Journal of Cardiovascular Pharmacology最新文献

Abstract: Chronic stress-induced cardiac hypertrophy remains a critical precursor to heart failure, with current therapies limited by incomplete mechanistic targeting. Cyclin-dependent kinases (CDKs), pivotal regulators of cell cycle and stress signaling, are emerging therapeutic targets in cardiovascular pathologies. Using bioinformatics analysis of human hypertrophic cardiomyopathy data sets (GSE5500, GSE136308) and a murine transverse aortic constriction (TAC) model, we investigated the therapeutic effects of the CDK inhibitor R547 (10 mg/kg, intraperitoneal every 3 days) on pressure overload-induced cardiac remodeling. Cardiac function was assessed by echocardiography, while molecular mechanisms were probed through proteomics and pathway analyses. CDKs were significantly upregulated in heart tissues of human heart failure and TAC mice. R547 treatment attenuated cardiac hypertrophy (↓37.7% cardiomyocyte cross-sectional area; P < 0.001) and fibrosis (↓70.8% collagen volume fraction; P < 0.05) versus TAC controls. Echocardiographic improvements included preserved left ventricular ejection fraction (66 ± 2.1% vs. 81 ± 4.9% in TAC; P < 0.05) and reduced ventricular wall thickening. Mechanistically, R547 concurrently inhibited PI3K/AKT/mTOR hypertrophic signaling and TGF-β/Smad3 fibrotic pathways, with corresponding downregulation of ANP, BNP, β-MHC, and collagen I. This study identifies CDK-driven signaling as a nodal regulator of pressure overload cardiomyopathy. The dual inhibition of PI3K/AKT and TGF-β/Smad3 pathways by R547 demonstrates superior efficacy in mitigating both structural and functional deterioration, positioning it as a promising multifactorial therapy for cardiac hypertrophy.

Abstract: Cardiometabolic complications represent a leading cause of morbidity and mortality among cancer survivors, who increasingly face a dual burden of residual oncologic risk and rising cardiovascular (CV) vulnerability. The shared pathophysiologic mechanisms linking cancer, dyslipidemia, insulin resistance, and chronic inflammation foster an environment conducive to accelerated atherosclerosis, heart failure, and metabolic dysregulation. Hyperglycemia and hyperlipidemia, frequently coexisting in long-term cancer survivors, especially those exposed to cardiotoxic chemotherapies, hormonal therapies, or corticosteroids, are key drivers of adverse CV outcomes. Despite this recognized risk, comprehensive preventive strategies in cardio-oncology remain limited and often rely on conventional therapies insufficient to fully address the complexity of cardiometabolic disease in this population. Notably, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have emerged as powerful tools in CV risk reduction. SGLT2i have demonstrated robust benefits in heart failure, renal protection, and glycemic control, while PCSK9i provide profound and sustained reductions in low-density lipoprotein cholesterol, with emerging pleiotropic anti-inflammatory and antiatherosclerotic effects. We propose that a combinatorial strategy integrating SGLT2i and PCSK9i may offer synergistic protection against the intertwined cardiometabolic risks seen in cancer survivors. This approach targets multiple mechanistic pathways, glucose and lipid metabolism, vascular inflammation, endothelial dysfunction, and organ remodeling, potentially redefining the standard of care in high-risk cardio-oncology populations. Further clinical investigation is warranted to validate this hypothesis and establish optimal therapeutic protocols.

Abstract: Nuclear factor erythrocyte 2-associated factor 2 (Nrf2) is an important transcriptional regulator that plays a protective role in myocardial remodeling. Omaveloxolone (Omav) acts as an activator of Nrf2 and plays a protective role by decreasing oxidative stress and inflammation. The purpose of this study was to explore the role of Omav in myocardial remodeling and investigate the potential mechanism involved. Transverse aortic constriction was performed to construct a mouse cardiac remodeling model, and sham surgery was used as a control. The results showed that Omav treatment significantly improved TAC-induced myocardial remodeling and cardiac dysfunction. In addition, Omav treatment mitigated M1 macrophage polarization, promoted M2 macrophage polarization, and reduced the cardiac inflammatory response and oxidative stress. Cell experiments revealed that Omav can reduce the expression of p-STAT3 induced by PE, thereby inhibiting the polarization of M1 macrophages and promoting the polarization of M2 macrophages. However, the Nrf2 inhibitor ML385 significantly inhibited OMAV-mediated reduction of p-STAT3, macrophage polarization, and activation of the NRf2-KEAP1 pathway. Omav activates the Nrf2-Keap1 pathway, affects STAT3 phosphorylation, ultimately alleviates M1 macrophage polarization, promotes M2 macrophage polarization, and improves myocardial remodeling. Omav may be a potential therapeutic agent for pathologic myocardial remodeling.

Abstract: Heart failure with preserved ejection fraction (HFpEF) is a prevalent and multifaceted clinical syndrome, often underdiagnosed because of its heterogeneous presentation and overlapping comorbidities. Recent randomized trials have demonstrated the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in reducing heart failure hospitalizations and cardiovascular mortality. In this review, we analyze the main challenges of HFpEF diagnosis and discuss current diagnostic algorithms. Based on recent evidence and recommendations, we propose a possible way to simplify and accelerate the diagnostic process of HFpEF, to support an early initiation of disease-modifying therapies. An interactive web-based version of the proposed algorithm is available at www.hfpefdiagnosis.com for research or exploratory purposes.

Abstract: Inflammation is increasingly recognized as a key mechanism driving impaired cardiac function and reduced cardiorespiratory fitness in heart failure. Interleukin-1 blockade with anakinra has shown consistent anti-inflammatory effects but inconclusive benefits on functional capacity in prior trials. In a pooled analysis of 73 patients, Hogwood et al reported that anakinra reduced hsCRP and modestly improved peak VO 2 across both younger (<60 years) and older (≥60 years) patients, with no difference in magnitude of benefit between age groups. These findings indicate that the functional response to IL-1 inhibition is preserved across age groups. Although the results are limited by small sample size, heterogeneous treatment duration, and lack of placebo control, they highlight the importance of age-stratified research and provide a rationale for larger randomized studies assessing long-term clinical outcomes.

Abstract: Although a solid pathophysiologic rationale supports intravenous vasodilators (IVV) for acute heart failure (AHF), trial evidence is conflicting and international guidelines offer only weak recommendations. We conducted an international survey to capture contemporary, real-world practice and clinician opinion regarding IVV use in AHF. A 29-item, web-based questionnaire was distributed to cardiologists involved in AHF management. Items explored indications, contraindications, preferred agents, monitoring strategies, and interaction with guideline-directed medical therapy. We analyzed responses from 170 physicians in 32 countries (67% male; mostly aged 30-50 years). Sixty-two percent treat <10 patients per month with IVV; nitroglycerin is the drug of choice for 48%, followed by sodium nitroprusside in 29%. Nearly half (48%) would start IVV also out of the intensive-care setting and 58% consider repeated noninvasive blood pressure monitoring sufficient. Key indications are acute decompensated heart failure (88%) and pulmonary edema (87%), yet 42% would also use IVV for advanced low-output HF, 25% for cardiogenic shock, and 24% for isolated right ventricular failure. Hypotension is cited as the principal contraindication (51%), although the reported thresholds for blood pressure vary widely. Respondents favor IVV in reduced or mildly reduced ejection fraction (55%) more often than in preserved ejection fraction (17%). Opinions diverge sharply on whether to pause or continue oral neurohormonal therapies during infusion. This survey shows that IVV are used in a limited number of patients with AHF and practice is highly heterogeneous across centers. These findings underscore the need for prospective trials to clarify which subsets derive hemodynamic or prognostic benefit.

Abstract: Cardiorespiratory fitness (CRF) in heart failure (HF) declines with age. Interleukin-1 is a proinflammatory cytokine involved in aging and HF. We aimed to determine the changes in CRF before and after treatment with anakinra, recombinant interleukin-1 receptor antagonist, in patients with HF stratified according to age younger and older than 60 years in phase II clinical trials. We analyzed data from 73 patients [37 (51%) female], 49 (67%) patients <60 years and 24 patients (33%) ≥60 years. All patients received anakinra 100 mg subcutaneously daily for a median of 4 (interquartile range from 2 to 12) weeks. We measured peak oxygen consumption (VO 2peak ) and high-sensitivity C-reactive protein (hsCRP). When compared with older patients, younger patients had higher baseline peak VO 2 [15.2 (12.4-17.7) vs. 12.4 (10.3-14.3) mL·kg -1 ·minute -1 , P = 0.001], yet no significant differences in hsCRP [6.6 (3.6-16.6) vs. 5.2 (2.7-11.2) mg/L, P = 0.18]. In both groups, anakinra decreased hsCRP [<60 years: -3.6 (-8.1 to -1.9) mg/L; P < 0.001; ≥60 years: -2.7 (-9.0 to -1.4) mg/L; P < 0.001] and increased peak VO 2peak [<60 years: +0.5 (-0.9 to 2.5) mL·kg -1 ·minute -1 ; P = 0.036; ≥60 years: +1.1 (0.2-2.3) mL·kg -1 ·minute -1 ; P < 0.001]. No significant differences in changes across time were observed between the age groups. Older patients with HF have a greater baseline impairment in CRF than younger patients despite similar levels of systemic inflammation, and they seem to have a similar improvement in CRF after treatment with anakinra. The lack of an active control group (placebo) is a significant limitation and additional studies are needed to validate and expand these findings assessing clinical outcomes.

Colchicine has been studied as an anti-inflammatory treatment for cardiovascular prevention, but findings from randomized trials have been inconsistent. This meta-analysis evaluated the efficacy and safety of colchicine in reducing major adverse cardiovascular events (MACE) and its individual components, using ChatGPT as an assistant throughout the process. Randomized trials of colchicine for cardiovascular prevention were systematically identified, and data extraction, risk of bias assessment, and meta-analyses were performed with ChatGPT under human supervision. The primary outcome was MACE, while secondary outcomes included myocardial infarction (MI), stroke, revascularization, cardiovascular mortality, and all-cause mortality. Eleven trials involving 30,888 patients were included. Colchicine significantly reduced MACE (risk ratio 0.75, 95% CI 0.63-0.88), though no significant effects were observed for MI, stroke, cardiovascular mortality, or all-cause mortality. In addition to its clinical findings, this study illustrates the potential of ChatGPT to assist in systematic reviews and meta-analyses by automating screening, data extraction, bias assessment, and statistical code generation. This integration reduced researcher time by over 70% while maintaining accuracy through human validation. Overall, colchicine appears to lower the risk of MACE but the results of the CLEAR trial have lowered certainty, while the findings highlight the feasibility and efficiency gains of using large language models in evidence synthesis workflows.