Metabolic dysfunction-associated steatotic liver disease (MASLD) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Currently, no approved targeted therapeutic interventions exist for MASLD. Hypoxia is known to exacerbate the progression of both MASLD and ASCVD. Notably, peroxisome proliferator-activated receptor α (PPARα), a key regulator of lipid metabolism, has also been implicated in modulating cellular adaptation to hypoxic conditions. This study aims to elucidate the role of PPARα in arterial endothelial cell dysfunction by investigating its involvement in lipid metabolism reprogramming within the context of MASLD under high-altitude hypoxia. We observed that chronic hypoxia exacerbates the increase in low-density lipoprotein (LDL) levels and elevates the risk of ASCVD in MASLD patients. In MASLD mice, chronic hypoxia activates hepatic hypoxia-inducible factor 2-alpha (HIF-2α), which suppresses PPARα, leading to decreased expression of low-density lipoprotein receptor (LDLR) and ATP-binding cassette subfamily G member 8 (ABCG8), consequently raising serum LDL levels and indirectly reducing endothelial nitric oxide synthase (eNOS) expression in arterial endothelial cells. Activation of PPARα can upregulate the expression of LDLR and ABCG8 in hepatocytes, thereby improving fatty liver and restoring the function of aortic endothelial cells. Our study identifies chronic hypoxia induces liver HIF-2α, which inhibits PPARα and impairs hepatic cholesterol metabolism. This leads to MASLD progression and increased ASCVD risk, as impaired cholesterol metabolism negatively affects endothelial cell function. Activation of PPARα enhances hepatic lipid metabolism, thereby indirectly improving endothelial cell function. Moreover, we demonstrate that fenofibrate represents a viable and cost-effective therapeutic strategy for ameliorating MASLD and preventing ASCVD under hypoxic conditions.

Ten-year risk prediction models for atherosclerotic cardiovascular disease in Chinese patients with schizophrenia-spectrum disorders: A population-based cohort study.

High cholesterol absorption efficiency is determined by genetic variation in small intestinal sterol transporters and affects one-third of individuals. Their risk for atherosclerotic cardiovascular disease (ASCVD) is increased compared with low cholesterol absorbers, despite similar serum lipid concentrations. We investigated the association of cholesterol absorption efficiency with proatherogenic properties of low-density lipoproteins (LDLs). The study cohort consisted of 90 middle-aged participants, 56 females and 34 males, without lipid-lowering therapy or ASCVD. They were divided into low (n=45) and high (n=45) cholesterol absorbers by the median value of serum cholestanol to cholesterol ratio. LDL aggregation susceptibility and binding of lipoproteins to proteoglycans were determined as biomarkers of lipoprotein atherogenicity. Nuclear magnetic resonance spectroscopy, mass spectrometry, and gas-liquid chromatography were used to determine lipoprotein subclass profile, LDL lipidome, and serum concentrations of cholesterol and noncholesterol sterols, respectively. Age, dietary cholesterol, and serum total cholesterol or lipoprotein cholesterol levels did not differ between the groups. In the high absorbers, LDL particles were larger, and LDL aggregation susceptibility and the binding of lipoproteins to proteoglycans were increased in the low absorbers. Of LDL surface lipids, sphingomyelin 42:3;O2, and phosphatidylcholine (PC) 32:0 correlated positively, whereas PC 32:1 correlated negatively with serum cholestanol levels. These LDL surface lipids were also associated with increased LDL aggregation susceptibility and proteoglycan-binding. The present findings suggest that increased proatherogenic properties in high cholesterol absorbers may contribute to increased ASCVD risk. https://clinicaltrials.gov/study/NCT01315964.

This review examines whether high high-density lipoprotein cholesterol (HDL-C) is protective, harmful, or simply misleading in relation to atherosclerotic cardiovascular disease (ASCVD), with emphasis on recent mechanistic, epidemiologic, genetic, and trial evidence. HDL is biologically important and multifunctional, but HDL-C is an imperfect surrogate for HDL function. Recent cohort studies show nonlinear associations, with very high HDL-C not consistently protective and in some settings associated with increased mortality. Mendelian randomization studies do not support HDL-C as a causal protective factor, and randomized trials of HDL-C-raising strategies have generally failed to reduce ASCVD events. These findings have shifted attention from HDL quantity to HDL quality, including cholesterol efflux capacity, particle characteristics, and pathway-specific biology. At the same time, modern cholesteryl ester transfer protein (CETP) inhibition has renewed interest in whether benefit, if any, relates to Apolipoprotein B-lowering rather than HDL-C elevation itself. HDL biology remains highly relevant, but HDL-C alone should not be interpreted as a reliable marker of atheroprotection or as a therapeutic target. Very high HDL-C should not be used to downplay established causal risk factors. Future research should prioritize functional HDL metrics, deeper phenotyping, and mechanism-aligned trials to determine whether improving HDL quality, rather than simply raising HDL-C, can reduce ASCVD risk.

Low-grade systemic inflammation, as determined by high-sensitivity C-reactive protein (hsCRP), plays a significant role in the progression and development of atherosclerotic cardiovascular disease (ASCVD) and is recognized as a risk enhancer for increased incidence of major adverse cardiovascular events (MACE). In 2024, the US Food and Drug Administration approved colchicine, as the first anti-inflammatory agent for secondary cardiovascular prevention. While this step signified a translational milestone, recent neutral colchicine trials, such as CLEAR- SYNERGY, have reignited controversy regarding the overall efficacy of colchicine, and the need for alternative anti-inflammatory therapies. As the understanding of inflammation's role in atherosclerosis grows, questions persist about the best management strategies and future therapeutic options. This review aims to provide an updated summary that includes insights from recent key trials, explores investigational anti-inflammatory treatments, and discusses considerations for future trial designs. This review will encompass recent trials involving colchicine, IL-1 antagonists, and interluekin-6 inhibitors. In this review, we will discuss mechanisms of inflammation as they pertain to ASCVD, significant contemporary trials, novel anti-inflammatory therapies, and considerations for future trial designs.

Current practices of SGLT2 inhibitor use and ketone monitoring in intensive care units: A multicentre observational study.

Hypertriglyceridemia is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). We aimed to evaluate the efficacy and safety of apolipoprotein C-III (ApoC-III) inhibitors in patients with hypertriglyceridemia. Electronic databases were systematically searched for randomised controlled trials (RCTs) comparing ApoC-III inhibitors (Volanesorsen, Olezarsen and Plozasiran) with placebo. A frequentist network meta-analysis was performed. Continuous outcomes were presented as mean differences (MDs), and dichotomous outcomes as risk ratios (RRs), both with 95% confidence intervals (CIs). A total of 15 RCTs involving 3934 patients were included. All ApoC-III inhibitors demonstrated significant reductions in TG, except for Volanesorsen 100 mg Q1W and Olezarsen 10 mg Q4W. Olezarsen 80 mg administered every 4 weeks had the highest SUCRA ranking for TG reduction (MD: -63.26; 95% CI: -70.04 to -56.47; p < 0.01). Moreover, ApoC-III inhibitors were associated with a significant reduction in the incidence of pancreatitis (HR: 0.16, 95% CI: 0.07-0.33, p < 0.01). None of the agents significantly increased the risk of serious adverse events. ApoC-III inhibitors significantly improved triglyceride levels and other lipid parameters and, most importantly, substantially reduced the risk of acute pancreatitis. Future trials are needed to evaluate their effects on cardiovascular outcomes.

Although therapies for hyperlipidemia and hypertension have been shown to be highly effective, they have not sufficiently mitigated overall cardiovascular disease risk. Endothelial cells (ECs) are an integral mediator in the development and progression of atherosclerotic cardiovascular disease. The purpose of this review is to provide an update on the current state of endothelial lipid metabolism research, with particular emphasis on atherosclerosis. Although it has been known that elevated palmitic acid (PA) levels were linked to metabolic dysfunction, inflammation and cardiovascular diseases, more recent studies presented here elucidate the mechanisms behind the negative effects induced by PA. Palmitoylation was found to be detrimental in the case of pyruvate kinase isozyme M2 (PKM2) activity, but also vital for the normal functioning of endothelial ciliation and cell health. Endothelial cholesterol metabolism and hemodynamic forces have also been further confirmed to be key regulators in vessel development and endothelial homeostasis. Perturbations in these pathways promote endothelial dysfunction and maladaptive lipid accumulation. Although atherosclerosis remains a complex, multifactorial disease that arises from the coordinated dysfunction across multiple vascular and immune cell types, substantial advances have been made in identifying mechanisms behind dysfunctional endothelial lipid metabolism. Despite this, further investigation is necessary to identify high impart therapeutic targets aimed at reducing overall cardiovascular disease risk.

Advances in the management of lipid disorders have expanded therapeutic options for hypercholesterolemia and beyond. We review the current advances in RNA interference (RNAi) therapies as small interfering RNA (siRNA) drugs, critically assess their clinical positioning, and explore their potential role in reshaping lipid management over the next years. RNAi enables targeted, durable suppression of key lipid-regulating proteins at the mRNA level. Inclisiran, the first approved RNAi therapy for hypercholesterolemia, achieves about 50% sustained LDL-c reduction with long-interval maintenance dosing, offering an alternative to monoclonal antibodies. Beyond LDL-c lowering, multiple RNAi drugs are in advanced development targeting lipoprotein(a), apolipoprotein C-III, and angiopoietin-like protein 3, aiming to address residual cardiovascular risk. Early safety and adherence data are encouraging, yet pivotal outcome trials and cost-effectiveness analyses are still pending. RNAi is a naturally occurring gene-silencing mechanism that can be harnessed therapeutically through siRNA molecules. In lipidology, siRNA-based therapies represent a disruptive technology with the potential to transform both prevention and treatment of atherosclerotic cardiovascular disease. If ongoing trials confirm cardiovascular benefit and safety, RNAi agents could become foundational in personalized lipid management, moving the field toward long-acting, target-specific, and potentially combination-based regimens. The coming years will determine whether RNAi fulfills its promise as the future standard of care in lipid disorders.

Glycoprotein non-metastatic melanoma protein B promotes pyroptosis of macrophages induced by homocysteine associated with the upregulation of the NOX-2/ NF-κB signaling pathway.

Sex differences in cardiovascular-kidney-metabolic syndrome and new onset cardiovascular outcomes.

Ischemic stroke (IS) accounts for 87% of all strokes and is a leading cause of disability worldwide. Women face higher lifetime IS risk and worse functional outcomes, yet predictive biomarkers remain limited. Moreover, inflammation is increasingly recognized as a contributor to IS pathogenesis, with inflammatory markers such as C-reactive protein (CRP) positively associated with IS. Yet, the metabolic pathways linking chronic inflammation to IS risk are poorly understood. We aimed to identify a metabolomic signature reflecting systemic inflammation and evaluate its association with incident IS in women. This study used nested case-control designs within the Nurses' Health Study (NHS), a prospective cohort of US female registered nurses aged 30-55 at enrollment. Using elastic net regression in a derivation cohort with inflammatory biomarker (high-sensitive CRP, interleukin 6, tumor necrosis factor receptor 2, adiponectin) and metabolomic data, we developed a metabolomic signature index of inflammation (i-MSI). The i-MSI's association with incident IS was examined in an independent NHS nested case-control study using conditional logistic regression, adjusting for cardiovascular risk factors. Generalizability to atherosclerotic disease was evaluated in a coronary heart disease (CHD) nested case-control study from the Women's Health Initiative (WHI). The derivation cohort included 1,699 women (mean age 58 years, 94% White). The i-MSI comprised 102 metabolites, with lysophosphatidylcholine species-promoters of endothelial activation, vascular inflammation, and plaque instability-contributing most significantly. In the independent IS case-control study (454 cases, 454 controls; mean age 66 years), women in the highest compared with lowest i-MSI quartile had a multivariable-adjusted odds ratio (OR) of 1.76 (95% CI 1.02-3.03) for IS, whereas each 1-SD increase in the i-MSI was associated with an OR of 1.35 (95% CI 1.09-1.67). In the WHI study (793 cases, 795 controls; mean age 67 years), each SD increase in the i-MSI was associated with an OR of 1.20 (95% CI 1.05-1.37) for CHD. An inflammatory metabolomic signature was associated with higher IS risk, independent of traditional cardiovascular disease risk factors, with consistent findings for CHD. Future studies should replicate these findings in other populations and evaluate whether these metabolites can improve risk stratification and serve as biomarkers for atherosclerotic cardiovascular diseases.

Cardiovascular disease (CVD) is the leading cause of death among patients with end-stage renal disease (ESRD). The majority of the randomized controlled trials (RCTs) evaluating statin therapy in patients with dialysis did not show statistically significant mortality benefit. In contrast, recent observational studies have consistently demonstrated improvement in mortality. Although the benefits of statin in this population remain controversial, there is also ambiguity regarding the benefit of statin therapy in patients with dialysis and established atherosclerotic cardiovascular disease (ASCVD). A systematic review and meta-analysis was conducted to evaluate the effects of statin therapy in patients with ESRD using the PubMed and Google Scholar databases. Our objective was to assess all-cause and cardiovascular mortality in mixed ESRD populations (with and without ASCVD), as well as in patients with ESRD and established ASCVD. A total of 396,163 patients in 28 studies were included. Overall, statin therapy significantly reduced all-cause mortality [hazard ratios (HR) = 0.75; 95% confidence intervals (CI, 0.68-0.83)] and cardiovascular mortality (HR = 0.75; 95% [CI, 0.60-0.94]). The majority of the benefits were associated with observational data whereas RCTs did not show any mortality benefits. Among patients with ESRD and established ASCVD in observational studies, statin therapy was associated with reduced all-cause mortality (HR = 0.84; 95% [CI, 0.74-0.95]), but there were little or no cardiovascular mortality benefits. There was substantial heterogeneity amongst the studies. In conclusion, real-world data demonstrated the beneficial role of statins in the ESRD population. These findings are hypothesis-generating and highlight the need for prospective trials focused on patients with ESRD and established ASCVD.

Dyslipidaemia in cancer patients presents several challenges with increasing survival of cancer patients. Dyslipidaemia and cancer treatments both increase atherosclerotic cardiovascular disease (ASCVD) risk; yet, most risk prediction scores for ASCVD do not include important cancer factors and thus underestimate true ASCVD. Some cancer therapies cause transient elevations of low-density lipoprotein cholesterol or triglycerides, or reduction in high-density lipoprotein cholesterol, occasionally to extreme levels requiring specific treatment and monitoring strategies. A range of lipid-lowering therapies can be used in cancer patients to manage cholesterol and triglycerides but of these, reliable data only exist for statins and ezetimibe for managing low-density lipoprotein cholesterol, and fibrates and Omega 3 fish oils for hypertriglyceridaemia. There are no robust randomized controlled trials conducted in cancer patients for reduction of adverse cardiovascular events and therefore current recommendations have been extrapolated from non-cancer trials. Cancer survivors may require combination therapies; yet, trials of newer lipid-lowering therapies excluded cancer patients and hence safety and efficacy data are limited. The initiation of lipid-lowering therapy in cancer patients requires an integration of several factors, which includes a careful assessment of ASCVD risk, drug-drug interactions, side-effect profiles, and prognosis. Further work is required to personalize individualized risk scores for ASCVD in cancer patients and survivors and new trials and 'real-world' or registry data would inform these existing data gaps. Beyond lipid management, the putative role of therapies such for statins as cardioprotective agent for anthracycline chemotherapy open novel avenues for further research as survival from many cancers continues to improve.

Atherosclerotic cardiovascular disease is the leading cause of mortality worldwide, with arterial stiffness being an important predictor of cardiovascular mortality. This study aimed to examine in the Swedish longitudinal cohort of males and females (SPAF-1958) whether aerobic capacity measured at early- (34years) and mid-adulthood (52years) can predict arterial stiffness assessed by pulse wave velocity later in life (63years). Further, we determined whether this association is modified by traditional cardiovascular risk factors such as obesity, smoking, blood pressure, advanced lipoprotein profiles and high-density lipoprotein (HDL) function determined as cholesterol efflux capacity. Multiple regression analysis revealed that a higher aerobic capacity at ages 34 (B = -0.04, P = 0.002) and 52 (B = -0.04, P = 0.005) significantly predicted lower arterial stiffness at age 63, independent of obesity, smoking, blood pressure, HDL, and HDL-cholesterol efflux capacity. In contrast, lipoprotein profiles and HDL-mediated cholesterol efflux at age 52 were not associated with arterial stiffness at age 63 (P > 0.05). These findings suggest that maintaining aerobic capacity from early adulthood can reduce arterial stiffness and cardiovascular risk in later life, independently of traditional and contemporary cardiovascular factors. This study emphasizes the need for further research on lifestyle modifications to enhance cardiovascular health.

It has been confirmed that cholesterol-lowering therapy, particularly the reduction of low-density lipoprotein cholesterol (LDL-C) levels, represents the most effective measure for decreasing the incidence of atherosclerotic cardiovascular disease and related cardiovascular events. Previous studies have shown that active reduction of cholesterol levels significantly increases the goal attainment rate of LDL-C and improves clinical outcomes. Although many cholesterol-lowering medications are currently available in clinical practice and the cholesterol lowering treatment status has improved, the real-world cholesterol management in China, especially the goal attainment rate of LDL-C, is not satisfactory. This issue is closely related to the selection of initial cholesterol-lowering treatment strategies. Furthermore, clinical research has demonstrated that the safety and adherence of cholesterol-lowering therapy are also critical factors influencing treatment effectiveness. In response, the National Cardiovascular Disease Expert Committee Cardiovascular Metabolic Medicine Professional Committee has organized domestic experts to systematically and comprehensively review methods and scientific choices for initiating cholesterol-lowering therapy in the Chinese population and developed a Chinese expert consensus on the selection of initial cholesterol-lowering strategies based on current evidence. It aims to propose optimized initial treatment regimens tailored to individual characteristics, thereby further improving the prevention and management of dyslipidemia in Chinese population.

Aortic valve calcification (AVC) is the primary process leading to aortic stenosis. We examined whether polygenic risk scores (PRS) are associated with AVC beyond traditional atherosclerotic cardiovascular disease risk factors. We included 6812 participants in MESA (Multi-Ethnic Study of Atherosclerosis) with computed tomography-measured AVC at Visit 1. Using previously published PRS we calculated weighted PRS, standardized within each ancestry group. The cross-sectional association per 1 SD higher PRS with AVC >0 was examined using multivariable logistic regression modeling with Bonferroni correction. The mean age was 62 years old, 53% were female, and 913 (13.4%) had AVC >0 at baseline. The PRS for coronary artery disease (hazard ratio [HR], 1.16 [95% CI, 1.07-1.26]), systolic blood pressure (HR, 1.1 [95% CI, 1.020-1.2]), low-density lipoprotein cholesterol (HR, 1.16 [95% CI, 1.06-1.25]), and lipoprotein(a) (HR, 1.11 [95% CI, 1.02-1.20]) were significantly associated with AVC, whereas the other PRS including coronary artery calcium (HR, 1.02 [95% CI, 0.94-1.10]) and C-reactive protein (HR, 0.97 [95% CI, 0.89-1.05]) were not. In sex-stratified analyses, the PRS for coronary artery disease, low-density lipoprotein cholesterol, and lipoprotein(a) were significantly associated with AVC >0 for both sexes (P<0.05), whereas the systolic blood pressure PRS was borderline significant for women (HR, 1.10 [95% CI, 0.97-1.25]) and significant for men (HR, 1.11 [95% CI 1.00-1.24]). Our results confirm the role of atherogenic lipids in the pathogenesis of AVC and suggest that systolic blood pressure and the genetic risk factors for CAD are also important risk factors. The lack of association for the coronary artery calcium PRS with AVC >0 strongly suggests significant differences exist in the calcification pathways for AVC and coronary artery calcium.

Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder marked by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels from birth and a very high risk of premature atherosclerotic cardiovascular disease (ASCVD). To address the global paucity of observational data, the HoFH International Clinical Collaborators (HICC) registry (NCT04815005) was established. To date, over 950 HoFH individuals from 45 countries have been included. The median age at diagnosis was 12 years (IQR: 5.5-27.0), and untreated LDL-C levels were markedly elevated [median 14.7 mmol/L (11.6-18.4)]. At diagnosis, 9% had ASCVD or (supra)aortic valve disease, and despite the widespread use of lipid-lowering therapy (LLT), only 4% achieved guideline-recommended LDL-C goals. Early initiation of lipoprotein-apheresis was associated with greater LDL-C reductions and delayed ASCVD onset. Cardiovascular burden remains substantial, with a median age at death of 37 years [20-50]. No sex differences were observed in age or clinical characteristics at diagnosis, treatment patterns, or timing of ASCVD, although the usual sex gap in cardiovascular disease onset was absent. Profound global disparities persist, including limited genetic screening, restricted access to LLT, and earlier onset of major adverse cardiovascular events in non-high-income countries. Reproductive care for women remains highly variable and understudied. The HICC aims to guide global stakeholders in improving clinical outcomes for individuals with HoFH through earlier diagnosis, equitable access to advanced therapies, and broader inclusion of underserved regions. By generating evidence from routine clinical care and patient-reported data, identifying gaps in care, and fostering international collaboration, HICC seeks to advance a more equitable and effective global approach to HoFH management.

Emulating a Target Trial of Surgical Removal of Uterine Fibroids on Atherosclerotic Cardiovascular Disease.

Residual cardiovascular risk persists in many patients despite optimal control of established factors such as low-density lipoprotein cholesterol (LDL-C), blood pressure and glycaemia. Mounting evidence indicates that hypertriglyceridemia (HTG) and triglyceride-rich lipoproteins (TRLs), including their remnant particles, contribute to atherogenesis and therefore constitute actionable targets for risk reduction. This narrative review summarizes current knowledge of TRL metabolism and its role in atherosclerotic cardiovascular disease (ASCVD), drawing on mechanistic studies, observational cohorts and Mendelian-randomization analyses. TRLs display pro-inflammatory and pro-thrombotic properties and are increasingly implicated in plaque initiation and progression. Traditional and emerging therapeutic strategies designed to lower TRL burden are critically examined with particular emphasis on their ability to address residual cardiovascular risk. Conventional interventions, fibrates and mixed omega-3 fatty-acid formulations, have yielded modest and inconsistent cardiovascular benefits. By contrast, icosapent ethyl, a highly purified ethyl ester of eicosapentaenoic acid, is the only TRL-targeted therapy that has demonstrated a significant reduction in major cardiovascular events in a large, randomized trial, irrespective of baseline triglyceride levels. Novel agents such as evinacumab (an ANGPTL3 monoclonal antibody) and antisense oligonucleotides against apolipoprotein C-III (volanesorsen, olezarsen, plozasiran) have produced marked decreases in triglycerides, apoB-containing lipoproteins and remnant cholesterol in recent clinical studies, even though cardiovascular outcome data are not yet available. Therefore, therapies targeting TRL metabolism represent a promising approach to reduce residual cardiovascular risk, particularly in high-risk or statin-treated patients.