The guidelines for the management of patients affected by propionic acidemia (PA) recommend standard cardiac therapy in the presence of cardiac complications. A recent revision questioned the impact of high doses of coenzyme Q10 on cardiac function in patients with cardiomyopathy (CM). Liver transplantation is a therapeutic option for several patients since it may stabilize or reverse CM. Both the patients waiting for liver transplantation and, even more, the ones not eligible for transplant programs urgently need therapies to improve cardiac function. To this aim, the identification of the pathogenetic mechanisms represents a key point. Aims: This review summarizes: (1) the current knowledge of the pathogenetic mechanisms underlying cardiac complications in PA and (2) the available and potential pharmacological options for the prevention or the treatment of cardiac complications in PA. To select articles, we searched the electronic database PubMed using the Mesh terms “propionic acidemia” OR “propionate” AND “cardiomyopathy” OR “Long QT syndrome”. We selected 77 studies, enlightening 12 potential disease-specific or non-disease-specific pathogenetic mechanisms, namely: impaired substrate delivery to TCA cycle and TCA dysfunction, secondary mitochondrial electron transport chain dysfunction and oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, carnitine deficiency, cardiac excitation–contraction coupling alteration, genetics, epigenetics, microRNAs, micronutrients deficiencies, renin–angiotensin–aldosterone system activation, and increased sympathetic activation. We provide a critical discussion of the related therapeutic options. Current literature supports the involvement of multiple cellular pathways in cardiac complications of PA, indicating the growing complexity of their pathophysiology. Elucidating the mechanisms responsible for such abnormalities is essential to identify therapeutic strategies going beyond the correction of the enzymatic defect rather than engaging the dysregulated mechanisms. Although these approaches are not expected to be resolutive, they may improve the quality of life and slow the disease progression. Available pharmacological options are limited and tested in small cohorts. Indeed, a multicenter approach is mandatory to strengthen the efficacy of therapeutic options.

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.