Atherosclerosis is a chronic inflammatory disease. Targeting inflammatory pathways provides a promising avenue to treat atherosclerosis. Osthole (OS), isolated from the Cnidium plant, has been reported diverse pharmacological activities, including anti-cancer, anti-oxidant, neuroprotective, anti-osteoporosis and anti-inflammatory effects. However, the role on atherosclerosis and molecular targets of osthole remains unclear. We aimed to explore the anti-atherosclerosis role of osthole and investigate the underlying molecular mechanism. Mouse primary peritoneal macrophages (MPMs) were isolated and treated with oxLDL in vitro. Protein microarray and molecular docking were used to identify the target/s of osthole. ApoE-/- mice were fed with a high-fat diet (HFD) for 8 weeks to induce atherosclerosis. Osthole inhibited the inflammatory factor secretion induced by oxLDL and then reduced oxLDL uptake in MPMs. In vivo, osthole administration alleviated atherosclerotic plaque formation and inflammatory response in HFD-fed ApoE-/- mice. Mechanistically, protein microarray incubated with biotin-labelled osthole identified doublecortin like kinase 1 (DCLK1/DCAMKL1) as the top-ranked binding protein of osthole. Osthole directly bound to DCLK1 at I396 and L518 sites, inhibited the phosphorylation of DCLK1, and then prevented its interaction with inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ). Through targeting DCLK1, osthole suppressed NF-κB pathway activation and inflammatory responses in both MPMs and aortic lesions. Taken together, our findings show the therapeutic potential of osthole against inflammatory atherosclerosis and establish a foundation for targeting DCLK1 therapy in atherosclerosis.
Phenotypic switching of vascular smooth muscle cells (VSMCs) plays diverse roles in the development of atherosclerosis. These cells are a primary contributor to plaque formation and can transition between contractile and synthetic states in response to inflammation or oxidized low-density lipoproteins, exacerbating atherosclerosis. Piperlonguminine (PLG), a bioactive compound obtained from Piper longum L., is commonly used as traditional Mongolian medicine. To elucidate the effects and mechanisms of PLG on atherosclerosis via inhibition of the phenotype switch of VSMCs, we investigated the effects of PLG in the phenotypic transformation, proliferation, and migration of VSMCs. From the view of the symptoms of atherosclerosis, PLG alleviated the pathological changes of atherosclerosis; downregulated total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels; and decreased the levels of inflammatory cytokines. PLG regulated VSMC phenotypic switch proteins and also inhibited the proliferation and migration of VSMCs. Matrix metalloproteinases (MMPs) play a fundamental role in the phenotypic switch of VSMCs. The expression of MMP-2 and MMP-9 was assessed to elucidate the effects of PLG. PLG reduced the expression of MMP-2 and MMP-9 to inhibit the proliferation and migration of VSMCs. The findings collectively illustrate that PLG inhibited the phenotypic transformation, proliferation, and migration of VSMCs, thereby impeding the advancement of atherosclerosis. This inhibition was, in part, linked to reduced MMP-2 and MMP-9 expression.
Myocardial ischemia of non-obstructive origin (INOCA) is a prevalent cause of chronic coronary syndromes (CCS). Risk factors for atherosclerosis have also been described to promote INOCA, raising the question whether these entities are clinically related. Our aim was to compare the prevalence and clinical characteristics of INOCA in patients with and without coronary atherosclerosis. Sub-analysis of the all-comers, prospective, multicentre AID-ANGIO study, enrolling consecutive CCS patients, referred for coronary angiography. Obstructive coronary artery disease (CAD) was investigated by angiography and pressure guidewires. In the absence of obstructive-CAD, functional coronary testing (FCT) was performed within the same procedure. All patients diagnosed with INOCA were classified according to the evidence of non-obstructive atherosclerosis (INOCA-Ath) or the presence of angiographically normal coronary arteries (INOCA-NoAth). In the AID ANGIO study, 89 patients presented non-obstructive coronary atherosclerosis and 104 had angiographically normal coronary arteries. Prevalence of INOCA-Ath and INOCA-NoAth was 78.7% and 70.2%, respectively (p = 0.181). Patients' symptoms, results from ischemia tests and endotype distribution were comparable in both groups. Vasomotor abnormalities were the most frequently identified (81.4% INOCA-Ath vs. 74.0% INOCA-NoAth; p = 0.285). INOCA endotype was not predicted by the presence of coronary atherosclerosis, typical anginal symptoms, a positive ischemia test or atherogenic risk factors, whereas a youger age was associated with vasomotor disorders. In an all-comers population of patients with CCS, prevalence of INOCA was similar in patients with and without non-obstructive CAD. Clinical features and endotype distribution were also comparable, highlighting the need for FCT to make a correct diagnosis. The present study was conducted as a sub-analysis of the AID-ANGIO trial (ClinicalTrials.gov NCT056359949).
Diabetes is a significant global public health issue, and atherosclerosis serves as the primary pathological basis for the occurrence and progression of cardiovascular and cerebrovascular events. Studies have shown that hyperglycemia can promote the occurrence and progression of atherosclerosis by damaging vascular endothelial cells, macrophages, and vascular smooth muscle cells. In recent years, Chinese herbal medicines and their active ingredients have demonstrated unique advantages in preventing and treating high-glucose-induced vascular cell damage. Their mechanisms of action primarily encompass two aspects: firstly, regulating blood glucose through multiple pathways such as modulating the insulin signaling pathway, enhancing peripheral glucose uptake and utilization, and delaying intestinal carbohydrate absorption; secondly, intervening in key pathological processes such as high-glucose-induced vascular cell inflammation, cell death, phenotypic transformation, and metabolic reprogramming. This, in turn, slows down the progression of diabetes-related atherosclerosis. This article systematically elucidates the molecular mechanisms underlying hyperglycemia-induced damage to vascular endothelial cells, macrophages, and vascular smooth muscle cells. It also summarizes the protective mechanisms of Chinese herbal medicine active ingredients (albiflorin, salvianolic acid B, scutellarin, vitexin, hydroxysafflor yellow A, ginsenoside Rb1, maslinic acid, paeonol, citronellal, matrine, Panax notoginseng saponins, astragalus polysaccharides, 6-gingerol, and sodium tanshinone IIA sulfonate) and traditional Chinese medicine compounds (buyang huanwu decoction, guanxining tablets, and fufang zhenzhu tiaozhi) against vascular endothelial cells, macrophages, and vascular smooth muscle cells. The aim is to provide a theoretical basis for the prevention and treatment of diabetes-related atherosclerosis, as well as the development of related therapeutic drugs.
Endothelial dysfunction is an early event in atherosclerosis development and is centrally linked with insufficient endothelial NO production. However, chronically increased NO levels, including NO from other cellular sources, may induce endothelial dysfunction. Here, we studied how chronically elevated NO production from erythrocytes, achieved by genetic deletion of ARG1 (arginase-1), impacts smooth muscle cell (SMC) lipid accumulation and atherosclerosis progression. Primary aortic SMCs from mice lacking ARG1 in red blood cell (RBC.ARG1-knockout [KO]) were subjected to RNA-sequencing, lipidomic, metabolic, and molecular analyses; atherosclerosis burden was quantified en face and at the aortic root. Increased lipid droplet formation in SMCs from RBC.ARG1-KO mice was observed using brightfield and electron microscopy and confirmed by Oil Red O and BODIPY lipid dye staining. RNA sequencing revealed the simultaneous overexpression of genes regulating lipid uptake (Cd36), catabolism (Cpt1a), and de novo lipogenesis (Acaca, Fasn) in RBC.ARG1-KO SMCs, and inhibiting fatty acid translocase (CD36), ACC (acetyl-CoA [coenzyme A] carboxylase), or fatty acid synthase prevented the lipid accumulation in RBC.ARG1-KO SMCs. Increased expression of CD36 downstream of NO and overactivated sGC (soluble guanylyl cyclase)-cyclic guanosine monophosphate signaling was identified as a mediator of increased lipid uptake in RBC.ARG1-KO SMCs. Loss of PDE (phosphodiesterase) 2A, coupling cyclic guanosine monophosphate with cyclic adenosine monophosphate and PKA (protein kinase A) activation, was also observed, resulting in AMPK (5' AMP-activated protein kinase) inhibition, thus unlocking acetyl-CoA carboxylase, catalyzing the rate-limiting step in fatty acid synthesis. Inhibiting PDE2A recapitulated the RBC.ARG1-KO SMC phenotype, while inhibiting PKA or ATP generation from cyclic adenosine monophosphate abrogated the lipid droplet accumulation in RBC.ARG1-KO SMCs. Increased Oil Red O-positive aortic atherosclerosis burden in hypercholesterolemic apolipoprotein E-deficient RBC.ARG1-KO mice was confirmed by histology and elevated levels of polyunsaturated long-chain cholesterol esters in aortic atheroma by mass spectrometry lipidomics. Our findings show the importance of erythrocyte-derived NO for metabolically reprogramming SMCs toward increased fatty acid uptake and lipogenesis, and identify PDE2A as a molecular switch linking chronically activated NO signaling with lipid accumulation and atheroma progression.
Despite effective lipid-lowering therapies, atherosclerosis continues to be a leading cause of death, with considerable residual cardiovascular risk. Atherosclerotic lesions develop preferentially at arterial regions exposed to disturbed flow (d-flow), which induces genomic stress, endothelial injury, and barrier dysfunction. Hemodynamic forces are known to reprogram endothelial metabolism, but the role of de novo purine synthesis (DNPS), which supplies nucleotides for genome maintenance and whose terminal steps are catalyzed by the bifunctional enzyme ATIC, remains undefined in atherosclerosis. By integrating bulk and single-cell multiomics with in vitro flow systems and in vivo models, we show that d-flow upregulates DNPS and ATIC genes in vitro and in vivo, in concert with a DNA damage/repair state. Endothelial-specific Atic deletion exacerbates DNA damage, apoptosis, barrier dysfunction, and accelerates atherogenesis, while purine-base supplementation rescues repair defects. We further identify MYC as a mechanosensitive driver of ATIC induction. These findings establish a d-flow-MYC-ATIC-DNPS axis that sustains nucleotide sufficiency for DNA repair and maintains endothelial barrier integrity, suggesting potential endothelial-targeted therapeutic strategies for atherosclerosis.
Molecular hydrogen (H2) is a safe gaseous signaling molecule with anti-inflammatory properties. This study aimed to explore the anti-atherosclerotic effects of hydrogen-rich water (H2W) and clarify the underlying mechanism involving the gut microbiota and its metabolites. ApoE-/- mice were administered H2W to evaluate atherosclerotic plaque development and stability. Gut microbiota composition and short-chain fatty acid levels were analyzed. Antibiotic-induced microbiota depletion and fecal microbiota transplantation (FMT) were used to verify the mediating role of the gut microbiota. In vitro assays were performed to examine the effects of propionate on macrophage inflammation and polarization. H2W consumption significantly attenuated plaque formation and enhanced plaque stability in ApoE-/- mice, accompanied by altered gut microbiota structure and short-chain fatty acid profiles. Antibiotic treatment abolished the protective effects of H2W, while FMT from H₂W-treated mice transferred the anti-atherosclerotic phenotype. H2W notably increased propionate levels in cecal contents and serum. Propionate directly suppressed inflammatory responses and M1 macrophage polarization in vitro. This study demonstrates that H2W alleviates atherosclerosis by modulating the gut microbiota-propionate-macrophage axis. Our findings highlight H2W as a promising and safe intervention for atherosclerosis and provide new mechanistic insights into the crosstalk between gut microbial metabolites and vascular inflammation.
Cellular senescence is increasingly recognized as a key mechanism linking aging to chronic disease. Diabetic atherosclerosis (DAS), a major macrovascular complication of type 2 diabetes, often progresses despite standard metabolic and lipid-lowering therapies, highlighting the involvement of aging-related processes beyond classical metabolic and inflammatory pathways. This review synthesizes evidence to propose a conceptual framework in which stress-induced senescence is a key disease-oriented aging mechanism contributing to DAS initiation and progression. Hyperglycemia and lipotoxicity induce premature senescence in endothelial cells, vascular smooth muscle cells, and macrophages through oxidative stress, mitochondrial dysfunction, and activation of the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome. Senescent cells secrete a senescence-associated secretory phenotype (SASP), which amplifies chronic vascular inflammation, promotes plaque instability, and facilitates systemic propagation of senescence, thereby contributing to multi-organ dysfunction in the heart, brain, and kidneys. Together, these features position DAS as a representative model of stress-accelerated vascular aging. From a therapeutic perspective, we discuss emerging senescence-targeted strategies, including senolytics, senomorphics, and multi-target interventions derived from integrative medicine, with emphasis on their potential to modulate the aging tissue microenvironment and delay disease progression. By framing diabetic atherosclerosis within the context of aging biology, this review provides a disease-focused perspective on mechanisms and therapeutic opportunities underlying age-associated vascular disorders.
With the continuous advancement of bionanomaterial technology, the design and fabrication strategies of drug delivery systems have undergone significant strategic transformations and innovations. Herein, we report a microfluidic chip that enables one-step production of cell membrane hybrid lipid nanoparticles by fusing synthetic phospholipids with M2-macrophage membrane fragments and simultaneously encapsulating simvastatin and rapamycin. This greatly simplifies the preparation process, improves efficiency and produces M2-macrophage-membrane hybrid lipid nanoparticles loaded with simvastatin and rapamycin (M2LNPs@SIM&RAPA) with small particle size, homogeneous distribution and enhanced cumulative release in vitro. Western blotting and SDS-PAGE confirm the successful embedding of M2-membrane proteins. The formulation merges the long-circulating stability of synthetic phospholipids with the inflammation-targeting capacity and biocompatibility of M2 macrophage membranes. Stability tests and cell uptake experiments both proved its excellent storage stability and inflammation targeting. Cell cytotoxicity tests optimized the safe dosages of simvastatin and rapamycin. In the subsequent experiments, M2LNPs@SIM&RAPA could significantly reduce the expression of TNF-α in inflammatory cells and inhibit the formation of lipid droplets in foam cells, demonstrating its excellent anti-inflammatory activity and enhanced cholesterol excretion ability. In summary, the M2LNPs@SIM&RAPA prepared based on microfluidics can precisely regulate lipid metabolism and inflammatory responses through the synergistic effect of low-dose drugs, and is expected to provide a theoretical basis for the future treatment of atherosclerosis.
Atherosclerosis (AS) and acquired immune deficiency syndrome (AIDS) are associated with autophagy-related pathways. This research was intended to ascertain the interplay between AS and AIDS through autophagy-related mechanisms and to identify potential common biomarkers. Single-cell datasets for AS and AIDS were extracted from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) from each dataset were identified and then intersected with autophagy-related genes (ATGs). Functional enrichment and protein-protein interaction (PPI) network analyses were performed. Hub genes were determined via CytoHubba and MCODE. Finally, the hub genes were validated via bulk transcriptomic data. ROC curves were plotted, and their correlations with immune cell infiltration were investigated. Transcription factor networks and drug-gene interactions were implemented. 17 key ATGs were found, which were primarily enriched in autophagy, apoptosis, and TGF-β signaling pathways. After intersecting the 17 ATGs with DEGs using four algorithms in the Cytoscape plugin, eight genes were identified. Finally, three hub genes, encompassing GAPDH, HSPA8, and REL, were determined. ROC curves confirmed their diagnostic value. Their expression levels were markedly correlated with immune cell infiltration, and potential drugs were forecast. This study demonstrates that GAPDH, HSPA8, and REL form a shared molecular pathway linking AS and AIDS via dysregulated autophagy, highlighting their potential as diagnostic biomarkers and therapeutic targets. Three hub genes, including GAPDH, HSPA8, and REL, were determined as potential biomarkers for AIDS and AS, providing insights into the molecular mechanisms of HIV-associated AS.
Atherosclerosis (AS), the fundamental pathological basis of most cardiovascular diseases, is a chronic and progressive inflammatory disorder characterized by lipid deposition and plaque formation within the arterial wall. Despite significant advances in pharmacological and interventional therapies, the global burden of AS remains substantial, emphasizing the need to identify novel molecular regulators and therapeutic targets. Caveolin-1 (Cav-1), a key scaffolding protein of plasma membrane caveolae, has emerged as a context-dependent modulator of lipid handling and vascular homeostasis in AS. Evidence from experimental and clinical studies indicates that Cav-1 participates in endothelial low-density lipoprotein (LDL) transcytosis and barrier function in endothelial cells (ECs), regulates cholesterol efflux and inflammatory signaling in macrophages (MΦs), and influences phenotypic plasticity in vascular smooth muscle cells (VSMCs). These coordinated actions position Cav-1 at the intersection of lipid metabolism and vascular inflammation. Notably, while global Cav-1 deficiency markedly attenuates atherosclerotic lesion formation in animal models, the cell type-specific and stage-dependent mechanisms underlying these effects remain incompletely understood. Cav-1 activity is further modulated by post-translational modifications (PTMs), particularly tyrosine-14 phosphorylation, which can influence its membrane localization, stability, and protein-protein interactions. In addition, emerging evidence suggests dynamic interplay between Cav-1 and autophagy-related pathways, highlighting its role in maintaining lipid and cellular homeostasis under metabolic stress. In this review, we systematically summarize current evidence regarding Cav-1 and caveolae across vascular cell types, delineate existing controversies and knowledge gaps, and evaluate the translational potential of targeting Cav-1-associated lipid regulatory pathways in AS.
As life expectancy rises, identifying causes and risk factors for incident acute ischemic stroke (AIS) among the oldest-old (≥80 years) is increasingly important. We examined whether the effect of age at stroke on AIS subtype is mediated by embolic risk factors and whether these factors improve AIS prediction. Stroke-free participants from the ARIC study (Atherosclerosis Risk in Communities) who developed AIS between visit 5 (2011-2013) and visit 10 (2023) were included for causal analysis; Stroke-free participants at visit 5 were included for prediction analysis. In logistics regression models, the association between age at stroke-onset (≥80 versus <80 years) and adjudicated AIS subtype (embolic ischemic stroke versus thrombotic ischemic stroke) was determined. Bootstrapped mediation analyses (1000-iterations) tested whether atrial fibrillation, myocardial infarction, coronary heart disease, heart failure, and electro/echocardiogram measures mediated the age-AIS subtype relationship. C statistics were calculated for AIS prediction (Predicting Risk of Cardiovascular Disease Events, CHA2DS2-VASc) and compared preinclusion and postinclusion of embolic risk factors. Of 6213 stroke-free participants at visit 5, 277 (4.4%) developed AIS during a median (Q1-Q3) of 5.1 (2.6-7.1) years (median [Q1-Q3] age: 76 [72-80] years; median [Q1-Q3] age at AIS: 81 [77-86] years; 62% female; 99 embolic ischemic stroke and 178 thrombotic ischemic stroke). Individuals with AIS ≥80 years had higher odds of embolic ischemic stroke (versus thrombotic ischemic stroke) compared with those aged <80 years (odds ratio, 1.90 [95% CI, 1.09-3.31]). The effect of age at stroke-onset on embolic ischemic stroke was mediated by atrial fibrillation (44%; P=0.03), an abnormal left atrium volume index (45%; P=0.048), or an abnormal P-wave axis (43%; P=0.04). The predictive performance for AIS ≥80 years using the Predicting Risk of Cardiovascular Disease Events equation (N=5702, C statistic, 0.49 [95% CI, 0.45-0.53]), or CHA2DS2-VASc score (N=5739, C statistic, 0.57 [95% CI, 0.55-0.59]) was poor, but inclusion of embolic risk factors improved the performance (Predicting Risk of Cardiovascular Disease Events: C statistics, 0.77 [95% CI, 0.74-0.80]; CHA2DS2-VASc: C statistics, 0.63 [95% CI, 0.59-0.67]). These findings suggest that identification and control of embolic risk factors are critical to reduce stroke risk as people age, and better stroke-specific prediction tools are needed.
Delirium is common among hospitalized adults, prevalence estimates ranging from 33% to 50% of hospitalized patients over age 65. Yet, little is known about the association between social determinants of health (SDOH) and delirium. To describe neighborhood-level risk factors for hospitalization with delirium. We examined the association between hospitalization with delirium and neighborhood disadvantage, measured by the Area Deprivation Index (ADI)-a tool that measures SDOH by assessing socioeconomic conditions and disadvantages within a geographic area. The Atherosclerosis Risk in Communities (ARIC) study is a community-based prospective cohort of adults recruited from four US communities. This analysis included ARIC participants that attended visit 5 (2011-2013) and had at least one hospitalization before visit 7 (2018-2019). Delirium was identified and quantified using hospital claim records. The association between ADI quartiles and incidence and number of delirium events was estimated with offset Poisson regression models for the time participants were observed. Associations were also examined by cognitive status. In this analytic cohort of 4130 participants, 486 (11.8%) experienced at least one hospitalization with delirium. Unadjusted regression analyses showed a higher incidence of delirium (proportion ratio, PR = 1.32; and 95% CI = 1.03, 1.69) and number of delirium events (incidence rate ratio, IRR = 1.30; 95% CI = 1.05, 1.63) among participants from the highest ADI quartile compared to the lowest quartile. In fully adjusted models, this association was attenuated. Among participants with mild cognitive impairment (MCI) and dementia, those from the most disadvantaged neighborhoods experienced a higher incidence and number of delirium events. In this cohort of hospitalized older adults, participants from more disadvantaged neighborhoods had a higher incidence of delirium; this association was attenuated in adjusted analyses. This suggests that neighborhood-level social disadvantage may be meaningful in studies on prevention and management of delirium, though overlapping demographic and clinical characteristics likely confound this relationship.
Low-density lipoprotein (LDL) plays a central role in the development of atherosclerosis, making its detection critical for cardiovascular disease management. Radionuclide imaging of LDL offers distinct advantages over other modalities but remains limited by poor specificity and the need for long-lived isotopes. We present a click chemistry-based PET imaging strategy using gallium-68 (68Ga), a short-lived radionuclide, for the specific detection of LDL accumulation in atherosclerotic plaques. The approach relies on a two-step inverse electron-demand Diels-Alder reaction between trans-cyclooctene (TCO)-modified LDL and tetrazine-functionalized iron oxide nanoparticles radiolabeled with 68Ga. In vivo PET/CT imaging in LDL receptor-deficient (LDLr-/-) mice showed selective uptake of the nanoparticles in atherosclerotic lesions, with minimal signal in wild-type controls. This method demonstrated high specificity and sensitivity, while reducing background signal and radiation exposure. Our results support the potential of this approach as a noninvasive and translatable platform for early diagnosis and risk assessment in cardiovascular disease.
Statins are the cornerstone of lipid-lowering therapy for the prevention of atherosclerotic cardiovascular disease (ASCVD); however, many patients are unable to achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) targets because of suboptimal tolerance to statins. The 2026 Taiwan Society of Lipid and Atherosclerosis (TSLA) Consensus Statement presents an updated, evidence-based framework for the identification and management of patients receiving suboptimally tolerable statins (STS)-a pragmatic concept that extends beyond the traditional and restrictive definition of statin intolerance (SI). STS encompasses patients who are unable to maintain recommended statin intensity because of real or perceived adverse effects, even when formal SI criteria are not met, thereby addressing a major treatment gap in real-world practice in Taiwan. This consensus integrates contemporary international evidence and Taiwanese guidelines, including the 2025 Taiwan cholesterol management pathway, and proposes structured, risk-based algorithms for STS management. A tiered therapeutic strategy is recommended: extremely high-risk patients should receive early combination therapy with ezetimibe and bempedoic acid, with prompt escalation to PCSK9 inhibition-based agents if LDL-C targets (<55 mg/dL) are not achieved. In high- and very high-risk patients, ezetimibe is the first-line add-on therapy, followed by bempedoic acid and PCSK9-targeted agents as needed, while lifestyle intervention and shared decision-making are emphasized in lower-risk groups. Non-pharmacological options are also reviewed; however, robust cardiovascular outcome data remain limited. By bridging conceptual and policy gaps between SI and STS, this consensus promotes a patient-centered, precision-based approach to improving LDL-C goal attainment and reducing residual ASCVD risk.
Poor physical function has been associated with higher cardiovascular disease (CVD) risk. However, the association between physical function and atrial fibrillation (AF) remains understudied. The comprehensive investigation of the association between physical function and incident AF risk could highlight a novel target for AF prevention. A total of 4,803 participants without diagnosed AF from the Atherosclerosis Risk in Communities (ARIC) Study cohort with physical function assessed in 2011-2013 were studied. Physical function was measured using Short Physical Performance Battery (SPPB), 4-meter walk time, and grip strength. Hospital discharge codes and death certificates were used to ascertain incident AF through 2022, and through 2020 for participants from Jackson. Cox regression was used to assess the association between physical function and incident AF risk, adjusting for multiple covariates. Z-score transformations were performed to identify the physical function measure most strongly associated with incident AF risk, and SPPB component analysis was performed to identify the most influential SPPB component. Mean age of the study participants was 75.1 ± 5.0 years, with 41.2% being male participants and 22.2% being black participants. During a median follow-up of 9.2 years, there were 809 incident AF events. SPPB (HR: 0.93, 95% CI: 0.90-0.96, per 1-point increase) and grip strength (HR: 0.87, 95% CI: 0.78-0.96, per 10kg increase) were inversely associated with incident AF risk, while 4-meter walk time (HR: 1.08, 95% CI: 1.03-1.13, per 1-second increase) was positively associated with incident AF risk. SPPB had the strongest association with incident AF risk. Within SPPB, only the chair stand component was significantly associated with incident AF risk. The findings suggest that better physical function is associated with reduced incident AF risk, with higher SPPB having the strongest association. Given the modifiable nature of physical function, these findings highlight a potential novel target for AF prevention in aging populations. Physical function has been associated with cardiovascular diseases, however, the relationship between physical function and incident atrial fibrillation (AF) remains understudied. This study found that better Short Physical Performance Battery (SPPB), 4-meter walk time, and grip strength were all independently associated with reduced risk of incident AF.In this study, higher SPPB was most strongly associated with reduced risk of incident AF, implying the importance of multi-domain measures of physical function.This study found that within SPPB, higher chair stand component score was the only component significantly associated with reduced risk of incident AF, highlighting the critical role of muscle strength in the association between physical function and risk of incident AF.The results suggest that physical function may be a novel modifiable target for AF prevention.
Exercise reduces cardiovascular events, yet its interactions with parathyroid hormone (PTH) and atherosclerotic calcification as well as their combined effects on cardiac remodeling remain unclear. Thus, we tested effects of constitutive activation of the PTH type I receptor (PTH1R) with and without exercise on aortic calcification and cardiovascular remodeling in a mouse model of atherosclerotic calcification. Female Ldlr-/-;Tagln-PTH1R transgenic (Tg) and Ldlr-/- littermate control (Ctrl) mice were fed a Western diet beginning at 9-10 weeks of age. At age 40 weeks, mice were assigned to sedentary (SED) or treadmill exercise (TM) regimens for 9 weeks. MicroPET/CT and echocardiography were performed at baseline and study completion. By microCT, aortic calcium content increased in all four groups. However, 18F-NaF uptake, reflecting mineral surface area, increased only in Ctrl/TM mice. Systolic function improved and left ventricular (LV) mass decreased in Tg/TM and Ctrl/TM groups. However, in Ctrl/TM mice, LV chamber diameter increased while anterior wall thickness decreased, consistent with eccentric remodeling. In contrast, in Tg/TM mice, diastolic wall thickness decreased without chamber enlargement, indicating preserved geometry and enhanced contractile efficiency. In sedentary mice (Tg/SED and Ctrl/SED), diastolic LV diameter increased without changes in wall thickness or systolic function, consistent with ventricular remodeling due to aortic stiffening in hyperlipidemia. These findings suggest that vascular PTH1R signaling selectively modulates cardiovascular adaptation to exercise. By preserving geometry and improving contractile efficiency, PTH1R activation augments the beneficial effects of exercise on adverse cardiac remodeling in atherosclerotic calcification, supporting endocrine and exercise contributions to ventricular-vascular coupling.
Coronary artery disease (CAD) is a multifactorial disorder influenced by both environmental and genetic factors. The PLAU gene, which plays a key role in fibrinolysis, inflammation, and extracellular matrix remodeling, has been implicated in atherosclerotic plaque progression. However, the relationship between PLAU polymorphisms and different clinical manifestations of CAD remains insufficiently clarified. This study aimed to investigate the distribution of the PLAU rs2227564 polymorphism in patients with acute coronary syndrome (ACS), chronic coronary syndrome (CCS), and angiographically normal controls, and to evaluate its potential association with CAD susceptibility. A total of 196 participants (ACS: 66, CCS: 65, controls: 65) who underwent coronary angiography were prospectively enrolled. Genotyping of the PLAU rs2227564 polymorphism was performed using real-time polymerase chain reaction with the TaqMan SNP Genotyping Assay. Genotype and allele frequencies were compared among groups. Dominant, recessive, and allelic genetic models were analyzed, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Overall genotype and allele distributions were similar across the study groups (p = 0.737). However, under the dominant genetic model (CT + TT vs. CC), carriers of at least one T allele showed significantly increased susceptibility to both ACS (OR: 6.84, 95% CI: 1.47-31.89, p = 0.009) and CCS (OR: 6.60, 95% CI: 1.43-30.48, p = 0.008) compared with controls. No significant associations were observed in the recessive or allelic models. Although the rs2227564 polymorphism was not independently associated with CAD based on the overall genotype distribution, the dominant model findings suggest that carrying at least one T allele may contribute to disease susceptibility in specific clinical and population contexts. These findings should be considered hypothesis-generating and require confirmation in larger multicenter studies with functional validation.
This study aimed to investigate the effect of ginsenoside Rb1 (Gs-Rb1) on endothelial cell (EC) pyroptosis in atherosclerosis (AS). ApoE-/- mice and mouse aortic endothelial cells (MAECs) were used as research subjects. An in vivo AS model was established by feeding ApoE-/- mice a high-fat diet (HFD) for 3 months, followed by intragastric administration of Gs-Rb1 at 40 mg/kg/day for 3 months. Pathological changes were evaluated by hematoxylin-eosin (HE) and Oil Red O staining. Caspase-1 expression was detected by immunofluorescence. Pyroptosis-related protein and mRNA levels were measured by Western blotting and RT-PCR. Inflammatory factors (IL-18 and IL-1β) and LDH were quantified by ELISA. For in vitro experiments, MAECs were stimulated with oxidized low-density lipoprotein (ox-LDL, 150 μg/mL) to induce pyroptosis, followed by treatment with Gs-Rb1 (60 or 80 μg/mL) for 12 h. Cell death was assessed by flow cytometry. Gs-Rb1 significantly reduced aortic plaque area in mice. It decreased the expression of pyroptosis-related proteins (caspase-1, cleaved caspase-1, GSDMD, and NLRP3) and mRNA levels in aortic tissues. Serum levels of LDH, IL-18, and IL-1β were also significantly reduced. In vitro, Gs-Rb1 reduced cell death rate and inhibited pyroptosis in endothelial cells (ECs). This study confirms the therapeutic effect of Gs-Rb1 on AS at both animal and cellular levels. Inhibition of EC pyroptosis may be the key mechanism underlying the anti-atherosclerotic effects of Gs-Rb1.
Despite statin therapy, cardiovascular disease remains a leading cause of mortality. CSL112 enhances HDL function and reverse cholesterol transport, offering a novel strategy for atherosclerotic cardiovascular disease (CVD). Following PRISMA guidelines, databases including PubMed, the Cochrane Library, Scopus, Google Scholar and EMBASE were searched from inception to May 2025 for studies evaluating efficacy and safety of CSL112 in adults at risk of Atherosclerotic CVD. Data were analyzed using RevMan version 5.4 with a random-effects model. Six trials (n = 1,824) showed that CSL112 significantly increased total cholesterol efflux capacity (CEC), most notably with the 6 g dose (MD 11.90; p < 0.00001), including ABCA1-dependent (MD 5.88; p < 0.00001) and ABCA1-independent CEC (MD 4.68; p < 0.0001) at 2 hours. HDL-C levels increased significantly (MD 6.89; p < 0.00001) without meaningful change in apolipoprotein A-I. Safety analyses showed no increased risk of serious adverse events (RR 1.05) or treatment-emergent adverse events (RR 0.88) versus placebo. CSL112 significantly enhances CEC and HDL-C levels with favorable safety profile with the 6 g dose at 2 hours, supporting its use as adjunctive therapy for immediate cardiovascular protection. Large outcome-driven trials are warranted to define long-term clinical benefits.