Cardiovascular Drugs and Therapy最新文献

Purpose: The use of doxorubicin (DOX), a potent chemotherapy drug, is limited by its detrimental effects on the heart. This cardiotoxicity is primarily driven by oxidative stress and inflammation. TRIM35 plays a key role in inflammatory responses; however, its exact function in DOX-induced cardiotoxicity (DIC) remains to be fully understood. This study investigates the effects of TRIM35 on DIC and explores the underlying biological mechanisms.

Methods: To assess the role of TRIM35, we reduced the expression of TRIM35 in the heart tissues of mice using an adeno-associated virus 9 (AAV9) system, delivered through tail vein injection. We then administered weekly doses of DOX (4 mg/kg) to C57BL/6 mice for 4 weeks to induce DIC. Echocardiography, histopathological assessments, and molecular techniques were employed to examine the effects and mechanisms of TRIM35 on DIC.

Results: Our research found that DOX treatment increases TRIM35 levels in the heart. By lowering TRIM35 expression, we observed an improvement in cardiac function and a decrease in myocardial damage in DOX-treated mice. Additionally, reduced TRIM35 expression lessened myocardial hypertrophy and fibrosis. It also mitigated the oxidative stress and inflammation caused by DOX. Furthermore, the down-regulation of TRIM35 expression resulted in the downregulation of TLR4 and phosphorylated P65 expression.

Conclusion: Downregulated TRIM35 expression mitigates the oxidative stress and inflammation caused by DOX, likely through impacting the TLR4/NF-κB signaling pathway. These insights indicate that TRIM35 holds promise as a therapeutic target for managing heart damage induced by DOX.

Purpose: Coronary endarterectomy combined with coronary artery bypass grafting (CE-CABG) effectively achieves coronary revascularization in patients with diffuse atherosclerotic coronary artery disease (CAD). However, the loss of the subendothelial tissue at the CE-CABG coronary artery accelerates local thrombosis, leading to CE-CABG graft failure. Dual antiplatelet therapy (DAT) and warfarin plus aspirin (WPA) are the two most common anticoagulation strategies post CE-CABG. This retrospective study compares the clinical outcomes and graft failure rates associated with these two approaches.

Methods: This study is a retrospective cohort study. Between July 2016 and April 2024, 102 patients with diffuse CAD underwent CE-CABG. Six patients were excluded. In total, 96 patients (mean age 59.8 ± 7.7 years) enrolled in the study (43 in DAT group and 53 in WPA group). The DAT group received aspirin (100 mg, qd) and clopidogrel (75 mg, qd) for 1 year postoperatively, transitioning to aspirin (100 mg, qd) after 1 year. The WPA group received warfarin (international normalized ratio, INR remained at 1.8-2.5) and aspirin (100 mg, qd) for 3 months postoperatively, followed by DAT after 3 months, changed to aspirin monotherapy after 1 year. The primary endpoint was graft failure of the CE-CABG graft.

Results: Four patients died during the perioperative period (1 in DAT group, 3 in WPA group), resulting in an overall perioperative mortality rate of 4.2%. Five patients were lost for follow-up. Mean follow-up time was 38 months. Three patients died during the follow-up period (1 in DAT group, 2 in WPA group). The CE-CABG graft patency of the WPA group was significantly higher compared to the DAT group (88.1% vs. 50.0%, P < 0.001). Kaplan-Meier analysis showed that the median graft failure time was significantly longer in the WPA group (77 months, 95% CI 69-85) compared to the DAT group (73 months, 95% CI 17-129, P = 0.017). A higher proportion of the DAT group was classified as NYHA III-IV compared to the WPA group (26.2% vs. 10.2%, P = 0.046). One patient of the WPA group had a gastrointestinal bleeding event, and the overall incidence of bleeding events was not statistically different between the two groups.

Conclusion: Using the WPA strategy after CE-CABG significantly reduces the rate of graft failure and improves cardiac function without increasing the risk of bleeding events.

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.