Synapses in the heart: sympathetic neuro‐cardiac interaction modulates myocardial remodelling in healthy and diseased myocardium

The communication between the brain and the heart via the sympathetic or parasympathetic nervous systems enables intricate regulation of heart rate, blood pressure and muscle contractility in the human heart. A neurological imbalance in the autonomous nervous system can thus result in cardiac arrhythmias, cardiac dysfunction and eventual heart failure. In the heart, the myocardium is densely innervated by sympathetic neurons (SNs), and increased sympathetic input or hyperactive cardiac SNs are often observed in heart disease, contributing to the arrhythmia burden in the heart as well as sudden cardiac death. In fact, beta-adrenoreceptor blockers, one of the most commonly used medications in the treatment of heart failure patients, decreases the sympathetic tone to the heart by blocking catecholamines such as noradrenaline and adrenaline (norepinephrine and epinephrine) and thus relaxes the heart. However, although postsynaptic adrenergic receptors are present on the surface of all ventricular cardiomyocytes (CMs) to mediate the effects of catecholamines in regulating cardiac contraction, the mechanisms by which this neuro-cardiac interaction is regulated remain unclear. Therefore, a better understanding of the interaction between the nervous system and the cardiovascular system is critical to determine the therapeutic potential of modulating autonomic tone to the heart in heart disease patients. In a recent study published in The Journal of Physiology, in a quest to further elucidate the role of sympathetic innervation in regulating CM organization and proteolytic machinery, Pianca et al. (2019) showed a positive correlation between sympathetic cardiac innervation and myocyte cell size in the heart. The authors aimed to determine the topology and distribution of SNs in the heart, as well as their role in modulating CM cell size. In vitro co-cultures of SNs and CMs were established and coupled with ex vivo multiphoton imaging of clarified rodent hearts to analyse the distribution and density of the cardiac sympathetic network and its effects on CM size in the ventricle in the heart. Notably, the authors reported that CMs at the neuro-cardiac junctions were evidently larger than non-innervated CMs. Moreover, this trophic effect of SNs was completely blunted upon genetic and pharmacological interference with SN signalling, further confirming the specific role of cardiac SNs in long-term remodelling of myocardium in the healthy heart. More impressively, three-dimensional multiphoton imaging analysis showed an uneven distribution pattern of cardiac SNs throughout the myocardial walls, with a particularly strong preference in the epicardial regions of both neonatal and adult mouse hearts, as well as fetal and adult human hearts. Direct neuro-cardiac coupling has been shown before; however, the inclusion of in vitro co-cultures of SNs with CMs and cardiac fibroblasts was a strength of the study, as these data demonstrated a long-term connection of SNs with CMs, but not fibroblasts, for up to 6 h in the heart, showing selective regulation of the cell size of different cell populations in the heart. However, certain concerns must be addressed in in vitro co-culture experiments. It is well-known that SNs and CMs utilize different energy substrates and therefore primary cultures of SNs and CMs in the same dish would be likely to introduce potential artifacts in experimental analysis. Although the authors have shown previously that neurotrophin-supplemented culture media has no effect on cardiomyocyte cell size, it is important to acknowledge that the inclusion of nerve growth factor (NGF) in the CM co-culture media may have contributed to cellular morphological modifications, as NGF has been shown to induce cell proliferation irrespective of any interaction with cardiac SNs. On the other hand, insulin- and lipid-supplemented CM media could lead to hyperactive SNs in SN/CM co-cultures. Additionally, prolonged culture of cardiomyocytes has been shown to result in cardiac t-tubule degeneration and altered ion channel activities in differentiated adult mouse cardiomyocytes, rendering them ill-suited for physiological measurements. Similarly, the high proliferative capacity of fibroblasts may have accounted for the low number of neuro-cardiac junctions observed between SNs and cardiac fibroblasts. Nevertheless, the authors were able to show selective enlargement of innervated CMs compared to non-innervated CMs in vitro, further confirming the notion of neurogenic control of cardiomyocyte trophism through direct signalling at specific neuro-cardiac junctions. Five different subtypes of adrenergic receptors (ARs) exist in the heart, with β1 and α1B being the most predominant ARs in ventricular cardiomyocytes (Myagmar et al. 2017). The authors in the current study report that the trophic effect of cardiac SNs is achieved in a β2-AR-dependent manner and further demonstrated that chemical inhibition of cardiac β2 adrenergic signalling via a β2-AR antagonist, ICI-118,551, resulted in cardiac atrophic remodelling with increased protein degradation and autophagic activities in innervated CMs. These data provide direct, compelling evidence of regional regulation of cell growth and remodelling via β2 sympathetic signalling in the myocyte in the heart. However, contrary to most studies, Myagmar et al. (2017) have shown that β2-AR is not the predominant myocyte AR and has low expression levels in the heart, and β2-ARs are estimated to be present in only about 5% of ventricular cardiomyocytes. In addition, the β2-AR antagonist ICI-118,551 has been reported to have an affinity of 30 nmol/l for β2-AR and 500 nmol/l for β1-AR (Baker, 2005). Therefore, the selectivity of ICI-118,551 remains questionable when used at concentrations over 30 nmol/l, resulting in potential overestimation of β2-AR effects in cardiomyocytes. Second, the detection of β2-AR mainly on non-myocytes warrants future investigations into the biological function of β2 signalling in cardiomyocytes, as they constitute about 30% of the total cell population in the heart. Investigating the trophic effect of cardiac SNs on fibroblasts and endothelial cells in the heart would serve as valuable controls to validate the specific role of sympathetic innervation in cardiomyocyte remodelling. Nevertheless, a recent study showed that early sympathetic innervation during development contributes to cardiomyocyte transition from proliferative growth to hypertrophic growth, functioning as a key determinant in defining ultimate adult heart size (Kreipke & Birren, 2015). These data suggest that cardiac sympathetic inputs may be responsible for the transition from proliferative to hypertrophic growth of cardiomyocytes. Additionally, Pianca et al. (2019) further elaborated this process by demonstrating preferential sympathetic-mediated cardiac remodelling in the epicardial regions of the heart. However, using cell membrane markers such as wheat germ agglutinin (WGA) to identify cardiomyocytes in the rodent and human myocardium raises doubts about whether the innervated cells are cardiomyocytes or other cardiac resident cell populations. Furthermore, the low sample size (n = 1) to confirm human relevance excludes statistical analysis and therefore renders the results inconclusive due to the high variability in human tissues, not to mention that sympathetic innervation network develops in a species-specific pattern. Nonetheless, the authors included cardiomyocyte-specific anti-dystrophin staining experiments for most analyses in the study. Cardiac sympathetic activity is without doubt one of the most important extrinsic regulators of heart function. Hyperactivity of cardiac SNs also represents a major contributing factor for many heart diseases – this suggests possible synaptic plasticity potential at these intercellular neuro-cardiac junctions. Interestingly, Shcherbakova et al. 2007 have demonstrated that stimulation of cardiac SNs can redistribute the density of postsynaptic adrenergic receptors on cardiomyocyte cell membrane, indicating that exploiting synaptic plasticity may be an alternative therapeutic approach to finetune autonomic innervation of the diseased heart. However, the detailed short-term and long-term plasticity mechanisms that modulate cardiac sympathetic tone remain to be elucidated. Finally, it is also important to acknowledge that regular exercise and a heart healthy diet play a crucial role in the management of cardiac and neurological diseases. A fine balance between cardiac sympathetic and parasympathetic innervation is required to maintain a healthy beating heart. Future investigations aimed at understanding the dynamics and modalities of the communication between SNs and CMs will provide a comprehensive understanding of the neurogenic control of heart diseases. In summary, Pianca et al. (2019) have elegantly demonstrated region-specific sympathetic innervation pattern in the heart and provided three-dimensional distribution of the cardiac sympathetic network in both rodent and human myocardium. These findings show that myocardial architecture and therefore the ultimate heart size is shaped by the topology of the cardiac sympathetic network. More importantly, this work sheds light on potential mechanisms of pathological hypertrophy of cardiomyocytes. Translationally, modulating the strength of cardiac sympathetic innervation through synaptic plasticity may be an alternative therapy for ageing- and cardiovascular-related diseases. None declared. S.H.L. and D.H.K. wrote the manuscript and have reviewed and approved the final version of the manuscript and agree to be accountable for all aspects of the work. S.H.L. was supported by an NSERC Postgraduate Scholarship, an Ontario Graduate Scholarship and a Ted Rogers Centre for Heart Research Doctoral Fellowship. We would like to acknowledge that we were not able to cite all relevant articles due to reference limitations.

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