Atrial fibrillation (AF) is the most common arrhythmia leading to cardioembolic stroke, with inflammation of epicardial adipose tissue (EAT) contributing to its pathogenesis. However, current therapies cannot specifically target EAT inflammation to alleviate AF. This study investigated the effects of sonodynamic therapy (SDT) on reducing macrophage-mediated inflammation in the EAT of rabbit AF models and explored its potential clinical application in AF patients. Rabbits were assigned to sham, paced (600 bpm for 4 w), and SDT groups. Macrophage infiltration and collagen deposition were evaluated using RAM11 immunohistochemistry and Masson staining, respectively. Transcriptomic analysis and network pharmacology identified TLR4/NF-κB pathway genes (including CXCL8 and CCL2) as SDT targets for AF treatment, which were validated by Western blot and RT-qPCR. Single-cell sequencing of human EAT and right atrial appendage confirmed the expression of these SDT-targeted genes in macrophages from AF patients. Mendelian randomization demonstrated that elevated plasma CXCL8, but not CCL2, was associated with an increased risk of atrial fibrillation. SDT reduced macrophage infiltration, fibrosis, and TLR4/NF-κB-mediated inflammation, supporting its therapeutic potential in AF via modulation of EAT inflammation.

Pulmonary hypertension (PH) causes right heart failure (RHF), leading to an unfavorable prognosis. This prospective single-arm study evaluated the acute effects of levosimendan in 105 patients with RHF secondary to PH. Levosimendan was administered as a continuous infusion at 0.1 μg/kg/min over 24 h. The primary endpoint was improvement in WHO Functional Class (WHO-FC) at day 7, with secondary endpoints including Borg dyspnea scores, systolic pulmonary artery pressure (SPAP), and echocardiographic parameters. Treatment resulted in significant clinical and hemodynamic improvements by day 7. WHO-FC decreased from a median of 4.00 (3.00, 4.00) to 3.00 (2.00, 3.00) ( P < 0.001), and Borg dyspnea scores improved from 8.00 (6.00, 8.00) to 4.00 (4.00, 5.00) (P < 0.001). SPAP decreased significantly from 57.51 (51.24, 68.00) mmHg to 50.16 (44.55, 59.83) mmHg ( P = 0.002). Echocardiography showed favorable changes, including reduced left ventricular end-systolic volume and tricuspid regurgitation velocity, alongside increased left ventricular fractional shortening. In a subgroup with left heart disease, left ventricular ejection fraction increased from 33.10 (27.58, 47.20) % to 36.50 (30.63, 49.50) % ( P = 0.025). Patients with heart failure with preserved ejection fraction also showed reduced SPAP and tricuspid regurgitation velocity. The findings suggest that levosimendan provides acute physiological benefits in PH-related RHF, with potential anti-inflammatory, hepatoprotective, and glycemic-modulating properties. Patient-specific medical history and concomitant medications may influence treatment response. This study offers preliminary evidence supporting the acute physiological effects and tolerability of levosimendan in this population.

Injectable PCSK9 inhibitors effectively lower LDL-C levels in patients with hypercholesterolemia; however, their high cost and requirement for parenteral administration limit their widespread use. Oral PCSK9 inhibitors have emerged as a convenient alternative. This review and meta-analysis of the literature evaluate the effectiveness and safety of oral PCSK9 inhibitor treatment for adults with hypercholesterolemia. PubMed, Embase, Cochrane CENTRAL, and Scopus were searched through September 2025 for randomized controlled trials comparing oral PCSK9 inhibitors with placebo. The primary outcome was percentage change in LDL-C, with secondary lipid and safety outcomes. We used Cochrane RoB 2.0 tool to assess risk of bias, and pooled estimates were calculated using a random-effects model. Certainty of evidence was evaluated with GRADE. From 1253 records, 3 trials were included. Participants were mostly men, aged 61-65 years, with elevated baseline LDL-C. Oral PCSK9 inhibitors significantly reduced LDL-C and ApoB in a dose-dependent manner and achieved modest reductions in triglycerides (MD -6.56 mg/dL; 95% CI, -12.30 to -0.83) and total cholesterol (MD -25.25 mg/dL; 95% CI, -30.67 to -19.83). Effects on lipoprotein(a) were inconsistent. Adverse events (RR 1.06; 95% CI, 0.91-1.23) and serious adverse events (RR 1.32; 95% CI, 0.41-4.26) were comparable with placebo. According to our review, oral PCSK9 inhibitors are a promising therapeutic option for treating hypercholesterolemia because of their potent lipid-lowering effects and an overall favorable safety profile. However, more trials are needed to confirm their impact on cardiovascular outcomes.

Aspirin (ASA) is the cornerstone of the acute coronary syndrome primary and secondary prevention. Still, its role is debated in some high bleeding risk patients or cases that underwent second-generation drug-eluting stents with a better scaffold. This study compared the efficacy and safety of aspirin-free versus aspirin-based strategies in patients with ACS undergoing PCI. We systematically searched PubMed, Embase, Scopus, and ScienceDirect for studies comparing aspirin-based versus aspirin-free strategies in patients with ACS undergoing PCI. Pooled relative risk (RR) with 95% CI was calculated using a fixed effects model or a random effects model if heterogeneity was present. Significance was set at P < 0.05. Thirty studies including 207,938 patients (N = 104,062 in the ASA arm, and 103,876 in the ASA-free arm) were included in this study. There was a statistically significant reduction in risk of all-cause mortality [RR 0.93, 95% CI, 0.87-0.99, P-value = 0.024, I2 = 0%], BARC 2-5 [RR = 0.68, 95% CI, 0.58-0.81, P-value = <0.01, I2 = 0%], BARC 3 or 5 [RR= 0.71, 95% CI, 0.60-0.82, P-value= <0.01, I2 = 0%], TIMI major bleeding [RR = 0.66, 95% CI, 0.50-0.86, P-value= 0.02, I2 = 0%], TIMI minor or major bleeding [RR= 0.61, 95% CI, 0.52-0.72, P-value= <0.01, I2 = 0%], and ISTH major bleeding with aspirin-free strategy [RR= 0.52, 95% CI, 0.42-0.64, P-value= <0.001, I2= 0%]. Other secondary outcomes showed statistically nonsignificant results. The aspirin-free strategy showed lower all-cause mortality and bleeding, supporting its efficacy and safety in high bleeding risk patients.

Myocardial ischemia-reperfusion (I/R) injury remains a major cause of acute cardiac dysfunction and is characterized by oxidative stress, inflammation, and apoptosis. Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has been reported to exert cardioprotective effects; however, its potential association with mitochondrial biogenesis-related signaling pathways remains incompletely understood. The aim of this study was to evaluate the cardioprotective potential of CBD in a rat myocardial I/R model and to investigate its possible association with SIRT-1/PGC-1α-related mitochondrial biogenesis and nuclear factor kappa B (NF-κB)-dependent inflammatory signaling. Forty rats were randomly assigned to 4 groups: sham, I/R, prophylactic CBD, and therapeutic CBD. Myocardial ischemia was induced by ligating the left anterior descending coronary artery for 30 minutes, followed by 30 minutes of reperfusion. Heart and aortic tissues were evaluated histopathologically, immunohistochemically, biochemically, and genetically to assess oxidative stress, inflammation, and mitochondrial biogenesis-related markers. The I/R group exhibited marked myocardial injury characterized by hyperemia, edema, hemorrhage, and inflammatory infiltration, accompanied by elevated levels of vascular cell adhesion molecule-1 (VCAM-1), vascular endothelial growth factor, and NF-κB. By contrast, SIRT-1, PGC-1α, and B-cell lymphoma 2 (Bcl-2) expression significantly declined, alongside increased total oxidant status and oxidative stress index. Prophylactic CBD treatment notably restored myocardial architecture, suppressed inflammatory and apoptotic responses, and enhanced mitochondrial biogenesis. Therapeutic CBD administration also provided partial protection. CBD confers robust cardioprotection against myocardial I/R injury by activating the SIRT-1/PGC-1α axis, promoting mitochondrial biogenesis, and attenuating oxidative, inflammatory, and apoptotic pathways. These findings indicated that it confers significant cardioprotection against myocardial IR injury and that this protective effect is associated with modulation of SIRT-1/PGC-1α-related mitochondrial biogenesis and NF-κB-dependent inflammatory signaling. Further mechanistic studies are warranted to establish definitive causal relationships.

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.