or after the QRS complex (Sherron et al. 1985) (Figure 4).

**3.3.6** *Work-up*: Depending on the frequency of the PJCs, an ECG can identify the premature complexes. If unsuccessful, a 24-hour Holter monitor may be used. An electrophysiology study maybe needed to identify the location of the origin of the PJCs; origin distal to the AV node can initiate ventricular tachycardia (Sherron et al. 1985).

**3.3.7** *Management and Prognosis*: Patients with PJCs are usually left untreated. The management of underlying causes is essential to decrease symptomatic PJCs. If symptoms are severe, medical management and pacing may be warranted to increase the heart rate.

Fig. 4. Premature junctional complex

### **4. Bradyarrhythmias**

### **4.1 Sinus node dysfunction (SND)**

**4.1.1** *Definition*: The inability of the sino-atrial (SA) node to discharge/activate (sinus pause/arrest) or inappropriately activate (tachycardia-bradycardia syndrome) the atrial tissue.

Arrhythmias in Children and Young Adults 47

2. Tachycardia-Bradycardia syndrome management is difficult. Drugs used to manage tachycardia may worsen sinus bradycardia and should be used judiciously and may

With failed medical therapy and the need for long-term anti-arrhythmic medications, pacemaker implantation is indicated. According to the 2002 ACC guidelines for pacemaker implantation (Gregaratos 2002), documented symptomatic bradycardia (Class I), symptomatic chronotropic incompetence (Class I), syncope of unknown etiology with electrophysiologic studies suggestive of SND (Class IIa), and chronic awake heart rate < 40 (Class IIb) are primary indicators for permanent pacing. Permanent pacing is indicated in bradycardia-tachycardia (Class IIa). In refractory or symptomatic SND patients who have failed medical therapy, permanent pacemaker implantation improves clinical status. Pacemaker implantation can provide anti-bradycardia pacing in severe bradycardia; in tachycardia-bradycardia syndrome, pacemaker can provide anti-tachycardia and anti-

**4.2.1** *Definition*: Delay in atrio-ventricular conduction at the level of the atrial tissue, AV

**4.2.2** *Incidence*: First degree AV block has been detected in 6% of neonates (Ferrer 1977).

**4.2.3** *Mechanism*: Common mechanism in pediatric patients is hypervagotonia. However, other causes include medications which prolong AV-node refractory period, electrolyte abnormalities, hypothermia, hypothyroidism, rheumatic fever, myocarditis, Lyme disease, congenital heart disease that stretches the atria at the AV node area, cardiac surgery, and myopathies (Weindling 2001). Four sites for first degree AV block with a normal QRS include: atrium (3-20%) (Sherron et al. 1985), AV node (35-90%) (Sherron et al. 1985), Bundle of His (15%) (Sherron et al. 1985) and infra-Hisian conduction system. It is more common in endocardial cushion defects and Ebstein's anomaly of the tricuspid valve due to intraatrial conduction delay (Sherron et al. 1985). Increased vagal tone, calcium-channel blockers, digoxin, and beta-blockers are common causes of AV nodal delay. Quinidine, procainamide, and disopyramide impair phase 0 depolarization and cause delay in bundle of His conduction. Finally, prolongation of conduction in the infra-Hisian region can be caused by sodium-channel blockers as above. With first degree AV block with a wide QRS complex, conduction in the AV node or the bundle of His is delayed; bilateral bundle branch conduction is slowed in most cases; two levels of conduction delay can also be seen (Peuch

**4.2.4** *Natural history*: First degree heart block has the potential, although rarely, to progress to higher-degree heart blocks in myocarditis, and adults with ischemic heart disease. In a 30 year follow up of adult males with moderate P-R interval prolongation, first degree heart

**4.2.5** *Clinical presentation*: Patients with first degree AV block are asymptomatic unless associated with significant left ventricular (LV) dysfunction. Marked prolongation of the PR

**4.2.6** *ECG*: There is prolongation of PR interval beyond the normal ranges for age. Normal P-R interval naturally varies with age in the pediatric population and prolongation of the P-R

interval can cause symptoms mimicking pacemaker-like syndrome.

interval should be viewed in this context (Figure 5).

Among 10-13 year old males, 8.5% had first degree heart block (Scott et al. 1980).

necessitate cardiac pacing.

**4.2 First-degree atrio-ventricular heart block** 

node, and/or the His-Purkinje system.

block was benign (Mymin et al. 1986).

bradycardia pacing.

et al. 1976).

**4.1.2** *Incidence*: SND is relatively uncommon in children with normal cardiac anatomy and the exact incidence is unknown. However, it is a common problem in those who have had surgery for congenital heart disease (CHD), especially in patients with Mustard, Senning, and Fontan procedures (Fishberger 2001). Approximately 2/3 of all immediate posttransplant patients have SND (Jacquet et al. 1990).

**4.1.3** *Mechanism*: In sinus node pause/arrest, there is a lack of discharge from the SA node; causing no activation of the atria. With sinus node exit block, the activation may be delayed significantly or blocked completely at the nodal region, without activation of the atria. In tachycardia-bradycardia syndrome, severe sinus bradycardia is followed by tachycardia in the form of atrial flutter in the pediatric population and atrial fibrillation/flutter in adults with repaired congenital heart disease (Duster et al. 1985; Gelatt et al. 1994).

**4.1.4** *Natural history*: Sinus node dysfunction may present as severe sinus bradycardia, sinus pause or arrest, periods of junctional rhythm, and/or alternating tachycardia-bradycardia periods. Sinus node dysfunction increases in frequency with age of the patient and time from surgery.

**4.1.5** *Clinical presentation*: It depends on the age, underlying cardiac conduction abnormality, and hemodynamic status. Although majority of children with structurally normal hearts remain asymptomatic; fatigue, exercise intolerance, palpitations, chest pain, dizziness, and syncope may occur (Fishberger 2001). These symptoms are more frequent in those with corrected congenital heart disease. Infants present with poor feeding, lethargy or heart failure. Sudden death is an uncommon presentation.

**4.1.6** *ECG*: ECG may show severe sinus bradycardia, sinus pause, junctional rhythm, and/or atrial fibrillation/flutter. Due to the short duration, significant episodes can be missed.

**4.1.7** *Work-up*: Non-invasive testing includes a 12-lead ECG, a Holter monitor, an event monitor and exercise stress test. Depending on the frequency of the symptoms and the age group, a 24-hour Holter monitor can be employed. In an older age group with less frequent symptoms, an event recorder can be used to record rhythm abnormalities. In patients who are able to exercise, a treadmill stress test will show lower heart rate response to maximal exercise and rapid decrease in heart rate during recovery time immediately after the test (Martin and Kugler 1999; Fishberger 2001). Intrinsic heart rate (IHR) is the heart rate with complete blockade of autonomic activity with atropine and propranolol (Jose AD and Collison D, 1970). Normal value of IHR is defined as 118.1 – (0.57 x age). The intrinsic heart rate decreases with age in complete autonomic blockade but decreases at a faster rate in patients with SND (Benditt et al. 1984). In invasive testing, an electrophysiology study is undertaken to evaluate sinus node automaticity, and conduction time. Sino-atrial conduction time (SACT) and sinus node recovery time (SNRT) are assessed with premature atrial stimulation and atrial overdrive pacing, respectively. The length of SNRT evaluates the sinus node automaticity; prolongation of SNRT indicates suppression of sinus node automatic function.

**4.1.8** *Management and Prognosis*: Medical treatment is dependent on the type of sinus node dysfunction and the presence of associated symptoms. Choice of medications should be selected cautiously and the patient should be monitored closely.

1. Sinus bradycardia and pause/arrest < 3 sec: no further management; pause/arrest > 3 sec requires evaluation. In severe sinus bradycardia with hemodynamic instability, sympathomimetic drugs such as atropine and isoproterenol or transcutaneous pacing are used.

**4.1.2** *Incidence*: SND is relatively uncommon in children with normal cardiac anatomy and the exact incidence is unknown. However, it is a common problem in those who have had surgery for congenital heart disease (CHD), especially in patients with Mustard, Senning, and Fontan procedures (Fishberger 2001). Approximately 2/3 of all immediate post-

**4.1.3** *Mechanism*: In sinus node pause/arrest, there is a lack of discharge from the SA node; causing no activation of the atria. With sinus node exit block, the activation may be delayed significantly or blocked completely at the nodal region, without activation of the atria. In tachycardia-bradycardia syndrome, severe sinus bradycardia is followed by tachycardia in the form of atrial flutter in the pediatric population and atrial fibrillation/flutter in adults

**4.1.4** *Natural history*: Sinus node dysfunction may present as severe sinus bradycardia, sinus pause or arrest, periods of junctional rhythm, and/or alternating tachycardia-bradycardia periods. Sinus node dysfunction increases in frequency with age of the patient and time

**4.1.5** *Clinical presentation*: It depends on the age, underlying cardiac conduction abnormality, and hemodynamic status. Although majority of children with structurally normal hearts remain asymptomatic; fatigue, exercise intolerance, palpitations, chest pain, dizziness, and syncope may occur (Fishberger 2001). These symptoms are more frequent in those with corrected congenital heart disease. Infants present with poor feeding, lethargy or heart

**4.1.6** *ECG*: ECG may show severe sinus bradycardia, sinus pause, junctional rhythm, and/or atrial fibrillation/flutter. Due to the short duration, significant episodes can be missed. **4.1.7** *Work-up*: Non-invasive testing includes a 12-lead ECG, a Holter monitor, an event monitor and exercise stress test. Depending on the frequency of the symptoms and the age group, a 24-hour Holter monitor can be employed. In an older age group with less frequent symptoms, an event recorder can be used to record rhythm abnormalities. In patients who are able to exercise, a treadmill stress test will show lower heart rate response to maximal exercise and rapid decrease in heart rate during recovery time immediately after the test (Martin and Kugler 1999; Fishberger 2001). Intrinsic heart rate (IHR) is the heart rate with complete blockade of autonomic activity with atropine and propranolol (Jose AD and Collison D, 1970). Normal value of IHR is defined as 118.1 – (0.57 x age). The intrinsic heart rate decreases with age in complete autonomic blockade but decreases at a faster rate in patients with SND (Benditt et al. 1984). In invasive testing, an electrophysiology study is undertaken to evaluate sinus node automaticity, and conduction time. Sino-atrial conduction time (SACT) and sinus node recovery time (SNRT) are assessed with premature atrial stimulation and atrial overdrive pacing, respectively. The length of SNRT evaluates the sinus node automaticity; prolongation of SNRT indicates suppression of sinus node

**4.1.8** *Management and Prognosis*: Medical treatment is dependent on the type of sinus node dysfunction and the presence of associated symptoms. Choice of medications should be

1. Sinus bradycardia and pause/arrest < 3 sec: no further management; pause/arrest > 3 sec requires evaluation. In severe sinus bradycardia with hemodynamic instability, sympathomimetic drugs such as atropine and isoproterenol or transcutaneous pacing

selected cautiously and the patient should be monitored closely.

with repaired congenital heart disease (Duster et al. 1985; Gelatt et al. 1994).

transplant patients have SND (Jacquet et al. 1990).

failure. Sudden death is an uncommon presentation.

from surgery.

automatic function.

are used.

2. Tachycardia-Bradycardia syndrome management is difficult. Drugs used to manage tachycardia may worsen sinus bradycardia and should be used judiciously and may necessitate cardiac pacing.

With failed medical therapy and the need for long-term anti-arrhythmic medications, pacemaker implantation is indicated. According to the 2002 ACC guidelines for pacemaker implantation (Gregaratos 2002), documented symptomatic bradycardia (Class I), symptomatic chronotropic incompetence (Class I), syncope of unknown etiology with electrophysiologic studies suggestive of SND (Class IIa), and chronic awake heart rate < 40 (Class IIb) are primary indicators for permanent pacing. Permanent pacing is indicated in bradycardia-tachycardia (Class IIa). In refractory or symptomatic SND patients who have failed medical therapy, permanent pacemaker implantation improves clinical status. Pacemaker implantation can provide anti-bradycardia pacing in severe bradycardia; in tachycardia-bradycardia syndrome, pacemaker can provide anti-tachycardia and antibradycardia pacing.

### **4.2 First-degree atrio-ventricular heart block**

**4.2.1** *Definition*: Delay in atrio-ventricular conduction at the level of the atrial tissue, AV node, and/or the His-Purkinje system.

**4.2.2** *Incidence*: First degree AV block has been detected in 6% of neonates (Ferrer 1977). Among 10-13 year old males, 8.5% had first degree heart block (Scott et al. 1980).

**4.2.3** *Mechanism*: Common mechanism in pediatric patients is hypervagotonia. However, other causes include medications which prolong AV-node refractory period, electrolyte abnormalities, hypothermia, hypothyroidism, rheumatic fever, myocarditis, Lyme disease, congenital heart disease that stretches the atria at the AV node area, cardiac surgery, and myopathies (Weindling 2001). Four sites for first degree AV block with a normal QRS include: atrium (3-20%) (Sherron et al. 1985), AV node (35-90%) (Sherron et al. 1985), Bundle of His (15%) (Sherron et al. 1985) and infra-Hisian conduction system. It is more common in endocardial cushion defects and Ebstein's anomaly of the tricuspid valve due to intraatrial conduction delay (Sherron et al. 1985). Increased vagal tone, calcium-channel blockers, digoxin, and beta-blockers are common causes of AV nodal delay. Quinidine, procainamide, and disopyramide impair phase 0 depolarization and cause delay in bundle of His conduction. Finally, prolongation of conduction in the infra-Hisian region can be caused by sodium-channel blockers as above. With first degree AV block with a wide QRS complex, conduction in the AV node or the bundle of His is delayed; bilateral bundle branch conduction is slowed in most cases; two levels of conduction delay can also be seen (Peuch et al. 1976).

**4.2.4** *Natural history*: First degree heart block has the potential, although rarely, to progress to higher-degree heart blocks in myocarditis, and adults with ischemic heart disease. In a 30 year follow up of adult males with moderate P-R interval prolongation, first degree heart block was benign (Mymin et al. 1986).

**4.2.5** *Clinical presentation*: Patients with first degree AV block are asymptomatic unless associated with significant left ventricular (LV) dysfunction. Marked prolongation of the PR interval can cause symptoms mimicking pacemaker-like syndrome.

**4.2.6** *ECG*: There is prolongation of PR interval beyond the normal ranges for age. Normal P-R interval naturally varies with age in the pediatric population and prolongation of the P-R interval should be viewed in this context (Figure 5).

Arrhythmias in Children and Young Adults 49

**4.3.7** *Work-up*: ECG is diagnostic. If ECG is inconclusive, a 24-hour monitor is suggested. If there is one conducted beat in a cycle as in a 2:1 block, it is difficult to differentiate between Mobitz types I and II blocks; atropine can be used to elicit a 3:2 conduction in Mobitz type I block. Response to atropine suggests the block to be at or proximal to the AV node. If exercise initiates or exacerbates Mobitz type I block, infranodal location of the block is suspected. An electrophysiology study is indicated if there is unexplained syncope, and AV block distal to the AV node, to identify the location of the block (Zipes et al. 1995). In complete or high grade second degree AV block, an echocardiogram is indicated (Cheitlin et

**4.3.8** *Management*: Medical management of Mobitz type I includes identification and treatment of underlying causes. Sympathomimetic agents such as scopolamine, theophylline, or glycopyrrolate can be used in symptomatic bradycardia secondary to increased vagal tone. In patients with Mobitz type II, syncope is a poor prognostic factor (Dhingra et al. 1974). Symptomatic chronic bradycardia in Mobitz type I and type II (Class I), Mobitz type II with bifascicular or trifascicular block (Class I), Mobitz type II with wide QRS (Class I), asymptomatic Mobitz type II (Class IIa), and neuromuscular disease with AV block (Class IIb) are all indications for permanent pacemaker implantation (Gregaratos 2002).

Fig. 6.a Second degree Type I AV block (Wenckebach)

Fig. 6.b Second degree Type II (Mobitz) AV block

**4.4 Third-degree (Complete) Atrio-Ventricular Heart Block** 

**4.4.1** *Definition*: Complete failure of conduction of atrial impulses to the ventricles.

**4.4.2** *Incidence*: Complete heart block may be acquired or congenital. The most common cause of acquired complete heart block in pediatric patients is surgery for left ventricular outflow tract obstruction, repair of corrected transposition of the great arteries (L-TGA), ventricular septal defects and TOF. Acquired complete AV block is also seen in Lyme carditis, myocarditis, myopathies, and metabolic diseases. Congenital complete heart block occurs 1 per 15,000 to 1 per 22,000 live births and is often associated with maternal

al. 2003).

**4.2.7** *Work-up*: An ECG can detect first degree block with or without infranodal disease based on QRS pattern. Atropine and exercise stress testing decrease the vagal tone and enhance AV nodal conduction, thereby shortening the PR interval. If the delay is due to infranodal disease, the conduction delay is worsened. Electrophysiology study can be used to determine the site of conduction delay.

**4.2.8** *Management and Prognosis*: Family history of rhythm or connective tissue disease should be obtained. Repeat ECGs are indicated in those with suspected progression to higher grade blocks. Indications for a pacemaker include first degree block with symptoms suggestive of a pacemaker-like syndrome (Class IIa), and presence of first degree block in neuromuscular diseases and LV dysfunction (Class IIb) (Gregaratos 2002).

Fig. 5. First degree AV block

### **4.3 Second-degree atrio-ventricular heart block**

**4.3.1** *Definition*: Second-degree heart block is atrio-ventricular block in which some atrial discharges are not conducted to the ventricles. It is classified as Mobitz type I (Wenckebach phenomena), Mobitz type II and high grade.

**4.3.2** *Incidence*: Wenckebach phenomena was detected in 2% of infants, 7% of toddlers and 6% of children at rest (von Bernuth et al. 1989).

**4.3.3** *Mechanism*: Mobitz type I (Wenckebach) block occurs at the AV node and His-Purkinje system in a ratio of 3:1, respectively (Peuch et al. 1976). Wenckebach phenomenon results from hypervagotonia in athletes and young subjects (Stein et al. 2002). Previous cardiac surgery and ischemic heart disease in adulthood are associated with Wenckebach phenomena. Mobitz type II block occurs infra-nodally in most cases (Dhingra et al. 1974).

**4.3.4** *Natural history*: Mobitz type I block is usually benign. However, in pediatric population without heart disease, Mobitz type I block may serve as intermediary prior to development of idiopathic complete heart block (Young et al. 1977). In adults, second degree AV-nodal block proximal to the His bundle has a benign course in those without heart disease; but is associated with poor prognosis in those with underlying heart disease (Strasberg et al. 1981). Mobitz type II can progress to symptomatic complete heart block and is associated with Stokes-Adams attacks and sudden death (Dhingra et al. 1974).

**4.3.5** *Clinical presentation*: Mobitz type I block is usually well tolerated; but may present with significant bradycardia. Patients with Mobitz type II block may be asymptomatic; but can present with bradycardia, exercise intolerance, syncope, postural hypotension, and sudden death.

**4.3.6** *ECG*: Mobitz type I shows progressive prolongation of PR interval followed by a nonconducted atrial discharge (Figure 6a). Mobitz type II is characterized by stable PR interval with intermittent failed conduction (Figure 6b). PR interval can be normal or prolonged.

**4.2.7** *Work-up*: An ECG can detect first degree block with or without infranodal disease based on QRS pattern. Atropine and exercise stress testing decrease the vagal tone and enhance AV nodal conduction, thereby shortening the PR interval. If the delay is due to infranodal disease, the conduction delay is worsened. Electrophysiology study can be used

**4.2.8** *Management and Prognosis*: Family history of rhythm or connective tissue disease should be obtained. Repeat ECGs are indicated in those with suspected progression to higher grade blocks. Indications for a pacemaker include first degree block with symptoms suggestive of a pacemaker-like syndrome (Class IIa), and presence of first degree block in

**4.3.1** *Definition*: Second-degree heart block is atrio-ventricular block in which some atrial discharges are not conducted to the ventricles. It is classified as Mobitz type I (Wenckebach

**4.3.2** *Incidence*: Wenckebach phenomena was detected in 2% of infants, 7% of toddlers and

**4.3.3** *Mechanism*: Mobitz type I (Wenckebach) block occurs at the AV node and His-Purkinje system in a ratio of 3:1, respectively (Peuch et al. 1976). Wenckebach phenomenon results from hypervagotonia in athletes and young subjects (Stein et al. 2002). Previous cardiac surgery and ischemic heart disease in adulthood are associated with Wenckebach phenomena. Mobitz type

**4.3.4** *Natural history*: Mobitz type I block is usually benign. However, in pediatric population without heart disease, Mobitz type I block may serve as intermediary prior to development of idiopathic complete heart block (Young et al. 1977). In adults, second degree AV-nodal block proximal to the His bundle has a benign course in those without heart disease; but is associated with poor prognosis in those with underlying heart disease (Strasberg et al. 1981). Mobitz type II can progress to symptomatic complete heart block and is associated with

**4.3.5** *Clinical presentation*: Mobitz type I block is usually well tolerated; but may present with significant bradycardia. Patients with Mobitz type II block may be asymptomatic; but can present with bradycardia, exercise intolerance, syncope, postural hypotension, and sudden

**4.3.6** *ECG*: Mobitz type I shows progressive prolongation of PR interval followed by a nonconducted atrial discharge (Figure 6a). Mobitz type II is characterized by stable PR interval with intermittent failed conduction (Figure 6b). PR interval can be normal or prolonged.

neuromuscular diseases and LV dysfunction (Class IIb) (Gregaratos 2002).

to determine the site of conduction delay.

Fig. 5. First degree AV block

death.

**4.3 Second-degree atrio-ventricular heart block** 

phenomena), Mobitz type II and high grade.

6% of children at rest (von Bernuth et al. 1989).

II block occurs infra-nodally in most cases (Dhingra et al. 1974).

Stokes-Adams attacks and sudden death (Dhingra et al. 1974).

**4.3.7** *Work-up*: ECG is diagnostic. If ECG is inconclusive, a 24-hour monitor is suggested. If there is one conducted beat in a cycle as in a 2:1 block, it is difficult to differentiate between Mobitz types I and II blocks; atropine can be used to elicit a 3:2 conduction in Mobitz type I block. Response to atropine suggests the block to be at or proximal to the AV node. If exercise initiates or exacerbates Mobitz type I block, infranodal location of the block is suspected. An electrophysiology study is indicated if there is unexplained syncope, and AV block distal to the AV node, to identify the location of the block (Zipes et al. 1995). In complete or high grade second degree AV block, an echocardiogram is indicated (Cheitlin et al. 2003).

**4.3.8** *Management*: Medical management of Mobitz type I includes identification and treatment of underlying causes. Sympathomimetic agents such as scopolamine, theophylline, or glycopyrrolate can be used in symptomatic bradycardia secondary to increased vagal tone. In patients with Mobitz type II, syncope is a poor prognostic factor (Dhingra et al. 1974). Symptomatic chronic bradycardia in Mobitz type I and type II (Class I), Mobitz type II with bifascicular or trifascicular block (Class I), Mobitz type II with wide QRS (Class I), asymptomatic Mobitz type II (Class IIa), and neuromuscular disease with AV block (Class IIb) are all indications for permanent pacemaker implantation (Gregaratos 2002).

Fig. 6.a Second degree Type I AV block (Wenckebach)

Fig. 6.b Second degree Type II (Mobitz) AV block

### **4.4 Third-degree (Complete) Atrio-Ventricular Heart Block**

**4.4.1** *Definition*: Complete failure of conduction of atrial impulses to the ventricles.

**4.4.2** *Incidence*: Complete heart block may be acquired or congenital. The most common cause of acquired complete heart block in pediatric patients is surgery for left ventricular outflow tract obstruction, repair of corrected transposition of the great arteries (L-TGA), ventricular septal defects and TOF. Acquired complete AV block is also seen in Lyme carditis, myocarditis, myopathies, and metabolic diseases. Congenital complete heart block occurs 1 per 15,000 to 1 per 22,000 live births and is often associated with maternal

Arrhythmias in Children and Young Adults 51

**4.5.1** *Definition*: Atrial escape rhythm arises from ectopic atrial foci during periods of severe sinus bradycardia or significant sinus node dysfunction. These atrial ectopic foci have slower spontaneous rates and are unstable. The exact incidence of atrial escape rhythm is

**4.5.2** *Mechanism*: The automaticity of an ectopic atrial focus generates a faster rate than the dysfunctional sinus node by escaping overdrive suppression of the SA node. Atrial escape

**4.5.3** *Natural history*: Atrial escape rhythm occurs in sinus node dysfunction and severe sinus bradycardia. Resolution or treatment of a slow underlying sinus rhythm resolves the atrial escape rhythm. Automaticity in ectopic foci are more responsive to autonomic control

**4.5.4** *Clinical presentation*: Most symptoms are secondary to underlying rhythm abnormalities such as sinus node dysfunction with severe sinus bradycardia, sinus pause and/or sinus

**4.5.5** *ECG*: The P-wave morphology differs from the sinus P-wave. The P-wave is smaller and shorter in duration with the P-wave axis dependent on the location of the ectopic focus. The PR interval may be shorter than the normal PR interval due to the proximity of the ectopic atrial focus to the AV node. The atrial escape rhythm is slower than the normal sinus

**4.5.6** *Work-up*: Work-up is focused on identifying the underlying abnormality leading to

**4.5.7** *Management and Prognosis*: In symptomatic patients, slow sinus rhythm is managed with sympathomimetic agents. If unresponsive to medical treatment, pacemaker implantation may be necessary for management of sinus node dysfunction or severe sinus

**4.6.1** *Definition*: AV junctional escape rhythm is defined as an ectopic rhythm starting in the AV junction due to failure of the atrial impulse to conduct. The ectopic rhythm may

**4.6.2** *Incidence*: Episodes of junctional escape rhythm were reported in 19% of full-term

**4.6.3** *Mechanism*: AV junctional escape rhythm occurs due to enhanced automaticity or a reentry mechanism. The ectopic focus can occur below the AV node and at or above the bundle of His, in the absence or suppression of an SA node or atrial impulse (Gamble et al. 2007). Due to the lack of overdrive suppression from the higher pacemakers, the AV

arrest. These include dizziness, exercise intolerance, and possible syncope.

Fig. 7. Third degree (complete) AV block

rhythm rate is between 60-80 beats per minute (Dubin 2000).

increased automaticity or suppression of the sinus node.

**4.6 Atrio-ventricular junctional escape rhythm** 

neonates (Southall et al; Southall et al. 1980).

originate between the AV node and the bundle of His.

compared to the SA node (Randall et al. 1981).

**4.5 Atrial escape rhythm** 

not known

rate.

bradycardia.

connective tissue disease, in particular systemic lupus erythematosis (Michaelsson and Engle 1972). Spontaneous complete heart block is seen in left atrial isomerism, endocardial cushion defects and in 20% of patients with L-TGA (Huhta et al. 1983; Lundstrom et al. 1990).

**4.4.3** *Mechanism*: Possible mechanisms include abnormal development of the conduction system and the AV node, or acquired most commonly after cardiac surgery. The escape rhythms below the AV node take over when the atrial discharge is not conducted to the ventricles. The rate of the escape rhythm correlates with the level of the block, with the proximal sites having a higher rate.

**4.4.4** *Natural history*: Complete heart block is associated with L-TGA and septal defects, as well as sequelae of maternal connective tissue. Mortality is highest during the neonatal period (Roberts and Gillette 1977). Congenital complete heart block in structurally normal heart, when uncorrected, leads to cardiac enlargement with impaired ventricular systolic function (Beaufort-Krol et al. 2007). There is a significant correlation between persistent heart rate of 50 or less and incidence of syncope, pre-syncope, and/or sudden death (Karpawich et al. 1981; Dewey et al. 1987).

**4.4.5** *Clinical presentation*: Many patients are asymptomatic in early life. Symptoms range from none to palpitations, chest pain, weakness, syncope, exercise intolerance, dizziness, and congestive heart failure in congenital complete heart block. Symptoms are usually dependent on ventricular rate, frequency of premature ventricular beats, and atrioventricular synchrony.

**4.4.6** *ECG*: Complete heart block is depicted by atrio-ventricular conduction blockade. In patients with normal hearts, the QRS complex is narrow if the block is at the AV node or His bundle; the QRS complex is wide if the block occurs after the bifurcation of the bundle of His (Weindling 2001). An ECG should be used to differentiate complete heart block from accelerated junctional rhythm or severe sinus bradycardia with appropriate junctional escape rate (Weindling 2001). Complete heart block is associated with a prior lesser-degree block (25%) and accompanied or preceded by bundle branch block (Levine et al. 1956). Associated prolongation of QT interval is seen in about 18% of congenital complete heart block (Figure 7).

**4.4.7** *Work-up*: A 12-lead ECG establishes the diagnosis. In symptomatic patients treated with a pacemaker and with a suspicion of another arrhythmia (Class I), and patients with premature, concealed junctional depolarizations as in pseudo-AV block (Class II), an electrophysiology study is indicated (Zipes et al. 1995). In patients with complete AV block or advanced second-degree AV block, an echocardiogram is used to visualize cardiac function, size, structure, and valvular regurgitation (Cheitlin et al. 2003; Beaufort-Krol et al. 2007). Exercise stress testing in asymptomatic patients with congenital complete heart block is used to determine degree of exercise tolerance and arrhythmias associated with exercise (Gibbons et al. 2002).

**4.4.8** *Management and Prognosis*: Primary mode of management of patients with complete heart block is pacemaker implantation. The time of pacemaker implantation is controversial. Third degree AV block with symptomatic bradycardia, post-operative complete heart block that does not resolve in 7-10 days, and congenital complete heart block with wide QRS escape rhythm and ventricular dysfunction, and congenital complete heart block with rate <50 bpm are Class I indications for pacemaker implantation (Gregaratos 2002). Prognosis for neonates and infants post pacemaker implantation is very good (Aellig et al. 2007).

connective tissue disease, in particular systemic lupus erythematosis (Michaelsson and Engle 1972). Spontaneous complete heart block is seen in left atrial isomerism, endocardial cushion defects and in 20% of patients with L-TGA (Huhta et al. 1983; Lundstrom et al.

**4.4.3** *Mechanism*: Possible mechanisms include abnormal development of the conduction system and the AV node, or acquired most commonly after cardiac surgery. The escape rhythms below the AV node take over when the atrial discharge is not conducted to the ventricles. The rate of the escape rhythm correlates with the level of the block, with the

**4.4.4** *Natural history*: Complete heart block is associated with L-TGA and septal defects, as well as sequelae of maternal connective tissue. Mortality is highest during the neonatal period (Roberts and Gillette 1977). Congenital complete heart block in structurally normal heart, when uncorrected, leads to cardiac enlargement with impaired ventricular systolic function (Beaufort-Krol et al. 2007). There is a significant correlation between persistent heart rate of 50 or less and incidence of syncope, pre-syncope, and/or sudden death

**4.4.5** *Clinical presentation*: Many patients are asymptomatic in early life. Symptoms range from none to palpitations, chest pain, weakness, syncope, exercise intolerance, dizziness, and congestive heart failure in congenital complete heart block. Symptoms are usually dependent on ventricular rate, frequency of premature ventricular beats, and atrio-

**4.4.6** *ECG*: Complete heart block is depicted by atrio-ventricular conduction blockade. In patients with normal hearts, the QRS complex is narrow if the block is at the AV node or His bundle; the QRS complex is wide if the block occurs after the bifurcation of the bundle of His (Weindling 2001). An ECG should be used to differentiate complete heart block from accelerated junctional rhythm or severe sinus bradycardia with appropriate junctional escape rate (Weindling 2001). Complete heart block is associated with a prior lesser-degree block (25%) and accompanied or preceded by bundle branch block (Levine et al. 1956). Associated prolongation of QT interval is seen in about 18% of congenital complete heart

**4.4.7** *Work-up*: A 12-lead ECG establishes the diagnosis. In symptomatic patients treated with a pacemaker and with a suspicion of another arrhythmia (Class I), and patients with premature, concealed junctional depolarizations as in pseudo-AV block (Class II), an electrophysiology study is indicated (Zipes et al. 1995). In patients with complete AV block or advanced second-degree AV block, an echocardiogram is used to visualize cardiac function, size, structure, and valvular regurgitation (Cheitlin et al. 2003; Beaufort-Krol et al. 2007). Exercise stress testing in asymptomatic patients with congenital complete heart block is used to determine degree of exercise tolerance and arrhythmias associated with exercise

**4.4.8** *Management and Prognosis*: Primary mode of management of patients with complete heart block is pacemaker implantation. The time of pacemaker implantation is controversial. Third degree AV block with symptomatic bradycardia, post-operative complete heart block that does not resolve in 7-10 days, and congenital complete heart block with wide QRS escape rhythm and ventricular dysfunction, and congenital complete heart block with rate <50 bpm are Class I indications for pacemaker implantation (Gregaratos 2002). Prognosis for

neonates and infants post pacemaker implantation is very good (Aellig et al. 2007).

1990).

proximal sites having a higher rate.

(Karpawich et al. 1981; Dewey et al. 1987).

ventricular synchrony.

block (Figure 7).

(Gibbons et al. 2002).

Fig. 7. Third degree (complete) AV block

### **4.5 Atrial escape rhythm**

**4.5.1** *Definition*: Atrial escape rhythm arises from ectopic atrial foci during periods of severe sinus bradycardia or significant sinus node dysfunction. These atrial ectopic foci have slower spontaneous rates and are unstable. The exact incidence of atrial escape rhythm is not known

**4.5.2** *Mechanism*: The automaticity of an ectopic atrial focus generates a faster rate than the dysfunctional sinus node by escaping overdrive suppression of the SA node. Atrial escape rhythm rate is between 60-80 beats per minute (Dubin 2000).

**4.5.3** *Natural history*: Atrial escape rhythm occurs in sinus node dysfunction and severe sinus bradycardia. Resolution or treatment of a slow underlying sinus rhythm resolves the atrial escape rhythm. Automaticity in ectopic foci are more responsive to autonomic control compared to the SA node (Randall et al. 1981).

**4.5.4** *Clinical presentation*: Most symptoms are secondary to underlying rhythm abnormalities such as sinus node dysfunction with severe sinus bradycardia, sinus pause and/or sinus arrest. These include dizziness, exercise intolerance, and possible syncope.

**4.5.5** *ECG*: The P-wave morphology differs from the sinus P-wave. The P-wave is smaller and shorter in duration with the P-wave axis dependent on the location of the ectopic focus. The PR interval may be shorter than the normal PR interval due to the proximity of the ectopic atrial focus to the AV node. The atrial escape rhythm is slower than the normal sinus rate.

**4.5.6** *Work-up*: Work-up is focused on identifying the underlying abnormality leading to increased automaticity or suppression of the sinus node.

**4.5.7** *Management and Prognosis*: In symptomatic patients, slow sinus rhythm is managed with sympathomimetic agents. If unresponsive to medical treatment, pacemaker implantation may be necessary for management of sinus node dysfunction or severe sinus bradycardia.

### **4.6 Atrio-ventricular junctional escape rhythm**

**4.6.1** *Definition*: AV junctional escape rhythm is defined as an ectopic rhythm starting in the AV junction due to failure of the atrial impulse to conduct. The ectopic rhythm may originate between the AV node and the bundle of His.

**4.6.2** *Incidence*: Episodes of junctional escape rhythm were reported in 19% of full-term neonates (Southall et al; Southall et al. 1980).

**4.6.3** *Mechanism*: AV junctional escape rhythm occurs due to enhanced automaticity or a reentry mechanism. The ectopic focus can occur below the AV node and at or above the bundle of His, in the absence or suppression of an SA node or atrial impulse (Gamble et al. 2007). Due to the lack of overdrive suppression from the higher pacemakers, the AV

Arrhythmias in Children and Young Adults 53

**5.1.1.1** *Definition*: Sinus tachycardia is an automatic rhythm characterized by rapid discharge from the sinus node due to physiologic influences (Walsh 2001b; Blomstrom-Lundqvist et al.

**5.1.1.2** *Incidence*: Dependent on the body's increased sympathetic response to physiologic phenomena, such as fever, dehydration, anxiety, pain, medications, anemia, hyperthyroidism

**5.1.1.3** *Mechanism*: Occurs due to increased automaticity with rate variability associated with

**5.1.1.4** *Natural history*: Decreasing the underlying enhanced sympathetic tone or increasing

**5.1.1.5** *Clinical presentation*: The inciting factor for sympathetic response or vagal withdrawal is the usual presenting symptom. Very high rate of sinus tachycardia can compromise

**5.1.1.6** *ECG*: There is a normal P-wave axis and a P-wave precedes each QRS complex (Van Hare 1999). P-waves may have larger amplitude and become peaked (Blomstrom-Lundqvist

**5.1.1.7** *Work-up*: Identify the extrinsic factors causing the tachycardia and treat them. It is

**5.1.1.8** *Management and Prognosis*: Prognosis depends on the nature of the underlying cause. No specific treatment is required for physiologic sinus tachycardia except treatment of the underlying causes. Beta-adrenergic receptor blockers may occasionally be used for treatment of physiologic symptomatic sinus tachycardia (Blomstrom-Lundqvist 2003).

**5.1.2.1** *Definition*: Elevated resting heart rate for the physiological state and/or an exaggerated

**5.1.2.2** *Incidence*: IST often follows a viral illness or physical trauma, usually in women (90%)

**5.1.2.3** *Mechanism*: Etiology is not known. The mechanism may involve a primary sino-atrial (SA) node disorder with increased automaticity, a dysautonomia with increased sympathetic tone, decreased parasympathetic tone, and/or increased SA node betaadrenergic sensitivity, or impaired baroreflex control (Krahn et al. 1995; Fogoros 2006; Morillo and Guzman 2007). Another mechanism is stimulation of the beta-adrenergic

**5.1.2.4** *Natural history*: IST is more common in women in the 20s and 30s, who are otherwise

**5.1.2.5** *Clinical presentation*: Palpitations, lightheadedness, exercise intolerance, and fatigue are common symptoms. Patients may also have orthostatic intolerance, chest pain, anxiety, depression, headache and myalgia, gastro-intestinal disturbances, and diaphoresis (Shen 2005; Fogoros 2006). Only consistent finding on physical exam is tachycardia (Shen 2005;

**5.1.2.6** *ECG*: P-wave morphology and axis is similar to that of normal sinus rhythm (Shen

heart rate response to exercise or stress (Krahn et al. 1995; Blomstrom-Lundqvist 2003).

2003; Blomstrom-Lundqvist 2003). The rate of sinus tachycardia is dependent on age.

**5. Tachy-arrhythmias** 

and heart failure.

2003).

Fogoros 2006).

**5.1 Atrial tachy-arrhythmias** 

**5.1.1 Physiologic (appropriate) sinus tachycardia** 

increased sympathetic response or vagal withdrawal.

cardiac output by decreasing the ventricular filling time.

also necessary to rule out inappropriate sinus tachycardia (see below).

who are generally healthy physically and emotionally (Fogoros 2006).

receptors by anti-beta adrenergic autoantibodies (Chiale et al. 2006).

healthy. It is likely to improve over time (Fogoros 2006).

2005). There is tachycardia at rest on ECG.

the vagal tone will decrease the sinus tachycardia.

**5.1.2 Inappropriate Sinus Tachycardia (IST)** 

junction has its intrinsic automaticity. The junctional escape rate ranges between 40-60 beats per minute (Dubin 2000).

**4.6.4** *Natural history*: The junctional pacemaker can exist in the region of the distal AV node or the proximal portion of the His-bundle near the AV-node (Alison et al. 1995). Nodal escape rhythm is associated with apnea (Valimaki and Tarlo 1971). The rate of AV junctional escape rhythm varies with underlying conditions, such as sick sinus syndrome, complete heart block, ablation of AV node, congenital heart surgery, hypertrophic cardiomyopathy, and ischemia (Kleinfeld and Boal 1978; Alison et al. 1995; Shepard et al. 1998). Inflammation, hypoxia, metabolic, drugs, or electrolyte disturbances are implicated in the etiology of junctional rhythms (Fisch and Knoebel 1970).

**4.6.5** *Clinical presentation*: Symptoms pertaining to AV junctional escape rhythm are related to suppression of the sino-atrial tissues and or failure to conduct to the junction. Symptoms include dizziness, exercise intolerance, near syncope or syncope.

**4.6.6** *ECG*: In AV junctional escape rhythm, there are no P-waves before the QRS complexes; they may occur simultaneously or follow the QRS complexes. The QRS complex is narrow if the focus is closer to the AV node or wide if proximal to the His bundle bifurcation. In the case of complete AV block, P-waves of sinus origin are dissociated from the QRS complexes. **4.6.7** *Work-up*: ECG may identify the rhythm; if unsuccessful, a Holter monitor can help identify the rhythm abnormality. Workup should also include identifying the causes listed above.

**4.6.8** *Management and Prognosis*: Pacemaker implantation may be needed in symptomatic bradycardia due to junctional escape rhythm.

### **4.7 Idioventricular escape rhythm**

**4.7.1** *Definition*: Ventricular escape (idioventricular) rhythm arises below the bifurcation of the His bundle. The ventricular escape results when the higher pacemaker systems are unable to generate and/or conduct an impulse to the ventricles. It is rare and incidence is not known.

**4.7.2** *Mechanism*: The automaticity of the ventricular myocardium is pronounced in the absence of supraventricular impulses. The overdrive suppression from higher pacemaker centers is absent, leading to the automaticity of the ventricular focus to conduct to the ventricles. Idioventricular rate ranges from 20-40 beats per minute (Dubin 2000).

**4.7.3** *Natural history*: Idioventricular rhythm is seen with hypothermia, drugs, and ischemia (Talbot and Greaves 1976).

**4.7.4** *Clinical presentation*: Stokes-Adams syncopal attacks are more prevalent in ventricular escape rhythm than atrial or junctional escape rhythms. This is also accompanied by dizziness and exercise intolerance.

**4.7.5** *ECG*: The ECG shows wide QRS complexes with a rate of 20-40 beats per minute. If Pwaves exist, they occur independently and are dissociated from the ventricular beats.

**4.7.6** *Work-up*: ECG is the first step in diagnosing ventricular escape rhythm. Holter and event recorders are alternatives when ECG is not diagnostic. Electrophysiology study is indicated (class IIA) in patients with suspected bradyarrhythmias with syncope (Zipes 2006). An EP study can establish the level of the AV block.

**4.7.7** *Management and Prognosis*: Symptomatic relief is important in patients with ventricular escape rhythm. Pacemaker implantation with ventricular pacing is essential to avoid Stokes-Adams attacks.

### **5. Tachy-arrhythmias**

52 Advances in Electrocardiograms – Clinical Applications

junction has its intrinsic automaticity. The junctional escape rate ranges between 40-60 beats

**4.6.4** *Natural history*: The junctional pacemaker can exist in the region of the distal AV node or the proximal portion of the His-bundle near the AV-node (Alison et al. 1995). Nodal escape rhythm is associated with apnea (Valimaki and Tarlo 1971). The rate of AV junctional escape rhythm varies with underlying conditions, such as sick sinus syndrome, complete heart block, ablation of AV node, congenital heart surgery, hypertrophic cardiomyopathy, and ischemia (Kleinfeld and Boal 1978; Alison et al. 1995; Shepard et al. 1998). Inflammation, hypoxia, metabolic, drugs, or electrolyte disturbances are implicated in the etiology of

**4.6.5** *Clinical presentation*: Symptoms pertaining to AV junctional escape rhythm are related to suppression of the sino-atrial tissues and or failure to conduct to the junction. Symptoms

**4.6.6** *ECG*: In AV junctional escape rhythm, there are no P-waves before the QRS complexes; they may occur simultaneously or follow the QRS complexes. The QRS complex is narrow if the focus is closer to the AV node or wide if proximal to the His bundle bifurcation. In the case of complete AV block, P-waves of sinus origin are dissociated from the QRS complexes. **4.6.7** *Work-up*: ECG may identify the rhythm; if unsuccessful, a Holter monitor can help identify the rhythm abnormality. Workup should also include identifying the causes listed

**4.6.8** *Management and Prognosis*: Pacemaker implantation may be needed in symptomatic

**4.7.1** *Definition*: Ventricular escape (idioventricular) rhythm arises below the bifurcation of the His bundle. The ventricular escape results when the higher pacemaker systems are unable to generate and/or conduct an impulse to the ventricles. It is rare and incidence is

**4.7.2** *Mechanism*: The automaticity of the ventricular myocardium is pronounced in the absence of supraventricular impulses. The overdrive suppression from higher pacemaker centers is absent, leading to the automaticity of the ventricular focus to conduct to the

**4.7.3** *Natural history*: Idioventricular rhythm is seen with hypothermia, drugs, and ischemia

**4.7.4** *Clinical presentation*: Stokes-Adams syncopal attacks are more prevalent in ventricular escape rhythm than atrial or junctional escape rhythms. This is also accompanied by

**4.7.5** *ECG*: The ECG shows wide QRS complexes with a rate of 20-40 beats per minute. If Pwaves exist, they occur independently and are dissociated from the ventricular beats.

**4.7.6** *Work-up*: ECG is the first step in diagnosing ventricular escape rhythm. Holter and event recorders are alternatives when ECG is not diagnostic. Electrophysiology study is indicated (class IIA) in patients with suspected bradyarrhythmias with syncope (Zipes

**4.7.7** *Management and Prognosis*: Symptomatic relief is important in patients with ventricular escape rhythm. Pacemaker implantation with ventricular pacing is essential to avoid Stokes-

ventricles. Idioventricular rate ranges from 20-40 beats per minute (Dubin 2000).

per minute (Dubin 2000).

above.

not known.

Adams attacks.

junctional rhythms (Fisch and Knoebel 1970).

bradycardia due to junctional escape rhythm.

**4.7 Idioventricular escape rhythm** 

(Talbot and Greaves 1976).

dizziness and exercise intolerance.

2006). An EP study can establish the level of the AV block.

include dizziness, exercise intolerance, near syncope or syncope.

### **5.1 Atrial tachy-arrhythmias**

### **5.1.1 Physiologic (appropriate) sinus tachycardia**

**5.1.1.1** *Definition*: Sinus tachycardia is an automatic rhythm characterized by rapid discharge from the sinus node due to physiologic influences (Walsh 2001b; Blomstrom-Lundqvist et al. 2003; Blomstrom-Lundqvist 2003). The rate of sinus tachycardia is dependent on age.

**5.1.1.2** *Incidence*: Dependent on the body's increased sympathetic response to physiologic phenomena, such as fever, dehydration, anxiety, pain, medications, anemia, hyperthyroidism and heart failure.

**5.1.1.3** *Mechanism*: Occurs due to increased automaticity with rate variability associated with increased sympathetic response or vagal withdrawal.

**5.1.1.4** *Natural history*: Decreasing the underlying enhanced sympathetic tone or increasing the vagal tone will decrease the sinus tachycardia.

**5.1.1.5** *Clinical presentation*: The inciting factor for sympathetic response or vagal withdrawal is the usual presenting symptom. Very high rate of sinus tachycardia can compromise cardiac output by decreasing the ventricular filling time.

**5.1.1.6** *ECG*: There is a normal P-wave axis and a P-wave precedes each QRS complex (Van Hare 1999). P-waves may have larger amplitude and become peaked (Blomstrom-Lundqvist 2003).

**5.1.1.7** *Work-up*: Identify the extrinsic factors causing the tachycardia and treat them. It is also necessary to rule out inappropriate sinus tachycardia (see below).

**5.1.1.8** *Management and Prognosis*: Prognosis depends on the nature of the underlying cause. No specific treatment is required for physiologic sinus tachycardia except treatment of the underlying causes. Beta-adrenergic receptor blockers may occasionally be used for treatment of physiologic symptomatic sinus tachycardia (Blomstrom-Lundqvist 2003).

### **5.1.2 Inappropriate Sinus Tachycardia (IST)**

**5.1.2.1** *Definition*: Elevated resting heart rate for the physiological state and/or an exaggerated heart rate response to exercise or stress (Krahn et al. 1995; Blomstrom-Lundqvist 2003).

**5.1.2.2** *Incidence*: IST often follows a viral illness or physical trauma, usually in women (90%) who are generally healthy physically and emotionally (Fogoros 2006).

**5.1.2.3** *Mechanism*: Etiology is not known. The mechanism may involve a primary sino-atrial (SA) node disorder with increased automaticity, a dysautonomia with increased sympathetic tone, decreased parasympathetic tone, and/or increased SA node betaadrenergic sensitivity, or impaired baroreflex control (Krahn et al. 1995; Fogoros 2006; Morillo and Guzman 2007). Another mechanism is stimulation of the beta-adrenergic receptors by anti-beta adrenergic autoantibodies (Chiale et al. 2006).

**5.1.2.4** *Natural history*: IST is more common in women in the 20s and 30s, who are otherwise healthy. It is likely to improve over time (Fogoros 2006).

**5.1.2.5** *Clinical presentation*: Palpitations, lightheadedness, exercise intolerance, and fatigue are common symptoms. Patients may also have orthostatic intolerance, chest pain, anxiety, depression, headache and myalgia, gastro-intestinal disturbances, and diaphoresis (Shen 2005; Fogoros 2006). Only consistent finding on physical exam is tachycardia (Shen 2005; Fogoros 2006).

**5.1.2.6** *ECG*: P-wave morphology and axis is similar to that of normal sinus rhythm (Shen 2005). There is tachycardia at rest on ECG.

Arrhythmias in Children and Young Adults 55

premature beat or atrial pacing, and e) termination with vagal maneuvers or adenosine

**5.1.3.7** *Work-up*: Electrophysiology study is indicated in patients with frequent and poorlytolerated episodes of tachycardia, unclear mechanism of tachycardia, and refractoriness to

**5.1.3.8** *Management and Prognosis*: Vagal maneuvers or adenosine may interrupt the tachycardia. Acutely, atrial pacing is effective. Beta blockers, calcium channel blockers, amiodarone, and digitalis can benefit patients with increased frequency of symptoms. However, prophylactic treatment of SNRT is not recommended. In patients undergoing an

**5.1.4.1** *Definition*: Ectopic or focal atrial tachycardia (EAT) is a tachycardia mediated by inappropriate atrial impulse generation from a single atrial focus outside of the SA node

**5.1.4.2** *Incidence*: EAT is commonly found in children and teenagers and makes up approximately 15% of all newly diagnosed supraventricular tachycardias across all ages (Walsh 2001a). Both genders are equally affected. Prevalence of EAT is 0.34% in asymptomatic male patients and 0.46% in symptomatic male patients (Poutiainen et al.

**5.1.4.3** *Mechanism*: EAT can be due to three mechanisms: a) enhanced automaticity, b) triggered activity, and c) microreentry (Roberts-Thomson et al. 2006). The tachycardia cannot be initiated or terminated with programmed stimuli (Walsh 2001a). However, the

**5.1.4.4** *Natural history*: In the majority of patients, the course is benign. Persistent incessant EAT can lead to ventricular dysfunction, congestive heart failure and low cardiac output states, termed tachycardia-mediated cardiomyopathy. However, termination of the rhythm can lead to improvement in ventricular function (Packer et al. 1986; Naheed et al. 1995). There is slowing of heart rate with time, with reversion to sinus rhythm or change in P-wave

**5.1.4.5** *Clinical presentation*: Young patients are often asymptomatic until onset of left ventricular dysfunction. Patients may also have palpitations, lightheadedness, and exercise

**5.1.4.6** *ECG*: ECG shows a supraventricular tachycardia with rates within normal range to 300 beats per minute. ECG criteria for diagnosis include: a) the P-wave morphology and axis different than that of normal sinus rhythm, b) acceleration after initiation and deceleration before termination, c) unaffected by presence of an atrio-ventricular block, and d) an initial P-wave of the tachycardia similar to the subsequent P-waves (Olgin and Zipes 2005a). The

**5.1.4.7** *Work-up*: The location of the ectopic focus can be determined by noting P-wave frontal plane axis. "Warm-up" and "cool-down" patterns can be appreciated and suggestive of an automatic mechanism. AV-block (Mobitz 1) can be appreciated episodically during sleep. Adenosine administration will demonstrate AV-block with continuous marching of Pwaves (Figure 8). When the ectopic focus is close to the sinus node and/or there is poor ventricular function, electrophysiology testing is necessary to differentiate between sinus tachycardia, atrial flutter, and ectopic atrial tachycardia. Difficulty to terminate tachycardia

electrophysiology study, catheter ablation can be successful (Goya et al. 1999).

(Narula 1974; Blomstrom-Lundqvist 2003).

**5.1.4 Ectopic (focal) Atrial Tachycardia** 

exact mechanism is difficult to ascertain.

morphology (Poutiainen et al. 1999).

intolerance even with normal LV function (Walsh 2001a).

QRS complex is similar to that of sinus rhythm.

medications.

(Walsh 2001a).

1999).

**5.1.2.7** *Diagnosis*: Criteria for diagnosis include: a) persistent sinus tachycardia during the day with increased rate in response to activity and normalization during sleep per 24-hour Holter recording, b) non-paroxysmal tachycardia and symptoms, c) P-wave morphology and activation similar to sinus rhythm, and d) exclusion of secondary causes of sinus tachycardia (Blomstrom-Lundqvist 2003).

**5.1.2.8** *Work-up*: In addition to the ECG, a 24-holter monitor will document elevated mean heart rates above normal for age, elevated daytime heart rates, and/or exaggerated elevation in sinus rate from supine to upright position (Shen 2005). A diagnostic electrophysiology (EP) study should be considered if the etiology of the tachycardia is unclear (to rule out sinus node re-entry tachycardia). EP study consistent with IST would include slow warm up and cool down phases suggesting sinus node involvement, surface Pwave similar to that of normal sinus rhythm, and earliest activation arising near the sinus node area along the crista terminalis during mapping. IST is not initiated with programmed stimulation of the atria (Lin and Callans 2004). In addition to electrophysiology testing, there is also a need for autonomic dysregulation testing. Neurologic, cardiovascular rehabilitation, and psychiatric consultations are often necessary because IST is a diagnosis of exclusion (Shen 2005).

**5.1.2.9** *Management and Prognosis*: Treatment involves a multidisciplinary approach. Medications including beta blockers, calcium channel blockers and class IC anti-arrhythmic agents decrease SA node automaticity (Chiale et al. 2006). However in patients with IST secondary to autonomic dysregulation, control of heart rate does not always lead to resolution of symptoms. In patients with no evidence of autonomic dysregulation if biofeedback, meditation, and medical therapy fail, superolateral crista terminalis ablation could be considered (Shen 2005; Fogoros 2006). Risks of RF ablation include SVC syndrome, diaphragmatic paralysis and persistent junctional rhythm. The prognosis of IST is benign over a mean follow-up of 6 years (Still et al. 2005).

### **5.1.3 Sinus Node Re-entry Tachycardia**

**5.1.3.1** *Definition*: Sino-atrial node re-entry tachycardia (SNRT) is a paroxysmal arrhythmia characterized by a re-entry mechanism that is located entirely within the SA node or the perisinus atrial tissue (Lin and Callans 2004).

**5.1.3.2** *Incidence*: Incidence of SNRT is underestimated due to lack of symptoms very often. In patients undergoing electrophysiology study for supraventricular tachycardia, incidence ranges from 1.8%-16.9% (Blomstrom-Lundqvist 2003). Incidence of SNRT is higher (10%) in those with underlying organic heart disease (Garson Jr. and Gillette 1981).

*5.1.3.3 Mechanism*: A re-entry mechanism is present but it is not known whether the entire circuit is within the SA node or involves perisinus atrial tissue.

**5.1.3.4** *Clinical presentation*: Patients are often asymptomatic. Symptoms include palpitations, lightheadedness, presyncope, and rarely syncope (Gomes et al. 1985).

**5.1.3.5** *ECG*: SNRT heart rate ranges from 80-200 beats/min. P-wave axis and morphology are similar to that of normal sinus rhythm. P-R interval is shorter than R-P interval. An atrio-ventricular (AV) nodal Wenckebach block may be present (Olgin and Zipes 2005a).

**5.1.3.6** *Diagnosis*: Criteria for diagnosis include: a) paroxysmal tachycardia, b) P-wave morphology and endocardial atrial activation similar to that of normal sinus rhythm, c) inducibility with programmed premature atrial stimuli irrespective of the location of stimulation or the AV junction, d) the ability to terminate the arrhythmia with atrial

**5.1.2.7** *Diagnosis*: Criteria for diagnosis include: a) persistent sinus tachycardia during the day with increased rate in response to activity and normalization during sleep per 24-hour Holter recording, b) non-paroxysmal tachycardia and symptoms, c) P-wave morphology and activation similar to sinus rhythm, and d) exclusion of secondary causes of sinus

**5.1.2.8** *Work-up*: In addition to the ECG, a 24-holter monitor will document elevated mean heart rates above normal for age, elevated daytime heart rates, and/or exaggerated elevation in sinus rate from supine to upright position (Shen 2005). A diagnostic electrophysiology (EP) study should be considered if the etiology of the tachycardia is unclear (to rule out sinus node re-entry tachycardia). EP study consistent with IST would include slow warm up and cool down phases suggesting sinus node involvement, surface Pwave similar to that of normal sinus rhythm, and earliest activation arising near the sinus node area along the crista terminalis during mapping. IST is not initiated with programmed stimulation of the atria (Lin and Callans 2004). In addition to electrophysiology testing, there is also a need for autonomic dysregulation testing. Neurologic, cardiovascular rehabilitation, and psychiatric consultations are often necessary because IST is a diagnosis of

**5.1.2.9** *Management and Prognosis*: Treatment involves a multidisciplinary approach. Medications including beta blockers, calcium channel blockers and class IC anti-arrhythmic agents decrease SA node automaticity (Chiale et al. 2006). However in patients with IST secondary to autonomic dysregulation, control of heart rate does not always lead to resolution of symptoms. In patients with no evidence of autonomic dysregulation if biofeedback, meditation, and medical therapy fail, superolateral crista terminalis ablation could be considered (Shen 2005; Fogoros 2006). Risks of RF ablation include SVC syndrome, diaphragmatic paralysis and persistent junctional rhythm. The prognosis of IST is benign

**5.1.3.1** *Definition*: Sino-atrial node re-entry tachycardia (SNRT) is a paroxysmal arrhythmia characterized by a re-entry mechanism that is located entirely within the SA node or the

**5.1.3.2** *Incidence*: Incidence of SNRT is underestimated due to lack of symptoms very often. In patients undergoing electrophysiology study for supraventricular tachycardia, incidence ranges from 1.8%-16.9% (Blomstrom-Lundqvist 2003). Incidence of SNRT is higher (10%) in

*5.1.3.3 Mechanism*: A re-entry mechanism is present but it is not known whether the entire

**5.1.3.4** *Clinical presentation*: Patients are often asymptomatic. Symptoms include palpitations,

**5.1.3.5** *ECG*: SNRT heart rate ranges from 80-200 beats/min. P-wave axis and morphology are similar to that of normal sinus rhythm. P-R interval is shorter than R-P interval. An atrio-ventricular (AV) nodal Wenckebach block may be present (Olgin and Zipes 2005a). **5.1.3.6** *Diagnosis*: Criteria for diagnosis include: a) paroxysmal tachycardia, b) P-wave morphology and endocardial atrial activation similar to that of normal sinus rhythm, c) inducibility with programmed premature atrial stimuli irrespective of the location of stimulation or the AV junction, d) the ability to terminate the arrhythmia with atrial

those with underlying organic heart disease (Garson Jr. and Gillette 1981).

circuit is within the SA node or involves perisinus atrial tissue.

lightheadedness, presyncope, and rarely syncope (Gomes et al. 1985).

tachycardia (Blomstrom-Lundqvist 2003).

over a mean follow-up of 6 years (Still et al. 2005).

**5.1.3 Sinus Node Re-entry Tachycardia** 

perisinus atrial tissue (Lin and Callans 2004).

exclusion (Shen 2005).

premature beat or atrial pacing, and e) termination with vagal maneuvers or adenosine (Narula 1974; Blomstrom-Lundqvist 2003).

**5.1.3.7** *Work-up*: Electrophysiology study is indicated in patients with frequent and poorlytolerated episodes of tachycardia, unclear mechanism of tachycardia, and refractoriness to medications.

**5.1.3.8** *Management and Prognosis*: Vagal maneuvers or adenosine may interrupt the tachycardia. Acutely, atrial pacing is effective. Beta blockers, calcium channel blockers, amiodarone, and digitalis can benefit patients with increased frequency of symptoms. However, prophylactic treatment of SNRT is not recommended. In patients undergoing an electrophysiology study, catheter ablation can be successful (Goya et al. 1999).

### **5.1.4 Ectopic (focal) Atrial Tachycardia**

**5.1.4.1** *Definition*: Ectopic or focal atrial tachycardia (EAT) is a tachycardia mediated by inappropriate atrial impulse generation from a single atrial focus outside of the SA node (Walsh 2001a).

**5.1.4.2** *Incidence*: EAT is commonly found in children and teenagers and makes up approximately 15% of all newly diagnosed supraventricular tachycardias across all ages (Walsh 2001a). Both genders are equally affected. Prevalence of EAT is 0.34% in asymptomatic male patients and 0.46% in symptomatic male patients (Poutiainen et al. 1999).

**5.1.4.3** *Mechanism*: EAT can be due to three mechanisms: a) enhanced automaticity, b) triggered activity, and c) microreentry (Roberts-Thomson et al. 2006). The tachycardia cannot be initiated or terminated with programmed stimuli (Walsh 2001a). However, the exact mechanism is difficult to ascertain.

**5.1.4.4** *Natural history*: In the majority of patients, the course is benign. Persistent incessant EAT can lead to ventricular dysfunction, congestive heart failure and low cardiac output states, termed tachycardia-mediated cardiomyopathy. However, termination of the rhythm can lead to improvement in ventricular function (Packer et al. 1986; Naheed et al. 1995). There is slowing of heart rate with time, with reversion to sinus rhythm or change in P-wave morphology (Poutiainen et al. 1999).

**5.1.4.5** *Clinical presentation*: Young patients are often asymptomatic until onset of left ventricular dysfunction. Patients may also have palpitations, lightheadedness, and exercise intolerance even with normal LV function (Walsh 2001a).

**5.1.4.6** *ECG*: ECG shows a supraventricular tachycardia with rates within normal range to 300 beats per minute. ECG criteria for diagnosis include: a) the P-wave morphology and axis different than that of normal sinus rhythm, b) acceleration after initiation and deceleration before termination, c) unaffected by presence of an atrio-ventricular block, and d) an initial P-wave of the tachycardia similar to the subsequent P-waves (Olgin and Zipes 2005a). The QRS complex is similar to that of sinus rhythm.

**5.1.4.7** *Work-up*: The location of the ectopic focus can be determined by noting P-wave frontal plane axis. "Warm-up" and "cool-down" patterns can be appreciated and suggestive of an automatic mechanism. AV-block (Mobitz 1) can be appreciated episodically during sleep. Adenosine administration will demonstrate AV-block with continuous marching of Pwaves (Figure 8). When the ectopic focus is close to the sinus node and/or there is poor ventricular function, electrophysiology testing is necessary to differentiate between sinus tachycardia, atrial flutter, and ectopic atrial tachycardia. Difficulty to terminate tachycardia

Arrhythmias in Children and Young Adults 57

**5.1.5.7** *ECG*: Diagnostic criteria include: 1) irregular atrial rates, 2) at least three different Pwave configurations, 3) isoelectric baseline between discrete P waves, 4) irregular P-P, P-R, and R-R intervals, and 5) absence of a dominant atrial pacemaker (Sokoloski 1999). Atrial

**5.1.5.9** *Management and Prognosis*: It is usually not responsive to DC cardioversion, vagal maneuvers, or IV antiarrhythmics. However, digoxin, beta blockers, amiodarone, and flecainide are options to consider. Calcium channel blockers are not indicated in neonates and infants less than one year of age. When drug therapy is successful, it should be continued for 6-12 months. In rare cases with medication refractory MAT, multiple foci ablation is required. In refractory cases, AV node ablation with ventricular pacemaker

**5.1.6.1** *Definition*: Atrial flutter is a regular atrial tachycardia due to a macro-reentrant rhythm confined to the atrium. There are two types of atrial flutter: 1) typical or Type I and 2) atypical or Type II. Typical atrial flutter is the most common, cavo-tricuspid isthmusdependent, terminated by rapid atrial pacing and is further divided into counter-clockwise and clockwise circuits. Atypical atrial flutter has a faster rate (>350 beats/minute), and is not cavo-tricuspid isthmus-dependent (Saoudi et al. 2001; Waldo 2004). Left atrial flutter is also

**5.1.6.2** *Incidence*: In a study of 380 patients with first flutter episode between 1 and 25 years of life, 81% had congenital heart disease, and 8% had normal hearts (Garson Jr. et al. 1985). Among adults, the incidence of atrial flutter overall was 88 per 100,000 person-years with male predominance (4:1) and is noted in patients with heart failure, pulmonary disease, thyrotoxicosis, post repair of congenital heart defects, and mitral valve disease (Granada et al. 2000; Waldo 2004). The incidence of atypical atrial flutter is rare in patients without prior cardiac surgery. Atypical right atrial flutter occurs in 8% of patients with atrial flutter (Yang et al. 2001). Persistent or recurrent atrial flutter is common in patients post-cardiac surgery

**5.1.6.3** *Mechanism*: The mechanism of atrial flutter is re-entry with an excitable gap, within the atrium, right more than left (Waldo 2004). The flutter circuit requires an initially activated region to repolarize as the action potential travels through the slow conduction tissue and reactivates the initial part, thereby creating a re-entry circuit. The atrial activation along the circuit proceeds from the coronary sinus superiorly to the high right atrium area and craniocaudally along the free wall and medially to the isthmus between the tricuspid valve and the inferior vena cava in a counter-clockwise manner. There is an area of slow

**5.1.5.8** *Work-up*: Meeting ECG criteria is sufficient for diagnosis of MAT (figure 9).

rate may range from 150-500 beats/minute.

implantation may be necessary (Walsh 2001a).

Fig. 9. Multifocal atrial tachycardia

considered to be atypical (Garan 2008).

**5.1.6 Atrial flutter** 

(Waldo 2004).

with pacing maneuvers and external cardioversion are suggestive of EAT (Walsh 2001a). Echocardiography at the time of diagnosis is important to document the ventricular function (Naheed et al. 1995).

**5.1.4.8** *Management and Prognosis*: Paroxysmal and incessant atrial tachycardia are difficult to treat medically (Blomstrom-Lundqvist 2003). Acute therapy includes IV verapamil and IV beta blockers. There is no termination of tachycardia with atrial pacing, except for mild slowing of the heart rate. DC cardioversion is usually not effective but may be effective in those with micro-re-entry mechanism. Class IA (e.g. quinidine) and IC (e.g. flecainide, propafenone) antiarrhythmics are indicated for those without cardiac failure and Class III (amiodarone) is recommended in those with poor ventricular function (Blomstrom-Lundqvist 2003). Chronic therapy includes calcium channel blockers, Classes IA, IC, and III anti-arrhythmics; Class IC is not indicated in those with coronary artery disease. Intravenous amiodarone or oral sotalol can reduce rates and restore sinus rhythm (Skinner and Sharland 2008). Catheter ablation is successful in 86-90% with recurrence rate of 8% (Walsh 2001a; Hsieh and Chen 2002). In children, 75% had restoration of normal sinus rhythm after medical therapy (Naheed et al. 1995). In patients with drug refractory EAT or incessant AT with tachycardia-induced cardiomyopathy, best option is ablation of the focus (Blomstrom-Lundqvist 2003). Because digitalis toxicity can elicit atrial tachycardia, check digitalis levels and avoid hypokalemia.

Fig. 8. Ectopic atrial tachycardia with effect of adenosine

### **5.1.5 Multifocal (chaotic) Atrial Tachycardia**

**5.1.5.1** *Definition*: Tachycardia characterized by electrocardiographic finding of multiple (at least three) distinct P-wave morphologies with irregular P-P intervals, isoelectric baseline between P-waves and ventricular rate >100 beats/min (Blomstrom-Lundqvist 2003).

**5.1.5.2** *Incidence*: MAT is a rare entity. In the pediatric age group, it is reported exclusively in neonates and infants, mostly associated with a normal heart (Kastor 1990). It is also associated with post-operative congenital heart disease, hypertrophic and dilated cardiomyopathies, and unrepaired atrial septal defects (Walsh 2001a). Incidence is 0.2% among infants presenting with new onset arrhythmias (Salim et al. 1995). It is associated with significant respiratory disease in adults. It is also associated with hypoxemia, glucose intolerance, hypokalemia, digitalis, and chronic renal failure (Kones et al. 1974).

**5.1.5.3** *Mechanism*: Exact mechanism of MAT is unclear; however, automaticity versus triggered activity is postulated (Walsh 2001a).

**5.1.5.4** *Natural history*: Spontaneous resolution may occur in 50-80% of patients with MAT by 12-18 months of age (Sokoloski 1999). There is no recurrence of MAT in infants with normal cardiac structure (Walsh 2001a).

**5.1.5.6** *Clinical presentation*: Most patients are asymptomatic at the time of detection. If tachycardia is persistent, cardiomyopathy develops and symptoms consistent with cardiomyopathy arise.

with pacing maneuvers and external cardioversion are suggestive of EAT (Walsh 2001a). Echocardiography at the time of diagnosis is important to document the ventricular function

**5.1.4.8** *Management and Prognosis*: Paroxysmal and incessant atrial tachycardia are difficult to treat medically (Blomstrom-Lundqvist 2003). Acute therapy includes IV verapamil and IV beta blockers. There is no termination of tachycardia with atrial pacing, except for mild slowing of the heart rate. DC cardioversion is usually not effective but may be effective in those with micro-re-entry mechanism. Class IA (e.g. quinidine) and IC (e.g. flecainide, propafenone) antiarrhythmics are indicated for those without cardiac failure and Class III (amiodarone) is recommended in those with poor ventricular function (Blomstrom-Lundqvist 2003). Chronic therapy includes calcium channel blockers, Classes IA, IC, and III anti-arrhythmics; Class IC is not indicated in those with coronary artery disease. Intravenous amiodarone or oral sotalol can reduce rates and restore sinus rhythm (Skinner and Sharland 2008). Catheter ablation is successful in 86-90% with recurrence rate of 8% (Walsh 2001a; Hsieh and Chen 2002). In children, 75% had restoration of normal sinus rhythm after medical therapy (Naheed et al. 1995). In patients with drug refractory EAT or incessant AT with tachycardia-induced cardiomyopathy, best option is ablation of the focus (Blomstrom-Lundqvist 2003). Because digitalis toxicity can elicit atrial tachycardia, check digitalis levels and avoid hypokalemia.

**5.1.5.1** *Definition*: Tachycardia characterized by electrocardiographic finding of multiple (at least three) distinct P-wave morphologies with irregular P-P intervals, isoelectric baseline

**5.1.5.2** *Incidence*: MAT is a rare entity. In the pediatric age group, it is reported exclusively in neonates and infants, mostly associated with a normal heart (Kastor 1990). It is also associated with post-operative congenital heart disease, hypertrophic and dilated cardiomyopathies, and unrepaired atrial septal defects (Walsh 2001a). Incidence is 0.2% among infants presenting with new onset arrhythmias (Salim et al. 1995). It is associated with significant respiratory disease in adults. It is also associated with hypoxemia, glucose

**5.1.5.3** *Mechanism*: Exact mechanism of MAT is unclear; however, automaticity versus

**5.1.5.4** *Natural history*: Spontaneous resolution may occur in 50-80% of patients with MAT by 12-18 months of age (Sokoloski 1999). There is no recurrence of MAT in infants with normal

**5.1.5.6** *Clinical presentation*: Most patients are asymptomatic at the time of detection. If tachycardia is persistent, cardiomyopathy develops and symptoms consistent with

between P-waves and ventricular rate >100 beats/min (Blomstrom-Lundqvist 2003).

intolerance, hypokalemia, digitalis, and chronic renal failure (Kones et al. 1974).

Fig. 8. Ectopic atrial tachycardia with effect of adenosine

**5.1.5 Multifocal (chaotic) Atrial Tachycardia** 

triggered activity is postulated (Walsh 2001a).

cardiac structure (Walsh 2001a).

cardiomyopathy arise.

(Naheed et al. 1995).

**5.1.5.7** *ECG*: Diagnostic criteria include: 1) irregular atrial rates, 2) at least three different Pwave configurations, 3) isoelectric baseline between discrete P waves, 4) irregular P-P, P-R, and R-R intervals, and 5) absence of a dominant atrial pacemaker (Sokoloski 1999). Atrial rate may range from 150-500 beats/minute.

**5.1.5.8** *Work-up*: Meeting ECG criteria is sufficient for diagnosis of MAT (figure 9).

**5.1.5.9** *Management and Prognosis*: It is usually not responsive to DC cardioversion, vagal maneuvers, or IV antiarrhythmics. However, digoxin, beta blockers, amiodarone, and flecainide are options to consider. Calcium channel blockers are not indicated in neonates and infants less than one year of age. When drug therapy is successful, it should be continued for 6-12 months. In rare cases with medication refractory MAT, multiple foci ablation is required. In refractory cases, AV node ablation with ventricular pacemaker implantation may be necessary (Walsh 2001a).

Fig. 9. Multifocal atrial tachycardia

### **5.1.6 Atrial flutter**

**5.1.6.1** *Definition*: Atrial flutter is a regular atrial tachycardia due to a macro-reentrant rhythm confined to the atrium. There are two types of atrial flutter: 1) typical or Type I and 2) atypical or Type II. Typical atrial flutter is the most common, cavo-tricuspid isthmusdependent, terminated by rapid atrial pacing and is further divided into counter-clockwise and clockwise circuits. Atypical atrial flutter has a faster rate (>350 beats/minute), and is not cavo-tricuspid isthmus-dependent (Saoudi et al. 2001; Waldo 2004). Left atrial flutter is also considered to be atypical (Garan 2008).

**5.1.6.2** *Incidence*: In a study of 380 patients with first flutter episode between 1 and 25 years of life, 81% had congenital heart disease, and 8% had normal hearts (Garson Jr. et al. 1985). Among adults, the incidence of atrial flutter overall was 88 per 100,000 person-years with male predominance (4:1) and is noted in patients with heart failure, pulmonary disease, thyrotoxicosis, post repair of congenital heart defects, and mitral valve disease (Granada et al. 2000; Waldo 2004). The incidence of atypical atrial flutter is rare in patients without prior cardiac surgery. Atypical right atrial flutter occurs in 8% of patients with atrial flutter (Yang et al. 2001). Persistent or recurrent atrial flutter is common in patients post-cardiac surgery (Waldo 2004).

**5.1.6.3** *Mechanism*: The mechanism of atrial flutter is re-entry with an excitable gap, within the atrium, right more than left (Waldo 2004). The flutter circuit requires an initially activated region to repolarize as the action potential travels through the slow conduction tissue and reactivates the initial part, thereby creating a re-entry circuit. The atrial activation along the circuit proceeds from the coronary sinus superiorly to the high right atrium area and craniocaudally along the free wall and medially to the isthmus between the tricuspid valve and the inferior vena cava in a counter-clockwise manner. There is an area of slow

Arrhythmias in Children and Young Adults 59

(Blomstrom-Lundqvist 2003). Catheter ablation is used to create a bidirectional conduction block across the cavo-tricuspid isthmus. In addition to palliating with catheter ablation, underlying causes of atrial flutter such as stimulants and sympathomimetic agents should

**5.1.7.1** *Definition*: Intra-atrial reentry tachycardia (IART) is a group of reentry tachycardia associated with repaired or unrepaired congenital heart disease (CHD). It is also known as slow atrial flutter, incisional atrial tachycardia, and macro-reentrant atrial tachycardia. It is very often a long-term complication of cardiac surgery involving the atrium (Triedman 2001). It is frequently associated with Fontan, Mustard, Senning, repaired tetralogy of Fallot, and TAPVR repairs. Risk factors for IART are older age of surgery and long-term follow-up. **5.1.7.2** *Incidence*: Incidence of IART often depends on the congenital heart disease and the surgery preceding the onset. Structural heart disease is evident in about 89% of patients

**5.1.7.3** *Mechanism*: IART has a re-entrant mechanism defined within the atrium and does not necessarily follow the atrial flutter circuit. Majority of the reentrant circuits are mainly

**5.1.7.4** *Natural history*: IART is intimately associated with atrial fibrillation and thromboembolic phenomena. Natural history is associated with increased frequency of recurrences, regardless of treatment with anti-arrhythmic medications or ablation (Triedman 2004). Intermediate follow-up post ablation of IART shows frequent recurrence with new IART configurations

**5.1.7.5** *Clinical presentation*: Symptoms in patients with IART can range from being asymptomatic to congestive heart failure to significant cardiovascular compromise, including sudden cardiac death (Triedman 2004). Sinus node dysfunction with symptomatic

**5.1.7.6** *ECG*: Flutter morphology or uniform P waves are frequently noted with constant cycle length longer than typical atrial flutter (figure 11). Multiple ECG morphologies can be obtained from a single patient due to various activation mechanisms. There is often 1:1 AV conduction based on the cycle length. There is sudden onset and termination with pacing

also be eliminated.

Fig. 10. Atrial flutter

(Triedman et al. 1997).

**5.1.7 Intra-atrial Reentry Tachycardia** 

with IART (Haines and DiMarco 1990).

confined to the right atrium (Triedman 2001).

bradycardia is a common association with IART.

and is entrainable (Triedman 2001; Triedman 2004).

conduction in the posteroinferior aspect of the circuit. The clockwise or reverse typical circuit proceeds in the opposite direction (Sokoloski 1999).

**5.1.6.4** *Natural history*: In patients less than one year of age and with no previous cardiac surgery, atrial flutter spontaneously converts in 26%. Congestive heart failure was more prevalent in those with atrial flutter of long duration. Of the infants with decreased ventricular function, all recovered normal function after conversion to sinus rhythm. If patients had additional arrhythmia, recurrence of atrial flutter was more likely (Texter et al. 2006). Atrial flutter persisting over a long period of time can evolve into atrial fibrillation (Waldo 2004).

**5.1.6.5** *Clinical presentation*: In neonates, 80% are asymptomatic and 20% may present with congestive heart failure (Texter et al. 2006). Older patients can experience palpitations, dizziness, chest tightness, chest pain, shortness of breath, and fatigue. Hypotension, poor exercise tolerance, congestive heart failure and impaired cardiac output can also result from atrial flutter (Blomstrom-Lundqvist 2003; Andrew and Montenero 2007).

**5.1.6.6** *ECG*: Counterclockwise (typical) atrial flutter has negative flutter (F) waves in the inferior leads II, III, and aVF and positive F waves in Lead V1 (figure 10). Clockwise (reverse typical) atrial flutter shows positive F waves in the inferior leads II, III, and aVF and negative F waves in lead V1 (Blomstrom-Lundqvist 2003). In typical atrial flutter, P waves are absent. The flutter rate can range from 240-340 beats/minute with no isoelectric interval between consecutive waves. Flutter rates in infants can be as high as 580 beats/minute with rapid ventricular response rates of 200 beats/minute with 2:1 AV conduction in 75% and variable block in the remainder (Texter et al. 2006). Flutter waves typically have 90-degree axis. The QRS complexes appear normal unless there is rate-dependent aberrancy or block.

**5.1.6.7** *Work-up*: Echocardiogram is indicated in those with congestive heart failure to evaluate ventricular function and structure.

**5.1.6.8** *Management and Prognosis*: Management of atrial flutter is accomplished through electrical cardioversion, rapid atrial pacing, pharmacological therapy, and catheter ablation. The goal of flutter management is to decrease the ventricular rate and to restore normal sinus rhythm. Chronic anti-arrhythmic therapy may not be needed in those with uncomplicated, asymptomatic atrial flutter after conversion to sinus rhythm (Texter et al. 2006; Skinner and Sharland 2008). Drugs are successful in controlling atrial flutter in about 58% of young patients. Amiodarone, digoxin, and propranolol are found to be effective (Garson Jr. et al. 1985). Atrial flutter causing hemodynamic instability should be terminated acutely with electrical cardioversion (2J/Kg) (Class 1 level of evidence) (Blomstrom-Lundqvist 2003; Texter et al. 2006). Although cardioversion is successful acutely, atrial flutter recurs frequently. Recurrences of atrial flutter can be prevented by administering Class IA, IC, and III anti-arrhythmic agents. Ventricular rate can be controlled with AVnodal blockers such as digitalis and class II (beta blockers), III (amiodarone, sotalol), and IV (calcium channel blockers) anti-arrhythmic agents. Flecainide (Class IC anti-arrhythmic) should be administered with an AV-node blocking agent. As flecainide slows the atrial rate, it may facilitate 1:1 AV conduction, leading to clinical compromise (Skinner and Sharland 2008). Calcium channel antagonists are contraindicated in children less than one year of age. When atrial flutter is refractory to medical management, transesophageal atrial overdrive pacing (TEAP) and catheter ablation are excellent options. In a study by Ajisaka (1997), paroxysmal atrial flutter was terminated in greater than 50 percent of the adult subjects with low-output, short-duration TEAP (Ajisaka et al. 1997). In young adults with repaired congenital heart disease, 50-88% had successful ablation of recurrent atrial flutter

conduction in the posteroinferior aspect of the circuit. The clockwise or reverse typical

**5.1.6.4** *Natural history*: In patients less than one year of age and with no previous cardiac surgery, atrial flutter spontaneously converts in 26%. Congestive heart failure was more prevalent in those with atrial flutter of long duration. Of the infants with decreased ventricular function, all recovered normal function after conversion to sinus rhythm. If patients had additional arrhythmia, recurrence of atrial flutter was more likely (Texter et al. 2006). Atrial flutter persisting over a long period of time can evolve into atrial fibrillation

**5.1.6.5** *Clinical presentation*: In neonates, 80% are asymptomatic and 20% may present with congestive heart failure (Texter et al. 2006). Older patients can experience palpitations, dizziness, chest tightness, chest pain, shortness of breath, and fatigue. Hypotension, poor exercise tolerance, congestive heart failure and impaired cardiac output can also result from

**5.1.6.6** *ECG*: Counterclockwise (typical) atrial flutter has negative flutter (F) waves in the inferior leads II, III, and aVF and positive F waves in Lead V1 (figure 10). Clockwise (reverse typical) atrial flutter shows positive F waves in the inferior leads II, III, and aVF and negative F waves in lead V1 (Blomstrom-Lundqvist 2003). In typical atrial flutter, P waves are absent. The flutter rate can range from 240-340 beats/minute with no isoelectric interval between consecutive waves. Flutter rates in infants can be as high as 580 beats/minute with rapid ventricular response rates of 200 beats/minute with 2:1 AV conduction in 75% and variable block in the remainder (Texter et al. 2006). Flutter waves typically have 90-degree axis. The QRS complexes appear normal unless there is rate-dependent aberrancy or block. **5.1.6.7** *Work-up*: Echocardiogram is indicated in those with congestive heart failure to

**5.1.6.8** *Management and Prognosis*: Management of atrial flutter is accomplished through electrical cardioversion, rapid atrial pacing, pharmacological therapy, and catheter ablation. The goal of flutter management is to decrease the ventricular rate and to restore normal sinus rhythm. Chronic anti-arrhythmic therapy may not be needed in those with uncomplicated, asymptomatic atrial flutter after conversion to sinus rhythm (Texter et al. 2006; Skinner and Sharland 2008). Drugs are successful in controlling atrial flutter in about 58% of young patients. Amiodarone, digoxin, and propranolol are found to be effective (Garson Jr. et al. 1985). Atrial flutter causing hemodynamic instability should be terminated acutely with electrical cardioversion (2J/Kg) (Class 1 level of evidence) (Blomstrom-Lundqvist 2003; Texter et al. 2006). Although cardioversion is successful acutely, atrial flutter recurs frequently. Recurrences of atrial flutter can be prevented by administering Class IA, IC, and III anti-arrhythmic agents. Ventricular rate can be controlled with AVnodal blockers such as digitalis and class II (beta blockers), III (amiodarone, sotalol), and IV (calcium channel blockers) anti-arrhythmic agents. Flecainide (Class IC anti-arrhythmic) should be administered with an AV-node blocking agent. As flecainide slows the atrial rate, it may facilitate 1:1 AV conduction, leading to clinical compromise (Skinner and Sharland 2008). Calcium channel antagonists are contraindicated in children less than one year of age. When atrial flutter is refractory to medical management, transesophageal atrial overdrive pacing (TEAP) and catheter ablation are excellent options. In a study by Ajisaka (1997), paroxysmal atrial flutter was terminated in greater than 50 percent of the adult subjects with low-output, short-duration TEAP (Ajisaka et al. 1997). In young adults with repaired congenital heart disease, 50-88% had successful ablation of recurrent atrial flutter

atrial flutter (Blomstrom-Lundqvist 2003; Andrew and Montenero 2007).

circuit proceeds in the opposite direction (Sokoloski 1999).

evaluate ventricular function and structure.

(Waldo 2004).

(Blomstrom-Lundqvist 2003). Catheter ablation is used to create a bidirectional conduction block across the cavo-tricuspid isthmus. In addition to palliating with catheter ablation, underlying causes of atrial flutter such as stimulants and sympathomimetic agents should also be eliminated.

Fig. 10. Atrial flutter

### **5.1.7 Intra-atrial Reentry Tachycardia**

**5.1.7.1** *Definition*: Intra-atrial reentry tachycardia (IART) is a group of reentry tachycardia associated with repaired or unrepaired congenital heart disease (CHD). It is also known as slow atrial flutter, incisional atrial tachycardia, and macro-reentrant atrial tachycardia. It is very often a long-term complication of cardiac surgery involving the atrium (Triedman 2001). It is frequently associated with Fontan, Mustard, Senning, repaired tetralogy of Fallot, and TAPVR repairs. Risk factors for IART are older age of surgery and long-term follow-up.

**5.1.7.2** *Incidence*: Incidence of IART often depends on the congenital heart disease and the surgery preceding the onset. Structural heart disease is evident in about 89% of patients with IART (Haines and DiMarco 1990).

**5.1.7.3** *Mechanism*: IART has a re-entrant mechanism defined within the atrium and does not necessarily follow the atrial flutter circuit. Majority of the reentrant circuits are mainly confined to the right atrium (Triedman 2001).

**5.1.7.4** *Natural history*: IART is intimately associated with atrial fibrillation and thromboembolic phenomena. Natural history is associated with increased frequency of recurrences, regardless of treatment with anti-arrhythmic medications or ablation (Triedman 2004). Intermediate follow-up post ablation of IART shows frequent recurrence with new IART configurations (Triedman et al. 1997).

**5.1.7.5** *Clinical presentation*: Symptoms in patients with IART can range from being asymptomatic to congestive heart failure to significant cardiovascular compromise, including sudden cardiac death (Triedman 2004). Sinus node dysfunction with symptomatic bradycardia is a common association with IART.

**5.1.7.6** *ECG*: Flutter morphology or uniform P waves are frequently noted with constant cycle length longer than typical atrial flutter (figure 11). Multiple ECG morphologies can be obtained from a single patient due to various activation mechanisms. There is often 1:1 AV conduction based on the cycle length. There is sudden onset and termination with pacing and is entrainable (Triedman 2001; Triedman 2004).

Arrhythmias in Children and Young Adults 61

**6.1.3** *Mechanism*: As the name suggests, AVRT has a reentrant mechanism. The reentrant mechanism is characterized by an accessory pathway in the left or right atrio-ventricular grooves, i.e. extranodal pathway. Atriofascicular and nodofascicular (Mahaim), and atrionodal (James) AP are other variants. The left free wall is the most common site of the AP, followed by posteroseptal and right free wall AP (Calkins et al. 1999). Even in patients with manifest AP, orthodromic narrow complex reciprocating tachycardia is still the most

**6.1.4** *Natural history*: In patients with WPW syndrome with onset less than 2 months of age, SVT disappeared in 93% and reappeared in 31% at an average age of 8 years (Perry and Garson Jr. 1990). In patients with onset after 5 years of age, seventy eight percent had persistence at 7 years of follow-up. Multiple and right-sided AP were more frequent in patients with congenital heart disease (Perry and Garson Jr. 1990). Congenital heart defects are present in 20 - 37% of patients with WPW (Deal et al. 1985; Perry and Garson Jr. 1990). Patients with WPW syndrome are also prone to develop atrial fibrillation with increased

**6.1.5** *Clinical presentation*: Symptoms are usually paroxysmal but may be incessant. Symptoms may occur with or without triggers, including activity and exertion. Location, rate, duration of tachycardia, and the type of AP very often determine the nature of symptoms. Infants tolerate higher rates of tachycardia compared to adolescents and adults. Patients perceive sensed tachycardia with or without associated symptoms including dizziness, lightheadedness, and mild chest discomfort. Heart failure symptoms with orthopnea, paroxysmal nocturnal dyspnea, fatigue, tachypnea, diaphoresis are often present in those with persistent tachycardia (Van Hare 1999). Sudden death is attributed to the presence of atrial fibrillation with rapid ventricular response across the accessory pathway (Van Hare 1999). In orthodromic AVRT, shortness of breath, fatigue, and dizziness are common; syncope is less common (Blaufox and Saul 2001). In antidromic AVRT, dizziness, syncope, and tendency towards unstable ventricular rhythm are more common than

**6.1.6** *ECG*: ECG findings are determined by presence of tachycardia, normal sinus rhythm, and type of accessory pathway. In normal sinus rhythm, WPW syndrome is evident by the presence of pre-excitation (delta wave) with short PR interval. The pre-excited complex is a fusion complex resulting from initial pre-excitation of ventricular myocardium adjacent to the AP giving rise to the delta wave, followed by fusion of depolarization of the remainder of the ventricular myocardium by normal conduction. In orthodromic AVRT, the QRS complexes are narrow due to normal prograde conduction through the AV node and bundle of His and retrograde conduction via the AP (figure 12). Orthodromic AVRT have RP interval shorter than the PR interval with a P-wave on the upstroke of the T-wave during tachycardia, which differentiates it from AVNRT (Van Hare 1999). In antidromic AVRT, the QRS complexes are wide due to antegrade conduction down the AP and retrograde conduction across the AV node or another AP. AV block terminates the tachycardia due to the role of AV node in the tachycardia. WPW is characterized by wide QRS complexes with short PR interval. Mahaim AP has pre-excitation with widened QRS complexes but normal PR interval and usually manifest as a wide complex tachycardia with left bundle branch block pattern. Though the terminology is obsolete, Lown-Ganong-Levine (LGL) syndrome

**6.1.7** *Work-up*: Baseline ECG during sinus rhythm may show pre-excitation. Depending on the frequency of sensed tachycardia or other symptoms, a Holter monitor or a loop recorder can be used. Echocardiogram may be obtained to rule out structural heart defects. In

common manifestation.

risk of sudden death (Hare 1999).

orthodromic AVRT (Blaufox and Saul 2001).

has normal QRS complexes with short PR interval.

**5.1.7.7** *Work-up*: In refractory atrial reentry arrhythmias, an electrophysiology study must be conducted to further elucidate the nature of the substrate responsible for IART.

**5.1.7.8** *Management and Prognosis*: Acute management in cardiovascular compromise consists of direct current (DC) cardioversion. Other options in clinically stable patients include antiarrhythmic medications, atrial overdrive pacing, and anti-tachycardia pacing with pacemakers and transesophageal pacing. For chronic therapy, sotalol and amiodarone have been reported to be effective in approximately 60% (Triedman 2001). Implanted anti-tachycardia pacemakers provide relief from symptomatic tachycardia and bradycardia associated with sinus node dysfunction. In cases refractory to medical management, catheter ablation can be attempted. Intra-operative surgical Maze procedure is reserved for patients that have failed catheter ablation or are scheduled to undergo surgery for another indication.

Fig. 11. Intra-atrial re-entrant tachycardia

### **6.1 Atrio-Ventricular Reciprocating Tachycardia**

**6.1.1** *Definition*: Atrio-ventricular reciprocating tachycardia (AVRT) is a re-entrant tachycardia with an accessory electrical connection between the atrial and ventricular myocardium in addition to the AV node (Blaufox and Saul 2001). The accessory pathway (AP) can be "concealed" with only retrograde conduction, "manifest" with antegrade or bidirectional conduction. The manifestation of antegrade conduction is presence of preexcitation with short PR on the electrocardiogram during sinus rhythm suggestive of Wolff-Parkinson-White (WPW) syndrome. Orthodromic AVRT employs prograde conduction through the AV node and bundle of His with retrograde conduction through the AP. Antidromic AVRT employs AP for atrio-ventricular conduction with retrograde conduction through the bundle of His and AV node.

**6.1.2** *Incidence*: AVRT is the most common cause of supraventricular tachycardia in children without prior cardiac surgery or neuromuscular disease, comprising 73 to 85 percent (Ko et al. 1992; Etheridge and Judd 1999). It is more common in infancy compared to AVNRT, the incidence of which increases in older children (Ko et al. 1992). Accessory pathways are associated with congenital heart defects in 6-26% of the children. The common heart defects associated with accessory pathways are Ebstein's anomaly of the tricuspid valve, ventricular inversion (L-TGA), hypertrophic cardiomyopathy, and mitral valve prolapse (Van Hare 1999).

**5.1.7.7** *Work-up*: In refractory atrial reentry arrhythmias, an electrophysiology study must be

**5.1.7.8** *Management and Prognosis*: Acute management in cardiovascular compromise consists of direct current (DC) cardioversion. Other options in clinically stable patients include antiarrhythmic medications, atrial overdrive pacing, and anti-tachycardia pacing with pacemakers and transesophageal pacing. For chronic therapy, sotalol and amiodarone have been reported to be effective in approximately 60% (Triedman 2001). Implanted anti-tachycardia pacemakers provide relief from symptomatic tachycardia and bradycardia associated with sinus node dysfunction. In cases refractory to medical management, catheter ablation can be attempted. Intra-operative surgical Maze procedure is reserved for patients that have failed catheter

**6.1.1** *Definition*: Atrio-ventricular reciprocating tachycardia (AVRT) is a re-entrant tachycardia with an accessory electrical connection between the atrial and ventricular myocardium in addition to the AV node (Blaufox and Saul 2001). The accessory pathway (AP) can be "concealed" with only retrograde conduction, "manifest" with antegrade or bidirectional conduction. The manifestation of antegrade conduction is presence of preexcitation with short PR on the electrocardiogram during sinus rhythm suggestive of Wolff-Parkinson-White (WPW) syndrome. Orthodromic AVRT employs prograde conduction through the AV node and bundle of His with retrograde conduction through the AP. Antidromic AVRT employs AP for atrio-ventricular conduction with retrograde conduction

**6.1.2** *Incidence*: AVRT is the most common cause of supraventricular tachycardia in children without prior cardiac surgery or neuromuscular disease, comprising 73 to 85 percent (Ko et al. 1992; Etheridge and Judd 1999). It is more common in infancy compared to AVNRT, the incidence of which increases in older children (Ko et al. 1992). Accessory pathways are associated with congenital heart defects in 6-26% of the children. The common heart defects associated with accessory pathways are Ebstein's anomaly of the tricuspid valve, ventricular inversion (L-TGA), hypertrophic cardiomyopathy, and mitral valve prolapse (Van Hare

conducted to further elucidate the nature of the substrate responsible for IART.

ablation or are scheduled to undergo surgery for another indication.

Fig. 11. Intra-atrial re-entrant tachycardia

through the bundle of His and AV node.

1999).

**6.1 Atrio-Ventricular Reciprocating Tachycardia** 

**6.1.3** *Mechanism*: As the name suggests, AVRT has a reentrant mechanism. The reentrant mechanism is characterized by an accessory pathway in the left or right atrio-ventricular grooves, i.e. extranodal pathway. Atriofascicular and nodofascicular (Mahaim), and atrionodal (James) AP are other variants. The left free wall is the most common site of the AP, followed by posteroseptal and right free wall AP (Calkins et al. 1999). Even in patients with manifest AP, orthodromic narrow complex reciprocating tachycardia is still the most common manifestation.

**6.1.4** *Natural history*: In patients with WPW syndrome with onset less than 2 months of age, SVT disappeared in 93% and reappeared in 31% at an average age of 8 years (Perry and Garson Jr. 1990). In patients with onset after 5 years of age, seventy eight percent had persistence at 7 years of follow-up. Multiple and right-sided AP were more frequent in patients with congenital heart disease (Perry and Garson Jr. 1990). Congenital heart defects are present in 20 - 37% of patients with WPW (Deal et al. 1985; Perry and Garson Jr. 1990). Patients with WPW syndrome are also prone to develop atrial fibrillation with increased risk of sudden death (Hare 1999).

**6.1.5** *Clinical presentation*: Symptoms are usually paroxysmal but may be incessant. Symptoms may occur with or without triggers, including activity and exertion. Location, rate, duration of tachycardia, and the type of AP very often determine the nature of symptoms. Infants tolerate higher rates of tachycardia compared to adolescents and adults. Patients perceive sensed tachycardia with or without associated symptoms including dizziness, lightheadedness, and mild chest discomfort. Heart failure symptoms with orthopnea, paroxysmal nocturnal dyspnea, fatigue, tachypnea, diaphoresis are often present in those with persistent tachycardia (Van Hare 1999). Sudden death is attributed to the presence of atrial fibrillation with rapid ventricular response across the accessory pathway (Van Hare 1999). In orthodromic AVRT, shortness of breath, fatigue, and dizziness are common; syncope is less common (Blaufox and Saul 2001). In antidromic AVRT, dizziness, syncope, and tendency towards unstable ventricular rhythm are more common than orthodromic AVRT (Blaufox and Saul 2001).

**6.1.6** *ECG*: ECG findings are determined by presence of tachycardia, normal sinus rhythm, and type of accessory pathway. In normal sinus rhythm, WPW syndrome is evident by the presence of pre-excitation (delta wave) with short PR interval. The pre-excited complex is a fusion complex resulting from initial pre-excitation of ventricular myocardium adjacent to the AP giving rise to the delta wave, followed by fusion of depolarization of the remainder of the ventricular myocardium by normal conduction. In orthodromic AVRT, the QRS complexes are narrow due to normal prograde conduction through the AV node and bundle of His and retrograde conduction via the AP (figure 12). Orthodromic AVRT have RP interval shorter than the PR interval with a P-wave on the upstroke of the T-wave during tachycardia, which differentiates it from AVNRT (Van Hare 1999). In antidromic AVRT, the QRS complexes are wide due to antegrade conduction down the AP and retrograde conduction across the AV node or another AP. AV block terminates the tachycardia due to the role of AV node in the tachycardia. WPW is characterized by wide QRS complexes with short PR interval. Mahaim AP has pre-excitation with widened QRS complexes but normal PR interval and usually manifest as a wide complex tachycardia with left bundle branch block pattern. Though the terminology is obsolete, Lown-Ganong-Levine (LGL) syndrome has normal QRS complexes with short PR interval.

**6.1.7** *Work-up*: Baseline ECG during sinus rhythm may show pre-excitation. Depending on the frequency of sensed tachycardia or other symptoms, a Holter monitor or a loop recorder can be used. Echocardiogram may be obtained to rule out structural heart defects. In

Arrhythmias in Children and Young Adults 63

"slow-fast" or typical form of the AVNRT is the most common form. A premature atrial or junctional beat blocks the fast pathway with subsequent antegrade conduction through the slow pathway. If the fast pathway recovers as the impulse conducts through the slow pathway, the substrate for reentry is present. In the less common "fast-slow" or atypical form of AVNRT, the premature atrial impulse is blocked in the slow pathway and is conducted antegrade along the fast pathway. If the slow pathway recovers, a reentry substrate is present; antegrade conduction down the fast pathway and retrograde conduction up the slow pathway is present (Zimmerman 2001). The least common form is the "slow-slow" dual node physiology. There is retrograde atrial activation with early atrial activation in the low right atrium, followed by left and remaining right atrial activation

**6.2.4** *Natural history*: AVNRT is not life-threatening and patients with minimal symptoms do well without therapy. Female patients are more symptomatic and tend to present with

**6.2.5** *Clinical presentation*: Symptoms include palpitations, chest pain, heart failure, and shock, and rarely syncope, dependent on the duration of the AVNRT. Tachycardia is

**6.2.6** *ECG*: AVNRT is a regular narrow QRS complex tachycardia with abrupt onset and termination. The QRS complex may appear wider in case of baseline bundle branch block or rate dependent aberrant conduction. There is no pre-excitation appreciated during normal sinus rhythm in sole AVNRT. In slow-fast AVNRT, retrograde P-waves are not appreciated and are located within the terminal part of the QRS complexes. In fast-slow AVNRT, the P

**6.2.7** *Work-up*: An electrophysiology study is indicated to definitively establish the diagnosis

**6.2.8** *Management and Prognosis*: Management of AVNRT is based on the frequency and the symptoms during the episodes. In those with infrequent, asymptomatic episodes, no treatment is necessary. Paroxysmal episodes may be terminated with Valsalva maneuver or carotid sinus massage. In acute decompensation, DC synchronized cardioversion, adenosine, IV beta blockers or digoxin can be employed (Zimmerman 2001). In patients with infrequent episodes desiring complete control, ablation is recommended. Patients with recurrent AVNRT refractory to beta blockers and calcium channel blockers, flecanide and sotalol are class IIA recommendations. In recurrent, symptomatic patients with significant side effects of medications and those with poorly tolerated AVNRT, catheter ablation of the

**7.1.1** *Definition*: Junctional ectopic tachycardia (JET), also called junctional automatic tachycardia, is an incessant tachycardia characterized by rapid heart rate with the focus of abnormal automaticity in the junction. Ventricular rates in patients with JET ranges from

**7.1.2** *Incidence*: Incidence of JET occurs in two cohorts: neonatal and post-operative patients. Congenital JET occurs in the first six months of life and a family history is usually present (Sarubbi et al. 2002). Overall, JET occurs in 1% of congenital heart repairs (Walsh 2001a). JET occurred in 22% of Tetralogy of Fallot (TOF) repairs, 10% of atrio-ventricular septal defect

waves have a superior axis with RP interval longer than PR interval.

slow AV nodal pathway is suggested (Blomstrom-Lundqvist 2003).

(Olgin and Zipes 2005a).

syncope (Drago et al. 2006).

of AVNRT and dual AV node physiology.

**7. Junctional Tachy-arrhythmias 7.1 Junctional Ectopic Tachycardia** 

140-370 beats/minute (Villain et al. 1990).

paroxysmal.

patients with pre-excitation, exercise stress test to stratify the risk of sudden catastrophic event can be performed. Persistent pre-excitation at peak exercise may suggest a short refractory period of the accessory fiber with a higher risk for sudden catastrophic event (Blaufox and Saul 2001). To differentiate between narrow complex tachycardias, including concealed pathways, AVNRT, and atrial tachycardias, an EP study is required. An EP study will also assist in differentiating antidromic AVRT from other wide-complex tachycardias.

**6.1.8** *Management and Prognosis*: Acute management in patients with significant hemodynamic compromise requires synchronized DC cardioversion. Adenosine administration is effective and esmolol may be used. Flecainide and procainamide are recommended in pre-excited SVT (Blomstrom-Lundqvist 2003). Digoxin and calcium channel blockers are contra-indicated in patients with WPW syndrome. In stable patients, vagal maneuvers may be effective in terminating the arrhythmia. Calcium channel blockers are contraindicated in infants. Catheter ablation is a class I indication for managing AVRT (Blomstrom-Lundqvist 2003). Left free wall AP was predictive of ablation success while right free wall, posteroseptal, septal, and multiple APs were predictive of recurrence (Calkins et al. 1999). Medical therapy includes beta blockers to block AV node conduction and decrease premature ectopic beats, and class IA, IC, and III antiarrhythmics (Triedman 2001).

Fig. 12. Orthodromic AV reciprocating tachycardia

### **6.2 Atrio-Ventricular Node Reentry Tachycardia**

**6.2.1** *Definition*: Atrio-ventricular node reentry tachycardia (AVNRT) is a re-entry tachycardia that is dependent on existence of dual discrete pathways within or in proximity of the AV node, one with slow conduction and short effective refractory period and the other with fast conduction and long refractory period (Zimmerman 2001; Lockwood et al. 2004). The typical ventricular rate in children ranges from 120 to 280 beats/minute (Zimmerman 2001). AVNRT is often associated with an accessory pathway.

**6.2.2** *Incidence*: AVNRT is the most common SVT in adults but consists of 13% of SVT in children without underlying heart disease and rarely in children under two years of age (Ko et al. 1992). In infants, 15% of SVT was due to AVNRT (Etheridge and Judd 1999).

**6.2.3** *Mechanism*: Dual AV node physiology is present in 33-35% of the children without clinical or inducible AVNRT in congenital or acquired heart disease (Casta et al. 1980). The

patients with pre-excitation, exercise stress test to stratify the risk of sudden catastrophic event can be performed. Persistent pre-excitation at peak exercise may suggest a short refractory period of the accessory fiber with a higher risk for sudden catastrophic event (Blaufox and Saul 2001). To differentiate between narrow complex tachycardias, including concealed pathways, AVNRT, and atrial tachycardias, an EP study is required. An EP study will also assist in differentiating antidromic AVRT from other wide-complex tachycardias. **6.1.8** *Management and Prognosis*: Acute management in patients with significant hemodynamic compromise requires synchronized DC cardioversion. Adenosine administration is effective and esmolol may be used. Flecainide and procainamide are recommended in pre-excited SVT (Blomstrom-Lundqvist 2003). Digoxin and calcium channel blockers are contra-indicated in patients with WPW syndrome. In stable patients, vagal maneuvers may be effective in terminating the arrhythmia. Calcium channel blockers are contraindicated in infants. Catheter ablation is a class I indication for managing AVRT (Blomstrom-Lundqvist 2003). Left free wall AP was predictive of ablation success while right free wall, posteroseptal, septal, and multiple APs were predictive of recurrence (Calkins et al. 1999). Medical therapy includes beta blockers to block AV node conduction and decrease premature ectopic beats, and class IA, IC, and III

**6.2.1** *Definition*: Atrio-ventricular node reentry tachycardia (AVNRT) is a re-entry tachycardia that is dependent on existence of dual discrete pathways within or in proximity of the AV node, one with slow conduction and short effective refractory period and the other with fast conduction and long refractory period (Zimmerman 2001; Lockwood et al. 2004). The typical ventricular rate in children ranges from 120 to 280 beats/minute (Zimmerman 2001). AVNRT

**6.2.2** *Incidence*: AVNRT is the most common SVT in adults but consists of 13% of SVT in children without underlying heart disease and rarely in children under two years of age (Ko

**6.2.3** *Mechanism*: Dual AV node physiology is present in 33-35% of the children without clinical or inducible AVNRT in congenital or acquired heart disease (Casta et al. 1980). The

et al. 1992). In infants, 15% of SVT was due to AVNRT (Etheridge and Judd 1999).

antiarrhythmics (Triedman 2001).

Fig. 12. Orthodromic AV reciprocating tachycardia

**6.2 Atrio-Ventricular Node Reentry Tachycardia** 

is often associated with an accessory pathway.

"slow-fast" or typical form of the AVNRT is the most common form. A premature atrial or junctional beat blocks the fast pathway with subsequent antegrade conduction through the slow pathway. If the fast pathway recovers as the impulse conducts through the slow pathway, the substrate for reentry is present. In the less common "fast-slow" or atypical form of AVNRT, the premature atrial impulse is blocked in the slow pathway and is conducted antegrade along the fast pathway. If the slow pathway recovers, a reentry substrate is present; antegrade conduction down the fast pathway and retrograde conduction up the slow pathway is present (Zimmerman 2001). The least common form is the "slow-slow" dual node physiology. There is retrograde atrial activation with early atrial activation in the low right atrium, followed by left and remaining right atrial activation (Olgin and Zipes 2005a).

**6.2.4** *Natural history*: AVNRT is not life-threatening and patients with minimal symptoms do well without therapy. Female patients are more symptomatic and tend to present with syncope (Drago et al. 2006).

**6.2.5** *Clinical presentation*: Symptoms include palpitations, chest pain, heart failure, and shock, and rarely syncope, dependent on the duration of the AVNRT. Tachycardia is paroxysmal.

**6.2.6** *ECG*: AVNRT is a regular narrow QRS complex tachycardia with abrupt onset and termination. The QRS complex may appear wider in case of baseline bundle branch block or rate dependent aberrant conduction. There is no pre-excitation appreciated during normal sinus rhythm in sole AVNRT. In slow-fast AVNRT, retrograde P-waves are not appreciated and are located within the terminal part of the QRS complexes. In fast-slow AVNRT, the P waves have a superior axis with RP interval longer than PR interval.

**6.2.7** *Work-up*: An electrophysiology study is indicated to definitively establish the diagnosis of AVNRT and dual AV node physiology.

**6.2.8** *Management and Prognosis*: Management of AVNRT is based on the frequency and the symptoms during the episodes. In those with infrequent, asymptomatic episodes, no treatment is necessary. Paroxysmal episodes may be terminated with Valsalva maneuver or carotid sinus massage. In acute decompensation, DC synchronized cardioversion, adenosine, IV beta blockers or digoxin can be employed (Zimmerman 2001). In patients with infrequent episodes desiring complete control, ablation is recommended. Patients with recurrent AVNRT refractory to beta blockers and calcium channel blockers, flecanide and sotalol are class IIA recommendations. In recurrent, symptomatic patients with significant side effects of medications and those with poorly tolerated AVNRT, catheter ablation of the slow AV nodal pathway is suggested (Blomstrom-Lundqvist 2003).

### **7. Junctional Tachy-arrhythmias**

### **7.1 Junctional Ectopic Tachycardia**

**7.1.1** *Definition*: Junctional ectopic tachycardia (JET), also called junctional automatic tachycardia, is an incessant tachycardia characterized by rapid heart rate with the focus of abnormal automaticity in the junction. Ventricular rates in patients with JET ranges from 140-370 beats/minute (Villain et al. 1990).

**7.1.2** *Incidence*: Incidence of JET occurs in two cohorts: neonatal and post-operative patients. Congenital JET occurs in the first six months of life and a family history is usually present (Sarubbi et al. 2002). Overall, JET occurs in 1% of congenital heart repairs (Walsh 2001a). JET occurred in 22% of Tetralogy of Fallot (TOF) repairs, 10% of atrio-ventricular septal defect

Arrhythmias in Children and Young Adults 65

prevention of post-operative JET (Dorman et al. 2000). JET is unresponsive to DC cardioversion, overdrive pacing, and programmed atrial or ventricular stimulation (Sarubbi et al. 2003). Pharmacologic treatment of congenital JET with monotherapy is less successful than combined therapy with amiodarone, digoxin or class IA medication (Sarubbi et al. 2002). Patients with drug-refractory congenital JET should undergo catheter ablation with maintenance of the normal atrio-ventricular conduction (Walsh 2001a). A pacemaker is recommended in those children with evidence of impaired conduction with atrial stimulation,

**7.2.1** *Definition*: Persistent or permanent junctional reciprocating tachycardia (PJRT) is an incessant tachycardia characterized by prograde conduction through the AV node and retrograde conduction through a slow accessory pathway located in the posteroseptal (74%) region with decremental conduction properties (Critelli, G. et al. 1984; Lindinger, A. et al. 1998; Vaksmann, G. et al. 2006). PJRT is a narrow complex tachycardia with rates ranging from 120-250 beats/min and infants having higher tachycardia rates than children

**7.2.2** *Incidence*: PJRT consists of 1% to 6% of all supraventricular tachycardia (Dorostkar et al.

**7.2.3** *Mechanism*: PJRT has a reentrant mechanism with accessory pathways which are mostly isolated and in patients without congenital heart disease (Vaksmann, G et al. 2006). **7.2.4** *Natural history*: In a recent study by Vaksmann et al (2006), PJRT resolved spontaneously in 22 percent (Vaksmann, G et al. 2006). Long term persistence of PJRT can lead to tachycardia-mediated cardiomyopathy, which resolves with appropriate rate control

**7.2.5** *Clinical presentation*: Patients often are asymptomatic in childhood. Symptomatic patients present with intermittent palpitations, exercise intolerance, and syncope (Dorostkar

**7.2.6** *ECG*: ECG shows retrograde P-wave in leads II, III, aVF, and left lateral leads, and R-P interval longer than P-R interval (Dorostkar et al. 1999). The long R-P interval is attributed to the slow retrograde conduction. In sinus rhythm, there is no delta wave and P-R interval

**7.2.7** *Work-up*: PJRT is likely under-diagnosed in childhood and patients present with heart failure with associated ventricular dysfunction. An ECG and Holter monitor should be considered. An echocardiogram should be performed to assess the cardiac function and structure and serial echocardiograms are necessary in those with depressed LV function. An electrophysiology study and catheter ablation may be performed in refractory PJRT

**7.2.8** *Management and Prognosis*: Many patients with stable infrequent episodes and slow tachycardia may not require medical therapy (Lindinger, A et al. 1998). In pediatric patients, amiodarone and verapamil alone had success rates of 84-94% (Vaksmann, G et al. 2006). Digoxin alone had a success rate of 50%. Hence, medical therapy with anti-arrhythmic drugs should be advocated prior to consideration of catheter ablation (Drago et al. 2001). Pediatric and adult patients with medication-refractory incessant PJRT should undergo direct current

1999; Blaufox and Saul 2001). It can present in infancy and into early childhood.

(Lindinger, A et al. 1998; Noe et al. 2002). Uncontrolled PJRT may lead to death.

is normal (Critelli, G et al. 1984). QRS complexes are narrow.

associated with decreased ventricular function (Dorostkar et al. 1999).

catheter ablation, with good safety and efficacy (Aguinaga et al. 1998).

sinus dysfunction, or spontaneous AV block on ECG or Holter monitor (Walsh 2001a).

**7.2 Persistent Junctional Reciprocating Tachycardia** 

(Dorostkar et al. 1999).

et al. 1999).

repairs, and 3.7% of VSD repairs (Dodge-Khatami et al. 2002). Predictors of post-operative JET were younger age (Hoffman et al. 2002), lower body weight (Rekawek et al. 2007), resection of muscle bundles, higher bypass temperatures, and relief of right ventricular outflow tract obstruction through the right atrium (Dodge-Khatami et al. 2002).

**7.1.3** *Mechanism*: Although the mechanism of JET is unclear, abnormal (enhanced) automaticity of the junction has been put forth. In post-operative congenital heart disease patients, it is hypothesized that direct trauma or infiltrative hemorrhage of the conduction system leads to enhanced automaticity of the His bundle (Dodge-Khatami et al. 2002).

**7.1.4** *Natural history*: Congenital JET is associated with high mortality, most of which is attributed to sudden cardiac death (Villain et al. 1990). Concurrent arrhythmias may co-exist with JET, such as complete heart block, ventricular tachycardia, and persistent junctional reciprocating tachycardia. Post-operative JET is a transient state lasting on average 36 hours (Walsh 2001a) and is associated with higher mortality and longer intensive care unit (ICU) stay (Andreasen et al. 2008).

**7.1.5** *Clinical presentation*: Congenital JET presents with cardiomegaly with concomitant heart failure in more than 50 percent, death in 35 percent (Villain et al. 1990), hydrops fetalis, and echocardiographic evidence of left ventricular dysfunction. In post-operative JET, the decreased ventricular filling time leads to cardiovascular compromise.

**7.1.6** *ECG*: ECG criteria include 1) QRS morphology similar to that of sinus rhythm, 2) rapid ventricular rate, and 3) dissociated sinus rhythm with atrial rate often less than ventricular rate or retrograde 1:1 conduction (Walsh 2001a). If variability exists in R-R interval, appropriately timed P-waves may conduct to the ventricular tissue (Figure 13).

Fig. 13. Junctional ectopic tachycardia

**7.1.7** *Work-up*: An electrophysiology study is generally not necessary in patients with JET, unless ablation is being considered for medication-refractory symptoms (Walsh 2001a). In cases of 1:1 retrograde conduction across the AV node, adenosine can clarify the underlying rhythm by blocking the AV node.

**7.1.8** *Management and Prognosis*: Management of post-operative JET includes achievement of AV synchrony and rate control. Atrial pacing above the rate of JET may establish rate control (Walsh 2001a). Post-operative JET is generally responsive to intravenous amiodarone, a class III antiarrhythmic (Shah and Rhodes 1998). Mean length of time for termination of postoperative JET after loading and infusion of amiodarone was 4.5 hours with majority achieving control within 12 hours (Plumpton et al. 2005). Decreasing the body core temperature to 32-34 °C, decreasing the sympathomimetic catecholamine levels, optimizing volume, electrolytes and hemoglobin contribute to decreased ventricular rate by decreasing the automaticity (Cabrera et al. 2002). Magnesium supplementation has been shown to be beneficial in

repairs, and 3.7% of VSD repairs (Dodge-Khatami et al. 2002). Predictors of post-operative JET were younger age (Hoffman et al. 2002), lower body weight (Rekawek et al. 2007), resection of muscle bundles, higher bypass temperatures, and relief of right ventricular

**7.1.3** *Mechanism*: Although the mechanism of JET is unclear, abnormal (enhanced) automaticity of the junction has been put forth. In post-operative congenital heart disease patients, it is hypothesized that direct trauma or infiltrative hemorrhage of the conduction system leads to enhanced automaticity of the His bundle (Dodge-Khatami et al. 2002). **7.1.4** *Natural history*: Congenital JET is associated with high mortality, most of which is attributed to sudden cardiac death (Villain et al. 1990). Concurrent arrhythmias may co-exist with JET, such as complete heart block, ventricular tachycardia, and persistent junctional reciprocating tachycardia. Post-operative JET is a transient state lasting on average 36 hours (Walsh 2001a) and is associated with higher mortality and longer intensive care unit (ICU)

**7.1.5** *Clinical presentation*: Congenital JET presents with cardiomegaly with concomitant heart failure in more than 50 percent, death in 35 percent (Villain et al. 1990), hydrops fetalis, and echocardiographic evidence of left ventricular dysfunction. In post-operative JET, the

**7.1.6** *ECG*: ECG criteria include 1) QRS morphology similar to that of sinus rhythm, 2) rapid ventricular rate, and 3) dissociated sinus rhythm with atrial rate often less than ventricular rate or retrograde 1:1 conduction (Walsh 2001a). If variability exists in R-R interval,

**7.1.7** *Work-up*: An electrophysiology study is generally not necessary in patients with JET, unless ablation is being considered for medication-refractory symptoms (Walsh 2001a). In cases of 1:1 retrograde conduction across the AV node, adenosine can clarify the underlying

**7.1.8** *Management and Prognosis*: Management of post-operative JET includes achievement of AV synchrony and rate control. Atrial pacing above the rate of JET may establish rate control (Walsh 2001a). Post-operative JET is generally responsive to intravenous amiodarone, a class III antiarrhythmic (Shah and Rhodes 1998). Mean length of time for termination of postoperative JET after loading and infusion of amiodarone was 4.5 hours with majority achieving control within 12 hours (Plumpton et al. 2005). Decreasing the body core temperature to 32-34 °C, decreasing the sympathomimetic catecholamine levels, optimizing volume, electrolytes and hemoglobin contribute to decreased ventricular rate by decreasing the automaticity (Cabrera et al. 2002). Magnesium supplementation has been shown to be beneficial in

outflow tract obstruction through the right atrium (Dodge-Khatami et al. 2002).

decreased ventricular filling time leads to cardiovascular compromise.

appropriately timed P-waves may conduct to the ventricular tissue (Figure 13).

stay (Andreasen et al. 2008).

Fig. 13. Junctional ectopic tachycardia

rhythm by blocking the AV node.

prevention of post-operative JET (Dorman et al. 2000). JET is unresponsive to DC cardioversion, overdrive pacing, and programmed atrial or ventricular stimulation (Sarubbi et al. 2003). Pharmacologic treatment of congenital JET with monotherapy is less successful than combined therapy with amiodarone, digoxin or class IA medication (Sarubbi et al. 2002). Patients with drug-refractory congenital JET should undergo catheter ablation with maintenance of the normal atrio-ventricular conduction (Walsh 2001a). A pacemaker is recommended in those children with evidence of impaired conduction with atrial stimulation, sinus dysfunction, or spontaneous AV block on ECG or Holter monitor (Walsh 2001a).

### **7.2 Persistent Junctional Reciprocating Tachycardia**

**7.2.1** *Definition*: Persistent or permanent junctional reciprocating tachycardia (PJRT) is an incessant tachycardia characterized by prograde conduction through the AV node and retrograde conduction through a slow accessory pathway located in the posteroseptal (74%) region with decremental conduction properties (Critelli, G. et al. 1984; Lindinger, A. et al. 1998; Vaksmann, G. et al. 2006). PJRT is a narrow complex tachycardia with rates ranging from 120-250 beats/min and infants having higher tachycardia rates than children (Dorostkar et al. 1999).

**7.2.2** *Incidence*: PJRT consists of 1% to 6% of all supraventricular tachycardia (Dorostkar et al. 1999; Blaufox and Saul 2001). It can present in infancy and into early childhood.

**7.2.3** *Mechanism*: PJRT has a reentrant mechanism with accessory pathways which are mostly isolated and in patients without congenital heart disease (Vaksmann, G et al. 2006).

**7.2.4** *Natural history*: In a recent study by Vaksmann et al (2006), PJRT resolved spontaneously in 22 percent (Vaksmann, G et al. 2006). Long term persistence of PJRT can lead to tachycardia-mediated cardiomyopathy, which resolves with appropriate rate control (Lindinger, A et al. 1998; Noe et al. 2002). Uncontrolled PJRT may lead to death.

**7.2.5** *Clinical presentation*: Patients often are asymptomatic in childhood. Symptomatic patients present with intermittent palpitations, exercise intolerance, and syncope (Dorostkar et al. 1999).

**7.2.6** *ECG*: ECG shows retrograde P-wave in leads II, III, aVF, and left lateral leads, and R-P interval longer than P-R interval (Dorostkar et al. 1999). The long R-P interval is attributed to the slow retrograde conduction. In sinus rhythm, there is no delta wave and P-R interval is normal (Critelli, G et al. 1984). QRS complexes are narrow.

**7.2.7** *Work-up*: PJRT is likely under-diagnosed in childhood and patients present with heart failure with associated ventricular dysfunction. An ECG and Holter monitor should be considered. An echocardiogram should be performed to assess the cardiac function and structure and serial echocardiograms are necessary in those with depressed LV function. An electrophysiology study and catheter ablation may be performed in refractory PJRT associated with decreased ventricular function (Dorostkar et al. 1999).

**7.2.8** *Management and Prognosis*: Many patients with stable infrequent episodes and slow tachycardia may not require medical therapy (Lindinger, A et al. 1998). In pediatric patients, amiodarone and verapamil alone had success rates of 84-94% (Vaksmann, G et al. 2006). Digoxin alone had a success rate of 50%. Hence, medical therapy with anti-arrhythmic drugs should be advocated prior to consideration of catheter ablation (Drago et al. 2001). Pediatric and adult patients with medication-refractory incessant PJRT should undergo direct current catheter ablation, with good safety and efficacy (Aguinaga et al. 1998).

Arrhythmias in Children and Young Adults 67

congenital/structural heart disease, those with unknown etiology of VT, and those with

**8.1.8** *Management and Prognosis*: All wide complex tachycardias need to be treated like ventricular tachycardia unless proven otherwise. A-V dissociation, superior QRS axis and positive or negative concordance of QRS complexes in the precordial leads suggest ventricular origin. In patients with normal hearts, episodes of non-sustained VT has good prognosis. Avoid medications that prolong QT interval and correct electrolyte abnormalities. In patients with sustained VT with hemodynamic compromise, direct current (DC) cardioversion is indicated (Zipes and Camm 2006). In stable monomorphic VT, IV procainamide or amiodarone, and/or transvenous catheter pace termination maybe employed. In patients with polymorphic VT, DC cardioversion, IV amiodarone and beta blockers maybe employed. Internal cardiac defibrillator is indicated in patients with congenital heart disease who have survived cardiac arrest, patients with severely impaired ventricular function, and those on chronic optimal medical therapy with a life expectancy of

syncope of unknown etiology with LV dysfunction (Zipes and Camm 2006).

at least one year (Zipes and Camm 2006).

Fig. 14. Ventricular tachycardia

Fig. 15. Torsades de pointe

### **8.1 Ventricular Tachycardia**

**8.1.1** *Definition*: Ventricular tachycardia (VT) is a tachycardia with rates greater than 120 beats per minute and originating within the ventricles or the lower conduction system with ventriculo-atrial dissociation. Non-sustained VT is defined as a three or more consecutive beats of ventricular origin that terminate spontaneously with no hemodynamic compromise and lasting less than 30 seconds. Sustained VT persists longer than 30 seconds or requires medical or electrical intervention to terminate the tachycardia (AHA 2007).

**8.1.2** *Incidence*: In healthy teenage boys, short episodes of ventricular tachycardia were present in 3% (Dickinson and Scott 1984). Incidence of VT is higher in patients with congenital heart disease. Approximately 30% of post-operative tetralogy of Fallot patients had sustained monomorphic VT and 4.4% had polymorphic VT, which contributes to 2% annual risk of sudden cardiac death (Khairy et al. 2004; Walsh, E. and Cecchin, F. 2007). VT originates in the RVOT in 60%-80% of structurally normal hearts (Lerman et al. 2004). Idiopathic VT is also associated with aortic valve disease, corrected transposition of the great arteries, Ebstein's anomaly of the tricuspid valve, Eisenmenger's syndrome, long QT syndrome, unrepaired tetralogy of Fallot, arrhythmogenic right ventricular dysplasia, and myocardial infarction (Callans, D. and Josephson, M. 2004; Fontaine et al. 2004; Walsh, E. P. and Cecchin, F. 2007).

**8.1.3** *Mechanism*: Ventricular tachycardia characterized by a re-entry mechanism can be initiated and terminated with programmed stimuli (Callans, D and Josephson, ME 2004). VT may also be secondary to automaticity or triggered activity.

**8.1.4** *Natural history*: Post-operative congenital heart disease patients are at high risk of VT and sudden cardiac death. In patients with normal hearts, younger children (90%) and older populations (50%-70%) have resolution of VT within 2 to 10 years (Alexander 2001b). However, symptomatic younger patients had worse prognosis (Davis et al. 1996). In patients with normal intracardiac anatomy, only 50% have an actual diagnosis such as hypertrophic cardiomyopathy, dilated cardiomyopathy, myocarditis, myocardial hamartoma, and metabolic disease (Davis et al. 1996). Ventricular tachycardia is present in 50%-60% of patients with dilated cardiomyopathy and responsible for 8%-50% of deaths (Galvin and Ruskin 2004).

**8.1.5** *Clinical presentation*: Clinical presentation is variable (Davis et al. 1996). Symptoms may range from palpitations, light headedness, syncope, shortness of breath, neck fullness, and chest pain to death (Silka and Garson Jr. 1999).

**8.1.6** *ECG*: Monomorphic VT is a wide complex tachycardia with same QRS morphology, which suggests a single re-entrant focus (figure 14). Polymorphic VT is a wide complex tachycardia with variable QRS morphology. Torsades de pointe is a form of polymorphic VT and associated with long QT syndrome and variable electrical activation. (Figure 15)

**8.1.7** *Work-up*: Obtain a thorough personal and family history including history of sudden cardiac death. An ECG of the arrhythmia is useful but very difficult to capture very often; however, a resting ECG is a class 1 recommendation (Zipes and Camm 2006). Check electrolytes, in particular hypokalemia, hyperkalemia, and hypomagnesemia. In patients with recurrent syncope, a holter monitor or event recorder is indicated. An echocardiogram is necessary to identify structural heart disease and evaluate cardiac function in those at risk for sudden cardiac death such as dilated, hypertrophic, and arrhythmogenic RV dysplasia, myocarditis, and inherited disorders (Zipes and Camm 2006). An exercise stress test is indicated in all individuals, regardless of age, known or suspected to have exercise-induced ventricular tachycardia. An electrophysiology study is warranted in patients with

**8.1.1** *Definition*: Ventricular tachycardia (VT) is a tachycardia with rates greater than 120 beats per minute and originating within the ventricles or the lower conduction system with ventriculo-atrial dissociation. Non-sustained VT is defined as a three or more consecutive beats of ventricular origin that terminate spontaneously with no hemodynamic compromise and lasting less than 30 seconds. Sustained VT persists longer than 30 seconds or requires

**8.1.2** *Incidence*: In healthy teenage boys, short episodes of ventricular tachycardia were present in 3% (Dickinson and Scott 1984). Incidence of VT is higher in patients with congenital heart disease. Approximately 30% of post-operative tetralogy of Fallot patients had sustained monomorphic VT and 4.4% had polymorphic VT, which contributes to 2% annual risk of sudden cardiac death (Khairy et al. 2004; Walsh, E. and Cecchin, F. 2007). VT originates in the RVOT in 60%-80% of structurally normal hearts (Lerman et al. 2004). Idiopathic VT is also associated with aortic valve disease, corrected transposition of the great arteries, Ebstein's anomaly of the tricuspid valve, Eisenmenger's syndrome, long QT syndrome, unrepaired tetralogy of Fallot, arrhythmogenic right ventricular dysplasia, and myocardial infarction (Callans, D. and Josephson, M. 2004; Fontaine et al. 2004; Walsh, E. P.

**8.1.3** *Mechanism*: Ventricular tachycardia characterized by a re-entry mechanism can be initiated and terminated with programmed stimuli (Callans, D and Josephson, ME 2004). VT

**8.1.4** *Natural history*: Post-operative congenital heart disease patients are at high risk of VT and sudden cardiac death. In patients with normal hearts, younger children (90%) and older populations (50%-70%) have resolution of VT within 2 to 10 years (Alexander 2001b). However, symptomatic younger patients had worse prognosis (Davis et al. 1996). In patients with normal intracardiac anatomy, only 50% have an actual diagnosis such as hypertrophic cardiomyopathy, dilated cardiomyopathy, myocarditis, myocardial hamartoma, and metabolic disease (Davis et al. 1996). Ventricular tachycardia is present in 50%-60% of patients with dilated cardiomyopathy and responsible for 8%-50% of deaths (Galvin and

**8.1.5** *Clinical presentation*: Clinical presentation is variable (Davis et al. 1996). Symptoms may range from palpitations, light headedness, syncope, shortness of breath, neck fullness, and

**8.1.6** *ECG*: Monomorphic VT is a wide complex tachycardia with same QRS morphology, which suggests a single re-entrant focus (figure 14). Polymorphic VT is a wide complex tachycardia with variable QRS morphology. Torsades de pointe is a form of polymorphic VT and associated with long QT syndrome and variable electrical activation. (Figure 15) **8.1.7** *Work-up*: Obtain a thorough personal and family history including history of sudden cardiac death. An ECG of the arrhythmia is useful but very difficult to capture very often; however, a resting ECG is a class 1 recommendation (Zipes and Camm 2006). Check electrolytes, in particular hypokalemia, hyperkalemia, and hypomagnesemia. In patients with recurrent syncope, a holter monitor or event recorder is indicated. An echocardiogram is necessary to identify structural heart disease and evaluate cardiac function in those at risk for sudden cardiac death such as dilated, hypertrophic, and arrhythmogenic RV dysplasia, myocarditis, and inherited disorders (Zipes and Camm 2006). An exercise stress test is indicated in all individuals, regardless of age, known or suspected to have exercise-induced ventricular tachycardia. An electrophysiology study is warranted in patients with

medical or electrical intervention to terminate the tachycardia (AHA 2007).

may also be secondary to automaticity or triggered activity.

chest pain to death (Silka and Garson Jr. 1999).

**8.1 Ventricular Tachycardia**

and Cecchin, F. 2007).

Ruskin 2004).

congenital/structural heart disease, those with unknown etiology of VT, and those with syncope of unknown etiology with LV dysfunction (Zipes and Camm 2006).

**8.1.8** *Management and Prognosis*: All wide complex tachycardias need to be treated like ventricular tachycardia unless proven otherwise. A-V dissociation, superior QRS axis and positive or negative concordance of QRS complexes in the precordial leads suggest ventricular origin. In patients with normal hearts, episodes of non-sustained VT has good prognosis. Avoid medications that prolong QT interval and correct electrolyte abnormalities. In patients with sustained VT with hemodynamic compromise, direct current (DC) cardioversion is indicated (Zipes and Camm 2006). In stable monomorphic VT, IV procainamide or amiodarone, and/or transvenous catheter pace termination maybe employed. In patients with polymorphic VT, DC cardioversion, IV amiodarone and beta blockers maybe employed. Internal cardiac defibrillator is indicated in patients with congenital heart disease who have survived cardiac arrest, patients with severely impaired ventricular function, and those on chronic optimal medical therapy with a life expectancy of at least one year (Zipes and Camm 2006).

Fig. 14. Ventricular tachycardia

Fig. 15. Torsades de pointe

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**5** 

Ajay Bahl

*Chandigarh,* 

*India* 

**Paced ECG Morphology** 

**– Reveals More than What It Conceals** 

*Department of Cardiology, Postgraduate Institute of Medical Education and Research,* 

Ventricular paced rhythms can mask ECG changes of several conditions. This is because the paced ventricular rhythm does not follow the normal pattern of depolarization through the bundle of His and the bundle branches. Instead, depolarization initially occurs at the tip of the pacemaker lead which is usually at the apex or the septum. The depolarization then proceeds through the myocardium from one cardiomyocyte to another rather than through the conduction system of the heart. This results in abnormal depolarization and repolarization patterns. Thus the QRS complex is usually widened and the T wave is usually of opposite polarity to the QRS complex. Reaching a diagnosis from a single ECG already rendered abnormal by the paced rhythm is not easy. It is thus useful to have a baseline ECG available for comparison. Changes in the axis, QRS width and QRS complex morphology can give important clues to the diagnosis. ECG changes of acute myocardial infarction in patients with a ventricular paced rhythm are well described. There is very limited data on the usefulness of

Like most other conditions, ECG finings of acute myocardial infarction can be masked by paced rhythms. Pacing leads are traditionally placed in the right ventricular apex. Most studies of ECG findings of myocardial infarction are in patients with pacing leads placed at this location. The ECG pattern of right ventricular apical pacing resembles a left bundle branch block (LBBB) and the diagnostic criteria are also similar. The increasing use of other pacing sites like the interventricular septum and outflow tract as well as biventricular pacing will result in different ECG findings but some general rules will still apply. There is lack of data on the ECG diagnosis of myocardial infarction when the pacing lead tip is placed at locations other than the apex. As these alternate pacing sites gain popularity, the

criteria for myocardial infarction recognition that is discussed below may not apply.

Traditionally ECG changes in myocardial infarction in the setting of LBBB include ST segment abnormalities, abnormal Q waves and Cabrera's sign.1 There are however some differences in the setting of LBBB and ventricular pacing. The most important difference is in value of Q waves in the diagnosis. Abnormal Q waves in leads V5 and V6 along with

**1. Introduction** 

paced ECG in the diagnosis of other conditions.

**2. Acute myocardial infarction** 

Zipes, D. P. and A. Garson, Jr. (1994). "26th Bethesda conference: recommendations for determining eligibility for competition in athletes with cardiovascular abnormalities. Task Force 6: arrhythmias." J Am Coll Cardiol 24(4): 892-9.

### **Paced ECG Morphology – Reveals More than What It Conceals**

Ajay Bahl

*Department of Cardiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India* 

### **1. Introduction**

76 Advances in Electrocardiograms – Clinical Applications

Zipes, D. P. and A. Garson, Jr. (1994). "26th Bethesda conference: recommendations for

abnormalities. Task Force 6: arrhythmias." J Am Coll Cardiol 24(4): 892-9.

determining eligibility for competition in athletes with cardiovascular

Ventricular paced rhythms can mask ECG changes of several conditions. This is because the paced ventricular rhythm does not follow the normal pattern of depolarization through the bundle of His and the bundle branches. Instead, depolarization initially occurs at the tip of the pacemaker lead which is usually at the apex or the septum. The depolarization then proceeds through the myocardium from one cardiomyocyte to another rather than through the conduction system of the heart. This results in abnormal depolarization and repolarization patterns. Thus the QRS complex is usually widened and the T wave is usually of opposite polarity to the QRS complex. Reaching a diagnosis from a single ECG already rendered abnormal by the paced rhythm is not easy. It is thus useful to have a baseline ECG available for comparison. Changes in the axis, QRS width and QRS complex morphology can give important clues to the diagnosis. ECG changes of acute myocardial infarction in patients with a ventricular paced rhythm are well described. There is very limited data on the usefulness of paced ECG in the diagnosis of other conditions.

### **2. Acute myocardial infarction**

Like most other conditions, ECG finings of acute myocardial infarction can be masked by paced rhythms. Pacing leads are traditionally placed in the right ventricular apex. Most studies of ECG findings of myocardial infarction are in patients with pacing leads placed at this location. The ECG pattern of right ventricular apical pacing resembles a left bundle branch block (LBBB) and the diagnostic criteria are also similar. The increasing use of other pacing sites like the interventricular septum and outflow tract as well as biventricular pacing will result in different ECG findings but some general rules will still apply. There is lack of data on the ECG diagnosis of myocardial infarction when the pacing lead tip is placed at locations other than the apex. As these alternate pacing sites gain popularity, the criteria for myocardial infarction recognition that is discussed below may not apply.

Traditionally ECG changes in myocardial infarction in the setting of LBBB include ST segment abnormalities, abnormal Q waves and Cabrera's sign.1 There are however some differences in the setting of LBBB and ventricular pacing. The most important difference is in value of Q waves in the diagnosis. Abnormal Q waves in leads V5 and V6 along with

Paced ECG Morphology – Reveals More than What It Conceals 79

Fig. 1. ECG at presentation showing that all ventricular beats are paced. The pacing spike is followed by a wide QRS complex (QRS duration 300 milliseconds). The QRS complex is merging with T waves. No definite P waves are seen. (With permission, Bahl A et al, Indian

Heart J 2009;61:93-4).

increased r in lead V1 is very specific for anterior wall myocardial infarction in the setting of LBBB. In right ventricular pacing, these Q waves however could simply reflect differences in the lead tip position rather than myocardial infarction.1,2 Thus Q in leads V5 and V6 could be normal finding in right ventricular pacing. A well positioned lead at the RV apex rarely generates a qR complex in lead I, and probably never produces a qR complex in V5 and V6 in the absence of an MI. Thus presence of Q waves in these leads, though useful should be used with the caveat that if the lead tip is not at the right ventricular apex, then Q waves may also be normally seen in these leads. Another important point is to differentiate a qR/ QR from a QS complex. This differentiation is important because a QS complex carries no diagnostic value during RV pacing in any of the leads (QS complexes can be normal in leads I, II, III, aVF, V5, and V6) whereas qR/ QR complex can have diagnostic value.2 One cannot determine the age of the MI from the QRS complex changes.

ST segment changes are the most useful findings in diagnosing myocardial infarction in patients with paced rhythms. The GUSTO-1 trial has provided useful information in this regard. In this trial, 32 patients had ventricular paced rhythm. The only ECG criterion with a high specificity and statistical significance for the diagnosis of an acute myocardial infarction was ST segment elevation 5 mm in leads with a negative QRS complex.3 Shape of the ST segment which exhibit upward convexity are useful in this context. Two other criteria with acceptable specificity were ST elevation 1 mm in leads with concordant QRS polarity and ST depression 1 mm in leads V1, V2, or V3.3,4 It is important to remember that though these criteria are fairly specific, their sensitivity is low. The ECG criterion with the highest sensitivity for the diagnosis of an acute myocardial infarction was ST segment elevation 5 mm in leads with a negative QRS complex and even this criterion has a sensitivity of only around 50%.

The GUSTO-1 trial also included 131 patients with LBBB.5 These ST segment diagnostic criteria were the similar for patients with LBBB and ventricular paced rhythms. The difference in the setting of paced rhythm as compared to LBBB was that of the 3 criteria, the one with the greatest value for the diagnosis of an acute MI in paced rhythm was ST segment elevation 5 mm in leads with a negative QRS complex, whereas in the setting of LBBB the criteria with the greatest value was ST elevation 1 mm in leads with concordant QRS polarity.

Another classical sign described is the Cabrera's sign.1,2 Like other signs, this has also been adapted from the criteria diagnosing myocardial infarction in the setting of LBBB. Cabrera's sign is described as notching of the ascending limb of the S wave usually in leads V3 and V4, and sometimes in leads V2 and V5. The notch should be ≥ 0.03 seconds and present in 2 leads.2 It has low sensitivity but is a very specific sign.

The diagnostic criteria described above are for anterior wall myocardial infarctions. Infarctions at other sites are usually masked by the paced rhythm. Cabrera's sign in both leads III and aVF may be of some value in diagnosing inferior wall myocardial infarction. Similarly ST elevation in lead V4R may occur in acute right ventricular infarction. This sign should however be taken with extreme caution unless accompanied by signs of inferior myocardial infarction.

There are a few important factors that could confound the diagnosis. Retrograde P waves in the terminal part of the QRS complex may mimic Cabrera's sign. Because of cardiac memory repolarization abnormalities, mostly T wave inversions may occur if the patient reverts to spontaneous rhythm. These T wave inversions are secondary to pacing per se and not related to ischemia. These can occur even after very short duration of pacing.

increased r in lead V1 is very specific for anterior wall myocardial infarction in the setting of LBBB. In right ventricular pacing, these Q waves however could simply reflect differences in the lead tip position rather than myocardial infarction.1,2 Thus Q in leads V5 and V6 could be normal finding in right ventricular pacing. A well positioned lead at the RV apex rarely generates a qR complex in lead I, and probably never produces a qR complex in V5 and V6 in the absence of an MI. Thus presence of Q waves in these leads, though useful should be used with the caveat that if the lead tip is not at the right ventricular apex, then Q waves may also be normally seen in these leads. Another important point is to differentiate a qR/ QR from a QS complex. This differentiation is important because a QS complex carries no diagnostic value during RV pacing in any of the leads (QS complexes can be normal in leads I, II, III, aVF, V5, and V6) whereas qR/ QR complex can have diagnostic value.2 One cannot

ST segment changes are the most useful findings in diagnosing myocardial infarction in patients with paced rhythms. The GUSTO-1 trial has provided useful information in this regard. In this trial, 32 patients had ventricular paced rhythm. The only ECG criterion with a high specificity and statistical significance for the diagnosis of an acute myocardial infarction was ST segment elevation 5 mm in leads with a negative QRS complex.3 Shape of the ST segment which exhibit upward convexity are useful in this context. Two other criteria with acceptable specificity were ST elevation 1 mm in leads with concordant QRS polarity and ST depression 1 mm in leads V1, V2, or V3.3,4 It is important to remember that though these criteria are fairly specific, their sensitivity is low. The ECG criterion with the highest sensitivity for the diagnosis of an acute myocardial infarction was ST segment elevation 5 mm in leads with a negative QRS complex and even this criterion has a sensitivity of only around 50%. The GUSTO-1 trial also included 131 patients with LBBB.5 These ST segment diagnostic criteria were the similar for patients with LBBB and ventricular paced rhythms. The difference in the setting of paced rhythm as compared to LBBB was that of the 3 criteria, the one with the greatest value for the diagnosis of an acute MI in paced rhythm was ST segment elevation 5 mm in leads with a negative QRS complex, whereas in the setting of LBBB the criteria with the greatest value was ST elevation 1 mm in leads with concordant

Another classical sign described is the Cabrera's sign.1,2 Like other signs, this has also been adapted from the criteria diagnosing myocardial infarction in the setting of LBBB. Cabrera's sign is described as notching of the ascending limb of the S wave usually in leads V3 and V4, and sometimes in leads V2 and V5. The notch should be ≥ 0.03 seconds and present in 2

The diagnostic criteria described above are for anterior wall myocardial infarctions. Infarctions at other sites are usually masked by the paced rhythm. Cabrera's sign in both leads III and aVF may be of some value in diagnosing inferior wall myocardial infarction. Similarly ST elevation in lead V4R may occur in acute right ventricular infarction. This sign should however be taken with extreme caution unless accompanied by signs of inferior

There are a few important factors that could confound the diagnosis. Retrograde P waves in the terminal part of the QRS complex may mimic Cabrera's sign. Because of cardiac memory repolarization abnormalities, mostly T wave inversions may occur if the patient reverts to spontaneous rhythm. These T wave inversions are secondary to pacing per se and not

related to ischemia. These can occur even after very short duration of pacing.

determine the age of the MI from the QRS complex changes.

leads.2 It has low sensitivity but is a very specific sign.

QRS polarity.

myocardial infarction.

Fig. 1. ECG at presentation showing that all ventricular beats are paced. The pacing spike is followed by a wide QRS complex (QRS duration 300 milliseconds). The QRS complex is merging with T waves. No definite P waves are seen. (With permission, Bahl A et al, Indian Heart J 2009;61:93-4).

Paced ECG Morphology – Reveals More than What It Conceals 81

Widening of the QRS complex is an important though non-specific sign in patients with paced rhythm. A baseline paced ECG is ideally required if this sign is to be used in clinical situations. QRS prolongation should trigger an alarm bell. Any observer during failed cardiopulmonary resuscitations in patients on temporary or permanent pacemakers would have noted gradual prolongation of the QRS complex with the passage of time. The QRS complex gradually becomes very wide and resembles a T wave. This is a poor prognostic

Studies using balloon inflation at time of percutaneous coronary intervention have shown that QRS prolongation could also be a marker of myocardial ischemia on the paced electrocardiogram.6 In addition, electrolyte imbalance as in hyperkalemia could also result in QRS prolongation. Thus any change in QRS duration from baseline should be noted as it

ECG is a useful guide in diagnosing hyperkalemia in patients in sinus rhythm. Initial change is usually a peaked T wave. This is followed by widening of QRS complexes, intraventricular conduction defects, prolongation of PR interval, absence of P wave, heart blocks, and the classical sine wave. This is because severe hyperkalemia decreases the phase 0 of the action potential resulting in widening of the QRS complex. The QRS complex continues to widen and ultimately blends with the T wave resulting in a sine wave morphology. Typical ECG changes of hyperkalemia can also be seen even during paced rhythm. These changes include QRS widening and reduction in amplitude of the QRS complex.7,8 The QRS widening can be quite marked in some cases. These changes are especially well appreciated if an old ECG is available for comparison. Typical sine waves may also be seen on a paced ECG rhythm. These changes revert back to the baseline with correction of hyperkalemia. These ECG findings of hyperkalemia that reverted back to

To summarize, a number of medical conditions are best diagnosed during paced rhythms when a baseline ECG is available. All patients with pacemakers should have a recorded baseline 12 lead ECG available. In case the patient with pacemaker has his own rhythm a 12 lead ECG with magnet should be kept as a taken. This would be available as a record of the paced rhythm in case the patient later becomes pacemaker dependant and has a

I thank the Honrary Editor, Indian Heart Journal for permission to use figures 1 and 2.

and ischemia during cardiac pacing. Cardiol Clin 2006;24:387–99.

[1] Barold SS, Falkoff MD, Ong LS, Heinle RA. Electrocardiographic diagnosis of myocardial infarction during ventricular pacing. Cardiol Clin 1987;5:403–17. [2] Barold SS, Herweg B, Curtis AB. Electrocardiographic diagnosis of myocardial infarction

sign and indicates progressive myocardial ischemia and dysfunction.

baseline after correction of hyperkalemia are illustrated in figures 1 and 2.

could be an important indicator of several pathologies.

**3. Widening of the QRS complex** 

**4. Hyperkalemia** 

continuously paced rhythm.

**5. Acknowledgements** 

**6. References** 

Fig. 2. ECG after correction of hyperkalemia. All ventricular beats are still paced but the QRS duration has narrowed to 190 milliseconds. The QRS complexes are greater in amplitude and the peaks are sharper in morphology. Definite P waves are seen in leads V1 and V2. (With permission, Bahl A et al, Indian Heart J 2009;61:93-4).

### **3. Widening of the QRS complex**

Widening of the QRS complex is an important though non-specific sign in patients with paced rhythm. A baseline paced ECG is ideally required if this sign is to be used in clinical situations. QRS prolongation should trigger an alarm bell. Any observer during failed cardiopulmonary resuscitations in patients on temporary or permanent pacemakers would have noted gradual prolongation of the QRS complex with the passage of time. The QRS complex gradually becomes very wide and resembles a T wave. This is a poor prognostic sign and indicates progressive myocardial ischemia and dysfunction.

Studies using balloon inflation at time of percutaneous coronary intervention have shown that QRS prolongation could also be a marker of myocardial ischemia on the paced electrocardiogram.6 In addition, electrolyte imbalance as in hyperkalemia could also result in QRS prolongation. Thus any change in QRS duration from baseline should be noted as it could be an important indicator of several pathologies.

### **4. Hyperkalemia**

80 Advances in Electrocardiograms – Clinical Applications

Fig. 2. ECG after correction of hyperkalemia. All ventricular beats are still paced but the QRS duration has narrowed to 190 milliseconds. The QRS complexes are greater in

and V2. (With permission, Bahl A et al, Indian Heart J 2009;61:93-4).

amplitude and the peaks are sharper in morphology. Definite P waves are seen in leads V1

ECG is a useful guide in diagnosing hyperkalemia in patients in sinus rhythm. Initial change is usually a peaked T wave. This is followed by widening of QRS complexes, intraventricular conduction defects, prolongation of PR interval, absence of P wave, heart blocks, and the classical sine wave. This is because severe hyperkalemia decreases the phase 0 of the action potential resulting in widening of the QRS complex. The QRS complex continues to widen and ultimately blends with the T wave resulting in a sine wave morphology. Typical ECG changes of hyperkalemia can also be seen even during paced rhythm. These changes include QRS widening and reduction in amplitude of the QRS complex.7,8 The QRS widening can be quite marked in some cases. These changes are especially well appreciated if an old ECG is available for comparison. Typical sine waves may also be seen on a paced ECG rhythm. These changes revert back to the baseline with correction of hyperkalemia. These ECG findings of hyperkalemia that reverted back to baseline after correction of hyperkalemia are illustrated in figures 1 and 2.

To summarize, a number of medical conditions are best diagnosed during paced rhythms when a baseline ECG is available. All patients with pacemakers should have a recorded baseline 12 lead ECG available. In case the patient with pacemaker has his own rhythm a 12 lead ECG with magnet should be kept as a taken. This would be available as a record of the paced rhythm in case the patient later becomes pacemaker dependant and has a continuously paced rhythm.

### **5. Acknowledgements**

I thank the Honrary Editor, Indian Heart Journal for permission to use figures 1 and 2.

### **6. References**


**6** 

*USA* 

**Electrocardiograms in Acute Pericarditis** 

The pericardium surrounds the heart and consists of a visceral layer, which is contiguous with the epicardium of the heart, and a parietal layer, which forms a sac around the heart (Wann & Passen, 2008). Located between the parietal and visceral layers is a potential space called the pericardial cavity. The pericardial cavity normally contains as much as 50 mL of an ultrafiltrate of plasma. Anatomically, the pericardium isolates the heart from the rest of the mediastinum and thorax. Physiologically and under normal circumstances, the pericardium may have little if any significant role. The pericardial structure and function may be impacted by numerous pathologic conditions. Many of these conditions are listed in Table 1. A common and nonspecific condition affecting the pericardium is acute pericarditis. Acute pericarditis is a clinical syndrome that may present with chest pain, a pericardial friction rub, and gradual repolarization changes in the electrocardiogram (ECG). The diagnosis of acute pericarditis requires at least 2 of these 3 elements (Imazio et al, 2003)

**Infectious** Viral Cocksacie A & B, Echovirus,

Pyogenic Pneumococcus, Streptococcus,

**Trauma** Iatrogenic Penetrating/Non-penetrating chest wall

Legionella Fungal Histoplasmosis, Coccidiomycosis Other Tuberculous, Syphilitic, Protozoal and Parasitic

**1. Introduction** 

**2. Etiology of acute pericarditis** 

**Metabolic** Uremia/ Dialysis

**Neoplasm** Primary or Metastatic

Tumors

Hypothyroidism

Anita Radhakrishnan and Jerome E. Granato *Department of Medicine and Division of Cardiology West Penn Allegheny Health System, Pittsburgh* 

Adenovirus, Mumps, Hepatitis, HIV

Primary tumors or tumors metastatic to

Post-irradiation, Post thoracic surgery, catheter or pacemaker perforation

Staphylococcus, Neisseria and

the pericardium (lung, breast, lymphoma, and leukemia)


## **Electrocardiograms in Acute Pericarditis**

Anita Radhakrishnan and Jerome E. Granato

*Department of Medicine and Division of Cardiology West Penn Allegheny Health System, Pittsburgh USA* 

### **1. Introduction**

82 Advances in Electrocardiograms – Clinical Applications

[3] Sgarbossa EB, Pinski SL, Gates KB, Wagner GS. Early electrocardiographic diagnosis of

[4] Brandt RR, Hammill SC, Higano ST. Electrocardiographic diagnosis of acute myocardial

[5] Sgarbossa EB, Pinski SL, Barbagelata A, Underwood DA, Gates KB, Topol EJ, Califf RM,

[6] Kilic H, Atalar E, Ozer N, Ovunc K, Aksoyek S, Ozmen F, Akdemir R. Early

[7] Bahl A, Swamy A, Jeevan H, Mahajan R, Talwar KK. ECG changes of hyperkalemia

[8] Howard JA, Kosowsky BD. Electrocardiographic diagnosis of hyperkalemia in the presence of ventricular pacing and atrial fibrillation. Chest 1980;78:491-2.

infarction during ventricular pacing. *Circulation* 1998;97:2274-5.

electrocardiogram. International J Cardiol 2008;130:14-18.

during paced rhythm. Indian Heart J 2009;61:93-4.

Investigators. Am J Cardiol 1996;77:423-4.

Investigators. N Engl J Med. 1996;334:481-7.

acute myocardial infarction in the presence of ventricular paced rhythm. GUSTO-I

Wagner GS. Electrocardiographic diagnosis of evolving acute myocardial infarction in the presence of left bundle-branch block. GUSTO-1 (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries)

electrocardiographic diagnosis of acute coronary ischemia on the paced

The pericardium surrounds the heart and consists of a visceral layer, which is contiguous with the epicardium of the heart, and a parietal layer, which forms a sac around the heart (Wann & Passen, 2008). Located between the parietal and visceral layers is a potential space called the pericardial cavity. The pericardial cavity normally contains as much as 50 mL of an ultrafiltrate of plasma. Anatomically, the pericardium isolates the heart from the rest of the mediastinum and thorax. Physiologically and under normal circumstances, the pericardium may have little if any significant role. The pericardial structure and function may be impacted by numerous pathologic conditions. Many of these conditions are listed in Table 1. A common and nonspecific condition affecting the pericardium is acute pericarditis. Acute pericarditis is a clinical syndrome that may present with chest pain, a pericardial friction rub, and gradual repolarization changes in the electrocardiogram (ECG). The diagnosis of acute pericarditis requires at least 2 of these 3 elements (Imazio et al, 2003)


### **2. Etiology of acute pericarditis**

Electrocardiograms in Acute Pericarditis 85

The ECG is a rapid, inexpensive and noninvasive test that can be very useful in establishing the diagnosis of acute pericarditis. In one study, 90% of patients with the diagnosis of acute pericarditis are found to have ECG changes (Marinella, 1998). The electrocardiogaphic patterns of acute pericarditis were first reported in 1929 by Scott, Feil and Katz. They described transitory elevation of the ST segments in all three limb leads of the electrocardiogram in a case of hemopericardium and in one of purulent pericarditis (Veer and Norris 1937). Since then, the diagnosis of pericarditis is often times made with ECG

In acute pericarditis, the observed electrocardiographic changes are a direct result of the inflammatory process taking place between the pericardial layers. The electrocardiogram is altered because of the extension of the inflammatory process to the sub epicardial myocardium (Bonow et al, 2008). The two classical ECG findings of acute pericarditis are ST elevation and PR depression. Elevation of the ST segment is the most sensitive and most consistent ECG finding. Typically the ST elevation is usually 1.0 - 2.0 mm and may be present in the majority of the standard ECG leads. The exception to this observation may be seen in leads AVR and V1 where the ST segment is always depressed (Koos et al, 2009). The morphology of the ST segment elevation in acute pericarditis is characteristically concave

Fig. 1. An electrocardiogram in acute pericarditis showing diffuse up sloping ST segment elevations seen best here in leads II, AVL, AVF and V2 to V6. There is also subtle PR segment deviation (positive in aVR, negative in most other leads) (Hewitt el al, 2010)

**4.2 Electrocardiography** 

changes.


Table 1. Causes of acute pericarditis (Zayas et al, 1995 )

### **3. Clinical features**

The chest pain associated with acute pericarditis is often described as severe, retrosternal, left sided precordial pain that is referred to the neck, arms, or the left shoulder. The pain is usually pleuritic, consequent to accompanying pleural inflammation and is characteristically, relieved by sitting up, leaning forward and may be intensified by lying supine (Troughten et al, 2004). The most specific sign of acute pericarditis is a pericardial friction rub, although it is intermittently present and often varies in intensity. It is characterized as a high-pitched scratchy sound and is heard best in end expiration and along the left sternal border with the patient leaning forward. A triple cadence is classically described, which coincides with atrial systole, ventricular systole, and rapid ventricular filling during early diastole. However, the triphasic rub occurs in only about half of patients. The origin of the sound has been attributed to the visceral and parietal layers of the pericardial sac rubbing together during different phases of the cardiac cycle (Spodick, 1975).

### **4. Diagnosis**

### **4.1 Serum boimarkers**

Laboratory testing for acute pericarditis is nonspecific and provides limited guidance in determining a cause. White blood cell count, erythrocyte sedimentation rate, and serum Creactive protein level are modestly elevated in acute pericarditis regardless of the etiology. Surprisingly, a significant number of patients with pericarditis, with or without myocarditis or myocardial infarction have elevated creatinine kinase MB fraction and or troponin I values. This observation suggests that there is a significant incidence of silent myocarditis in patients who present with acute pericarditis (Imazio et al, 2003). If a particular etiology for pericarditis is suspected, the clinical presentation and associated co-morbid conditions should direct decisions for additional laboratory studies, such as rheumatoid factor, cardiac enzymes, antinuclear antibodies, or sputum samples to assess for mycobacteria.

### **4.2 Electrocardiography**

84 Advances in Electrocardiograms – Clinical Applications

**Hypersensitivity** Drug Induced Procainamide, Hydralazine, Phenytoin,

The chest pain associated with acute pericarditis is often described as severe, retrosternal, left sided precordial pain that is referred to the neck, arms, or the left shoulder. The pain is usually pleuritic, consequent to accompanying pleural inflammation and is characteristically, relieved by sitting up, leaning forward and may be intensified by lying supine (Troughten et al, 2004). The most specific sign of acute pericarditis is a pericardial friction rub, although it is intermittently present and often varies in intensity. It is characterized as a high-pitched scratchy sound and is heard best in end expiration and along the left sternal border with the patient leaning forward. A triple cadence is classically described, which coincides with atrial systole, ventricular systole, and rapid ventricular filling during early diastole. However, the triphasic rub occurs in only about half of patients. The origin of the sound has been attributed to the visceral and parietal layers of the pericardial sac rubbing together during different phases of the cardiac cycle

Laboratory testing for acute pericarditis is nonspecific and provides limited guidance in determining a cause. White blood cell count, erythrocyte sedimentation rate, and serum Creactive protein level are modestly elevated in acute pericarditis regardless of the etiology. Surprisingly, a significant number of patients with pericarditis, with or without myocarditis or myocardial infarction have elevated creatinine kinase MB fraction and or troponin I values. This observation suggests that there is a significant incidence of silent myocarditis in patients who present with acute pericarditis (Imazio et al, 2003). If a particular etiology for pericarditis is suspected, the clinical presentation and associated co-morbid conditions should direct decisions for additional laboratory studies, such as rheumatoid factor, cardiac

enzymes, antinuclear antibodies, or sputum samples to assess for mycobacteria.

SLE, Rheumatoid Arthritis, Ankylosing Spondylitis, Scleroderma, Wegeners ,

INH, Minoxidil, Methysergide,

Rheumatic Fever

Anticoagulation

Aortic dissection With leakage into the pericardial sac

Syndromes Loefflers Syndrome /Whipples Disease Familial Familial Mediterranean Fever/Familial Pericarditis

Dresslers Pericarditis

**Autoimmune** Sarcoidosis

**Others** Acute Myocardial

IBD

**3. Clinical features** 

(Spodick, 1975).

**4. Diagnosis** 

**4.1 Serum boimarkers** 

Collagen Vascular

Disorders

Infarction

Table 1. Causes of acute pericarditis (Zayas et al, 1995 )

The ECG is a rapid, inexpensive and noninvasive test that can be very useful in establishing the diagnosis of acute pericarditis. In one study, 90% of patients with the diagnosis of acute pericarditis are found to have ECG changes (Marinella, 1998). The electrocardiogaphic patterns of acute pericarditis were first reported in 1929 by Scott, Feil and Katz. They described transitory elevation of the ST segments in all three limb leads of the electrocardiogram in a case of hemopericardium and in one of purulent pericarditis (Veer and Norris 1937). Since then, the diagnosis of pericarditis is often times made with ECG changes.

In acute pericarditis, the observed electrocardiographic changes are a direct result of the inflammatory process taking place between the pericardial layers. The electrocardiogram is altered because of the extension of the inflammatory process to the sub epicardial myocardium (Bonow et al, 2008). The two classical ECG findings of acute pericarditis are ST elevation and PR depression. Elevation of the ST segment is the most sensitive and most consistent ECG finding. Typically the ST elevation is usually 1.0 - 2.0 mm and may be present in the majority of the standard ECG leads. The exception to this observation may be seen in leads AVR and V1 where the ST segment is always depressed (Koos et al, 2009). The morphology of the ST segment elevation in acute pericarditis is characteristically concave

Fig. 1. An electrocardiogram in acute pericarditis showing diffuse up sloping ST segment elevations seen best here in leads II, AVL, AVF and V2 to V6. There is also subtle PR segment deviation (positive in aVR, negative in most other leads) (Hewitt el al, 2010)

Electrocardiograms in Acute Pericarditis 87

**Classic ECG Finding Illustration** 

**Classic ECG Finding Illustration** 

The ECG findings of acute pericarditis can often times be both subtle and confusing. In evaluating patients with chest discomfort and an abnormal ECG, there are other conditions that may mimic acute pericarditis and must be considered as well. These include an acute myocardial infarction and the early pattern of repolarization. Table 6 lists useful clues in

While both acute pericarditis and acute myocardial infarction can present with chest pain and elevations in cardiac biomarkers, the electrocardiographic changes in acute pericarditis

 Morphology — The ST segment elevation in acute pericarditis begins at the J point, which represents the junction between the end of the QRS complex and the beginning of the ST segment. The ST segment elevation rarely exceeds 5 mm, and usually retains its normal concavity. In contrast the typical finding in a STEMI presentation is convex (dome-shaped) ST elevation that may be more than 5 mm in height (Surawicz &

 Distribution — ST segment elevations in infarction are characteristically limited to anatomical groupings of leads that correspond to the localized vascular area of the infarct (anteroseptal and anterior leads V1 to V4; lateral leads I, aVL, V5, V6; inferior leads II, III, aVF). The pericardium envelops the heart therefore the ST changes are more

Reciprocal changes — STEMI is often associated with reciprocal ST segment changes,

differ from those in ST elevation myocardial infarctions ( STEMI) in several ways.

generalized and typically are present in most leads in pericarditis.

which are not seen with pericarditis except in leads aVR and V1.

inversions, generally after the ST segments have become isoelectric

Normalization of the

 Indefinite persistence of T wave inversions ("chronic" pericarditis)

ECG or

differentiating acute pericarditis from these conditions.

**Stage Time of** 

**Onset** 

Table 4. Stage 3 of pericarditis

**Onset** 

months

Table 5. Stage 4 of pericarditis

Knilans, 2008).

**Stage Time of** 

Stage 4 Up to 3

Stage 3 2-3 Weeks Diffuse T wave

and facing upwards. Some causes of pericarditis do not result in significant inflammation of the epicardium and may not be associated with the typical ECG changes. An illustration of this is uremic pericarditis, in which there is prominent fibrin deposition but little or no epicardial inflammation. As a result, the ECG usually does not exhibit the previously described ECG changes (Rutsky & Rostand, 1989). The ST segment elevations observed with acute pericarditis are often transient and are sometimes followed (after a variable time) by diffuses T wave inversions. The T wave inversions are also transient and may resolve completely with time (Maisch et al, 2004). Accordingly, there are some patients with clinical signs and symptoms of pericarditis, yet have a normal or non specific pattern on ECG. In the majority of patients, however, some electrocardiographic abnormality persists for an extended period of time. This is usually in the form of persistent T wave inversion (especially chronic pericarditis syndromes) (Maisch et al, 2004). The PR segment depression is another electrocardiographic sign of acute pericarditis. It is a very specific sign and is attributed to subepicardial atrial injury and is visible in all leads except aVR and V1. Conversely, these leads may exhibit PR-segment elevation as a manifestation of atrial wall inflammation (Hurst 2006). Thus, in acute pericarditis, the PR and ST segments typically change in opposite directions.

In acute pericarditis, the observed ECG changes typically evolve in four stages. Although all cases of pericarditis may not include each of these stages, as many as 50% do ( Spodick, 2003) . The typical evolution of ECG changes in pericarditis is described below in Tables 2-5.


Table 2. Stage 1 of pericarditis


Table 3. Stage 2 of pericarditis

and facing upwards. Some causes of pericarditis do not result in significant inflammation of the epicardium and may not be associated with the typical ECG changes. An illustration of this is uremic pericarditis, in which there is prominent fibrin deposition but little or no epicardial inflammation. As a result, the ECG usually does not exhibit the previously described ECG changes (Rutsky & Rostand, 1989). The ST segment elevations observed with acute pericarditis are often transient and are sometimes followed (after a variable time) by diffuses T wave inversions. The T wave inversions are also transient and may resolve completely with time (Maisch et al, 2004). Accordingly, there are some patients with clinical signs and symptoms of pericarditis, yet have a normal or non specific pattern on ECG. In the majority of patients, however, some electrocardiographic abnormality persists for an extended period of time. This is usually in the form of persistent T wave inversion (especially chronic pericarditis syndromes) (Maisch et al, 2004). The PR segment depression is another electrocardiographic sign of acute pericarditis. It is a very specific sign and is attributed to subepicardial atrial injury and is visible in all leads except aVR and V1. Conversely, these leads may exhibit PR-segment elevation as a manifestation of atrial wall inflammation (Hurst 2006). Thus, in acute pericarditis, the PR and ST segments typically

In acute pericarditis, the observed ECG changes typically evolve in four stages. Although all cases of pericarditis may not include each of these stages, as many as 50% do ( Spodick, 2003) . The typical evolution of ECG changes in pericarditis is described below in Tables 2-5.

**Classical ECG Findings Illustration** 

**Classical ECG findings Illustration** 

 Diffuse concave ST elevation with reciprocal ST depression

PR segment elevation in lead

 Depression of the PR segment in all other limb leads

> Normalization of ST segments, with J point returning to normal T wave amplitude begin to

> > decrease

in AVR and V1

AVR

change in opposite directions.

**Onset** 

Table 2. Stage 1 of pericarditis

**Onset** 

week

Table 3. Stage 2 of pericarditis

**Stage Time of** 

Stage 2 Within 1st

**Stage Time of** 

Stage 1 Hours to days


Table 4. Stage 3 of pericarditis


Table 5. Stage 4 of pericarditis

The ECG findings of acute pericarditis can often times be both subtle and confusing. In evaluating patients with chest discomfort and an abnormal ECG, there are other conditions that may mimic acute pericarditis and must be considered as well. These include an acute myocardial infarction and the early pattern of repolarization. Table 6 lists useful clues in differentiating acute pericarditis from these conditions.

While both acute pericarditis and acute myocardial infarction can present with chest pain and elevations in cardiac biomarkers, the electrocardiographic changes in acute pericarditis differ from those in ST elevation myocardial infarctions ( STEMI) in several ways.


Electrocardiograms in Acute Pericarditis 89

The early repolarization variant seen on an ECG may be present in as many as 30% of young adults and is often confused with acute pericarditis (Klatskey et al, 2003). The following electrocardiographic features can be helpful in distinguishing acute pericarditis from early

 ST elevations occur in both the limb and precordial leads in most cases of acute pericarditis (47 of 48 in one study), whereas about one-half of subjects with early repolarization have no ST deviations in the limb leads . In early repolarization, ST elevation is most often present in the anterior and lateral chest leads (V3-V6), although

PR deviation and evolution of the ST and T changes strongly favor pericarditis, as

While uncommon, one of the most feared seqealae of acute pericarditis is the progression to cardiac tamponade. Cardiac tamponade is the result of the accumulation of fluid in the pericardial space to the point that it causes obstruction to the inflow of blood to the heart. This condition, if not recognized and treated promptly, is often fatal. The most common ECG sign of a large pericardial effusion is low voltage of the QRS complexes. This finding is most likely due to the attenuation of cardiac potentials caused by the fluid surrounding the heart as well as inflammatory mechanisms affecting the pericardium and myocardium (Brusch et al, 2001). Low voltage on the ECG (Figure 2) is said to be present when the cumulative amplitude of the QRS complexes in each of the six limb leads is 5 mm (0.5 mV) or less (Luenn et al, 2006). Another ECG pattern that may be observed in patients with a large pericardial effusion is total electrical alternans (Figure 3). The pattern of electrical alternans is characterized by a cyclic beat-to-beat variation in the QRS axis in the limb and precordial leads. This is a direct result of the beat to beat movement of the heart, both to and fro, that can occur in the presence of a large pericardial effusion (Billakanty and Bashir , 2006). The observations of electrical alternans with low QRS voltage and sinus tachycardia is a highly specific sign of pericardial effusion. Unfortunately, this triad of observations is only modestly sensitive in that there may be situation where larger pericardial effusion is present

Fig. 2. An ECG in a patient with a large pericardial effusion. Note the presence of low

other leads can be involved ( Spodick, 1976).

and some or all of these findings are absent.

voltage QRS in all leads.

neither is seen in early repolarization( Ginzton & Laks, 1972)

repolarization:


Table 6. A comparison of ECG's in acute pericarditis, acute myocardial infarction and early repolarization.


**ECG Findings Acute Pericarditis Myocardial Infarction Early Repolarization** 

Absent Present Absent

>0.25 N/A <0.25

Absent Present Absent

Present Absent Absent

Table 6. A comparison of ECG's in acute pericarditis, acute myocardial infarction and early

 Concurrent ST and T wave changes — ST segment elevation and T wave inversions do not generally occur simultaneously in pericarditis, while they commonly coexist in a STEMI. Peaked T waves (>10mm high in precordial leads, >5 mm high in limb leads), can be seen in STEMI but are not typical of pericarditis (Surawicz & Knilans, 2008). Q waves — Pathologic Q waves, which may occur with extensive injury in STEMI, are generally not seen in pericarditis. The abnormal Q waves in MI reflect the loss of positive depolarization voltages because of transmural myocardial necrosis. Pericarditis, on the other hand, generally causes only superficial inflammation. Abnormal Q waves are not seen unless there is concomitant myocarditis or preexisting

 PR segment — PR elevation in aVR with PR depression in other leads due to a concomitant atrial current of injury is frequently seen in acute pericarditis but rarely

 QT prolongation — Prolongation of the QT interval with regional T wave inversion (in the absence of drug effects or relevant metabolic disorders) favors the diagnosis of myocardial ischemia (or myopericarditis) over pericarditis alone (Marinella, 2008).

cardiomyopathy or myocardial infarction (Imazio, 2011).

**Q waves** Absent Present Absent

Limb and precordial

leads

Concave upward Convex upward Concave upward

Area of involved artery Precordial Leads

**ST Segment Change** 

**Reciprocal ST changes** 

**Location of ST elevation** 

**ST/T ratio in lead V6** 

**Loss of R wave** 

**PR segment depression** 

**Illustrative Example** 

repolarization.

seen in acute STEMI.

**voltage** 

The early repolarization variant seen on an ECG may be present in as many as 30% of young adults and is often confused with acute pericarditis (Klatskey et al, 2003). The following electrocardiographic features can be helpful in distinguishing acute pericarditis from early repolarization:


While uncommon, one of the most feared seqealae of acute pericarditis is the progression to cardiac tamponade. Cardiac tamponade is the result of the accumulation of fluid in the pericardial space to the point that it causes obstruction to the inflow of blood to the heart. This condition, if not recognized and treated promptly, is often fatal. The most common ECG sign of a large pericardial effusion is low voltage of the QRS complexes. This finding is most likely due to the attenuation of cardiac potentials caused by the fluid surrounding the heart as well as inflammatory mechanisms affecting the pericardium and myocardium (Brusch et al, 2001). Low voltage on the ECG (Figure 2) is said to be present when the cumulative amplitude of the QRS complexes in each of the six limb leads is 5 mm (0.5 mV) or less (Luenn et al, 2006). Another ECG pattern that may be observed in patients with a large pericardial effusion is total electrical alternans (Figure 3). The pattern of electrical alternans is characterized by a cyclic beat-to-beat variation in the QRS axis in the limb and precordial leads. This is a direct result of the beat to beat movement of the heart, both to and fro, that can occur in the presence of a large pericardial effusion (Billakanty and Bashir , 2006). The observations of electrical alternans with low QRS voltage and sinus tachycardia is a highly specific sign of pericardial effusion. Unfortunately, this triad of observations is only modestly sensitive in that there may be situation where larger pericardial effusion is present and some or all of these findings are absent.

Fig. 2. An ECG in a patient with a large pericardial effusion. Note the presence of low voltage QRS in all leads.

Electrocardiograms in Acute Pericarditis 91

atrium or right ventricle during diastole or marked variation in the transmitral and transpulmonary valve velocity profiled with respiration (Fowler 1993). In one series of 300 consecutive patients with acute pericarditis, pericardial effusion was present in 180 patients (60%). In most cases the effusion was small or moderate in size without hemodynamic consequences. Cardiac tamponade was present in only 5% of patients (Imazio et al, 2004). TTE is not needed in every patient with pericarditis, it is recommended in patients with clinical features that would suggest the presence of a systemic disorder. These might include prolonged fever, an immunocompromised state, recent trauma, elevation of cardiac enzymes greater than 2 weeks, and abnormal chest x-ray or clinical signs of cardiac

The presence of pericardial fluid or thickening may be confirmed by a CT or MRI scan. These techniques may be superior to echocardiography in detecting loculated pericardial effusions, pericardial thickening presence of pericardial masses or any associated intrathoracic pathology (Verhaert et al, 2010). Neither CT nor MRI scanning however is needed to establish the diagnosis of pericarditis. Rather, these studies are generally reserved

The foundation of treatment for pericarditis is to reduce and ultimately eliminate the inflammatory process that exists between the pericardial layers. For patients with idiopathic pericarditis, nonsteroidal anti-inflammatory drugs (NSAIDs) should be used with the goal of relieving chest pain, inflammation, and fever. Aspirin, ibuprofen, and indomethacin are the most commonly prescribed NSAIDs. Ibuprofen may be preferred given its reportedly lower incidence of side effects compared to the other medications. (Zayas et al, 1995) Indomethacin is an acceptable alternative, but it should be avoided in patients with coronary artery disease because of its adverse effects on coronary blood flow and blood pressure (Maisch et al, 2004). Aspirin is favored in patients with a recent history of myocardial infarction since other NSAIDs tend to impede scar formation (Hammerman et al, 1984). The use of NSAIDs in the setting of acute myocardial infarction has been associated with an increased incidence of ventricular aneurysm formation and cardiac rupture (Imazio et al, 2004). Patients who respond slowly or inadequately to NSAIDS may require supplementary narcotic analgesics and or a brief course of colchicine or steroids. In cases where the etiology of pericarditis has been identified, treatment should be focused on the underlying cause. For patients who have chronic kidney failure, increasing the frequency of dialysis usually results in improvement in the signs and symptoms of uremic pericarditis. Patients who have cancer may show some response to chemotherapy or radiation therapy. For purulent pericarditis related to a bacterial or fungal process, treatment consists of antimicrobials and surgical drainage of purulent material from the pericardium space. For patients with pericardial effusion causing a tamponade, drainage of the effusion is indicated. Needle pericardiocentesis, via a sub xiphoid approach, is effective in most medical patients with cardiac tamponade when the effusion is circumferential and

the evaluation of other pathologic conditions which may be the cause of pericarditis.

tamponade. (Imazio et al, 2004, 2007)

moderately large (Imazio et al, 2007).

**4.5 CT/MRI** 

**5. Treatment** 

Fig. 3. An ECG in a patient with a large pericardial effusion. Note the alternating QRS axis in all precordial leads.

### **4.3 Chest radiograph**

The chest radiograph is usually normal in uncomplicated acute idiopathic pericarditis. It is frequently useful to exclude pathology in the mediastinum or lung fields that may be the cause of pericarditis, such as thoracic malignancy or infection. A pericardial effusion should be suspected when cardiomegaly is observed and the cardiac silhouette takes on a symmetric "flask like" appearance, shown in Figure 4. (Spodick, 2003).

Fig. 4. Chest X ray suggestive of a large pericardial effusion*.*

### **4.4 Echocardiography**

The transthoracic echocardiography (TTE) is frequently normal in patients with acute idiopathic pericarditis. The main reason for its performance is for assessing the size and nature of any associated pericardial effusion. The observation of fibrin strand within the pericardial effusion is indicative of a pericardial inflammatory response (Verhaert et al, 2010). Transthoracic echocardiography is also essential in evaluating for presence or absence cardiac tamponade. This physiologic condition may be recognized by collapse of the right

atrium or right ventricle during diastole or marked variation in the transmitral and transpulmonary valve velocity profiled with respiration (Fowler 1993). In one series of 300 consecutive patients with acute pericarditis, pericardial effusion was present in 180 patients (60%). In most cases the effusion was small or moderate in size without hemodynamic consequences. Cardiac tamponade was present in only 5% of patients (Imazio et al, 2004). TTE is not needed in every patient with pericarditis, it is recommended in patients with clinical features that would suggest the presence of a systemic disorder. These might include prolonged fever, an immunocompromised state, recent trauma, elevation of cardiac enzymes greater than 2 weeks, and abnormal chest x-ray or clinical signs of cardiac tamponade. (Imazio et al, 2004, 2007)

### **4.5 CT/MRI**

90 Advances in Electrocardiograms – Clinical Applications

Fig. 3. An ECG in a patient with a large pericardial effusion. Note the alternating QRS axis in

The chest radiograph is usually normal in uncomplicated acute idiopathic pericarditis. It is frequently useful to exclude pathology in the mediastinum or lung fields that may be the cause of pericarditis, such as thoracic malignancy or infection. A pericardial effusion should be suspected when cardiomegaly is observed and the cardiac silhouette takes on a

The transthoracic echocardiography (TTE) is frequently normal in patients with acute idiopathic pericarditis. The main reason for its performance is for assessing the size and nature of any associated pericardial effusion. The observation of fibrin strand within the pericardial effusion is indicative of a pericardial inflammatory response (Verhaert et al, 2010). Transthoracic echocardiography is also essential in evaluating for presence or absence cardiac tamponade. This physiologic condition may be recognized by collapse of the right

symmetric "flask like" appearance, shown in Figure 4. (Spodick, 2003).

Fig. 4. Chest X ray suggestive of a large pericardial effusion*.*

all precordial leads.

**4.3 Chest radiograph** 

**4.4 Echocardiography** 

The presence of pericardial fluid or thickening may be confirmed by a CT or MRI scan. These techniques may be superior to echocardiography in detecting loculated pericardial effusions, pericardial thickening presence of pericardial masses or any associated intrathoracic pathology (Verhaert et al, 2010). Neither CT nor MRI scanning however is needed to establish the diagnosis of pericarditis. Rather, these studies are generally reserved the evaluation of other pathologic conditions which may be the cause of pericarditis.

### **5. Treatment**

The foundation of treatment for pericarditis is to reduce and ultimately eliminate the inflammatory process that exists between the pericardial layers. For patients with idiopathic pericarditis, nonsteroidal anti-inflammatory drugs (NSAIDs) should be used with the goal of relieving chest pain, inflammation, and fever. Aspirin, ibuprofen, and indomethacin are the most commonly prescribed NSAIDs. Ibuprofen may be preferred given its reportedly lower incidence of side effects compared to the other medications. (Zayas et al, 1995) Indomethacin is an acceptable alternative, but it should be avoided in patients with coronary artery disease because of its adverse effects on coronary blood flow and blood pressure (Maisch et al, 2004). Aspirin is favored in patients with a recent history of myocardial infarction since other NSAIDs tend to impede scar formation (Hammerman et al, 1984). The use of NSAIDs in the setting of acute myocardial infarction has been associated with an increased incidence of ventricular aneurysm formation and cardiac rupture (Imazio et al, 2004). Patients who respond slowly or inadequately to NSAIDS may require supplementary narcotic analgesics and or a brief course of colchicine or steroids. In cases where the etiology of pericarditis has been identified, treatment should be focused on the underlying cause. For patients who have chronic kidney failure, increasing the frequency of dialysis usually results in improvement in the signs and symptoms of uremic pericarditis. Patients who have cancer may show some response to chemotherapy or radiation therapy. For purulent pericarditis related to a bacterial or fungal process, treatment consists of antimicrobials and surgical drainage of purulent material from the pericardium space. For patients with pericardial effusion causing a tamponade, drainage of the effusion is indicated. Needle pericardiocentesis, via a sub xiphoid approach, is effective in most medical patients with cardiac tamponade when the effusion is circumferential and moderately large (Imazio et al, 2007).

Electrocardiograms in Acute Pericarditis 93

Ginzton LE, Laks MM. The differential diagnosis of acute pericarditis from the normal variant:

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### **6. Follow-up**

Most cases of acute pericarditis subside within 2 weeks. In approximately 15%of cases, symptoms may recur (Marinella, 1998). This is particularly true if the pericarditis is related to an ongoing and underlying illness such as an autoimmune disease or uremia. Typically, physicians should schedule a follow-up visit with these patients two weeks after the onset of their illness unless additional symptoms or medication related problems intervene. An ECG should also be considered at four weeks, bearing in mind that residual T-wave inversion may be present for several weeks during stage III of acute pericarditis.

### **7. Conclusion**

In conclusion, acute pericarditis can be caused by many underlying conditions. Acute pericarditis can be diagnosed clinically with when associated with chest pain, pericardial friction rub and typical ECG changes. The ECG changes associated with acute pericarditis have been described as evolving through four stages including PR segment depression, ST segment elevation, T wave inversion and eventual normalization. Certain features of the ECG can help in differentiate the diagnosis of pericarditis from acute myocardial infarction or early repolarization, though this differentiation may be difficult. Treatment should be focused on the relief of symptoms and specific to any underlying cause. For patients with idiopathic pericarditis, NSAIDs are typically most effective. The prognosis associated with acute pericarditis is very good. Prompt recognition and treatment of this condition may prevent its progression to more serious complications.

### **8. Acknowledgments**

Words alone cannot express the thanks I owe to Chocku Radhakrishnan, my husband and Mrs. Valli Radhakrishnan, my mother-in-law for their encouragement, patience and support while I wrote this paper. I would like to express gratitude to my father Mr. Ramanathan Vairavan who has encouraged me to work hard and efficiently and has always had a special interest in my personal growth. And last but not least I would like to thank my mother, Mrs. Alagu Vairavan for reminding me everyday that her love is absolutely unconditional.

### **9. References**


Most cases of acute pericarditis subside within 2 weeks. In approximately 15%of cases, symptoms may recur (Marinella, 1998). This is particularly true if the pericarditis is related to an ongoing and underlying illness such as an autoimmune disease or uremia. Typically, physicians should schedule a follow-up visit with these patients two weeks after the onset of their illness unless additional symptoms or medication related problems intervene. An ECG should also be considered at four weeks, bearing in mind that residual T-wave inversion

In conclusion, acute pericarditis can be caused by many underlying conditions. Acute pericarditis can be diagnosed clinically with when associated with chest pain, pericardial friction rub and typical ECG changes. The ECG changes associated with acute pericarditis have been described as evolving through four stages including PR segment depression, ST segment elevation, T wave inversion and eventual normalization. Certain features of the ECG can help in differentiate the diagnosis of pericarditis from acute myocardial infarction or early repolarization, though this differentiation may be difficult. Treatment should be focused on the relief of symptoms and specific to any underlying cause. For patients with idiopathic pericarditis, NSAIDs are typically most effective. The prognosis associated with acute pericarditis is very good. Prompt recognition and treatment of this condition may

Words alone cannot express the thanks I owe to Chocku Radhakrishnan, my husband and Mrs. Valli Radhakrishnan, my mother-in-law for their encouragement, patience and support while I wrote this paper. I would like to express gratitude to my father Mr. Ramanathan Vairavan who has encouraged me to work hard and efficiently and has always had a special interest in my personal growth. And last but not least I would like to thank my mother, Mrs. Alagu Vairavan for reminding me everyday that her love is absolutely unconditional.

Billakanty Sreedhar, MD; Riyaz Bashir, MD Echocardiographic Demonstration of Electrical

Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. Sunders 8th ed. 2008.

Borys Surawicz, MD, MACC and Timothy Knilans, MD, (2008) Chou's Electrocardiography

Bruch C, Schmermund A, Dagres N, et al. Changes in QRS voltage in cardiac tamponade and

Fowler No. Cardiac tamponade. (1993)A clinical or an echocardiographic diagnosis?

pericardial effusion: reversibility after pericardiocentesis and after anti-inflammatory

may be present for several weeks during stage III of acute pericarditis.

prevent its progression to more serious complications.

Alternans *JAMA. 1976;235(1):39-41.*

Circulation, Vol 87, 1738-1741

Pages 1076-1078

Bonow Robert, Mann Douglas, Libby Peter, and Zipes Douglas.(2008)

in Clinical Practice, 6th Edition, 2008 pages 235-236

drug treatment. J Am Coll Cardiol 2001; 38:219.

**6. Follow-up** 

**7. Conclusion** 

**8. Acknowledgments** 

**9. References** 


**7** 

*China* 

**The Remodeling of Connexins Localized at** 

**Maintenance of Atrial Fibrillation** 

Guo-qiang Zhong1, Ri-xin Xiong, Hong-xing Song,

*The Department of Cardiology, The First Affiliated Hospital* 

Yun Ling, Jing-chang Zhang and Zhe Wei

*1The Department of Cardiology, The People's Hospital* 

*of Guangxi Medical University,* 

*of Guangxi Zhuang Autonomous Region,* 

**Pulmonary Vein – Left Atria in Triggering and** 

Atrial fibrillation is the most common sustained arrhythmia and the major cardiac cause of stroke (Sellers & Newby, 2011). Recent studies in patients and animals with paroxysmal atrial fibrillation had shown that the arrhythmia was triggered by focal sources from muscular sleeves originated in the left atria extending into pulmonary veins (Date et al.,2007; Chen et al.,2001; Patterson et al., 2007; Honjo et al., 2003). What is more, the autonomic nervous system has a crucial role in the genesis, maintenance and abruption of atrial fibrillation (Duffy& Wit, 2008; Sandres et al.,2004), and there is a fat pad localized in superior vena cava and the root of aorta as the origin of cardiac nerve, being called SVC-Ao fat pad (Kapa et al.,2010; Volders ,2010; Ji et al.,2010). The mechanism of atrial fibrillation involves multiple effects (Chiou et al.,1997; Tsuboi et al.,2000; Hoffmann et al., 2006; Haissaguerre et al.1998; Wit & Boyden,2007), the expression of connexins is changed and is associated with increased propensity for arrhythmias (Kanagaratnam et al., 2002, Herve et al., 2007, Stergiopoulos et al., 1999, Verheule S et al., 2002, Kanagaratnam et al., 2007; Valiunas et al.,2001; Valiunas et al.,2000; Cottrell et al.,2002; Elenes et al.,1999). Pulmonary veins and left atria are the primary structure of genesis, persistence of atrial fibrillation. Vagus nerve plays a key role in the initiation and maintenance of atrial fibrillation, it can mediate the electrical remodeling of atria and pulmonary vein, enhance the maintenance and stability of atrial fibrillation,. However, these effects can be

The name "gap junction" was cioned from their appearance in electron micrographs in the 60s (Revel & Karnovsky, 1967). They are specialized at cell-cell contact regions that contain tens to thousands of intercellular channels that link two apposed cells. These channels facilitate a form of intercellular communication by permitting the regulated passage of ions and small molecules from one cell to another (Bennett & Goodenough, 1978). The gap junction

**1. Introduction** 

inhibited by avianizing vagus nerve.

**2. Overview of gap junction structure** 

Zayas R, Anguita M, Torres F, et al. ( 1993) Incidence of specific etiology and role of methods for specific etiologic diagnosis of primary acute pericarditis. Am J Cardiol 1995; 75:378.

## **The Remodeling of Connexins Localized at Pulmonary Vein – Left Atria in Triggering and Maintenance of Atrial Fibrillation**

Guo-qiang Zhong1, Ri-xin Xiong, Hong-xing Song, Yun Ling, Jing-chang Zhang and Zhe Wei *The Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, 1The Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region, China* 

### **1. Introduction**

94 Advances in Electrocardiograms – Clinical Applications

Zayas R, Anguita M, Torres F, et al. ( 1993) Incidence of specific etiology and role of methods

75:378.

for specific etiologic diagnosis of primary acute pericarditis. Am J Cardiol 1995;

Atrial fibrillation is the most common sustained arrhythmia and the major cardiac cause of stroke (Sellers & Newby, 2011). Recent studies in patients and animals with paroxysmal atrial fibrillation had shown that the arrhythmia was triggered by focal sources from muscular sleeves originated in the left atria extending into pulmonary veins (Date et al.,2007; Chen et al.,2001; Patterson et al., 2007; Honjo et al., 2003). What is more, the autonomic nervous system has a crucial role in the genesis, maintenance and abruption of atrial fibrillation (Duffy& Wit, 2008; Sandres et al.,2004), and there is a fat pad localized in superior vena cava and the root of aorta as the origin of cardiac nerve, being called SVC-Ao fat pad (Kapa et al.,2010; Volders ,2010; Ji et al.,2010). The mechanism of atrial fibrillation involves multiple effects (Chiou et al.,1997; Tsuboi et al.,2000; Hoffmann et al., 2006; Haissaguerre et al.1998; Wit & Boyden,2007), the expression of connexins is changed and is associated with increased propensity for arrhythmias (Kanagaratnam et al., 2002, Herve et al., 2007, Stergiopoulos et al., 1999, Verheule S et al., 2002, Kanagaratnam et al., 2007; Valiunas et al.,2001; Valiunas et al.,2000; Cottrell et al.,2002; Elenes et al.,1999). Pulmonary veins and left atria are the primary structure of genesis, persistence of atrial fibrillation. Vagus nerve plays a key role in the initiation and maintenance of atrial fibrillation, it can mediate the electrical remodeling of atria and pulmonary vein, enhance the maintenance and stability of atrial fibrillation,. However, these effects can be inhibited by avianizing vagus nerve.

### **2. Overview of gap junction structure**

The name "gap junction" was cioned from their appearance in electron micrographs in the 60s (Revel & Karnovsky, 1967). They are specialized at cell-cell contact regions that contain tens to thousands of intercellular channels that link two apposed cells. These channels facilitate a form of intercellular communication by permitting the regulated passage of ions and small molecules from one cell to another (Bennett & Goodenough, 1978). The gap junction

The Remodeling of Connexins Localized at

**3. Connexon and the heart development** 

Pulmonary Vein – Left Atria in Triggering and Maintenance of Atrial Fibrillation 97

cell expression systems as well as in other settings. Connexin43 and connexin40 are coexpressed in several tissues, including cardiac atrial and ventricular myocytes and vascular smooth muscle. It has been shown that these connexins form functional

In the certebrate embryo, a single outflow vessel initially develops from the common ventricules undergo septation to form the four-chamber heart (Kirby & Waldo, 1995). The four-chambered heart develops from a single straight tube composed of three layers: an inner endocardium and outer myocardium separated by a thick extracellular matrix called cardiac jelly. The growing tube loops, with the convexity of the loop demarcating a functional inflow from an outflow portion of the looped tube. This original convexity forms the two ventricles by expansion and septation, and as the ventricular septum forms, the inflow and outflow must be redefined. Initially, all of the inflow is through the atrioventricular canal connecting a common atrium to the presumptive left ventricle; the entire outflow is from the presumptive right ventricle into the aortic sac via the conotruncus. Several septa are formed simultaneously, making a rearrangement of inflow and outflow critical. The atrioventricular canal is divided into left and right channels, the nascent right and left ventricles are separated by the ventricular septum, the conotruncus is converted into aortic vestibule and semilunar valve continuous with the left ventricle, and the pulmonary infundibulum and semilunar valve originating from the right ventricle (see Fig1.). Concomitantly, the outflow tract septates and rotates to generate the pulmonary and

Fig. 1. Major events in development of the heart from a single straight tube. Early looping is probably a function of the myocardium. Convergence of the outflow and inflow tracts occurs during late looping and is critical for normal wedging. Wedging produces alignment

of the three components that complete outflow septation. A, aorta; V, ventricle; P, pulmonary trunk; RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle.

homomeric/homotypic channels with distinct permeability and gating properties.

membrane channel is composed of macular aggregations of intercellular channels permitting the direct intercellular transfer of ions and small molecules. Each intercellular channel is formed by the apposition of two hexameric transmembrane channels (connexons), one from each cell (Yeager & Gilula, 1992). Each intercellular channel is composed of two oligomers with each of two adjacent tissue cells contributing one oligomer. Each connexon is built from six copies of one or more members of a protein family called the connexins (Unger et al., 1999; Perkins et al., 1998). The functional cell-cell channel is formed by the end-to-end docking of the extracellular domains of the two connexons. Therefore, the gap junction membrane channel can be thought of as a dimmer of two hexamers joined together in the gap region. In this manner, the membrane channel extends across both cell membranes.

Vertebrate gap junction channels are assembled to form multimers of one or more different proteins from a multigene family of homologous protein, which are composed of an entirely different gene family but the sequences predict a similar folding pattern. Up to now, more than 20 different connexin genes have been identified in the mouse genome and at least 6 others have been identified in other vertebrates. Connexins are highly homologous proteins with 50%-80% identity between amino acid sequences and display considerable amino acid sequences conservation between species. The distribution and developmental regulation of connexins are tissue specific. The predicted molecular mass of the connexin protein family ranges from ~26 to ~60KDa, and the proteins are named "connexin" followed by their predicted molecular mass. The connexin family can be subdivided into two classifications called α and β based on similarities in certain regions of the primary sequence. The x-ray diffraction analysis by Tibbitts etal. (1990) indicated that there was more α-helical content that could be accounted for by four transmembrane helices. The El and E2 loops are thought to be as rigid as the transmembrane domain (Hoh et al., 1993; Sosinsky, 1992). Hence, the extracellular region is visible with the crystallographic averaging used. Each extracellular protrusion may therefore include an extension of the intramembrane α-helical structure (Tibbitts et al., 1990). Mutagenesis studies have suggested that the extracellular loops contain disulfide-bonded β-sheet conformation (Foote & Nicholson, 1997), which would be expected to act as a rigid domain, for instance, connexin43 (isolated from heart tissue, Yeager & Gilula, 1992), connexin32 and connexin 26 (isolated from liver tissue, Fallon & Goodenough, 1981; Hertzberg, 1984) would be seen for the same structure . In the human heart, 4 main isoforms are expressed. Connexin43 is expressed in all chambers of the heart, but predominantly in the ventricles. Connexin45 is found in the conduction system of the heart and at low levels in the atrial and ventricular working myocardium and connexin37 is located in the endothelial gap junctions in many vessels. Finally, connexin40 is expressed mainly in the atrial working myocardium, the conduction system, and the vasculature. Connexin40 was first described in a range of animal species and subsequently mapped to human chromosome. It became apparent that connexin40 was expressed in the atrioventricular conduction system and abundantly expressed in the atrial but not in the ventricular gap junctions. Recently, a new connexin was described in the mouse heart, i.e. connexin30.2 (the human equivalent is connexin31.9), which in mice seems responsible for slowing of impulse conduction in the atrioventricular node. However, the role of connexin31.9 in the human heart is unclear, for it is not detectable in the human cardiac conduction system. Connexons formed the functional intercellular channel, which is defined as homotypic when the connexin composition of the contributing connexons is identical or heterotypic when different. The ability of connexins to form homomeric/ heterotypic channels has been examined in the Xenopus oocyte and HeLa cell expression systems as well as in other settings. Connexin43 and connexin40 are coexpressed in several tissues, including cardiac atrial and ventricular myocytes and vascular smooth muscle. It has been shown that these connexins form functional homomeric/homotypic channels with distinct permeability and gating properties.

### **3. Connexon and the heart development**

96 Advances in Electrocardiograms – Clinical Applications

membrane channel is composed of macular aggregations of intercellular channels permitting the direct intercellular transfer of ions and small molecules. Each intercellular channel is formed by the apposition of two hexameric transmembrane channels (connexons), one from each cell (Yeager & Gilula, 1992). Each intercellular channel is composed of two oligomers with each of two adjacent tissue cells contributing one oligomer. Each connexon is built from six copies of one or more members of a protein family called the connexins (Unger et al., 1999; Perkins et al., 1998). The functional cell-cell channel is formed by the end-to-end docking of the extracellular domains of the two connexons. Therefore, the gap junction membrane channel can be thought of as a dimmer of two hexamers joined together in the gap region. In this

Vertebrate gap junction channels are assembled to form multimers of one or more different proteins from a multigene family of homologous protein, which are composed of an entirely different gene family but the sequences predict a similar folding pattern. Up to now, more than 20 different connexin genes have been identified in the mouse genome and at least 6 others have been identified in other vertebrates. Connexins are highly homologous proteins with 50%-80% identity between amino acid sequences and display considerable amino acid sequences conservation between species. The distribution and developmental regulation of connexins are tissue specific. The predicted molecular mass of the connexin protein family ranges from ~26 to ~60KDa, and the proteins are named "connexin" followed by their predicted molecular mass. The connexin family can be subdivided into two classifications called α and β based on similarities in certain regions of the primary sequence. The x-ray diffraction analysis by Tibbitts etal. (1990) indicated that there was more α-helical content that could be accounted for by four transmembrane helices. The El and E2 loops are thought to be as rigid as the transmembrane domain (Hoh et al., 1993; Sosinsky, 1992). Hence, the extracellular region is visible with the crystallographic averaging used. Each extracellular protrusion may therefore include an extension of the intramembrane α-helical structure (Tibbitts et al., 1990). Mutagenesis studies have suggested that the extracellular loops contain disulfide-bonded β-sheet conformation (Foote & Nicholson, 1997), which would be expected to act as a rigid domain, for instance, connexin43 (isolated from heart tissue, Yeager & Gilula, 1992), connexin32 and connexin 26 (isolated from liver tissue, Fallon & Goodenough, 1981; Hertzberg, 1984) would be seen for the same structure . In the human heart, 4 main isoforms are expressed. Connexin43 is expressed in all chambers of the heart, but predominantly in the ventricles. Connexin45 is found in the conduction system of the heart and at low levels in the atrial and ventricular working myocardium and connexin37 is located in the endothelial gap junctions in many vessels. Finally, connexin40 is expressed mainly in the atrial working myocardium, the conduction system, and the vasculature. Connexin40 was first described in a range of animal species and subsequently mapped to human chromosome. It became apparent that connexin40 was expressed in the atrioventricular conduction system and abundantly expressed in the atrial but not in the ventricular gap junctions. Recently, a new connexin was described in the mouse heart, i.e. connexin30.2 (the human equivalent is connexin31.9), which in mice seems responsible for slowing of impulse conduction in the atrioventricular node. However, the role of connexin31.9 in the human heart is unclear, for it is not detectable in the human cardiac conduction system. Connexons formed the functional intercellular channel, which is defined as homotypic when the connexin composition of the contributing connexons is identical or heterotypic when different. The ability of connexins to form homomeric/ heterotypic channels has been examined in the Xenopus oocyte and HeLa

manner, the membrane channel extends across both cell membranes.

In the certebrate embryo, a single outflow vessel initially develops from the common ventricules undergo septation to form the four-chamber heart (Kirby & Waldo, 1995). The four-chambered heart develops from a single straight tube composed of three layers: an inner endocardium and outer myocardium separated by a thick extracellular matrix called cardiac jelly. The growing tube loops, with the convexity of the loop demarcating a functional inflow from an outflow portion of the looped tube. This original convexity forms the two ventricles by expansion and septation, and as the ventricular septum forms, the inflow and outflow must be redefined. Initially, all of the inflow is through the atrioventricular canal connecting a common atrium to the presumptive left ventricle; the entire outflow is from the presumptive right ventricle into the aortic sac via the conotruncus. Several septa are formed simultaneously, making a rearrangement of inflow and outflow critical. The atrioventricular canal is divided into left and right channels, the nascent right and left ventricles are separated by the ventricular septum, the conotruncus is converted into aortic vestibule and semilunar valve continuous with the left ventricle, and the pulmonary infundibulum and semilunar valve originating from the right ventricle (see Fig1.). Concomitantly, the outflow tract septates and rotates to generate the pulmonary and

Fig. 1. Major events in development of the heart from a single straight tube. Early looping is probably a function of the myocardium. Convergence of the outflow and inflow tracts occurs during late looping and is critical for normal wedging. Wedging produces alignment of the three components that complete outflow septation. A, aorta; V, ventricle; P, pulmonary trunk; RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle.

The Remodeling of Connexins Localized at

atrial fibrillation.

Pulmonary Vein – Left Atria in Triggering and Maintenance of Atrial Fibrillation 99

From the gene level to protein expression, noval methods of detection of gap junctions can lead us to realize the therapeutic potential, including morphological diversities, ultrastructure and spatial heterogeneity. The authors induced rapid persistent atrial pacing dogs and did a comparison between removal and retention of cardiac vagus nerve in dogs (superior vena cava and aorta root fat pad, SVC-Ao fat pad ), then recorded the effective refractory period and the dispersion of effective refractory period, analyzed the expression of atrial and pulmonary vein connexin40, connexin43 and the heterogeneity of its spatial distribution and the changs of atrial collagen volume fraction, tried to illuminate the correlation of atrial fibrillation with connexin40, connexin43 remodeling and the function of vagus nerve. There was obvious shortness of effective refractory period in atrial fibrillation animal models, while the removal of vagus nerve could attenuate this effect, meanwhile, the quantity and distribution of connexin40 and connexin43 changed at different locations and the deposit of collagen fibers, which might explain the mechanism of electrical heterogeneity and the structural remodeling originated from the pulmanory vein and left atria for the

**5. The distribution of connexins in heart and the relationship with arrhythmia**  Gap junction remodeling is a common response to many forms of heart disease (Strom et al.,2010; Burstein et al.,2009; Kieken et al.,2009; Qu et al., 2009; Yamada et al.,2008). Previous studies have demonstrated that loss of cell-cell coupling is highly arrhythmic (Chaldoupi et al., 2009), however, a detailed understanding of arrhythmia dynamics has been lacking. With respect to mechanistically link a primary perturbation of gap junction function with arrhythmia, conduction properties, arrhythmia dynamics, and cellular electrophysiological characteristics have been detected (Zhou et al., 2008; Severs et al., 2008; Gutstein et al., 2001). Accumulative evidences showed that ventricular gap junctions contain at least 20 times more connexin43 than connexin40, while atrial gap junctions contain much more connexin40 than connexin43 (Kontogeorgis et al., 2008; Lin et al., 2010). In the ventricle, the heterogeneous loss of connexin43 gap junctions in a murine conditional cardiac connexin43 knockout model best exemplified how the focal loss of cardiac gap junctions lead to significant dispersion of conduction, increased incidence of spontaneous arrhythmias, and loss of ventricular systolic function with only minor reductions in overall connexin43 expression. The gating of connexin43-containing ventricular gap junctions during the action potential is also proposed to promote cardiac arrhythmias via inactivation and recovery that depends on transjunctional voltage (Vj) and contributes to conduction slowing or block and the formation of reentrant arrhythmias. In the atria, targeted gene deletion of connexin40 in mice produced multiple aberrations: P wave and PQ interval prolongation, prolonged sinusnode-recovery time, prolonged Wenckebach period, burst-pacing induced atrial tachyarrhythmias, reduced atrial, A-V node, and left bundle branch conduction velocity, right bundle branch block, and reduced interatrial conduction heterogeneity(Leaf et al., 2008; Gutstein et al., 2005). There are close correlation between electrical properties and the anatomy of pulmonary veins and left atria. In animal studies, data showed that segmental muscle disconnection and differential muscle narrowing at pulmonary vein and left atria junctions and complex fiber orientations within the pulmonary vein provide robust anatomical bases for conduction disturbance at the pulmonary vein and left atria junction

and complex intra pulmonary vein conduction patterns (Date et al., 2007).

aortic outflow tracts, becoming connected to the right and left ventricular chambers, respectively. This morphogenetic sequence is significantly affected by the activity of neural crest cells. With the development of heart, the co-expression of multiple connexins in diverse tissues support the idea that communication between cells does not depend on just one type of connexin, which results in forming heterotypic channels with properties different from those homotypic parental connexons.

Pluripotent mammalian embryonic stem cells, which are derived from the inner cell mass of preimplantation blastocysts, have the capacity to differentiate into cells of all three germ layers. Under suitable conditions, embryonic stem cells remain pluripotent through repeated rounds of cell division in culture. The recent isolation of human embryonic stem cells has spurred great interest in their potential use for therapeutic tissue repair because appropriate manipulation of the culture environment can induce both mouse and human embryonic stem cells to differentiate in vitro into specific somatic cell types, and the result shows human embryonic stem cells express RNA encoding most of the known human connexin genes. The mRNA of Cx25, Cx26, Cx30.3, Cx31, Cx31.1, Cx31.9, Cx37, Cx40, Cx43, Cx45, and Cx46 for all of the undifferentiated human embryonic stem cultures that were detected. The remaining connexins (Cx30, Cx30.2, Cx32, Cx36, Cx47, Cx59, and Cx62) were also reliably detected (Rackauskas et al., 2010).

### **4. Cardiac electrical properties of connexins and the methods for detection**

For effective cardiac output, it is essential that electrical excitation spread rapidly throughout the atria and ventricles. This is effected by electrical coupling through gap junction channels at contact sites between myocytes (Danik te al., 2008; Harris, 2001; Söhl & Willecke, 2004; Moreno, 2004). These channels form a low-resistance pathway between adjacent myocytes and consist of connexin proteins. The connexin family is a large multigene family, and the channels formed by different members of this family have distinct electrical and regulatory properties (Reisner et al., 2009; Gros & Jongsma, 1996; Verheijck et al., 2001; Valiunas et al., 2002). Voltage sensitivity is particularly important in regulating the intercellular coupling between excitable cells. Cx43 channels are relatively insensitive to changes in transjunctional voltage compared with channels composed of Cx45 (Rackauskas et al., 2007; Bruzzone et al., 1993; Haubrich et al., 1996). Each gap junction composing hemichannel contains two Vj sensitive gates. The fast gate is located at the cytoplasmic entrance of hemichannels and operates from open to residual state. The slow, or "loop" gate is located toward extracellular ends of hemichannels and exhibits slow gating transition to the fully closed state. Cx26, Cx30, Cx50 close at positive voltages, and Cx31, Cx32, Cx37, Cx40, Cx43, Cx45, Cx57 at negative. Interestingly, Cx46 hemichannels close at both, positive and negative voltages. Besides, each type of connexon has a certain sensitivity to H+, it is showed the order of decreasing sensitivity to PH: Cx50>Cx46>Cx45>Cx26>Cx37>Cx43>Cx40>Cx32, anyway, it is not completely clear whether H+ acts directly on GJ channels. Cytoplasmic C-tail of connexins contains multiple serine, threonine, and tyrosine residues that may be phosphorylated by various protein kinases (Valiunas et al., 2000; Haubrich et al., 1996). Phosphorylation modifies electrical and metabolic communication between contiguous cells by changing channel molecular structure that affects channel unitary conductance, mean open time, or open probability. Moreover, phosphorylation alters the net charge of C-terminus that in turn may modulate voltage or pH sensitivity of the connexins(Kirchhoff et al.,2000,1998; Bukauskas et al., 2004).

aortic outflow tracts, becoming connected to the right and left ventricular chambers, respectively. This morphogenetic sequence is significantly affected by the activity of neural crest cells. With the development of heart, the co-expression of multiple connexins in diverse tissues support the idea that communication between cells does not depend on just one type of connexin, which results in forming heterotypic channels with properties

Pluripotent mammalian embryonic stem cells, which are derived from the inner cell mass of preimplantation blastocysts, have the capacity to differentiate into cells of all three germ layers. Under suitable conditions, embryonic stem cells remain pluripotent through repeated rounds of cell division in culture. The recent isolation of human embryonic stem cells has spurred great interest in their potential use for therapeutic tissue repair because appropriate manipulation of the culture environment can induce both mouse and human embryonic stem cells to differentiate in vitro into specific somatic cell types, and the result shows human embryonic stem cells express RNA encoding most of the known human connexin genes. The mRNA of Cx25, Cx26, Cx30.3, Cx31, Cx31.1, Cx31.9, Cx37, Cx40, Cx43, Cx45, and Cx46 for all of the undifferentiated human embryonic stem cultures that were detected. The remaining connexins (Cx30, Cx30.2, Cx32, Cx36, Cx47, Cx59, and Cx62) were

**4. Cardiac electrical properties of connexins and the methods for detection**  For effective cardiac output, it is essential that electrical excitation spread rapidly throughout the atria and ventricles. This is effected by electrical coupling through gap junction channels at contact sites between myocytes (Danik te al., 2008; Harris, 2001; Söhl & Willecke, 2004; Moreno, 2004). These channels form a low-resistance pathway between adjacent myocytes and consist of connexin proteins. The connexin family is a large multigene family, and the channels formed by different members of this family have distinct electrical and regulatory properties (Reisner et al., 2009; Gros & Jongsma, 1996; Verheijck et al., 2001; Valiunas et al., 2002). Voltage sensitivity is particularly important in regulating the intercellular coupling between excitable cells. Cx43 channels are relatively insensitive to changes in transjunctional voltage compared with channels composed of Cx45 (Rackauskas et al., 2007; Bruzzone et al., 1993; Haubrich et al., 1996). Each gap junction composing hemichannel contains two Vj sensitive gates. The fast gate is located at the cytoplasmic entrance of hemichannels and operates from open to residual state. The slow, or "loop" gate is located toward extracellular ends of hemichannels and exhibits slow gating transition to the fully closed state. Cx26, Cx30, Cx50 close at positive voltages, and Cx31, Cx32, Cx37, Cx40, Cx43, Cx45, Cx57 at negative. Interestingly, Cx46 hemichannels close at both, positive and negative voltages. Besides, each type of connexon has a certain sensitivity to H+, it is showed the order of decreasing sensitivity to PH: Cx50>Cx46>Cx45>Cx26>Cx37>Cx43>Cx40>Cx32, anyway, it is not completely clear whether H+ acts directly on GJ channels. Cytoplasmic C-tail of connexins contains multiple serine, threonine, and tyrosine residues that may be phosphorylated by various protein kinases (Valiunas et al., 2000; Haubrich et al., 1996). Phosphorylation modifies electrical and metabolic communication between contiguous cells by changing channel molecular structure that affects channel unitary conductance, mean open time, or open probability. Moreover, phosphorylation alters the net charge of C-terminus that in turn may modulate voltage or pH

sensitivity of the connexins(Kirchhoff et al.,2000,1998; Bukauskas et al., 2004).

different from those homotypic parental connexons.

also reliably detected (Rackauskas et al., 2010).

From the gene level to protein expression, noval methods of detection of gap junctions can lead us to realize the therapeutic potential, including morphological diversities, ultrastructure and spatial heterogeneity. The authors induced rapid persistent atrial pacing dogs and did a comparison between removal and retention of cardiac vagus nerve in dogs (superior vena cava and aorta root fat pad, SVC-Ao fat pad ), then recorded the effective refractory period and the dispersion of effective refractory period, analyzed the expression of atrial and pulmonary vein connexin40, connexin43 and the heterogeneity of its spatial distribution and the changs of atrial collagen volume fraction, tried to illuminate the correlation of atrial fibrillation with connexin40, connexin43 remodeling and the function of vagus nerve. There was obvious shortness of effective refractory period in atrial fibrillation animal models, while the removal of vagus nerve could attenuate this effect, meanwhile, the quantity and distribution of connexin40 and connexin43 changed at different locations and the deposit of collagen fibers, which might explain the mechanism of electrical heterogeneity and the structural remodeling originated from the pulmanory vein and left atria for the atrial fibrillation.

### **5. The distribution of connexins in heart and the relationship with arrhythmia**

Gap junction remodeling is a common response to many forms of heart disease (Strom et al.,2010; Burstein et al.,2009; Kieken et al.,2009; Qu et al., 2009; Yamada et al.,2008). Previous studies have demonstrated that loss of cell-cell coupling is highly arrhythmic (Chaldoupi et al., 2009), however, a detailed understanding of arrhythmia dynamics has been lacking. With respect to mechanistically link a primary perturbation of gap junction function with arrhythmia, conduction properties, arrhythmia dynamics, and cellular electrophysiological characteristics have been detected (Zhou et al., 2008; Severs et al., 2008; Gutstein et al., 2001). Accumulative evidences showed that ventricular gap junctions contain at least 20 times more connexin43 than connexin40, while atrial gap junctions contain much more connexin40 than connexin43 (Kontogeorgis et al., 2008; Lin et al., 2010). In the ventricle, the heterogeneous loss of connexin43 gap junctions in a murine conditional cardiac connexin43 knockout model best exemplified how the focal loss of cardiac gap junctions lead to significant dispersion of conduction, increased incidence of spontaneous arrhythmias, and loss of ventricular systolic function with only minor reductions in overall connexin43 expression. The gating of connexin43-containing ventricular gap junctions during the action potential is also proposed to promote cardiac arrhythmias via inactivation and recovery that depends on transjunctional voltage (Vj) and contributes to conduction slowing or block and the formation of reentrant arrhythmias. In the atria, targeted gene deletion of connexin40 in mice produced multiple aberrations: P wave and PQ interval prolongation, prolonged sinusnode-recovery time, prolonged Wenckebach period, burst-pacing induced atrial tachyarrhythmias, reduced atrial, A-V node, and left bundle branch conduction velocity, right bundle branch block, and reduced interatrial conduction heterogeneity(Leaf et al., 2008; Gutstein et al., 2005). There are close correlation between electrical properties and the anatomy of pulmonary veins and left atria. In animal studies, data showed that segmental muscle disconnection and differential muscle narrowing at pulmonary vein and left atria junctions and complex fiber orientations within the pulmonary vein provide robust anatomical bases for conduction disturbance at the pulmonary vein and left atria junction and complex intra pulmonary vein conduction patterns (Date et al., 2007).

The Remodeling of Connexins Localized at

Pulmonary Vein – Left Atria in Triggering and Maintenance of Atrial Fibrillation 101

Fig. 3. Electrical remodeling of atria, Acetylcholine injecting at RAA activates ganglion to output impulse and effects on the excited foci in pulmanory veins, therefore, the arrhythmia

The autopsied heart showed that myocardial cells were localized to pulmonary vein between 9 and 38 mm from the pulmonary vein and left atria junction (Roux et al., 2004). The sleeve was composed of circularly and longitudinally oriented bundles of cardiomyocytes. The peripheral end of the myocardial sleeve was irregular. The longest myocardial sleeves were found in the superior veins and were longitudinally oriented. At the pulmonary vein and left atria junction, the circular bundles were not often circumferential. Pulmonary vein myocardial architecture confirmed the possibility of initiating atrial fibrillation. Tan (Tan et al., 2006) examined 192 sections in 32 veins obtained from 8 healthy human heart, each segment included between 7 and 20 mm of the adjoining left atria, and found 1) pulmonary vein and left atria muscular discontinuities and abrupt 90° changes in myober orientation were present in the pulmonary vein and left atria junction in over half of all segments examined; 2) These anisotropic features were found more frequently in the anterosuperior than posteroinferior junctions; 3) Adrenergic and cholinergic nerve densities were highest in the left atria within 5 mm from the pulmonary vein and left atria junction, higher in the superior aspect of left superior pulmanory vein, anterosuperior aspect of right superior pulmanory vein, and inferior aspects of the both inferior pulmanory veins than diametrically opposite, and higher in the epicardial than endocardial half of the tissue; 4) adrenergic and cholinergic nerves were highly co-located at tissue and cellular levels of spatial organization. Tan suggest that: 1) the pulmonary vein and left atria junction contains anatomical substrates (muscular discontinuities and abrupt ber orientation changes) to support reentry; 2) there are no good empiric targets for segmental pulmonary vein isolation because of the widespread distributions of pulmonary vein and left atria muscular discontinuities; 3) the left atria region close to the pulmonary vein and left atria junction rather than farther away in the left atria or pulmonary vein would be the most appropriate target for autonomic modulation procedures; 4) it is not possible to selectively ablate either adrenergic or cholinergic nerves in this location because

perpetuates. Ach, acetylcholine; RAA: right atrial appendage; RSPV: right superior

pulmanory vein; LSPV: left superior pulmanory vein. (Lu et al. 2008)

### **6. The anatomy and electrical activation in pulmonary vein and left atria**

Catheter radiofrequency ablation of triggers originated from the pulmonary veins may successfully terminate paroxysmal atrial fibrillation (Jais et al., 1994). Because ablation within the pulmonary veins may result in stenosis of the pulmonary veins, the junctions between the pulmonary veins and the left atria have become new ablation targets for achieving electrical pulmonary vein isolation (Haissaguerre et al., 1998, 2000). Segmental ablation can successfully isolate the pulmonary vein by placing radiofrequency lesions in only 21% to 59% of the circumference of the pulmonary veins ostia (Pappone et al., 2000; Oral et al., 2002). Previous studies showed that ectopic beats originated from the pulmonary vein propagated to the left atria with characteristically long conduction time, often with conduction delay or block within the pulmonary vein or at the pulmonary vein and left atria junction (Nathan & Eliakim, 1966). The complex arrangement of myocardial fibers in the pulmonary vein and/or in the pulmonary vein and left atria junction is a possible reason for conduction delay or block in the pulmonary vein and left atria junction and within the pulmonary vein (Saito et al., 2000). Ho et al reported that a differential thickness of muscle sleeves could also account for a variable safety factor of propagation across the pulmonary vein and left atria junction (Ho et al., 2001). Hocini reported that zones of activation delay were observed in canine pulmonary veins and correlated with abrupt changes in fascicle orientation (Hocini et al., 2002). Hamabe identified that segmental muscle disconnection and differential muscle narrowing at pulmonary vein and left atria junctions and complex fiber orientations within the pulmonary vein provide robust anatomical bases for conduction disturbance at the pulmonary vein and left atria junction and complex intra pulmonary vein conduction patterns (Hamabe et al., 2003, see Fig2. and Fig3).

Fig. 2. Ectopic excitement exsiting in pulmanory veins and left atria conjunction, propagating into atria and forming reentry, which is so called"Atrial firbrillation begets Atrial fibrillation". SVC, superior vena cava; IVC, inferior vena cava; LIPV, left inferior pulmanory vein; RIPV, right inferior pulmanory vein; LSPV: left superior pulmanory vein; RSPV: right superior pulmanory vein. LA: left atria; RA: right atria.

Catheter radiofrequency ablation of triggers originated from the pulmonary veins may successfully terminate paroxysmal atrial fibrillation (Jais et al., 1994). Because ablation within the pulmonary veins may result in stenosis of the pulmonary veins, the junctions between the pulmonary veins and the left atria have become new ablation targets for achieving electrical pulmonary vein isolation (Haissaguerre et al., 1998, 2000). Segmental ablation can successfully isolate the pulmonary vein by placing radiofrequency lesions in only 21% to 59% of the circumference of the pulmonary veins ostia (Pappone et al., 2000; Oral et al., 2002). Previous studies showed that ectopic beats originated from the pulmonary vein propagated to the left atria with characteristically long conduction time, often with conduction delay or block within the pulmonary vein or at the pulmonary vein and left atria junction (Nathan & Eliakim, 1966). The complex arrangement of myocardial fibers in the pulmonary vein and/or in the pulmonary vein and left atria junction is a possible reason for conduction delay or block in the pulmonary vein and left atria junction and within the pulmonary vein (Saito et al., 2000). Ho et al reported that a differential thickness of muscle sleeves could also account for a variable safety factor of propagation across the pulmonary vein and left atria junction (Ho et al., 2001). Hocini reported that zones of activation delay were observed in canine pulmonary veins and correlated with abrupt changes in fascicle orientation (Hocini et al., 2002). Hamabe identified that segmental muscle disconnection and differential muscle narrowing at pulmonary vein and left atria junctions and complex fiber orientations within the pulmonary vein provide robust anatomical bases for conduction disturbance at the pulmonary vein and left atria junction and complex intra pulmonary vein

**6. The anatomy and electrical activation in pulmonary vein and left atria** 

conduction patterns (Hamabe et al., 2003, see Fig2. and Fig3).

Fig. 2. Ectopic excitement exsiting in pulmanory veins and left atria conjunction, propagating into atria and forming reentry, which is so called"Atrial firbrillation begets Atrial fibrillation". SVC, superior vena cava; IVC, inferior vena cava; LIPV, left inferior pulmanory vein; RIPV, right inferior pulmanory vein; LSPV: left superior pulmanory vein;

RSPV: right superior pulmanory vein. LA: left atria; RA: right atria.

Fig. 3. Electrical remodeling of atria, Acetylcholine injecting at RAA activates ganglion to output impulse and effects on the excited foci in pulmanory veins, therefore, the arrhythmia perpetuates. Ach, acetylcholine; RAA: right atrial appendage; RSPV: right superior pulmanory vein; LSPV: left superior pulmanory vein. (Lu et al. 2008)

The autopsied heart showed that myocardial cells were localized to pulmonary vein between 9 and 38 mm from the pulmonary vein and left atria junction (Roux et al., 2004). The sleeve was composed of circularly and longitudinally oriented bundles of cardiomyocytes. The peripheral end of the myocardial sleeve was irregular. The longest myocardial sleeves were found in the superior veins and were longitudinally oriented. At the pulmonary vein and left atria junction, the circular bundles were not often circumferential. Pulmonary vein myocardial architecture confirmed the possibility of initiating atrial fibrillation. Tan (Tan et al., 2006) examined 192 sections in 32 veins obtained from 8 healthy human heart, each segment included between 7 and 20 mm of the adjoining left atria, and found 1) pulmonary vein and left atria muscular discontinuities and abrupt 90° changes in myober orientation were present in the pulmonary vein and left atria junction in over half of all segments examined; 2) These anisotropic features were found more frequently in the anterosuperior than posteroinferior junctions; 3) Adrenergic and cholinergic nerve densities were highest in the left atria within 5 mm from the pulmonary vein and left atria junction, higher in the superior aspect of left superior pulmanory vein, anterosuperior aspect of right superior pulmanory vein, and inferior aspects of the both inferior pulmanory veins than diametrically opposite, and higher in the epicardial than endocardial half of the tissue; 4) adrenergic and cholinergic nerves were highly co-located at tissue and cellular levels of spatial organization. Tan suggest that: 1) the pulmonary vein and left atria junction contains anatomical substrates (muscular discontinuities and abrupt ber orientation changes) to support reentry; 2) there are no good empiric targets for segmental pulmonary vein isolation because of the widespread distributions of pulmonary vein and left atria muscular discontinuities; 3) the left atria region close to the pulmonary vein and left atria junction rather than farther away in the left atria or pulmonary vein would be the most appropriate target for autonomic modulation procedures; 4) it is not possible to selectively ablate either adrenergic or cholinergic nerves in this location because

The Remodeling of Connexins Localized at

electrical and signal conduction.

right atrial appendage; AS: atrial septum.

Pulmonary Vein – Left Atria in Triggering and Maintenance of Atrial Fibrillation 103

Fig. 5. Collagen fibers wrap the cardiac muscle cells and interrupt the normal intercellular

Fig. 6. Collagen Volume Fraction compared among three different groups. There was no significant spatial difference on collagen distribution in sham operated group and SVC-Ao fat pad removal group, while significant spatial difference on collagen distribution in SVC-Ao fat pad reserved group. CVF: collagen volume fraction; SVC-Ao fat pad: superior vena cava and aorto root fat pad; LA: left atria; RA: right atria; LAA: left atrial appendage; RAA:

both nerve types are highly co-located in this region. Steiner found that pulmanory vein myocardial sleeves frequently harbour pathological lesions, particularly senile atrial amyloid, and scarring in atrial fibrillation (Steiner et al., 2005). The degree of scarring of the sleeves did not correlate with the degree of coronary atherosclerosis, and inferred the genesis of the scarring is not post necrotic but degenerative, due to diffuse hypoxia of the sleeve myocardium. Amyloidosis and particularly scarring of pulmanory vein myocardial sleeves appear generally in the elderly population as an arrhythmogenic substrate for atrial fibrillation.

In animal studies, pacing had different effects on connexin40 and connexin43 gap junctions, collagen content increased as well (Yeh et al., 2006). They found there was a 98% increase in connexin43 in pacing 2 weeks, and a 74% increase in pacing 6-8weeks animals. In contrast, connexin40 decreased 47% in pacing 2 weeks but increased 44% in pacing 6-8weeks animals. Our studies also found the moderate to severe deposit of collagen fibers in canine atria after persistent rapid atrial pacing (XIONG et al., 2010, see Fig4. and Fig5.), connexin40 mRNA expression decreased in left atria and right atria, but increased in left atria appendage, right atria appendage and atrial septum; connexin43 mRNA expression was reduced in left atria, right atria, left atrial appendage and right atrial appendage while increased in atiral septum (see Fig6., Fig7. and Fig8.). The pacing induced collagen remodeling and modulation on connexin40 mRNA and connexin43 mRNA expressions could be partially attenuated by removing SVC-Ao fat pad suggesting vagal nervation plays a key role in the initiation and preservation of atrial fibrillation.

Fig. 4. Different degree of collagen fibers deposits at intercellular substance.1A to 1E: normal distribution of collagen fibers in the whole atria; 2A to 2E: severe degree of collagen fibers deposits at different locations of atria after persistent atrial pacing; 3A to 3E: moderate degree of collagen fibers deposits at different locations of atria after persistent atrial pacing without SVC-Ao fat pad.A: left atria; B: right atria; C: left atrial appendage; D: right atrial appendage; E: atrial septum; SVC-Ao fat pad: superior vena cava and aorto root fat pad.

both nerve types are highly co-located in this region. Steiner found that pulmanory vein myocardial sleeves frequently harbour pathological lesions, particularly senile atrial amyloid, and scarring in atrial fibrillation (Steiner et al., 2005). The degree of scarring of the sleeves did not correlate with the degree of coronary atherosclerosis, and inferred the genesis of the scarring is not post necrotic but degenerative, due to diffuse hypoxia of the sleeve myocardium. Amyloidosis and particularly scarring of pulmanory vein myocardial sleeves appear generally in the elderly population as an arrhythmogenic substrate for atrial

In animal studies, pacing had different effects on connexin40 and connexin43 gap junctions, collagen content increased as well (Yeh et al., 2006). They found there was a 98% increase in connexin43 in pacing 2 weeks, and a 74% increase in pacing 6-8weeks animals. In contrast, connexin40 decreased 47% in pacing 2 weeks but increased 44% in pacing 6-8weeks animals. Our studies also found the moderate to severe deposit of collagen fibers in canine atria after persistent rapid atrial pacing (XIONG et al., 2010, see Fig4. and Fig5.), connexin40 mRNA expression decreased in left atria and right atria, but increased in left atria appendage, right atria appendage and atrial septum; connexin43 mRNA expression was reduced in left atria, right atria, left atrial appendage and right atrial appendage while increased in atiral septum (see Fig6., Fig7. and Fig8.). The pacing induced collagen remodeling and modulation on connexin40 mRNA and connexin43 mRNA expressions could be partially attenuated by removing SVC-Ao fat pad suggesting vagal nervation plays a key role in the initiation and

Fig. 4. Different degree of collagen fibers deposits at intercellular substance.1A to 1E: normal distribution of collagen fibers in the whole atria; 2A to 2E: severe degree of collagen fibers deposits at different locations of atria after persistent atrial pacing; 3A to 3E: moderate degree of collagen fibers deposits at different locations of atria after persistent atrial pacing without SVC-Ao fat pad.A: left atria; B: right atria; C: left atrial appendage; D: right atrial appendage; E: atrial septum; SVC-Ao fat pad: superior vena cava and aorto root fat pad.

fibrillation.

preservation of atrial fibrillation.

Fig. 5. Collagen fibers wrap the cardiac muscle cells and interrupt the normal intercellular electrical and signal conduction.

Fig. 6. Collagen Volume Fraction compared among three different groups. There was no significant spatial difference on collagen distribution in sham operated group and SVC-Ao fat pad removal group, while significant spatial difference on collagen distribution in SVC-Ao fat pad reserved group. CVF: collagen volume fraction; SVC-Ao fat pad: superior vena cava and aorto root fat pad; LA: left atria; RA: right atria; LAA: left atrial appendage; RAA: right atrial appendage; AS: atrial septum.

The Remodeling of Connexins Localized at

**7. Acknowledgment** 

(No. 200633).

**8. References** 

Pulmonary Vein – Left Atria in Triggering and Maintenance of Atrial Fibrillation 105

This work was supported by grants from the Science Foundation for Returnees of Guangxi Zhuang Autonomous Region of China (No. 0575014) and the Key Scientific Research Subject of Medical Treatment and Public Health of Guangxi Zhuang Autonomous Region of China

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Fig. 8. Expression of Cx43 mRNA compared among three different groups. There was significant difference of increased Cx43 mRNA expression in SVC-Ao fat pad removal group but decreased Cx43 mRNA expression in SVC-Ao fat pad reserved group. The most interesting locations are left and right atria. SVC-Ao fat pad: superior vena cava and aorto root fat pad; LA: left atria; RA: right atria; LAA: left atrial appendage; RAA: right atrial appendage; AS: atrial septum; Cx43: connexin 43.

### **7. Acknowledgment**

104 Advances in Electrocardiograms – Clinical Applications

Fig. 7. Expression of Cx40 mRNA compared among three different groups. There was significant difference of increased Cx40 mRNA expression after persistent atrial pacing, the expression at atria in SVC-Ao fat pad removal group but that at atrial appendage in SVC-Ao fat pad reserved group are the significant difference. SVC-Ao fat pad: superior vena cava and aorto root fat pad; LA: left atria; RA: right atria; LAA: left atrial appendage; RAA: right

Fig. 8. Expression of Cx43 mRNA compared among three different groups. There was significant difference of increased Cx43 mRNA expression in SVC-Ao fat pad removal group but decreased Cx43 mRNA expression in SVC-Ao fat pad reserved group. The most interesting locations are left and right atria. SVC-Ao fat pad: superior vena cava and aorto root fat pad; LA: left atria; RA: right atria; LAA: left atrial appendage; RAA: right atrial

atrial appendage; AS: atrial septum; Cx40: connexin 40.

appendage; AS: atrial septum; Cx43: connexin 43.

This work was supported by grants from the Science Foundation for Returnees of Guangxi Zhuang Autonomous Region of China (No. 0575014) and the Key Scientific Research Subject of Medical Treatment and Public Health of Guangxi Zhuang Autonomous Region of China (No. 200633).

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**Part 2** 

**Myocardial Infarction** 

