Publications

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.

Receptor-targeted polypharmacology is emerging as a promising strategy for the treatment of obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis. GLP-1-GIP-lanifibranor, a unimolecular conjugate combining GLP-1R/GIPR co-agonism with pan-PPAR activation, enables receptor-guided intracellular delivery of lanifibranor to incretin receptor-expressing cells while limiting systemic off-target exposure. In obese mouse models, the conjugate produced greater reductions in body weight, adiposity, food intake, and hyperglycemia than semaglutide, GLP-1-GIP co-agonism, or lanifibranor alone, while significantly improving insulin sensitivity. Mechanistic analyses demonstrated receptor-dependent delivery and identified PPARδ signaling as a principal mediator of glycemic improvement independent of weight loss. Unlike unconjugated lanifibranor, the conjugate did not induce anemia, fluid retention, renal dysfunction, or adipocyte differentiation, supporting the concept that tissue-restricted PPAR activation may mitigate classical adverse effects of systemic PPAR agonism. These findings establish peptide-directed nuclear receptor targeting as a potentially important platform for next-generation metabolic therapeutics, although substantial translational uncertainties remain regarding clinical efficacy, safety, and long-term applicability.

BACKGROUND: Exercise-induced hypertension (EIH) is recognized as an independent cardiovascular risk factor. Epicardial fat thickness (EFT) has been implicated in various cardiovascular pathologies. However, the relationship between EFT, EIH, and ventricular arrhythmias remains poorly characterized. This study aimed to investigate the predictive value of EFT for both EIH and premature ventricular beats (PVB).

METHODS: A total of 2658 participants were initially screened for eligibility, and normotensive participants of age > 18 were considered for enrollment. All participants underwent a comprehensive clinical evaluation. Data were analyzed considering EIH and PVB. Multivariable logistic regression, ROC and decision curve analysis (DCA) were performed to evaluate the clinical utility of predictive models with and without EFT parameters.

RESULTS: ROC curve analysis demonstrated that EFT had moderate ability for predicting EIH (AUC 0.73, 95% CI 0.69-0.78). Multivariable logistic regression revealed that EFT was independently associated with EIH (OR 2.27, 95% CI 1.72-2.98). For the prediction of PVB among individuals with EIH, EFT demonstrated good accuracy (AUC 0.78, 95% CI 0.69-0.86). Among patients with EIH, epicardial fat was strongly associated with increased odds of arrhythmias (OR 3.58, 95% CI 2.35-5.46, p < 0.001). DCA revealed that incorporating EFT scores into predictive models provided superior net benefit improving the clinical utility of the predictive model.

CONCLUSIONS: EFT is an independent predictor of both exercise-induced hypertension and ventricular arrhythmias, with strong predictive value for premature ventricular beats in patients with EIH. The incorporation of EFT into risk prediction models provides superior clinical net benefit compared to traditional risk factors alone.

Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency, leading to progressive accumulation of Gb3 and lyso-Gb3 and a complex multisystem phenotype extending beyond substrate storage. Cardiovascular involvement remains the leading cause of morbidity and mortality, yet early detection and risk stratification remain challenging. In this context, a new proteomic study leveraging high-throughput proximity extension assays and machine learning has defined a cardiovascular risk signature in Fabry disease. Differential expression analysis identified widespread proteomic remodeling involving inflammatory signaling, extracellular matrix organization, angiogenesis, and metabolic pathways, supporting a systems-level view of disease pathogenesis. A 10-protein biosignature integrating markers of mitochondrial stress, lysosomal function, vascular remodeling, and immune activation demonstrated the ability to discriminate patients with cardiovascular involvement. Notably, proteins such as GDF15, NT-proBNP, NOS1, CTSF, and TNFRSF11B highlight the interplay between mitochondrial dysfunction, lysosomal impairment, and vascular inflammation. These findings suggest that Fabry cardiomyopathy reflects coordinated dysregulation across metabolic and inflammatory networks and that multi-protein signatures may improve precision phenotyping and cardiovascular risk prediction beyond conventional biomarkers.