Premature ventricular contractions activate vagal afferents and alter autonomic tone: implications for premature ventricular contraction-induced cardiomyopathy

Abstract

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.

Keywords: afferent; autonomic; nodose ganglia; parasympathetic; premature ventricular contractions; vagus nerve.

Conflict of interest statement

M. Vaseghi and J. L. Ardell have founder shares in Neurcures, Inc. University of California, Los Angeles, has patents developed by M. Vaseghi and J. L. Ardell relating to cardiac neural diagnostics.

Figures

Fig. 1.

Nodose ganglia in vivo neuronal recordings. A: anatomic locations of the nodose ganglion and carotid artery are shown. Protein gene product (PGP) 9.5 staining of the nodose ganglion was used to confirm location of the ganglion at the end of the experiments. B: customized 16-channel linear microelectrode array was used for individual neuronal recordings. C: representative sorted neuronal action potentials from the nodose ganglion of 1 animal. Representative action potentials from individual neurons are illustrated in the boxes. D: representative activities generated by 6 nodose neuronal soma in response to premature ventricular contractions (PVCs) in 1 animal. Increase in the activity of these nodose neurons (P < 0.05) can be observed during PVCs in this animal. CH, electrode channel; LVP, left ventricular pressure (mmHg).

Fig. 2.

Response of neurons to cardiovascular stimuli. A: 89 cardiac afferent neurons (each row is an individual neuron) were identified based on their response to cardiovascular interventions, including PVCs. B: percentage of cardiac neurons that responded to each stressor is shown. PVCs engaged the highest number of afferent neurons. *P < 0.05 vs. other interventions (ANOVA). C: average change in firing rate of all nodose cardiac afferent neurons (n = 89). PVCs, left anterior descending (LAD) occlusion, and IVC occlusion caused the greatest change in firing rates of neurons. *P < 0.01 (ANOVA).

Fig. 3.

Type of afferent neurons modulated by premature ventricular contractions (PVCs). A: location of right ventricular (RV) and left ventricular (LV) application of mechanical and chemical stimuli is shown by the shaded area (white square). Mechanical and chemical stimuli were applied to the same receptive field. B: PVCs activated both mechanosensitive and chemosensitive neurons. C: percentages of mechanical, chemical, and multimodal neurons that responded to PVCs are shown. ADE, adenosine; BRA, bradykinin; C, chemical neurons; CAP, capsaicin; CHEM, chemical stimulation; EMS, epicardial mechanical stimulation; LAD, left anterior descending; M, mechanical neurons; MM, multimodal neurons; VER, veratridine.

Fig. 4.

Response of cardiac afferent neurons activated with premature ventricular contractions (PVCs). A: response of neurons that were activated during PVCs shows elevated firing rates even after cessation of PVCs (response evaluated over the minute following discontinuation of PVCs). B: response of neurons as a function of the PVC number during the 1-min period is shown. C: representative example of a PVC coupling interval and underlying sinus cycle length. Ratio of the coupling interval to the sinus cycle length was used to assess effect of early vs. late-coupled PVCs on neuronal activation. Representative sinus cycle length (569 ms, as shown) and PVC coupling interval (395 ms, as shown) are shown. D: response of neurons to PVCs as a function of the coupling interval to sinus rhythm ratio. Late-coupled PVCs (ratio of 80–90%) caused the greatest neuronal activity. *P < 0.05 (ANOVA). BL, baseline; CI, coupling interval; CL, cycle length; LVP, left ventricular pressure.