Journal of Cardiovascular Pharmacology最新文献

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.

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.

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.

Abstract: Heart failure (HF), with varied symptoms caused by cardiac strain or damage, has high morbidity and mortality. Protein lactylation, a post-translational modification, regulates immune and cardiovascular processes, but its role in HF's immune microenvironment remains underexplored. Differentially expressed lactylation-related genes (LacRGs) were identified by intersecting HF differentially expressed genes with LacRG data sets. Unsupervised clustering categorized patients with HF into LacRG-based subgroups. An LacRG diagnostic model was developed to assess associations with immune cell infiltration, immunotherapy potential, and single-cell RNA sequencing expression patterns. HF mouse models were constructed and verified for LacRG expression. In 200 HF versus 166 non-HF samples, 38 differentially expressed LacRGs were identified, revealing distinct immune landscapes. Two LacRG clusters exhibited unique functional enrichment and immunologic features. A 14-gene LacRG signature distinguished HF from controls with high accuracy (area under the curve: 0.999, 1.000, 0.744). Single-cell RNA sequencing (GSE145154) revealed reduced lactylation scores in fibroblast, macrophage, T-cell, and NK-cell subsets in HF, alongside characterization of altered cellular subtypes and activated signaling pathways within these populations. External data sets (GSE46224, GSE116250) identified 6 hub genes-HBB, EXT1, CENPA, NT5E, STAT4, and CAPN5, which were validated in HF mouse models. In addition, analysis of HF dataset further indicated higher LacRG scores in heart failure with preserved ejection fraction than in reduced ejection fraction. Lactylation modification is closely linked to HF's immune microenvironment. A 14-gene LacRG signature and 6 hub genes provide novel insights into HF pathophysiology and potential therapeutic avenues. Further studies are warranted to validate their regulatory roles in HF through immune microenvironmental mechanisms.

Abstract: Excessive surgical bleeding is a potential risk in patients taking ticagrelor who must undergo urgent cardiothoracic (CT) surgery before adequate washout of the drug can occur. The DrugSorb-Antithrombotic removal (ATR) device is a polymer sorbent-filled hemoadsorption cartridge that can remove unbound (active) fractions of ticagrelor and ticagrelor active metabolite (TAM) from blood. STAR-T was a randomized double-blind sham-controlled clinical trial investigating whether the intraoperative use of the device could reduce perioperative bleeding complications in patients undergoing CT surgery within 2 days of ticagrelor discontinuation. Blood samples were collected during the study for total drug level measurements because the ability to measure unbound ticagrelor and TAM (0.2% of total levels) requires an ultra-high sensitivity assay, which is not commercially available. A published and validated pharmacokinetic (PK) model was used to explore the effect of the device on unbound ticagrelor/TAM using the total drug concentrations from the study. The model performed well for simulations of total ticagrelor and TAM, which indicated that the unbound concentrations were also appropriate. The model demonstrated that DrugSorb-ATR significantly reduced unbound ticagrelor and TAM concentrations. Linear and logistic regression analyses of summed ticagrelor and TAM concentrations showed that the DrugSorb-ATR device reduced the probability of clinically relevant bleeding in STAR-T because of the reduction in unbound ticagrelor and TAM.

Immune checkpoint inhibitors (ICIs) have successfully revolutionized cancer therapy, but their immune-mediated adverse events include rare, often severe myocarditis. While dual ICI blockade is associated with increased cardiotoxic risk, little is known about the potential effects of triplet combinations currently under clinical investigation. We developed a co-culture model of human cardiomyocytes and human peripheral blood mononuclear cells (hPBMCs) to evaluate immune-mediated cytotoxicity induced by ICIs. HFCs were exposed for 48h to Nivolumab plus Relatlimab, Ipilimumab, or Atezolizumab, either alone or in triplet combinations. Cell lysis was quantified by LDH release. Cytokine secretion (IL-2, granzyme B, and additional inflammatory mediators including NLRP3 activation pathway) was measured by ELISA. Digital microscopy was used for morphological assessment. Triplet combinations of Nivolumab-Relatlimab with Ipilimumab or Atezolizumab induced significantly higher cardiomyocyte lysis compared to single agents or doublets (p < 0.001). This effect correlated with a robust increase in IL-2 and granzyme B secretion, as well as activation of pro-inflammatory cytokines and NLRP3 inflammasome-related mediators. Microscopic analyses confirmed immune cell activation and reduced density of HFCs exposed to triplets. Our findings demonstrate that ICI triplets elicit potent immune activation against cardiomyocytes, providing the first preclinical evidence of direct cardiotoxic potential in this setting. These results highlight the need for enhanced clinical surveillance and cardio-oncology monitoring in patients receiving triple ICI combinations, as these regimens expand in clinical practice.

Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, exhibits cardioprotective effects; however, the underlying epigenetic and molecular mechanisms remain poorly understood. This study investigated whether DAPA mitigates myocardial ischemia/reperfusion injury (MI/RI) by modulating enhancer of zeste homolog 2 (EZH2), tri-methylation of lysine 27 on histone H3 (H3K27me3), and sirtuin 1 (SIRT1) expression. Wistar rats were randomly assigned to Sham, MI, and MI+DAPA groups (n=12/group). MI groups underwent 30 minutes of left anterior descending coronary artery (LAD) ligation. For 14 days, animals in the MI+DAPA group received orally 1 mg/kg/day DAPA. Heart function, fibrosis, inflammatory factors (TNF-α, NF-κB, IL-1β, IL-6), and oxidative stress were assessed using echocardiography, Masson's trichrome staining, Western blotting, and ELISA respectively. EZH2, H3K27me3, and SIRT1 expressions were also determined by Western blotting 14 days after MI induction. Tissue damage was evaluated using hematoxylin and eosin (H&E) staining. DAPA administration significantly improved MI-induced myocardial damage by decreasing serum levels of LDH, cTnI, and CK-MB. DAPA also improved left ventricular function by increasing ejection fraction (EF) and fractional shortening (FS), decreased left ventricular fibrosis, and reduced myocardial inflammation by improving myocardial TNF-α, NF-κB, IL-1β, IL-6. Additionally, DAPA reduced oxidative stress by decreasing malondialdehyde (MDA) levels and increasing superoxide dismutase (SOD) activity. Finally, DAPA downregulated EZH2, reducing H3K27me3 and subsequently increasing SIRT1 levels compared to the MI group. This study's results indicate that DAPA attenuates MI/RI in male rats by modulating epigenetic mechanisms, specifically through EZH2, and H3K27me3 suppression and SIRT1 upregulation, offering novel insights into its cardioprotective potential.

Protamine is frequently used to reverse unfractionated heparin, yet contemporary data on its safety and long-term outcomes in chronic total occlusion percutaneous coronary intervention (CTO PCI)-related perforation are limited. We retrospectively analyzed all CTO PCI procedures performed at a single center between January 2019 and December 2023. Patients who experienced coronary perforation were stratified by protamine administration. Inverse probability of treatment weighting (IPTW) and doubly robust logistic regression were used to adjust for baseline and procedural differences. Clinical endpoints included protamine-related reactions, cardiac tamponade requiring pericardiocentesis, periprocedural myocardial infarction (MI), acute stent thrombosis, in-hospital all-cause death, and 1-year all-cause death. Among 1,503 CTO PCI cases, perforation occurred in 199 patients (13.2%); 108 (54.3%) received protamine, and 91 (45.7%) did not. Protamine use increased over time (p-for-trend <0.001). In-hospital outcomes were comparable between groups, including death (4.6% vs. 4.4%; p>0.999), pericardiocentesis (8.3% vs. 9.9%; p=0.806), and periprocedural MI (0.9% vs. 2.2%; p=0.594). IPTW-adjusted analyses yielded similar results. No acute stent thrombosis or protamine reactions occurred. Doubly robust analysis showed no association between protamine use and in-hospital death (aOR 0.85, 95% CI 0.05-13.86; p=0.917), pericardiocentesis (aOR 0.45, 95% CI 0.10-1.98; p=0.294), or either outcome (aOR 0.53, 95% CI 0.21-2.85; p=0.390). At 1 year, all-cause death remained similar (7.4% vs. 6.6%; p>0.999), with no association on adjusted analysis (aOR 0.63, 95% CI 0.12-3.40; p=0.591). Protamine administration for CTO PCI-related perforation appears safe, without evidence of additional clinical benefit compared with no protamine use.