Autonomic control of ventricular function in health and disease: current state of the art

Abstract

Purpose Cardiac autonomic dysfunction is one of the main pillars of cardiovascular pathophysiology. The purpose of this review is to provide an overview of the current state of the art on the pathological remodeling that occurs within the autonomic nervous system with cardiac injury and available neuromodulatory therapies for autonomic dysfunction in heart failure. Methods Data from peer-reviewed publications on autonomic function in health and after cardiac injury are reviewed. The role of and evidence behind various neuromodulatory therapies both in preclinical investigation and in-use in clinical practice are summarized. Results A harmonic interplay between the heart and the autonomic nervous system exists at multiple levels of the neuraxis. This interplay becomes disrupted in the setting of cardiovascular disease, resulting in pathological changes at multiple levels, from subcellular cardiac signaling of neurotransmitters to extra-cardiac, extra-thoracic remodeling. The subsequent detrimental cycle of sympathovagal imbalance, characterized by sympathoexcitation and parasympathetic withdrawal, predisposes to ventricular arrhythmias, progression of heart failure, and cardiac mortality. Knowledge on the etiology and pathophysiology of this condition has increased exponentially over the past few decades, resulting in a number of different neuromodulatory approaches. However, significant knowledge gaps in both sympathetic and parasympathetic interactions and causal factors that mediate progressive sympathoexcitation and parasympathetic dysfunction remain. Conclusions Although our understanding of autonomic imbalance in cardiovascular diseases has significantly increased, specific, pivotal mediators of this imbalance and the recognition and implementation of available autonomic parameters and neuromodulatory therapies are still lagging.

Thoracic epidural blockade after myocardial infarction benefits from anti-arrhythmic pathways mediated in part by parasympathetic modulation

“…Given that the effects of TEA are canonically mediated via inhibition of spinal sympathetic outflow, 38 we sought to determine whether the improvement in BRS was at least partially mediated by reductions in sympathetic efferent tone. To this end, in a separate group of animals ( N =6), we measured BRS pre and post administration of the β-adrenergic receptor blocker metoprolol (5 mg, IV; 0.096±0.002 mg/kg).…”

The Intrinsic Cardiac Nervous System: From Pathophysiology to Therapeutic Implications

“…In physiological conditions, βAR activation leads to increased inotropism and bathmotropism [75] as a consequence of the facilitation of sarcoplasmic release of calcium by PKA activation and RyR2 modulation; increased lusitropism by phosphorylation of phospholamban and disinhibition of SERCA2a; increased chronotropism by increased conductance of HCN channels; and increased dromotropism by increased conductance of CACNA1C channels. From a purely electrophysiological point of view, βAR activation affects both depolarization (increase in excitability and conduction velocity) and repolarization (reduction in action potential duration, increase in spatial and temporal dispersion of repolarization, mostly with neuronal sympathetic activation compared to circulating catecholamines, and increase in the steepness of the slope of action potential duration restitution curve [76]).…”

Cardiac vagal afferent neurotransmission in health and disease: review and knowledge gaps

“…Cardiac injury induces pathological changes in the autonomic nervous system, resulting in autonomic imbalance ( Fukuda et al, 2015 ; Ardell and Armour, 2016 ; Van Weperen et al, 2023 ). The consequent sympathoexcitation and parasympathetic withdrawal lead to progression of heart failure and predispose to fatal ventricular arrhythmias, increasing the incidence of sudden death ( Vaseghi and Shivkumar, 2008 ; Florea and Cohn, 2014 ; Shen and Zipes, 2014 ; Ardell and Armour, 2016 ; Wu and Vaseghi, 2020 ).…”

“…Upon cardiac injury, autonomic balance becomes disrupted, characterized by increased cardiac sympathetic tone and parasympathetic withdrawal ( Florea and Cohn, 2014 ; Ardell and Armour, 2016 ; Van Weperen et al, 2023 ). These changes subsequently lead to further progression of cardiac disease, including heart failure, and increased susceptibility to ventricular arrhythmias after myocardial infarction, and therefore, sudden cardiac death ( Vaseghi and Shivkumar, 2008 ; Ardell and Armour, 2016 ; Wu and Vaseghi, 2020 ).…”