Journal of Cardiovascular Pharmacology最新文献

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.

Inclisiran, the first small interfering RNA (siRNA) lipid lowering drug, has reported muscle adverse events (MAEs), but long-term safety is unclear. This study is based on data obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, covering the period from December 22, 2021, to December 31, 2024. MAEs signals of Inclisiran were mined by calculating reporting odds ratios (ROR) and the Bayesian confidence propagation neural network (BCPNN). Stratification analysis, serious and non-serious cases were compared, and signals were prioritized using a rating scale. Additionally, we employed mendelian randomization (MR) to investigate the causal relationship between Inclisiran and musculoskeletal system diseases. Among 4,685 adverse event reports of Inclisiran, 523 MAEs reports were found. Inclisiran has potential signals in terms of MAEs (ROR:7.51, 95%CI:6.86-8.23; IC:2.75, IC025:2.60). Inclisiran-related MAEs signal intensity was lower compared to statins (ROR:0.40, 95%CI:0.37-0.44), but higher than other PCSK9 inhibitors (ROR:5.85, 95%CI:5.26-6.50). Combination with statins/fibrates rarely increased MAE risk or signal strength. Notably, the signal between Inclisiran and MAEs can still be detected when stratified by gender, age, reporter type and serious report. Among the 7 PTs identified, muscle spasms and myalgia are of moderate clinical priority signals and should be given particular attention. MR analysis further validated that Inclisiran may be potentially associated with an increased risk of musculoskeletal system diseases. This study revealed that MAEs associated with Inclisiran. Additional laboratory and clinical monitoring should be considered for patients taking Inclisiran for timely diagnosis and management of MAEs.

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.

Heart failure (HF), with varied symptoms caused by cardiac strain or damage, has high morbidity and mortality. Protein lactylation, a post-translational modification, regulates immune and cardiovascular processes, but its role in HF's immune microenvironment remains underexplored. Differentially expressed lactylation-related genes (LacRGs) were identified by intersecting HF differentially expressed genes with LacRG datasets. Unsupervised clustering categorized HF patients into LacRG-based subgroups. A LacRG diagnostic model was developed to assess associations with immune cell infiltration, immunotherapy potential, and single-cell RNA sequencing (scRNA-seq) expression patterns. HF mouse models were constructed and verified for LacRGs expression. In 200 HF vs. 166 non-HF samples, 38 differentially expressed LacRGs were identified, revealing distinct immune landscapes. Two LacRG clusters exhibited unique functional enrichment and immunological features. A 14-gene LacRG signature distinguished HF from controls with high accuracy (AUCs: 0.999, 1.000, 0.744). scRNA-seq (GSE145154) revealed reduced lactylation scores in fibroblast, macrophage, T cell, and NK cell subsets in HF, alongside characterization of altered cellular subtypes and activated signaling pathways within these populations. External datasets (GSE46224, GSE116250) identified six hub gene-HBB, EXT1, CENPA, NT5E, STAT4, and CAPN5, which were validated in HF mouse models. Additionally, analysis of Zenodo.4114617 further indicated higher LacRG scores in heart failure with preserved ejection fraction than in reduced ejection fraction. Lactylation modification is closely linked to HF's immune microenvironment. A 14-gene LacRG signature and six hub genes provide novel insights into HF pathophysiology and potential therapeutic avenues. Further studies are warranted to validate their regulatory roles in HF via immune microenvironmental mechanisms.

Preeclampsia is a hypertensive disorder of pregnancy associated with substantial maternal morbidity and long-term cardiovascular risk, but the consistency of echocardiographic remodeling remains unclear. We conducted a mega-meta-analysis of left ventricular function and geometry, enabled by a large language model based suite of tools. A PROSPERO-registered review (CRD420251109103) searched PubMed, Scopus, and Embase without date limits. Synthesa AI screened more than 138,000 abstracts, extracted data, assessed risk of bias, and generated Bayesian analytic code, with all outputs validated by human reviewers. Seventy-five studies including met eligibility criteria. Preeclampsia was associated with a small but statistically significant reduction in ejection fraction (mean difference -0.87%, 95% CrI -1.58 to -0.16) and a clinically meaningful impairment in global longitudinal strain (-3.08%, 95% CrI -4.13 to -2.06). Left ventricular mass index was substantially higher in the preeclampsia group (+13.10 g/m 2 , 95% CrI 10.06 to 16.21), as was relative wall thickness (+0.062, 95% CrI 0.042 to 0.081), whereas fractional shortening showed no significant difference (-0.60%, 95% CrI -2.15 to +0.86). Moderator analyses revealed that BMI and parity significantly influenced strain, while gestational age at diagnosis accounted for nearly all variance in ventricular mass. This mega-meta-analysis defines a remodeling phenotype of preserved ejection fraction, impaired strain, and hypertrophic adaptation consistent with subclinical systolic dysfunction. Equally, it demonstrates the transformative role of LLM-based tools, showing that evidence syntheses of this magnitude can be automated, scaled, and standardized in ways previously unattainable.