Cardiovascular Drugs and Therapy最新文献

Purpose: Reperfusion of the ischaemic heart is essential to limit myocardial infarction. However, reperfusion can cause cardiomyocyte hypercontracture. Recently, cardiac myosin-targeted inhibitors (CMIs), such as Mavacamten (MYK-461) and Aficamten (CK-274), have been developed to treat patients with cardiac hypercontractility. These CMIs are well tolerated and safe in clinical trials. We hypothesised that, by limiting hypercontraction, CMIs may reduce hypercontracture and protect hearts in the setting of ischaemia and reperfusion (IR).

Methods: We investigated the ability of MYK-461 and CK-274 to inhibit hypercontracture of adult rat cardiomyocytes (ARVC) in vitro following ATP depletion. A suitable dose of CMIs for subsequent in vivo IR studies was identified using cardiac echocardiography of healthy male Sprague Dawley rats. Rats were anaesthetized and subject to coronary artery ligation for 30 min followed by 2 h of reperfusion. Prior to reperfusion, CMI or vehicle was administered intraperitoneally. Ischaemic preconditioning (IPC) was used as a positive control group. Infarct size was assessed by tetrazolium chloride staining and extent of hypercontracture was assessed by histological staining.

Results: Treatment with CMIs inhibited ARVC hypercontracture in vitro. MYK-461 (2 mg/kg) and CK-274 (0.5 mg/kg to 2 mg/kg) significantly reduced infarct size vs. vehicle. IR caused extensive contraction band necrosis, which was reduced significantly by IPC but not by CMIs, likely due to assay limitations. GDC-0326, an inhibitor of PI3Kα, abrogated CK-274-mediated protection following IR injury. GDC-0326 reduced phosphorylation of AKT when administered together with CK-274.

Conclusion: This study identifies CMIs as novel cardioprotective agents in the setting of IR injury.

Purpose: Angiotensin receptor-neprilysin inhibitors (ARNi) have been shown to improve cardiovascular outcomes in heart failure (HF) patients. However, their impact on HF patients with concurrent acute kidney disease (AKD) remains underexplored. This study investigated the outcomes of ARNi compared to angiotensin-converting enzyme inhibitors (ACEi) in HF patients with AKD.

Methods: The study included 20,009 hospitalized HF and AKD patients who underwent dialysis during hospitalization, recovered from dialysis within 90 days after discharge, and were followed until November 30, 2022, using data from TriNetX. The study period began in July 2015, coinciding with the availability of ARNi in the market. Propensity score matching (1:1) was applied to balance ARNi and ACEi groups. Adjusted hazard ratios (aHR) with 95% confidence intervals (CI) were calculated to assess the risks of mortality, major adverse kidney events (MAKE), readmission and major adverse cardiac events (MACE). The follow-up period was conducted with a maximum duration of 5 years.

Results: A total of 20,009 AKD patients (mean [SD] age, 59.1 [12.2] years) were enrolled, of whom 21.9% received ARNi, with a median follow-up of 2.3 years. After matching, 4391 patients (mean age, 58.6 years; male, 67.9%) were identified in both the ARNi and control groups. ARNi users exhibited a significantly lower risk of mortality (aHR, 0.32, 95% CI 0.13-0.80, p = 0.01), MAKE (aHR, 0.58, 95% CI 0.51-0.66, p < 0.01 ), and readmission (aHR, 0.61, 95% CI 0.55-0.68, p <0.01) versus controls. However, no significant difference in the risk of MACE was observed between the two groups (aHR, 0.94, 95% CI 0.82-1.09, p = 0.78). Subgroup analysis revealed ARNi users, when concomitantly treated with mineralocorticoids, diuretics, or beta-blockers had significantly lower risks of mortality, readmission, and MAKE than the control group. In addition, ARNi significantly reduced mortality and MAKE in patients with GFR 30-60 mL/min/1.73 m², irrespective of proteinuria status. However, no significant benefit was observed in patients with GFR <30 mL/min/1.73 m².

Conclusions: In HF patients with AKD, ARNi was associated with reduced all-cause mortality, MAKE, and readmission risks compared to ACEi, particularly with concurrent mineralocorticoids, diuretics, or beta-blockers. Future research is necessary to further investigate the impact of ARNi on outcomes in patients with HF and AKD.

Purpose: Spironolactone has been reported to increase the risk of upper gastrointestinal bleeding in patients. We aimed to validate this perspective in a population of patients undergoing percutaneous coronary intervention with high bleeding risk (PCI-HBR).

Methods: We prospectively included a total of 1616 PCI-HBR patients who were treated at West China Hospital of Sichuan University from May 2022 to July 2024. These patients were divided into a spironolactone treatment group (n = 301) and a non-spironolactone treatment group (n = 1315). A propensity score matching was performed at a 1:4 ratio, and Cox regression analysis was conducted on the matched data. Additionally, Kaplan-Meier curves were plotted to evaluate the direct correlation between spironolactone use and gastrointestinal bleeding. And the subgroup analysis is used to assess the robustness of the results.

Results: In this study, after propensity score matching, a total of 927 patients were included in the outcome analysis, with 259 in the spironolactone group and 668 in the non-spironolactone group. Throughout the follow-up period, 14 (5.4%) and 42 (6.3%) patients experienced BARC 2-5 gastrointestinal bleeding events in the spironolactone and non-spironolactone groups, respectively, while 6 (2.3%) and 24 (3.6%) patients experienced BARC 3-5 gastrointestinal bleeding. The incidence of BARC 2-5 gastrointestinal bleeding was comparable between the groups (14/259 [5.4%] vs. 42/668 [6.3%]; HR 0.88 [0.48-1.62], p = 0.689), as was the incidence of BARC 3-5 gastrointestinal bleeding (6/259 [2.3%] vs. 24/668 [3.6%]; HR 0.69 [0.28-1.68], p = 0.410). No statistically significant interactions were found between spironolactone use and clinical variables such as acute coronary syndrome, diabetes, and chronic kidney disease concerning the risk of gastrointestinal bleeding.

Conclusions: In summary, our prospective cohort study, which used propensity score matching, represents the first comprehensive investigation of spironolactone usage in PCI-HBR patients. Our results underscore that cardiologists need not routinely consider the risk of spironolactone-induced bleeding when making decisions about its use in patients. Larger randomized trials or analyses from existing randomized trials on spironolactone are warranted to draw definitive conclusions about the potential association between spironolactone and bleeding.

Purpose: Myocardial ischemia/reperfusion injury (MIRI) is closely associated with ferroptosis. Dexmedetomidine (Dex) has good therapeutic effects on MIRI. This study investigates whether dexmedetomidine (Dex) regulates ferroptosis during MIRI by affecting ferroportin1 (FPN) levels and elucidates the underlying mechanisms.

Methods: A murine MIRI model was established using male C57BL/6 J mice subjected to 30 min of left anterior descending coronary artery ligation followed by 48 h of reperfusion. In vitro, cardiomyocyte hypoxia/reoxygenation (H/R) models were created with 16 h of hypoxia and 8 h of reoxygenation. Triphenyltetrazolium chloride (TTC) staining was employed to determine infarct size. The pathological changes in myocardial tissues were assessed using hematoxylin-eosin (HE) staining. Lipid reactive oxygen species (ROS) level was detected using BODIPY™ 581/591 C11, and ferrous iron (Fe²⁺) and malondialdehyde (MDA) levels were measured using the kits. Cardiomyocyte viability was examined using cell counting kit-8 (CCK8) assay. The histone H3 lysine 27 acetylation (H3K27Ac) level in the FPN promoter region was determined using DNA pulldown assay. Chromatin immunoprecipitation (ChIP) assay was used to investigate the relationship between histone deacetylase 2 (HDAC2) and FPN promoter.

Results: Dex alleviated ferroptosis in cardiomyocytes by upregulating FPN levels, which mitigated H/R-induced oxidative damage. FPN knockdown abolished the protective effects of Dex, confirming its dependence on FPN expression. Additionally, HDAC2 knockdown alleviated I/R-induced myocardial injury and ferroptosis in mice. Moreover, H/R-induced HDAC2 upregulation transcriptionally inhibited FPN expression by reducing the H3K27Ac level in the FPN promoter region, but Dex therapy restored this impact via inhibition of HDAC2. As expected, HDAC2 overexpression partially reversed the inhibitory effect of Dex on H/R-mediated cardiomyocyte ferroptosis.

Conclusion: Dex alleviated H/R-mediated cardiomyocyte ferroptosis through regulating the HDAC2/FPN axis. Our findings lend theoretical support to the use of Dex in MIRI therapy.

Purpose: The idea behind this study was to assess the effects of empagliflozin and sacubitril/valsartan and their combination on isoproterenol-induced heart failure (HF) and underlying molecular mechanisms.

Methods: HF was induced with 7-day isoproterenol (5 mg/kg daily), confirmed by ejection fraction below 55% after 4 weeks. HF rats received empagliflozin, sacubitril/valsartan, or both for 4 weeks. Parameters measured included hemodynamics, cardiac function, redox status, and histomorphology.

Results: Isoproterenol impaired hemodynamics and cardiac function, increased oxidative damage, and altered cardiac structure. All treatments were cardioprotective; however, combined empagliflozin and sacubitril/valsartan therapy had the most pronounced effect.

Conclusion: Combined empagliflozin and sacubitril/valsartan showed superior cardioprotection in HF, primarily by enhancing antioxidative effects. These findings support early use of both drugs in HF treatment.

Purpose: Heart failure (HF) management is well-defined for reduced ejection fraction (HFrEF) but less so for mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF). This meta-analysis evaluates the impact of Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, on cardiovascular and renal outcomes in these patient populations.

Methods: A systematic search in PubMed and Embase identified randomized controlled trials (RCTs) on Finerenone's cardiovascular and renal effects. Three RCTs were included-FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF-encompassing 19,027 participants. Primary outcomes included cardiovascular death, HF hospitalization, and renal failure. Secondary outcomes focused on safety and adverse events like acute kidney injury and hyperkalemia. Meta-analyses were performed using hazard ratios (HR), confidence intervals (CI), and Relative Risk (RR).

Results: Finerenone was associated with a 20% reduction in HF hospitalization risk (HR 0.80, 95% CI: 0.72-0.90) and a 14% reduction in all-cause mortality (RR 0.86, 95% CI: 0.77-0.97). Finerenone did not significantly reduce cardiovascular death (HR 0.91, 95% CI: 0.82-1.01, p = 0.06). Renal failure rates were similar between Finerenone and placebo (RR 1.05, 95% CI: 0.65-1.68). Hyperkalemia incidence was significantly higher with Finerenone, with a RR of 2.31 (95% CI: 1.98-2.69).

Conclusion: This meta-analysis shows that Finerenone significantly reduces HF hospitalizations and all-cause mortality in patients with chronic kidney disease and heart failure. Further studies are needed to clarify its effects on cardiovascular death and renal failure.

Purpose: Proton pump inhibitors (PPIs) are effective in preventing gastrointestinal (GI) bleeding in high-risk patients on dual antiplatelet therapy (DAPT). Existing criteria for high GI bleeding risk, such as those from the American Heart Association (AHA), may not fully reflect East Asian patient profiles. This study aimed to evaluate the effectiveness of PPIs in preventing GI bleeding across DAPT combinations, stratified by GI bleeding risk using the Academic Research Consortium High Bleeding Risk (ARC-HBR) criteria in patients with acute coronary syndrome (ACS).

Methods: A retrospective cohort of 93,153 patients with ACS initiating DAPT (2018-2020) was analyzed using the Korean National Health Insurance database. Modified ARC-HBR (mARC-HBR) criteria tailored to claims data were compared with AHA criteria in terms of concordance and performance. PPI effects on GI bleeding were analyzed by mARC-HBR risk groups over a 3-year observation period.

Results: The mARC-HBR criteria identified three times more high-risk patients than the AHA criteria, demonstrating higher sensitivity (38.9% vs. 11.1%, p < 0.001) while maintaining a relatively high specificity (both > 70%). While PPI use offered no benefit for low-risk patients, it was associated with a 25.8% lower GI bleeding risk in high-risk patients, with the most pronounced effect observed in those on the aspirin/ticagrelor combination.

Conclusion: The mARC-HBR criteria enhance the identification of high GI bleeding risk patients with ACS and may inform targeted PPI use, given the observed associations suggesting potential benefit in high-risk ticagrelor users and limited effect in low-risk groups.

Purpose: Cardiac inflammation is a basic pathological process of diabetic cardiomyopathy (DCM). Inflammatory response is closely related to pyroptosis, which is a recently identified programmed cell death type. Curcumin (CUR) is a polyphenol extracted from turmeric and has been reported to be crucial in alleviating pyroptosis in DCM. However, the exact mechanism by which CUR improves pyroptosis remains unclear. Therefore, we aimed to investigate the effect of CUR on pyroptosis in DCM and explore the potential mechanisms.

Methods: The molecular docking (MOD) analysis was performed using AutoDock Tools to evaluate the binding patterns and affinities between CUR and tripartite motif containing 21 (TRIM21), as well as between TRIM21 and gasdermin D (GSDMD). Subsequently, DCM models were established in Sprague-Dawley (SD) rats (in vivo) by administering streptozotocin (STZ) and feeding them a high-fat diet. In addition, H9C2 cells were cultured in a high glucose and palmitate environment to construct in vitro models of DCM. Rats or cells were treated by CUR directly. Subsequently, body weight (BW), heart weight (HW)/BW ratio, fasting blood glucose level, and lipid metabolism were measured. Pathological changes were analyzed using hematoxylin and eosin (H&E) and Masson staining. Small interfering RNA (si-RNA) was used to knockdown TRIM21 expression, and the pyroptosis protein expression and cellular activity were evaluated in different groups.

Results: MOD analysis revealed that CUR had a strong binding affinity with TRIM21, and TRIM21 showed a robust interaction with GSDMD. STZ-induced diabetic SD rats showed metabolic abnormalities, structural changes in the ventricle, and the expression of TRIM21 and pyroptosis markers, including nod-like receptor protein-3 (NLRP3), Caspase-1, and GSDMD, were upregulated. CUR reduced cardiac remodeling and improved cardiac function in vivo. CUR inhibited pyroptosis by regulating TRIM21 through in vivo and in vitro studies.

Conclusion: CUR improves DCM by regulating TRIM21 expression to inhibit pyroptosis. Furthermore, this study provides novel approaches and experimental evidence for the research and treatment of DCM and presents new insights into its potential mechanisms.

Background: Cardiac fibroblasts (CFs) are numerically a highly abundant cell type in the heart and are responsible for the homeostasis of the extracellular matrix (ECM) in the myocardium under normal conditions. Upon cardiac stress, these cells become activated and transdifferentiate into myofibroblasts (MyCFs), which are characterized by their increased capacity to proliferate, migrate, and secrete ECM components and bioactive molecules. The trans-differentiation of CFs is induced by several factors like angiotensin II (Ang II) and transforming growth factor-ß (TGF-ß and is crucial in cardiac remodeling. In recent years, signal mechanisms playing a role in MyCFs behavior have been intensively investigated, including the role of the universal second messenger calcium (Ca²⁺).

Aims and scope: Here, we review the current knowledge on Ca²⁺ handling and Ca²⁺-dependent signal transduction in cardiac (myo)fibroblasts, with a focus on the mechanisms leading to intracellular Ca²⁺ release and Ca²⁺ entry from the extracellular space, which is involved in the generation of Ca²⁺ transients and regulation of Ca²⁺ oscillation. Moreover, the activation of Ca²⁺-induced signal transduction involving different kinases and the phosphatase calcineurin in CFs is described.