Publications

BACKGROUNDChronic kidney disease (CKD) and hypertension share common pathophysiological pathways contributing to vascular damage, endothelial dysfunction, and physical decline, particularly in older adults with prefrailty. To evaluate the relationship among renal injury, physical performance, and frailty progression in hypertensive older adults with CKD and assess whether dapagliflozin associates with reduced frailty progression, we designed the study DAPA-FORTRESS (DAPAgliflozin and Frailty prOgression in hypeRTension and chRonic kidnEy diSeaSe).METHODSWe enrolled 135 prefrail hypertensive patients with CKD aged >65 years and followed them for 1 year. After coarsened exact matching, our balanced cohort had 105 patients (52 dapagliflozin). Associations between albuminuria, estimated glomerular filtration rate (eGFR), and physical performance were analyzed using correlation and regression models. Effect of dapagliflozin on frailty progression was evaluated using multivariable logistic regression.RESULTSA significant inverse association between gait speed and albuminuria (r2 = 0.48, P < 0.0001) and significant positive linear association between gait speed and eGFR (r2 = 0.18; P < 0.0001) were observed. Patients with eGFR <60 mL/min/1.73 m2 exhibited significantly worse physical performance than those with higher eGFR (P = 0.0003). In adjusted analyses, receiving dapagliflozin was independently associated with lower odds of progressing to frailty at 1 year (OR = 0.130; CI 0.045-0.381; P < 0.001).CONCLUSIONIn older hypertensive patients with CKD, greater renal injury is associated with worse physical performance, while dapagliflozin use reduces the risk of frailty progression. These findings indicate a potential protective role of sodium-glucose cotransporter 2 inhibition in mitigating functional decline in this high-risk population.FUNDINGNIH: National Heart, Lung, and Blood Institute (R01-HL146691), National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK123259); American Heart Association (AHA- 24IPA1268813, AHA-22-915561, AHA-24-1195524).

Mitofusin (MFN) 1 and MFN2 are large outer mitochondrial membrane GTPases. Dimerization of MFNs on adjacent mitochondria mediates mitochondrial fusion. MFN2, but not MFN1, also resides at the endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR) membrane, and dimerization of MFNs on ER/SR and mitochondria tethers the two organelles. Here we report that cell-permeable peptides that perturb MFN conformations regulate myocardial infarct size by impacting ER/SR-mitochondria interactions and Ca2+ transfer independently of changes in mitochondrial fusion. MFN activators increase ER/SR-mitochondria proximity, promote ER/SR to mitochondria Ca2+ transfer and exacerbate infarct size in mice, with effects dependent on MFN2, but not MFN1, and on mitochondrial calcium uniporter, which transports Ca2+ into the mitochondrial matrix. Conversely, although ER/SR-mitochondria proximity is not affected, MFN inhibitors reduce mitochondrial Ca2+ transfer and infarct size, even when their administration is delayed until reperfusion. These findings demonstrate the feasibility of acutely modulating ER/SR-mitochondria interactions and Ca2+ dynamics and suggest that pharmacological MFN inhibition may provide a new therapeutic strategy to limit cardiac damage during reperfused myocardial infarction.

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.