**2. Incidence, prevalence and prognosis**

Although tachycardia-induced cardiomyopathy is considered to be a relatively rare instance, its precise incidence is not described well yet. In fact, this disease is very likely to be under‐ diagnosed in the clinical practice despite that the link between tachycardia and dilated cardiomyopathy pattern has been known for a long time [3-5]. One reason for its underesti‐ mation may be the uncertainty whether the detected tachycardia is the primary cause of the cardiomyopathy, or whether it is rather a consequence of cardiomyopathy of different origin.

Tachycardia-induced cardiomyopathy may develop at any age. It has been documented in fetuses with persistent supraventricular tachycardias [6], in children and adolescents [7] as well as in adults [8].

Virtually, any type of arrhythmia is capable of inducing ventricular dysfunction or cardiomy‐ opathy; however, supraventricular arrhythmias are the most commonly reported causes of tachycardia-induced cardiomyopathy. It has been predominanly described in association with atrial fibrillation, but other supraventricular arrhythmias may lead to this pathology too. Tachycardia-induced cardiomyopathy may also develop as a result of persistent ventricular tachycardia, rapid atrial and/or ventricular pacing or as a consequence of some extracardiac diseases that are associated with persistent tachycardia (Table 1). Importantly, it may also occur in patients with "only" frequent ventricular premature beats [9].

**Atrial fibrillation** (the most frequently reported arrhythmia associated with tachycardiainduced cardiomyopathy development) is a frequent type of supraventricular tachycardia


sion, congenital heart diseases or valvular diseases. Although tachycardia-induced cardiomy‐ opathy may be seen as secondary due to well-defined causal cardiovascular factor, this disorder ranks among cardiomyopathies also in the current definition and classification of

Tachycardia-induced cardiomyopathy is a disease with attributes of dilated cardiomyopathy that develop as a consequence of persistent tachycardia. It is characterized by systolic ventric‐ ular dysfunction and dilatation with heart failure symptoms that occur as a result of long-term tachycardia of either supraventricular or ventricular origin. This disease should be also considered as a cause of ventricular dysfunction in the absence of tachycardia at the time of patient presentation since the tachyarrhythmia could disappear spontaneously before the initiation of patient examination, while the hemodynamic and especially structural changes of the heart induced by long-term tachycardia may persist even weeks after arrhythmia

The key feature of tachycardia-induced cardiomyopathy is the reversibility of both functional and structural changes as soon as the heart rate/rhythm is well controlled. In such case, improvement or even complete functional and structural normalization may be found. A correct diagnosis is thus often stated retrospectively based on the observation of ventricular systolic function improvement and regression of ventricular dilatation after appropriate rate/

Although tachycardia-induced cardiomyopathy is considered to be a relatively rare instance, its precise incidence is not described well yet. In fact, this disease is very likely to be under‐ diagnosed in the clinical practice despite that the link between tachycardia and dilated cardiomyopathy pattern has been known for a long time [3-5]. One reason for its underesti‐ mation may be the uncertainty whether the detected tachycardia is the primary cause of the cardiomyopathy, or whether it is rather a consequence of cardiomyopathy of different origin. Tachycardia-induced cardiomyopathy may develop at any age. It has been documented in fetuses with persistent supraventricular tachycardias [6], in children and adolescents [7] as

Virtually, any type of arrhythmia is capable of inducing ventricular dysfunction or cardiomy‐ opathy; however, supraventricular arrhythmias are the most commonly reported causes of tachycardia-induced cardiomyopathy. It has been predominanly described in association with atrial fibrillation, but other supraventricular arrhythmias may lead to this pathology too. Tachycardia-induced cardiomyopathy may also develop as a result of persistent ventricular tachycardia, rapid atrial and/or ventricular pacing or as a consequence of some extracardiac diseases that are associated with persistent tachycardia (Table 1). Importantly, it may also occur

**Atrial fibrillation** (the most frequently reported arrhythmia associated with tachycardiainduced cardiomyopathy development) is a frequent type of supraventricular tachycardia

in patients with "only" frequent ventricular premature beats [9].

cardiomyopathies [1, 2].

76 Abnormal Heart Rhythms

rhythm control.

well as in adults [8].

disappearance and/or rate control achievement.

**2. Incidence, prevalence and prognosis**

**Table 1.** Disorders associated with tachycardia-induced cardiomyopathy development (adapted from [81])

in patients with dilated cardiomyopathy and heart failure. It appears that there is a close relationship between atrial fibrillation and heart failure: heart failure progression sup‐ ports electrical and structural remodeling of the heart, which finally leads to atrial fibrilla‐ tion development. On the other hand, epidemiological studies have demonstrated that patients with atrial fibrillation are at higher risk of heart failure [10] and that abnormal leftventricular systolic function is 2.5 times more likely in elderly patients (> 65 years) with atrial fibrillation than in those without this arrhythmia [11]. In addition, sinus rhythm restoration or adequate rate control of ongoing arrhythmia are associated with the improve‐ ment or even normalization of left-ventricular ejection fraction in some of these patients. These findings indicate that at least in some cases, left-ventricular dysfunction is primari‐ ly caused by rapid heart rate during atrial fibrillation rather than by preexisting dilated cardiomyopathy. Moreover, some studies indicate that approximately 25–50% of patients with atrial fibrillation, who simultaneously suffer from ventricular dysfunction, have some degree of tachycardia-induced cardiomyopathy [12, 13].

Another instance of tachyarrhythmia that used to be associated with a relatively higher prevalence of cardiomyopathy pattern is **atrial flutter**. Some observational studies indicated that left-ventricular systolic dysfunction is present in up to 25% of patients reported to atrial flutter ablation, and in more than half of these, it is possible to observe a significant improve‐ ment or even normalization of ejection fraction during the first twelve months after successful elimination of the tachycardia [14].

Prevalence of ventricular dysfunction is relatively high also in incessant **atrial tachycardia,** since it has been reported in approximately 10–19% of cases [15, 16]. It seems that children are more susceptible to tachycardia-induced cardiomyopathy than adults. Among adults, tachycardia-induced cardiomyopathy appears to be present more often in younger adult patients with persistent atrial tachycardia than in those of a higher age, although the lower prevalence in the older population may be partially caused by difficulties to distinguish the effect of tachycardia alone from that of the underlying heart disease with regard to the systolic ventricular function. Interestingly, elimination of the arrhytmia leads to the restoration of leftventricular function in up to 97% [16].

**Supraventricular reentrant tachycardias** (atrioventricular nodal reentry tachycardia (AVNRT) and atrioventricular reciprocating tachycardia (AVRT)) have usually only paroxys‐ mal nature. If persistent, these may also induce cardiomyopathy and heart failure that are reversible after catheter ablation [17-20].

**Ventricular tachycardias** are usually associated with some forms of underlying structural heart diseases. Therefore, it is difficult to distinguish whether and to what extent is the observed systolic ventricular dysfunction caused by the primary disease, and how much has persistent tachycardia contributed to its severity. This may be determined more precisely in patients with idiopathic ventricular tachycardias, which (if persistent or repetitive enough) may lead to cardiomyopathy. Restoration of normal systolic performance of the left ventricle has been described in patients with successful elimination of both right-ventricular outflow tract tachycardia [8] and left-ventricular outflow tract tachycardia [7].

However, cardiomyopathy with or without symptomatic heart failure may be present also in patients with "only" **frequent premature beats.** It has been described mainly in patients with frequent ventricular ectopy [9, 21-23], but high burden of atrial premature beats may also lead to reversible cardiomyopathy [24, 25]. A prospective multicenter study that included patients with reduced left-ventricular ejection fraction due to suspected ventricu‐ lar premature beat-associated cardiomyopathy has found that both systolic function and neurohumoral response (levels of natriuretic peptide) improve as soon as the ectopy is successfully eliminated and that the extent of improvement is comparable between patients with and without known structural heart disease [26]. These authors suggested that the higher the burden of ventricular premature beats (VPB), the higher the probability of systolic function improvement after ectopy elimination, with 13% baseline VPB burden being 100% sensitive and 85% specific to predict left-ventricular ejection fraction increase by ≥5% after elimination of the ectopic focus. Although not confirmed in all studies [26], some research‐ ers have also suggested that the QRS duration of VPB is an important factor in the development of cardiomyopathy, with wider QRS complexes more likely to lead to cardiomyopathy pattern with a lower total burden of PVBs [27, 28] and that epicardial origin of VPBs is also associated with delayed LV function recovery [29].

**Prognosis** of dilated cardiomyopathy may vary depending on the cause. Tachycardia-induced cardiomyopathy ranks among forms of dilated cardiomyopathy with (if treated appropriately) generally good prognoses. Although studies describing recovery of patients with tachycardiainduced cardiomyopathy after sinus rhythm restoration or rate control include only small samples of patients, it appears that these causal therapeutic options may result in an improve‐ ment of left-ventricular function, positive change in neurohumoral cascade (reduced levels of natriuretic peptides) [26] and that it is likely to be linked to a generally good prognosis of tachycardia-induced cardiomyopathy.

### **3. Pathogenesis**

prevalence in the older population may be partially caused by difficulties to distinguish the effect of tachycardia alone from that of the underlying heart disease with regard to the systolic ventricular function. Interestingly, elimination of the arrhytmia leads to the restoration of left-

**Supraventricular reentrant tachycardias** (atrioventricular nodal reentry tachycardia (AVNRT) and atrioventricular reciprocating tachycardia (AVRT)) have usually only paroxys‐ mal nature. If persistent, these may also induce cardiomyopathy and heart failure that are

**Ventricular tachycardias** are usually associated with some forms of underlying structural heart diseases. Therefore, it is difficult to distinguish whether and to what extent is the observed systolic ventricular dysfunction caused by the primary disease, and how much has persistent tachycardia contributed to its severity. This may be determined more precisely in patients with idiopathic ventricular tachycardias, which (if persistent or repetitive enough) may lead to cardiomyopathy. Restoration of normal systolic performance of the left ventricle has been described in patients with successful elimination of both right-ventricular outflow

However, cardiomyopathy with or without symptomatic heart failure may be present also in patients with "only" **frequent premature beats.** It has been described mainly in patients with frequent ventricular ectopy [9, 21-23], but high burden of atrial premature beats may also lead to reversible cardiomyopathy [24, 25]. A prospective multicenter study that included patients with reduced left-ventricular ejection fraction due to suspected ventricu‐ lar premature beat-associated cardiomyopathy has found that both systolic function and neurohumoral response (levels of natriuretic peptide) improve as soon as the ectopy is successfully eliminated and that the extent of improvement is comparable between patients with and without known structural heart disease [26]. These authors suggested that the higher the burden of ventricular premature beats (VPB), the higher the probability of systolic function improvement after ectopy elimination, with 13% baseline VPB burden being 100% sensitive and 85% specific to predict left-ventricular ejection fraction increase by ≥5% after elimination of the ectopic focus. Although not confirmed in all studies [26], some research‐ ers have also suggested that the QRS duration of VPB is an important factor in the development of cardiomyopathy, with wider QRS complexes more likely to lead to cardiomyopathy pattern with a lower total burden of PVBs [27, 28] and that epicardial

tract tachycardia [8] and left-ventricular outflow tract tachycardia [7].

origin of VPBs is also associated with delayed LV function recovery [29].

**Prognosis** of dilated cardiomyopathy may vary depending on the cause. Tachycardia-induced cardiomyopathy ranks among forms of dilated cardiomyopathy with (if treated appropriately) generally good prognoses. Although studies describing recovery of patients with tachycardiainduced cardiomyopathy after sinus rhythm restoration or rate control include only small samples of patients, it appears that these causal therapeutic options may result in an improve‐ ment of left-ventricular function, positive change in neurohumoral cascade (reduced levels of natriuretic peptides) [26] and that it is likely to be linked to a generally good prognosis of

ventricular function in up to 97% [16].

78 Abnormal Heart Rhythms

reversible after catheter ablation [17-20].

tachycardia-induced cardiomyopathy.

Our current knowledge about the pathogenesis of tachycardia-induced cardiomyopathy is predominantly based on animal models that have been introduced to study heart failure [30-35]. In these experiments, heart failure is induced by rapid cardiac pacing of certain duration, at the atrial and/or ventricular level. Hemodynamic changes that result from such pacing strongly resemble findings in humans [31-35]. Similar abnormalities have been also identified in animals with "only" ventricular premature beats delivered artificially in bigemi‐ nal pattern, and these changes are reminiscent of those in humans as well [36]. Observations proving that all these alterations are fully or at least partially reversible with cessation of tachycardia also correspond with results found in humans [32, 37].

**Figure 1.** Tachycardia-induced cardiomyopathy in a 38-years old male with no previous history of any heart disease or arrhythmia. First episode of persistent atrial fibrillation with rapid heart rate (1a, 1b) in his life caused progressive de‐ terioration of ventricular systolic function leading to clinical manifestation of heart failure during 4 weeks. 1c shows significantly reduced ejection fraction of the left ventricle with its incipient enlargement during the tachycardia. Both heart failure symptoms and left-ventricular systolic function rapidly improved during the following 3 weeks after si‐ nus rhythm restoration (2a). Size and systolic function of the left ventricle then almost normalized in the horizon of 3 months after the tachycardia termination (2b).

#### **3.1. Hemodynamic changes**

Rapid atrial or ventricular pacing in experimental models leads to biventricular systolic and diastolic dysfunctions that occur relatively early after the onset of tachycardia [38, 39]. Typical findings include reduced systolic function of both ventricles reaching up to 55%, decline in cardiac output, elevation of ventricular filling pressures, systemic vascular resistance as well as ventricular systolic wall stress [33-35, 40, 41]. Systolic ventricular dysfunction is caused by the loss of contractility. In addition, contractile reserve in response to volume, inotropic agents or post-extrasystolic potentiation is affected [42, 43] and myocardial relaxation is impaired [44]. As a consequence of altered hemodynamic situation, mitral regurgitation may develop in longer-term perspective that leads to volume overload of the failing heart [45].

#### **3.2. Structural changes**

Persistent tachycardia, either induced artificially by chronic cardiac pacing or resulting from persistent tachyarrhythmia, finally leads to the dilatation of all cardiac chambers. Left ventricle increases both its end-systolic and end-diastolic volume (with end-systolic volume being affected more [33, 34]) and it further changes its geometry to a spherical shape [46]. This dilatation is usually associated with wall thinning or preservation of wall thickness without either increased heart weight or hypertrophy [45, 46].

On microscopical level, remodeling of both cardiomyocytes and extracellular matrix may be detected: disruptions of sarcolemma-basement membrane interface, myofibrillar misalign‐ ment, cellular elongation and myocyte loss (up to 39% of the total myocyte mass) have been found [40, 47, 48]. Architecture of the extracellular matrix is usually remarkably modified as well and this also contributes to myocyte misalignment and adversely affects force coupling and transmission.

In addition to functional and structural changes, electrophysiologic remodeling has been documented. Abnormal functioning of calcium channels, stretch-sensitive channel dysfunc‐ tion and other abnormalities often affect and prolong repolarization that can finally result in ventricular tachycardias manifestation [49].

#### **3.3. Neurohumoral changes**

Similar to other forms of heart failure, marked neurohumoral activation occurs and leads to elevated plasma levels of natriuretic peptides, epinephrine, norepinephrine, aldosterone and renin activity [39]. Downregulation of beta-1 receptor density with the resulting decrease in beta-adrenergic responsiveness have been found as well [50, 51].

All the above-mentioned hemodynamic, structural and neurohumoral changes have been demonstrated also in humans, which supports the conclusion that pacing-induced model of heart failure could be a useful tool to study pathogenesis of tachycardia-induced cardiomyopathy.

#### **3.4. Pathophysiology of tachycardia-induced cardiomyopathy**

**3.1. Hemodynamic changes**

80 Abnormal Heart Rhythms

**3.2. Structural changes**

and transmission.

cardiomyopathy.

Rapid atrial or ventricular pacing in experimental models leads to biventricular systolic and diastolic dysfunctions that occur relatively early after the onset of tachycardia [38, 39]. Typical findings include reduced systolic function of both ventricles reaching up to 55%, decline in cardiac output, elevation of ventricular filling pressures, systemic vascular resistance as well as ventricular systolic wall stress [33-35, 40, 41]. Systolic ventricular dysfunction is caused by the loss of contractility. In addition, contractile reserve in response to volume, inotropic agents or post-extrasystolic potentiation is affected [42, 43] and myocardial relaxation is impaired [44]. As a consequence of altered hemodynamic situation, mitral regurgitation may develop in

Persistent tachycardia, either induced artificially by chronic cardiac pacing or resulting from persistent tachyarrhythmia, finally leads to the dilatation of all cardiac chambers. Left ventricle increases both its end-systolic and end-diastolic volume (with end-systolic volume being affected more [33, 34]) and it further changes its geometry to a spherical shape [46]. This dilatation is usually associated with wall thinning or preservation of wall thickness without

On microscopical level, remodeling of both cardiomyocytes and extracellular matrix may be detected: disruptions of sarcolemma-basement membrane interface, myofibrillar misalign‐ ment, cellular elongation and myocyte loss (up to 39% of the total myocyte mass) have been found [40, 47, 48]. Architecture of the extracellular matrix is usually remarkably modified as well and this also contributes to myocyte misalignment and adversely affects force coupling

In addition to functional and structural changes, electrophysiologic remodeling has been documented. Abnormal functioning of calcium channels, stretch-sensitive channel dysfunc‐ tion and other abnormalities often affect and prolong repolarization that can finally result in

Similar to other forms of heart failure, marked neurohumoral activation occurs and leads to elevated plasma levels of natriuretic peptides, epinephrine, norepinephrine, aldosterone and renin activity [39]. Downregulation of beta-1 receptor density with the resulting decrease in

All the above-mentioned hemodynamic, structural and neurohumoral changes have been demonstrated also in humans, which supports the conclusion that pacing-induced model of heart failure could be a useful tool to study pathogenesis of tachycardia-induced

longer-term perspective that leads to volume overload of the failing heart [45].

either increased heart weight or hypertrophy [45, 46].

ventricular tachycardias manifestation [49].

beta-adrenergic responsiveness have been found as well [50, 51].

**3.3. Neurohumoral changes**

The development of tachycardia-induced myocardial dysfunction appears to be a result of multiple factors. Various alternations of neurohumoral and cellular activation have been identified; however, it is still uncertain whether they represent the causal factor of the functional and subsequent structural changes in all cases, or whether they are rather a consequence of tachycardia. Although the precise mechanism behind contractile dysfunc‐ tion with the resulting structural changes is not fully understood yet, the research has focused mainly on three potential factors: *1) depletion of high-energy stores in the myocardi‐ um with impaired energy utilization, 2) myocardial ischemia and 3) abnormality in calcium handling*.

On subcellular level, persistent tachycardia leads to energy-stores depletion, which is associated with the reduction of adenosin-triphosphate (ATP), phosphocreatinine and creatinine levels in the myocardium. In addition, a reduced activity of the Na/K-ATPase pump has been described [52, 53a, 53b]. It is very likely due to enhanced activity of Krebs cycle oxidative enzymes and mitochondrial injury [40, 41].

Similar findings have been described in the case of myocardial ischemia. In the ischemic model, rapid depletion of energy-stores and left-ventricular dysfunction occur shortly after vessel occlusion [54]. However, their return to normal values lasts mostly about days long after the ischemic attack, which also corresponds with findings in tachycardia-induced cardiomyop‐ athy where altered hemodynamic and structural changes resolve in prolonged time interval. Proceeding from these facts, myocardial ischemia is considered to be a potential factor that contributes to the tachycardia-induced cardiomyopathy development. In fact, abnormal coronary flow and changed ratios of subendocardial and subepicardial flow have been observed in tachycardia-induced cardiomyopathy [55, 56].

The hypothesis that abnormal handling of calcium plays a role in the genesis of tachycardiainduced cardiomyopathy has received substantial support, because the severity of calcium cycling abnormalities has been shown to correlate with the extent of ventricular dysfunction [41]. Abnormal calcium handling occurs already in the first 24 hours of rapid cardiac pacing and it may persist for more than 4 weeks after tachycardia termination [41]. Altered functions of calcium channels and transport system of the sarcoplasmatic reticulum have been identified [41, 57] and they may thus contribute to myocardial dysfunction observed in tachycardiainduced cardiomyopathy due to lower calcium availability to myocytes with the resulting contractility reduction. Some other studies suggest altered calcium-sensitivity and excitationcontraction coupling [57, 58].

An observation that tachycardia-induced cardiomyopathy does not evolve in every patient with the same type, duration and rate of a tachycardia implies *possible genetic predisposition* of some patients to develop a dilated cardiomyopathy pattern during tachycardia. In fact, one study [59] suggests that polymorphism in angiotensin-converting enzyme (ACE) gene may be involved, since one type of such polymorphism (which is associated with higher serum levels of ACE) is more frequently linked to idiopathic and ischemic cardiomyopathy manifestation. Looking at the prevalence of this polymorphism among 20 patients with tachycardia-induced cardiomyopathy as compared to another sample of 20 patients without this pattern, the authors reported a higher detection of this ACE polymorphism in the cardiomyopathic group [59].

#### **3.5. Course of the changes over time and their reversibility**

Experimental studies demonstrate that changes of hemodynamics with the reduction of cardiac output or altered systemic arterial pressure occur already in the first 24 hours of rapid pacing [32]. When continued, fast cardiac pacing then induces an elevation of ventricular filling pressures, pulmonary artery pressure and a decrease of systemic arterial pressure that reach certain plateau after one week, while cardiac output, volumes and ejection fraction deteriorate continually for 3–5 weeks with the final end-stage heart failure development [35, 45].

Cessation of tachycardia results in a resolution of these changes: in the first 48 hours after termination of cardiac pacing, a significant improvement of cardiac output, systemic vascular resistance, mean arterial pressure and filling pressures are present [39]. Left-ventricular ejection fraction also improves dramatically and normalizes within 1–2 weeks [39]. All hemodynamic variables normalize within the horizon of four weeks after tachycardia inter‐ ruption, but diastolic dysfunction remains detectable even after the first month period. Importantly, elevated end-diastolic and end-systolic volumes are still present after twelve weeks of pacing discontinuation, which is consistent with substantial ventricular remodeling [33, 46], that requires longer time for its resolution.

Although the hallmark of tachycardia-induced cardiomyopathy is an improvement or even normalization of cardiac function and size with the resulting disappearance of heart failure symptoms after cessation of tachycardia or rate control achievement, there is growing evidence that the ultrastructural abnormalities of the myocardium and residual contractility dysfunc‐ tion may persist. This has already been suggested in the experimental studies [53b], but similar conclusions have also been made in clinical observational reports [60, 61]. In one of these studies, ventricular function has been assessed using specle tracking and contrast-enhanced MRI with ventricular T1 mapping used as an index of diffuse fibrosis. Although the ejection fraction normalized three months after a successful ablation of initial tachycardia already, it has been possible to detect a somewhat greater indexed end-diastolic and end-systolic volume of the left ventricle in patients with tachycardia-induced cardiomyopathy as compared to healthy controls. Moreover, patients with previous tachycardia-induced cardiomyopathy have demonstrated reduced global left-ventricular corrected T1 time that implies a diffuse fibrosis [61]. In addition, another study [60] suggests that tachycardia tends to recur in some patients initially diagnosed with tachycardia-induced cardiomyopathy pattern and this recurrence of arrhythmia leads to a new decline of systolic ventricular function. Moreover, sudden death may occur in some of these patients despite normal or almost normal systolic function during the last evaluation [60].
