Defining a role for AMP-activated protein kinase in the autonomic regulation of heart rate

The autonomic nervous system (ANS) is a fundamental regulator of heart rate (HR) and cardiovascular homeostasis. Dysregulation of cardiac autonomic balance – specifically excessive sympathetic drive and reduced vagal activity – contributes to the development and progression of many cardiovascular disorders, including hypertension, atrial fibrillation and heart failure. Therapies such as vagal nerve stimulation, are used that address this. Humans bearing activating mutations in the cell’s energy sensor, AMP-activated protein kinase (AMPK), express a phenotype (PRKAG2 cardiomyopathy) notable for high prevalence of symptomatically low HR (sinus bradycardia).

We have used gene-targeted mice to identify that AMPK both inhibits intrinsic sinoatrial pacemaker mechanisms, and may promotes a vagal contribution to the bradycardia, raising the possibility that AMPK regulates HR in physiology and disease through combined intrinsic sinoatrial and autonomic influences. This proposal will evaluate autonomic function in a unique cohort of patients with PRKAG2 cardiomyopathy and mouse models of altered AMPK function to determine the ANS contribution to AMPK-dependent bradycardia and investigate whether AMPK may physiologically effect neural HR control.

The findings will have therapeutic implications for PRKAG2 cardiomyopathy and common disease states of pathologically-altered cardiac autonomic tone.