Cardiovascular Drugs and Therapy最新文献

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: The purpose of this study was to investigate the protective effects of biochanin A (BCA) on cardiac hypertrophy and to elucidate the underlying molecular mechanisms. The research question was whether BCA can reverse heart dysfunction and attenuate cardiomyocyte hypertrophy induced by pressure overload and AngII, respectively, and how it interacts with the NLRP3 pyroptosis pathway to achieve these effects.

Methods: We employed an animal model of pressure overload-induced cardiac hypertrophy and an in vitro model of AngII-induced cardiomyocyte hypertrophy to assess the effects of BCA. The expression of NLRP3 and its related signaling molecules was analyzed by western blotting, and the activity of the NLRP3 pathway was measured using pyroptosis assays. The role of Cbl-b, an E3 ubiquitin ligase, in BCA-mediated NLRP3 inhibition was also investigated.

Results: BCA was found to reverse heart dysfunction and attenuate cardiomyocyte hypertrophy induced by pressure overload and AngII. Mechanistically, BCA mitigated cardiac hypertrophy by targeting the NLRP3 pyroptosis pathway. The reduction in NLRP3 expression by BCA was predominantly mediated through the upregulation of Cbl-b, which enhanced the ubiquitination and subsequent degradation of NLRP3. Additionally, BCA facilitated the upregulation of Cbl-b expression by interacting with NF-κB, preventing NF-κB binding to the promoter region of Cbl-b and reversing its suppressive action on Cbl-b expression.

Conclusion: This study provides initial evidence that BCA can protect against cardiac hypertrophy. Its mechanism of action involves interacting with NF-κB to promote the expression of Cbl-b, which facilitates the ubiquitination and degradation of NLRP3, ultimately inhibiting pyroptosis. This finding suggests that BCA may be a potential therapeutic agent for the treatment of cardiac hypertrophy.

Purpose: Transcatheter aortic valve replacement (TAVR) has emerged as a critical innovation for managing severe aortic stenosis, prompting the development of numerous clinical practice guidelines worldwide. This study systematically evaluates the guideline development methodologies of major international TAVR guidelines using the AGREE II and AGREE-REX instruments, aiming to enhance understanding of current development processes.

Methods: A comprehensive search was conducted in PubMed, Embase, Web of Science, and specialized guideline repositories. Twenty-four TAVR-specific guidelines were independently evaluated by four reviewers using the AGREE II and AGREE-REX instruments. The guidelines were categorized as evidence- or consensus-based, and statistical analysis was performed using SPSS to standardize scores and assess inter-rater reliability.

Results: Systematic assessment revealed significant methodological variations across guidelines. The AGREE II evaluation showed the highest performance in scope and purpose (83.9 ± 10.0%) but lower scores in rigor of development (43.5 ± 29.0%) and applicability (42.4 ± 26.8%). The AGREE-REX analysis demonstrated stronger performance in implementability (78.6 ± 14.5%) while identifying gaps in the integration of values and preferences (35.7 ± 17.2%). Evidence-based guidelines consistently outperformed consensus-based ones across multiple domains, particularly in terms of methodological rigor and implementation planning.

Discussion: This evaluation highlights key areas for improving guideline development methodology, including standardized evidence evaluation processes, systematic stakeholder engagement, and structured implementation planning. The considerable variability in methodological quality underscores the need for more standardized approaches.

Conclusion: Current TAVR guidelines exhibit significant heterogeneity in methodological quality, with evidence-based guidelines demonstrating superior performance in development rigor and implementation planning. Systematic approaches to evidence synthesis and stakeholder engagement are crucial for high-quality guideline development.

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: 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: 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.

Backgrounds: Neuronal guidance proteins (NGPs) have been demonstrated to guide the elongation of neuronal axonal growth cones in the developing central nervous system. Non-neuronal functions of NGPs have also been described, especially in relation to atherosclerosis.

Findings: Netrin-1 and repulsive guidance molecule a (RGMa) are NGPs that have been shown to regulate endothelial cell adhesion and angiogenesis, macrophage migration and apoptosis, smooth muscle cells (SMCs) phenotypic dedifferentiation and mobility, chemokine activities, and inflammatory responses during atherosclerosis initiation and progression.

Purposes: However, mechanistic studies have generated controversy about the specific role of Netrin-1 in atherosclerosis due to the diversity of its structure, receptors and cell sources, and the actions of RGMa in atherosclerosis have not been reported in previous reviews. Therefore, the current work reviews the evidence for roles of Netrin-1 and RGMa in the initiation and progression of atherosclerosis and discusses potential therapeutic targets in the future.

Objective: Cardiopulmonary bypass (CPB) is a requisite technique for thoracotomy in advanced cardiovascular surgery. However, the consequent myocardial ischemia-reperfusion injury (MIRI) is the primary culprit behind cardiac dysfunction and fatal consequences post-operation. Prior research has posited that myocardial insulin resistance (IR) plays a vital role in exacerbating the progression of MIRI. Nonetheless, the exact mechanisms underlying this phenomenon remain obscure.

Methods: We constructed pyruvate dehydrogenase E1 α subunit (PDHA1) interference and overexpression rats and used ascending aorta occlusion in an in vivo model of CPB-MIRI. We devised an in vivo model of CPB-MIRI by constructing rat models with both pyruvate dehydrogenase E1α subunit (PDHA1) interference and overexpression through ascending aorta occlusion. We analyzed myocardial glucose metabolism and the degree of myocardial injury using functional monitoring, biochemical assays, and histological analysis.

Results: We discovered a clear downregulation of glucose transporter 4 (GLUT4) protein content expression in the CPB I/R model. In particular, cardiac-specific PDHA1 interference resulted in exacerbated cardiac dysfunction, significantly increased myocardial infarction area, more pronounced myocardial edema, and markedly increased cardiomyocyte apoptosis. Notably, the opposite effect was observed with PDHA1 overexpression, leading to a mitigated cardiac dysfunction and decreased incidence of myocardial infarction post-global ischemia. Mechanistically, PDHA1 plays a crucial role in regulating the protein content expression of GLUT4 on cardiomyocytes, thereby controlling the uptake and utilization of myocardial glucose, influencing the development of myocardial insulin resistance, and ultimately modulating MIRI.

Conclusion: Overall, our study sheds new light on the pivotal role of PDHA1 in glucose metabolism and the development of myocardial insulin resistance. Our findings hold promising therapeutic potential for addressing the deleterious effects of MIRI in patients.