Cardiac Denervation and Reinnervation After Heart Transplantation: Assessment and Clinical Impact

The heart is innervated by an intricate network involving sympathetic, parasympathetic, and sensory afferent pathways, which together regulate heart rate, contractility, and vascular tone in response to physiological demands. This innervation is anatomically organized along the neurocardiac axis, from the intrinsic cardiac ganglia to central autonomic centers, and molecularly shaped during development by neurotrophic and repulsive signaling cues. Orthotopic heart transplantation inevitably severs all afferent and efferent neural connections between the donor heart and the recipient, producing a state of complete cardiac denervation that manifests as resting tachycardia, blunted heart rate variability, and abolished reflex chronotropic responses. Over time, a variable degree of sympathetic and, less consistently, parasympathetic reinnervation may occur in a subset of recipients, predominantly in the anterior wall of the left ventricle, typically beginning after the first post-transplant year and progressing gradually, with a characteristic base-to-apex and epicardium-to-endocardium pattern that often remains incomplete even at long-term follow-up. Reinnervation is currently assessed through complementary non-invasive approaches: heart rate variability analysis provides an indirect functional readout of autonomic modulation, while nuclear imaging techniques (including ¹²³I-metaiodobenzylguanidine scintigraphy and ¹¹C-metahydroxyephedrine positron emission tomography) allow direct visualization and quantification of regional sympathetic nerve density and integrity. The extent and pattern of reinnervation appear clinically relevant, as denervation and its recovery have been associated with exercise capacity, arrhythmic risk, silent myocardial ischemia, and long-term prognosis after transplantation, although findings across studies remain heterogeneous. This narrative review summarizes current knowledge of cardiac autonomic anatomy and neurotransmission, the molecular determinants of innervation patterning, the physiological consequences of heart transplant-related denervation, the evidence on post-transplant reinnervation and its non-invasive assessment, and the impact of reinnervation on clinical outcomes.