Journal of Cardiovascular Pharmacology最新文献

Clinical evidence suggests that the lipid-lowering efficacy of statins may be diminished by concurrent β-lactam administration in patients with coronary heart disease (CHD), yet the mechanisms driving this potential drug-drug interaction, particularly the role of gut microbiota as a mediator, remain undefined. To address this gap, we conducted a retrospective analysis of data from a tertiary hospital spanning 5 years, enrolling 436 CHD patients on statin therapy who had two hospital admissions within a 3-month window. Patients were stratified into β-lactam-treated and antibiotic-free cohorts to assess the correlation between β-lactam exposure and statin efficacy. Additionally, 16S ribosomal RNA gene sequencing was employed to characterize and compare gut microbiota profiles between CHD patients receiving combined rosuvastatin and β-lactam therapy versus those on rosuvastatin monotherapy. Our findings demonstrated that β-lactam exposure was associated with elevated low-density lipoprotein cholesterol and total cholesterol levels. Both rosuvastatin and β-lactams induced significant alterations in gut microbiota composition, with distinct shifts in bacterial taxa abundances: rosuvastatin increased the relative abundance of Faecalibacterium and Dysosmobacter, whereas β-lactams disrupted the abundance of Faecalibacterium, Roseburia, and Dysosmobacter. Collectively, these results indicate that concomitant β-lactam use impairs rosuvastatin efficacy in CHD patients, likely via perturbation of gut microbiota composition. Rosuvastatin may exert a portion of its cardioprotective effects through modulation of gut microbiota, and β-lactams may abrogate this benefit by depleting key bacterial taxa linked to statin-mediated lipid regulation. Notably, Dysosmobacter emerges as a potential mediating species in this interaction, supporting a microbiome-dependent mechanism underlying the reduced lipid-lowering efficacy of rosuvastatin during β-lactam co-administration.

Myocardial ischemia-reperfusion (I/R) injury remains a major cause of acute cardiac dysfunction and is characterized by oxidative stress, inflammation, and apoptosis. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has been reported to exert cardioprotective effects; however, its potential association with mitochondrial biogenesis-related signaling pathways remains incompletely understood. This study aimed to evaluate the cardioprotective potential of CBD in a rat myocardial I/R model and to investigate its possible association with SIRT-1/PGC-1α-related mitochondrial biogenesis and NF-κB-dependent inflammatory signaling. Forty rats were randomly assigned to four groups: sham, I/R, prophylactic CBD, and therapeutic CBD. Myocardial ischemia was induced by ligating the left anterior descending coronary artery for 30 min followed by 30 min of reperfusion. Heart and aortic tissues were evaluated histopathologically, immunohistochemically, biochemically, and genetically to assess oxidative stress, inflammation, and mitochondrial biogenesis-related markers. The I/R group exhibited marked myocardial injury characterized by hyperemia, edema, hemorrhage, and inflammatory infiltration, accompanied by elevated vascular cell adhesion molecule-1 (VCAM-1), vascular endothelial growth factor (VEGF), and NF-κB levels. Conversely, SIRT-1, PGC-1α, and B-cell lymphoma 2 (Bcl-2) expression significantly declined, alongside increased total oxidant status and oxidative stress index. Prophylactic CBD treatment notably restored myocardial architecture, suppressed inflammatory and apoptotic responses, and enhanced mitochondrial biogenesis. Therapeutic CBD administration also provided partial protection. CBD confers robust cardioprotection against myocardial I/R injury by activating the SIRT-1/PGC-1α axis, promoting mitochondrial biogenesis, and attenuating oxidative, inflammatory, and apoptotic pathways. These findings indicated that confers significant cardioprotection against myocardial IR injury and that this protective effect is associated with modulation of SIRT-1/PGC-1α-related mitochondrial biogenesis and NF-κB-dependent inflammatory signaling. Further mechanistic studies are warranted to establish definitive causal relationships.

Hypertrophic Cardiomyopathy (HCM) is the most commonly inherited cardiomyopathy worldwide, characterized by left ventricular hypertrophy and hypercontractility. Many cases of HCM are due to pathogenic changes in cardiac sarcomere proteins. Traditional therapies including B-blockers, non-dihydropyridine calcium channel blockers and septal reduction therapy have long provided symptomatic relief, but they have not necessarily addressed the disease state at the cellular level. The treatment landscape for HCM has evolved significantly over the last decade with the emergence of new targeted therapies, including a new class of medication called cardiac myosin inhibitors (CMI). CMI therapy represents a paradigm shift in the management of obstructive variants of HCM, offering meaningful improvement in symptoms and cardiac function parameters. CMI therapy remains investigational in the treatment of non-obstructive variants of HCM. This review examines the evolving understanding of HCM and highlights both traditional management strategies and emerging therapies.

Lipoprotein(a) [Lp(a)] is a genetically determined independent risk factor for atherosclerotic cardiovascular disease (ASCVD) that drives a significant residual risk through pro-atherogenic, pro-inflammatory, and prothrombotic pathways. However, current mainstay lipid-lowering therapies such as statins have limited efficacy in reducing Lp(a) levels, highlighting a critical therapeutic gap. This review aims to synthesize evidence on the role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors in targeting Lp(a). We systematically searched PubMed and Embase for clinical trials and mechanistic studies (2010-2025), utilizing the PRISMA and AMSTAR-2 frameworks to ensure methodological rigor and demonstrated that PCSK9 inhibitors (e.g., alirocumab, evolocumab, and tafolecimab) not only reduced low-density lipoprotein(LDL-C),by 55-60% but also lowered Lp(a) by 20-30%. The efficacy of these agents varies ethnically, with tafolecimab showing superior performance in East Asian populations, which is partly attributable to the higher prevalence of the PCSK9 R46L loss-of-function allele. Mechanistically, PCSK9 inhibitors lowered Lp(a) levels via two pathways: suppression of hepatic synthesis and enhanced plasma clearance. This evidence supports the 2023 ESC guidelines, which issued a Class IIa recommendation for PCSK9 inhibitor use in patients with ASCVD and elevated Lp(a) levels. Given the evolving landscape, further research is warranted to confirm the role of these therapies in precision medicine paradigms for managing Lp(a)-associated risks.

Cardiovascular diseases remain the leading cause of global morbidity and mortality, highlighting the urgent need for more efficient, precise, and cost-effective drug development strategies. Traditional drug discovery pipelines face persistent challenges, including elevated expenses, prolonged timelines, and high attrition rates, particularly with the complex pathophysiology of cardiovascular conditions. Artificial intelligence (AI) has emerged as a transformative force capable of addressing these barriers across all stages of cardiovascular drug development. This review explores the integration of AI in target identification, compound screening, drug design, pharmacokinetic and toxicity prediction, and clinical trial optimization. We highlight state-of-the-art AI tools such as large language models (e.g., BioGPT, Geneformer), generative frameworks (e.g., Generative Tensorial Reinforcement Learning (GENTRL), Variational Autoencoders (VAEs), Generative Adversarial Networks (GANs)), and neural ordinary differential equations, illustrating their ability to accelerate drug discovery, personalize therapy, and improve clinical success rates. In the context of clinical trials, platforms such as Trial Pathfinder have been employed to optimize patient recruitment and improve generalizability. Despite these advancements, several challenges persist, particularly those related to data quality, population representativeness, interpretability, and regulatory oversight. Future directions involving the integration of AI with quantum computing, blockchain technology, and precision medicine offer additional opportunities to advance the field. Collectively, these innovations mark a paradigm shift toward faster, safer, and more personalized cardiovascular drug development.

Abstract: Inclisiran, the first small interfering RNA (siRNA) lipid lowering drug, has reported muscle adverse events (MAEs), but long-term safety is unclear. This study is based on data obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, covering the period from December 22, 2021, to December 31, 2024. MAEs signals of inclisiran were mined by calculating reporting odds ratios (ROR) and the Bayesian confidence propagation neural network (BCPNN). Stratification analysis, serious, and nonserious cases were compared, and signals were prioritized using a rating scale. In addition, we used Mendelian randomization (MR) to investigate the causal relationship between inclisiran and musculoskeletal system diseases. Among 4685 adverse event reports of inclisiran, 523 MAEs reports were found. Inclisiran has potential signals in terms of MAEs (ROR: 7.51, 95% CI, 6.86-8.23; IC: 2.75, IC 025 : 2.60). Inclisiran-related MAEs signal intensity was lower than statins (ROR: 0.40, 95% CI, 0.37-0.44), but higher than other PCSK9 inhibitors (ROR: 5.85, 95% CI, 5.26-6.50). Combination with statins/fibrates rarely increased MAE risk or signal strength. Notably, the signal between inclisiran and MAEs can still be detected when stratified by sex, age, reporter type, and serious report. Among the 7 PTs identified, muscle spasms and myalgia are of moderate clinical priority signals and should be given particular attention. MR analysis further validated that inclisiran may be potentially associated with an increased risk of musculoskeletal system diseases. This study revealed that MAEs associated with inclisiran. Additional laboratory and clinical monitoring should be considered for patients taking inclisiran for timely diagnosis and management of MAEs.

Abstract: Vericiguat improves outcomes in heart failure (HF) by promoting vasodilation of the systemic and pulmonary arterial beds. Little is known about its impact on pulmonary artery pressure (PAP). We aimed to study this effect using measurements from implanted PAP sensors. A retrospective analysis was performed on patients with HF treated with vericiguat and implanted with CardioMEMS. PAP was followed for 90 days before and after vericiguat initiation. We recorded laboratory values, echocardiographic and hemodynamics before vericiguat initiation. Fifteen patients were included (age 70, 67% men). At baseline, median EF was 27.5%, 42% had RV dysfunction, mildly elevated mean PAP (24 mm Hg) and pulmonary vascular resistance of 1.6 Wood. When comparing the average of measurements 90 days before and after vericiguat, there were no changes in systolic (34 (28-42) versus 33 (30-40), P = 0.4), diastolic (17 (14-20) versus 16 (13-20), P = 0.75), and mean (24 (18-28) versus 23 (19-28), P = 0.55) PAP. We compared average measurements in the 3-week period before starting vericiguat to various 3-week intervals after vericiguat and found no difference. At 90 days, the median loop diuretic dose (Furosemide equivalent) was 40 mg [0-160], compared with 42 mg [0-240] before vericiguat. NTproBNP did not change significantly before and after vericiguat initiation (log(NTproBNP) 3.1 (2.4-3.2) versus 2.9 (2.5-3.1), P = 0.4). In conclusion, vericiguat was well tolerated in stable HF patients with mild pulmonary hypertension, but no significant effect on PAP was observed. Larger studies, including patients with higher PAP, are needed to clarify its impact.

Abstract: Hypertension is associated with significant changes in the vascular system and is an important risk factor for cerebrovascular disease. Moreover, hypertension is a dominant determinant of heart failure, and both contribute to the development of cognitive decline and dementia. Despite these links, there is limited understanding of how hypertension and risk of heart failure influence the structure, function, and mechanical properties of cerebral arterioles. We examined the effects of hypertension, alone or with predisposition for heart failure, on penetrating arterioles. Using arterioles isolated from rats with genetic hypertension, structural properties, mechanical behavior, and functional responses were characterized by pressure myography. Penetrating arterioles from spontaneously hypertensive heart failure (SHHF) rats exhibited eutrophic remodeling, reduced compliance, and increased stiffness. In contrast, penetrating arterioles from spontaneously hypertensive rats (SHR) were more compliant and less stiff despite similar structural remodeling. Increased collagen deposition in SHHF arterioles was consistent with reduced compliance, whereas SHR arterioles had unchanged collagen-elastin ratio. SHHF and SHR arterioles were functionally different when exposed to pharmacologic mediators of vasomotor response. After exposure to endothelial N-methyl- d -aspartate receptor coagonists, glutamate and d -serine, vasorelaxation was reduced in SHHF rats but not in SHR relative to normotensive controls. In contrast, acetylcholine-induced vasorelaxation was maintained in SHHF rats but enhanced in SHR. Furthermore, sodium nitroprusside caused vasorelaxation in normotensive arterioles, whereas vasoconstriction was observed in both hypertensive strains. Therefore, penetrating arterioles undergo compensatory adaptations in hypertension, but not when there is a genetic propensity for developing heart failure.

Myocardial ischemia/reperfusion (I/R) injury remains a major clinical challenge, because blood flow restoration can exacerbate tissue damage. Apelin, an endogenous peptide acting through the APJ receptor, has demonstrated cardioprotective effects in experimental models. The APJ receptor, a G-protein-coupled receptor widely expressed in cardiovascular tissues, mediates vasodilation, cardiac contractility, and angiogenesis. This systematic review and meta-analysis evaluates its efficacy in myocardial I/R injury. A systematic search in Medline (PubMed), Embase, Scopus, and Web of Science was conducted up to 2024, identifying rodent studies of cardiac I/R injury (Langendorff/in vivo) treated with apelin. Studies on pretreatment or chronic ischemia were excluded. A random-effects meta-analysis reported standardized mean differences with 95% confidence intervals, assessing heterogeneity using the I 2 statistic. From 1765 records, 26 preclinical studies met inclusion criteria. Apelin significantly improved +LVdp/dtmax, -LVdp/dtmax, left ventricular end-diastolic pressure, left ventricular end-systolic pressure, left ventricular ejection fraction, left ventricular developed pressure × heart rate, cardiac output, stroke volume, coronary flow, and left ventricular developed pressure, but did not affect heart rate, mean arterial pressure, left ventricular end-diastolic volume, or left ventricular end-systolic volume. It reduced infarct size, fibrosis, lactate dehydrogenase, malondialdehyde, and apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling assay), while also reducing creatine kinase-MB and improving adenosine triphosphate, energy charge, and phosphocreatine. Meta-regression indicated most outcomes were dose independent, although a few (eg, mean arterial pressure, terminal deoxynucleotidyl transferase dUTP nick end labeling) showed dose-related responses. The risk of bias was high in most studies, and publication bias was observed for some outcomes. Apelin exerts cardioprotective effects in rodent I/R models, enhancing cardiac function and metabolism while reducing infarct size, oxidative stress, and apoptosis. Further standardized preclinical and clinical studies are warranted to optimize dosing protocols and define therapeutic applicability.