Premature Ventricular Contraction-induced Cardiomyopathy Research Articles

Functional-Molecular Mechanisms of Sympathetic-Parasympathetic Dysfunction in PVC-Induced Cardiomyopathy Revealed by Dual Stressor PVC-Exercise Challenge.

The significance of autonomic dysfunction in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remain unknown. Utilizing a novel "dual stressor" provocative challenge combining exercise with premature ventricular contraction (PVCs), the authors characterized the functional and molecular mechanisms of cardiac autonomic (cardiac autonomic nervous system) remodeling in a PVC-CM animal model. In 15 canines (8 experimental, 7 sham), we implanted pacemakers and neurotelemetry devices and subjected animals to 12weeks of bigeminal PVCs to induce PVC-CM. Sympathetic nerve activity (SNA), vagal nerve activity (VNA), and heart rate were continuously recorded before, during, and after treadmill exercise challenge with and without PVCs, at baseline and after development of PVC-CM. Western blot and enzyme-linked immunosorbent assay were used to evaluate molecular markers of neural remodeling. Exercise triggered an increase in both SNA and VNA followed by late VNA withdrawal. With PVCs, the degree of exercise-induced SNA augmentation was magnified, whereas late VNA withdrawal became blunted. After PVC-CM development, SNA was increased at rest but failed to adequately augment during exercise, especially with PVCs, coupled with impaired VNA and heart rate recovery after exercise. In the remodeled cardiac autonomic nervous system, there was widespread sympathetic hyperinnervation and elevated transcardiac norepinephrine levels but unchanged parasympathetic innervation, indicating sympathetic overload. However, cardiac nerve growth factor was paradoxically downregulated, suggesting an antineurotrophic counteradaptive response to PVC-triggered sympathetic overload. Sympathetic overload, sympathetic dysfunction, and parasympathetic dysfunction in PVC-CM are unmasked by combined exercise and PVC challenge. Reduced cardiac neurotrophic factor might underlie the mechanisms of this dysfunction. Neuromodulation therapies to restore autonomic function could constitute a novel therapeutic approach for PVC-CM.

Premature Ventricular Contraction-Induced Cardiomyopathy: Contemporary Evidence from Risk Stratification, Pathophysiology, and Management.

Premature ventricular complexes (PVCs) are commonly encountered problems in clinical settings. The range of symptoms can be from asymptomatic to palpitations, fatigue, or heart failure symptoms. A higher burden of PVCs is a risk factor for development of PVC-induced cardiomyopathy (PIC). Rhythm evaluation by 12-lead ECG and an ambulatory monitoring device are essential. Currently, several imaging modalities, such as echocardiography and cardiac magnetic resonance imaging, are utilized to evaluate the underlying structure that may be related to PIC. Beta blockers and antiarrhythmic drugs are typically part of the initial management strategy. If these fail, catheter ablation of PVCs is typically the next step. The purpose of this article is to summarize the current evidence/knowledge about PIC.

Are antiarrhythmic agents indicated in premature ventricular complex-induced cardiomyopathy and when?

Premature ventricular complexes (PVCs) are the most common ventricular arrhythmia that are encountered in the clinical practice. Recent data suggests that high PVC burden may lead to the development of PVC-induced cardiomyopathy (PVC-CM) even in patients without structural heart disease. Treatment for effective suppression of PVCs, can reverse PVC-CM. Both antiarrhythmic drugs (AADs) and catheter ablation (CA) are recognized treatment modalities for any cardiac arrhythmias. However, with increasing preference of CA, the role of AADs needs further defining regarding their efficacy, safety, indications and patient selection to treat PVC-CM. To ascertain the role of AADs to treat PVC-CM; whether they are indicated to treat PVC-CM, and if so, when, we interrogated PubMed and other search engines for English language publications with key words premature ventricular complexes (PVCs), cardiomyopathy, anti-arrhythmic drugs, catheter ablation, and pharmacological agents. All publications were carefully reviewed and scrutinized by the authors for their inclusion in the review paper. For illustration of cases, ethical standard was observed as per the 1975 Declaration of Helsinki, and the patient was treated as per the prevailing standard of care. Informed consent was obtained from the patient for conducting the ablation procedure. Our literature search specifically the pharmacological treatment of PVC-CM with AADs revealed significant paradigm shift in treatment approach for PVCs and PVC-induced cardiomyopathy. No major large, randomized control trials of AADs versus CA for PVC-CM were found. We found that beta-blockers and calcium channel blockers are particularly effective in the treatment of PVCs originating from right ventricular outflow tract. For Class Ic AADs - flecainide and propafenone, small clinical studies showed Class Ic AADs to be effective in PVC suppression, but their usage was not recommended in patients with significant coronary artery disease. Mexiletine was found to have modest effect on PVC suppression. Studies showed sotalol to significantly reduce PVCs frequency in patients receiving both low and high doses. Studies also showed amiodarone to have higher successful PVC suppression, but not recommended as a first-line treatment for patients with idiopathic PVCs in the absence of symptoms and left ventricular dysfunction. For dronedarone, no major clinical data were available. Based on the available data in the literature, we conclude that AADs play important role in the treatment of PVC-induced cardiomyopathy. However, appropriate patient selection criteria are vitally important, and in general terms AADs are indicated or polymorphic PVCs, epicardial PVCs; and when CA procedure is contraindicated, or not feasible or failed.

Left ventricular remodeling in premature ventricular contraction-induced cardiomyopathy: Effect of coupling intervals and atrioventricular dissociation.

Left ventricular dyssynchrony (LVD) and postextrasystolic potentiation (PESP) associated with premature ventricular contractions (PVCs) may play a role in the development of premature ventricular contraction-induced cardiomyopathy (PVC-CM). Long-coupled (LC) PVCs have a greater LVD than short-coupled (SC) PVCs, whereas SC-PVCs have a stronger PESP than LC-PVCs. The purpose of this study was to compare SC-PVCs and LC-PVCs to evaluate the roles of LVD, PESP, and atrioventricular dissociation (AVD) in the development of PVC-CM. Thirty-six canines underwent pacemaker implantation to induce bigeminal right ventricular apical epicardial PVCs (50% burden) for 12 weeks. Telemetry assessed PVC burden and AVD. Animals were grouped as SC-PVC (coupling interval [CI] 200-220ms), LC-PVC (CI 330 ms), or sham (control). Echocardiographic changes, AVD, and hemodynamics were monitored for 12 weeks. PVC burden was similar between SC-PVC and LC-PVC groups but was statistically higher in the SC-PVC group (50% vs 47.5%; P = .028). After 12 weeks, left ventricular ejection fraction (LVEF) significantly decreased in both SC-PVC and LC-PVC groups (47.1% ± 1.4% and 45.5% ± 2%, respectively) compared to sham group (61% ± 1.6%; P <.001). Overall AVD was similar between SC-PVC and LC-PVC groups, and there was no significant correlation between AVD and reduction in LVEF at 12 weeks (r = 0.09, P = .5; and r = 0.06, P = .8, respectively). Additionally, both SC-PVC and LC-PVC groups experienced substantial declines in max and min dP/dt after 12 weeks compared to baseline. Neither PVC CI nor AVD played an independent role in the development or severity of PVC-CM. LVD and PESP make equal relative contributions to the development of PVC-CM.

Mechanisms of adaptive hypertrophic cardiac remodeling in a large animal model of premature ventricular contraction-induced cardiomyopathy.

Frequent premature ventricular contractions (PVCs) promoted eccentric cardiac hypertrophy and reduced ejection fraction (EF) in a large animal model of PVC-induced cardiomyopathy (PVC-CM), but the molecular mechanisms and markers of this hypertrophic remodeling remain unexplored. Healthy mongrel canines were implanted with pacemakers to deliver bigeminal PVCs (50% burden with 200-220 ms coupling interval). After 12 weeks, left ventricular (LV) free wall samples were studied from PVC-CM and Sham groups. In addition to reduced LV ejection fraction (LVEF), the PVC-CM group showed larger cardiac myocytes without evident ultrastructural alterations compared to the Sham group. Biochemical markers of pathological hypertrophy, such as store-operated Ca2+ entry, calcineurin/NFAT pathway, β-myosin heavy chain, and skeletal type α-actin were unaltered in the PVC-CM group. In contrast, pro-hypertrophic and antiapoptotic pathways including ERK1/2 and AKT/mTOR were activated and/or overexpressed in the PVC-CM group, which appeared counterbalanced by an overexpression of protein phosphatase 1 and a borderline elevation of the anti-hypertrophic factor atrial natriuretic peptide. Moreover, the potent angiogenic and pro-hypertrophic factor VEGF-A and its receptor VEGFR2 were significantly elevated in the PVC-CM group. In conclusion, a molecular program is in place to keep this structural remodeling associated with frequent PVCs as an adaptive pathological hypertrophy.

PO-02-183 ATRIO-VENTRICULAR DISSOCIATION IN PREMATURE VENTRICULAR CONTRACTION WITH DIFFERENT COUPLING INTERVALS

The pathophysiology of Premature ventricular contraction (PVC) induced cardiomyopathy (PVC-CM) remains unclear. AV dissociation (AVD) during PVCs is known as atrial contraction at the time of the PVC. AVD has been implicated as a potential trigger and predictor of PVC-CM, especially early AVD since it results in an increase in LA pressure due to mitral valve closure. The goal of this study was to assess AVD during short- and long-coupled PVCs, and its correlation with the development of PVC-CM. Thirty-one canines underwent implantation of 1) a modified pacemaker to reproduce RV apical PVCs and 2) a telemetry device with a bipole implanted in the LA appendage and RV to record local electrograms and assess AVD during PVCs. Animals were randomized to short-coupled (200ms, n=14), long-coupled (330ms, n=8) bigeminal PVCs, or no PVCs (sham, n=11). AVD was categorized as absent (no P wave during QT interval), early (P wave present between QRS and the peak of the T wave of PVC), or late AVD (P wave between peak and end of T wave of PVC). AVD for four 1-minute segments (6 AM, 12 PM, 6 PM, and 12 AM) for 24 hours and LV ejection fraction were assessed after weeks 1, 4, and 12 of bigeminal PVCs. Ponemah software was used for HR analysis to calculate the minimum, maximum, and average HR and PVC burden. Overall AVD was similar between short- and long-coupled PVCs throughout the 12 weeks (Panel A). Short-coupled PVCs had 35% and 21% of early and late AVD, respectively and no AVD in 44%. Long-coupled PVCs had 50% and 13% of early and late AVD, respectively, without AVD in 37% (Panel B). The early AVD was significantly higher in long-coupled PVCs compared to short-coupled PVCs (50% vs. 35%, Two-Way ANOVA P<0.001), while late AVD was higher in short-coupled PVCs compared to long-coupled PVCs (22% vs. 13%, Two-Way ANOVA, p=0.018) (Panel A &C). Neither short nor long-coupled PVCs showed a significant correlation between AVD and reduction in LVEF at 12 weeks (r=0.09, r=0.06 with p=0.5, p=0.8, respectively). The short- and long-coupled PVCs had increased HR relative to the sham groups (121 vs. 105 vs. 83, Two-Way ANOVA p<0.001). Moreover, HR was significantly higher in short-coupled PVCs than in Long-coupled PVCs (121 vs. 105, Two-Way ANOVA p< 0.001). Early AVD is more pronounced in long-coupled PVCs. AVD does not predict the development of PVC-CM regardless of PVC coupling interval, suggesting that AVD does not play a role in the pathophysiology of PVC-CM.

Temporal and Spatial Changes of Proarrhythmic Substrate in Premature Ventricular Contraction–Induced Cardiomyopathy

BackgroundThe changes in proarrhythmic substrates and malignant ventricular arrhythmia mechanisms caused by premature ventricular contraction–induced cardiomyopathy (PVCCM) remain unclear. ObjectivesThe goal of this study was to establish the electrophysiological mechanism of how high-load PVC causes malignant arrhythmia. MethodsThirteen swine were exposed to 50% paced PVC from the right ventricular apex for 12 weeks (PVCCM, n = 6) and no pacing for 12 weeks (control, n = 7). Cardiac function was quantified biweekly with echocardiography. Computed tomography scans and electrophysiological examinations were performed monthly to dynamically evaluate the changes in the cardiac structure and the arrhythmogenic substrate. ResultsThe decreases in the cardiac function and ventricular enlargement in the PVCCM group were significant after 12 weeks of PVC stimulation compared with the control group (P < 0.001). Electrophysiological examination found that the ventricular effective refractory period dispersion (0.071 ± 0.008), area of the low-voltage zone (9.41 ± 1.55 cm2), and malignant ventricular arrhythmia inducibility (33.3%) of the PVCCM group increased significantly at week 8 after pacing (P < 0.001 vs the control group); these changes slowed down after 8 weeks. Moreover, the distribution of the low-voltage zone presented obvious spatial heterogeneity, especially in the anterior wall of the right ventricle, accompanied by delayed activation in the sinus rhythm (67 ± 13 milliseconds). Consistently, the proportion of ventricular fibrosis– and expression-related proteins were significantly increased in the PVCCM group (P < 0.001), especially in the right ventricle. Moreover, proteomic analysis confirmed the spatial profile of these fibrotic changes in the PVCCM group. ConclusionsHigh-burden PVC can cause significant temporal and spatial heterogeneity changes in proarrhythmic substrates, which are potentially related to the upregulation of calcium signaling caused by asynchronous activation.

Angiogenesis and activated fibroblast in a model of premature ventricular contraction-induced cardiomyopathy.

Premature ventricular contractions (PVCs) are the most common ventricular arrhythmia in the elderly, and when frequent, can result in PVC-induced cardiomyopathy (PVC-CM). PVC-CM canine model showed eccentric hypertrophy and fibrosis in the left ventricle (LV). The underlying structural and molecular mechanism behind this LV remodeling is unknown. In situ structural adaptations of the LV tissue and the activation of the VEGF/ERK1/2 signaling pathway were studied in the PVC-CM model. Pacemakers were implanted in healthy canines where PVCs were enabled only in the PVC-CM group (50% of PVC burden, 200-220-ms coupling interval) for 12 weeks. Fixed LV longitudinal- and cross-sections were stained with anti-α-SMA antibody, a marker of activated fibroblast (myofibroblasts) and smooth muscle cells (blood vessels), and WGA-AF633 (a marker of cell membranes). Confocal images were analyzed using artificial intelligence (AI)-powered autonomous software, AIVIA. Western blot (WB) analysis was used to study the pro-angiogenic signaling pathway and proteins associated with fibroblast activation. In situ analysis showed a significant increase in the total area and number of blood vessels, along with an increase in activated fibroblasts in PVC-CM LV sections. Also, the PVC group showed a 30% increase in the number of activated fibroblasts per cardiomyocyte compared with the sham group. The endothelial marker, eNOS, and IL-1β, a cytokine involved in fibroblast activation, were elevated in the PVC-CM group. Additionally, the VEGF-A, VEGF-B, and VEGF receptor 2 were upregulated in PVC-CM vs Sham; downstream ERK1/2 was hyperphosphorylated and overexpressed, and MMP9 (marker of fibroblast activation linked to this pathway) was elevated in PVC-CM vs Sham. In conclusion, activated fibroblasts and angiogenesis are a feature of the cardiac LV hypertrophic remodeling in PVC-CM.

Does Premature Ventricular Complex Impair Left Ventricular Diastolic Functions?

A higher frequency of premature ventricular complexes is associated with a higher risk of premature ventricular complex-induced cardiomyopathy. Although there are several studies on the systolic functions of the left ventricle in this patient group, it is clearly not known how the diastolic functions of the left ventricle are affected. This study examined the effect of premature ventricular complex on left ventricle diastolic functions using diastolic strain rate. The trial included 57 patients with frequent premature ventricular complexes and 54 healthy volunteers. The patient was evaluated using echocardiography in its entirety. The vendor-independent software system determined systolic and diastolic strain parameters via 2-dimensional speckle tracking analysis. Using the auto strain 3P semi-automated endocardial boundary tracking instrument, the global longitudinal strain was measured from the apical 4-chamber, 2-chamber, and long axis. The diastolic strain rate was determined by averaging the strain rates of 17 cardiac segments at 2 distinct periods of diastole. In the patient group, early diastolic strain rate was significantly lower than that in the control group (1.62 ± 0.58 vs. 1.25 ± 0.38, P <.001). There were found to be significant negative connections between PVC's electrocardiographic QRS wave length and early diastolic strain rate and coupling interval and early diastolic strain rate. Significant positive associations between coupling interval and early diastolic strain rate were discovered (P <.001 and P <.001, respectively). Patients with premature ventricular complex exhibited a lower early diastolic strain rate than healthy individuals. The early diastolic strain rate can be used to predict left ventricle diastolic dysfunction, and persons with premature ventricular complex may have a higher risk of left ventricle diastolic dysfunction than the general population.

Risk factors for the development of premature ventricular complex-induced cardiomyopathy: a systematic review and meta-analysis

BackgroundPremature ventricular complexes (PVCs) are a potentially reversible cause of heart failure. However, the characteristics of patients most likely to develop impaired left ventricular function are unclear. Hence, the objective of this study is to systematically assess risk factors for the development of PVC-induced cardiomyopathy.MethodsWe performed a structured database search of the scientific literature for studies investigating risk factors for the development of PVC-induced cardiomyopathy (PVC-CM). We investigated the reporting of PVC-CM risk factors (RF) and assessed the comparative association of the different RF using random-effect meta-analysis.ResultsA total of 26 studies (9 prospective and 17 retrospective studies) involving 16,764,641 patients were analyzed (mean age 55 years, 58% women, mean PVC burden 17%). Eleven RF were suitable for quantitative analysis (≥ 3 occurrences in multivariable model assessing a binary change in left ventricular (LV) function). Among these, age (OR 1.02 per increase in the year of age, 95% CI [1.01, 1.02]), the presence of symptoms (OR 0.18, 95% CI [0.05, 0.64]), non-sustained ventricular tachycardias (VT) (OR 3.01, 95% CI [1.39, 6.50]), LV origin (OR 2.20, 95% CI [1.14, 4.23]), epicardial origin (OR 4.72, 95% CI [1.81, 12.34]), the presence of interpolation (OR 4.93, 95% CI [1.66, 14.69]), PVC duration (OR 1.05 per ms increase in QRS-PVC duration [1.004; 1.096]), and PVC burden (OR 1.06, 95% CI [1.04, 1.08]) were all significantly associated with PVC-CM.ConclusionsIn this meta-analysis, the most consistent risk factors for PVC-CM were age, non-sustained VT, LV, epicardial origin, interpolation, and PVC burden, whereas the presence of symptoms significantly reduced the risk. These findings help tailor stringent follow-up of patients presenting with frequent PVCs and normal LV function.

Abstract 12757: Competing Neurotrophic and Anti-Neurotrophic Remodeling Processes in PVC-Induced Cardiomyopathy

Introduction: We previously demonstrated evidence of pro-arrhythmic sympathetic hyperinnervation and hyperactivity of the stellate ganglia in Premature Ventricular Contraction-induced Cardiomyopathy (PVC-CM). However, the presence of neural remodeling within the myocardium remains unclear. Methods: In a canine model of PVC-CM induced by a novel premature pacing algorithm with 12-weeks of bigeminal short-coupled (200ms) PVC exposure, we performed ELISA of serial plasma norepinephrine levels at baseline vs PVC-CM (N=7), and western blotting of neural proteins and beta-adrenoreceptors using snap-frozen left ventricular free wall myocardium in 6 sham controls and 7 PVC-CM hearts. Results: We found increased trans-cardiac norepinephrine (NE) levels in PVC-CM vs controls (Fig. 1A), increased LV myocardial sympathetic nerve protein Tyrosine Hydroxylase (TH) (Fig.1B) but interestingly, decreased Growth Associated Protein (GAP) 43 (Fig.1C), a marker of sprouting nerve cones. There was no change in synaptophysin (SYN), a neural synapse protein, or Choline acetyltransferase (ChAT), a parasympathetic nerve marker (Fig.1D). Further downstream, we found reduced ß-1 receptor levels similar to other forms of heart failure but markedly increased ß-2 receptor levels (Fig.1E), a finding unique to PVC-CM. Functionally, ß-2 effects are known to oppose the ß-1 inotropic and pro-apoptotic effects in the human myocardium Conclusions: There are competing neurotrophic vs anti-neurotrophic processes occurring within the LV myocardium, along with downstream beta-receptor changes. We hypothesize that these changes are a chronic adaptive response to PVC-induced chronic sympathetic surge, that ultimately protect against sympathetic excess and its consequent downstream effects on myocardial calcium handling and inotropy. These changes may have implications for the pathogenesis of PVC-CM and its pro-arrhythmic consequences. !

Risk factors for the development of premature ventricular complex-induced cardiomyopathy: a systematic review and meta-analysis

Abstract Background Premature ventricular complexes (PVCs) can be a reversible cause of heart failure. To date, it is unclear which risk factors contribute to the development of impaired left ventricular function. Objective Systematically assessing risk factors for the development of PVC-induced cardiomyopathy (PVC-CM). Methods We performed a structured database search of the scientific literature for studies investigating risk factors for the development of PVC-induced Cardiomyopathy. We investigated the reporting of PVC-induced Cardiomyopathy risk factors (RF) and assessed the comparative association of the different RF using random-effect meta-analysis. Results A total of 26 studies (9 prospective and 17 retrospective studies) involving 16.764.641 patients were analyzed (mean age 55 y, 58% women, mean PVC burden 17%). Suitable for quantitative analysis were 25 studies examining 6738 (0.04%) patients and 11 RF (≥3 occurrences in multivariable model assessing a binary change in left ventricular - LV- function). Among these risk factors, age (OR 1.02 per increase in the year of age, 95%-CI [1.01, 1.02]), the presence of symptoms (OR 0.18, 95%-CI [0.05, 0.64]), non-sustained VTs (OR 3.01, 95%-CI [1.39, 6.50]), LV origin (OR 2.20, 95%-CI [1.14, 4.23]), epicardial origin (OR 4.72, 95%-CI [1.81, 12.34]), the presence of interpolation - PVCs that do not reset the RR interval (OR 4.93, 95%-CI [1.66, 14.69]) and overall PVC burden (OR 1.06, 95%-CI [1.04, 1.08]) were all significantly associated with PVC-induced Cardiomyopathy. (Figures 1,2) Conclusion In this meta-analysis, the most consistent risk factors for PVC-CM were age, non-sustained VTs, LV and epicardial origin, interpolation, and PVC burden, while the presence of symptoms significantly reduced the risk. These findings help tailor stringent follow-up to patients presenting with frequent PVCs and normal LV function. Funding Acknowledgement Type of funding sources: None.

Left ventricular dyssynchrony as marker of early dysfunction in premature ventricular contraction-induced cardiomyopathy.

BackgroundStrain imaging has been suggested as a tool to detect early left ventricular (LV) dysfunction due to frequent premature ventricular contractions (PVCs) in patients with preserved LV ejection fraction (EF). However, the progression of intraventricular dyssynchrony (IVD), radial, and circumferential strain (RS, CS) in PVC-cardiomyopathy (CM) are unknown. The aim of this study was to elucidate the progression patterns of CS, IVD, and electro-mechanical latency (EML) in PVC-CM.Methods and resultsPacemakers were implanted in 20 canines to reproduce ventricular bigeminy at 200ms (PVCs n = 11) for 12 weeks and compared to a sham group (n = 9). We obtained echocardiograms at baseline, 4-, 8- and 12-weeks. RS and CS were obtained at the LV mid-cavitary level. IVD was defined as the time between the earliest and latest peak RS. EML was defined as the time between the onset of QRS and the earliest peak RS. LVEF (62 ± 5 to 42 ± 7%, p < 0.01), CS (–18 ± 3 to –12 ± 3, p < 0.01), and EML (219 ± 37 to 283 ± 46ms, p = 0.02) changed significantly in the PVC group. Peak CS (–18 ± 3 to –14 ± 4, p = 0.02) and IVD (49 ± 31 to 122 ± 103, p = 0.05) had a significant change at 4-weeks despite preserved LVEF (51 ± 5%). IVD normalized while EML increased at weeks 8 and 12.ConclusionOur findings consolidate the existing theory that changes in strain precede changes in LVEF in PVC-CM. While IVD becomes abnormal early in the development of PVC-CM, it pseudo-normalizes at advanced stages due to further increases in EML suggestive of cardiac contractility remodeling. These findings are consistent with recent published data where abnormal LV mechanics could be part of a substrate that can predispose to worse outcome in PVC-Cardiomyopathy.

Recovery of mental health parameters after ablation in patients with premature ventricular complex induced cardiomyopathy.

The diagnosis of premature ventricular complex-induced cardiomyopathy (PVC-CMP) is based on the presence of common PVCs associated with cardiomyopathy without a reasonable etiology for the cardiomyopathy. The treatment strategies for PVCs include radiofrequency catheter ablation (RFCA) and drug therapy. In addition to physiological symptoms, PVCs also cause psychological symptoms. Impaired quality of life and sleep quality parameters have been observed in these patients. The aim of the study was to investigate the effects of RFCA treatment on cardiac function and psychiatric health parameters. A total of 60 consecutive patients undergoing catheter ablation for cardiomyopathy-associated idiopathic PVCs were included in this study. Each patient underwent a three-lead ECG recording over a 24-hour period during normal daily ambulatory activities at a screening visit before and 3 months after RFCA. The Beck Depression Inventory Index (BDI-I), Beck Anxiety Inventory Index (BAI-I), and Global Pittsburgh Sleep Quality Index (GPSQI) were assessed before and after RFCA. PVC frequency decreased from 21.99±6.10 to 1.2% after RFCA. Left ventricular ejection fraction (LVEF) increased from 0.41±0.05 to 0.50±0.06 after RFCA (p<0.001). GPSQI (4.90±1.99 to 3.80±1.75, p <0.001), BDI-I (14.12±7.05 to 8.67±5.13, p<0.001), BAI-I (15.12±6.89 to 9.40±5.11, p<0.001) values decreased after RFCA. We found a moderate negative correlation between GPSQI, BDI-I, BAI-I and LVEF (rs=-0.56; p <0.001, rs=-0.55; p<0.001 and rs=-0.62; p<0.001). In addition to the recovery of systolic and diastolic cardiac functions, mental and psychiatric health parameters also showed great improvement.

Abstract 13878: Activated Fibroblasts and IL-1β Mediate Fibrotic Cardiac Remodeling Observed in Premature Ventricular Contraction-Induced Cardiomyopathy

Introduction: The relevance of fibrosis in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remains unclear. Recent studies suggest that fibrosis promotes adverse extracellular matrix (ECM) remodeling that has been implicated in arrhythmogenesis. However, fibrotic areas and fibroblast activation have not been characterized in PVC-CM. The objective of this study was to assess cardiac remodeling by collagen fiber deposition, fibroblast activation (using αSMA as a marker), and the pro-fibrotic cytokine IL-1β level in LV myocardium. Hypothesis: Activation of fibroblasts promotes adverse cardiac remodeling in PVC-CM. Methods: Modified pacemakers were implanted in canines, half of them developing PVC-CM after 12 weeks of bigeminal PVCs (50% burden at 200-220 ms coupling interval), while the remaining were not exposed to PVCs (sham). Paraffin-embedded or simple formalin-fixed cardiac samples were sectioned and stained with Sirius Red/Fast Green (SR/FG) or immunofluorescence (IF) to assess collagen fiber deposits and αSMA content, respectively. Expression of IL-1β and αSMA were assessed by Western blot. Results: The percentage of fibrosis was three times greater in PVC-CM tissues compared to sham (10.2 ± 0.98 vs 3.3 ± 0.53, p = 0.014), consistent with an increase in αSMA (1 ± 0.08 vs 1.93 ±0.33, p &lt; 0.05) and IL-1β expression (1 ± 0.09 vs 1.69 ± 0.11, p &lt; 0.01). The figure shows differences in collagen fibers with SR/FG and αSMA with IF in (A) sham and (B) PVC-CM. Increased αSMA and IL-1β support the hypothesis that fibroblast activation is a key component in the PVC-CM phenotype. Conclusion: These findings strongly suggest that fibroblast activation during PVCs promote ECM expansion causing persistent structural remodeling which may disrupt electrical signal propagation and potentially contribute to arrhythmogenesis and worsening ventricular function associated with PVC-CM.

Abstract 10671: Similar Left Ventricular Remodeling Despite Different Coupling Intervals of Frequent Premature Ventricular Contractions

Introduction: Left ventricular (LV) post-extrasystolic potentiation (PESP) and dyssynchrony (LVD) are proposed mechanisms that may trigger premature ventricular contraction-induced cardiomyopathy (PVC-CM). While long-coupled (LC) PVCs are characterized by higher LVD and lower PESP, short-coupled (SC) PVCs have higher PESP and lower LVD. Methods: Twenty-four mongrel dogs implanted with right ventricular epicardial pacemakers were randomized to short-coupled (PVC-SC; 200 to 220-ms, n = 10), long-coupled (PVC-LC; 320 to 340-ms, n = 7) bigeminal PVCs, or no PVCs (sham; n = 7). Holter monitors were obtained to confirm PVC burdens. Echocardiograms were performed at baseline and regular intervals up to 12 weeks after assignment to assess for LV remodeling by investigators blinded to group assignments. Intra- and inter-group comparisons were performed at each time point. PVC-CM was defined as LV ejection fraction &lt; 50%. Results: Holter monitors confirmed similar PVC burdens in PVC-LC and PVC-SC groups. After 12 weeks (Table 1), PVC-CM developed in 9 (90%) PVC-SC and 5 (71%) PVC-LC animals (p = 0.5368) with similar LVEF reduction in both groups (PVC-SC: 44.4 ± 1.5%; PVC-LC: 44.7 ± 4.0%; p = 0.9953) compared to sham (62.6 ± 1.5%). LV end-diastolic volume was greater in the PVC-LC (67.5 ± 4.6 mL) compared to PVC-SC (57.5 ± 2.7 mL; p = 0.0171) and sham (52.1 ± 1.5 mL; p = 0.0004) groups. LV end-systolic volume and indices of LV mass were similarly elevated in PVC-SC and PVC-LC groups compared to sham. Conclusions: Short- and long-coupled PVCs did not differentially impact the incidence or severity of LV remodeling in this translational animal model of PVC-CM. This finding is compatible with preliminary clinical observations that PVC coupling interval does not predict the development of PVC-CM in humans. Our data suggest that PESP and LV dyssynchrony play equally important roles in the development of PVC-CM.

Presence of dysfunction and myocardial remodeling in patients with premature ventricular complex-induced cardiomyopathy - a cardiovascular MR study

Abstract Funding Acknowledgements Type of funding sources: None. Background Premature ventricular complexes (PVCs) in the absence of underlying structural heart disease are considered to be benign. However, cardiac dysfunction has been observed in patients with a high PVC burden. The characterization of a PVC-induced cardiomyopathy with structural remodeling including myocardial fibrosis and the determination of a specific PVC burden leading to subclinical cardiac dysfunction remains to be determined. Objectives We aimed to evaluate cardiac function, remodeling and myocardial fibrosis patterns in patients with PVCs using cardiac magnetic resonance imaging (CMR). Additionally, we aimed to determine a PVC cut-off value leading to subclinical cardiac dysfunction. Methods Patients who underwent CMR and 24-hour, 12-lead ECG monitoring (Holter ECG) within six months were retrospectively studied. Patients with evidence of structural heart disease were excluded. The cohort was subdivided based on the number of PVCs in Holter ECG; Group-1 = 0-100, Group-2 = 100-5000 and Group-3 &amp;gt; 5000 PVCs. CMR parameters were extracted from our local databank. Myocardial strain was measured using feature tracking. For quantification of myocardial fibrosis, T1 mapping and late gadolinium enhancement (LGE) were investigated. Z-scores were calculated in order to combine T1 values from a 1.5 and 3Tesla CMR vendor. Results 443 patients (52 ± 20 years, 45% females) were included in the study. Compared to Group-1, Group-3 revealed a significantly reduced LV-EF, an increased indexed LV-EDV and increased indexed LV-ESV, indicating cardiac dysfunction and LV enlargement. PVCs frequency was inversely correlated with LV-EF (r=-0.23, p &amp;lt; 0.001) and positively correlated with indexed LV-EDV (r = 0.13; p &amp;lt; 0.01). Feature tracking showed significantly higher global circumferential strain (GCS) indicating subclinical dysfunction. Global T1 times were significantly prolonged in Group-3. Elevated global T1 Z-scores were found in Group-2 and Group-3 compared to Group-1. Significantly more intramural LGE was present in Group-2. The PVC cut-off value characterized by reduced GCS was defined by 216 PVCs (AUC = 0.61, p = 0.02). Conclusion CMR revealed cardiac dysfunction, left ventricular enlargement and diffuse myocardial fibrosis in patients with PVC in the absence of structural heart disease. These changes indicate the development of a PVC-induced cardiomyopathy depending on the PVC burden. Interestingly, subclinical myocardial dysfunction was determined at already low PVC frequencies. Further investigations are necessary in order to examine the influence of different origins of PVCs and the development of structural remodeling.

CARDIAC AFFERENT SIGNALING PARTIALLY UNDERLIES PREMATURE VENTRICULAR CONTRACTION-INDUCED CARDIOMYOPATHY

Background The mechanisms underlying premature ventricular contraction (PVC)–induced cardiomyopathy (PIC) remain unknown. Transient receptor potential vanilloid-1 (TRPV1) afferent fibers are implicated in the reflex processing of cardiac stress. Objective The purpose of this study was to determine whether cardiac TRPV1 afferent signaling promote PIC. Methods A PIC swine model (50% PVC burden) was created via an implanted pacemaker. We selectively depleted cardiac TRPV1 afferent fibers using percutaneous epicardial application of resiniferatoxin (RTX). Animals were randomized to PVC only (n = 11), PVC+RTX (n = 11), or control (n = 6). We examined early-stage (4 weeks after implantation; n = 5) and late-stage PIC (8 weeks after implantation; n = 6). At terminal experimentation, animals underwent echocardiography, serum sampling, and physiological and autonomic reflex testing. Results Depletion of cardiac TRPV1 afferents by RTX treatment was confirmed by absent sensory fibers and absent functional responses to TRPV1 activators. Left ventricular ejection fraction was worse in late-stage than early-stage PIC (P Conclusion TRPV1 afferent depletion alleviates left ventricular dysfunction in early- but not late-stage PIC. This temporal effect suggests that multiple pathways promote PIC, of which TRPV1 afferents are a part.

Cardiac afferent signaling partially underlies premature ventricular contraction-induced cardiomyopathy.

The mechanisms underlying premature ventricular contraction (PVC)-induced cardiomyopathy (PIC) remain unknown. Transient receptor potential vanilloid-1 (TRPV1) afferent fibers are implicated in the reflex processing of cardiac stress. The purpose of this study was to determine whether cardiac TRPV1 afferent signaling promote PIC. A PIC swine model (50% PVC burden) was created via an implanted pacemaker. We selectively depleted cardiac TRPV1 afferent fibers using percutaneous epicardial application of resiniferatoxin (RTX). Animals were randomized to PVC only (n = 11), PVC+RTX (n = 11), or control (n = 6). We examined early-stage (4 weeks after implantation; n = 5) and late-stage PIC (8 weeks after implantation; n = 6). At terminal experimentation, animals underwent echocardiography, serum sampling, and physiological and autonomic reflex testing. Depletion of cardiac TRPV1 afferents by RTX treatment was confirmed by absent sensory fibers and absent functional responses to TRPV1 activators. Left ventricular ejection fraction was worse in late-stage than early-stage PIC (P <.01). At 4 weeks (early stage), left ventricular ejection fraction was higher in PVC+RTX vs PVC animals (51.7% ± 1.6% vs 45.0% ± 2.1%; P = .030), whereas no significant difference between PVC and PVC+RTX was observed at 8 weeks (late stage). Histologic studies demonstrated reduced fibrosis in PVC+RTX vs PVC alone at 4 weeks (2.27% ± 0.14% vs 3.01% ± 0.21%; P = .020), suggesting that RTX mitigated profibrotic pathways induced by persistent PVCs. TRPV1 afferent depletion alleviates left ventricular dysfunction in early- but not late-stage PIC. This temporal effect suggests that multiple pathways promote PIC, of which TRPV1 afferents are a part.

Eccentric hypertrophy in an animal model of mid- and long-term premature ventricular contraction-induced cardiomyopathy.

BackgroundTachycardia and heart rate irregularity are proposed triggers of premature ventricular contraction–induced cardiomyopathy (PVC-cardiomyopathy). Bigeminal premature atrial and ventricular contractions (PACs and PVCs) increase heart rate and result in rhythm irregularities but differ in their effects on ventricular synchrony. Comparing chronic bigeminal PACs with PVCs would provide insights into mechanisms of PVC-cardiomyopathy.ObjectiveTo compare the impact of chronic PACs and PVCs on ventricular hemodynamics, structure, and function.MethodsPacemakers were implanted in 27 canines to reproduce atrial (PACs, n = 7) or ventricular bigeminy (PVCs, n = 11) for 12 weeks, and compared to sham-operated animals (n = 9). Four additional animals were exposed to long-term bigeminal PVCs (48 weeks). Hemodynamic changes were assessed using a pressure-transducing catheter at baseline and 12 weeks. Cardiac remodeling was monitored by transthoracic echocardiography throughout the 12- and 48-week protocols in the respective groups.ResultsPVC group demonstrated a significant decrease in left ventricular (LV) ejection fraction and contractility (max dP/dt), impaired LV lusitropy (min dP/dt), and increase in LV dimensions and LV mass at 12 weeks without further deterioration beyond 16 weeks. Despite increased LV mass, relative wall thickness decreased, consistent with eccentric hypertrophy. No significant cardiac remodeling was noted in either sham or PAC groups at 12 weeks.ConclusionIn contrast to bigeminal PACs, PVCs result in a cardiomyopathy characterized by reduced LV ejection fraction, LV dilation, and eccentric hypertrophy that plateaus between 12 and 16 weeks. The lack of remodeling in chronic PACs suggests that tachycardia and heart rate irregularity do not play a significant role on the development of PVC-cardiomyopathy.