Background and purpose: Artificial intelligence (AI) is increasingly being applied to automate image interpretation, including in coronary optical coherence tomography (OCT), the gold standard for in vivo assessment of atherosclerotic plaques. Most AI models are trained using expert annotations; however, human interpretation is inherently subjective and may limit model performance. Therefore, validation against the true reference standard—histology—remains essential. The study aims to evaluate and compare the performance of an AI-powered plaque characterization model with that of clinicians, using co-registered histology as the reference standard. Methods: Matched OCT pullbacks and serial histological sections from 25 plaques in 11 swine atherosclerotic arteries were analyzed. Precise OCT–histology co-registration was achieved using a hierarchical coarse-to-fine approach, with stent edges and anatomical landmarks as references. Plaque components (fibrous, lipidic, and calcific) were manually labeled on histology and automatically segmented on OCT by the AI model. Meanwhile, three blinded readers with different levels of OCT expertise independently annotated the corresponding frames. The relative percentages of plaque components derived from OCT were compared with histology. Results: Across all histological sections, the median percentages of fibrous, lipidic, and calcific components were 65.0% (interquartile range [IQR]: 53.9%–92.5%), 34.3% (IQR: 6.5%–44.7%), and 0.2% (IQR: 0%–1.9%), respectively. The AI model demonstrated excellent correlation with histology, with Spearman’s ρ = 0.907 (P < 0.001) for fibrous and ρ = 0.900 (P < 0.001) for lipidic components. The mean absolute discrepancy relative to histology was comparable between the AI model and the senior reader and smaller than that of the intermediate and junior readers. Agreement with histology improved with reader’s experience (fibrous: intraclass correlation coefficients [ICC] = 0.666, 0.720, and 0.821; lipidic: ICC = 0.593, 0.684, and 0.803), yet remained lower than that of the AI model (fibrous: ICC = 0.938; lipidic: ICC = 0.939). Conclusions: Despite being trained on human-annotated data, the AI model demonstrated superior agreement with histology compared with clinicians. AI-driven plaque characterization may reduce interpretative subjectivity and enhance the clinical utility of coronary OCT in the management of coronary artery disease.

Background and purpose: The global burden of peripheral artery disease (PAD) attributable to high fasting plasma glucose (HFG) has not been comprehensively characterized. This study aimed to quantify the global deaths and disability-adjusted life years (DALYs) of PAD attributable to HFG and to project their trends through 2036. Methods: Data on PAD-related deaths and DALYs were obtained from the Global Burden of Disease 2021 Study. Temporal trends were evaluated using estimated annual percentage change (EAPC) and age-period-cohort (APC) models, while future projections were derived from a Bayesian (Bayesian APC) model. Cross-national inequalities were assessed in relation to the sociodemographic index (SDI). All analyses were performed in 2024. Results: Globally, from 1990 to 2021, the overall age-standardized mortality rate (ASMRs) and DALY rate (age-standardized disability rates [ASDRs]) for all-cause PAD decreased by 35.9% and 30.1%, respectively. However, the ASMRs and ASDRs for PAD specifically attributable to HFG increased by 15.3% (95% uncertainty interval [95% UI]: 6.6–24.7) and 20.0% (95% UI: 11.9–29.1). This rise was more pronounced in women, with increases of 15.9% (95% UI: 5.0–26.9) in ASMRs and 21.9% (95% UI: 13.2–31.5) in ASDRs, compared to 12.5% (95% UI: 2.0–24.4) and 17.1% (95% UI: 7.3–27.2) in men, respectively. In 2021, HFG was responsible for 67,744 (95% UI: 59,937–74,257) PAD-related deaths and 1,558,243 (95% UI: 1,266,999–2,045,869) DALYs. Absolute inequality (slope index of inequality) in PAD burden widened over time, with the burden disproportionately concentrated in low- and middle-SDI countries. Projections to 2036 indicate a continued increase in the HFG-attributable PAD burden among women, while a slight decline is projected for men. Conclusions: The global burden of PAD is increasingly driven by HFG, with a disproportionate and growing impact on women and populations in low- and middle-SDI countries. Our findings underscore an urgent need for targeted public health policies that address gender and socioeconomic disparities. Implementing evidence-based interventions focused on glycemic control is critical to mitigating the rising global burden of HFG-attributable PAD.

Elevated triglyceride levels have been associated with an elevated risk of cardiovascular disease, even when triglyceride levels are below common guidelines. This elevated risk of cardiovascular disease exists independent of total cholesterol or low-density lipoprotein cholesterol levels. Genetic analyses have demonstrated that elevated remnant lipoprotein, a product of triglyceride-rich lipoprotein, is a factor for coronary heart disease, indicating that the association between elevated triglyceride levels and elevated cardiovascular disease risk is causal rather than correlated. Despite this correlation between triglyceride levels and cardiovascular disease risk, treatments targeted at lowering triglyceride levels in patients receiving statin therapy, such as niacin or fibrates, have not demonstrated reduction in cardiovascular disease risk despite lowering triglyceride levels. In addition, omega-3 fatty acids containing a combination of docosahexaenoic acid plus eicosapentaenoic acid failed to demonstrate significant reductions in cardiovascular events in similar patients. Triglyceride-lowering therapies in development include monoclonal antibodies targeted against angiopoietin-like 3 (ANGPTL3); however, these newer ANGPTL3-targeted agents have not yet demonstrated a reduction in cardiovascular disease risk. In contrast, the landmark REDUCE-IT trial demonstrated significant cardiovascular protective effects for icosapent ethyl (IPE) in high cardiovascular risk patients with hypertriglyceridemia despite statin therapy. The protective effects of IPE may be due to unique mechanisms affecting the metabolism of E-series resolvins that may reduce atherosclerotic plaque. IPE also exhibits antiplatelet, antithrombotic, anti-inflammatory, and anti-oxidant effects, all of which contribute to an overall anti-atherosclerotic effect and an overall reduction in cardiovascular disease risk. As a result, treatment guidelines in the United States, China, and other countries recommend IPE for patients with hypertriglyceridemia that persists despite statin therapy.

Background and purpose: There is growing interest in messenger ribonucleic acid (mRNA) drugs for a wide variety of applications including cardiovascular disease. Typically, mRNA drug substances are generated from linear deoxyribonucleic acid (DNA) templates using in vitro transcription (IVT). Thus, the sequence design of the linear DNA templates containing the gene of interest (GOI) plays a critical role in the quality of mRNA therapeutics. A conserved sequence motif ATCTGTT was identified as an endogenous T7 RNA polymerase (RNAP) class II pause site decades ago. However, we do not fully understand the impact of this pause site on the IVT process. This study aimed to characterize T7 RNAP class II pause sites and their impact on mRNA production to optimize therapeutic mRNA design. Methods: Site-directed mutagenesis was performed on DNA templates (e.g., 376, 406, and nuclear green fluorescent protein [nGFP]) to manipulate potential T7 RNAP pause sites. IVT was used to synthesize mRNA, followed by the analysis of transcript integrity using Agilent TapeStation. The effects of mutations on mRNA yield, purity, and immune response (e.g., interleukin-6 [IL-6] secretion in transfected fibroblasts) were evaluated. Results: We found that additional dinucleotides (specifically tc, cc, and ta) downstream of ATCTGTT, or trinucleotides (specifically aaa) immediately downstream of ATCTGT (to give the sequence ATCTGTTtc, ATCTGTTcc, ATCTGTTta, or ATCTGTaaa in the encoded GOI) could cause T7 RNAP termination and produce short abortive transcripts during IVT. The strength of these T7 RNAP pause sites is ATCTGTTtc > ATCTGTaaa > ATCTGTTcc > ATCTGTTta. Furthermore, we find that the location of the T7 RNAP pause site in the GOI also plays a role in the strength of terminating transcription in IVT. The more distant the T7 RNAP pause site from the transcriptional initiation site, the greater the probability of termination. In addition, mRNAs derived from DNA templates harboring T7 RNAP pause sites generated mRNAs with impaired integrity, purity, and mRNA yield. Conclusion: Our study provides insight into the effect of T7 RNAP class II pause sites that may be useful in designing mRNA therapeutics for better integrity, purity, and higher yield.

Background and purpose: Echocardiographic features and levels of N-terminal of pro-brain natriuretic peptide (NT-proBNP) have been associated with adverse outcomes in patients on maintained hemodialysis (HD). This study aims to investigate whether combining NT-proBNP with echocardiographic parameters enhances the accuracy of mortality risk prediction in this patient population. Methods: A cohort of 199 patients undergoing maintenance HD (45.7% female; mean age, 56.4 years) was analyzed. Hazard ratios (HRs) were calculated using Cox regression models to estimate the risk of all-cause mortality related to a 1-standard deviation increase in echocardiographic parameters. The performance of the models was assessed by the area under the receiver operating characteristic curve. Results: During a median follow-up of 31.7 months (interquartile range [IQR]: 20.1–42.5 months), 37 patients (18.6%) died. Multivariable-adjusted analysis showed that larger left atrial diameter indexed to body surface area (LADi; HR: 1.85; 95% confidence interval [CI]: 1.30–2.62, P < 0.001) and higher E/e’ ratio (HR: 1.49; 95% CI: 1.05–2.12; P = 0.025) were significantly associated with increased mortality risk. Elevated log-transformed NT-proBNP levels were also correlated with a significantly higher risk of death (HR: 2.35; 95% CI: 1.33–4.17; P = 0.003). In addition, patients with both elevated NT-proBNP levels and either a larger LADi or higher E/e’ ratios exhibited the largest mortality risk (P ≤ 0.006). Incorporating E/e’ or LADi with NT-proBNP into the base model significantly improved the area under the receiver operating characteristic curve (AUC) from 0.79 to 0.84 (P = 0.034) and 0.86 (P = 0.022), respectively. Conclusions: The combination of NT-proBNP levels with echocardiographic parameters, particularly LADi and E/e’ ratio, significantly enhances all-cause mortality risk prediction in maintenance HD patients. These findings suggest that integrating NT-proBNP with echocardiographic parameters could improve risk stratification in HD patients.

Background and purpose: Cepharanthine, an alkaloid purified from the earthnut Stephania Epigaea, exhibits antitumor, anti-inflammatory, and immunomodulatory effects. During the coronavirus disease 2019 (COVID-19) epidemic, cepharanthine was identified to restrain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and reduced the inflammatory response. Viral infections, which disrupt internal homeostasis, often exacerbate atherosclerosis, contributing to cardiovascular complications. Based on the antiviral and anti-inflammatory efficacy of cepharanthine and the recognition of atherosclerosis as a chronic inflammatory disease, this study aimed to evaluate whether cepharanthine could attenuate atherogenesis in two established mouse models of atherosclerosis. Methods: Atherosclerosis was induced in Apoe −/− and Ldlr −/− mice through feeding with a high-fat and high-cholesterol diet. Mice were administered 20 mg/kg cepharanthine daily for 8 weeks. Atherosclerotic lesions in the aorta and aortic sinus were evaluated using Oil Red O staining. Liver tissues were analyzed for liver injury and fibrosis using hematoxylin and eosin (H&E) and Sirius Red staining. Results: Contrary to expectations, cepharanthine aggravated atherosclerosis in both Apoe −/− and Ldlr −/− mice. Treated mice exhibited significant liver injury, characterized by hepatocyte swelling and fibrosis, with increased collagen deposition and the increased expression of Vimentin. Cepharanthine also decreased hepatic Abcg5 expression while upregulating Fabp4 expression. Elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) levels indicated worsened liver and heart injury in cepharanthine-treated mice. Conclusions: This study highlights potential safety concerns with cepharanthine especially for patients with hyperlipidemia, atherosclerosis, and COVID-19. These findings underscore the need for careful monitoring of its clinical use.

Cardiovascular diseases remain the leading cause of death worldwide. Despite significant progress and the development of numerous effective drugs, substantial morbidity and mortality persist. This review highlights one potentially fruitful avenue for discovering novel therapeutics: leveraging ribonucleic acid (RNA) to tip the immunological balance toward tissue repair. Decades of research have primed the three disciplines of cardiology, immunology, and RNA drug development, to bring potent intersectional therapies to the clinic. We discuss both coding and non-coding RNA interventions across multiple cell types, such as monocytes, macrophages, and T cells, throughout different cardiovascular diseases. Altogether, advanced RNA-based medicines targeting the immune system are primed to transform how cardiovascular diseases are treated.

Background and purpose: Percutaneous coronary intervention (PCI) is the gold standard for managing chronic total occlusion (CTO), but data on characteristics of the patients undergoing PCI for CTO are scarce. The present study was designed to evaluate the clinical profile of the patients who underwent PCI to CTO. Methods: This single-center, prospective, and observational study included consecutive patients who successfully underwent PCI for angiographically confirmed CTO at author’s center from March 2017 to March 2019. Follow-up was conducted at 6 and 12 months. Results: The final analysis included a total of 108 patients. The mean age was 64.5 ± 8.2 years. Majority of the patients (72.2%) were men. The most common morbid risk factors were diabetes mellitus (56.5%), hypertension (53.7%), and dyslipidemia (52.8%). Mean left ventricular ejection fraction (LVEF) was 51% ± 0.0% and 73% had New York Heart Association (NYHA) class II. The most common site of CTO was the right coronary artery (34.3%). PCI was conducted using an antegrade approach, 75.9% of the cases. The majority of patients underwent wire escalation PCI technique (52.8%) followed by adverse drug reaction (34.3%), reverse-controlled antegrade and retrograde tracking (CART) (8.3%) and CART (4.6%). Stress test was negative in 63% and 64.8% of the patients at 6 and 12 months, respectively. The 6-month symptom-free survival rate was higher in patients without hypertension. Symptom-free survival rate was 96.9%, 95.9% and 88.9% in patients with Japanese Multicenter CTO Registry (J-CTO) score of 0, 1 and >3, respectively. The rate of abnormal electrocardiogram at 12 months was higher in patients with J-CTO score of 0 or 1 versus >3. Conclusion: PCI is a viable option for patients who are not willing to undergo coronary artery bypass grafting, particularly in those with low J-CTO score.

Background and purpose: Previous observational studies have yielded conflicting results regarding the association between cheese intake and atherosclerosis. Also, relative contribution to each subtype (coronary atherosclerosis, peripheral atherosclerosis, cerebral atherosclerosis, and arterial stiffness) remains unclear. The primary objective of this investigation was to assess the causal association between cheese intake and atherosclerosis. Methods: A two-sample Mendelian randomization (MR) study was conducted based on summary statistics from published genome-wide associations of cheese intake (n = 451,486 individuals), coronary atherosclerosis (n = 14,334 cases, 346,860 controls), peripheral atherosclerosis (n = 6,631 cases, 162,201 controls), arterial stiffness (n = 151,053 individuals, no available cases/controls), cerebral atherosclerosis (n = 104 cases, 218,688 controls), and atherosclerosis (excluding cerebral, coronary, and peripheral arterial disease [PAD]) (n = 6,599 cases, 212,193 controls). Primary analysis was conducted using an inverse-variance weighted (IVW) method. Sensitivity analyses included weighted median, MR Egger, and weighted mode analyses. Results are shown as odds ratio (OR) and 95% confidence interval (CI). Results: In the IVW analysis, genetically predicted cheese intake was inversely associated with coronary atherosclerosis (OR: 0.98, 95% CI: 0.97–0.99; P = 0.002), peripheral atherosclerosis (OR: 0.56, 95% CI: 0.37–0.84; P = 0.006), arterial stiffness (OR: 0.87, 95% CI: 0.81–0.94; P = 0.001), and atherosclerosis (excluding cerebral, coronary, and PAD) (OR: 0.65, 95% CI: 0.43–0.98; P = 0.037), but not with cerebral atherosclerosis (OR; 0.91, 95% CI: 0.07–11.28: P = 0.941). The sensitivity analyses supported an association of cheese intake with coronary atherosclerosis, peripheral atherosclerosis, arterial stiffness, and atherosclerosis (excluding cerebral, coronary, and PAD), but not cerebral atherosclerosis. Conclusions: This study suggested that cheese intake is inversely associated with coronary atherosclerosis, peripheral atherosclerosis, arterial stiffness, and atherosclerosis (excluding cerebral, coronary, and PAD), but not cerebral atherosclerosis. These findings support dietary interventions, especially increasing cheese intake, in subjects with high risk to cardiovascular diseases.

Pan-vascular disease is a systemic condition characterized by vascular lesions, with atherosclerosis comprising 95% of cases, manifesting as coronary artery disease, cerebrovascular disease, peripheral artery disease, or combinations thereof, known as multivascular disease. In China, the burden of pan-vascular diseases is substantial, necessitating urgent improvements in patient prognosis. Despite being managed by different disciplines, pan-vascular diseases often share common risk factors and pathophysiological mechanisms, underscoring the need for standardized treatment strategies. Anti-thrombotic therapy for pan-vascular diseases primarily involves antiplatelet and anticoagulant therapy. Currently, there is a lack of unified guidance across various disciplines for patients with differing ischemic and bleeding risks and disease stages. Recognizing the pivotal role of standardized anti-thrombotic therapy in pan-vascular disease treatment, the Chinese College of Cardiovascular Physicians organized a consensus working group comprising 33 senior experts from cardiology, vascular surgery, neurology, and endocrinology. The “Chinese expert consensus on anti-thrombotic therapy for pan-vascular diseases (2023 Edition)” was developed based on specific treatment needs in China, incorporating published clinical research evidence, specialized guidelines and consensus, and recommendations from the consensus expert group. The primary aim of this consensus is to standardize the application of anti-thrombotic therapy in pan-vascular diseases, thereby optimizing clinical outcomes, improving patient prognosis, and mitigating the economic and societal burdens associated with pan-vascular disease.