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. 2020 Jan 7;75(1):1-13.
doi: 10.1016/j.jacc.2019.10.046.

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

Alex Y Tan  1 , Khalid Elharrif  2 , Ricardo Cardona-Guarache  2 , Pranav Mankad  2 , Owen Ayers  3 , Martha Joslyn  3 , Anindita Das  4 , Karoly Kaszala  2 , Shien-Fong Lin  5 , Kenneth A Ellenbogen  2 , Anthony J Minisi  2 , Jose F Huizar  2
Affiliations

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

Alex Y Tan et al. J Am Coll Cardiol. .

Abstract

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.

Keywords: autonomic nervous system; cardiomyopathy; idiopathic ventricular arrhythmia; nonsustained ventricular tachycardia.

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Figures

Figure 1.
Figure 1.. Experimental Protocol.
(A) Sequence of events. (B) Left thoracotomy showing left stellate ganglion and cardiac branch of left thoracic vagal nerve (arrow). (C) Initiation of bigeminal PVC associated with SNA increase. (D): Left ventricular ejection fraction (LVEF) and dP/dT during development of and recovery from PVC-induced cardiomyopathy (PVC-CM). Intermediate stage was obtained after 4-weeks of bigeminal PVC exposure. Abbreviations: SNA, sympathetic nerve activity; VNA, vagal NA; ABP, arterial blood pressure.
Figure 2.
Figure 2.. Changes in resting SNA and VNA with development of and recovery from PVC-CM.
Diurnal profiles of resting SNA (A) and VNA (B) during 24-hour of SR at baseline, PVC-CM and after recovery from PVC-CM. Every point represents 30-second integrated NA. (C) Mean 24-hour resting SNA and VNA in experimental vs sham control groups. ✼: P<0.01 vs Baseline, μ: P<0.05 vs Baseline, ⍦: P<0.01 vs PVC-CM, ⍭: P<0.05 vs PVC-CM.
Figure 3.
Figure 3.. SNA response during exercise.
(A) SNA profile during ETT (up to 3.3mph). (B) Mean and maximal SNA, VNA and RR intervals during ETT.
Figure 4.
Figure 4.. Neural triggers of atrial and ventricular arrhythmias in PVC-CM.
(A) Paroxysmal atrial tachyarrhythmia (PAT). (B) Non-sustained ventricular tachycardia (NSVT). (C) Premature ventricular contractions (PVCs).
Figure 5.
Figure 5.. Pro-arrhythmia in PVC-CM and Recovery.
(A) Increased atrial and ventricular arrhythmia burden with PVC-CM and. Temporal relationship between autonomic nerve activity (NA) and onset of atrial (B) and ventricular (C) arrhythmia.
Figure 6.
Figure 6.. Effect of acute (1-minute) quadrigeminal PVC challenge (200 ms coupling) on NA and BP at baseline, PVC-CM and recovery.
(A) Acute SNA increase within seconds after PVC onset, followed by a slower rise in systolic BP. (B) Mean systolic BP and integrated NA over 5-sec period, before and after PVC onset. (C) Comparison of NA and mean systolic BP in 30-sec segments before vs after PVC onset.
Figure 7.
Figure 7.. Sympathetic Neural Remodeling in PVC-CM.
Immunostaining with Tyrosine Hydroxylase (TH) antibodies of left and right stellate ganglia (LSG, RSG) in sham control (N=5), PVC-CM (N=5) and PVC-CM recovered (N=7) groups. (A) LSG Sham control. (B) LSG PVC-CM. (C) LSG Recovered PVC-CM. (D) Comparison of TH nerve density in R vs LSG. (E) Lack of interstitial fibrosis in PVC-CM. (F) Choline Acetyltransferase (ChAT) staining of L cardiac vagus nerve.
Central Illustration.
Central Illustration.. Neural Remodeling in Premature Ventricular Contraction-Induced Cardiomyopathy.
(A) Proposed Neural Mechanism of Premature Ventricular Contraction-induced Cardiomyopathy (PVC-CM) and consequent pro-arrhythmia. Chronic frequent PVCs cause PVC-CM and neural remodeling. (B) Neural Remodeling in PVC-CM is characterized by increased SNA and VNA. Neural remodeling (increased SNA) persists despite recovery from PVC-CM. (C) In neurally remodeled hearts in PVC-CM and recovered PVC-CM, increased SNA triggers ventricular arrhythmias. ✼ P<0.01 vs Baseline; μ P<0.05 vs Baseline; ⍭ P<0.05 vs PVC-CM; ⍦ P<0.01 vs PVC-CM. Abbreviations: SNA, sympathetic nerve activity; VNA, vagal nerve activity; PVC-CM, premature ventricular contraction-induced cardiomyopathy; VT, ventricular tachycardia.
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