Publications

Increasing evidence supports a pathogenic role for impaired energy metabolism in organ damage. Genetic diseases provide opportunities to investigate these mechanisms, as exemplified by Fabry disease (FD), caused by an α-galactosidase A (GLA) deficiency and globotriaosylceramide (Gb3) accumulation, with cardiomyopathy as the leading cause of death. Beyond Gb3 storage, impaired energy metabolism may contribute to cardiomyopathy. Here, we demonstrate mitochondrial dysfunction in FD heart and its therapeutic targeting. Using a humanized FD mouse model (R301Q-Tg/GLA knockout), embryonic fibroblasts, and neonatal and adult cardiomyocytes, we found impaired mitophagy and mitochondrial respiration, increased reactive oxygen species, and a vicious cycle aggravating lysosomal dysfunction. These defects progressed with age, causing accumulation of dysfunctional mitochondria, energetic failure, apoptosis, cardiac hypertrophy, and diastolic dysfunction. L-arginine, promoting NO/PGC-1α-dependent mitochondrial rescue, prevented cardiac abnormalities. Our findings identify mitochondrial dysfunction as a key driver of FD cardiomyopathy and reveal the lysosome-mitochondria axis as a targetable pathway in FD and beyond.

Cardiovascular disease (CVD) remains the leading cause of death worldwide, and metabolic dysfunction is increasingly recognized as an important component of its pathophysiology. Clinical evidence supports a role for dysregulated lipid and glucose metabolism in atherosclerosis, heart failure, and cardiometabolic disease, while alterations in amino acid metabolism, mitochondrial energetics, redox signaling, and immunometabolic pathways are supported by growing experimental and observational evidence. Advances in metabolomics, systems biology, and multi-omics approaches have further identified metabolic signatures associated with cardiovascular phenotypes and have provided new insights into pathways regulating endothelial function, vascular inflammation, oxidative stress, and cardiac remodeling. This review synthesizes established clinical evidence and emerging experimental findings on metabolic mechanisms in CVD, with particular emphasis on their potential therapeutic and biomarker implications. We discuss current and investigational strategies targeting lipid and glucose metabolism, mitochondrial dysfunction, oxidative stress, and immunometabolic signaling, while distinguishing clinically validated approaches from those that remain primarily preclinical or hypothesis-generating. Key translational challenges include the complexity and tissue specificity of metabolic networks, limitations of existing experimental models, potential safety liabilities, and the need for longitudinal studies integrating metabolic and clinical phenotypes. Finally, we examine how metabolomics, AI, organ-on-chip models, and systems-level approaches could improve target identification, patient stratification, and therapeutic development. These advances provide a framework for translating mechanistic insights into metabolism-informed cardiovascular therapies and biomarkers, while highlighting the evidence gaps that must be addressed before broader clinical implementation.

PURPOSE OF REVIEW: Subclinical atherosclerosis represents an important stage in the continuum of cardiovascular disease, characterized by structural or functional vascular abnormalities in the absence of overt clinical events. This review examines the biological mechanisms and clinical evidence supporting exercise as both a preventive and potential disease-modifying intervention in individuals with imaging-detected subclinical atherosclerosis, with particular emphasis on endothelial function, vascular remodeling, inflammation, plaque composition, and cardiovascular risk.

RECENT FINDINGS: Increasing evidence indicates that exercise exerts vascular effects that extend beyond conventional risk-factor modification. Exercise improves endothelial function, vascular compliance, and nitric oxide bioavailability through shear stress-mediated activation of endothelial nitric oxide synthase (eNOS), while also modulating oxidative stress, myokine signaling, vascular inflammation, and macrophage phenotype. These effects may promote plaque stabilization and influence atherosclerotic lesion composition. Importantly, exercise-associated increases in coronary artery calcium observed in highly active individuals may reflect a shift toward more densely calcified and potentially more stable plaque rather than an accumulation of high-risk lipid-rich lesions. Clinical and meta-analytic evidence further suggests modality-specific effects, with interval training showing favorable effects on arterial stiffness and combined aerobic-resistance training improving endothelial function. Exercise may therefore complement pharmacological risk-factor modification by targeting vascular pathways that are not fully addressed by conventional therapies. Exercise should be considered an integral component of cardiovascular risk management in individuals with subclinical atherosclerosis rather than solely a primary-prevention strategy. Its potential benefits extend from improving vascular function and reducing inflammation to modifying plaque characteristics and promoting plaque stability. Future studies should determine whether exercise prescriptions can be individualized according to atherosclerotic burden, plaque phenotype, imaging characteristics, and circulating biomarkers to establish the optimal exercise modality, intensity, and dose across different patient populations.