Translational neurocardiology: preclinical models and cardioneural integrative aspects

Abstract

Neuronal elements distributed throughout the cardiac nervous system, from the level of the insular cortex to the intrinsic cardiac nervous system, are in constant communication with one another to ensure that cardiac output matches the dynamic process of regional blood flow demand. Neural elements in their various 'levels' become differentially recruited in the transduction of sensory inputs arising from the heart, major vessels, other visceral organs and somatic structures to optimize neuronal coordination of regional cardiac function. This White Paper will review the relevant aspects of the structural and functional organization for autonomic control of the heart in normal conditions, how these systems remodel/adapt during cardiac disease, and finally how such knowledge can be leveraged in the evolving realm of autonomic regulation therapy for cardiac therapeutics.

Figure 1. Network interactions occurring within and between peripheral ganglia and the central nervous system for control of the heart

The cardiac nervous system is composed of multiple (distributed) processing centres from which independent and interdependent neural feedback and feed‐forward neural circuits interact to control regional cardiac electrical and mechanical function. Afferent projections are indicated in blue and efferent projections in red (dashed lines, preganglionic; continuous lines, postganglionic). The intrinsic cardiac nervous system (ICNS) possesses sympathetic (Sympath) and parasympathetic (Parasym) efferent postganglionic neurons, local circuit neurons (LCN) and afferent neurons. Extracardiac intrathoracic ganglia contain afferent neurons, LCN and sympathetic efferent postganglionic neurons. Neurons in intrinsic cardiac and extracardiac networks form nested feedback loops that act in concert with CNS feedback loops (spinal cord, brainstem, hypothalamus and forebrain) to coordinate cardiac function on a beat to beat basis. These systems demonstrate plasticity which underlies adaptations to acute and chronic stressors. Ang I, angiotensin I; Ang II, angiotensin II; AC, adenylate cyclase.

Figure 2. A schematic diagram of cardiac sympathetic afferents (T1–T6) transmitting nociceptive information in response to myocardial ischaemia that is relayed to ascending pathways terminating in supraspinal nuclei that participate in the signalling of cardiac pain

The spinoreticular tract (SRT), lateral spinothalamic tract (lSTT) and medial spinothalamic tract (mSTT) ascend to the reticular formation (medulla (MED), PONS, mesencephalon (MES)) and the ventral posterior lateral (VPL), central lateral (CL) and medial posterior (POm) nuclei of the thalamus. The cardiac sympathetic afferents also mediate sympatho‐excitatory responses when stimulated by a variety of substances. Adapted from Foreman (1991) with permission.

Figure 3. A schematic overview of a potential role for cardiac sympathetic afferents in mediating both sympatho‐excitatory and cardiac remodelling effects in heart failure and the use of resiniferatoxin (RTX) to antagonize these effects by ablation of TRPV1‐expressing afferents

SNA, sympathetic nerve activity; CSNA, cardiac sympathetic nerve activity; MMP, matrix metalloprotease; ECM, extracellular matrix; NA, noradrenaline. RAS, renin angiotensin system; CGRP, calcitonin gene‐related peptide.