Journal of Cardiovascular Pharmacology最新文献

A 25% flecainide dose reduction has been recommended for intermediate metabolizers (IMs); however, studies have yielded contradictory results, likely because of the lack of standardization in CYP2D6 pharmacogenetic classifications. We aimed to address this gap. This cohort study included atrial fibrillation patients prescribed flecainide between 2017 and 2021. CYP2D6 was analyzed, and patient phenotypes were classified using the current standard. For the primary outcome-6-month toxicity or recurrence-normal metabolizers (NMs) were compared with IMs. As a secondary objective, outcomes in poor metabolizers (PMs) and 12-month results were evaluated. A total of 104 patients were enrolled. Overall, 50% were NMs, 36.5% IMs, 6.7% PMs, and 6.7% others. There were no differences between IMs and NMs in the incidence of the primary outcome (29.0% vs. 28.9%, P = 0.99). No significant differences were observed in multivariate analysis ( P = 0.97) or 12-month follow-up ( P = 0.57). PMs had a lower event rate at 6 months ( P = 0.1), which became significant when the follow-up was extended to 1 year (univariate P = 0.04; multivariate P = 0.03). Using a standardized CYP2D6 classification, IMs and NMs showed similar rates of toxicity and recurrence when treated with 100 mg flecainide every 12 hours. Although the small sample size limits definitive conclusions, our findings challenge current recommendations to adjust dosing between NMs and IMs. By contrast, better outcomes were observed in PMs. This raises the question of whether, in an effort to minimize flecainide toxicity, dosing has inadvertently been standardized to subtherapeutic levels for all groups except PMs.

Abstract: Phthalates, widely used as plasticizers in industrial and medical products, are increasingly recognized as cardiovascular health disruptors. Their ubiquity poses a significant threat, particularly to patients with or at risk of cardiovascular disease. This review examines the multifactorial risks linked to phthalate exposure, including oxidative stress, epigenetic (re)programming, mitochondrial dysfunction, and endocrine disruption. Preclinical models-ranging from isolated cardiomyocytes to whole-animal systems demonstrate direct cardiotoxic effects, whereas epidemiological studies suggest a considerable global cardiovascular burden. Iatrogenic exposure through drug packaging, tubing, dialysis, and surgical equipment is especially concerning in frail patients yet remains underrecognized in clinical guidelines. Vulnerable populations such as neonates, pregnant women, and patients undergoing cardiovascular procedures may face disproportionately high exposure levels. Despite the availability of safer alternatives, regulatory responses are inconsistent and clinical awareness is limited. Further longitudinal studies and biomarker-based surveillance are needed to quantify cumulative risk. Addressing this overlooked hazard is essential to protect patients from preventable harm and promote safer, precision cardiovascular care in the era of pervasive plastic use. We call for urgent reassessment of current practices, integration of environmental toxicology into medical training, and systematic adoption of phthalate-free materials.

Abstract: To investigate the potential effects of aerobic exercise rehabilitation training (AET) on the progression of myocardial infarction (MI) in a left anterior descending (LAD) coronary artery ligation model in mice, and to explore the underlying mechanisms. MI was induced in male C57BL/6 mice by ligating the LAD coronary artery. After 1 week rest, the mice underwent either adaptive ladder training or treadmill training for 5 consecutive days. The H9C2 cell model was used to simulate AngII-induced myocardial injury, cardiac function was assessed by echocardiography, and gastrocnemius muscle laminin expression was analyzed by immunofluorescence. Skeletal muscle-related gene expression was evaluated by immunoblotting, and the effects of AET on mitochondrial function were assessed using immunoblotting and commercial kits. In addition, JC-1 staining was used to examine mitochondrial dysfunction and further confirm the underlying mechanisms. AET significantly improves cardiac function in MI mice and could mitigate skeletal muscle atrophy in these mice. Further analysis revealed that activation of the SIRT1/PGC-1α pathway by AET enhances mitochondrial function in MI mice. In addition, SIRT1 activation was shown to alleviate skeletal muscle mitochondrial dysfunction induced by heart failure in vitro. AET can alleviate skeletal muscle atrophy induced by heart failure in mice through the SIRT1/PGC-1α pathway.

Abstract: Histone deacetylase 4 (HDAC4) is highly expressed in patients with essential hypertension and is closely related to myocardial injury. Therefore, this study aims to explore the effects and mechanisms of HDAC4 on cardiac injury in spontaneously hypertensive rats, with the aim of providing new directions for the diagnosis and treatment of hypertensive myocardial disease. Compared with those in the WKY group, the blood pressure, myocardial injury markers, myocardial cell apoptosis rate, cleaved-caspase9 protein, TNF-α, HDAC4 mRNA, HDAC4 protein, IL-6, cleaved-caspase3 protein, MDA, β-catenin protein, IL-1β, and Wnt3a protein levels in the SHR group significantly increased ( P < 0.05), while LVEF and SOD levels significantly decreased ( P < 0.05); interfering with HDAC4 expression can reduce the cardiomyocyte apoptosis rate, cleaved-caspase9 protein, TNF-α, HDAC4 mRNA, HDAC4 protein, IL-6, cleaved-caspase3 protein, MDA, β-catenin protein, IL-1β, and Wnt3a protein levels, and increase LVEF and SOD levels; overexpression of HDAC4 has the opposite effect. HDAC4 may play a role in regulating cardiac injury in SHR rats by regulating β-catenin signaling pathway.

Abstract: Diabetic cardiomyopathy is a major complication of diabetes marked by myocardial dysfunction, inflammation, and fibrosis. Immune cell infiltration and macrophage polarization are critical in diabetic cardiomyopathy progression. This study examined the role of thrombospondin-1 (THBS1) and its upstream regulatory mechanism, particularly focusing on the transcription factor ETS1, in diabetic myocardial injury. Using an streptozotocin-induced diabetic rat model, we observed significantly elevated THBS1 expression in the myocardium, accompanied by increased M1 macrophage infiltration and myocardial injury markers. Specific inhibition of THBS1 using shRNA lentiviral vectors significantly alleviated myocardial injury, reduced M1 macrophage polarization, and improved cardiac function. In addition, ETS1 was identified as a transcriptional regulator of THBS1, and its knockdown resulted in decreased THBS1 expression, further reducing myocardial inflammation and fibrosis. In vitro, ETS1 knockdown in high glucose-treated H9C2 cells reduced THBS1 expression, cell injury, and fibrosis-related marker expression. These findings demonstrate that the ETS1-THBS1 axis contributes to diabetic myocardial injury by promoting M1 macrophage polarization and fibrosis. Targeting this axis may uncover a novel regimen for alleviating myocardial damage in diabetic patients.

Abstract: The transient receptor potential cation channel subfamily member 6 (TRPC6) represents an emerging druggable target with a broad therapeutic spectrum. TRPC6 Inhibitors are currently investigated for focal segmental glomerulosclerosis, acute respiratory distress syndrome due to COVID-19, and pulmonary hypertension. In the cardiovascular system, there is evidence that TRPC6 is critically involved in the development of cardiac hypertrophy, arrhythmia susceptibility and risk of restenosis after coronary stent implantation. However, data on systemic effects of TRPC6 modulation remain scarce. To assess the phenotypic consequences of inhibiting TRPC6 in different organ systems, we explored public databases to identify single nucleotide polymorphisms (SNPs) that are associated with TRPC6 expression in different tissues. A phenome-wide association study was then performed in 475,739 individuals of UK Biobank to associate genetically mediated reduced TRPC6 expression with 64 phenotypes in nine organ/disease categories. Lower TRPC6 expression was nominally associated with reduced risk of anxiety, heart failure, and stroke, as well as an increased risk of venous thromboembolism, hypertension, appendicitis, and liver cirrhosis. After correction for multiple testing, lower TRPC6 expression remained significantly associated with reduced risk of coronary artery disease and atrial fibrillation. Notably, no deleterious phenotypes were observed, suggesting a favorable profile of systemic TRPC6 inhibition. While these findings indicate potential therapeutic benefits, nominally associated phenotypes, however, mandate careful clinical investigation and provide a basis for further experimental exploration.

Abstract: Paraquat, a widely used herbicide, is known to induce oxidative stress and inflammation, which leads to myocardial injury. Klotho, a protein with antioxidative and anti-inflammatory properties, has garnered as a potential cardioprotective factor. This study aimed to investigate whether cardiac-specific overexpression of klotho mitigates paraquat-induced myocardial injury through the activation of the NF-E2-related factor-2 (Nrf-2)/antioxidant response element (ARE) signaling pathway. Our results revealed that both mRNA and protein expression levels of Klotho were significantly reduced in the myocardial tissue of paraquat-exposed rats. However, cardiac-specific overexpression of Klotho significantly restored Klotho levels and attenuated paraquat-induced myocardial injury, as evidenced by the decreased lactate dehydrogenase and cardiac troponin I contents, and creatine kinase (CK) activity, alongside with apoptosis. Furthermore, cardiac-specific overexpression of Klotho inhibited oxidative stress and inflammation in myocardial tissue of paraquat-subjected rats. Mechanistically, Klotho activated the Nrf2/ARE signaling pathway, upregulating cytoprotective genes such as NAD(P)H quinone oxidoreductase 1, heme oxygenase-1, glutamate cysteine ligase catalytic subunit, and glutamate cysteine ligase modifier subunit. Our findings indicate that Klotho protects against paraquat-induced myocardial injury by suppressing oxidative stress and inflammation, primarily through the activation of the Nrf2/ARE signaling pathway. These results underscore the potential therapeutic role of Klotho in preventing paraquat-induced myocardial damage.

Abstract: Not long ago, the concept that patients could experience heart failure without having left ventricular systolic dysfunction was considered an exception rather than the rule. Now, heart failure with preserved ejection fraction (HFpEF) is recognized as a common, if not the most prevalent, form of heart failure. During the past weeks, I had the privilege to participate in two outstanding educational events focused on HFpEF: the 2025 HFpEF Summit organized by David Lefer, PhD (Cedars-Sinai Medical Center, Los Angeles, CA) and Fadi Salloum, PhD (Virginia Commonwealth University, Richmond, VA), and the UPenn HFpEF Symposium 2025 led by Payman Zamani, MD, and Stuart Prenner, MD (University of Pennsylvania, Philadelphia, PA). I truly enjoyed these sessions and left with a sense of satisfaction and optimism. Indeed, while there is a lot left to discover and develop in HFpEF, so much progress has been made since the first iterations of these meetings, both now in their third edition.

Abstract: To investigate the impact of antimiR-132, a miR-132 antisense inhibitor, on cardiac remodeling and function in a two-hit mouse model of heart failure with preserved ejection fraction (HFpEF), as well as its underlying mechanism. Male C57BL/6 mice were fed N(omega)-nitro- l -arginine methyl ester plus a high-fat diet to establish an HFpEF model and then intraperitoneally injected with antimiR-132 or normal saline. Cardiac fibroblasts treated with transforming growth factor β1 (TGF-β1) were cultured in the presence of antimiR-132 or vehicle to examine collagen synthesis and potential mechanisms. Compared with control mice, HFpEF mice showed significant increases in blood pressure, triglycerides, cholesterol, body weight, myocardial hypertrophy, and fibrosis. They also had elevated E/E' ratios and plasma NT-proBNP levels. antimiR-132 did not significantly affect blood pressure or metabolic parameters in HFpEF mice; however, it notably ameliorated myocardial hypertrophy and fibrosis, while concurrently reducing E/E' ratios and plasma NT-proBNP levels. Mechanistically, the cardioprotective effects of antimiR-132 were accompanied by inhibition of the upregulated expression of miR-132 and P-Smad3 protein in the myocardium, as well as reduction in TGF-β1-induced collagen synthesis and Smad3 phosphorylation in cardiac fibroblasts. Taken together, miR-132 inhibition ameliorated myocardial remodeling and diastolic dysfunction in HFpEF mice through downregulation of the miR-132/Smad3 pathway.