Published in Heart Rhythm
The official Journal of the Heart Rhythm Society
April 2015 Volume 12, Issue 4, Pages 714–715
by David J. Callans, MD, FHRS
Andrew E. Epstein, MD, FHRS
Cardiovascular Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
Published Online: December 26, 2014
Using a healthy degree of editorial license, we wanted to set the scene for the excellent study by El Kadri et al1 in this issue of HeartRhythm by reflecting on how much we have learned about premature ventricular complexes (PVCs) in the span of 5 decades or so. PVCs were first considered a harbinger of risk in patients with structural heart disease. This was largely informed by the initial observations in the critical care unit caring for patients early after myocardial infarction. The association between PVCs and increased risk of sudden death in ambulatory patients was demonstrated in an analysis from the Tecumseh Study. Patients with PVCs had a 6-fold increase in sudden death over a follow-up period of 6 years.2 Reports by Bigger et al3 for the Multicenter Post Infarction Research Group clearly demonstrated that in patients convalescing from acute infarction, a high burden of PVCs (>3 per hour) as well as reduced ejection fraction was associated with an increased risk of total mortality and death caused by arrhythmia. The PVC hypothesis—that frequent PVCs served as the trigger that launched life-threatening ventricular arrhythmias and that successful antiarrhythmic drug treatment would reduce risk—was tested in the Cardiac Arrhythmia Suppression Trial (CAST) and soundly refuted.4 Furthermore, the Electrophysiologic Study versus Electrocardiographic Monitoring (ESVEM) study, among other findings, further dissociated PVC burden and specifically successful treatment of PVCs with antiarrhythmic drugs from subsequent risk of sustained ventricular arrhythmias.5 These disappointing results turned focus away from PVC burden as a risk factor for poor outcome in patients with structural heart disease.
Interest in PVCs was reawakened by initial case reports6 followed by an initial clinical series of patients without preexisting heart disease who had frequent PVCs and potentially reversible left ventricular (LV) dysfunction. Yarlagadda et al7 studied 27 patients with “repetitive monomorphic ventricular ectopy” who were referred for catheter ablation. Their study demonstrated several important findings: (1) successful ablation (achieved in 7/8 patients with LV dysfunction) resulted in dramatic improvement in LV function; (2) LV dysfunction was observed with as few as 5500 PVCs per day; and (3) there was no difference in PVC burden between patients with and those without LV dysfunction.
Important studies attempting to more completely characterize this syndrome followed. The causality and response to treatment were validated by comparison with untreated controls.8 Originally, PVC-related myopathy was considered tachycardia-related cardiomyopathy. Subsequent studies have not arrived at an accurate mechanism, although dyssynchrony and even bradycardia-dependent hypotheses have been offered. Considerable effort was expended trying to determine the “dose” of PVCs required to cause cardiomyopathy. Work by the Michigan group was important in establishing a typical “threshold” dose of 20% in patients without preexisting heart disease.9 Nonetheless, as presaged by the original Cornell experience, there is considerable variability in susceptibility to PVC-related myopathy. In fact, referral bias aside, it seems as though most patients without structural heart disease who have frequent PVCs will not develop cardiomyopathy, although serial monitoring is still recommended.10 The key characteristics of those who develop myopathy include frequent PVCs and lack of symptoms related to PVCs (implying some effect of duration). Although not fully characterized in the literature, it was clear that PVCs that caused myopathy were idiopathic in mechanism and in location, that is, they arose from typical sites, particularly the right ventricular outflow tract and the sinuses of Valsalva, associated with sites of origin with normal bipolar voltage.
Closer to the present, focus again turned to the effect of frequent PVCs in patients with established heart disease. Sarrazin et al11 studied a group of 30 patients with remote myocardial infarction and LV dysfunction, 15 with a high burden of PVC (>5%) and 15 without. All 15 patients with frequent PVCs had successful ablation procedures, resulting in a reduction of PVC burden and improvement in LV function (0.38 ± 0.11 to 0.51 ± 0.09); no improvement was observed in the control group. Although the authors state that PVCs were ablated from areas of voltage map defined scar in 13 of 15 patients, many of these PVCs arose from sites associated with idiopathic mechanisms (aortic cusps, which are not associated with infarction; papillary muscles, which often are spared). Mountantonakis et al12 evaluated the effects of catheter ablation on 69 patients with cardiomyopathy and frequent outflow tract PVCs (mean 29 ± 13%). Twenty of these patients had a history of cardiomyopathy that preexisted the development of PVCs. In these 20 patients, successful ablation resulted in significant improvement in LV function, but less dramatic than that observed in patients with “pure” PVC-related myopathy. After these studies, the message was still fairly clear: even patients with structural heart disease who have “idiopathic looking” PVCs may benefit from ablation.
El Kadri et al1 add an important new dimension to this discussion. They studied a series of 30 consecutive patients with frequent PVCs (>5%) and unrelated nonischemic cardiomyopathy, as evidenced by the presence of scar on delayed gadolinium enhancement imaging (26 patients) or documented LV dysfunction before the diagnosis of frequent PVCs (4 patients). Magnetic resonance imaging demonstrated intramural scar in 50% of patients, endocardial or transmural scar in 37%, and multifocal scar distribution in 2%. Compared to previous studies, this population was more likely to have pleomorphic PVCs (18 patients, this finding negatively affected success) and multiple PVC morphologies. Ablation was successful in 18 patients; in these patients a secure site of origin could be established. Imaging data were available for 16 of these patients. Magnetic resonance imaging and voltage map–defined scar was present at the site of origin in 12 patients. The most frequent cause of ablation failure was an intramural site of origin. In 10 of 18 patients with successful procedures, the ejection fraction normalized (pre/post ejection fraction: 39% ± 7%/55% ± 3%). The authors conclude that in patients with frequent PVCs and preexisting nonischemic cardiomyopathy, LV function can be improved by successful ablation and that the arrhythmogenic substrate in this clinical setting often involves scar tissue.