Journal of Cardiovascular Pharmacology最新文献

Cardiovascular-kidney-metabolic (CKM) syndrome represents the interconnected pathophysiology of metabolic risk factors, chronic kidney disease (CKD), and cardiovascular disease, leading to multiorgan dysfunction and elevated adverse outcomes. Overactivation of the mineralocorticoid receptor (MR), via aldosterone-dependent and ligand-independent pathways, drives inflammation, fibrosis, and oxidative stress and facilitates CKM progression. Finerenone is a selective non-steroidal MR antagonist (nsMRA) that exhibits high MR affinity, has balanced cardiac and renal distribution, and minimal off-target steroidal effects, which make it mechanistically different from steroidal MRAs. Large phase 3 trials such as FIDELIO-DKD and FIGARO-DKD in type 2 diabetes with CKD, and FINEARTS-HF in heart failure (HF) with a left ventricular ejection fraction (LVEF) > 40%, demonstrated consistent cardiorenal benefits. The prespecified FINE-HEART pooled analysis showed finerenone reduced all-cause mortality (HR 0.91, 95% CI 0.84-0.99), HF hospitalizations (HR 0.83, 95% CI 0.75-0.92), and the kidney composite outcome (HR 0.80, 95% CI 0.72-0.90), with benefits consistent across CKM components and background therapies including sodium-glucose cotransporter 2 (SGLT2) inhibitors. Recent data from FIND-CKD extend utility to non-diabetic CKD. Various guidelines incorporate finerenone as an additive therapy for patients with persistent albuminuria on maximal renin-angiotensin system inhibition (RASi) + SGLT2i. This review summarizes the MR pathophysiology in CKM syndrome, compares the mechanisms of non-steroidal versus steroidal MRAs, synthesizes clinical trial evidence, safety, and guideline-directed place in therapy, addresses implementation barriers, including cost, and outlines future research directions. Finerenone may fill a critical gap in multimodal CKM management, enabling comprehensive pillar-based therapy to mitigate residual cardiorenal risk.

Vascular smooth muscle cells (VSMCs) play a central role in maintaining vascular tone, structural integrity, and adaptive remodeling. With aging and chronic cardiometabolic stress, however, VSMCs undergo senescence driven by telomere attrition, oxidative stress, persistent DNA-damage signaling, and dysregulation of the p53/p21 and p16/Rb pathways. This transition is accompanied by acquisition of a senescence-associated secretory phenotype (SASP), which promotes inflammation, extracellular matrix remodeling, calcification and vascular stiffening. Together, these accelerate atherosclerosis, hypertension, aneurysm formation, and related vasculopathies. Growing evidence identifies VSMC senescence as a promising therapeutic entry point for cardiovascular drug discovery. Emerging strategies include senolytics, senomorphics, metabolic modulators, and molecular reprogramming approaches designed to either eliminate senescent cells or attenuate their pathogenic secretome and downstream signaling networks. In this review, the molecular basis of VSMC senescence, its contribution to major vascular disorders, and the therapeutic landscape targeting senescence-associated pathways are discussed, with emphasis on translational opportunities and current barriers to clinical application. A clearer understanding of VSMC senescence may inform the development of mechanism-based interventions to limit vascular dysfunction and age-related cardiovascular disease.

Cardiac hypertrophy, a response to pathological stimuli, eventually progresses to heart failure. Ovarian tumor-associated proteinase B1 (OTUB1), a deubiquitinase of the ovarian tumor (OUT) family, regulates inflammation, cell survival, and oxidative stress in various diseases, but its role in cardiac hypertrophy remains unclear. Here, we investigated OTUB1 expression, function, and mechanism in pathological cardiac hypertrophy. OTUB1 expression was significantly downregulated in human hypertrophic hearts, transverse aortic constriction (TAC)-induced mouse hypertrophic hearts, and phenylephrine-stimulated neonatal rat ventricular myocytes (NRVMs). OTUB1 knockout (KO) mice exhibited exacerbated TAC-induced cardiac hypertrophy, dysfunction, and fetal gene reactivation, whereas OTUB1 overexpression attenuated PE-induced cardiomyocyte enlargement. Mechanistically, OTUB1 directly bound to, deubiquitinated, and stabilized Sirt2, thereby promoting AMPK phosphorylation. Silencing Sirt2 abolished the anti-hypertrophic effects of OTUB1 and blocked AMPK activation. In conclusion, OTUB1 protects against pathological cardiac hypertrophy by stabilizing Sirt2 and activating the AMPK signaling pathway, suggesting that OTUB1 is a promising therapeutic target for hypertrophy-associated heart failure.

Ischemic cardiomyopathy (ICM) is a major cause of chronic heart failure with impaired left ventricular (LV) function. Trimetazidine, a metabolic modulator that shifts energy utilization from fatty acid oxidation to glucose oxidation, may improve cardiac function in ischemic myocardium. This meta-analysis aimed to evaluate trimetazidine's effect in patients with ICM compared to standard therapy alone. A systematic search was conducted across PubMed, ProQuest, SAGE, EBSCO Host, Wiley, Science Direct, and SpringerLink databases until November 2024. Clinical trials assessing trimetazidine versus standard therapy in ICM were included. Data were analyzed using a random-effects model to calculate mean differences (MD) and relative risk (RR), with heterogeneity evaluated using the I2 statistic. Ten studies met the inclusion criteria. Trimetazidine significantly improved left ventricular ejection fraction (MD 6.35%, 95% CI: 4.63-8.07; p<0.05), reduced LV end-systolic diameter (MD -4.51 mm, p<0.05), LV end-diastolic diameter (MD -3.13 mm, p<0.05), and LV end-systolic volume (MD -14.20 ml, p<0.05). Exercise capacity improved markedly with a mean increase of 83.64 meters in the 6-minute walking test (p<0.05). NYHA class also improved (MD -0.80, p<0.05). However, no significant differences were found in anginal episodes or nitrate consumption. Trimetazidine as an adjunct to standard therapy improves cardiac function and exercise capacity in ischemic cardiomyopathy patients. It may be considered in patients with persistent symptoms or exercise intolerance despite optimal medical therapy. Further large-scale trials are warranted to assess long-term outcomes such as mortality and hospitalization.

Lipoprotein(a) [Lp(a)] is a genetically determined apolipoprotein B-containing lipoprotein independently associated with atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). Circulating Lp(a) concentrations are largely inherited, minimally responsive to lifestyle modification, and not adequately addressed by conventional lipid-lowering pharmacotherapy. Patients with established ASCVD continue to experience recurrent cardiovascular events despite intensive guideline-directed therapy, and this residual risk reflects mechanisms - including persistently elevated Lp(a) - that are not captured by standard low-density lipoprotein cholesterol (LDL-C) management. In this narrative review, current evidence on Lp(a) biology, genetics, and pathophysiology is integrated with a critical appraisal of contemporary management, the emerging Lp(a)-lowering pharmacological landscape, and unresolved clinical implementation challenges. Current management relies on once-in-adulthood Lp(a) measurement for cardiovascular risk stratification, aggressive optimization of modifiable risk factors, and, in highly selected patients, lipoprotein apheresis; no Lp(a)-specific pharmacotherapy is approved by any major regulatory agency. RNA-targeted therapies - antisense oligonucleotides and small interfering RNA agents - and an oral inhibitor of Lp(a) particle assembly have produced pharmacodynamic Lp(a) reductions of 80-95% or more in phase 2 randomized trials. However, topline results from the phase 3 Lp(a)HORIZON trial showed that pelacarsen, despite lowering Lp(a), did not reduce the primary composite cardiovascular endpoint. Full trial data are awaited, while four other phase 3 cardiovascular outcome trials - OCEAN(a)-Outcomes, ACCLAIM-Lp(a), MOVE-Lp(a), and OCEAN(a)-PreEvent - remain ongoing. Should positive outcome data emerge, clinical implementation will require regulatory approval, evidence-based patient selection, standardized treatment thresholds, and equitable access strategies across diverse populations.

Chimeric Antigen Receptor (CAR)-T cell therapy has emerged as an innovative treatment of haematologic malignancies; however, its use is frequently complicated by Cytokine Release Syndrome (CRS), an increasingly recognized driver of cancer therapy-related cardiovascular toxicity (CTR-CVT) able to provoke a wide spectrum of manifestations, from paucysimptomatic and reversible effects to potentially fatal cardiovascular damage. The 2022 European Society of Cardiology (ESC) guidelines on cardio-oncology highlighted the need for systematic cardiovascular assessment in patients receiving CAR-T therapy, yet specific monitoring protocols are lacking at this point in time. The CARdio-Tox study was conceived to address this surveillance gap, testing the hypothesis that acute systemic inflammation, particularly mediated by high levels of interleukin (IL)-1 and IL-6 pathways, might represent the key determinant of early myocardial dysfunction. The primary endpoint of this protocol is to assess the incidence of acute CTR-cardiac dysfunction (CTRCD) occurring within 7 and 30 days after CAR-T cell infusion. Key secondary endpoints include the assessment of the relationship between CTRCD occurrence and CRS diagnosis and grade, as well as the association of inflammatory biomarkers increase with cardiac imaging and/or serum biomarker abnormalities. Data collection will continue over 30 days to assess middle and long-term cardiovascular toxicity. Despite its single-center design, the CARdio-Tox results might provide clinically relevant insights into early cardiovascular effects of CAR-T cell administration, identify key risk factors for CTR-CVT and support more tailored, pathophysiology-driven monitoring strategies in this rapidly evolving field.

P2Y12-inhibitor monotherapy after abbreviated dual antiplatelet therapy (DAPT) reduces bleeding after percutaneous coronary intervention, but whether aspirin can be stopped after one month rather than three remains uncertain. We reconstructed time-to-event data from published Kaplan-Meier or cumulative-incidence curves of 11 randomised trials (37,443 patients) using the Guyot algorithm, grouped trials by aspirin-withdrawal timing, and analysed within-trial monotherapy-versus-continued-DAPT effects using stratified Cox regression and random-effects meta-analysis across 0 to 30, 30 to 90, and 90 to 360-day intervals. Reconstructed event totals matched published totals exactly for all 12 curves, and reconstructed hazard ratios agreed with published estimates to within 2.2%. Monotherapy approximately halved major or minor bleeding (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.44-0.59). One-month and three-month withdrawal produced comparable ischaemic-composite effects (risk ratio 0.88, CI 0.75-1.03, and 0.92, CI 0.74-1.15); these trials were not randomised against one another, so comparable estimates do not establish clinical equivalence. The only early excess arose with near-immediate withdrawal, driven entirely by NEO-MINDSET (0 to 30-day interval rate ratio 2.09, CI 1.33-3.28); excluding this trial left no ischaemic excess in the remaining trial. Myocardial infarction (HR 1.02, CI 0.82-1.28) and stent thrombosis (Peto odds ratio 1.19, CI 0.77-1.86) showed no overall excess. These hypothesis-generating findings, derived from reconstructed rather than true individual-participant data and from an indirect comparison across trials, suggest the relevant distinction may be immediate versus deferred aspirin withdrawal rather than one versus three months, though the early hazard rests on a single trial and requires independent replication.