Intrinsic Sinoatrial Node Dysfunction Impairs Autonomic Regulation of Heart Rate Variability in Hypertensive Heart Disease

Abstract

Vagal control of the sinoatrial node (SAN) is a major mechanism that regulates beat-to-beat heart rate variability (HRV) at rest. Classically, reduced HRV in the setting of hypertensive heart disease and heart failure has been attributed to chronically elevated sympathetic and reduced vagal regulation of heart rate. However, both of these conditions are also associated with intrinsic SAN dysfunction which may change the gain and dynamic response of the SAN to autonomic stimulation. The relationship between autonomic nerve activity and the responsiveness of SAN myocytes to descending neural signals in hypertension remain unclear. Here, we investigated how intrinsic SAN dysfunction impacts autonomic regulation of HRV in a mouse model of angiotensin II (AngII) mediated hypertensive heart disease. Mice infused with AngII via mini-osmotic pumps (2.5mg/kg/day for 3 weeks) had reduced HRV and increased adrenergic tone indicated by elevated renal sympathetic nerve activity and circulating catecholamine levels. Interestingly, AngII infused mice had no change in vagal nerve activity compared to saline treated controls. Electrograms recorded from isolated atrial preparations devoid of neural input, as well as isolated SAN myocytes assessed through patch clamp electrophysiology, demonstrated increased beating rate variability and reduced responsiveness to both the β-adrenergic agonist isoproterenol and the muscarinic agonist carbachol. Together, these data suggest that the SAN is a major contributor to the loss of regular HRV in hypertensive heart disease due to desensitization of descending neural signals. Our data suggests that elevated sympathetic tone, in conjunction with reduced responsiveness of the SAN to parasympathetic agonists, are responsible for diminished HRV in the setting of hypertensive heart disease. Thus, the interpretation of HRV as a pure measure of cardiac autonomic tone may be inappropriate in the setting of diseases with concurrent SAN dysfunction.