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. Author manuscript; available in PMC: 2012 Aug 1.
Published in final edited form as: Circ Arrhythm Electrophysiol. 2011 May 16;4(4):543–549. doi: 10.1161/CIRCEP.111.962381

Left Ventricular Systolic Dysfunction Induced by Ventricular Ectopy: a Novel Model for PVC-induced Cardiomyopathy

Jose F Huizar 1,2, Karoly Kaszala 1,2, Jonathan Potfay 1,2, Anthony J Minisi 1,2, Edward J Lesnefsky 1,2, Antonio Abbate 2, Eleonora Mezzaroma 2, Qun Chen 1,2, Rakesh C Kukreja 2, Nicholas N Hoke 2, Leroy R Thacker II 2, Kenneth A Ellenbogen 1,2, Mark A Wood 2
PMCID: PMC3175603  NIHMSID: NIHMS303044  PMID: 21576277

Abstract

Background

Premature ventricular contractions (PVCs) commonly coexist with cardiomyopathy. Recently, PVCs have been identified as possible cause of cardiomyopathy. We developed a PVC-induced cardiomyopathy animal model using a novel premature pacing algorithm to assess timeframe and reversibility of this cardiomyopathy and examine the associated histopathological abnormalities.

Methods and Results

Thirteen mongrel dogs were implanted with a specially programmed pacemaker capable of simulating ventricular extrasystoles. Animals were randomly assigned to either 12 weeks of bigeminal PVCs (n=7) or no PVCs (control, n=6). Continuous 24-hr Holter corroborated ventricular bigeminy in the PVC group (PVC 49.8% vs. control <0.01%, P < 0.0001). After 12 weeks, only the PVC group developed cardiomyopathy with a significant reduction in left ventricular (LV) ejection fraction (PVC 39.7±5.4% vs. control 60.7±3.8%, P<0.0001) and an increase in LV end-systolic dimension (LVESD, PVC 33.3±3.5mm vs. control 23.7±3.6mm, P<0.001). Ventricular effective refractory period showed a trend to prolong in the PVC group. PVC-induced cardiomyopathy was resolved within 2-4 weeks after discontinuation of PVCs. No inflammation, fibrosis, or changes in apoptosis and mitochondrial oxidative phosphorylation were observed with PVC-induced cardiomyopathy.

Conclusions

This novel PVC animal model demonstrates that frequent PVCs alone can induce a reversible form of cardiomyopathy in otherwise structurally normal hearts. PVC-induced CM lacks gross histopathological and mitochondrial abnormalities seen in other canine models of CM.

Keywords: Premature ventricular contractions, LV dysfunction, Cardiomyopathy, Ventricular bigeminy, PVC-induced cardiomyopathy

Introduction

Premature ventricular contractions (PVCs) are a very common entity associated with cardiomyopathy (CM) and other cardiac diseases and yet their effects on the cardiovascular system are not well understood. While the presence of PVCs may carry adverse prognosis especially in structural heart disease, PVCs in general are thought to be benign or secondary to the cardiomyopathic process. Recently, a few small studies have reported a relationship between high PVC burden and LV systolic dysfunction1-4. Moreover, other observational and non-randomized studies demonstrated improvement of LV function after a successful PVC suppression strategy1, 4-8. These observations led to the description of an entity called PVC-induced cardiomyopathy (PVC-induced CM)1-6. Consequently, a current clinical conundrum is to recognize when PVCs are responsible for the development of a CM or secondary to a CM9.

The cardiovascular effects of PVCs have not been prospectively or systematically studied primarily due to the lack of an animal model and the unpredictability and variability of PVCs in the clinical setting 10, 11. We describe a novel PVC animal model using a unique pacemaker algorithm to demonstrate the link between frequent PVCs and LV systolic dysfunction.

Methods

a. Animal preparation & pacemaker implantation

Under general anesthesia, fourteen mongrel dogs (2-3 years old, weight 35-45 lbs.) underwent implantation of an experimental pacemaker (details in supplemental material). Through a left thoracotomy, a bipolar epicardial single-lead (Medtronic model 4968) was sutured in the right ventricular (RV) apex. Appropriate lead position was acceptable for R wave sensing above 4mV and pacing threshold less than 2V @ 0.5 msec. Experiments were approved by McGuire VAMC Institutional Animal Care and Use Committee (IACUC). Three weeks after surgical recovery, baseline echocardiogram and 24-hour continuous 3-lead Holter monitor were obtained prior to initiation of PVC protocol (outlined below). One animal was excluded from the cohort due to a baseline abnormal LV ejection fraction.

b. Simulation of frequent PVCs

A persistent high PVC burden originating from the RV apex was simulated via premature pacing algorithm (described below). Premature pacing algorithm was programmed to deliver PVCs in a bigeminal pattern (1:1 ratio or 50% PVC burden) with a fixed coupling interval of 250 ms (240 bpm) after each intrinsic ventricular sensed event (Figure 1). Pacing threshold was obtained during implantation and on a biweekly basis. Pacing voltage output was programmed at least twice the diastolic threshold to assure ventricular capture.

Figure 1.

Figure 1

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Intracardiac electrograms and markers before and after the premature pacing algorithm is enabled. Initial tracing demonstrates normal sinus rhythm (cycle length close to 500 ms,120 bpm). After premature pacing algorithm is enabled, a VP event occurs 250ms (240 bpm) following every VS event reproducing ventricular bigeminy. Furthermore, a compensatory pause can be noted after paced event. VS, Ventricular sensed event; VP, ventricular paced event.

Novel Premature Pacing algorithm

A single-chamber pacemaker (St. Jude Medical, Inc., St. Paul, MN, USA) with a unique experimental algorithm (patent submitted) was developed to reproduce chronic exposure to frequent PVCs. This pacing algorithm, when enabled in a single-chamber ventricular-lead pacemaker (VVI), can simulate PVCs (Figure 1). PVC burden is programmable from 5% up to 75%, as the algorithm will introduce 1-3 pacing stimuli after a chosen number of sensed events (supplemental Table 1). For instance, 75% PVC burden is reproduced by introducing 3 pacing stimuli after each sensed events (3:1 ratio), whereas 50%, 25% and 20 % PVC burden is reproduced with 1 pacing stimulus after 1, 3 and 4 sensed events, respectively (Figure 2 A-D).

Figure 2.

Figure 2

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Examples of the programmability of the Premature Pacing Algorithm in a single canine. Panel (a), premature pacing algorithm programmed to 75% ventricular pacing burden (3 VP out of 4 beats) with 200ms fixed coupling interval. Panel (b), premature pacing algorithm programmed to 50 % ventricular pacing burden (1 VP out of 2 beats, ventricular bigeminy) with 300ms fixed coupling interval. An adaptive coupling interval cannot be programmed due to the lack of at least 2 intrinsic R-R intervals. Panel (c), the premature pacing algorithm set for 20 % PVC burden (1 VP out of 5 beats, ventricular pentageminy) and 55% adaptive coupling interval. The initial tracing demonstrates an average cycle length of 2 prior R-R = 450ms, thus VP is delivered at 247ms (55 % of average R-R). Later portion of same panel demonstrates a longer average intrinsic R-R interval (660ms) with subsequent VP delivered at 55% (363ms). Panel (d) depicts 25% PVC burden and 65% adaptive coupling interval. The initial tracing has an average R-R interval=1080ms, thus VP is delivered at 702ms, whereas, the last segment has an average R-R interval=650ms with a VP triggered at 409ms. VP, ventricular paced event; CI, coupling interval; R, Intrinsic ventricular sensed event.

The PVC coupling interval may be programmed as either fixed (programmable between 190-375ms) or adaptive. The adaptive coupling interval is determined as a percentage of average cycle length (CL) of prior cardiac sensed events (Figure 2). In contrast to fixed coupling interval, adaptive coupling interval can only be used when premature pacing burden is programmed to less than 33% (as a minimum of 2 R-R intervals are needed to obtain an average cycle length of cardiac sensed events).

c. PVC protocol

The dogs were randomly assigned to either PVC (n=7, enabled premature pacing algorithm) or control groups (n=6, disabled premature pacing algorithm). The control group had a device programmed for sensing only (ODO). After group assignment and initiation of PVC protocol, an echocardiogram was repeated at 2-, 4-, 8- and 12- weeks to follow changes in LV function in all dogs. A 24-hour continuous 3-lead ECG Holter was repeated at the end of the 3-month protocol. After 3 months, 4 animals from the PVC group and 3 from the control group were euthanized and cardiac tissue was excised and frozen for further analysis. The remaining 3 animals assigned to the PVC group were allowed to recover for 4-weeks (recovery phase) by disabling the PVC algorithm (supplemental Figure 1).

d. Cardiac Evaluation

Two-Dimensional echocardiogram

Echocardiograms were performed at baseline, 2-weeks and every 4 weeks throughout the duration of the PVC protocol using a commercially available system (Sequoia c256 Siemens). Those animals assigned to recovery phase had additional echocardiograms at 2 and 4 weeks after discontinuation of PVCs. LV ejection fraction, fractional shortening (FS), end-systolic and end-diastolic LV and left atrial (LA) dimensions, LV thickness, LV compliance (E/A and E/E’ ratios), as well as the severity of mitral regurgitation (MR) were evaluated using standard criteria by the American Society of Echocardiography12, 13 (supplemental material). Tissue Doppler imaging was used to assess the timing of local contractility (QRS-to-contraction) in four different LV locations in reference to the QRS complex (lateral base, septal base, mid lateral wall and mid-septum). LV dysynchrony was assessed by the standard deviation of QRS-to contraction time between these locations14. PVCs were suspended (algorithm disabled) at least 15 minutes prior to echocardiogram in order to obtain an accurate calculation of described parameters. The echocardiographic measurements were performed offline by a cardiologist blinded to the randomization arm.

Ventricular effective refractory period (VERP)

Programmed ventricular stimulation (S1S2) with different drive trains (S1 300ms, 350 and 400ms) were performed in order to determine VERP. VERP was defined as the longest S1S2 that did not cause myocardial capture.

Myocardial microscopic evaluation

Four different LV samples (2 from the LV apex and 2 from the LV anterior wall) in each canine (PVC group n=4, control group n=3, supplemental Figure 1) were obtained and stained with hematoxylin/eosin and Masson trichrome to assess inflammation and fibrosis, respectively. Leukocytic infiltrates, grade of fibrosis (score 0 to 4+) and percentage of fibrosis were assessed in 10 random fields per sample (x10 and x40 magnification, respectively). Two LV samples (LV apex and anterior wall) in each animal underwent TUNEL (terminal deoxynucleotide transferase-mediated nick-end labeling assay) technique (DNA fragmentation – Oncor, Gaithersburg, MD) to assess apoptosis as previously described15. Apoptotic nuclei were counted in 4-5 random fields per sample. The apoptotic index was expressed as the number of apoptotic cells of all cardiomyocytes per field16 (supplemental material).

Isolation and analysis of cardiac mitochondria

Cardiac mitochondria were isolated and analyzed according to Palmer et al.17, with minor modifications as previously published 18, 19. Oxygen consumption in subsarcolemmal mitochondria and interfibrillar mitochondria were measured using a Clark-type oxygen electrode at 30°C with glutamate (complex I substrate) and succinate + rotenone (complex II substrate) 18. Further details are provided in supplemental material.

e. Statistical Analysis

Sample size was calculated to reach statistical power of 80% with type-I error of 0.05 for LV dysfunction after 12-week period of ventricular bigeminy (details in supplemental material). All data is expressed in mean ± SD. Statistical analysis was performed using with SAS/STAT® Software (SAS Institute, Inc. Cary, NC). A repeated-measures ANOVA was performed to compare temporal changes in LV ejection fraction between study and control groups. We calculated the change score (delta) from baseline to 12 weeks for all echocardiographic and VERP data for each animal in both PVC and control groups. A two sample T-test was used to compare the mean change score at 12-weeks between PVC and control groups. The degree of mitral regurgitation at 12-weeks was compared between PVC and control groups using a Mann-Whitney U test. A P value less than 0.05 was considered significant.

Results

Premature Pacing algorithm

Thirteen animals underwent device implantation without surgical complications. Canines were randomized to PVC (n=7) or control (n=6, without PVCs) groups. No device or algorithm malfunctions were noted during the study. Twenty-four-hour Holter monitoring showed ventricular bigeminy in the frequent PVC group with an average PVC burden of 49.8 ± 0.01% compared to 0.01 ± 0.001% in the control group (P<0.001). The PVC protocol increased the average heart rate from 81 ± 7 to 130 ± 13 bpm (P<0.001). Figure 3 illustrates ventricular bigeminy with a 2-lead ECG tracing and rate histogram in a single animal before and after premature pacing algorithm is enabled.

Figure 3.

Figure 3

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Two-lead ECG tracings and ventricular rate histograms in 24-hour holters at baseline and after premature pacing algorithm is enabled. Panel A (disabled premature pacing algorithm) shows normal ECG tracings (without PVCs) and normal bell-curve shape of intrinsic heart rate distribution with a median R-R interval of 600ms (100 bpm). Panel B (enabled premature pacing algorithm) confirms ventricular bigeminy with one PVC or “V” after every normal beat or “N”. Histogram demonstrates a dominant R-R interval of 250ms due to bigeminal PVCs (R-PVC interval). In contrast, to baseline, the median intrinsic R-R interval (PVC-R interval) increased to 750ms (80 bpm), which can be explained due to a compensatory pause as noted in Figure 1.

Cardiac Function

Echocardiographic findings are summarized in table 1. A new LV systolic dysfunction was observed in the PVC group after 12 weeks of ventricular bigeminy with a 34 % relative reduction in LV ejection fraction (Figure 4), a 45% decrease in fractional shortening (FS), and a 39% increase in LV end-systolic dimension (LVESD) (Table 1). In contrast, no change in LVEF, FS, LVESD were noted in the control group. LVEF and FS were significantly lower and LVESD was significantly greater in the PVC group after 12 weeks compared to the control group. Mitral regurgitation (semi-quantitative, zero to 3+) reached significant difference between PVC and control groups (control 0.58 ± 0.2 vs. PVC 1.29 ± 0.7, Mann-Whitney U test P=0.04, Table 1). However, no animal developed signs of overt heart failure such as lethargy, decrease activity, fluid retention or tachypnea. Furthermore, no significant difference in LV end-diastolic dimension (LVEDD), LV wall thickness, LA size and LA area was found after 3-months between PVC and control groups (Table 1).

Table 1.

Changes in echocardiographic parameters in control and PVC groups. Data are expressed as Mean ± SD.

Control Group (n=6) PVC Group (n=7) Control vs. PVC
Baseline 12-weeks Delta (95% CI) Baseline 12-weeks Delta (95% CI) P value
LVEF (%) 61 ± 6 60.7 ± 4 1.08 (-3,5) 59.7 ± 2 39.7 ± 5 -19.21 (-29.3,-9.1) <0.0001
FS (%) 31.5 ± 2 32 ± 5 0.5 (-8.6,9.6) 33 ± 3 18.3 ± 5 -14.7 (-26,-3.4) 0.0004
LVEDD (mm) 33.9 ± 5 34.8 ± 4 0.9 (-6.4,8.2) 35.8 ± 3 40.2 ± 2 4.5 (-3,12) 0.11
LVESD (mm) 23.1 ± 3 23.7 ± 4 0.6 (-3.6,4.8) 24 ± 2 33.3 ± 3 9.3 (2.5,16.1) 0.0002
PW (mm) 7.8 ± 1.1 8.3 ± 0.8 0.5 (-1.1,2.1) 8.7 ± 0.5 8.7 ± 0.8 0 (-2,2) 0.33
SW (mm) 8 ± 0.6 7.8 ± 1 -0.2 (-2.5,2.1) 8.7 ± 1.1 8.7 ± 0.8 0 (-1.1,1.1) 0.72
MR (grade 0-3+) 0.5 ± 0 0.6 ± 0.2 0.1 (-0.3,0.5) 0.5 ± 0 1.29 ± 0.7 0.8 (-0.6,2) 0.03
LA size (mm) 26.7 ± 3 26.2 ± 3 -0.6 (-5,4) 29 ± 3 28.7 ± 2 -0.3 (-6.4,5.9) 0.86
LA Area (cm2) 5.7 ± 2 5.7 ± 1 -0.05 (-1.6,1.5) 6.6 ± 2 6.9 ± 1 0.2 (-2,2.4) 0.65
E/A ratio 1.7 ± 0.2 1.6 ± 0.1 -0.1 (-0.6,0.3) 1.6 ± 0.2 1.3 ± 0.3 -0.3 (-1,0.4) 0.23
E/E’ ratio 4.2 ± 0.8 3.8 ± 0.8 -0.4 (-3,2) 3.8 ± 0.6 4.3 ± 0.6 0.4 (-1,2) 0.19
SD QRS-to-contraction 4.4 ± 5 7.3 ± 7 3 (-10,16) 4.7 ± 2 17.6 ±11 13 (-9,35) 0.2
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P value determined using a two-group independent t-test comparing the individual change score (delta) at 12 weeks between groups. CI, confidence interval; FS, Fractional shortening; LVEDD, LV end-diastolic dimension; LVESD, LV end-systolic dimension; PW, posterior wall thickness; SW, septal wall thickness; MR, mitral regurgitation (semi-quantitative, graded from 0 to 3+); SD QRS-to-contraction, standard deviation of the timing of local contractility in reference to the QRS initiation.

Figure 4.

Figure 4

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LV ejection fraction in PVC (n=7) and control groups (n=6) during 3-month follow up. A 4-week recovery period in the non-euthanized PVC group canines (n=3) demonstrates normalization of LV ejection fraction (bars represent standard deviation).

The recovery phase (disabled premature pacing algorithm) in the PVC group (n=3) demonstrated normalization of LVEF (Figure 4), FS and LVESD (LVEF 58 ± 9%, FS 37 ± 3%, LVESD 24.3 ± 2.5mm) after elimination of PVCs for 4 weeks.

Ventricular refractoriness - Ventricular programmed stimulation at 350ms demonstrated a significant increase of VERP in the PVC group (change score 22.5, 95%CI 12.75, 32.25) when compared to the control group (change score 8.3, 95% CI -14.46, 31.13, p= 0.02). In contrast, no significant difference in VERP at 400ms (PVC mean change 20, 95% CI -2.5, 42.52 vs. control mean change 5, 95% CI -15.5, 25.5, p=0.08) and 300ms (PVC mean change 15, 95% CI 3.74, 26.3 vs. control mean change 5, 95% CI -15.5, 25.5, p=0.08) was found between groups.

Myocardial microscopic evaluation

Despite LV systolic dysfunction, the PVC group (n=4) did not demonstrate increased inflammation, degree of fibrosis (PVC 1.75 ± 0.5 vs. control 1.3 ± 0.8), percentage of fibrosis (PVC 5.4 ± 1.7% vs. control 6.5 ± 3.9%) or apoptotic index (PVC 2.85 ± 1.77 vs. control 2.59 ± 0.64, supplemental Figure 2) when compared to the control group (n=3). Inflammatory infiltrates were absent in both groups (supplemental Figure 3). These findings are purely descriptive and no statistical results were performed due to small sample size.

Oxidative phosphorylation of cardiac mitochondria

Maximal rates of ADP-stimulated respiration and the coupling of respiration were unchanged in cardiac mitochondria in PVC group compared to control animals (supplemental Table 2).

Discussion

The cardiovascular effects of PVCs have not been systematically studied due to the absence of animal models. In the present study, we have developed a novel animal model using a unique premature pacing algorithm to reproduce PVCs and corroborate the clinical entity of PVC-induced CM. The major findings of this model are: a) ventricular bigeminy induced CM characterized by a reduced LV ejection fraction and enlarged LV systolic dimension; b) PVC-induced CM was reversible within 4 weeks after cessation of PVCs; and c) PVC-induced CM lacks histopathological abnormalities such as inflammation, fibrosis, increased apoptosis or abnormal mitochondrial oxidative phosphorylation.

Canines were selected in our PVC model because of their similarity of the cardiac His Purkinje system to humans 20 and their extensive description in tachycardia-induced CM models 21. The premature pacing algorithm is capable of reproducing different PVC burdens (Figure 2). Ventricular bigeminy was chosen as a clinically significant PVC burden (50%) that would likely result in PVC-induced CM and demonstrate the concept that frequent PVCs alone can induce LV dysfunction in otherwise normal hearts. Since the heart rate of the dog ranges from 60-200 bpm, the pacing stimulus (PVC) was delivered at a fixed coupling interval of 240ms (250 bpm) after ventricular sensed event to assure bigeminal pacing even at faster rates of 200 bpm (300ms).

The echocardiographic findings in our animal model are consistent with previous results of retrospective/observational clinical studies of PVC-induced CM 1, 2, 4-8. As our manuscript was finalized, an animal model using two RV leads connected to a dual-chamber pacemaker reported similar echocardiographic findings after 4-weeks of ventricular bigeminy22. In addition, our model demonstrated that 1) LV dysfunction developed as early as 2 weeks and continued to decline for the following 10 weeks (Figure 4) after initiation of ventricular bigeminy without clinical evidence of heart failure, 2) severity of mitral valve regurgitation increased and 3) VERP was likely to prolong after chronic bigeminy, while 4) CM was reversible as demonstrated by the recovery of LV function and normalization of LV dimensions within 4 weeks after cessation of PVCs.

Importantly, we found a trend of VERP to prolong in this PVC-induced CM model. This was not surprising as VERP prolongation and “electrical remodeling” has been previously reported in failing hearts23. Electrical remodeling has been characterized by alterations in intercellular ion channels, which result in prolongation of action potential duration, VERP and slowing of conduction23. Further investigations are needed to clarify and explain electrophysiologic changes and how these relate to the pro-arrhythmic effects of frequent PVCs reported in patients with and without LV systolic dysfunction24,25.

The histopathological and metabolic features of PVC-induced CM have never been described. Tissue analysis in this animal model did not show inflammation, fibrosis or increased apoptosis after 3-months of high PVC burden. The unaltered respiration with complex I and complex II substrates suggest that mitochondrial electron transport was not significantly altered by exposure to PVCs despite the decrease in left ventricular systolic function. Based on complete recovery of LV systolic function following cessation of PVCs, it is not surprising that there were no gross structural abnormalities. We believe that this CM is secondary to a functional rather than structural abnormality due to the lack of gross structural abnormalities in our animal model. For Instance, abnormalities in calcium handling could potentially translate in myocardial dysfunction.

The mechanism(s) by which PVCs induce CM are unknown. Two major theories have emerged: 1) a short PVC coupling interval 6, 26 and 2) LV dyssynchrony during PVCs. A short PVC coupling interval in subjects with high PVC burden would result in an overall increase in the average heart rate and “tachycardia”, possibly leading to a pathophysiology similar to a tachycardia-induced CM. We believe that this animal model of CM is clearly distinct from tachycardia-induced CM since the average heart rate with PVCs (130 ± 13 bpm) is significantly lower than described in tachycardia-induced CM dog model (heart rate > 180 bpm) 14, 21, 27. In addition, the absence of fibrosis, increased apoptosis and mitochondrial dysfunction as well as the normalization of LV diastolic dilatation after cessation of PVCs supports a distinct mechanism from tachycardia-induced CM. 14, 21, 28-31 Alternatively, frequent PVCs may cause LV dysynchrony similar to chronic right ventricular pacing 32-35, which has been associated with higher mortality and a greater incidence of LV dysfunction 6, 36. The abnormal pattern of electrical activation and LV dyssynchrony 34, 37-39 resulting from these PVCs may cause disruption and further progression of dysynergic LV wall motion40-42. However, the time course to develop LV dysfunction in this model is quite different from the sole effects of long-term RV pacing43, 44. Finally, we propose the chronic effects of “post-extrasystolic potentiation” as a third mechanism of PVC-induced CM. This phenomenon was studied extensively in the 1970’s when coupled pacing was postulated to be beneficial for the treatment of heart failure. An increase in intracellular Ca2+ concentration and myocardial oxygen consumption was demonstrated with post-extrasystolic potentiation45, 46, which could also contribute to the development of CM.

To the best of our knowledge, our PVC canine model with chronic ventricular bigeminy describes for the first time the time course of echocardiographic findings, changes in VERP and the histopathological and mitochondrial characteristics of PVC-induced CM. Nevertheless, the minimum PVC burden required to induce CM remains unclear. Furthermore, it is uncertain if different sites of PVC origin and coupling intervals would affect the development and/or severity of PVC-induced CM. In contrast to the use of a dual-chamber pacemaker recently reported 22 to reproduce ventricular bigeminy, our novel premature pacing algorithm is be able to provide different PVC burden (from 5% up to 75%) and coupling interval that mimic different clinical scenarios (Figure 2).

Limitations

PVCs simulated via a pacemaker in our animal model are not intrinsic but cardiac bipolar pacing represents local myocardial depolarization similar to a spontaneous ventricular event. RV apical pacing was performed and it is unclear if these results may be extrapolated to PVCs from other cardiac sites. We cannot exclude that tachycardia plays a lesser role since average heart rate was increased with premature pacing algorithm. However, this is similar to the clinical scenario investigated in patients with high burden PVCs. Our histopathological analysis was limited to anterior and apical segments of the LV. We cannot exclude the presence of regional abnormalities in the remaining LV walls. Similarly, we cannot exclude the possibility that extended exposure to frequent PVCs beyond 12-weeks could result in significant cardiac remodeling with chronic irreversible structural changes.

Novelty and Significance

This study validates the premise that frequent PVCs can result in a reversible LV dysfunction in structurally normal hearts. Even if PVCs are the result of the CM, PVCs by themselves may contribute to and further worsen CM and heart failure symptoms8, 9. This findings support further clinical studies in patients with CM associated with frequent PVCs. Most importantly, this novel premature pacing algorithm and PVC animal model will facilitate further scientific evaluation of the cardiovascular effects of PVCs in structurally normal hearts and other established heart failure models.

Conclusions

In summary, a novel premature pacing algorithm has allowed the study of the clinical entity of PVC-induced CM in structurally normal hearts. PVC-induced CM canine model demonstrates that frequent PVCs with a bigeminal pattern alone can cause reversible LV dysfunction within two weeks, which appears to progress throughout the 3 months of continuous PVCs. Finally, PVC-induced CM lacks histopathological and mitochondrial abnormalities seen in other canine models of CM.

Supplementary Material

1

Premature ventricular contractions (PVCs) are a very common entity associated with cardiomyopathy and other cardiac diseases and yet their effects on the cardiovascular system are not well understood. This is primarily due to the lack of animal models and the unpredictability and variability of PVCs in the clinical setting. Using a novel premature pacing algorithm capable of reproducing different clinical scenarios of ventricular ectopy, the effects of chronic ventricular bigeminy in structurally normal hearts were studied in an animal model. Our canine model validates and describes for the first time the time course of echocardiographic findings, changes in ventricular effective refractory period and the histopathological and mitochondrial characteristics of PVC-induced cardiomyopathy. These findings support further clinical studies in patients with cardiomyopathy associated with frequent PVCs since the minimum PVC burden, origin and coupling interval required to induce cardiomyopathy remains unclear. Finally, this novel premature pacing algorithm and PVC animal model will facilitate further scientific evaluation of the cardiovascular effects of PVCs in structurally normal hearts and other established heart failure models.

Acknowledgments

We acknowledge St. Jude Medical (SJM) for providing experimental devices, as well as Susan Quinn and Richard Klaty for their commitment to this project and animal care, and Mr. Harsha Kannan (VCU) for his technical help in the pathological laboratory.

Funding Sources: A.D. Williams Grant Foundation (Virginia Commonwealth University) and SJM grant support to JFH; Department of Veterans Affairs Merit Review Award (McGuire VA Medical Center) granted to EJL; NIH grants to RCK (HL51045, HL59469, and HL79424); and Wallace Foundation, W.K. Kellogg Foundation and NIH (UL1RR031990) grants to VCU CTSA.

Non-standard abbreviations and acronyms

PVC

Premature ventricular contraction

CM

Cardiomyopathy

FS

Fractional shortening

LVEDD

LV end-diastolic dimension

LVESD

LV end-systolic dimension

LA

Left atrium

VERP

Ventricular effective refractory period

QRS-to-contraction

timing of local contractility in reference to the QRS initiation

Footnotes

Conflict of Interest Disclosures: JFH, grant support from SJM and clinical investigator for Biotronik. KK – Clinical investigator for Boston Scientific, SJM and Sorin. KAE, grant, clinical investigator, honoraria and consultant for Boston Scientific, Medtronic, SJM and Biotronik. MAW, clinical investigator & speaker for Boston Scientific, Medtronic and SJM.

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