By Joshua Moss, MD

Associate Professor of Clinical Medicine, Cardiac Electrophysiology, Division of Cardiology, University of California, San Francisco

Dr. Moss reports he is a consultant for Abbott, Boston Scientific, and Medtronic.

SYNOPSIS: Premature ventricular contraction-induced cardiomyopathy was phenotypically different than a tachycardia-mediated cardiomyopathy in a swine model. Paced ventricular bigeminy led to left ventricular (LV) dyssynchrony, a decline in LV ejection fraction associated with biventricular myocardial fibrosis, and a widening of the sinus QRS.

SOURCE: Walters TE, Rahmutula D, Szilagyi J, et al. Left ventricular dyssynchrony predicts the cardiomyopathy associated with premature ventricular contractions. J Am Coll Cardiol 2018;72:2870-2882.

Frequent premature ventricular contractions (PVCs) can lead to the development of a cardiomyopathy in some patients. Elimination of PVCs can facilitate recovery of left ventricular (LV) function. The pathophysiology of this finding remains unclear. Additionally, in asymptomatic patients with frequent PVCs, it is difficult to predict who is likely to develop a cardiomyopathy and who should be considered for prophylactic PVC elimination.

Walters et al sought to create a swine model to explore PVC-mediated cardiomyopathy and prospectively evaluate the association between LV dyssynchrony during ectopic beats with development of cardiomyopathy. Phase 1 of the study was aimed at assessing the effects of ventricular pacing on the development of cardiomyopathy by exposing animals to 14 weeks of paced bigeminy from the RV apex (n = 10 swine), continuous pacing at 140 beats/minute from the RV apex (n = 5), or sham pacing (n = 5). In Phase 2, the ventricles were paced from various locations to determine the association of resultant degrees of LV dyssynchrony with development of cardiomyopathy. Paced bigeminal PVCs were delivered from the RV free wall (n = 5) or LV epicardial free wall (n = 5). In five additional animals, paced atrial bigeminy was delivered as a control. Biweekly transthoracic echocardiograms were performed on all animals, followed by a hemodynamic study (Phase 2 only) to further assess LV dyssynchrony prior to histological and molecular analysis.

During Phase 1, there was a significant decline in mean LVEF after 14 weeks in both paced groups compared to sham pacing. The irregular pacing of the bigeminal PVC group was associated with a greater decline in LVEF than continuous tachycardia pacing (68% to 45% vs. 70% to 55%). A molecular analysis showed significant differences in levels of various cellular calcium-handling proteins in the paced PVC group compared with control animals. These protein levels did not differ significantly between control animals and the tachycardia group.

After Phase 2, with pacing from various ventricular sites, there was a significantly greater reduction in LVEF after 12 weeks of paced PVCs from the LV epicardial free wall (65% to 40%) compared with paced PVCs from the RV free wall (66% to 49%). Similar patterns were observed for between-group divergence in the LV chamber dimensions, calculated fractional shortening, and sinus QRS duration. A histological analysis showed significant myocardial fibrosis in both paced PVC groups compared to control animals, with the highest extent of fibrosis in the LV epicardial free wall PVC group. There were no statistically significant differences in measured calcium-handling protein levels between the two paced groups. A univariate analysis showed that longer ectopic beat QRS duration and greater ectopic beat dyssynchrony were significantly associated with larger declines in LVEF over the 12-week study period. The authors concluded that in a swine model, PVC-induced cardiomyopathy is phenotypically distinct from a tachycardia-induced cardiomyopathy and is strongly related to the extent of LV dyssynchrony.

COMMENTARY

This study revealed numerous important findings. In a swine model, cardiomyopathy induced with paced ectopic beats is phenotypically different from that induced with paced ventricular tachycardia, specifically regarding changes in cellular proteins associated with calcium handling. Additionally, the severity of the induced cardiomyopathy was strongly associated with the degree of ventricular dyssynchrony during ectopic beats, as demonstrated by comparing animals with ectopic beats delivered from different ventricular sites. The molecular calcium-handling changes observed in the paced PVC-cardiomyopathy animals were similar to those seen in other cardiomyopathy disease states.

While it is well recognized clinically that frequent PVCs may lead to LV dysfunction, many questions remain regarding the mechanisms of this process and which patients are at highest risk. Retrospective data have suggested that cardiomyopathy is more likely to develop when ectopic beats account for more than 10-14% of all heartbeats, but many patients with an even higher PVC burden maintain normal LV function indefinitely. Therefore, exposing asymptomatic patients to the treatment risks for PVCs before the development of any LV dysfunction generally is not advised. Furthermore, elimination of PVCs in some patients with suspected PVC-mediated cardiomyopathy does not always result in improvement or normalization of LV function. The results of this study add valuable knowledge about the potential mechanisms of PVC-mediated cardiomyopathy, forming the basis of additional investigation that could help clinicians predict LV dysfunction in advance and provide therapeutic targets to interrupt the process.

The authors noted that the majority of decline in LVEF in the paced PVC group occurred within the first six to eight weeks of pacing, followed by a subsequent lengthening of the sinus QRS complex. This observation suggests that changes mediated by LV dyssynchrony result in development of myocardial fibrosis and subsequent QRS widening, as opposed to QRS widening causing LV dyssynchrony. Irreversible myocardial fibrosis may contribute to the lack of LVEF recovery following PVC suppression in some patients. The primary limitation of this study was its generalizability, given the swine model with a 50% paced ectopic beat burden (bigeminy) from the RV apex, RV free wall, or LV epicardium. Somewhat different molecular changes were noted in a previously published canine model of PVC-cardiomyopathy with shorter PVC coupling intervals. Mechanisms could be different still in humans with less frequent PVCs originating from other more common anatomic sites (such as the ventricular outflow tracts and papillary muscles). Nevertheless, a prospective evaluation of ectopic beat dyssynchrony and likelihood of cardiomyopathy development is warranted, as this may provide clinicians with a tool to help risk-stratify and treat patients with frequent PVCs.