Cardiovascular Drugs and Therapy最新文献

Purpose: Atrial fibrillation (AF) requires treatment that focuses on two main goals: symptom control and prevention of thromboembolic events. Catheter ablation and left atrial appendage occlusion (LAAO) constitute two well-established treatment methods in selected patients that accomplish these two goals correspondingly. Recently, there is increasing interest in performing the two procedures concomitantly in a so-called "combined" or "one-stop" procedure. This review aims to summarize the current data on the combined procedure, from the rationale and the techniques to its clinical efficacy, indications and future directions.

Methods: An extensive search has been conducted using the MEDLINE/PubMed database to identify the relevant studies.

Results: The reported success rates of the combined procedure are very high and frequently reach 100% when performed by experienced operators. The periprocedural and follow-up complications are low, the procedure is cost-effective, while there is significant stroke, bleeding and arrhythmia incidence reduction that does not seem to be undermined by interference between the two interventions. There are also a few indications that the one-stop procedure has a positive effect on left atrial mechanical function as it has been correlated with left atrial reverse remodeling. On the other hand, some studies suggest possible increase in peri-device leaks (PDLs), compared with LAAO alone, which could in turn negatively affect the clinical outcomes. Most available studies are small and observational, with a lack of randomized controlled trials.

Conclusion: Catheter ablation and left atrial appendage occlusion can be safely and effectively combined in a cost-effective single procedure in carefully selected patients.

Background: The therapeutic prowess of doxorubicin in oncology is marred by its cardiotoxic consequences, manifesting as cardiac remodeling. Pathophysiological alterations triggered by doxorubicin include inflammatory cascades, fibrotic tissue deposition, vascular and valvular changes, and finally cardiomyopathy. These multifarious consequences collectively orchestrate the deterioration of cardiac architecture and function.

Method: By charting the molecular underpinnings and remedial prospects, this review aspires to contribute a novel perspective using latest publications to the ongoing quest for cardioprotection in cancer therapy.

Results and discussion: Experimental analyses demonstrate the pivotal roles of oxidative stress and subsequent necrosis and apoptosis of cardiomyocytes, muscle cells, endothelial cells, and small muscle cells in different parts of the heart. In addition, severe and unusual infiltration of macrophages, mast cells, and neutrophils can amplify oxidative damage and subsequent impacts such as chronic inflammatory responses, vascular and valvular remodeling, and fibrosis. These modifications can render cardiomyopathy, ischemia, heart attack, and other disorders. In an endeavor to counteract these ramifications, a spectrum of emerging adjuvants and strategies are poised to fortify the heart against doxorubicin's deleterious effects.

Conclusion: The compendium of mitigation tactics such as innovative pharmacological agents hold the potential to attenuate the cardiotoxic burden.

Purpose: Verapamil, an L-type calcium channel blocker treating hypertension, arrhythmia, and other cardiovascular diseases, has emerged as a potential drug for lowering blood glucose by regulating cellular calcium homeostasis and affecting expression of apoptosis-related proteins in pancreatic β-cells. However, this promising effect must be weighed against potential risks, including cardiovascular adverse effects of this drug.

Methods: We conducted a systematic review and meta-analysis and included randomized controlled trials (RCTs) assessing verapamil in individuals with type 1 or type 2 diabetes. The primary outcomes were glycated hemoglobin (HbA1c) and serum glucose concentration. The secondary outcomes were area under the curve (AUC) values for C-peptide level, body weight, changes in HbA1c and blood glucose concentration pre- and post-intervention, and adverse drug reactions.

Results: A total of eight RCTs involving 1100 patients were included in the analysis. Meta-analysis showed that verapamil effectively lowered blood glucose levels (weighted mean difference [WMD] -6.38, 95% CI -12.52, -0.25 mg/dL, P = 0.04; 6 trials), decreased HbA1c (WMD -0.45, 95% CI -0.66, -0.23%, P < 0.001; 7 trials), and increased C-peptide AUC (WMD 0.27, 95% CI 0.21, 0.32 pmol/mL, P < 0.0001; 2 trials) in patients with both type 1 and type 2 diabetes, without significant trial-related adverse events (OR 1.33, 95% CI 0.85, 2.09, P = 0.21).

Conclusion: The adjunctive use of verapamil to standard hypoglycemic therapy is a safe and effective means of improving glycemic control in diabetic patients. However, the limited scale of RCTs and heterogeneity of basic glucose-lowering regimens across studies might constrain generalizability of these findings. Future high-quality research is warranted to further elucidate the role of verapamil in diabetes management.

Purpose: This study aims to identify therapeutic targets for coronary atherosclerosis (CA) using publicly available datasets while exploring its pathophysiologic mechanisms, mediators and potential side effects.

Methods: We conducted a two-sample Mendelian randomization (MR) and single-cell MR analyses integrating identified druggable genes to evaluate the causal relationship between expression quantitative trait loci (eQTL) and CA in both peripheral and central tissues. Using peripheral protein quantitative trait loci (pQTL) data, we further validated the identified targets at the proteomic level through summary data-based MR (SMR) and HEIDI tests. Concurrently, mediation MR analysis was employed to investigate potential mechanistic pathways underlying the role of these targets in CA. Additionally, a phenotype-wide MR (Phe-MR) analysis was performed to explore other potential indications for the therapeutic application of the identified targets.

Results: In conclusion, we identified three CA-associated genes in peripheral tissues (VAMP8, MFGE8 and PDGFD) two CA-associated genes in central tissues (GGCX and NPEPPS). In addition, single-cell MR analyses revealed that GGCX was associated with increased CA risk in excitatory, inhibitory and oligodendrocyte precursor cells, whereas NPEPPS was associated with protection in oligodendrocyte lineage cells. Finally, Phe-MR analyses indicated possible indications and side effects of the targets.

Conclusion: Our study provides genetic evidence for VAMP8, MFGE8, PDGFD, GGCX and NPEPPS as potential therapeutic targets for CA, highlighting their clinical relevance, associated risks and mediators, and providing valuable insights for the development of novel CA therapeutics.

Purpose: This study aimed to investigate the effects of transcutaneous auricular vagus nerve stimulation (ta-VNS) on heart failure with preserved ejection fraction (HFpEF) and explore the related mechanisms.

Methods: Sprague-Dawley rats were fed a high-fat diet and N^[w]-nitro-L-arginine methyl ester to establish an HFpEF model. Ta-VNS was achieved by electrical stimulation of the auricular concha. Histology and echocardiography were used to identify changes in cardiac function and pathology. RNA sequencing was used to explore the underlying mechanism. RT‒PCR, WB, and immunofluorescence staining were used to determine the effects of ta-VNS on macrophage polarization. In vitro, RAW264.7 cells were induced into the M1 or M2 type. An α7nAChR agonist and an α7nAChR inhibitor were used to explore the effects of α7nAChR on macrophage polarization. Finally, an α7nAChR inhibitor was used to determine whether the therapeutic effects of ta-VNS are related to α7nAChR.

Results: In vivo, ta-VNS alleviated cardiac dysfunction and pathological remodeling in rats with HFpEF. RNA sequencing demonstrated that the protective effects of ta-VNS on HFpEF were related to macrophage-mediated inflammatory responses. Ta-VNS decreased the expression of M1-type macrophage markers but increased the expression of M2-type markers. In vitro studies revealed that the α7nAChR agonist decreased the polarization of macrophages toward the M1 type, whereas the α7nAChR inhibitor reduced the polarization toward the M2 type. Furthermore, the α7nAChR inhibitor abolished the protective effects of ta-VNS on macrophage polarization and myocardial remodeling in rats with HFpEF.

Conclusion: Ta-VNS ameliorated HFpEF-induced cardiac remodeling, which was associated with the modulation of macrophage polarization.

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: 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.