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

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

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2 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalJournal of the American College of Cardiology
Issue number1
StatePublished - Jan 7 2020


  • autonomic nervous system
  • cardiomyopathy
  • idiopathic ventricular arrhythmia
  • nonsustained ventricular tachycardia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Tan, A. Y., Elharrif, K., Cardona-Guarache, R., Mankad, P., Ayers, O., Joslyn, M., Das, A., Kaszala, K., Lin, S. F., Ellenbogen, K. A., Minisi, A. J., & Huizar, J. F. (2020). Persistent Proarrhythmic Neural Remodeling Despite Recovery From Premature Ventricular Contraction-Induced Cardiomyopathy. Journal of the American College of Cardiology, 75(1), 1-13.