Low-density lipoprotein cholesterol (LDL-C) is a causal risk factor for atherosclerotic cardiovascular (CV) disease development and progression. The European Society of Cardiology guidelines recommend combination treatment to achieve CV risk-based LDL-C treatment goals. Inclisiran, a small interfering ribonucleic acid (siRNA) that targets hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) messenger RNA, can provide sustained and effective LDL-C reduction. VICTORION-Difference, a phase 4 double-blind, placebo-controlled randomized clinical trial included adults with hypercholesterolaemia at high- or very high CV risk. Participants were randomized 1:1 to receive inclisiran sodium (300 mg subcutaneous injections; equivalent to 284 mg inclisiran) or placebo together with individually optimized lipid-lowering therapy (ioLLT), including up-titration with rosuvastatin (open-label) until either their individual LDL-C goal or maximally tolerated statin dose (open-label rosuvastatin) was achieved. The primary objective was assessment of LDL-C goal achievement at Day 90. Key secondary objectives were muscle-related adverse events (MRAEs) and mean LDL-C reduction. Overall, 1770 individuals (mean age, 63.7 years) were randomized to receive inclisiran (n = 898) or ioLLT (n = 872). At Day 90, a significantly higher proportion of participants receiving inclisiran vs. ioLLT achieved their individual LDL-C goals [84.9% vs 31.0%; odds ratio (OR) 12.09, P < .001]. The mean percentage reduction in LDL-C from baseline to Day 360 was -59.5% and -24.3% in the inclisiran and ioLLT arms, respectively [least squares mean treatment difference (LSMTD) = -35.14%, P < .001]. Fewer participants receiving inclisiran vs ioLLT reported a MRAE (11.9% vs 19.2%; OR 0.57, P < .001). The mean reduction in Short Form-Brief Pain Inventory pain severity and interference scores favoured inclisiran over ioLLT (LSMTD = -0.11, P = .039; LSMTD = -0.11, P = .029, respectively). No new safety concerns were identified. Overall, 1770 individuals (mean age, 63.7 years) were randomized to receive inclisiran (n=898) or ioLLT (n=872). At Day 90, a significantly higher proportion of participants receiving inclisiran vs. ioLLT achieved their individual LDL-C goals (84.9% vs. 31.0%; odds ratio [OR] 12.09, p<0.001). The mean percentage reduction in LDL-C from baseline to Day 360 was -59.5% and -24.3% in the inclisiran and ioLLT arms, respectively (least squares mean treatment difference [LSMTD]=-35.14%, p<0.001). Fewer participants receiving inclisiran vs. ioLLT reported a MRAE (11.9% vs. 19.2%; OR 0.57, p<0.001). The mean reduction in Short Form-Brief Pain Inventory pain severity and interference scores favoured inclisiran over ioLLT (LSMTD=-0.11, p=0.039; LSMTD=-0.11, p=0.029, respectively). No new safety concerns were identified. An inclisiran-based treatment strategy was superior to ioLLT in LDL-C goal achievement, delivering early and sustained LDL-C reduction, with fewer MRAEs in individuals with hypercholesterolaemia.

Circadian rhythms, governed by the body's endogenous clock mechanism, regulate daily fluctuations in cardiovascular function, optimizing physiological processes like blood pressure regulation, cardiac metabolism, and myocardial repair. Rhythms also align cardiovascular reactivity with predictable environmental and behavioral cycles, enabling normal function and affecting disease susceptibility. Major adverse cardiovascular events, including myocardial infarction, ventricular arrhythmias, and stroke, exhibit a distinct morning peak, with evidence for circadian regulation in cardiovascular health. Indeed, controlled human laboratory studies demonstrate that beyond the influences of sleep and other behaviors, endogenous circadian rhythms independently regulate blood pressure, autonomic nervous system activity, blood clotting, vascular tone, and metabolic function. Additionally, the kidney plays a critical role in circadian sodium handling, fluid balance, and blood pressure control, with disruptions in renal circadian rhythms contributing to hypertension and progression to heart failure. Chronic circadian misalignment resulting from shift work, irregular sleep-wake cycles, or misaligned lifestyle habits is strongly associated with increased cardiovascular risk and disease progression. The emerging field of Circadian Medicine applies circadian principles to clinical care, leveraging interventions such as optimizing light exposure, meal timing, and physical activity to restore biological alignment. Chronotherapy, the strategic timing of medications or procedures to align with a patient's diurnal or circadian rhythms, offers further potential for enhancing treatments and reducing adverse effects. By integrating circadian biology into cardiovascular medicine, novel strategies are emerging to help prevent disease, improve patient outcomes, and enhance therapeutic precision. Understanding the interplay between circadian regulation and cardiovascular physiology provides a foundation for advancing cardiovascular prevention and treatment strategies.

Endothelial-to-mesenchymal transition (EndMT) has emerged as a key contributor to the development and progression of atherosclerotic cardiovascular disease. Driven by biomechanical, inflammatory, and metabolic cues within the vascular microenvironment, EndMT leads to the loss of endothelial identity and the acquisition of mesenchymal characteristics, thereby promoting vascular dysfunction and plaque progression. In this review, we present a comprehensive and up-to-date (as of April 15, 2026) overview of the molecular drivers and experimental models of EndMT in atherosclerosis, and critically evaluate current and emerging therapeutic strategies aimed at modulating this process. Furthermore, we emphasize the unresolved methodological challenges, which include the absence of standardized and quantitative approaches for EndMT detection, and the strong context dependency of existing experimental models. Emerging technologies, including genetic lineage tracing and single-cell transcriptomics, have revealed previously unrecognized cellular heterogeneity, context-dependent functional roles, and sex-specific EndMT signatures within human atherosclerotic plaques. Integrating recent advances in molecular biology, in vivo modeling, and translational research, this review provides a structured framework for understanding the multifaceted role of EndMT in atherosclerosis and outlines key challenges to be addressed to facilitate the translation of basic discoveries into clinical applications.

Cell death regulation: A novel way of natural products to treat myocardial hypertrophy.

As cancer survival rates improve, the long-term burden of treatment has become increasingly evident. Cancer survivors face a markedly higher risk of cardiovascular-related complications and premature, non-cancer-related mortality. In particular, cardiovascular disease (CVD) is disproportionately prevalent, with survivors approximately 40% more likely to develop and die from CVD compared to the general population. Although this increased morbidity reflects both acute cardiotoxic events and the later development and progression of more chronic CVDs, traditionally viewed as direct consequences of cancer therapies, the underlying mechanisms, especially those that are feasible to modify, are poorly understood. Emerging evidence positions the gut-heart axis as a central regulator of cardiovascular risk in cardio-oncology. This avenue is especially compelling to explore as the gut microbiome is well documented to be altered by cancer therapies, including chemotherapy, immune checkpoint inhibitors, targeted therapies, and radiation, with profound and persistent changes in diversity, composition and function widely reported across clinical cohorts. Comparable microbial changes have been observed in non-cancer cohorts with cardiovascular disease. For example, specific microbial metabolites have been reported to exert cardiovascular protective benefits in hypertension. Thus, there is a compelling opportunity to explore the gut microbiome to advance our understanding and ability to prevent cardiovascular disease in cancer survivors. This review synthesises current evidence linking the gut microbiome to cancer therapy-related cardiac dysfunction (CTRCD), evaluates microbial metabolites as predictive biomarkers of cardiotoxicity, and discusses microbiome-targeted modulation as an emerging strategy for improving cardiovascular outcomes in cancer survivors.

Protein-bound uremic toxins (PBUTs), including indoxyl sulfate (IxS), p-cresol sulfate (pCS), indole-3-acetic acid (IAA), and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), accumulate in patients with End-Stage Kidney Disease (ESKD) due to their resistance to conventional dialysis clearance and have been implicated in cardiovascular complications, oxidative stress, and disease progression. Accurate quantification of both total and free fractions of these toxins is essential for understanding their clinical significance, yet validated methods with population-specific reference intervals remain scarce. In this study, a rapid, sensitive, and fully validated LC-MS/MS method was developed for the simultaneous quantification of total and free serum concentrations of four PBUTs using a 4-minute chromatographic run and a single-step protein precipitation with an acetonitrile/acetone (1:1, v/v) solvent system. For the first time, indole-3-carboxylic acid was employed as an internal standard for IAA and CMPF quantification, while dihydrochlorothiazide (DHCT) was used for IxS and pCS. Method validation was performed in accordance with European Medicine Agency (EMA) guidelines, demonstrating excellent linearity (R² > 0.99), recovery (90-110%), minimal matrix effects (95-105%), and intra- and inter-day precision below 10% coefficient of variation (CV) for all analytes. Reference intervals for total PBUT concentrations were established using data from 120 healthy volunteers from a Turkish population cohort, representing the largest reference dataset reported to date for these analytes. The validated method was applied to serum samples from 118 maintenance hemodialysis patients, revealing significantly elevated total PBUT concentrations compared to healthy controls (p < 0.001 for all analytes), with IxS and pCS showing the most pronounced accumulation (approximately 29- and 23-fold higher, respectively). ROC curve analysis demonstrated excellent diagnostic performance for IxS (AUC = 0.986), pCS (AUC = 0.980), and CMPF (AUC = 0.943) in discriminating hemodialysis patients from healthy controls, while IAA showed limited discriminatory ability (AUC = 0.633), likely reflecting its distinct protein binding dynamics in uremic conditions. Spearman correlation analysis revealed significant associations between total PBUT levels and biochemical markers of renal function, further supporting the clinical relevance of the developed method. This validated LC-MS/MS approach offers a practical and reliable tool for simultaneous PBUT monitoring in clinical and research settings.

Ubiquitination in cardiovascular diseases: From molecular mechanisms to therapeutic targeting.

Ubiquitin-specific proteases in cardiovascular disease particularly in aging: mechanisms and therapeutic prospects.

Ferroptosis is reported to have a role in cardiovascular disease (CVD) progression. Recent emerging evidences demonstrate the role of Sodium-Glucose Co-Transporter 2 (SGLT-2) inhibitors in CVD owing to its promising cardioprotective benefits. However, the detailed molecular mechanism underlying its cardioprotective effects remain incompletely understood. We aimed to investigate the potential ferroptosis-inhibitory mechanism of SGLT-2 inhibitor in HL-1 mouse cardiomyocytes. Cardiomyocytes were incubated for 5h under hypoxic conditions (1% O2) to simulate ischemic injury with or without dapagliflozin (DAPA, 10 µM), a SGLT-2 inhibitor. Reactive oxygen species (ROS) was detected by immunofluorescence. Ferroptosis activity was analysed by measuring levels of intracellular iron, lipid peroxidation, malondialdehyde (MDA), and glutathione (GSH). Increase in ROS generation, intracellular iron, MDA concentration, and lipid peroxidation indicated increasing ferroptosis activity during hypoxic stress in cardiomyocytes. Treatment with DAPA caused reduction in ferroptosis. Pathway-specific gene analysis showed that interferon-gamma (IFN-γ) was upregulated during hypoxia, and was downregulated with DAPA treatment. Silencing of IFN-γ by using small interfering RNA (siRNA) resulted in inhibition of lipid peroxidation; on the other hand, incorporating recombinant IFN-γ resulted in the reversal of this phenomenon, thus validating the role of IFN-γ in hypoxia-induced ferroptosis. Our findings reveal IFN-γ pathway as a novel intracellular target of ferroptosis inhibition by DAPA in cardiomyocytes, providing molecular insight into the mechanisms underlying the cardioprotective effects of SGLT-2 inhibitor.

Alcohol intake reprograms hepatic immune-metabolic circuits to exacerbate murine atherosclerosis and human cardiovascular risk.

Inflammation plays a central role in the pathogenesis and progression of cardiovascular diseases, including atherosclerosis, myocardial infarction and heart failure. Despite advances in conventional diagnostic and therapeutic strategies, limitations in sensitivity, specificity and targeted drug delivery still remain. Nanomedicine has emerged as a promising yet underexplored approach to address these challenges by enabling precise molecular imaging and site-specific therapeutic interventions. This review summarizes current and emerging nanotechnology-based approaches for the diagnosis and treatment of cardiovascular inflammation, highlighting their potential in clinical practice and remaining challenges. In addition, recent advances, including the development of biomimetic nanoplatforms, are discussed, along with future perspectives and the potential integration of artificial intelligence to further enhance precision in cardiovascular medicine.

From urinalysis to photoacoustic imaging: A versatile probe for malondialdehyde in atherosclerosis.

Growth differentiation factor 15 (GDF-15) is a circulating biomarker reflecting oxidative stress, inflammation, and cellular aging. However, its role in disease risk assessment amongst individuals with cardiovascular-kidney-metabolic (CKM) syndrome stages 0-3 remains unclear. This study included 29,697 UK Biobank participants with CKM stages 0-3 defined in accordance with the American Heart Association criteria. Associations of GDF-15 with metabolic, inflammatory and liver fibrosis markers and CKM stage were examined using linear or multinomial logistic regression models. Fine-Gray competing risk regression models were used to evaluate associations with incident atherosclerotic cardiovascular disease (ASCVD), metabolic dysfunction-associated steatotic liver disease (MASLD) and their comorbidity (coexistence of both conditions). Bidirectional disease transitions were assessed using a multi-state Markov model. The relative importance of GDF-15 was evaluated using SHapley Additive exPlanations (SHAP) and likelihood ratio (LR) statistics. Improvements in risk prediction models were assessed using time-dependent area under the receiver operating characteristic curve, Brier score, integrated discrimination improvement and continuous net reclassification improvement. Amongst 29,697 participants (mean age of 56.16years; 57.32% female), 2,786 developed ASCVD and 456 developed MASLD during follow-up. Higher GDF-15 levels were associated with poorer CKM health and showed the strongest associations with renal function markers, followed by insulin resistance indices. Each 1-unit increase in GDF-15 (normalised protein expression, log2 scale) was associated with increased risks of ASCVD (HR = 1.25, 95%CI 1.15-1.36, P = 1.35 × 10-7), MASLD (HR = 1.62, 95%CI 1.41-1.86, P = 2.06 × 10-11) and their comorbidity (HR = 1.62, 95%CI 1.32-2.18, P = 4.36 × 10-7) after multivariable adjustment for age, sex, smoking status, body mass index, diabetes mellitus, glycated haemoglobin, systolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, C-reactive protein, creatinine, estimated glomerular filtration rate, urinary albumin-to-creatinine ratio, cystatin C, Townsend deprivation index, physical activity, and CKM stage. These associations remained consistent across subgroup analyses. Multi-state analyses indicated that GDF-15 predicted bidirectional progression between ASCVD and MASLD, with 10-year cumulative incidences of ASCVD and MASLD reaching 15.75% and 2.03%, respectively, among individuals in the top 10% of GDF-15 levels, and further increasing to 20.05% and 2.32% in those in the top 5%. SHAP and LR analyses showed that GDF-15 had high relative importance in predicting ASCVD and MASLD. Incorporating GDF-15 into established risk scores (PREVENT, SCORE2, FLI, FIB-4 and ARPI) showed modest improvements in risk discrimination, reclassification, and prediction error, particularly for ASCVD. In several settings, GDF-15 outperformed established biomarkers, including insulin resistance, systemic inflammation, apolipoprotein A/B, lipoprotein(a), cardiac troponin I, and N-terminal prohormone of brain natriuretic peptide. GDF-15 may serve as a promising biomarker for cardiovascular-kidney-liver-metabolic syndrome risk stratification and management.

Targeting HDAC6 and Its Novel E3 Ligase Activity: A Dual-Strategy for Cardiovascular Therapy.

Biomimetic flowing vessel-on-a-chip recruiting glycocalyx features for investigating dexmedetomidine function.

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.

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.

Mechanical forces significantly influence the initiation, progression, and remodeling of cardiovascular disease. In this study, CT-based patient-specific computational models were constructed to investigate the effects of the successful septal myectomy on myocardial stress distribution in the left ventricle. CT imaging data from five patients, collected both before and after successful septal myectomy, were used to create 10 patient-specific finite element models. Myocardial stress and strain of all integral nodes in the myocardium of the left ventricle were extracted from the simulation results. All the nodes in the left ventricular wall were divided into apex, midventricular, and basal region groups according to their position in the left ventricle. It was found that the mean stress decreased by 27.7% (p < 0.001) and the mean strain decreased by 26.3% (p < 0.001) after the surgery. The reduction in myocardial stress was more pronounced in the midventricular (50.3% decrease) and apex (54.0% decrease) regions compared to the basal region (23.5% decrease). These findings suggest that successful septal myectomy significantly reduces myocardial stress within the left ventricle, particularly in the midventricular and apex regions. Beyond alleviating left ventricular outflow tract obstruction, this surgery may also lower the risk of myocardial ischemia, acute myocardial injury, and subsequent myocardial fibrosis by reducing myocardial stress.

Simultaneous determination of trimethylamine N-oxide (TMAO) and its 15 related metabolites by UPLC-MS/MS in human serum.

Beyond cholesterol: targeting inflammatory biomarkers in cardiovascular disease.