Influence of cardiac nerve status on cardiovascular regulation and cardioprotection

Abstract

Neural elements of the intrinsic cardiac nervous system transduce sensory inputs from the heart, blood vessels and other organs to ensure adequate cardiac function on a beat-to-beat basis. This inter-organ crosstalk is critical for normal function of the heart and other organs; derangements within the nervous system hierarchy contribute to pathogenesis of organ dysfunction. The role of intact cardiac nerves in development of, as well as protection against, ischemic injury is of current interest since it may involve recruitment of intrinsic cardiac ganglia. For instance, ischemic conditioning, a novel protection strategy against organ injury, and in particular remote conditioning, is likely mediated by activation of neural pathways or by endogenous cytoprotective blood-borne substances that stimulate different signalling pathways. This discovery reinforces the concept that inter-organ communication, and maintenance thereof, is key. As such, greater understanding of mechanisms and elucidation of treatment strategies is imperative to improve clinical outcomes particularly in patients with comorbidities. For instance, autonomic imbalance between sympathetic and parasympathetic nervous system regulation can initiate cardiovascular autonomic neuropathy that compromises cardiac stability and function. Neuromodulation therapies that directly target the intrinsic cardiac nervous system or other elements of the nervous system hierarchy are currently being investigated for treatment of different maladies in animal and human studies.

Keywords: Autonomic neuropathy; Coronary blood flow regulation; Intrinsic cardiac nervous system; Ischemic conditioning; Myocardial ischemia.

Figure 1

A schematic overview of efferent and afferent autonomic pathways on normal cardiac regulation, they also play a role in arrhythmogenesis caused by ischemic injury. Various pharmacologic/non-pharmacologic interventions that target autonomic pathways (IC: Ischemic conditioning; rIC: Remote IC; VNS: Vagus nerve stimulation) attenuate cardiac or renal symptoms. Sensory pathways are involved in renal regulation; injury (all cause) affects renal function that can be attenuated by different interventions (IC, rIC, RDN: Renal denervation). Inter-organ interactions also directly affect organ function; development of comorbidities is related to pathogenesis of disease in multiple organs (ex. heart-kidneys-brain, etc.). Pathology in one organ system can result in significant progression of disease in a distant organ; neuromodulation interventions may be beneficial to these patients.

Figure 2

Myocardial infarct size (% anatomic area at risk: AAR) is shown for different study groups subject to ischemia-reperfusion injury. Data are means ± 1SD; ^bP ≤ 0.01 vs respective control (CTR), HEXA (hexmethonium; 20 mg/kg, IV), or DCN (acute cardiac decentralized) group; ^dP ≤ 0.01 vs CTR groups. Group differences determined by ANOVA. PC: Ischemic preconditioning; rPC: Remote preconditioning. Data reported in earlier studies from our laboratory[76,137].