Dataset Information

Impact of ventricular ectopic burden in a premature ventricular contraction-induced cardiomyopathy animal model.

ABSTRACT: BACKGROUND:Frequent premature ventricular contractions (PVCs) have been associated with PVC-induced cardiomyopathy (CM) in some patients. OBJECTIVE:The purpose of this study was to understand the cardiac consequences of different PVC burdens and the minimum burden required to induce left ventricular (LV) dysfunction. METHODS:Right ventricular apical PVCs at a coupling interval of 240 ms were introduced at different PVC burdens in 9 mongrel canines. A stepwise increase in PVC burden was implemented every 8 weeks from 0% (baseline), 7%, 14%, 25%, 33% to 50% using our premature pacing algorithm. Echocardiogram and 24-hour Holter were obtained at 4- and 8-week period for each PVC burden with a single blinded reader assessing all echocardiographic parameters including those assessed by speckle tracking imaging (EchoPAC workstation, General Electric). CM was defined as left ventricular ejection fraction (LVEF) <50% or LVEF drop >10% points. Interleukin-6 and pro-brain natriuretic peptide levels were obtained at the end of each PVC burden. RESULTS:The mean LVEF (mean heart rate) at 8 weeks for each PVC burden (0%, 7%, 14%, 33%, and 50%) were 57% ± 2.9% (85 ± 13 beats/min), 54.4% ± 3% (81 ± 10 beats/min), 53.3% ± 5% (77 ± 12 beats/min), 51.1% ± 4.2% (79 ± 14 beats/min), 47.7% ± 3.8% (80 ± 14 beats/min), and 44.7% ± 1.9% (157 ± 43 beats/min). PVC-induced CM was present in 11.1%, 44.4%, and 100% of animals with 25%, 33%, and 50% PVC burden, respectively. E/A ratio and radial strain decreased while left atrial size increased beyond 33% PVC burden. No changes in pro-brain natriuretic peptide and interleukin-6 levels were noted at any PVC burden. CONCLUSION:LV systolic function (LVEF and radial strain) declined linearly as PVC burden increased. PVC-induced CM developed in some canines with 25% and 33% PVC burden, but developed in all animals with 50% PVC burden.

SUBMITTER: Tan AY

PROVIDER: S-EPMC4762722 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Impact of ventricular ectopic burden in a premature ventricular contraction-induced cardiomyopathy animal model.

Tan Alex Y AY Hu Yuhning L YL Potfay Jonathan J Kaszala Karoly K Howren Maureen M Sima Adam P AP Shultz Michael M Koneru Jayanthi N JN Ellenbogen Kenneth A KA Huizar Jose F JF

Heart rhythm 20151114 3

<h4>Background</h4>Frequent premature ventricular contractions (PVCs) have been associated with PVC-induced cardiomyopathy (CM) in some patients.<h4>Objective</h4>The purpose of this study was to understand the cardiac consequences of different PVC burdens and the minimum burden required to induce left ventricular (LV) dysfunction.<h4>Methods</h4>Right ventricular apical PVCs at a coupling interval of 240 ms were introduced at different PVC burdens in 9 mongrel canines. A stepwise increase in PV ...[more]

PMID: 26586453

Similar Datasets

Project description:Mechanisms behind development of premature ventricular contraction (PVC)-induced cardiomyopathy remain unclear. PVCs may adversely modulate the autonomic nervous system to promote development of heart failure. Afferent neurons in the inferior vagal (nodose) ganglia transduce cardiac activity and modulate parasympathetic output. Effects of PVCs on cardiac parasympathetic efferent and vagal afferent neurotransmission are unknown. The purpose of this study was to evaluate effects of PVCs on vagal afferent neurotransmission and compare these effects with a known powerful autonomic modulator, myocardial ischemia. In 16 pigs, effects of variably coupled PVCs on heart rate variability (HRV) and vagal afferent neurotransmission were evaluated. Direct nodose neuronal recordings were obtained in vivo, and cardiac-related afferent neurons were identified based on their response to cardiovascular interventions, including ventricular chemical and mechanical stimuli, left anterior descending (LAD) coronary artery occlusion, and variably coupled PVCs. On HRV analysis before versus after PVCs, parasympathetic tone decreased (normalized high frequency: 83.6?±?2.8 to 72.5?±?5.3; P < 0.05). PVCs had a powerful impact on activity of cardiac-related afferent neurons, altering activity of 51% of neurons versus 31% for LAD occlusion (P < 0.05 vs. LAD occlusion and all other cardiac interventions). Both chemosensitive and mechanosensitive neurons were activated by PVCs, and their activity remained elevated even after cessation of PVCs. Cardiac afferent neural responses to PVCs were greater than any other intervention, including ischemia of similar duration. These data suggest that even brief periods of PVCs powerfully modulate vagal afferent neurotransmission, reflexly decreasing parasympathetic efferent tone.NEW & NOTEWORTHY Premature ventricular contractions (PVCs) are common in many patients and, at an increased burden, are known to cause heart failure. This study determined that PVCs powerfully modulate cardiac vagal afferent neurotransmission (exerting even greater effects than ventricular ischemia) and reduce parasympathetic efferent outflow to the heart. PVCs activated both mechano- and chemosensory neurons in the nodose ganglia. These peripheral neurons demonstrated adaptation in response to PVCs. This study provides additional data on the potential role of the autonomic nervous system in PVC-induced cardiomyopathy.

Project description:BACKGROUND:The presence and significance of neural remodeling in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remain unknown. OBJECTIVES:This study aimed to characterize cardiac sympathovagal balance and proarrhythmia in a canine model of PVC-CM. METHODS:In 12 canines, the investigators implanted epicardial pacemakers and radiotelemetry units to record cardiac rhythm and nerve activity (NA) from the left stellate ganglion (SNA), left cardiac vagus (VNA), and arterial blood pressure. Bigeminal PVCs (200 ms coupling) were applied for 12 weeks to induce PVC-CM in 7 animals then disabled for 4 weeks to allow complete recovery of left ventricular ejection fraction (LVEF), versus 5 sham controls. RESULTS:After 12 weeks of PVCs, LVEF (p = 0.006) and dP/dT (p = 0.007) decreased. Resting SNA (p = 0.002) and VNA (p = 0.04), exercise SNA (p = 0.01), SNA response to evoked PVCs (p = 0.005), heart rate (HR) at rest (p = 0.003), and exercise (p < 0.04) increased, whereas HR variability (HRV) decreased (p = 0.009). There was increased spontaneous atrial (p = 0.02) and ventricular arrhythmias (p = 0.03) in PVC-CM. Increased SNA preceded both atrial (p = 0.0003) and ventricular (p = 0.009) arrhythmia onset. Clonidine suppressed SNA and abolished all arrhythmias. After disabling PVC for 4 weeks, LVEF (p = 0.01), dP/dT (p = 0.047), and resting VNA (p = 0.03) recovered to baseline levels. However, SNA, resting HR, HRV, and atrial (p = 0.03) and ventricular (p = 0.03) proarrhythmia persisted. There was sympathetic hyperinnervation in stellate ganglia (p = 0.02) but not ventricles (p = 0.2) of PVC-CM and recovered animals versus sham controls. CONCLUSIONS:Neural remodeling in PVC-CM is characterized by extracardiac sympathetic hyperinnervation and sympathetic neural hyperactivity that persists despite normalization of LVEF. The altered cardiac sympathovagal balance is an important trigger and substrate for atrial and ventricular proarrhythmia.

Project description:BackgroundIn a canine model of premature ventricular contraction-induced cardiomyopathy (PVC-CM), Cav1.2 is downregulated and misplaced from transverse tubules (T tubules). Junctophilin-2 (JPH-2) is also downregulated.ObjectivesThe objectives of this study were to understand the role of JPH-2 in PVC-CM and to probe changes in other proteins involved in dyad structure and function.MethodsWe quantify T-tubule contents (di-8-ANEPPS fluorescence in live myocytes), examine myocyte ultrastructures (electron microscopy), probe JPH-2-interacting proteins (co-immunoprecipitation), quantify dyad and nondyad protein levels (immunoblotting), and examine subcellular distributions of dyad proteins (immunofluorescence/confocal microscopy). We also test direct JPH-2 modulation of channel function (vs indirect modulation through dyad formation) using heterologous expression.ResultsPVC myocytes have reduced T-tubule contents but otherwise normal ultrastructures. Among 19 proteins examined, only JPH-2, bridging integrator-1 (BIN-1), and Cav1.2 are highly downregulated in PVC hearts. However, statistical analysis indicates a general reduction in dyad protein levels when JPH-2 is downregulated. Furthermore, several dyad proteins, including Na/Ca exchanger, are missing or shifted from dyads to the peripheral surface in PVC myocytes. JPH-2 directly or indirectly interacts with Cai-handling proteins, Cav1.2 and KCNQ1, although not BIN-1 or other scaffolding proteins tested. Expression in mammalian cells that do not have dyads confirms direct JPH-2 modulation of the L-type Ca channel current (Cav1.2/voltage-gated Ca channel β subunit 2) and slow delayed rectifier current (KCNQ1/KCNE1).ConclusionJPH-2 is more than a "dyad glue": it can modulate Cai handling and ion channel function in the dyad region. Downregulation of JPH-2, BIN-1, and Cav1.2 plays a deterministic role in PVC-CM. Dissecting the hierarchical relationship among the three is necessary for the design of therapeutic interventions to prevent the progression of PVC-CM.

Dataset Information

Impact of ventricular ectopic burden in a premature ventricular contraction-induced cardiomyopathy animal model.

Publications

Impact of ventricular ectopic burden in a premature ventricular contraction-induced cardiomyopathy animal model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets