The non-neuronal cholinergic system in the heart: A comprehensive review

The autonomic influences on the heart have a ying-yang nature, albeit oversimplified, the interplay between the sympathetic and parasympathetic system (known as the cholinergic system) is often complex and remain poorly understood. Recently, the heart has been recognized to consist of neuronal and non-neuronal cholinergic system (NNCS). The existence of cardiac NNCS has been confirmed by the presence of cholinergic markers in the cardiomyocytes, which are crucial for synthesis (choline acetyltransferase, ChAT), storage (vesicular acetylcholine transporter, VAChT), reuptake of choline for synthesis (high-affinity choline transporter, CHT1) and degradation (acetylcholinesterase, AChE) of acetylcholine (ACh). The non-neuronal ACh released from cardiomyocytes is believed to locally regulate some of the key physiological functions of the heart, such as regulation of heart rate, offsetting hypertrophic signals, maintenance of action potential propagation as well as modulation of cardiac energy metabolism via the muscarinic ACh receptor in an auto/paracrine manner. Apart from this, several studies have also provided evidence for the beneficial role of ACh released from cardiomyocytes against cardiovascular diseases such as sympathetic hyperactivity-induced cardiac remodeling and dysfunction as well as myocardial infarction, confirming the important role of NNCS in disease prevention. In this review, we aim to provide a fundamental overview of cardiac NNCS, and information about its physiological role, regulatory factors as well as its cardioprotective effects. Finally, we propose the different approaches to target cardiac NNCS as an adjunctive treatment to specifically address the withdrawal of neuronal cholinergic system in cardiovascular disease such as heart failure.