Prediabetes is an umbrella term which refers to a collection of blood parameters related to glucose regulation exceeding their normal threshold, but not meeting the criteria for overt diabetes. Its prevalence is rising worldwide, largely driven by overweight/obesity, diet, lack of exercise and familiarity. OBJECTIVES:To provide a state-of-the-art overview of epidemiology, pathophysiology, cardiovascular (CV) implications, and emerging therapeutic strategies in prediabetes. METHODS:Narrative review with structured discussion of randomized controlled trials (RCTs) and meta-analyses addressing progression to T2DM and cardiovascular outcomes. RESULTS:The risk of prediabetes progressing to T2DM is well established, with modest differences across phenotypes (impaired fasting glucose, impaired glucose tolerance, elevated HbA1c). In contrast, whether prediabetes independently increases CV risk remains debated. Observational studies and meta-analyses suggest a mild but statistically significant increase in CV events and mortality; however, randomized evidence demonstrating CV benefit from treating prediabetes is limited and methodologically heterogeneous. Current management of prediabetes primarily relies on lifestyle interventions, while metformin is recommended only in selected high-risk individuals. Glucagon-like peptide receptor-1 agonists and sodium-glucose cotransporter-2 inhibitors have shown disease-modifying effects in T2DM and related cardiometabolic conditions. Emerging data suggest potential benefits in individuals with prediabetes, although dedicated adequately powered CV outcome trials are lacking. CONCLUSIONS:Prediabetes is a clinically relevant cardiometabolic state. While progression to T2DM is well documented, its role as an independent CV therapeutic target remains uncertain. Future trials should address phenotype-specific risk stratification and evaluate contemporary cardiometabolic therapies in appropriately powered populations.
Background Interleukin-21 (IL-21) is a pro-inflammatory cytokine involved in the regulation of both innate and adaptive immune responses and has been associated with atherosclerotic cardiovascular disease (ASCVD). However, the exact role of IL-21/IL-21R signaling in atherosclerosis and the therapeutic potential of targeting this axis remain unclear. Methods and Results scRNAseq of human carotid plaques revealed that IL-21R is highly expressed on Tregs, with increased levels in women versus men and in fibrous plaques versus other phenotypes. In line with these findings, we showed that IL-21R blockade using an anti-IL-21R monoclonal antibody in young (20 weeks) Ldlr-/- mice increased Treg frequencies in secondary lymphoid organs (SLOs), accompanied by increased serum IL-10. Moreover, we observed reduced pro-inflammatory monocytes in the aorta and spleen of anti-IL-21R-treated mice. This contributed to a reduction of 38% in atherosclerotic plaque area (p<0.05) and 61% less macrophage content (p=0.053) upon IL-21R blockade. Furthermore, scRNAseq analysis of the spleen and aorta of female Ldlr-/- mice demonstrated an age-associated increase in Il21/Il21r expression within Tregs and Tfh cells. Subsequent IL-21R blockade in aged (88 weeks) Ldlr-/- mice with well-established plaques reduced inflammation, as shown by an increase in aortic Tregs, elevated Foxp3 expression in Tregs from SLOs and reduced pro-inflammatory monocytes. Additionally, anti-IL-21R-treated aged mice showed reduced Tfh cells, as well as reduced plasmablasts and plasma cells. Conclusions Collectively, we show that IL-21R blockade attenuates plaque initiation, promotes atheroprotective Tregs, inhibits pro-inflammatory monocytes and impairs Tfh-B cell dynamics upon aging, representing a promising novel therapeutic strategy to combat ASCVD.
BACKGROUND AND AIMS:Decreased removal and increased production of apolipoprotein B (apoB) containing lipoproteins cause hypercholesterolemia, a major causal risk factor of atherosclerotic cardiovascular disease. By a genome-wide siRNA screen, we previously identified subunits of the Coat protein I (COPI) complex to limit low density lipoprotein (LDL) uptake into Huh-7 hepatocarcinoma cells. This study investigated the underlying mechanism and the role of impaired COPI function for hypercholesterolemia. METHODS:Targeted loss of function experiments in vitro as well as genetic association studies in humans and three mouse models with mutated or disrupted COPI genes were performed. RESULTS:Silencing of COPA, COPB1, COPB2, ARCN1, COPG1, and COPZ1 in Huh-7 cells resulted in decreased uptake of LDL and aberrant glycosylation and reduced cell surface abundance of the LDL receptor (LDLR) as well as increased apoB secretion and cellular lipid storage. Single nucleotide polymorphisms of ARCN1 were associated with lower ARCN1 expression and higher levels of LDL-cholesterol. While patients and mice carrying rare immunopathogenic missense variants of the WD40- or appendage domains of COPA and COPG1, respectively, had normal LDL-cholesterol levels, rare variants altering other domains of these proteins were enriched among patients with hypercholesterolemia. The hepatic knockdown of Copg1 increased the concentrations of nonHDL-cholesterol in plasma and triglycerides in the liver of mice. CONCLUSIONS:The COPI coatomer regulates LDLR activity and apoB secretion as well as hepatic lipid content. Deficiency of Copg1 in mice and some but not all rare damaging COPI gene variants in humans are associated with higher LDL-cholesterol levels.
BACKGROUND:Fatty liver is the most common chronic liver disease globally and is associated with increased cardiovascular risk. Evidence specifically addressing fatty liver and cardiovascular outcomes in young adults from European population-based cohorts remains scarce. METHODS:Fatty liver was assessed by abdominal ultrasound in 2008 participants of the Young Finns Study (age 34-49 years) in 2011. Incident composite cardiovascular disease (CVD) and coronary heart disease (CHD) were ascertained from national registries through 2024. Cox proportional hazards regression was used to examine associations between fatty liver and incident outcomes, with sequential adjustment for sex, age, waist circumference, apolipoprotein B (apoB), and C-reactive protein (CRP). RESULTS:Fatty liver was detected in 377 participants (19%). Over a median follow-up of 13 years, 124 CVD events and 71 CHD events occurred. Fatty liver was associated with incident CVD (HR 1.76, 95% CI 1.20-2.57) and CHD (HR 2.10, 95% CI 1.30-3.39) after adjustment for sex and age. The CVD association was attenuated to non-significance after further adjustment for apoB (HR 1.39, 95% CI 0.91-2.13, p = 0.134). The CHD association remained significant after adjustment for apoB (HR 1.82, 95% CI 1.06-3.12, p = 0.031) and was unchanged after additional adjustment for CRP (HR 1.81, 95% CI 1.06-3.10, p = 0.031), but was slightly attenuated after additional adjustment for markers of insulin resistance, such as HOMA-IR (HR 1.72, p = 0.056). CONCLUSIONS:Fatty liver in young adults was associated with incident CHD after adjustment for atherogenic dyslipidaemia and systemic inflammation, with modest attenuation after adjustment for insulin resistance. The association with composite CVD was substantially attenuated after adjustment for apoB. These findings support fatty liver as a marker of later CVD risk in young adults.
BACKGROUND AND AIMS:Serum low-density lipoprotein (LDL)-cholesterol varies in response to the isonergetic replacement of saturated (SFA) with unsaturated fats (UFA), as reported in our previous screening study, 'Reading, Imperial, Surrey, Saturated fat Cholesterol Intervention-1' (RISSCI-1). In the present study, we aimed to determine if differences in postprandial absorption and metabolic handling of SFA could explain variability in responsiveness of serum LDL-cholesterol to dietary SFA intake. METHODS:Male participants classified according to their fasting LDL-cholesterol response to the replacement of SFA with UFA in our screening study (RISSCI-1) as higher (HR, n = 19) or lower responders (LR, n = 17), were placed on two, 4-week isoenergetic diets (higher-SFA/lower-UFA followed by lower-SFA/higher-UFA). After each diet, [U-13C]palmitic acid was given in the first of two sequential meals to trace postprandial saturated fat absorption. RESULTS:Repeating the previous dietary regime in the same participants resulted in similar inter-individual variation in LDL-cholesterol response, with greater reductions in lipid ratios (total cholesterol:high density lipoprotein (HDL) and LDL-cholesterol:HDL-cholesterol) and largest LDL-1-subfraction in the HR versus the LR group (p < 0.0001 for all). There was no difference in the absorption of SFA between groups but a significantly greater recovery of [U-13C]palmitic acid-triacylglycerol in the postprandial period in LR relative to the HR group after SFA replacement with UFA was observed (p = 0.019). CONCLUSIONS:Dietary SFA absorption did not explain individual variation in serum LDL-cholesterol response to SFA replacement with UFA. Exploratory findings of a difference in postprandial [U-13C]palmitic acid-triacylglycerol warrants further investigation.
BACKGROUND AND AIMS:Despite effective LDL-cholesterol reduction, residual cardiovascular risk persists. We investigated whether a specific fatty-acid phenotype predicts structural plaque instability and cardiovascular events independent of lipoprotein burden. METHODS:This multi-cohort study integrated a clinical discovery cohort (n = 201, GC-MS profiling) with the UK Biobank validation cohort (n = 263,481, NMR profiling). Unsupervised clustering derived fatty-acid phenotypes. Structural vulnerability was assessed via optical coherence tomography (OCT) in 138 patients. The primary endpoint was MACE (cardiovascular death, non-fatal MI, stroke). RESULTS:Two phenotypes emerged: Phenotype B, characterized by omega-3 depletion. Paradoxically, despite lower LDL-cholesterol (2.7 vs 3.0 mmol/L; p = 0.050) and triglycerides (1.5 vs 2.0 mmol/L; p = 0.041), Phenotype B exhibited significantly thinner fibrous caps (68.0 vs 94.2 μm; p = 0.003) and higher thin-cap fibroatheroma prevalence (49.0% vs 20.0%; p = 0.002) on OCT. In the UK Biobank, Phenotype B was associated with increased MACE risk in participants aged >60 years (HR 1.16; 95% CI 1.12-1.21; p < 0.001). In fully adjusted models, the hazard ratio was 1.12 (95% CI 1.08-1.16; p < 0.001), with 72% of excess risk mediated through glycemic, inflammatory, and adiposity pathways. CONCLUSIONS:A latent fatty acid phenotype defined by omega-3 depletion and elevated omega-6/omega-3 ratio was associated with structural plaque vulnerability despite favorable atherogenic lipoprotein levels. In the UK Biobank, this phenotype was independently associated with increased MACE, most pronounced in participants aged 60 years and older. These observational findings warrant prospective validation.
BACKGROUND AND AIMS:Previous hypothesis-driven studies focused on limited risk factors for ischemic stroke (IS) with inconsistent findings. We aimed to systematically identify modifiable factors, assess causality, quantify joint impact, and evaluate public health implications of conservative versus radical multi-domain IS intervention strategies. METHODS:We conducted a large prospective cohort study using UK Biobank and a bidirectional two-sample Mendelian randomization study. Exposures included 323 modifiable factors in seven domains: early life, health and medical history, lifestyle, local environment, physical measures, psychosocial factors, and sociodemographics. Exposome-wide association scan was used to investigate the associations between exposures and IS onset, and multivariable Cox models to assess their joint impact. Weighted population attributable fraction was estimated by partially eliminating exposures. RESULTS:497,856 IS-free UK adults were enrolled during 2006-2010, and 10,593 experienced IS with a median follow-up of 14.53 years. Among 68 modifiable factors significantly associated with IS, 18 demonstrated robust causality. Controlling for the overlapping hazards of exposures, worsening risk profiles in each domain independently increased IS risk. Eradicating all modifiable risk factors would prevent 72.21% (95% CI 69.37%-74.83%) of IS, whereas a one-third reduction in the exposure levels of modifiable factors would prevent 68.19% (95% CI 64.22%-71.81%). These findings remained consistent across populations stratified by age, sex, and polygenic risk score-based genetic risk. CONCLUSIONS:This hypothesis-free and triangulated study provided comprehensive information on the modifiable exposome for IS. Our findings suggested that a moderate reduction in risk factor exposure achieved a preventive impact comparable to total eradication, supporting the potential for efficient public health strategies.
BACKGROUND AND AIMS:Cardiovascular disease (CVD) remain the leading cause of mortality and disability. Most risk prediction tools rely on risk factors measured at a single time point, ignoring changes in biomarkers over time. We aimed to develop and validate a dynamic CVD risk prediction tool using joint modelling that incorporates repeated measurements of cardiovascular risk factors. METHODS:We analysed 6637 participants aged 45-84 years from the Multi-Ethnic Study of Atherosclerosis. A Bayesian joint model was used to simultaneously analyze longitudinal risk factor trajectories and time to CVD. Repeated measurements of total cholesterol, systolic blood pressure, HDL-C, and use of lipid-lowering and antihypertensive medications were incorporated as time-varying covariates. Predictive performance was assessed using discrimination, calibration, overall accuracy, and reclassification measures. RESULTS:The joint model identified significant temporal trends, including declining cholesterol (-1.14 mg/dL/year) and increasing HDL-C (0.43 mg/dL/year), while systolic blood pressure remained stable. All risk factors were independently associated with CVD risk. Compared with a conventional model based on a single baseline measurement, the joint model demonstrated improved discrimination, calibration, overall accuracy, and reclassification, with gains becoming more pronounced as longer longitudinal histories were incorporated. A web-based application was developed to support individualized dynamic CVD risk prediction. CONCLUSIONS:Incorporating longitudinal risk factor trajectories provides more accurate CVD risk estimates than conventional models. This approach improves risk stratification and may enhance clinical decision-making for preventive interventions. To our knowledge, this is among the first studies to translate joint modelling methodology into a clinically applicable CVD risk prediction tool.
Background and aims Universal screening for familial hypercholesterolaemia (FH) has been proposed; but implementation remains limited. This pilot study assesses the feasibility and efficacy of a screening based on a capillary blood test in children during a school medical visit. Additionally, we review published screening strategies and cut-off values. Methods Screening consisted of a questionnaire and capillary blood test in children aged 7-12 years. Further diagnostic work-up (fasting blood test under low-cholesterol diet and genetic analysis) was proposed if total cholesterol (TC) > 230 mg/dL (>5.9 mmol/L) and/or low-density lipoprotein cholesterol (LDL) > 160 mg/dL (>4.1 mmol/L). If FH was confirmed, the child was commenced on lipid-lowering therapy, and reverse cascade screening was performed within the family. Results 1860 children of 3733 invited children participated (49.8%). 30 refused the blood test (1.6%). Median TC was 158 mg/dL (4.1 mmol/L; Q25/75,141/174 [3.6/4.5]; P99 230 [5.9]); median LDL 74 mg/dL (1.9 mmol/L; 61/89 [1.6/2.3]; 139 [3.6]). Recall rate 1%.In the sub-cohort with LDL >160 mg/dL (>4.1 mmol/L), (n = 6): detection of three pathogenic variants and five additional affected family members, while three declined further follow-up. Conclusions FH screening based on a capillary lipid panel is an efficient screening method. However, 50% of highly suspicious cases declined further follow-up. We therefore advocate screening in the presence of parents to allow discussion of the results and explanation of further diagnostic work-up and long-term health risks. Cut-off levels should be adapted to the methodology used and re-evaluated during the course of the screening programme.
BACKGROUND AND AIMS:Clinical guidelines recommend statin intensities based on average low-density lipoprotein cholesterol (LDL-C) lowering in clinical trials, but individual response in routine care, especially among non-White patients, is not well described. We therefore aimed to quantify individual LDL-C response and variability of statins in real-world practice in Hong Kong Chinese. METHODS:This cohort study included 28,647 incident statin users (2004-2019) with or without cardiovascular diseases from Hong Kong's public healthcare system. Absolute and percentage changes in LDL-C at one year were assessed by statin type and daily dose (1-<10, 10-<20, 20-80 mg). Generalized estimating equations were used to identify predictors of individual LDL-C response in mmol/L. RESULTS:Despite a modest dose-response trend in absolute LDL-C reduction, interindividual variability was profound, from >80% reductions to >200% increases on the same statin and dose. Across all statin types and dose groups, over 30% of patients exhibited a suboptimal LDL-C response, while each group also included individuals achieving reductions of at least 50%. Greater LDL-C response was associated with more potent statin, higher statin dose, men, older age, chronic kidney disease, diabetes, and higher baseline LDL-C. CONCLUSIONS:This study demonstrates a discordance between the fixed statin intensities recommended in clinical guidelines and the high interindividual variability observed in clinical practice. While low-dose statin initiation is effective at the population level in Hong Kong, variability in LDL-C response supports personalized statin dosing and follow-up monitoring of LDL-C.
BACKGROUND AND AIMS:To evaluate the association between the atherogenic index of plasma (AIP) and cardiovascular disease (CVD) mortality, with a particular focus on young adults, individuals with low-density lipoprotein cholesterol (LDL-C) <100 mg/dL, and those with established diabetes. METHODS:We analyzed data from 8922312 adults without prior CVD or cancer in the Korean National Health Insurance Service database (2011-2012). Average AIP, calculated from repeated measurements as the base-10 logarithm of the triglyceride-to-high-density lipoprotein cholesterol ratio, was used as the exposure. The primary outcome was CVD mortality, including deaths from ischaemic heart disease (IHD), acute myocardial infarction (AMI), haemorrhagic stroke, ischaemic stroke, and heart failure. RESULTS:During a mean follow-up of 11.7 years, 83220 CVD deaths occurred. Among adults aged 18-44 years, each 0.1-unit increase in AIP was associated with higher CVD mortality in both men (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.29-1.86) and women (HR 3.00, 95% CI 1.85-4.85; both P < 0.001). Higher AIP was also independently associated with increased CVD mortality among individuals with LDL-C <100 mg/dL (HR 1.48, 95% CI 1.41-1.54) and those with diabetes (HR 2.33, 95% CI 2.18-2.48; both P < 0.001). Similar associations were consistently observed across these subgroups for IHD- and AMI-related mortality. CONCLUSIONS:Elevated AIP was independently associated with increased CVD mortality, even among young adults, individuals with well-controlled LDL-C, and those with diabetes. AIP may provide incremental value for residual cardiovascular risk stratification in primary prevention.
Hypertension is a leading risk factor for cardiovascular disease, promoting atherosclerosis through interrelated mechanisms of mechanical stress and vascular inflammation. The adventitia and perivascular adipose tissue have emerged as critical sites of immune cell accumulation and cytokine production in hypertension. This review examines the cellular and molecular mechanisms linking adventitial inflammation to vascular stiffening and end-organ damage. Hypertension induces accumulation of effector memory T cells in the adventitia and perivascular fat, driven by chemokines including RANTES/CCL5. Immune cell derived cytokines including IL-17A and IFN-γ promote endothelial dysfunction, vascular superoxide production, and adventitial collagen deposition via p38 MAP kinase activation. Chronic vascular oxidative stress generates isolevuglandin (IsoLG)-protein adducts that act as neoantigens, activating dendritic cells and T cells to drive aortic stiffening that precedes frank hypertension. Stiffened arteries impair Windkessel function and activate microvascular endothelial signaling to adjacent immune cells, further promoting an injurious response in the kidney, brain and vessels. Adventitial and perivascular inflammation are thus not merely consequences of elevated blood pressure but active drivers of vascular disease and end-organ damage through feed-forward immune mechanisms. Targeting these pathways represents a promising therapeutic strategy in hypertension-associated vascular disease.
Background Atherosclerotic plaques are complex tissues comprised of various cell types. Monocytes contribute to the growth of atherosclerotic plaques through infiltration, differentiation and accumulation. Previous studies exhibiting this behaviour have been derived from experimental animals. Here, we tracked the movement of human monocytes into live atherosclerotic plaque samples via gold labelling, using spectral photon counting computed tomography (SPCCT). Methods Monocytes isolated from human peripheral blood were incubated with gold nanoparticles for 24 h and uptake measured using microwave plasma atomic emission spectroscopy (MP-AES) and SPCCT imaging. Excised carotid plaques were sliced into 3-5 mm thick sections and incubated with the gold-labelled monocytes in tissue culture media for up to 24 h at 37°C. At selected times the plaque sections were imaged using the MARS SPCCT X-ray scanner with an energy range from 20 to 120 keV. Material identification and quantification images of the carotid plaque were generated using proprietary software at 0.09 mm3 volumetric pixels (voxels). Results Analysis of gold uptake in monocytes from MP-AES and SPCCT imaging provided comparable results, indicating uptake of 135 pg Au/cell. SPCCT imaging showed rapid movement of gold-labelled monocytes deep into the soft tissue rich regions of plaque, while excluding calcified regions. Quantitative analysis indicated an average uptake rate of 2.5 x 104 monocytes per hour. Conclusion SPCCT imaging of live atherosclerotic plaques demonstrated the dynamic environment of the tissue and the ease in which monocytes can penetrate deep into the tissue.
BACKGROUND AND AIMS:To evaluate the real-world impact of early in-hospital Proprotein Convertase Subtilisin-Kexin Type 9 (PCSK9) inhibitor initiation on clinical outcomes in Chinese acute coronary syndrome (ACS) patients. METHODS:This retrospective study analyzed ACS patients (2021-2023) from the CCA Database-Chest Pain Center, comparing alirocumab-treated (n = 6414) and control (n = 25,656) groups after propensity score matching. Outcomes included 1-year major adverse cardiovascular events (MACE) (defined as the composite of non-fatal myocardial infarction, non-fatal ischemic stroke, all-cause mortality, or any coronary revascularization) via Kaplan-Meier analysis and low-density lipoprotein cholesterol (LDL-C) goal attainment (<1.4 mmol/L) at 1/3/6 months. Logistic regression was performed to identify predictors. RESULTS:The alirocumab group showed a significantly lower MACE incidence rate during 1-year of follow-up (2.76 vs 3.95 per 100 person-years, p = 0.003). At follow-up, LDL-C measurements were available in 293, 123, and 33 patients in the alirocumab group and 1759, 984, and 424 patients in the control group at 1, 3, and 6 months, respectively. More patients in the alirocumab group reached the LDL-C goal at 1-month (58.02% vs. 24.33%, p < 0.001). This trend remained consistent during the subsequent 3-month (52.85% vs. 23.88%, p < 0.001) and 6-month follow-up (51.52% vs. 26.18%, p = 0.002). Participation in the ACS Pathway Optimization project (OR = 0.49; 95% CI 0.29, 0.77; p = 0.004), in-hospital initiation of alirocumab (OR = 0.62; 95% CI 0.48, 0.78; p < 0.001), male (OR = 0.71; 95% CI 0.58, 0.87; p < 0.001) were significantly negatively associated with the occurrence of MACE event, and in-hospital initiation of alirocumab (OR = 4.29; 95% CI 3.23, 5.71; p < 0.001), male (OR = 1.47; 95% CI 1.09, 2.00; p = 0.014), hypertension (OR = 1.31; 95% CI 1.06, 1.63; p = 0.012) and lipid lowering treatment statin and ezetimibe (OR = 2.20; 95% CI 1.58, 3.07; p < 0.001) were significantly positively associated with 1-month LDL-C goal attainment. CONCLUSION:In-hospital initiation of alirocumab was associated with a lower risk of MACE and with higher LDL-C goal attainment in China real-world ACS patients.
BACKGROUND AND AIMS:Dyslipidemia, including elevated low-density lipoprotein cholesterol (LDL-C) and decreased high-density lipoprotein cholesterol (HDL-C), is common among patients with lysosomal acid lipase deficiency (LAL-D). The aim of this analysis was to assess the lipid profile of patients with LAL-D treated with sebelipase alfa enzyme replacement therapy. METHODS:Children and adults enrolled in the International LAL-D Registry who had a confirmed diagnosis of LAL-D were treated with sebelipase alfa, and had not received lipid-modifying medications were included. The proportions of patients with lipid parameters outside the limits of normal or clinically relevant cutoffs were analyzed before first treatment (baseline) and for up to 3 years of follow-up. RESULTS:Data from 144 patients (median age at diagnosis, 9.5 years; 92% White; 54% male) were analyzed. From baseline to after 1 year of sebelipase alfa treatment, decreases were observed in the proportion of patients with LDL-C >160 mg/dL (78% to 46%), non-HDL-C >190 mg/dL (70% to 47%), and triglycerides above the upper limit of normal (63% to 32%); the proportion of patients with HDL-C at or above the lower limit of normal increased (21% to 35%). Results were sustained through 3 years of follow-up and were similar in a cohort of patients who had results for all lipid components over 3 consecutive years of treatment. CONCLUSIONS:In patients with LAL-D not receiving lipid-modifying medication, sebelipase alfa treatment improved lipid abnormalities, with sustained reductions of LDL-C and triglycerides and elevations of HDL-C.
Calcific aortic valve stenosis (AS) is the most prevalent valvular heart disease in high-income countries, affecting 9.4 million persons globally. While surgical and transcatheter aortic valve replacement have transformed outcomes, they address end-stage disease rather than the underlying pathobiology. The development of pharmacological therapies to slow or halt AS progression would represent a paradigm shift in disease management.Recent advances have substantially expanded our understanding of AS pathogenesis. Large-scale genome-wide association studies have identified over 260 risk loci, with the LPA locus confirming lipoprotein(a) as the most robustly validated genetic risk factor. Single-cell transcriptomics have revealed unexpected cellular heterogeneity and novel mechanisms including macrophage-to-mesenchymal transition. Emerging insights into metabolic reprogramming, epigenetic regulation, innate immunity and clonal hematopoiesis have identified multiple therapeutic targets.Despite these pathophysiological advances, no pharmacological therapy has yet demonstrated efficacy in adequately powered randomized trials. Statin therapy and skeletal bone metabolism-targeted agents have proven ineffective previously and multiple mechanistically diverse approaches are now under investigation. The most promising developments center on lipoprotein(a) reduction with antisense oligonucleotides, with the first dedicated AS trial ongoing. Additional strategies include PCSK9 inhibition, supplementation of omega-3 fatty acids, treatment with colchicine, soluble guanylate cyclase activation with ataciguat, and DPP-4 inhibition. Success in any of these trials would represent the first disease-modifying therapy for AS, with potential to delay valve replacement, preserve myocardial function, and improve outcomes for millions of patients worldwide.
Background The aryl hydrocarbon receptor (AhR) is a well-described regulator of xenobiotic stimuli, but recent studies highlight a potential bidirectional role in mediating lipid metabolism. The precise mechanisms underlying these effects are not yet fully understood. Therefore, this study aimed to investigate the impact of a genetic aberration in the AhR in hepatocytes and intestinal epithelial cells on lipid metabolism and the development of atherosclerosis. Methods By injecting Albumin-iCre containing AAVs into PCSK9 overexpressing Ahrfl/fl mice, hepatocyte-specific Ahr-deficient mice were created. Additionally, mice with an intestinal epithelial cell-specific deficiency of the Ahr (Ahrfl/fl VillinCre+) and control mice (Ahrfl/fl) were injected with AAV8-PCSK9. Both mouse models were fed a high-fat diet (HFD) for 12 weeks, after which alterations in plasma lipid levels and the development of atherosclerosis were assessed. Findings Mice lacking hepatocyte-specific Ahr did not exhibit significant differences in lipid levels or atherosclerosis. In contrast, male mice lacking Ahr in intestinal epithelial cells (IECs) showed significant changes in intestinal and systemic lipid levels, which coincided with altered RNA transcription and intestinal kinase activity, whereas female mice were unaffected. Interestingly, female mice showed reduced circulating leukocyte counts, whereas males were unaffected. Combined, these alterations resulted in decreased atherosclerosis development in both sexes. Interpretation This study reveals a major impact of intestinal epithelial cell-specific Ahr on lipid metabolism, with effects on atherosclerosis development, particularly in male mice, whereas atherosclerosis development in female intestinal epithelial cell-specific Ahr-deficient mice is accompanied by reduced circulating leukocytes, thereby suggesting apparent sex dimorphism.
BACKGROUND AND AIMS:Vitamin K is essential for processes that inhibit vascular and valvular calcification, attributes of atherosclerotic cardiovascular diseases (ASCVDs) and aortic stenosis (AS). Relationships between dietary vitamin K1 and K2 intakes, ASCVD and AS were explored. METHODS:In 112,111 participants from the UK Biobank without ASCVD or AS (median age 59.7 years, 57.3% female), dietary vitamin K1 (μg/day) and K2 (μgPKeq/day) intakes were calculated from Oxford WebQ 24-h dietary questionnaires, using vitamin K food composition databases. Associations with incident ASCVD, ASCVD subtypes and AS, obtained from self-reports, primary care data, hospital records and death registries, were examined using restricted cubic splines within multivariable-adjusted Cox proportional hazards models. RESULTS:Over a median follow-up of 10.5 years, 8696 ASCVD cases were recorded. Non-linear associations between vitamin K1 intakes and ASCVD were observed within multivariable-adjusted models (pnon-linearity≤0.01). Higher vitamin K1 intakes were associated with a 7-10% lower risk of ASCVD, with no advantage observed beyond moderate intakes (HRQ3vsQ1 0.90 [0.85-0.95]). Lower risk relationships were also found for ischemic heart disease (IHD), ischemic stroke and peripheral arterial disease but not AS. The highest vitamin K2 intakes were associated with a greater risk of incident ASCVD (HRQ5vsQ1 1.07 [1.01-1.14]), IHD and AS. CONCLUSIONS:Among adults without prevalent ASCVD, those with higher dietary vitamin K1, but not K2, intakes had lower ASCVD risk. Positive associations with vitamin K2 may reflect food source confounding warranting further investigation. These findings reinforce the promotion of vitamin K1-rich vegetable consumption (e.g. spinach and broccoli) to support cardiovascular health.
