Autonomic nervous system and cardiac neuro-signaling pathway modulation in cardiovascular disorders and Alzheimer's disease

Abstract

The heart is a functional syncytium controlled by a delicate and sophisticated balance ensured by the tight coordination of its several cell subpopulations. Accordingly, cardiomyocytes together with the surrounding microenvironment participate in the heart tissue homeostasis. In the right atrium, the sinoatrial nodal cells regulate the cardiac impulse propagation through cardiomyocytes, thus ensuring the maintenance of the electric network in the heart tissue. Notably, the central nervous system (CNS) modulates the cardiac rhythm through the two limbs of the autonomic nervous system (ANS): the parasympathetic and sympathetic compartments. The autonomic nervous system exerts non-voluntary effects on different peripheral organs. The main neuromodulator of the Sympathetic Nervous System (SNS) is norepinephrine, while the principal neurotransmitter of the Parasympathetic Nervous System (PNS) is acetylcholine. Through these two main neurohormones, the ANS can gradually regulate cardiac, vascular, visceral, and glandular functions by turning on one of its two branches (adrenergic and/or cholinergic), which exert opposite effects on targeted organs. Besides these neuromodulators, the cardiac nervous system is ruled by specific neuropeptides (neurotrophic factors) that help to preserve innervation homeostasis through the myocardial layers (from epicardium to endocardium). Interestingly, the dysregulation of this neuro-signaling pathway may expose the cardiac tissue to severe disorders of different etiology and nature. Specifically, a maladaptive remodeling of the cardiac nervous system may culminate in a progressive loss of neurotrophins, thus leading to severe myocardial denervation, as observed in different cardiometabolic and neurodegenerative diseases (myocardial infarction, heart failure, Alzheimer's disease). This review analyzes the current knowledge on the pathophysiological processes involved in cardiac nervous system impairment from the perspectives of both cardiac disorders and a widely diffused and devastating neurodegenerative disorder, Alzheimer's disease, proposing a relationship between neurodegeneration, loss of neurotrophic factors, and cardiac nervous system impairment. This overview is conducive to a more comprehensive understanding of the process of cardiac neuro-signaling dysfunction, while bringing to light potential therapeutic scenarios to correct or delay the adverse cardiovascular remodeling, thus improving the cardiac prognosis and quality of life in patients with heart or neurodegenerative disorders.

Keywords: Alzheimer’s disease; autonomic nervous system; cardiac innervation; heart failure; myocardial infarction; neurochemical pathways; neurotrophic factors.

FIGURE 1

Neuro-signaling pathway dysregulation in relation to the development of heart damage. The gradual loss of neurotrophic factors (i.e.; NGF, BDNF) severely affects the neuro-signaling pathway of the brain/heart axis, increasing the incidence to develop cardiovascular disorders of different etiology. In Alzheimer’s disease (AD), amyloid-β accumulation significantly impacts the expression of neurotrophins, resulting in a maladaptive remodeling of the neuro-signaling pathway with a dramatic cognitive decline and dementia development. It is reasonable to hypothesize that the progressive degeneration of the neuro signaling pathway associated with neuronal impairment observed in the brain of AD patients may trigger a gradual decline in neurotrophic factors circulating levels, leading to a severe derangement of the cardiac nervous system, culminating in lethal heart disorders (such as AF, MI, HF). During heart failure, progressively, the blood pressure drops together with the cardiac output, resulting in brain hypoperfusion, thus leading to sympathetic nervous system hyperactivation. This induces norepinephrine (NE) over-release from sympathetic fibers, culminating in the upregulation of catecholamine circulating levels. In parallel, neuro-signaling is downregulated in the myocardium (green triangle), with progressive impoverishment of autonomic nerve fibers, leading to extended myocardial denervation.

FIGURE 2

Schematic illustration of therapeutic approaches to modulate the cardiac autonomic nervous system. RAAS, renin-angiotensin aldosterone system; VNS, Vagal Nerve Stimulation.