Reviews Premature Ventricular Contraction Induced Cardiomyopathy Address for correspondence: Aiman Smer, MBBCh 3006 Webster Street Omaha, NE 68131 aimansmer@creighton.edu Alok Saurav, MD; Aiman Smer, MBBCh; Ahmed Abuzaid, MBBCh; Ojas Bansal, MD; Hussam Abuissa, MD Cardiology Department, Creighton University Medical Center, Omaha, Nebraska Premature ventricular contractions are of common occurrence in routine clinical practice. Though generally perceived as of benign consequence in healthy people in the absence of heart disease, their presence can be a harbinger of fatal ventricular tachyarrhythmia in individuals with structural heart disease. With some of the latest insights into the treatment of ventricular tachyarrhythmia, especially with the advent of catheter ablation, there has been renewed interest in premature ventricular contractions, not only as a predictor of arrhythmia, but also for their potential etiological association with cardiomyopathy. Prevalence in Normal Population Premature ventricular contractions (PVCs) are commonly encountered in apparently healthy individuals with a reported incidence of approximately 1% on standard 12-lead electrocardiograms (ECG) and 40% to 75% on routine 24- hour to 48-hour Holter monitoring. In an early database of 122 043 clinically healthy males age 16 to 50 years, PVCs were recorded in 0.78% on a 48-second tracing of a 12-lead ECG. 1 Kostis et al studied the characteristics of PVCs on a 24-hour ambulatory ECG monitoring in healthy males and females, in whom any preexisting heart disease had been previously excluded by ECG, echocardiogram, stress test, left and right heart catheterization, and coronary angiogram. 2 They found that as many as 40% of the subjects had 1 PVC during the 24-hour monitoring period, only 5% of the subjects had >5 PVCs in any given hour, and 4% had >100 PVCs per 24 hours. They also showed that increased age is a risk factor for having frequent PVCs, even in the absence of coronary artery disease (CAD), whereas alcohol and caffeine use and hypokalemia did not increase the incidence of PVCs. Because the authors excluded patients with known PVCs or symptoms of palpitation even if they had otherwise-normal hearts, this could possibly account for the lower incidence rates of PVCs reported in this study as compared with others. 3 The authors have no funding, financial relationships, or conflicts of interest to disclose. Received: September 5, 2014 Accepted with revision: November 13, 2014 Premature Ventricular Contractions in the Absence of Heart Disease: Clinical Significance Although PVCs occur very commonly in healthy individuals, their long-term effect on survival in such a population without any heart disease is still uncertain, especially when the PVCs are frequent and complex in nature. Kennedy et al followed a cohort of apparently healthy subjects with frequent and complex PVCs, in whom heart disease had been excluded by noninvasive tests, for a mean period of 6.5 years. 4 Premature ventricular contractions were noticed at baseline on a 24-hour ambulatory recording with a mean frequency of 566 beats per hour per individual, out of which multiform beats occurred in 63% and ventricular couplets and ventricular tachycardia were seen in 60% and 26%, respectively. They found that the actual number of deaths at the end of follow-up was significantly lower than anticipated, even though severe CAD was demonstrated in 19% of the cases of a subgroup of this cohort who underwent coronary angiography. However, when compared with controls with known CAD of severity varying from mild to severe, this cohort showed favorable prognosis against all classes. This led to the general belief that PVCs, even when frequent and complex in nature, are usually inconsequential in healthy individuals. Similarly, it is generally believed that PVCs in children without structural heart disease are generally benign, especially if they disappear during exercise. Beaufort- Krol et al studied the natural history of PVCs in children with anatomically normal hearts. They classified the PVCs according to the site of origin. 5 They followed a cohort of 51 children with a mean duration of 3.1 ± 3.1 years 251 DOI:10.1002/clc.22371 2015 Wiley Periodicals, Inc.
Figure 1. A 12-lead ECG shows LBBB morphology PVCs with inferior axis in bigeminy pattern. Abbreviations: ECG, electrocardiogram; LBBB, left bundle branch block; PVCs, premature ventricular contractions. Figure 2. A 12-lead ECG shows RBBB morphology PVCs with superior axis in trigeminy pattern. Abbreviations: ECG, electrocardiogram; PVCs, premature ventricular contractions; RBBB, right bundle branch block. who were first examined at a mean age of 7.1 ± 4.3 years. Premature ventricular contractions with left bundle branch block pattern (PVC-LBBB) were seen in 41% of the children (Figure 1), those with a right bundle branch block pattern (PVC-RBBB) were seen in 36% (Figure 2), and the morphology was undetermined in 23%. It was observed that although the mean percentage PVC-LBBB did not change, PVC-RBBB decreased significantly at the end of follow-up. Another important observation was that PVCs tended to disappear in younger children more often than in older children, though this was not statistically significant when comparing the age group of 1 to 3 years and those age >16 years (P = 0.08). Although the authors did not recommend follow-up in children with PVC-RBBB in the absence of heart disease, they still thought those with PVC-LBBB needed to be seen every 2 to 3 years for 252
the development of left ventricular (LV) dysfunction. This is in the wake of recent data showing association between PVCs of right ventricular outflow tract (RVOT) origin and development of LV dysfunction. 6 In contrast, Gaita and colleagues followed 61 patients with PVC-LBBB for 15 ± 2 years and found out that there was no increase in the incidence of sudden cardiac death (SCD) or arrhythmogenic right ventricular dysplasia (ARVD) among their subjects. 7 Premature Ventricular Contractions and Risk of Disease Despite PVCs being considered as benign in the absence of structural heart disease, some of the recent data on PVCs casts serious doubt on this hitherto-perceived notion. Although the majority of the recent studies focus on the role of PVCs in causing cardiomyopathy, other disease associations such as CAD, stroke, and SCD are worth mentioning. The prospective Atherosclerosis Risk In Communities (ARIC) study demonstrated that PVCs were present in 6.2% of the subjects at baseline. 8 This was associated with an increased risk of stroke, especially in the subgroups of subjects without traditional risk factors for stroke (eg, diabetes and hypertension). Whereas the latter occurred in 4.9% of all subjects, the cumulative proportion of incident stroke in individuals with PVCs was 7.3%, compared with 4.8% in those without PVCs. Another interesting observation in this study was the demonstration of association between PVCs and embolic stroke, as thrombotic stroke occurred with equal frequency irrespective of the presence of PVCs. The increased incidence of embolic stroke underscores the possible association between PVCs and atrial fibrillation, as previously cited by other studies. 9 In the same ARIC study, Massing et al found that PVCs increased the risk of cardiovascular-event rates independent of the presence of CAD at baseline. 10 The presence of PVCs on a 2-minute rhythm strip at baseline was associated with 3 increased risk of mortality (7.8% vs 2.1%; P < 0.05) from CAD in this study, compared with those without PVCs. The event rate still remained as high as 2 after adjusting for age, sex, and other risk factors using proportional hazards regression. An important implication of this observation is that regardless of whether PVCs inherently increase mortality, their presence certainly incurs a higher cardiovascular risk, which should be at least managed by aggressive modification of traditional risk factors. Cheriyath et al studied the association of atrial premature contractions (APCs) and PVCs and risk of SCD in the ARIC cohort. 11 They found that PVCs were in fact associated with an increased risk of SCD with a hazard ratio of 2.1, whereas APCs did not show any significant association. They also could demonstrate an increased incidence of CAD and fatal CAD in association with PVCs, as already reported by previous investigators. The exact mechanism responsible for SCD in patients with PVCs is still not well understood; however, a large PVC burden, LV dysfunction, short coupling interval with R-on-T phenomena, increased automaticity, as well as sympathetic overdrive are potential substrates for more malignant ventricular arrhythmias. 12,13 Premature Ventricular Contractions and Cardiomyopathy: Cause or Effect Similar to other structural diseases of the heart, cardiomyopathies, which primarily affect the heart muscle, are also associated with increased incidence of PVCs. This is corroborated by the fact that not only PVCs, but also nonsustained ventricular tachycardias (NSVTs) and ventricular tachycardias (VTs), which share a similar pathophysiologic substrate, are commonly seen in the presence of cardiomyopathy. It is also frequently observed that the incidence of PVCs, NSVTs, and VTs is further increased by progression of cardiomyopathy characterized by falling left ventricular ejection fraction (LVEF) and increasing end-diastolic dimensions. However, to prove the causality of association between PVCs and cardiomyopathy, one also must unequivocally demonstrate the following: significant association, isolation of effect, temporal sequencing, dose response relationship, and reversal after modification. In one of the earliest studies to suppress PVCs in patients with depressed LV function, Hohnloser et al used sotalol, a class III antiarrhythmic agent, which effectively suppressed PVCs in 63% of the patients by >75% as demonstrated during ambulatory monitoring. 14 Contrary to the concern about β- blockers causing further depression of LV function at that time, sotalol improved the LVEF by a small yet significant 2% (P < 0.05) from baseline, and the effect persisted until at least 6 months into follow-up. In another randomized trial, amiodarone, also a class III antiarrhythmic agent, significantly reduced the occurrence of PVCs and improved the LVEF by 42% in heart failure patients with LVEF <40% and frequent PVCs (>10 PVCs/h at baseline) at 2-year follow-up compared with placebo, though this effect did not translate into any benefit in terms of survival or prevention of sudden death. 15 However, these 2 studies provided the earliest indication that suppression of PVCs might improve LV function. In a retrospective analysis of Holter data, Duffee et al identified 14 patients with reduced LVEF 40% who had >20 000 PVCs in 24 hours. 16 Only half of them received additional therapy with and without amiodarone to suppress the PVCs. Five patients achieved 75% suppression of the PVCs at 1 year follow-up. In terms of outcome, there was improvement in the LVEF from 27% ± 10% to 49% ± 17% (P = 0.04) in 4 patients with idiopathic cardiomyopathy. This finding supports the causality relationship between PVCs and cardiomyopathy. This led the authors to reclassify these 4 cases as PVC cardiomyopathy. Massie et al looked at the correlation between improvement in LVEF with amiodarone with the clinical improvement in signs, symptoms, and hospitalization due to heart failure in the double-blind, placebo-controlled Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT). 17 They found that despite significant improvement in LVEF compared with placebo, amiodarone did not lead to any significant improvement in symptoms, signs, diuretic requirement, or hospitalization rates from heart failure, though there was a significant improvement in the combined outcome of hospitalization and death in the subgroup with nonischemic cardiomyopathy (P = 0.01). Because of the potential reversibility of PVC cardiomyopathy and improvement in LV function and dimensions after 253
suppression therapy, it is reasonable to consider β-blockers with or without antiarrhythmics in such patients. However, long-term outcome and effect on mortality have not been established yet, and further studies are needed. Morphology and Site of Origin Del Caprio et al studied the morphological characteristics of PVCs in relation to their association with LV dysfunction in a retrospective analysis of 70 consecutive patients (mean age, 42 years) who underwent ablation of PVCs for frequent symptoms. 18 They showed that the presence of LV dysfunction (LVEF <50% on echocardiography) was associated with not only higher prevalence of PVCs (29.3% ± 14.6% vs 16.7% ± 13.7%; P = 0.004) and NSVT runs (76% vs 40%; P = 0.01), but also with a longer QRS duration of the PVCs (154.3 ± 22.9 ms vs 145.6 ± 20.8 ms; P = 0.03) and higher occurrence of multiform PVCs (88% vs 58%; P = 0.04). However, there was no significant difference as far as the QRS duration of the normal beats, coupling interval of the PVCs, intrinsicoid deflection, nor prevalence of sustained VTs. As far as the anatomical location of the origin of the PVCs was concerned, fascicular PVCs were more likely associated with normal LV function (LVEF >50%) than PVCs from other locations. Although there was no relation between the RBBB or LBBB morphology of PVCs with regard to the LV dysfunction, the threshold of PVC burden was lower with the former. Postablation, the LVEF improved significantly in both normal and low- LVEF groups, though it was more pronounced in the latter (2.8% ± 1.1% vs 9.5% ± 3.4%; P < 0.02). On the other hand, a recent study by Nucifora et al demonstrated that cardiac magnetic resonance imaging (cmri) has a potential prognostic value in the evaluation of patients with apparently idiopathic ventricular arrhythmias of LV origin compared with right ventricular (RV) origin. 19 A total of 120 consecutive patients with monomorphic ventricular arrhythmias (ie, frequent PVCs >1000 per 24 hours, NSVT, or sustained ventricular tachycardia) and negative routine diagnostic workup underwent cmri. Forty-six patients (65% males; mean age, 44 ± 15 years) with LV-origin ventricular arrhythmias and 74 patients (60% males; mean age, 40 ± 17years) with RV-origin ventricular arrhythmias had a cmri study and were followed up for a median of 14 months (range, 7 37 months). There was no significant difference between the 2 groups in terms of biventricular volumes and systolic function. However, cmri revealed subtle myocardial structural abnormalities (eg, myocardial fatty replacement, edema, and necrosis/fibrosis) in 19 (41%) patients with LV-origin ventricular arrhythmias vs 4 (5%) patients with RV-origin ventricular arrhythmias (P < 0.001). The outcome events of SCD, nonfatal ventricular fibrillation, or appropriate implantable cardioverter-defibrillator therapy occurred in 9 patients with LV-origin ventricular arrhythmias and positive cmri findings. This study highlights the importance of cmri in the routine diagnostic workup of patients with apparently idiopathic LV-origin ventricular arrhythmias. In addition to the prognostic implications, cmri provides better identification of the ventricular arrhythmia substrate. This could influence the remodeling effects of antiarrhythmic therapy and ablation strategies. Furthermore, cmri is extremely useful in identifying many underlying structural heart diseases, such as ARVD/cardiomyopathy, sarcoidosis, scar, and myocarditis, that could be potential causes of ventricular arrhythmias. 20 Right Ventricular Origin The RVOT is a common source of VTs in structurally normal heart associated with a LBBB morphology and inferior axis. There are several reports of reversible tachycardiainduced cardiomyopathy associated with RVOT-VT that responds well to radiofrequency ablation (RFA) with complete recovery of the LV function. Premature ventricular contractions originating from RVOT can be expected to cause impairment of LV function, and this has been shown by various investigators in individual series and case reports. In fact, most of the reported cases of successful recovery of LV function following ablation of PVCs are related to the RVOT-PVCs. Apart from the critical burden of the PVCs as reported by some, the site of origin from the RVOT itself might be predisposing to cardiomyopathy by reversing the activation sequence of the LV. 21 Interpolated Premature Ventricular Contractions Olgun et al studied the association of interpolation with cardiomyopathy in a retrospective analysis of 51 patients (mean age, 48 years) with frequent PVCs. 22 They found that patients with cardiomyopathy (LVEF <50%) had a significantly higher prevalence of interpolated PVCs (Figure 3) compared with those with normal LVEF (67% vs 20%; P < 0.01). Although patients with interpolated PVCs had a higher total PVC burden (28% ± 12% vs 15 ± 15%; P < 0.002), the presence of interpolation in these patients was strongly correlated and predictive of PVC cardiomyopathy (21% ± 30% vs 4% ± 13%; P < 0.008) over the PVC burden alone. Burden of Premature Ventricular Contractions Is there a critical burden of PVCs that would result in cardiomyopathy? In a series of 174 consecutive patients (mean age, 48 years) referred for catheter ablation for frequent symptomatic PVCs in whom the PVC burden was determined by 24-hour Holter monitoring, Baman et al found that approximately one-third had reduced LVEF (<50% defined per study criteria). 23 When compared with those with normal LVEF (>50%), the low-lvef subgroup was associated with a significantly higher prevalence of PVCs on 24-hour monitoring (33% ± 13% vs 13% ± 12%; P < 0.0001). When the receiver operating characteristic curve was constructed based on the PVC burden with relation to presence or absence of LV dysfunction, it was found that a critical amount of >24% PVCs in 24 hours was independently associated with cardiomyopathy, with a sensitivity and specificity of approximately 80% (sensitivity 79%, specificity 78%, area under curve: 0.89). Although there was a significant improvement in the LVEF after successful ablation (determined by elimination of >80% of PVCs), no definite association between site of origin (LV, RV, or RVOT) or multiform nature of PVCs and the reduced LVEF 254
Figure 3. A 12-lead ECG shows sinus rhythm with interpolated PVCs in trigeminy pattern. Note that there is no compensatory pause after the interpolated PVCs. Abbreviations: ECG, electrocardiogram; PVCs, premature ventricular contractions. could be demonstrated in this study as described previously. In another series of 40 patients who underwent ablation for symptomatic RVOT-PVC, Takemoto et al analyzed the result of ablation with relation to 3 prespecified subgroups (<10%, 10% 20%, >20%) based on the burden of PVCs on 24-hour Holter monitoring. 21 They found that, compared with the other 2 subgroups, the subgroup with >20% of PVCs at baseline had the most benefit from ablation, with significant improvement in LVEF and LV dimensions. When the PVC burden was expressed in the tertiles of the absolute number of PVCs before RFA, the subgroup with >20 000 PVCs per day was shown to be associated with highest risk of LV dysfunction and heart failure. However, it is to be noted that 24-hour monitoring may not be a true measure of the actual burden of PVCs, and as little as 4% of PVCs in 24 hours has been shown to be associated with LV dysfunction and consequent improvement following ablation in individual case reports. 24 Probably a more prolonged monitoring of 48 hours or more is needed to determine the true burden of PVCs. Duration of Premature Ventricular Contractions The relationship of duration of symptoms from PVCs to development of cardiomyopathy was studied by Yokokawa et al in a retrospective analysis of 241 patients who underwent ablation therapy for frequent PVCs. 25 They found that patients with cardiomyopathy (LVEF <50%) not only had a significantly higher PVC burden (28% ± 12% vs 15% ± 13%; P < 0.0001), but also a significantly longer duration of symptoms (135 ± 118 months vs 35 ± 52 months; P < 0.0001) compared with patients with PVCs in the presence of normal LV systolic function (LVEF >50%). In multivariate analysis, symptom duration of 30 to 60 months, >60 months, absence of symptoms, and the PVC burden in asymptomatic patients were found to be independent predictors of impaired LV function. Because asymptomatic patients are at risk for lack of knowledge of exact time of onset of PVCs, they should probably be followed more frequently through regular echocardiograms for the early detection of LV dysfunction. This observation contradicts the previously held notion of the benign nature of PVCs in asymptomatic individuals, though the study is limited by its nonrandomized nature. Mechanism of Disease Even though the exact mechanism of development of cardiomyopathy from PVCs is hitherto unknown, there are several postulations (eg, tachycardia-induced cardiomyopathy [TIC]-like mechanism, electromechanical dyssynchrony, extrasystolic potentiation, interpolation, R-R variability, remodeling of the myocardium from shortcoupled PVCs). As TIC, the most commonly hypothesized mechanism for PVC cardiomyopathy, is by itself an established clinical entity, there is ample evidence to support that elimination of the tachycardia leads to improvement in the LV function. Sustained tachycardia from any cause leads to a state of myocardial stunning by various alterations in the cellular subcellular level such as Na + -K + -ATPase activity, action potential, myocardial calcium handling, receptor downregulation, and oxidative stress. 26,27 However, despite improvement in LVEF following elimination of tachycardia, some of the echocardiographic parameters, such as LV end-systolic and diastolic dimensions, may persist for a longer period due to persistent negative remodeling from heightened neurohormonal activity and receptor downregulation. 28 255
Premature ventricular contractions also result in a form of electromechanical dyssynchrony by causing a sequential instead of normal parallel activation of the myocardium. We know from the pacemaker trials that chronic RV pacing is associated with subsequent impairment of LV function. Premature ventricular contractions, especially with LBBB morphology, which cause inhomogeneous contraction of the septum and the posterior wall of the LV, can be expected to cause impairment of LVEF on the basis of a similar electromechanical phenomenon. In a randomized animalmodel study, PVCs were induced by pacing in mongrel dogs over a period of 12 weeks. At the end of the study period, paced animals (n = 7) had a significant deterioration of their LV function (39.7% ± 5.4% vs 60.7% ± 3.8%, P < 0.0001) compared with the control group (n = 6), and the LV function recovered completely over a 2-week to 4-week period after the pacing was stopped. 29 An important finding was that paced dogs lacked the typical histological features including inflammation, fibrosis, apoptosis, and mitochondrial abnormalities of cardiomyopathies. As discussed earlier, the PVC QRS duration remains the most independent predictor for the development of PVC-induced cardiomyopathy. This fact best supports the concept that PVC QRS duration reflects subtle underlying myocardial substrate abnormalities that may lead to LV dysfunction. It has been also shown that PVC QRS duration can be used as an accurate measurement of the degree of cell-tocell electrical uncoupling, which precedes the development of cardiomyopathy. 30 In addition, Deyell et al proposed that PVC QRS duration is a manifestation of the degree of myofibril disarray and myocardial fibrosis, which are common histopathological findings in idiopathic cardiomyopathy. 31 The same group showed that PVC QRS duration at the time of ablation was associated with the reversibility of PVC-induced cardiomyopathy. A wider PVC QRS duration was associated with increased myocardial substrate abnormalities and a lower chance for recovery of cardiomyopathy following ablation. It is likely that ventricular remodeling is due to a repetitive abnormal electromechanical activation pattern in the context of subtle abnormal myocardial substrates, as elucidated by wider PVC QRS duration and histopathological as well as cmri findings, which could predispose certain patients to develop cardiomyopathy. On the other hand, interpolated PVCs, as discussed earlier, are associated with cardiomyopathy independent of increasing PVC burden. Interpolated PVCs have a longer ventriculoatrial block cycle length compared with PVCs without interpolation. The exact mechanism by which interpolation produces cardiomyopathy is unknown. Although the total PVC burden increased with interpolation, TIC-like phenomenon was unlikely in the study by Olgun et al. 22 Treatment Options As it appears from the above discussion, PVCs, when present in certain quantity and duration, can lead to impairment of LV function and can either be suppressed by use of medications or eliminated by use of RFA. Though these strategies differ in their ability to suppress PVCs and thereby improve the LV dysfunction, their effect has not translated into improvement in survival, as evidenced by the current data. Medical Therapy Typically, in mildly symptomatic patients without structural heart disease, a trial of β-blockers or a nondihydropyridine calcium channel blocker should be considered as first-line therapy. 32 Class Ic and III antiarrhythmic agents such as flecainide and sotalol are more effective than β-blockers and calcium channel blockers in suppression of PVC burden. 14,33 For instance, Capacci et al demonstrated that 91% of patients on flecainide achieved >70% reduction of PVC burden. 34 Nevertheless, these agents, with the exception of amiodarone, should not be used in patients with structural heart disease. 15,35,36 Catheter Ablation Since the first report of improvement of cardiomyopathy following successful ablation of PVCs by Chugh et al, radiofrequency catheter ablation has been increasingly used in preference to medical therapy for treatment of PVCs. 37 Despite the growing evidence in favor of ablation therapy for PVCs, especially in the presence of LV dysfunction, its utility remains conjectural in the absence of any mortality data. There have been multiple studies demonstrating high efficacy of catheter ablation of PVCs, with success rates ranging from 80% to 100%. 38 41 However, most of these studies have typically included very symptomatic patients with a high burden of PVCs. It is also not clear as yet when to intervene in those individuals with a significant burden of PVCs in the presence of a normal LVEF. In addition, procedural success may be dependent on the site of origin, with lower efficacy for epicardial foci than other sites, multiple PVC morphologies, or inability to induce the clinical PVC at the time of the procedure. 42 In a large cohort of contemporary catheter ablations, the major-complication rate of PVC ablation was 3.4%. 43 As mentioned before, although the majority of the data on the ablation of PVCs accompanied by impairment of LV function pertains to the RVOT origin of the ectopic beats, similar efficacy has also been demonstrated for non-rvot site of origin as well. 44 In the study by Kim et al, there was a similar improvement in LVEF and end-diastolic volume index irrespective of the site of origin of PVCs, although RVOT-PVCs far outnumbered non RVOT-PVCs. 45 Bogun et al compared a cohort of patients with LV dysfunction associated with both RVOT and non RVOT-PVCs who underwent catheter ablation with a group of controls who remained on conservative treatment and found that although 82% of the patients in the ablation group improved their LVEF at 6 months of follow-up, there was no improvement noticed in the control group. 46 However, it is to be remembered that although ablation therapy in appropriate cases significantly improves the pump function, the risks of this invasive approach have to be kept in mind. Conclusion Premature ventricular contraction cardiomyopathy is an emerging clinical entity and warrants further research to elucidate its importance. Not all individuals with PVCs develop cardiomyopathy, nor do they respond equally to various therapies. The question also remains whether it is justifiable to treat PVCs in the absence of any data on survival 256
when it is unclear whom and when to treat. Future research defining actual PVC burden in terms of quantity and duration leading to cardiomyopathy will help delineate optimal timing of initiation therapy, especially in asymptomatic individuals and those with normal LV systolic function. Moreover, it is also imperative to know whether there is any other structural or genetic predisposition underlying the development of PVC-induced cardiomyopathy, and also the role of any currently available therapy in modifying the natural history of this disease entity. Until more data are generated, preferably through randomized trials, treatment of PVCs should be individualized based on the clinician s own judgment of the case. References 1. Hiss RG, Lamb LE. Electrocardiographic findings in 122 043 individuals. Circulation. 1962;25:947 961. 2. Kostis JB, McCrone K, Moreyra AE, et al. Premature ventricular complexes in the absence of identifiable heart disease. Circulation. 1981;63:1351 1356. 3. 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