Introduction:Stroke is a leading cause of morbidity and mortality in Saudi Arabia, with its incidence projected to double by 2030. Diabetes and smoking are major modifiable risk factors. This study assessed their association with stroke type and mortality in a tertiary stroke unit. Methods:We conducted a retrospective review of 336 adults admitted with acute ischemic or hemorrhagic stroke at King Fahad Hospital, Al Ahsa, between January 2023 and December 2024. Demographic characteristics, risk factors, stroke type, and mortality were analyzed using descriptive statistics and multivariable logistic regression. Results:Among 336 patients, 83.9% were younger than 65 years, 66.4% were male, and 86.6% had ischemic stroke. Overall mortality was 4.2%. Diabetes was present in 56.3% of patients, smoking in 21.4%, and both risk factors in 11.3%. Older age (>65 years) was independently associated with hemorrhagic stroke [odds ratio (OR) = 2.29, P = 0.041] and mortality (OR = 4.77, P = 0.013). Non-Saudi nationality was associated with higher odds of hemorrhagic stroke (OR = 2.52, P = 0.014) and mortality (OR = 9.64, P = 0.001). Diabetes independently increased mortality risk (OR = 5.49, P = 0.037). Smoking was not significantly associated with mortality because no deaths occurred among smokers. Conclusion:Ischemic stroke predominated, and mortality was independently associated with older age, non-Saudi nationality, and diabetes. Given the low number of deaths and limited adjustment for confounders, these findings should be interpreted cautiously and validated in larger multicenter setudies.
Metabolic syndrome (MetS) and cardiovascular-kidney-metabolic syndrome represent escalating global health challenges characterized by complex lipid derangements. While traditional lipid panels are standard, the atherogenic index of plasma (AIP) has emerged as a potentially superior marker for capturing the presence of small, dense low-density lipoprotein particles and overall cardiovascular risk. This systematic review evaluates the prognostic value and longitudinal risk prediction of AIP in patients with MetS and related metabolic disorders. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic search was conducted across PubMed/MEDLINE, Scopus, Embase, and Web of Science through January 2026. Nine high-quality studies encompassing 197 279 patients were identified. Synthesis of the evidence consistently demonstrates that elevated baseline AIP is consistently and independently associated with major adverse cardiovascular events (hazard ratio: 1.07-1.19), acute myocardial infarction, and cardiovascular death. Longitudinal data reveal that cumulative AIP exposure significantly increases stroke risk (hazard ratio: 2.49) and coronary heart disease. Notably, in patients with diabetic kidney disease, a nonlinear 'U-shaped' association was identified, with a critical inflection point at 0.14, suggesting that both excessively high and low AIP levels correlate with increased mortality. AIP is an accessible and promising biomarker that warrants further comparative validation in predicting long-term cardiometabolic progression. These findings support further evaluation of AIP's role in clinical risk stratification, pending prospective validation and establishment of standardized thresholds across population subgroups.
Cardiovascular outcome trials suggest that glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events in individuals with type 2 diabetes (T2DM), but the magnitude of benefit, including recent evidence from the landmark SOUL trial and oral formulations, remains uncertain. We performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (International Prospective Register of Systematic Reviews ID: CRD420251034652), searching PubMed, Embase, Cochrane CENTRAL, Scopus and ClinicalTrials.gov on 6 May 2025 for randomised controlled trials comparing GLP-1RAs with placebo or usual care in adults with T2DM and established atherosclerotic cardiovascular disease. Seven trials, including 56 191 participants (mean follow-up: 3.5 years), were analysed. GLP-1RAs reduced major adverse cardiovascular events by 11% [hazard ratio: 0.89, 95% confidence interval (CI): 0.83-0.96], all-cause mortality by 11% (hazard ratio: 0.89, 95% CI: 0.82-0.97) and hospitalisation for heart failure by 7% (hazard ratio: 0.93, 95% CI: 0.89-0.98), all with high-certainty evidence. Overall, GLP-1RAs - available in subcutaneous and oral formulations - provide clinically meaningful cardiovascular benefits in high-risk adults with T2DM.
Background:Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular and cardiorenal events in people across the spectrum of heart failure. Using proteomics analysis, this study investigated the potential benefits of SGLT2 inhibitors in primary prevention at a protein level in patients without diabetes or heart failure. Methods:This is a sub-study of the EMPA-HEART 2 CardioLink-7 trial, which randomized people without diabetes or clinically overt heart failure but with risk factors for adverse cardiac remodeling to empagliflozin (10 mg/day) or placebo for 6 months. Blood samples were collected during the randomization visit and at the 6-month follow-up visit for proteomics analysis. Our investigation involved two phases of approach: discovery and verification. Results:Samples from individuals assigned to empagliflozin (n = 21) and placebo (n = 22) (median baseline N-terminal pro-B-type natriuretic peptide levels: 33.9 and 78.4 pg/ml, respectively) were analyzed. In the discovery phase, 28 of 1622 proteins fulfilled our threshold for being differentially expressed at 6 months. Ten proteins were verified, including calmodulin-like protein 5, desmoplakin, hornerin, peroxiredoxin-2, macrophage colony-stimulating factor 1 receptor, endosialin, high-temperature requirement serine protease A1, immunoglobulin epsilon heavy chain, proteasome subunit beta type-5, and cerebellin-4. Compared to the placebo group, the expression of these proteins from baseline to 6 months was all significantly decreased in the empagliflozin group. Their functions involved ion channel signaling, fibrosis, oxidative stress, inflammation, apoptosis, immune response, proteolysis, and neuromodulation. Conclusion:Empagliflozin modified multiple biologically relevant pathways in the nondiabetes and non-heart failure setting. These findings should be considered hypothesis-generating and warrant validation in larger, adequately powered studies.
BACKGROUND:Hypertrophic cardiomyopathy (HCM) is characterized by substantial heterogeneity in both clinical phenotype and risk of adverse outcomes, including heart failure and sudden cardiac death. This highlights the need for robust biomarkers for risk stratification, and while previous studies have identified the role of select plasma proteins, comprehensive large-scale proteomic analyses have been limited in HCM.METHODS:We performed a case-control analysis of 2922 plasma proteins in 49 588 UK Biobank participants (100 HCM cases) to identify proteins associated with HCM. External replication analyses were performed in the deCODE Genetics Icelandic study (51 cases/38 904 controls) and All of Us (546 cases/41 049 controls) data sets. Associations with adverse clinical outcomes and cardiac endophenotypes of disease severity were further identified, and causal relationships were evaluated using Mendelian randomization. Relative biomarker importance was also assessed by joint modeling via machine learning.RESULTS:We identified novel associations of ANGPT2 (angiopoietin-2) and LTBP2 (latent transforming growth factor-beta binding protein 2) with HCM, with both also showing prognostic utility for heart failure-related outcomes in HCM cases. We also confirmed the associations of established biomarkers (eg, NT-proBNP [N-terminal pro-B-type natriuretic peptide], troponins I and T) with HCM cases, cardiac imaging markers of disease severity, and adverse outcomes. Mendelian randomization analyses supported a causal effect of HCM on increasing NT-proBNP and troponin T levels.CONCLUSIONS:This biobank-scale plasma proteomic study in HCM identified ANGPT2 and LTBP2 as novel HCM biomarkers with potential diagnostic and prognostic utility. These findings highlight the potential for plasma proteomics to improve risk prediction and provide insight into HCM pathobiology.
BACKGROUND:Lymphedema is a chronic condition characterized by the accumulation of fluid due to impaired lymphatic drainage, frequently occurring secondary to chronic venous insufficiency (CVI), malignancy, or obesity. Despite known environmental and clinical risk factors, the genetic contributors to lymphedema and CVI have been understudied. METHODS:We conducted a multipopulation genome-wide association study in participants of the Million Veteran Program without cancer to identify genetic variants associated with CVI, lymphedema, and their cooccurrence. Individuals were categorized into 3 case groups: CVI only (n=34 664), lymphedema only (n=2452), and lymphedema+CVI (n=3283) and were compared with 367 684 controls. RESULTS:We identified 11 genome-wide significant variants (P<5×10-8) in the multipopulation analysis, including 8 for CVI only, 1 for lymphedema only, and 2 for lymphedema+CVI, and 2 population-specific genetic variants. Three independent variants replicated in the UK Biobank for CVI only near CASZ1, SLC12A2, and NDP. Polygenic risk scores derived from the Million Veteran Program were associated with CVI in the UK Biobank and phenome-wide associations of CVI-associated variants revealed pleiotropic associations with cardiometabolic traits. CONCLUSIONS:These findings enhance our understanding of the genetic architecture of lymphatic dysfunction.
Background Cardiovascular disease (CVD) is the predominant cause of morbidity and mortality among patients with type 1 or type 2 diabetes. The association between hyperglycemia and intracellular metabolic changes can result in oxidative stress, low-grade inflammation, and endothelial dysfunction. The management of hyperglycemia and prediabetes-associated vascular complications rely on pharmacotherapy and lifestyle intervention strategies. Research investigated the cardio-protective effects of Momordica balsamina in a diet-induced prediabetic rats. Materials and methods Prediabetes was induced using a laboratory established protocol in male Sprague Dawley rats. Thereafter, M. balsamina (250 mg/kg) was administered to prediabetic rats once a day every third day in the presence or absence of dietary intervention. Blood pressure and plasma glucose concentration were monitored throughout the study. Blood and tissue were collected for biochemical analysis. Results M. balsamina with or without dietary intervention resulted into a reduction in mean arterial blood pressure. In addition, there was a significant decrease in the heart tissue malondialdehyde and increased plasma superoxide dismutase and glutathione peroxidase concentration. Furthermore, there was a decrease in plasma triglycerides, low-density lipoprotein with an increased high-density lipoprotein concentration Lastly, M. balsamina with or without dietary intervention demonstrated a reduced plasma tumor necrosis factor alpha and reduced interleukin-6 concentrations in the absence of dietary intervention. Conclusion M. balsamina coupled with or without dietary intervention decreased the risk of developing cardiac injury, thus preventing cardiovascular disease in prediabetes. Therefore, this medicinal plant may be a beneficial therapeutic agent in the prevention of prediabetic cardiovascular complications.
BACKGROUND:Arrhythmogenic cardiomyopathy is an inherited disorder characterized by fibro-fatty myocardial replacement and ventricular arrhythmias. Although desmosomal mutations such as desmoglein-2 (DSG2) are well-established causes, the pathogenic mechanisms of specific missense variants remain incompletely defined. METHODS:We generated a physiologically relevant Dsg2F536C/F536C knock-in mouse model using CRISPR/Cas9 to mimic the human DSG2 p.Phe531Cys mutation. Comprehensive phenotyping included histopathology, immunostaining, transcriptomic profiling, in vitro cardiomyocyte and fibroblast assays, in vivo imaging and ECG analysis, and ex vivo optical mapping. Therapeutic potential was assessed using the PPAR-γ (peroxisome proliferator-activated receptor gamma) antagonist GW9662. RESULTS:Dsg2F536C/F536C mice developed progressive cardiac hypertrophy, interstitial fibrosis, lipid accumulation, and inducible ventricular arrhythmias following isoproterenol infusion and programmed electrical stimulation. These changes led to severe cardiac dysfunction and reduced survival. Mechanistically, the mutation caused reduced DSG2 and nuclear accumulation of β-catenin and PPAR-γ, promoting triacylglycerol biosynthesis, oxidative stress, cardiomyocyte death, and calcium-handling abnormalities. We also identified activation of epicardial epithelial-to-mesenchymal transition and paracrine fibroblast activation via IL-6 (interleukin-6) and PDGF-BB (platelet-derived growth factor-BB) as key contributors to fibrotic remodeling. Optical mapping revealed prolonged and heterogeneous action potential duration, with both reentrant and focal ectopic mechanisms of ventricular tachycardia. Treatment with GW9662 attenuated lipid accumulation, fibrosis, reactive oxygen species production, and arrhythmogenic susceptibility. CONCLUSIONS:The Dsg2F536C/F536C knock-in mouse is a genotype-specific arrhythmogenic cardiomyopathy model that links desmosomal dysfunction to metabolic remodeling, epicardial epithelial-to-mesenchymal transition, and electrophysiological instability. PPAR-γ inhibition ameliorated structural and arrhythmogenic remodeling, supporting PPAR-γ as a potential therapeutic target and advancing precision strategies for desmosome-related cardiomyopathies.
BACKGROUND:Sudden arrhythmic death syndrome (SADS) refers to sudden cardiac death with structurally normal hearts at autopsy, most frequently attributed to inherited arrhythmia syndromes or concealed cardiomyopathies. Postmortem genetic testing may help identify underlying genetic causes. We aimed to investigate the yield of postmortem genetic testing in SADS cases by determining the prevalence of pathogenic or likely pathogenic variants in channelopathy- and cardiomyopathy-associated genes in autopsy-negative SADS victims. METHODS:This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered in PROSPERO (REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD420251067244). PubMed and Embase were searched on June 4, 2025, for observational studies including individuals aged 1 to 50 years with SADS and negative or nonspecific findings at autopsy. Eligible studies reported postmortem genetic testing for channelopathy and cardiomyopathy genes. Pathogenic or likely pathogenic variant classification followed American College of Medical Genetics and Genomics criteria and ClinGen gene-disease associations. Pooled prevalence was estimated using random-effects models. RESULTS:A total of 45 studies involving 2498 SADS cases were included. Among 1697 SADS victims tested for both channelopathy and cardiomyopathy genes (33 studies), the pooled prevalence of pathogenic or likely pathogenic variants was 11.1% (95% CI, 4.1%-26.6%, I2=50.7%). Testing for cardiomyopathy genes (33 studies, 1697 cases) and for channelopathy genes (42 studies, 2354 cases) yielded a prevalence of 7.0% (95% CI, 1.9%-22.9%, I2=51.9%) and 6.3% (95% CI, 2.0%-18.4%, I2=49.8%), respectively. The most frequently involved genes encoded sarcomeric proteins and ion channels, with TTN, MYBPC3, MYH7, KCNH2, and SCN5A among the most commonly affected. CONCLUSIONS:Postmortem genetic testing identifies pathogenic or likely pathogenic variants in a significant subset of SADS cases, supporting its utility in postmortem evaluation.
BACKGROUND:Hypertrophic cardiomyopathy (HCM) arises from genetic mutations in sarcomere proteins, resulting in major structural abnormalities and limited treatment options. Patients with HCM had reduced expression of the FGF12 (fibroblast growth factor 12), but its precise functional role remains unclear. METHODS:To explore FGF12's function and interactions, we utilized clustered regularly interspaced short palindromic repeats-Cas9 technology in cardiomyocytes derived from human induced pluripotent stem cells-induced cardiomyocytes, as well as in other cell lines and mouse models (MYH7R403Q/+, MYBPC3c790GtoA/c790GtoA, and transverse aortic constriction models). We transfected HCM or mice model with FGF12-coding sequence and FGF12-ΔNLS plasmids or adeno-associated virus 9 vectors to reduce myocardial hypertrophy. As hypertrophy progressed, we used cleavage under targets and tagmentation) sequencing and AlphaFold3 on myocardial tissues from patients and induced pluripotent stem cells-induced cardiomyocytes. To predict mitochondrial function in cardiomyocytes, we measured mitochondrial Ca2+ concentrations and reactive oxygen species content. RESULTS:First, we observed a decrease in FGF12 expression and a difference in its subcellular localization in patients with HCM compared with healthy volunteers. In hypertrophic mouse models, injecting adeno-associated virus 9 reduced myocardial hypertrophy. FGF12 binds to calmodulin and inhibits its phosphorylation. This interaction also suppresses the expression and phosphorylation of downstream proteins, including CaMKII, ERK1/2, CREB1, and MCU. The nuclear-localization FGF12 binds to the promoter region of CREB1. FGF12 inhibits the expression of the CREB1-MCU axis expression, leading to reductions in both mitochondrial Ca2+ concentration and mitochondrial reactive oxygen species. CONCLUSIONS:This study reveals a pathological mechanism associated with HCM linked to FGF12. FGF12, located outside the nucleus, suppresses the expression of metabolism-related genes by reducing the phosphorylation levels within the calmodulin-ERK1/2-CREB1-MCU axis. In contrast, the nuclear localization of FGF12 facilitates its binding to the promoter regions of CREB1, inhibiting CREB1 expression. This dual action maintains cardiomyocyte function and mitochondrial homeostasis. Our findings position FGF12 as a promising therapeutic target for HCM.
BACKGROUND:Current genetic testing for coronary artery disease (CAD) primarily targets monogenic variants in individuals with severe hypercholesterolemia. Whether supplementing monogenic testing with polygenic risk scores for CAD and Lp(a; lipoprotein[a]) levels [PRSLp(a)] improves identification of high-risk individuals in the general population remains understudied. METHODS:A genetic probability for CAD (GenProbCAD), incorporating monogenic pathogenic variants (PVs), polygenic risk scores for CAD, and PRSLp(a) was developed using Cox regression in 226 145 UK Biobank participants, validated in the remaining 226 145 UK Biobank participants, and applied to 20 477 participants of the Genomic Health Initiative, a community-based health care biobank. Predictive performance was evaluated and adjusted for clinical risk factors. RESULTS:In the UK Biobank development cohort, PVs, polygenic risk scores for CAD and PRSLp(a) were each independently associated with CAD. In the UK Biobank validation cohort, GenProbCAD outperformed PVs and the polygenic risk score in predicting CAD and reclassified risk among PV carriers. GenProbCAD identified 16% of participants as high risk, 46-fold more than PV carriers (0.35%), with comparable observed CAD prevalence (15.60% versus 15.43%). Nearly 50% of CAD with high-risk GenProbCAD were premature. GenProbCAD also independently predicted incident CAD after adjusting for clinical risk factors. Importantly, high-risk individuals defined by GenProbCAD showed consistently elevated CAD incidence across all low-density lipoprotein cholesterol strata. When UK Biobank-derived coefficients and cutoffs were applied in the Genomic Health Initiative, GenProbCAD substantially outperformed the PV-only strategy, identifying 1966 high-risk participants (345 developed CAD), far exceeding the 20 PV carriers detected among those with low-density lipoprotein cholesterol ≥190 mg/dL (5 developed CAD). A universal genetic testing strategy using GenProbCAD would hypothetically identify 20.75% of all incident CAD, 69-fold higher than current monogenic testing (0.3%). Results were generally consistent across ancestry populations, although the sample size of non-European participants was limited. CONCLUSIONS:GenProbCAD, a novel integrated genetic risk tool combining monogenic PVs, polygenic risk scores for CAD, and PRSLp(a), improves identification of individuals at high genetic risk for CAD across diverse populations.
BACKGROUND: International guidelines suggest prophylactic anticoagulation for patients with cancer at high risk of venous thromboembolism (VTE). Here, we evaluated whether tumor whole-genome sequencing data may improve the selection of high-risk patients. METHODS: In a pan-cancer cohort of 3087 patients, associations of candidate clinical predictors, the germline extended 297-single nucleotide polymorphism polygenic risk score, tumor mutational characteristics, and somatic tumor mutations with VTE were estimated by calculating hazard ratios (HRs). RESULTS: During 12-month follow-up, 237 (7.7%) developed VTE. The germline extended 297-single nucleotide polymorphism score was associated with VTE (HR per point increase, 2.11 [95% CI, 1.45-3.06]), as well as the total number of somatic structural variants (HR per 1000 increase, 1.21 [95% CI, 1.07-1.37]) and 129 somatic mutations (unadjusted P<0.05), including POLR2E (HR, 3.34 [95% CI, 1.68-6.97]), PALM (HR, 3.73 [95% CI, 1.74-7.99]), TBX22 (T-box Transcription Factor 22; HR, 2.47 [95% CI, 1.40-4.35]), and ELANE (HR, 3.22 [95% CI, 1.51-6.87]). To further explore the potential of tumor whole-genome sequencing, prediction models were constructed including selected clinical predictors only (model 1), clinical predictors and germline variants (model 2), and the combination of clinical predictors, germline variants, and 14 top discriminating somatic mutations (model 3). The optimism corrected concordance index was 0.66 (95% CI, 0.62-0.69) for model 1, 0.67 (95% CI, 0.62-0.72) for model 2, and 0.77 (95% CI, 0.72-0.81) for model 3. This was significantly higher than that of the currently endorsed clinical Khorana VTE risk score (concordance index, 0.55 [95% CI, 0.51-0.59]; P<0.005). CONCLUSIONS: These data indicate that tumor whole-genome sequencing may improve VTE prediction by clinical risk scores. Validation studies to confirm these findings are needed.
BACKGROUND:TMEM43 (transmembrane protein 43) is a ubiquitously expressed 4-transmembrane-protein localized in the endoplasmic reticulum and nuclear lamina. The missense mutation TMEM43-p.S358L causes fully penetrant ARVC5 (arrhythmogenic right ventricular cardiomyopathy type 5) especially in males. The TMEM43 function of the protein and the pathomechanisms of TMEM43-p.S358L remain poorly understood. We analyzed carrier-derived human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), human myocardial tissue from TMEM43-wild-type, and TMEM43-p.S358L and identified differentially interacting proteins. Here we provide evidence for a novel pathomechanism contributing to the onset of ARVC5. METHODS:Microsomes of human wild-type myocardium were separated by sucrose-gradient ultracentrifugation and characterized by mass-spectrometry to identify potential interacting proteins. Proteome and metabolome analyses of a TMEM43-p.S358L explanted human myocardium were performed. hiPSC-derived cardiomyocytes of TMEM43-p.S358L carrier and a corresponding isogenic control were generated. A 3'-end HA-Tag was introduced in TMEM43 for pull-down experiments under optimized conditions. Lipidomics, proteomics, contractility, and ATP-content were measured in hiPSC-CMs. RESULTS:Pull-down analyses of TMEM43-WT and mutant showed altered interacting proteins involved in metabolic pathways. Lipidomics revealed the accumulation of lipids and decreased lipid metabolism capacity in mutant hiPSC-CMs. The ATP to ADP ratio was lower in mutant hiPSC-CMs and could be associated with diminished contraction frequency. The human TMEM43-p.S358L myocardial proteome revealed altered protein-expression of metabolic pathways comparable to mutant hiPSC-CMs. Metabolic remodeling was also found in the mutant human myocardium. Ultracentrifugation fraction with the highest protein amount of TMEM43 and pull-down experiments of hiPSC-CMs revealed differentially interacting proteins of TMEM43-p.S358L from endoplasmic reticulum and mitochondrial membranes. CONCLUSIONS:We suggest differential interaction of mutant TMEM43 with proteins of mitochondria and endoplasmic reticulum influences endoplasmic reticulum-mitochondrial contact sites. TMEM43-p.S358L primarily contributes to changes in mitochondrial function affecting lipid homeostasis and energy supply.
BACKGROUND:The coronary microvasculature is crucial for proper cardiac function, and coronary microvascular disease (CMVD) has emerged as an underdiagnosed and undertreated cause of ischemic heart disease. FOG2 (friend of GATA 2) is a transcriptional co-regulator crucial for coronary development and the maintenance of the coronary microvasculature in adult mice. Little is known about the role of FOG2 in humans or its role in CMVD. Here, we report a genotype-first approach to determine the role of FOG2 in human CMVD.METHODS:We performed phenome-wide association studies and deep cardiac phenotyping through the Electronic Health Record in individuals with FOG2 coding variants. We interrogated MagNET heart tissue data to identify genes and pathways associated with rs28374544. We then overexpressed FOG2S657G in a cardiomyocyte cell line and assessed the effects on cardiac metabolism and paracrine angiogenic signaling.RESULTS:We identified an association between rs28374544 (A1969G, p.S657G) and CMVD. Using phenome-wide association studies and deep cardiac phenotyping through the Electronic Health Record in individuals with FOG2 coding variants, we identified an association between rs28374544 (A1969G, p.S657G) and CMVD. Individuals carrying the S657G variant, almost all of African ancestry, had increased chest pain, a smaller burden of obstructive coronary artery disease, and altered coronary blood flow. Differential gene and pathway analysis using several genomic data sets showed that carriers of S657G have increased expression of genes involved in angiogenesis, glycolysis, and the HIF (hypoxia-inducible factor) pathway. In vitro functional studies show that compared with the FOG2 wild-type protein, the FOG2S657G variant protein promotes angiogenic gene expression and angiogenesis while decreasing oxygen consumption rate.CONCLUSIONS:A common functional coding variant in FOG2, S657G, is associated with CMVD in humans. Altered angiogenic gene expression, regulated in part by FOG2, may contribute to CMVD.
Background and aims Lower limb vascular diseases significantly impact patient quality of life, with emerging evidence suggesting a potential link between serum uric acid levels and these conditions. This research aimed to explore the causal link between serum uric acid levels and the risk of lower limb vascular diseases utilizing a Mendelian randomization method. Methods and results We used aggregated data from genome-wide association studies to pinpoint single-nucleotide polymorphisms associated with serum uric acid levels. Our analysis revealed that genetically predicted elevated serum uric acid levels increased the risk of lower limb atherosclerosis (odds ratio = 1.341, 95% confidence interval: 1.119-1.607, P = 0.002) while reducing the incidence of lower limb varicose veins (odds ratio = 0.996, 95% confidence interval: 0.993-0.999, P = 0.023). No significant associations were found for deep vein thrombosis, phlebitis, or artery embolism. Conclusion This study provides genetic evidence indicating that elevated serum uric acid levels may contribute to the risk of lower limb atherosclerosis while potentially protecting against lower limb varicose veins, highlighting the complex role of uric acid in lower limb vascular health.
Introduction A proportion of adrenal adenomata exhibit autonomous cortisol secretion, now termed mild autonomous cortisol secretion (MACS), as defined by post-1mg overnight dexamethasone suppression test (ONDST) cortisol 51-137 nmol/l. Here, we characterized the cardiometabolic profile of MACS. Methods Clinical records of 98 individuals with adrenal adenomata were examined. Subcategorization into MACS1 (ONDST cortisol of 50-137 nmol/l) and MACS2 (ONDST cortisol of >137 nmol/l was created to take account of individuals with ONDST cortisol of more than 137 nmol/l and no diagnosis of Cushing's syndrome. Results Diagnosis of MACS1 associated with a higher diagnosis rate of cardiovascular disease (CVD) (17.7% MACS1) vs. non-MACS = nonfunctioning adenoma (NFA) (3.7%) (P = 0.009) and higher rates of prescription of lipid-lowering agents (51.6%) vs. (29.6%) (P = 0.01). ONDST cortisol levels in MACS1 patients correlated with a more adverse lipid profile (for higher low-density lipoprotein cholesterol, r(2) = 0.404, P = 0.007; high-density lipoprotein cholesterol r(2) = -0.346, P = 0.023; for higher serum triglycerides r(2) = 0.282, P = 0.02) in spite of higher rates of statin prescribing. There was a gradient of increasing numbers of antihypertensives prescribed, going from non-MACS NFA to MACS1 to MACS2. Dunn's post hoc analysis indicated an overall more adverse lipid profile in MACS1. Conclusion The positive direction of associations between serum cortisol and lipid measures highlights that MACS carries a metabolically adverse lipid profile. Diagnosis of MACS was associated with a higher diagnosis rate of CVD and appropriately higher rates of prescription of lipid-lowering agents and a greater number of antihypertensive agents prescribed. The question remains about whether a specific directed treatment of MACS should be offered beyond risk-factor-mitigating management.
BACKGROUND:Coronary artery disease (CAD) is a major contributor to cardiovascular morbidity (including myocardial infarction and heart failure) and mortality. Although the burden of CAD (number and degree of coronary artery stenosis) has been observationally linked to these outcomes, the causal contribution and independence from traditional cardiovascular risk factors have been poorly defined. METHODS:We developed a polygenic risk score for angiographic CAD burden using data from the VA Million Veteran Program (n=41 507) and validated this score using data from the Penn Medicine Biobank (n=41 660 with genotyping, N=3771 with angiogram data). We then used publicly available GWAS data and a mediation framework using Mendelian Randomization to investigate whether angiographic CAD burden contributes to adverse cardiovascular outcomes independent of traditional risk factors. RESULTS:We first demonstrated that increasing levels of the polygenic risk score were strongly associated with increased prevalence of nonobstructive and obstructive CAD on coronary angiography (odds ratio, 1.26 [95% CI, 1.14-1.39]; odds ratio, 2.23 [95% CI, 1.94-2.55], respectively) and was associated with other forms of cardiometabolic disease including peripheral artery disease and atherosclerotic risk factors including hyperlipidemia, hypercholesterolemia and hypertension. Through Mendelian randomization analyses, we found that lipid measures (apolipoprotein B, high-density lipoprotein, low-density lipoprotein, total cholesterol, triglycerides) and type 2 diabetes significantly influenced myocardial infarction risk through their effects on angiographic CAD burden. Furthermore, low-density lipoprotein and total cholesterol demonstrated significant indirect effects on heart failure through angiographic CAD burden, suggesting these lipids primarily influence heart failure through their impact on coronary atherosclerosis. CONCLUSIONS:Our findings indicate that angiographic burden of coronary atherosclerosis mediates a substantial proportion of the relationship between traditional cardiovascular risk factors and adverse outcomes. These results support prioritizing primary prevention efforts targeting modifiable risk factors to prevent the development and progression of coronary plaques before clinical disease manifestation.
BACKGROUND:Atrial septal defects (ASDs) are a prevalent type of congenital heart disease. Previous GWAS (Genome-Wide Association Studies) have identified common variants associated with ASDs, though their mechanisms remain unknown. We aimed to expand insights into the architecture of common variants associated with ASD risk and elucidate functional mechanisms.METHODS:We conducted a GWAS using isolated ASD cases and healthy controls and replicated findings in an independent cohort. We examined epigenetic marks within this ASD locus in human induced pluripotent stem cell-derived cardiomyocytes and fetal human hearts. We characterized the consequences of deletions introduced by CRISPR-Cas9 mutagenesis of human induced pluripotent stem cells to assess the effect on downstream gene expression. In addition, we investigated the 3-dimensional genome architecture of the locus using chromosome conformation capture sequencing.RESULTS:We identified a novel ASD locus on chromosome 3p12.3 encompassing the ROBO2 gene, which encodes the Roundabout guidance receptor 2 for Slit ligands. This locus includes 15 common single nucleotide polymorphisms, an enhancer, and a CCCTC-binding factor (CTCF)-binding site. Deletions of varying lengths within the ASD-associated locus in human induced pluripotent stem cell-derived cardiomyocytes reduced ROBO2 expression and dysregulated the expression of extracellular matrix genes. Chromosome conformation capture sequencing indicated that this region physically interacts with the ROBO2 promoter and demonstrates that the CTCF-binding site is essential for this contact.CONCLUSIONS:Novel common single nucleotide polymorphisms in regulatory elements controlling ROBO2 transcription contribute to risk for ASDs. These data infer key roles for the Roundabout guidance receptor 2 and Slit ligands in embryogenic development and maturation of the atrial septa.
BACKGROUND:Genetic variation affects clinical outcomes, prognosis, and family planning decisions in individuals with congenital heart disease (CHD). While genetic testing recommendations for infants and children with CHD have expanded, similar broad guidelines are lacking for patients with adult CHD (ACHD). Here, we investigated the current state of genetic testing in patients with ACHD and their perceptions toward testing, which has not been previously reported. METHODS:A single-center prospective cohort survey of patients with ACHD aged ≥18 years was evaluated in a large ACHD clinic over a 12-month period. RESULTS:Among 336 survey respondents (median age, 29 years; 52% male), CHD lesions were wide ranging, albeit largely represented by conotruncal (35%) or left ventricular outflow tract (35%) lesions. Most patients did not have children (64%) or a family history of CHD (79%). Thirteen percent had evidence of prior genetic testing despite 41% to 98% meeting criteria by current pediatric recommendations. Most desired genetic testing (68%) though interest varied by sex, education level, and family status. Individual and family health factors were reported as the most influential considerations for genetic testing. CONCLUSIONS:Few patients with ACHD have had genetic testing despite most being eligible based on current pediatric guidelines, likely related to birth era. Patients were interested in genetic testing though demographic factors and family status affected interest. The lack of broad recommendations for genetic testing in the ACHD population likely represents a significant barrier to increased utilization of genetic tests.
BACKGROUND:PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition is a potent cholesterol-lowering strategy. This study examined the effects of PCSK9 monoclonal antibodies (mAbs) and high-intensity statins beyond low-density lipoprotein cholesterol reduction, which are not fully defined, particularly in patients with acute myocardial infarction (MI). METHODS:Proteomic and lipidomic analyses were conducted on plasma from 265 patients with acute MI from the PACMAN-AMI (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction) randomized, placebo-controlled PCSK9 mAb trial and 34 patients without MI with hyperlipidemia from the Vienna Lipid Clinic registry, also receiving PCSK9 mAbs. RESULTS:Discovery proteomics revealed changes in apolipoproteins and increased PCOLCE (procollagen C-endopeptidase enhancer 1) levels in both the PCSK9 mAb and placebo groups after MI. UK Biobank data confirmed PCOLCE and PCSK9 upregulation as associated with statin use. Hepatoma cell experiments demonstrated a dose-dependent PCOLCE induction on statin treatment. Compared with placebo (statins only), PCSK9 mAb therapy resulted in greater reductions in APOB (apolipoprotein B), APOE (apolipoprotein E), APOC2 (apolipoprotein C2), and APOC3 (apolipoprotein C3), as shown by targeted proteomics. Mediation analysis indicated that these changes were largely explained by low-density lipoprotein cholesterol lowering. Lipidomics identified more pronounced reductions in cholesteryl esters, ceramides, sphingomyelins, phosphatidylcholines, triglycerides, and diglycerides in PCSK9 mAb-treated patients with MI. Results were largely consistent in patients without MI. However, levels of LPA (apolipoprotein[a]), the characteristic protein component of lipoprotein(a), remained unchanged in PCSK9 mAb-treated patients with MI, since a rise of LPA was observed in the placebo group post-MI. CONCLUSIONS:Most apolipoprotein changes after PCSK9 mAb therapy following MI were mediated by low-density lipoprotein cholesterol lowering. Statin use is associated with increased circulating PCOLCE, with hepatoma cell experiments supporting a predominant hepatic origin. Combining PCSK9 mAbs with high-intensity statins mitigates post-MI increases in lipoprotein(a). REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03067844.
