Cardiac innervation and sudden cardiac death

Abstract

Afferent and efferent cardiac neurotransmission via the cardiac nerves intricately modulates nearly all physiological functions of the heart (chronotropy, dromotropy, lusitropy, and inotropy). Afferent information from the heart is transmitted to higher levels of the nervous system for processing (intrinsic cardiac nervous system, extracardiac-intrathoracic ganglia, spinal cord, brain stem, and higher centers), which ultimately results in efferent cardiomotor neural impulses (via the sympathetic and parasympathetic nerves). This system forms interacting feedback loops that provide physiological stability for maintaining normal rhythm and life-sustaining circulation. This system also ensures that there is fine-tuned regulation of sympathetic-parasympathetic balance in the heart under normal and stressed states in the short (beat to beat), intermediate (minutes to hours), and long term (days to years). This important neurovisceral/autonomic nervous system also plays a major role in the pathophysiology and progression of heart disease, including heart failure and arrhythmias leading to sudden cardiac death. Transdifferentiation of neurons in heart failure, functional denervation, cardiac and extracardiac neural remodeling has also been identified and characterized during the progression of disease. Recent advances in understanding the cellular and molecular processes governing innervation and the functional control of the myocardium in health and disease provide a rational mechanistic basis for the development of neuraxial therapies for preventing sudden cardiac death and other arrhythmias. Advances in cellular, molecular, and bioengineering realms have underscored the emergence of this area as an important avenue of scientific inquiry and therapeutic intervention.

Keywords: arrhythmias, cardiac; autonomic nervous system; death, sudden cardiac; physiopathology.

Figure 1. Cardiac Neurotransmission

ICN (intrinsic nervous system of the heart). Figure modified from W.Jänig (with permission).

Figure 2. Neurohumoral control and anatomical organization of cardiac innervation

LCN=local circuit neuron, DRG=dorsal root ganglion, Aff=afferent, C=cervical, T=thoracic, Ang=angiotensin

Figure 3. Regulation of cardiac innervation patterning and sudden cardiac death

Left, Overexpression or lack of sema3A in endocardium causes unbalanced patterning of sympathetic nerves, which alters the potential for lethal arrhythmia. Appropriate sema3A-mediated sympathetic innervation is crucial for maintenance of arrhythmia-free heart. Middle, Up-regulation of secreted nerve growth factor (NGF) from cardiomyocytes in diseased heart may cause lethal arrhythmia and sudden cardiac death (SCD). Right, Down-regulation of NGF in diabetic heart induces denervation of cardiac sensory nerve, which leads to silent ischemia and lethal arrhythmia.

Figure 4. Systemic autonomic interactions and crosstalk between cardiomyocyte and sympathetic nerve terminal via humoral factors in diseased heart

This figure shows that central and peripheral mechanism of the heart and brain interaction including the cardiac autonomic efferent (sympathetic & parasympathetic), and sensory nerves (sympathetic & parasympathetic) but only the sympathetic afferents (labeled sensory nerve) is shown in this figure for an illustration. See Figure 2 for a full schematic. Representative promising interventional therapies are also described in the figure. In addition, alteration of cardiac sympathetic nerves occur in post ganglionic fiber. Failing cardiomyocytes induces NGF via endothelin-1 (ET-1) mediated pathway and leukemia inhibitory factor (LIF). NGF and LIF leads to hyper-innervation (anatomical modulation) and rejuvenation/ cholinergic differentiation (functional modulation), respectively. This phenomenon shows the expression of catecholaminergic marker such as tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH) reduced, and of cholinergic (CHT, ChAT) and juvenile (PSA-NCAM) increase. Abbreviations, CHT, choline transporter; ChAT, choline acetyltransferase; PSA-NCAM, polysialylated neural cell adhesion molecule; NE, norepinephrine; ROS, reactive oxygen species; NO, nitric oxide; PVN, paraventricular nucleus; RVLM, rostral ventrolateral medulla; NTS, solitary tract; SG, stellate ganglia; DRG, dorsal root ganglia; CG, cardiac ganglia. Details of these pathways are referenced in the text^{, ,}

Figure 5. Temporal changes in cardiac innervation with disease progression

NGF= nerve growth factor, LIF=leukemia inhibitory factor, NE=nor-epinephrine

Figure 6. Functional remodeling of cardiac innervation in an experimental infarct model and humans with post-infarct cardiomyopathy

Innervation patterns of the mammalian heart are altered following myocardial infarction. Left upper panel: polar maps of global epicardial activation recovery intervals (ARIs) recorded from a control and an infarcted porcine heart at baseline (BL), and during stimulation of the right, left, and bilateral stellate ganglion (RSG, LSG, & BSG, respectively). The focal region of myocardial infarction in the antero-apical left ventricle is indicated by the dashed circle in bottom row. The altered pattern of ARI distribution in the infarcted heart extends beyond the region of focal myocardial infarction. Right upper panel: graphical representation of the regional responses of the porcine heart to stimulation of RSG, LSG, and BSG in control and infarcted hearts respectively. The anterior and posterior predominance of RSG and LSG stimulations respectively, are completely lost following infarction. Left lower panel: ARIs recorded from a patient with ischemic cardiomopathy and a large antero-apical scar. The location of the recording multi-electrode catheter on fluoroscopy in the right and left anterior oblique (RAO and LAO, respectively) projections; and the corresponding electroanatomic map are shown. On the electroanatomic map, the purple regions indicate tissue with normal voltage (non-scar tissue), while the dense grey regions represent dense scar. All other colors represent border zones (tissue with voltage ≥0.5 mV but ≤1.5 mV). Right lower panel: The degree of change in ARI from baseline in response to direct (isoproterenol) and indirect reflex-mediated (nitroprusside) sympathetic stimulation in cardiomyopathic and normal hearts is shown. With isoproterenol, ARI shortening is exaggerated in CM-NL (normal voltage regions in cardiomyopathic hearts) and CM-scar (scarred tissue) regions of the cardiomyopathic heart. Border zone regions are slightly less responsive to isopreterenol. With nitroprusside, CM-NL and CM-Scar zones paradoxically demonstrate ARI increase compared with the border zone regions. These observations, when compared to normal hearts, indicate the severe degree of adrenergic nerve dysfunction in human hearts with ischemic cardiomyopathy. AICD=automatic internal cardioverter defibrillator lead, CS=coronary sinus electrode, RV= right ventricular lead