Contribution of Autonomic Reflexes to the Hyperadrenergic State in Heart Failure

Abstract

Heart failure (HF) is a complex syndrome representing the clinical endpoint of many cardiovascular diseases of different etiology. Given its prevalence, incidence and social impact, a better understanding of HF pathophysiology is paramount to implement more effective anti-HF therapies. Based on left ventricle (LV) performance, HF is currently classified as follows: (1) with reduced ejection fraction (HFrEF); (2) with mid-range EF (HFmrEF); and (3) with preserved EF (HFpEF). A central tenet of HFrEF pathophysiology is adrenergic hyperactivity, featuring increased sympathetic nerve discharge and a progressive loss of rhythmical sympathetic oscillations. The role of reflex mechanisms in sustaining adrenergic abnormalities during HFrEF is increasingly well appreciated and delineated. However, the same cannot be said for patients affected by HFpEF or HFmrEF, whom also present with autonomic dysfunction. Neural mechanisms of cardiovascular regulation act as "controller units," detecting and adjusting for changes in arterial blood pressure, blood volume, and arterial concentrations of oxygen, carbon dioxide and pH, as well as for humoral factors eventually released after myocardial (or other tissue) ischemia. They do so on a beat-to-beat basis. The central dynamic integration of all these afferent signals ensures homeostasis, at rest and during states of physiological or pathophysiological stress. Thus, the net result of information gathered by each controller unit is transmitted by the autonomic branch using two different codes: intensity and rhythm of sympathetic discharges. The main scope of the present article is to (i) review the key neural mechanisms involved in cardiovascular regulation; (ii) discuss how their dysfunction accounts for the hyperadrenergic state present in certain forms of HF; and (iii) summarize how sympathetic efferent traffic reveal central integration among autonomic mechanisms under physiological and pathological conditions, with a special emphasis on pathophysiological characteristics of HF.

Keywords: autonomic nervous system; cardiovascular variability; heart failure; sympathetic nerve activity.

Figure 1

Representative tracings of muscle sympathetic nerve activity (MSNA), blood pressure (BP) and respiration rate (RR) in a healthy subject, a patient with heart failure with preserved ejection fraction (HFpEF) and a patient with heart failure with reduced ejection fraction (HFrEF), at rest. Note the difference in the discharge patterns of the sympathetic outflow between healthy control subjects vs. HFpEF vs. HFrEF patients. Representative tracings of MSNA, BP and RR are unpublished material.

Figure 2

Classical schematic diagram of arterial baroreflex control (A), cardiopulmonary reflex (B), cardiac sympathetic afferent reflex (C), and arterial chemoreflex (D). NTS, nucleus tractus solitarii; NA, nucleus ambiguus; DMV, dorsal motor nucleus of the vagus; CVLM, caudal ventrolateral medulla; RVLM, rostral ventrolateral medulla; PVN, paraventricular nucleus of the hypothalamus; A5, noradrenergic neurons of the ventrolateral pons; RTN/pFRG, retrotrapezoid nucleus/parafacial respiratory group; VRC, ventral respiratory column; BötC, Bötzinger complex; pre-BötC, pre-Bötzinger complex; Rvrg, rostral ventral respiratory group; eSN, efferent sympathetic nerve; PN, phrenic nerve; VN, vagus nerve.

Figure 3

Hypothetical representation of the reflex mechanisms considered as “controller units,” and their complex and dynamic interaction in a physiological condition (A) and during heart failure (B). CSAR, cardiac sympathetic afferents reflex; PVN, paraventricular nucleus of the hypothalamus; SN, sympathetic nerve; VN, vagus nerve. Note that the sustained hyperadrenergic state in patients with HF occurs due to the predominance of inputs of excitatory mechanisms on inhibitory mechanisms.