Parasympathetic Nervous System and Heart Failure

Abstract

A bundant evidence links sympathetic nervous system activation to outcomes of patients with heart failure (HF). 1 In contrast, parasympathetic activation has complex cardiovascular effects that are only beginning to be recognized. In particular, the pathophysiological roles of normal and disordered parasympathetic innervation in patients with HF are not understood as comprehensively. [2][3][4][5] In the present article, we review cardiovascular responses to parasympathetic activation, address the modulating factors that can affect parasympathetic function, discuss the role of the vagus nerve in ventricular dysfunction, and consider how activation of the parasympathetic nervous system may have important therapeutic implications for patients with congestive HF. Structure of the Parasympathetic Limb of the Autonomic Nervous SystemThe parasympathetic nervous system originates from medial medullary sites (nucleus ambiguous, nucleus tractus solitarius, and dorsal motor nucleus) and is modulated by the hypothalamus. Vagal efferents extend from the medulla to postganglionic nerves that innervate the atria via ganglia located in cardiac fat pads with neurotransmission that is modulated via nicotinic receptors. Postganglionic parasympathetic and sympathetic cholinergic nerves then affect cardiac muscarinic receptors (the Figure). 6 -8 Vagus nerve afferent activation, originating peripherally, can modulate efferent sympathetic and parasympathetic function centrally and at the level of the baroreceptor.Efferent vagus nerve activation can have tonic and basal effects that inhibit sympathetic activation and release of norepinephrine at the presynaptic level. Acetylcholine release from parasympathetic nerve terminals will activate ganglionic nicotinic receptors that in turn activate muscarinic receptors at the cellular level. Cardiovascular effects include heart rate reduction by inhibition of the sympathetic nervous system and by direct hyperpolarization of sinus nodal cells. Parasympathetic activation can affect atrioventricular nodal conduction mediated predominantly through the left vagus nerve. Furthermore, muscarinic receptors on blood vessel walls can cause vasorelaxation through a nitric oxide (NO)-modulated pathway but can also cause vasoconstriction by directly activating smooth muscle. 6 -8 Therefore, although the sympathetic nervous system has global effects on cardiovascular physiology in an all-or-none type of response, the parasympathetic nervous system can have selective modulation at various levels. Parasympathetic/Sympathetic InteractionsThe sympathetic and parasympathetic nervous systems are not "opposites"; rather, the interactions are complex. 9 A dynamic interaction occurs between them; these interactions are modulated partially by secondary messengers (cAMP and cGMP). The parasympathetic nervous system can inhibit sympathetic nerve traffic presynaptically. Likewise, sympathetic activation can inhibit parasympathetic activation presynaptically.Vagal "tone" (tonic parasympathetic activation) predominates...

Reduced N‐Type Ca 2+ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis

“…The vagal preganglionic efferent extends to the intracardiac ganglia, located in cardiac fat pads, to form synapses with intracardiac ganglion neurons 20. Intracardiac ganglion neurons provide local neural coordination independent of high brain centers 21.…”

Autonomic regulation therapy to enhance myocardial function in heart failure patients: the ANTHEM‐HFpEF study

“…Whether enhancing parasympathetic tone by VNS may be beneficial in patients with HFpEF and HFmrEF has not been examined. However, existing pre‐clinical and clinical evidence is available, demonstrating that sympathoinhibition using parasympathetic interventions leads to improvements in central and peripheral neural network functions, baroreceptor reflexes, myocyte energetics, and regression of LV hypertrophy 15, 17, 30, 31…”

“…Vagus nerve stimulation increases parasympathetic activity, reduces sympathetic tone, and stabilizes the neural network in the autonomic nervous system regulating cardiovascular function 14. Increased parasympathetic activity results in increased muscarinic receptor activation and decreases excess adrenergic receptor activation 15. Muscarinic receptor activation at the level of the cardiac myocyte reduces oxidative stress, increases contractile function, improves calcium signalling function in the heart, and normalizes gene expression 15, 16.…”

“…Increased parasympathetic activity results in increased muscarinic receptor activation and decreases excess adrenergic receptor activation 15. Muscarinic receptor activation at the level of the cardiac myocyte reduces oxidative stress, increases contractile function, improves calcium signalling function in the heart, and normalizes gene expression 15, 16. At the same time, cholinergic trans‐differentiation of sympathetic neurons takes place, providing a protective role against sympathetically mediated pathogenesis 17.…”

Neuro-cardiac interaction in malignant ventricular arrhythmia and sudden cardiac death

“…Over the years, the vagus nerve has been found to do a lot more than just slowing down the sinus rate and its stimulation has far-reaching effects in many processes related to cardiac function (Olshansky et al 2008) some of which may play an important role in protecting the heart against ventricular arrhythmias (Brack et al 2013) (Figure 5). …”