Chemogenetic activation of intracardiac cholinergic neurons improves cardiac function in pressure overload-induced heart failure
American Journal of Physiology - Heart and Circulatory Physiology
© 2020 the American Physiological Society. Chemogenetic activation of intracardiac cholinergic neurons improves cardiac function in pressure overload-induced heart failure. Am J Physiol Heart Circ Physiol 319: H3-H12, 2020. First published May 15, 2020; doi:10.1152/ajpheart.00150.2020.-Heart failure (HF) is characterized by autonomic imbalance with sympathetic hyperactivity and loss of parasympathetic tone. Intracardiac ganglia (ICG) neurons represent the final common pathway for vagal innervation of the heart and strongly regulate cardiac functions. This study tests whether ICG cholinergic neuron activation mitigates the progression of cardiac dysfunction and reduces mortality that occurs in HF. HF was induced by transaortic constriction (TAC) in male transgenic Long-Evans rats expressing Cre recombinase within choline acetyltransferase (ChAT) neurons. ChAT neurons were selectively activated by expression and activation of excitatory designer receptors exclusively activated by designer receptors (DREADDs) by clozapine-N-oxide (TAC + treatment and sham-treated groups). Control animals expressed DREADDs but received saline (sham and TAC groups). A separate set of animals were telemetry instrumented to record blood pressure (BP) and heart rate (HR). Acute activation of ICG neurons resulted in robust reductions in BP (∼20 mmHg) and HR (∼100 beats/min). All groups of animals were subjected to weekly echocardiography and treadmill stress tests from 3 to 6 wk post-TAC/sham surgery. Activation of ICG cholinergic neurons reduced the left ventricular systolic dysfunction (reductions in ejection fraction, fractional shortening, stroke volume, and cardiac output) and cardiac autonomic dysfunction [reduced HR recovery (HRR) post peak effort] observed in TAC animals. Additionally, activation of ICG ChAT neurons reduced mortality by 30% compared with untreated TAC animals. These data suggest that ICG cholinergic neuron activation reduces cardiac dysfunction and improves survival in HF, indicating that ICG neuron activation could be a novel target for treating HF.
Dyavanapalli, J., Hora, A., Escobar, J., Schloen, J., Dwyer, M., Rodriguez, J., Spurney, C., Kay, M., & Mendelowitz, D. (2020). Chemogenetic activation of intracardiac cholinergic neurons improves cardiac function in pressure overload-induced heart failure. American Journal of Physiology - Heart and Circulatory Physiology, 319 (1). http://dx.doi.org/10.1152/ajpheart.00150.2020