The sympathetic/parasympathetic imbalance in heart failure with reduced ejection fraction

Abstract

Cardiovascular autonomic imbalance, a cardinal phenotype of human heart failure, has adverse implications for symptoms during wakefulness and sleep; for cardiac, renal, and immune function; for exercise capacity; and for lifespan and mode of death. The objectives of this Clinical Review are to summarize current knowledge concerning mechanisms for disturbed parasympathetic and sympathetic circulatory control in heart failure with reduced ejection fraction and its clinical and prognostic implications; to demonstrate the patient-specific nature of abnormalities underlying this common phenotype; and to illustrate how such variation provides opportunities to improve or restore normal sympathetic/parasympathetic balance through personalized drug or device therapy.

Keywords: Baroreceptor reflex; Chemoreceptor reflex; Exercise; Heart failure; Human; Parasympathetic nervous system; Sleep apnoea; Sympathetic nervous system.

Figure 1

Number and percentage of total identified efferent muscle sympathetic single units in healthy controls and heart failure that increase firing rate reflexively in response to non-hypotensive lower body negative pressure (LBNP; −10 mmHg) and decrease firing rate reflexively in response to non-hypertensive lower body positive pressure (LBPP; +10 mmHg): ‘anticipated’, or that decrease firing rate reflexively in response to non-hypotensive lower body negative pressure (LBNP; −10 mmHg) and increase firing rate reflexively in response to non-hypertensive lower body positive pressure (LBPP; +10 mmHg): ‘paradoxical’. P-values for proportion of anticipated : paradoxical responses observed in heart failure patients compared with healthy controls. Reproduced from Millar et al.

Figure 2

Hypothetical mechanisms linking altered myocardial function to central and peripheral disturbances of the immune and autonomic systems resulting in mutual facilitation of heart failure progression. Reproduced from Jankowska et al. with permission of the European Society of Cardiology.

Figure 3

Similar heart rate (top panel) but divergent muscle sympathetic nerve activity burst frequency (lower panel) responses to graded one-legged dynamic exercise in subjects with and without heart failure. Heart rate increased significantly in response to increasing exercise intensity during the second minute of one-legged cycling in both healthy control (white bars) and heart failure (black bars) subjects (+, P < 0.003 for 50% vs. zero load cycling) with no between-group difference (P = 0.10). Muscle sympathetic nerve activity burst frequency (bursts/min) decreased significantly from baseline during both exercise intensities in healthy control subjects but decreased significantly during both exercise intensities in heart failure patients (*, P < 0.001 HFrEF vs. control). This divergence became more pronounced as exercise intensity increased (P = 0.01) with no between-group interaction. There was no significant difference in muscle sympathetic nerve activity between exercise intensities within groups (P = 0.78). Adapted from Notarius et al.

Figure 4

Mechanisms involved in the autonomic disturbances of HFrEF. Input from arterial and cardiac mechano- and chemoreceptor afferents, arterial chemoreceptor, pulmonary stretch receptor, muscle metabo- and mechanoreceptor, and renal afferent nerves converse to modulate sympathetic outflow about a centrally mediated set point increase, involving an angiotensin II-AT₁ receptor-NADPH-superoxide pathway. As systolic dysfunction progresses, input effecting sympatho-inhibition (−) by stimulating ventricular and a population of atrial mechanoreceptor nerve afferents decreases (thin line), whereas inhibitory modulation of efferent sympathetic nerve traffic by arterial baroreceptors (thick line) is preserved. Efferent vagal heart rate responses to arterial baroreflex perturbations are attenuated (thin line). Excitatory (+) afferent input arises from: a normally quiescent atrial reflex, activated by increases in cardiac filling pressures; chemically sensitive ventricular afferent nerve endings, triggered by ischaemia; augmented sympatho-excitatory input from arterial chemoreceptors; exercising skeletal muscle in heart failure; and renal afferent nerves (thick lines). The central set point for sympathetic outflow (arrow pointing down) is raised further by central chemoreceptor sensitization, by sleep apnoeas, and possibly by obesity. Efferent mechanisms for increased NE spillover include pre-junctional facilitation of its release and impaired NE uptake. The time course through which these mechanisms are engaged differs between individuals. Relatively asymptomatic systolic dysfunction is characterized by a selective increase in cardiac NE release, and a reduction in tonic and reflex vagal heart rate modulation; as heart failure advances there is a generalized increase in sympathetic nerve traffic to the heart, adrenal, kidney, skeletal muscle, and other vascular beds (thick arrow shafts, thick lines). Ach, acetylcholine; CNS, central nervous system; E, epinephrine; Na⁺, sodium; NE, norepinephrine. (Reproduced with the first author's permission).

Figure 5

Present and future therapeutic opportunities to restore autonomic balance in heart failure.