Persistent Proarrhythmic Neural Remodeling Despite Recovery From Premature Ventricular Contraction-Induced Cardiomyopathy

Q: What are the key findings of this study?

Chronic bigeminal PVCs caused sympathetic neural hyperactivity (p=0.004 vs baseline) and atrial/ventricular pro-arrhythmia (p=0.03) that persisted 4 weeks after LVEF normalization.

Q: What is the clinical evidence from this study?

Population: Premature ventricular contraction-induced cardiomyopathy (PVC-CM) (n=12). Intervention: Chronic bigeminal premature ventricular contractions (200 ms coupling interval) followed by 4 weeks of PVC disabling vs. Sham controls (identical surgery and chronic instrumentation without PVCs). Primary outcome: Resting left stellate ganglion sympathetic nerve activity (SNA) after 4-week recovery from PVC-CM vs baseline (p=0.004).

Q: What does this research mean for the field?

Premature ventricular contraction-induced cardiomyopathy causes stellate ganglion hyperinnervation and persistent sympathetic neural hyperactivity that sustains pro-arrhythmia despite complete recovery of left ventricular ejection fraction. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Alex Y. Tan; Khalid Elharrif; Ricardo Cardona‐Guarache; Pranav Mankad; Owen Ayers; Martha Joslyn; Anindita Das; Károly Kaszala; Shien‐Fong Lin; Kenneth A. Ellenbogen; Anthony J. Minisi; José F. Huizar

doi:10.1016/j.jacc.2019.10.046

January 1, 2020Journal of the American College of CardiologyOpen Access

Persistent Proarrhythmic Neural Remodeling Despite Recovery From Premature Ventricular Contraction-Induced Cardiomyopathy

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Key result

Chronic bigeminal PVCs cause persistent sympathetic hyperactivity and pro-arrhythmia despite normalized LVEF.

P=0.004
n=12

Why the study?

The presence and significance of neural remodeling in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remained unknown.

Does chronic premature ventricular contraction-induced cardiomyopathy cause persistent proarrhythmic autonomic neural remodeling despite complete recovery of left ventricular ejection fraction in a canine model?

Key Points

To characterize cardiac sympatho-vagal balance, neural remodeling, and susceptibility to arrhythmias in a canine model of premature ventricular contraction-induced cardiomyopathy before and after systolic recovery.
Implanted epicardial pacemakers and radiotelemetry in 12 canines to continuously record left stellate ganglion nerve activity, left cardiac vagus nerve activity, and blood pressure.
Applied bigeminal premature ventricular contractions (200 ms coupling) for 12 weeks to induce cardiomyopathy in 7 animals, followed by 4 weeks of cessation to permit left ventricular ejection fraction recovery, alongside 5 sham controls.
Evaluated autonomic responses to exercise, acute premature ventricular contraction challenge, intravenous clonidine administration (10 μg/kg), and histological tyrosine hydroxylase immunoreactivity.
After 12 weeks of premature ventricular contractions, left ventricular ejection fraction decreased (p=0.006), resting sympathetic nerve activity increased (p=0.002), and spontaneous atrial (p=0.02) and ventricular (p=0.03) arrhythmias emerged, immediately preceded by sympathetic surges.
Following 4 weeks of cessation, ejection fraction recovered to baseline (p=0.001 vs cardiomyopathy, p=0.38 vs baseline), but resting sympathetic nerve activity (p=0.004 vs baseline) and spontaneous atrial and ventricular arrhythmias (both p=0.03 vs baseline) persisted.
Histology demonstrated sympathetic hyperinnervation in the left (p=0.02) and right (p=0.008) stellate ganglia of cardiomyopathy and recovered animals compared with sham controls, while ventricular innervation (p=0.2) and fibrosis (p=0.1) remained unchanged.

Structured PICO

Does chronic premature ventricular contraction-induced cardiomyopathy cause persistent proarrhythmic autonomic neural remodeling despite complete recovery of left ventricular ejection fraction in a canine model?

P

Population

12 Mongrel canines (20-30 kg) implanted with epicardial pacemakers and radiotelemetry units, studied over 16 weeks (152±3 days in the experimental group).

I

Intervention

Chronic bigeminal premature ventricular contractions (200 ms coupling interval) via right ventricular apex epicardial pacing for 12 weeks to induce PVC-CM, followed by disabling PVCs for 4 weeks to allow LVEF recovery (plus acute IV clonidine 10 μg/kg and phenylephrine 0.1 mg challenges).

C

Comparator

Sham-operated control canines (n=5) undergoing identical surgery and chronic instrumentation with serial assessments in sinus rhythm without PVCs over 8 weeks (58±2 days).

O

Outcome

Cardiac autonomic nerve activity (left stellate ganglion sympathetic nerve activity [SNA] and left thoracic vagus nerve activity [VNA]), left ventricular function (LVEF, dP/dT), and spontaneous atrial and ventricular arrhythmia burden at baseline, after 12 weeks of PVC-CM, and after 4 weeks of recovery.surrogate

Main Result

p-value: p=0.004

In a canine model of PVC-induced cardiomyopathy, extracardiac stellate ganglion sympathetic hyperinnervation, heightened sympathetic tone, and atrial and ventricular pro-arrhythmia persist even after complete normalization of LVEF following PVC suppression.

Limitations

Did not record nerve activity from the intrinsic cardiac autonomic nervous system
Did not measure serum norepinephrine levels
4-week recovery period may have been too short to determine if further recovery of sympathetic nerve activity occurs
Animal model was limited by the use of fixed coupled PVCs from the right ventricular apex
Unclear whether elevated sympathetic tone per se is causative of PVC-CM
4-week recovery duration may not be long enough to determine if further recovery of sympathetic nerve activity occurs
Whether elevated sympathetic tone per se is causative of PVC-CM remains unresolved

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

May warrant extended arrhythmia monitoring after LVEF recovery; leaves open translation to human PVC-cardiomyopathy.

Abstract

Background The presence and significance of neural remodeling in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remain unknown. Objectives To characterize cardiac sympatho-vagal balance and pro-arrhythmia in a canine model of PVC-CM. Methods In 12 canines, we implanted epicardial pacemakers and radiotelemetry unit to record cardiac rhythm and nerve activity (NA) from the left stellate ganglion (SNA), left cardiac vagus (VNA) and arterial blood pressure. Bigeminal PVCs (200ms 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), vs 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, while 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) pro-arrhythmia persisted. There was sympathetic hyperinnervation in stellate ganglia (p=0.02) but not ventricles (p=0.2) of PVC-CM and recovered animals vs sham controls. Conclusion Neural remodeling in PVC-CM is characterized by extracardiac sympathetic hyperinnervation and sympathetic neural hyperactivity that persists despite normalization of LVEF. The altered cardiac sympatho-vagal balance is an important trigger and substrate for atrial and ventricular pro-arrhythmia.

Discussion

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Cite This Study

Tan et al. (2020) studied Premature ventricular contraction-induced cardiomyopathy (PVC-CM) (n=12). Chronic bigeminal premature ventricular contractions (200 ms coupling interval) followed by 4 weeks of PVC disabling vs. Sham controls (identical surgery and chronic instrumentation without PVCs) was evaluated on Resting left stellate ganglion sympathetic nerve activity (SNA) after 4-week recovery from PVC-CM vs baseline (p=0.004). Chronic bigeminal PVCs caused sympathetic neural hyperactivity (p=0.004 vs baseline) and atrial/ventricular pro-arrhythmia (p=0.03) that persisted 4 weeks after LVEF normalization.

synapsesocial.com/papers/6af1e39aa3039a5872532d1a https://doi.org/10.1016/j.jacc.2019.10.046

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Persistent Proarrhythmic Neural Remodeling Despite Recovery From Premature Ventricular Contraction-Induced Cardiomyopathy

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Persistent Proarrhythmic Neural Remodeling Despite Recovery From Premature Ventricular Contraction-Induced Cardiomyopathy

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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