Population aging is changing the needs of patients seen in cardio-oncology. Older adults with cancer often have cardiovascular disease, multimorbidity, and reduced physiological reserve, which can complicate treatment and recovery. Patients of the same chronological age may differ considerably in cardiovascular health, functional capacity, and treatment tolerance. Frailty and geriatric assessment can help characterize these differences and inform care.This review examines the biological mechanisms linking aging, cancer, and cardiovascular disease and discusses their implications for cardiovascular risk assessment, cancer treatment decisions, and long-term survivorship. Treatment decisions require consideration of the expected oncological benefit, cardiovascular risk, physiological reserve, life expectancy, and patient preferences. Identifying and addressing reversible vulnerabilities may help patients tolerate effective anticancer therapy while preserving function and quality of life. During survivorship, cardiovascular care should account for previous treatment exposure, changing health status, and adherence to preventive therapies.Closer collaboration between cardio-oncology and geriatric medicine may improve the assessment and management of older patients. Evidence specific to frail and very old adults remains limited. Prospective studies are needed to determine whether geriatric and biological aging measures improve cardiovascular risk prediction, treatment decisions, and patient outcomes.
Introduction Optic atrophy 1 (OPA1) is a mitochondrial inner-membrane GTPase that coordinates mitochondrial fusion, cristae organization, and respiratory efficiency. Beyond mitochondrial bioenergetics, OPA1 contributes to cardiovascular homeostasis, including the maintenance of vascular cell function and phenotype. Although increasing OPA1 expression has been proposed to improve mitochondrial performance, the consequences of sustained OPA1-driven oxidative activation in the lipid-exposed cardiovascular system remain incompletely defined. Here, we investigated cardiac structure, tissue metabolism, and cardiomyocyte bioenergetics in mice with systemic OPA1 overexpression maintained on a high-fat diet (HFD). Methods OPA1-overexpressing mice were fed high-fat diet for 20 weeks, followed by indirect calorimetry and echocardiographic analysis. Tissues were used for OMICs investigation and metabolic analysis. Results OPA1-overexpressing mice displayed preserved global left-ventricular systolic function and ventricular volumes but presented reduced anterior and lateral wall thickness. Histological analysis further revealed a decrease in cardiomyocyte cross-sectional area accompanied by increased myocardial collagen deposition. Cardiac triglyceride content was elevated, whereas cholesterol content was unchanged. In neonatal cardiomyocytes, OPA1 overexpression resulted in increased oxygen consumption, with the strongest response observed in cells co-incubated with very-low-density lipoprotein. Under this lipid-rich condition, ATP-linked respiration, maximal respiration, and spare respiratory capacity were increased. Discussion Collectively, these findings indicate that systemic OPA1 overexpression was associated with myocardial lipid accumulation and early fibrotic remodeling during HFD feeding, despite preserved systolic function. In vitro, OPA1 overexpression increased cardiomyocyte respiratory capacity under lipid-rich conditions. These data identify a context-dependent effect of OPA1 in which enhanced respiratory capacity may become maladaptive when lipid supply exceeds coordinated oxidative and storage capacity.
Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease lacking effective pharmacological therapies. To identify potential therapeutic targets and candidate compounds, we performed integrative genetic analyses for drug repurposing by combining Mendelian randomization (MR), summary-data-based Mendelian randomization (SMR), and Bayesian colocalization. This framework prioritized multiple druggable candidates, among which STAT3 emerged as a key regulatory node. Subsequent functional studies demonstrated that emodin suppressed vascular smooth muscle cell proliferation, migration, phenotypic switching, and inflammatory responses. These effects were accompanied by reduced STAT3 phosphorylation and nuclear localization. Molecular docking suggested a potential binding mode of emodin within the STAT3 SH2 domain, while cellular thermal shift assays demonstrated thermal stabilization of STAT3 by emodin in intact cells, consistent with target engagement. Notably, emodin and the selective STAT3 inhibitor STAT3-IN-13 produced comparable effects, and co-treatment did not yield additive efficacy, suggesting overlapping mechanisms. In vivo, emodin attenuated aneurysm development and reduced vascular inflammation in experimental models. Collectively, these findings identify emodin as a candidate modulator of AAA progression acting through suppression of STAT3-associated signaling pathways, and demonstrate the potential of genetic evidence–guided drug repurposing strategies in complex vascular diseases.
Smooth muscle cells (SMCs) are essential for the normal function of the cardiovascular, respiratory, gastrointestinal, and urogenital systems, and SMC dysfunction contributes to a wide range of genetic and acquired diseases. CRISPR-based genome editing provides new approaches for studying SMC biology and developing therapies for smooth muscle disorders. In particular, base editing and prime editing enable precise nucleotide changes without introducing DNA double-strand breaks. In this review, we summarize recent applications of CRISPR technologies in smooth muscle biology, with a primary focus on vascular diseases. We discuss how CRISPR-engineered primary cells, induced pluripotent stem cell-derived SMCs (iPSC-SMCs), and animal models have been used to investigate disease mechanisms and validate pathogenic variants. We further review therapeutic genome editing strategies for correcting disease-causing variants in patient-derived iPSC-SMCs, vascular organoids, and preclinical animal models. Finally, we discuss major challenges for clinical translation, including efficient and SMC-specific delivery, immunogenicity, editing precision, off-target effects, and long-term safety. Continued advances in genome-editing technologies, delivery platforms, and human disease models may expand the application of these approaches to smooth muscle disorders.
