**4. Risk of sudden cardiac death in cardiomyopathy: Epidemiology and risk stratification**

The epidemiologic risk of sudden cardiac death in cardiomyopathy is often difficult to assess because it is frequently impossible to determine the size of the population at risk. Determina‐ tion of risk is skewed by referral bias. The risk of sudden death has been studied with these limitations in several groups of patients, most notably in those with ICM but also in hyper‐ trophic cardiomyopathy and arrhythmogenic cardiomyopathy. Attempts to identify features predicting higher risk of sudden cardiac death have helped in management decisions. In this section we will discuss available knowledge about risk of sudden death and risk stratification in patients with cardiomyopathy.


**Table 1.** Risk predictors for SCD in cardiomyopathies

death due to bradyarrhythmia or ventricular tachyarrhythmia. [37] Frequently the cause of sudden death in these patients is pulseless electrical activity, presumably resulting from the

**Figure 5.** Photomicrographs of myocardium from a patient with LV noncompaction. Panel A shows low-power hema‐ toxylin- and eosin-stained photograph from noncompacted layer shoing 'fingerlike' projections. Panel B has a photo‐ micrograph with Masson's t trichrome stain showing prominent endocardial and subendocardial fibrosis, which is a feature of this disease due to abnormal myocardial microperfusion. **Adapted from chapter 'Cardiomyopathy' by Sian Hughes from the book 'Cardiac Pathololgy: A Guide to Current Practice' eds' S. Kim Suvarna ISBN:**

Inherited muscular dystrophies like Duchenne and Becker muscular dystrophies have skeletal and cardiac muscle involvement and cardiac pathology essentially manifests as dilated cardiomyopathy with associated heart failure and risk of sudden cardiac death. However, muscular dystrophies like Emery-Dreifuss (X-linked and autosomal variants), limb girdle muscular dystrophy type 1B, entity of DCM with conduction system disease (associated with lamin A/C mutations) and myotonic dystrophy are associated with high risk of sudden cardiac death. In these conditions sudden cardiac death was traditionally thought to be primarily due to conduction system disease and bradyarrhythmia. However, after routine implantation of pacemakers, it has been recognized that ventricular arrhythmias also contribute to sudden cardiac death in these patients. These conditions are associated with cardiomyopathy, with LV dysfunction as a late feature in the natural course of disease; sudden cardiac death is an early feature of cardiac involvement. The molecular pathogenesis of cardiac arrhythmias and

**4. Risk of sudden cardiac death in cardiomyopathy: Epidemiology and risk**

The epidemiologic risk of sudden cardiac death in cardiomyopathy is often difficult to assess because it is frequently impossible to determine the size of the population at risk. Determina‐ tion of risk is skewed by referral bias. The risk of sudden death has been studied with these

conduction system disease in these patients is an area of active research. [39]

**stratification**

174 Cardiomyopathies

severe diastolic dysfunction associated with amyloidosis. [38]

**978-1-4471-2406-1 (Print) 978-1-4471-2407-8 (Online) (Springer).**

#### **4.1. Ischemic cardiomyopathy**

Attempts at risk stratification for SCD initially included patient with history of myocardial infarction and LV systolic dysfunction emerged as the strongest predictor of overall mortality and SCD in them. [40]-[45] Many other potential risk factors have been studied, but LVEF remains the strongest and most widely used predictor of SCD risk. ICD trials for prevention of SCD have established the role of LV systolic function as the most important risk predictor. Other important predictors of SCD in these patients include electrocardiographic parameters, functional class, inducibility of ventricular arrhythmia with programmed ventricular stimu‐ lation, autonomic and neuro-humoral predictors and disturbances in autonomic innervation of the myocardium.

1970s and 1980s, VPBs (≥10 per hour) and NSVT in post-MI patients showed increased risk of overall mortality. [40], [42], [52], [53] Similar effect of ventricular ectopy and NSVT in post-MI patients has also been seen in the era of thrombolytic therapy for acute MI. [45], [54]-[57] GISSI-2 trial showed a mortality of 5.5% at six months after MI in patients with more than 10 VPBs per hour compared to 2% in those with less frequent VPBs. [57] Positive predictive value of VPBs in predicting cardiac arrhythmic events is in the range of 5% to 15% with negative predictive value of in the range of 90%. [58] However, when combined with LV ejection fraction, ventricular ectopy becomes a stronger risk predictor of SCD in post-MI patients. In European Myocardial Infarction Amiodarone Trial (EMIAT), post-MI patients with LVEF ≤ 40% had higher mortality in the presence of frequent or complex arrhythmias on ambulatory ECG than in their absence (20% vs. 10%). [59] Moreover, MADIT-I and MUSTT enrolled patients based on the presence of NSVT and showed benefit in terms of reduction in all-cause mortality and SCD with ICD, all these patients had to have inducible ventricular arrhythmia for being enrolled into the study. [50], [51]

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**5.** *Electrocardiographic parameters* have been studied in multiple studies and can be divided into parameters assessing ventricular conduction abnormality and parameters of ventric‐ ular repolarization abnormality. Parameters of conduction abnormality including QRS duration, abnormalities on signal averaged ECG, and fractionation of QRS have been studied in many studies. Parameters of repolarization abnormality including QT interval prolongation, QT dispersion, T wave variance, QT dynamics, QT/RR slope and T-wave alternans have all been studies in many studies. Each of these parameters confer a small

**6.** *Parameters of autonomic function* include heart rate variability, heart rate turbulence, baroreceptor sensitivity and deceleraltion capacity. These again have been found to increase the risk of sudden death in patients history of myocardial infarction with in many small

**7.** *Myocardial scar* is instrumental in the pathogenesis of ventricular tachycardia by providing the substrate for reentry circuit. Myocardial scar area assessed by cardiac MRI has been demonstrated to be a predictor of inducible VT on electrophysiological study. [3] More‐ over, heterogeneity of scar in the border zone of infarct can be assessed by MRI and has been shown to be a predictor of inducible and spontaneous ventricular arrhythmias. [63],

**8.** *Cardiac autonomic denervation* has been suggested a potential risk for arrhythmogenesis in post-MI patients. Although denervation of peri-infarct tissue was found to be a risk factor for inducible ventricular arrhythmia in animal model, [65] it failed to show any value in a small clinical study. [66] However, a study in a population of heart failure patients including both ischemic and nonischemic cardiomyopathy, showed increased risk of ventricular arrhythmia with disturbances in myocardial innervation assessed by mIBG

risk of sudden cardiac death individually. [60]-[62]

studies. [60]-[62]

scintigraphy. [67]

[64]


1970s and 1980s, VPBs (≥10 per hour) and NSVT in post-MI patients showed increased risk of overall mortality. [40], [42], [52], [53] Similar effect of ventricular ectopy and NSVT in post-MI patients has also been seen in the era of thrombolytic therapy for acute MI. [45], [54]-[57] GISSI-2 trial showed a mortality of 5.5% at six months after MI in patients with more than 10 VPBs per hour compared to 2% in those with less frequent VPBs. [57] Positive predictive value of VPBs in predicting cardiac arrhythmic events is in the range of 5% to 15% with negative predictive value of in the range of 90%. [58] However, when combined with LV ejection fraction, ventricular ectopy becomes a stronger risk predictor of SCD in post-MI patients. In European Myocardial Infarction Amiodarone Trial (EMIAT), post-MI patients with LVEF ≤ 40% had higher mortality in the presence of frequent or complex arrhythmias on ambulatory ECG than in their absence (20% vs. 10%). [59] Moreover, MADIT-I and MUSTT enrolled patients based on the presence of NSVT and showed benefit in terms of reduction in all-cause mortality and SCD with ICD, all these patients had to have inducible ventricular arrhythmia for being enrolled into the study. [50], [51]

**4.1. Ischemic cardiomyopathy**

176 Cardiomyopathies

of the myocardium.

Attempts at risk stratification for SCD initially included patient with history of myocardial infarction and LV systolic dysfunction emerged as the strongest predictor of overall mortality and SCD in them. [40]-[45] Many other potential risk factors have been studied, but LVEF remains the strongest and most widely used predictor of SCD risk. ICD trials for prevention of SCD have established the role of LV systolic function as the most important risk predictor. Other important predictors of SCD in these patients include electrocardiographic parameters, functional class, inducibility of ventricular arrhythmia with programmed ventricular stimu‐ lation, autonomic and neuro-humoral predictors and disturbances in autonomic innervation

**1.** *LV systolic function* emerged from studies in post-MI patients as a predictor of SCD. An analysis of 20 studies found the relative risk of a major arrhythmic event in patients with LVEF≤30% to 40% to be 4.3. [46] The Second Multicenter Automatic Defibrillator Implan‐ tation Trial (MADIT-II) and the Sudden Cardiac Death Heart Failure Trial (SCD-HeFT) clearly demonstrated the benefit of ICD implantation in patients with LVEF less than 30% or 35% respectively in preventing sudden death and reducing absolute mortality in

**2.** *Functional class* is a surrogate of severity of heart failure and heart failure severity predisposes to arrhythmogenesis by neuro-humoral mechanisms and homeostatic and hemodynamic changes. NYHA class has been used as criterion to enroll patients in the ICD trials and some of these studies have found its predictive value. Subgroup analysis of SCD-HeFT enrolling patients with congestive heart failure with either ischemic or nonischemic cardiomyopathy showed that patients with NYHA class III did not appear to benefit as opposed to patients with NYHA class II. [48] On the other hand in MADIT-II patients, there were no significant differences in the outcomes based on NYHA class. [47] NYHA functional class III was found to be the strongest independent predictor of

ICD therapy in the Trigger Of Ventricular Arrhythmia (TOVA) trial. [49]

**3.** *Programmed ventricular stimulation* with inducible VT/VF has been recognized as a predictor of sudden cardiac death in patients with history of myocardial infarction. MADIT-I study which included patients with inducible VT/VF and LVEF ≤ 35% showed a 26% absolute reduction in mortality at 27 months follow-up. [50] The reduction in mortality was much lower at 6-7% absolute reduction in mortality in patients with MADIT-II trial which enrolled patients with LVEF ≤ 30% and in a mixed population of ischemic and nonischemic cardiomyopathy patients in SCD-HeFT enrolling patients with LVEF ≤ 35% without electrophysiological assessment of inducibility. [47], [48] The Multicenter UnSustained Tachycardia Trial (MUSTT), enrolling patients with LVEF≤40 and inducible VT on invasive assessment showed similarly high absolute reduction in

**4.** *Ventricular ectopy and NSVT* has been shown to increase the risk of sudden cardiac death in patients with history of MI in multiple studies. In the early observational studies from

patients with history of myocardial infarction. [47], [48]

mortality of 31% at five years of follow up. [51]


**9.** *Combinations of risk factors:* As individual risk factor are not strong enough to predict SCD and probably in isolation do not justify the use of ICD therapy to prevent SCD with the current level of evidence, there has been an attempt to combine multiple risk factors to create a model to enhance the predictability of SCD. Although there are multiple small studies combining various risk factors to achieve the goal of refining the risk stratification strategy, there is a need to assess these risk models in a prospective manner. [61], [68]

**4.2. Hypertrophic cardiomyopathy**

intensive investigation.

4.35, 95% CI1.54-12.28). [77]

with increasing Wigle score. [81]

decades of life.

Hypertrophic cardiomyopathy is frequently complicated by sudden cardiac death, and SCD in, for example, athletes is frequently caused by HCM. This being said, early estimates of the gravity of the prognosis of HCM were probably driven by referral bias of difficult cases to specialist centers, and studies of more inclusive cohorts of patients indicate a much more favorable prognosis. [69] A study by Maron et al analyzing a cohort of 774 non-referral-based HCM patients showed an incidence of SCD of 0.7% per year. [70] They showed that although SCDs occur across the age groups in patients with HCM, there are two peaks of SCD risk during life, one in the early childhood and the other later in older age group in seventh and eighth

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Several risk factors associated with SCD in HCM have been identified and it is important to recognize this high-risk subset of patients for management strategies and prognostication.

**1.** *History of syncope:* In patients with HCM syncope is an important predictor of SCD. This has been confirmed by multiple survival studies and a systematic review of 11 survival studies. [71] Five of these survival studies showed a significant association between history of syncope and SCD in these patients. [72]-[76] and in the systematic review the hazard ratio was 2.68 (95% CI 0.97-4.38) for SCD. This association is clinically important and a history of syncope in a HCM patient is worrisome and should prompt further

**2.** *Non-sustained ventricular tachycardia (NSVT)* with ≥3 consecutive ventricular beats at a rate of 120 beats per minute lasting for <30 seconds has been shown to be significantly associated with SCD in patients with HCM. [73], [77]-[79] The systematic study evaluating the risk of SCD with NSVT showed a hazard ratio of SCD of 2.89 (95%CI 2.2-3.6). [71] The risk of SCD associated with NSVT is lower in patients with older age (31-75 years), whereas younger patient (14-30 years of age) have more than a four-fold increased risk of SCD (HR

**3.** *Severe left ventricular hypertrophy (LVH)* has been found to be a predictor of sudden cardiac death in multiple studies. [8], [72], [77], [80]-[82]In a recent systematic review the risk of SCD was found to be three-fold (hazard ratio 3.1, 95%CI 1.81-4.4) despite variable definitions. [71] Although most of the studies used a cut off for maximum wall thickness of ≥30 mm, there has been concern about variability in measurement across the studies and lack of data about pattern of LVH. One study used Wigle scores, a semi-quantitative scoring system described earlier, [83] for LVH severity and showed increased risk of SCD

**4.** *Family history of SCD and Genetic markers:* Familial association of SCD has been described in patients with HCM in early studies. [84]-[86] A systematic review of survival studies showed an increased risk of SCD in patients with family history of SCD with hazard ratio of 1.27(95%CI 1.16-1.38) [71]Family members tend to share genetic abnormality, and certain specific genetic mutations have been associated with higher risk of SCD. For example, troponin T mutations have been reported to have association with high risk of

SCD, often disproportionate to the other phenotypic expression. [87]


**Table 2.** ICD trials

#### **4.2. Hypertrophic cardiomyopathy**

**9.** *Combinations of risk factors:* As individual risk factor are not strong enough to predict SCD and probably in isolation do not justify the use of ICD therapy to prevent SCD with the current level of evidence, there has been an attempt to combine multiple risk factors to create a model to enhance the predictability of SCD. Although there are multiple small studies combining various risk factors to achieve the goal of refining the risk stratification strategy, there is a need to assess these risk models in a prospective manner. [61], [68]

> **LVEF of enrolled patients (%)**

**CASH** VFib, VT 46 44 36 23 8

**MADIT II** Prior MI (>1 month), EF ≤30% 23 22 16 28 6

**SCD-HeFT** Class II-III CHF, EF ≤35% 25 36 29 23 7

**Control ICD Relative Absolute**

VFib, out-of-hospital cardiac arrest due to VFib or VT, VT with syncope, VT with symptoms and EF ≤35%, unmonitored syncope with

subsequent spontaneous or induced

Prior MI, EF ≤35%, N-S VT, inducible VT non-suppressible with IV

Nonischemic CM, Hx HF, EF ≤35%,

Recent MI (6-40 days), EF ≤35%, abnormal HRV or mean 24-hr heart **All-cause mortality (%) Risk reduction (%)**

32 25 18 27 7

34 21 15 30 6

26 32 13 59 19

27 18 18 - -

30 55 24 58 31

21 14 8 44 6

28 17 19 - -

**Study Patient population**

*Primary prevention ICD trials*

**CIDS**

178 Cardiomyopathies

**MADIT**

**DEFINITE**

**DINAMIT**

**Table 2.** ICD trials

≤40%

VT

*Primary prevention ICD trials*

procainamide

**CABG Patch** Coronary bypass surgery, EF <36%, SAECG (+)

**MUSTT** CAD (prior MI ~95%), EF ≤40%, N-S VT, inducible VT

≥10 PVCs/hr or N-S VT

rate >80/min

**AVID** VFib, VT with syncope, VT with EF

Hypertrophic cardiomyopathy is frequently complicated by sudden cardiac death, and SCD in, for example, athletes is frequently caused by HCM. This being said, early estimates of the gravity of the prognosis of HCM were probably driven by referral bias of difficult cases to specialist centers, and studies of more inclusive cohorts of patients indicate a much more favorable prognosis. [69] A study by Maron et al analyzing a cohort of 774 non-referral-based HCM patients showed an incidence of SCD of 0.7% per year. [70] They showed that although SCDs occur across the age groups in patients with HCM, there are two peaks of SCD risk during life, one in the early childhood and the other later in older age group in seventh and eighth decades of life.

Several risk factors associated with SCD in HCM have been identified and it is important to recognize this high-risk subset of patients for management strategies and prognostication.


**5.** *Left ventricular outflow tract obstruction (LVOTO):* The severity of the dynamic LVOTO is associated with an increased risk of SCD. The mechanism of this could be reduction of cardiac output and electromechanical dissociation, but myocardial ischemia induced by increased ventricular stress is also of possible etiologic significance. An instantaneous pressure gradient of 50 mmHg across the LVOT is considered to be clinically significant. Five studies have shown significant association between LVOTO and SCD in patients with HCM. [73], [76], [79], [88]

probands showed much lower annual incidence of SCD at 0.08% per year. [98] This suggests a strong selection bias of high-risk patients in the previous follow-up studies and with current approach of aggressive screening of the family members of probands; the previous estimates of the degree of risk of SCD may not be applicable. Many studies have tried to establish

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**1.** *History of syncope* has been documented as a precursor of SCD in multiple studies. [93] In a study by Nava et al syncope was the only clinical variable predictive of SCD in probands, while none of the family members of the proband had history of syncope. [98] The Darvin II study and data from the Johns Hopkins arrhythmogenic cardiomyopathy clinic have evaluated the importance of history of syncope in patients receiving ICD. The multi-center Darvin II study showed that syncope is a strong predictor of life-saving device interven‐ tion in patients with ICD. In the Johns Hopkins cohort, although 75% of the patients with AC receiving appropriate ICD therapy did not have history of syncope, one half of patients with history of syncope prior to the implantation of ICD received appropriate ICD therapy (9%/year). A recent history of syncope was even stronger predictor of appropriate ICD

**2.** *Prior history of hemodynamically unstable ventricular arrhythmia or cardiac arrest* is a strong predictor of SCD. A history of arrhythmic cardiac arrest or hemodynamically unstable VT, but not a history of hemodynamically stable VT, was found to be independent predictor of life-saving ICD therapy in a study by Corrado et al. [96] In another study by Canu et al with retrospective analysis of 22 patients, previous history of resuscitated VF

**3.** *Electrocardiographic parameters* including QRS dispersion, right precordial QRS prolonga‐ tion and late potentials on signal-averaged ECG (SAECG) have been found to be associ‐ ated with risk of SCD. Turrini et al demonstrated longer QRS duration in right precordial leads in patients with SCD as compared to those without. [101] QRS dispersion of >40 msec was strong independent predictor of SCD in this study. Late potential on SAECG have not been found to predict arrhythmic risk in these patients. [102]-[104] Although in the study by Turrini et al late potentials were univariate predictors of sustained VT, decreased RV ejection fraction remained the only independent predictor in multivariate

**4.** *RV dilatation/dysfunction and LV involvement* are important predictors of poor outcome [105] and SCD [106] in arrhythmogenic cardiomyopathy. RV dysfunction has been associated with increased risk of ICD discharges and sustained VT. [97], [104], [107] It is not clear as yet if LV involvement detected by tissue characterization without LV dilata‐

**5.** *Other factors:* Most of the *genetic variants* of arrhythmogenic cardiomyopathy have similar risks of SCD. However a very malignant genetic variant with TMEM43 gene mutation significantly increases the risk of SCD. [108] Studies evaluating the significance of *programmed ventricular stimulation* as a predictor of SCD in the patients with arrhythmo‐ genic cardiomyopathy has shown mixed results. The DARVIN studies and the study by

parameters to predict the risk of sudden death.

analysis. [104]

therapy compared to remote history of syncope. [99]

tion or dysfunction increases the risk of SCD.

was present in two out of three patients who died suddenly. [100]


#### **4.3. Arrhythmogenic cardiomyopathy**

Ventricular arrhythmia, principally VF is the mode of SCD in patients with arrhythmogenic cardiomyopathy. The absolute risk of SCD in a patient with ARVC has been reported, although inconsistencies between different studies make it hard to establish the degree of risk. The annual risk of SCD in studies from the pre-ICD era in high-risk cohorts was in the range of 1-1.5%. [92]-[94] Sports activity increases the risk of SCD by five fold. [95] Although more recent follow-up studies of patients with ICDs have shown a higher annual rate of ICD intervention, of 5-8%, [96], [97] an ICD intervention may not be a good surrogate for SCD. A follow-up study of patients diagnosed on the basis of aggressive screening of the family members of the probands showed much lower annual incidence of SCD at 0.08% per year. [98] This suggests a strong selection bias of high-risk patients in the previous follow-up studies and with current approach of aggressive screening of the family members of probands; the previous estimates of the degree of risk of SCD may not be applicable. Many studies have tried to establish parameters to predict the risk of sudden death.

**5.** *Left ventricular outflow tract obstruction (LVOTO):* The severity of the dynamic LVOTO is associated with an increased risk of SCD. The mechanism of this could be reduction of cardiac output and electromechanical dissociation, but myocardial ischemia induced by increased ventricular stress is also of possible etiologic significance. An instantaneous pressure gradient of 50 mmHg across the LVOT is considered to be clinically significant. Five studies have shown significant association between LVOTO and SCD in patients with

**6.** *Systolic blood pressure response to exercise* is altered in many patients with HCM probably due to decreased systemic vascular resistance. [89] Sadoul et al demonstrated in 161 HCM patients ≤40 years old that failure of systolic blood pressure to rise ≥20 mmHg during exercise or a fall of >20 from the peak systolic blood pressure was associated with an increased risk of SCD (15% vs 3%, p<0.009). [90] However, analysis of multiple survival studies with data from a wider age range did not confirm this association (hazard ratio 1.23, 95%CI 0.64-1.96) [71] but four of these studies did show abnormal systolic blood pressure response to be a risk factor for SCD in subjects ≤40 years old. [73], [76], [77], [80]

**7.** *Other factors: Atrial fibrillation* and *left atrial size* may reflect the risk of SCD as they reflect the severity of left ventricular pathology. [74], [91] *NYHA functional class* is also a function of diastolic dysfunction, myocardial ischemia, LVOTO, atrial arrhythmias and adverse remodeling, and potentially can be associated with SCD, but studies reporting survival analysis for SCD did not report any significant association. *Late gadolinium enhancement* on MRI, which is suggestive of presence of extracellular myocardial collagen deposition and a potential substrate for ventricular arrhythmias, was not associated with SCD in a recent study, although it was associated with cardiovascular morbidity and mortality. [10] *Increased fractionation* of the paced right ventricular electrogram at invasive electrophy‐ siological study has been found to be associated with SCD in patients with HCM and this is presumably a reflection of myofibrillar disarray. HCM patients with *LV systolic dysfunction* should be considered at a higher risk of SCD similar to other causes of LV systolic dysfunction. *Age* of the patient modifies the risk of SCD in patients with HCM as suggested by multiple studies with higher risk in adolescence and early adulthood. The survival study by Spirito et al showed a significant reduction in SCD risk with increasing age, however, this study did not include other established risk factors in multivariate

Ventricular arrhythmia, principally VF is the mode of SCD in patients with arrhythmogenic cardiomyopathy. The absolute risk of SCD in a patient with ARVC has been reported, although inconsistencies between different studies make it hard to establish the degree of risk. The annual risk of SCD in studies from the pre-ICD era in high-risk cohorts was in the range of 1-1.5%. [92]-[94] Sports activity increases the risk of SCD by five fold. [95] Although more recent follow-up studies of patients with ICDs have shown a higher annual rate of ICD intervention, of 5-8%, [96], [97] an ICD intervention may not be a good surrogate for SCD. A follow-up study of patients diagnosed on the basis of aggressive screening of the family members of the

HCM. [73], [76], [79], [88]

180 Cardiomyopathies

analysis.[74]

**4.3. Arrhythmogenic cardiomyopathy**


Wichter et al did not show any significant predictive value of programmed ventricular stimulation in predicting ICD discharges. [96], [97], [109] Although the Johns Hopkins study did show some relationship between programmed stimulation of ventricular arrhythmia and later ICD shocks, the association did not confer good positive and negative predictive values (65% and 75% respectively). [99] Hence, withholding ICD therapy on the basis of negative EP study should not be recommended and other param‐ eters for risk stratification should be taken into consideration to make a decision for ICD implantation.

cardiomyopathy associated lamin A/C gene (LMNA), which is also associated with cardiac conduction defects, has been found to have particularly high risk of SCD. A significant proportion of these patients received appropriate ICD therapy even before the development of heart failure. [116], [117] These patients are at a higher risk of sudden death with lower degree of LV systolic dysfunction and a recent study has suggested high risk of malignant ventricular arrhythmia in patients who are male, have dilated LV, have NSVT or LVEF < 45%. [118] SCN5A overlap syndrome with dilated cardiomyopathy are

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**5.** *NSVTs and PVBs* have not been found to have predictive value in of arrhythmic event in patients with DCM. In medically stabilized patients Zecchin et al failed to show any difference in arrhythmic event between patients with and without NSVTs. [119] NSVT was not evaluated for prediction of SCD in the large primary prevention trial like

**6.** *Others factors: Electrocardiographic parameters* have been evaluated to identify the groups of dilated cardiomyopathy patients with risk of SCD. [120], [121] Prolongation of QRS and presence of left bundle branch block are independent predictors of SCD. Parame‐ ters of QT dynamicity and QRS fragmentation may be useful in risk stratification of SCD. [122], [123] SAECG, heart rate variability, heart rate turbulence, heart rate recovery, baroreflex sensitivity and T-wave alternans have been evaluated and each individual risk factor has a small effect size. [61], [62] As discussed earlier in the section on ischemic cardiomyopathy, these ECG parameters and parameter of autonomic function have small effect when used individually and may have a stronger risk predictive value in combination. [61], [68] Assessment of myocardial fibrosis by various methods includ‐ ing serum markers of fibrosis and cardiac MRI with late gadolinium enhancement may potentially become a tool in risk stratification for sudden cardiac death in patients with

*Left ventricular noncompaction* is associated with left ventricular dysfunction and risk of ventricular arrhythmia. Studies to assess the degree of risk and parameters to stratify the risk have not been done in this group of patients, but it is noteworthy that the diagnosis has only recently been recognized. LV systolic dysfunction may be a predictor of SCD in these patients, although concerns have been raised about its value. [125] Any other parameter to stratify the

Patients with *cardiac sarcoidosis* have poorer prognosis compared to idiopathic dilated cardio‐ myopathy with similar degree of LV systolic dysfunction. [126], [127] Patients ventricular tachycardia or atrioventricular block are at a high risk of adverse cardiac events. Presence of AV block in patients with cardiac sarcoidosis younger than 55 years increase the risk of adverse cardiac outcomes over 2 years by ten-fold as compared to patients without cardiac sarcoidosis. [32] Asymptomatic cardiac involvement in sarcoidosis has been largely reported to have benign prognosis, [128]-[130] although one recent report recorded 19% mortality (5 out of 21 patients with MRI diagnosed cardiac sarcoidosis) over a follow-up period of 21 months. [131]

at increased risk of SCD.

DEFINITE and SCD-HeFT, [48], [113]

dilated cardiomyopathy. [124]

**4.5. Other cardiomyopathies**

risk is still speculative.

#### **4.4. Dilated cardiomyopathy**

SCD in patients with dilated cardiomyopathy is one of the major causes of mortality, consti‐ tuting nearly one-third of all deaths. Left ventricular systolic function as determined by LVEF and NYHA functional class have become the most extensively used variable to stratify risk of SCD in this group of patients. Other parameters including a history of syncope, genetic factors and programmed ventricular stimulation have been evaluated to stratify the risk of SCD in these patients, and these are summarized below.


cardiomyopathy associated lamin A/C gene (LMNA), which is also associated with cardiac conduction defects, has been found to have particularly high risk of SCD. A significant proportion of these patients received appropriate ICD therapy even before the development of heart failure. [116], [117] These patients are at a higher risk of sudden death with lower degree of LV systolic dysfunction and a recent study has suggested high risk of malignant ventricular arrhythmia in patients who are male, have dilated LV, have NSVT or LVEF < 45%. [118] SCN5A overlap syndrome with dilated cardiomyopathy are at increased risk of SCD.


#### **4.5. Other cardiomyopathies**

Wichter et al did not show any significant predictive value of programmed ventricular stimulation in predicting ICD discharges. [96], [97], [109] Although the Johns Hopkins study did show some relationship between programmed stimulation of ventricular arrhythmia and later ICD shocks, the association did not confer good positive and negative predictive values (65% and 75% respectively). [99] Hence, withholding ICD therapy on the basis of negative EP study should not be recommended and other param‐ eters for risk stratification should be taken into consideration to make a decision for ICD

SCD in patients with dilated cardiomyopathy is one of the major causes of mortality, consti‐ tuting nearly one-third of all deaths. Left ventricular systolic function as determined by LVEF and NYHA functional class have become the most extensively used variable to stratify risk of SCD in this group of patients. Other parameters including a history of syncope, genetic factors and programmed ventricular stimulation have been evaluated to stratify the risk of SCD in

**1.** *Left Ventricular systolic function* is associated with increased overall mortality and SCD in patients with nonischemic dilated cardiomyopathy. [110]-[112] This has been reaffirmed by the reduction in SCD seen with ICD implantation in patients with NIDCM with LV

**2.** *NYHA functional class* is important determinant of overall survival and SCD in patients with systolic heart failure. [114] However, with worsening NYHA functional class, nonsudden death becomes relatively more important in patients with heart failure compared to SCD. Patients with NYHA class III were significantly more likely to receive ICD therapy for ventricular arrhythmia even after adjusting for LVEF in TOVA study, however, there were very few patients with NYHA class IV in this study. [49] NYHA class IV patients, although at risk of arrhythmic death, are less likely to benefit from ICD due to competing risk of non-sudden heart failure death. Majority of patients in the major ICD trials (SCD-HeFT and DEFINITE) were class II and class III patients, and the reduction in SCD in these groups of patients is well established. [48], [113] However, NYHA class I patients were largely under-represented in majority of the ICD trials with the exception of DEFINITE

**3.** *History of syncope* increases the risk of SCD in patients with heart failure with dilated cardiomyopathy. In a SCD-HeFT sub-study patients with history of syncope had higher frequency of receiving appropriate ICD therapy compared to those without a history of syncope. Moreover, patients with history of syncope had similarly increased risk of mortality in ICD (HR: 1.54, 95% CI 10.4-2.27), amiodarone (HR: 1.33, 95% CI 0.91-1.93) and placebo (HR: 1.39, 95% CI 0.96-2.02) arms (p=0.86 for test of difference between the three

**4.** *Genetic factors:* There has been a recent recognition of certain genetic mutations associated with increased risk of SCD in patients with dilated cardiomyopathy. For example, dilated

systolic dysfunction in DEFINITE and SCD-HeFT ICD trials. [48], [113]

implantation.

182 Cardiomyopathies

arms).

**4.4. Dilated cardiomyopathy**

these patients, and these are summarized below.

study which had 21.6% patients in NYHA class I.

*Left ventricular noncompaction* is associated with left ventricular dysfunction and risk of ventricular arrhythmia. Studies to assess the degree of risk and parameters to stratify the risk have not been done in this group of patients, but it is noteworthy that the diagnosis has only recently been recognized. LV systolic dysfunction may be a predictor of SCD in these patients, although concerns have been raised about its value. [125] Any other parameter to stratify the risk is still speculative.

Patients with *cardiac sarcoidosis* have poorer prognosis compared to idiopathic dilated cardio‐ myopathy with similar degree of LV systolic dysfunction. [126], [127] Patients ventricular tachycardia or atrioventricular block are at a high risk of adverse cardiac events. Presence of AV block in patients with cardiac sarcoidosis younger than 55 years increase the risk of adverse cardiac outcomes over 2 years by ten-fold as compared to patients without cardiac sarcoidosis. [32] Asymptomatic cardiac involvement in sarcoidosis has been largely reported to have benign prognosis, [128]-[130] although one recent report recorded 19% mortality (5 out of 21 patients with MRI diagnosed cardiac sarcoidosis) over a follow-up period of 21 months. [131] Assessment of SCD risk in *cardiac amyloidosis* is not well defined. Little data is available on risk stratification, and the usual approach in these patients is secondary prophylaxis or extrapolation of risk factors from other types of cardiomyopathies, e.g., LV systolic dysfunc‐ tion. The degree of myocardial involvement in sarcoidosis may be important in clinical decision-making. Patients with *hereditary dystrophies* behave largely like dilated cardiomyop‐ athy and risk stratification in these patients again conforms to the risk stratification of dilated cardiomyopathy.

controlled trial in patients with ICD showed a reduction in mortality and ICD shocks in patients receiving d,l-sotalol. Moreover, the mortality benefit in this study did not differ

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http://dx.doi.org/10.5772/55636

*Beta-blockers* has a proven role in reducing cardiovascular mortality and SCD in patients with heart failure either from non-ischemic cardiomyopathy or ischemic heart disease. [114], [137]- [139] Similarly, ACE inhibitors, ARBs and aldosterone antagonist are used in heart failure patients to reduce all-cause mortality, however, neither ACE inhibitors nor ARB actually reduce SCD in patients with LV systolic dysfunction. [140]-[142] ELITE did show an unex‐ pected reduction of SCD with losartan but this was a non-prespecified endpoint and was never

Class I antiarrhythmic drugs have not been found to reduce SCD in patients with history of MI and LV systolic dysfunction, and in fact most often result in an increase in mortality. The Cardiac Arrhythmia Suppression Trial (CAST) and CAST-II trials, for example, showed increased mortality with the use of class Ic antiarrhythmic drugs in post MI patients. [144] Similarly, propafenone showed increased mortality compared to ICD in Cardiac Arrest Study

As the data of ICD trials showed reduction in all-cause mortality and SCD in patients with cardiomyopathy as compared to amiodarone, the role of antiarrhythmic drugs in prevention of SCD has become adjunctive, with the goal of reducing ICD shocks. Beta-blockers and other humoral modifiers are generally used in the management of heart failure and improve survival

The role of amiodarone for prevention of SCD in HCM is controversial. In a study by McKenna et al, [146] amiodarone found to be effective but it is noteworthy that this study was used historical controls receiving either mexiletine, disopyramide or quinidine. In other studies antiarrhythmic drugs for the prevention of SCD in HCM have not been found to be effective. [147] Similarly, beta-blockers, sotalol and amiodarone have been used to suppress ventricular arrhythmias in ARVC. Efficacy has been variable [148], [149] and, with the increasing practice of use of ICD in the prevention of SCD in these patients, antiarrhythmic drugs are again used

Implantable cardioverter-defibrillator therapy has emerged as the most important manage‐ ment strategy for prevention of SCD in patients with cardiomyopathy at high risk of sudden cardiac death. The high incidence and high individual risk of SCD in cardiomyopathy patients with impaired left ventricular function, especially in those who had survived a ventricular arrhythmia, and the relative ineffectiveness of antiarrhythmic drugs in these patients led to a series of trials aimed at assessing the role of ICD therapy. This strategy was first tested in trials of patients with highest degree of risk. These were sudden death and ventricular arrhythmia survivors, and the studies are collectively referred to as secondary prevention trials. These trials were followed by trials of increasingly lower risk patients, principally those with heart failure, in primary prevention trials. The major message of these trials is that cost effectiveness

between patients with LVEF <30% and >30%. [136]

confirmed prospectively. [143]

Hamburg (CASH). [145]

in heart failure patients.

to reduce the need for ICD intervention.

**5.2. Device therapy: Implantable cardioverter-defibrillator**
