Journal of Cardiovascular Pharmacology最新文献

Understanding the severity and anatomical pattern of coronary artery disease (CAD), particularly whether lesions are focal or diffuse, is critical in determining the most effective treatment strategy for patients with significant left anterior descending (LAD) disease. While percutaneous coronary intervention (PCI) remains the preferred treatment for focal disease, diffuse CAD presents therapeutic challenges, with options ranging from optimal medical therapy (OMT) to coronary artery bypass grafting (CABG). The COMMIT LAD registry is a prospective, multicenter observational study initiated in the Netherlands in January 2024, enrolling patients with symptomatic and significant LAD disease. The registry collects longitudinal data at multiple follow-up points over 12 months. The primary aim is to assess the one-year incidence of major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, stroke, or unplanned revascularization, in patients receiving either surgical or pharmacological treatment for diffuse LAD disease. Key secondary endpoints include patient-reported symptom burden and quality of life, assessed using validated questionnaires. This study provides a real-world overview of current treatment approaches to LAD disease, emphasizing differences in outcomes between diffuse and focal CAD. Despite limitations such as non-randomized design and variability in treatment selection, COMMIT LAD offers valuable insights into practice patterns and patient experiences across centers. Findings from this registry are expected to inform clinicians about comparative outcomes and guide more tailored treatment strategies for diffuse CAD.

Non-obstructive hypertrophic cardiomyopathy (nHCM) is a condition that has significant therapeutic challenges due to its complicated pathophysiology. Beta-blockers (BB) and calcium channel blockers (CCB) are the existing treatment modalities that offer limited symptom relief and fail to address underlying metabolic deficits. This review evaluates emerging targeted therapies, focusing on ninerafaxstat, a cardiac metabolic modulator that inhibits 3-ketoacyl-CoA thiolase (3-KAT) to shift myocardial substrate utilization from fatty acids to glucose, thereby improving energy efficiency. Clinical trials of novel agents, including myosin inhibitors (aficamten, mavacamten) and metabolic modulators, highlight ninerafaxstat's unique potential. The Phase 2 IMPROVE-HCM trial demonstrated improved ventilatory efficiency (VE/VCO2 slope: -2.1, P=0.005), reduced left atrial remodeling (-0.9 mm, P=0.01), and enhanced quality of life in severe subgroups, with a favorable safety profile. Unlike myosin inhibitors, which reduce hypercontractility but not energy deficits, ninerafaxstat directly resolves metabolic dysfunction, synergizing with sarcomere-targeted therapies for dual-pathway efficacy. While myosin inhibitors (e.g., REDWOOD-HCM, MAVERICK-HCM) show robust biomarker improvements, ninerafaxstat addresses the core energy mismatch driving nHCM progression. Innovative gene therapies (MyPEAK-1) and exercise programs broaden the range of available treatments. Ninerafaxstat represents a paradigm shift toward precision medicine in nHCM, offering a metabolic foundation for combination strategies. Future Phase 3 trials must validate long-term benefits on functional capacity, metabolic markers, arrhythmia risk, and survival, positioning ninerafaxstat as a cornerstone therapy for restoring cardiac energetics in nHCM.

Protein kinase C (PKC) isoforms are crucial in hypertension-associated vascular dysfunction. Our previous study suggested that upregulated PKCβ2 contributed to aorta hypercontraction in spontaneously hypertensive rats (SHR). However, its role in resistance arteries remains unclear. Considering the implications of sphingosine 1-phosphate (S1P) and its receptors (S1PRs) in hypertensive vascular dysfunction, we investigated whether PKCβ2 is regulated by S1P in SHR mesenteric arteries and elucidated its underlying mechanisms. Functional studies were performed on endothelium-denuded mesenteric arteries isolated from SHR and Wistar-Kyoto (WKY) rats. Expression of PKCβ2, S1P2, S1P3, and phosphorylation levels of PKCβ2 and key proteins in calcium sensitization pathway were assessed by Western blotting using mesenteric arteries and mesenteric arterial smooth muscle cells (MASMCs). PKCβ2 expression was significantly elevated in SHR. LY333531, a PKCβ inhibitor, attenuated contraction induced by norepinephrine and S1P in SHR. S1P significantly increased PKCβ2 phosphorylation in SHR, an effect suppressed by sphingosine kinase 1 inhibitor PF-543. Inhibition or silencing of PKCβ2 significantly suppressed S1P-induced calcium sensitization. The expression levels of S1P2 and S1P3 were markedly higher in SHR, and the inhibitory effect of LY333531 on S1P-induced contraction was not altered by JTE-013 (an S1P2 antagonist) or TY-52156 (an S1P3 antagonist). Furthermore, inhibition or silencing of S1P2 or S1P3 suppressed the activation of PKCβ2 and downstream calcium sensitization pathway. These findings demonstrate that S1P activates PKCβ2 via S1P2 and S1P3, enhancing calcium sensitization pathway and promoting hypercontraction in SHR. Thus, the S1P/PKCβ2 pathway is a potential therapeutic target for hypertensive vascular dysfunction.

This study aims to evaluate the efficacy of angiotensin-converting enzyme inhibitors (ACEi) in preventing anthracycline-induced cardiotoxicity in patients undergoing anthracycline-based chemotherapy. PubMed, Embase, and Cochrane databases were searched for randomized controlled trials (RCTs) comparing ACEi to standard treatment/placebo for cardiotoxicity prevention in patients undergoing anthracycline-based chemotherapy. We pooled outcomes of echocardiographic and cardiac biomarker changes. A random-effects model was used for all outcomes. We included 7 RCTs with 686 patients, of whom 346 (50%) received prophylaxis with ACEi. The most common malignancy was breast cancer, and the follow-up ranged from 6 to 31 months. Prophylactic use of ACEi was associated with a significantly smaller reduction in left ventricular ejection fraction (LVEF) compared to the control group (mean difference -5% [95% CI -8% - -2%]; p<0.010). Subgroup analysis limited to studies excluding trastuzumab from the chemotherapy regimens showed no significant difference (MD -7% [95% CI - 16% - 2%]; p=0.110). In contrast, in studies including trastuzumab-containing regimens, ACEi demonstrated a statistically significant effect in limiting LVEF reduction (MD -3%, [95% CI -4 - -1]; p<0.010). Diastolic function (E/A ratio) changes (MD 0.0 [95% CI -0.1 - 0.09]; I2=36.3%) and relative risk of increased troponin I at follow-up (RR 0.58 [95% CI 0.17 - 1.94]; I2=69.6%) were not statistically significant. Prophylactic ACEi administration in patients undergoing anthracycline-based chemotherapy was associated with a smaller decline in LVEF. This protective role may be more relevant in patients also receiving trastuzumab. More powered and longer follow-up studies are needed to confirm these findings.

Coronary heart disease (CHD) remains a leading cause of cardiovascular morbidity and mortality worldwide, posing a global health threat. In recent years, angiotensin-like proteins (ANGPTLs) have emerged as a research focus in CHD due to their critical role in regulating lipid metabolism and inflammation. ANGPTLs are a class of secreted glycoproteins that primarily regulate lipid metabolism by influencing lipoprotein lipase activity. Dysfunction of these proteins leads to dyslipidemia, thereby promoting the formation of atherosclerotic plaques. Additionally, ANGPTLs act as pro-inflammatory factors, accelerating the development of endotheliitis. Current ANGPTL-targeted therapeutic strategies (monoclonal antibodies, small interfering RNA) have advanced to clinical trial stages, demonstrating favorable safety, tolerability, and lipid-lowering effects in humans. These approaches hold promise as novel preventive and therapeutic measures for CHD. This paper aims to elucidate the multifaceted role of ANGPTLs in CHD, summarize existing drug research, and outline future research directions, emphasizing the broad prospects of ANGPTL-targeted therapies in CHD prevention and treatment.

Abstract: Although S-amlodipine is known to have similar effects in lowering blood pressure and fewer side effects than amlodipine (= mixture of S- and R-amlodipine), there are no available data on its impact on long-term cardiovascular prognosis. This retrospective cohort study analyzed claims data from Korean subjects with hypertension treated with either S-amlodipine or amlodipine from 2010 to 2020. Subjects with history of cardiovascular disease or stroke were excluded. The composite end points of all-cause death, myocardial infarction, and stroke as 3P-major adverse cardiovascular event (MACE) and the composite end points of 3P-MACE and heart failure hospitalization as 4P-MACE were assessed. The study included 1:2 propensity score-matched groups of subjects taking S-amlodipine (n = 15,709) and amlodipine (n = 29,951). The mean clinical follow-up duration was 4.9 ± 0.3 years (median 5.0 years). After adjusting for clinical factors, S-amlodipine was associated with a reduced incidence of 3P-MACE (adjusted hazard ratio, 0.87; 95% confidence interval, 0.81-0.94; P < 0.001), and 4P-MACE (adjusted hazard ratio, 0.86; 95% confidence interval, 0.80-0.93; P < 0.001) compared with amlodipine. The better impact of S-amlodipine than amlodipine on 3P-MACE and 4P-MACE was also observed in the subgroup analysis based on various clinical factors. S-amlodipine showed better adherence than amlodipine (proportions of days covered ≥0.8: 96.7% vs. 91.8%; P < 0.001). In conclusion, S-amlodipine seems to potentially reduce the risk of long-term MACE compared with amlodipine in patients with hypertension who have no history of cardiovascular disease. However, these findings should be interpreted with caution and confirmed through further prospective studies.

Abstract: Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, exhibits cardioprotective effects; however, the underlying epigenetic and molecular mechanisms remain poorly understood. This study investigated whether DAPA mitigates myocardial ischemia/reperfusion injury (MI/RI) by modulating enhancer of zeste homolog 2 (EZH2), trimethylation of lysine 27 on histone H3 (H3K27me3), and sirtuin 1 (SIRT1) expression. Wistar rats were randomly assigned to Sham, MI, and MI+DAPA groups (n = 12/group). MI groups underwent 30 minutes of left anterior descending coronary artery (LAD) ligation. For 14 days, animals in the MI+DAPA group received orally 1 mg/kg/day DAPA. Heart function, fibrosis, inflammatory factors (TNF-α, NF-κB, IL-1β, IL-6), and oxidative stress were assessed using echocardiography, Masson trichrome staining, Western blotting, and ELISA, respectively. EZH2, H3K27me3, and SIRT1 expression levels were also determined by Western blotting 14 days after MI induction. Tissue damage was evaluated using hematoxylin and eosin (H&E) staining. DAPA administration significantly improved MI-induced myocardial damage by decreasing serum levels of LDH, cTnI, and CK-MB. DAPA also improved left ventricular function by increasing ejection fraction (EF) and fractional shortening (FS), decreased left ventricular fibrosis, and reduced myocardial inflammation by improving myocardial TNF-α, NF-κB, IL-1β, and IL-6. In addition, DAPA reduced oxidative stress by decreasing malondialdehyde (MDA) levels and increasing superoxide dismutase (SOD) activity. Finally, DAPA downregulated EZH2, reducing H3K27me3 and subsequently increasing SIRT1 levels compared with the MI group. This study's results indicate that DAPA attenuates MI/RI in male rats by modulating epigenetic mechanisms, specifically through EZH2, and H3K27me3 suppression and SIRT1 upregulation, offering novel insights into its cardioprotective potential.

Abstract: Previously, we showed that vasorelaxant effects of trans -4-methoxy-β-nitrostyrene (T4MN) in rat aorta were mediated through stimulation of the soluble guanylate cyclase (sGC) pathway. This study tested the hypothesis that bonding of the methoxy electron-donor group at the meta-position instead of the para-position into the aromatic moiety might enhance the interaction of the nitroderivative with sGC. For this purpose, vascular effects of the trans -3-methoxy-β-nitrostyrene (T3MN) were studied in rat aorta. In endothelium-intact preparations, T3MN was 100 times more potent as a vasorelaxant than its stereoisomer, T4MN. T3MN-induced vasodilatory effects remained unaffected by indomethacin, MDL-12,330A, or glibenclamide but were significantly reduced by endothelium removal, l -NAME, ODQ, LY294002, TEA, 4-AP, and apamin. Under Ca 2+ -free conditions, T3MN was unresponsive to transient contractions evoked by caffeine, whereas it inhibited contractions induced by (1) the protein kinase C activator phorbol 12-myristate 13-acetate, (2) the tyrosine phosphatase inhibitor sodium orthovanadate, (3) exogenous calcium influx through receptor- or voltage-operated Ca 2+ channels, and (4), in an ODQ-preventable manner, those evoked by PHE or Ca 2+ influx through stores-operated Ca 2+ channels activated by thapsigargin-induced Ca 2+ store depletion. In conclusion, T3MN induced a potent vasorelaxant effect that seems to be mediated partly by an endothelium-dependent mechanism involving activation of the Akt/eNOS/NO pathway and partly by an endothelium-independent mechanism through activation of the sGC/cGMP/PKG pathway in vascular smooth muscle, leading to inhibition of Ca 2+ influx from the extracellular milieu and IP 3 -sensitive intracellular Ca 2+ release as well as activation of potassium channels.