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: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: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.
BACKGROUND:Cardiac involvement is the main determinant of adverse outcomes in Fabry disease. The study aimed to investigate cardiovascular outcomes in patients with Fabry disease. METHODS:This was a multicenter, retrospective, longitudinal study of consecutively referred adult patients with Fabry disease. The primary end point was the occurrence of major adverse cardiovascular events defined as a composite of cardiovascular death, major arrhythmic events, bradyarrhythmias requiring pacemaker implantation, and stroke. RESULTS:A total of 680 patients (age, 42.3±15.9 years; 41.0% male; 68.7% on disease-specific therapy) were included. During a median follow-up of 7.1 (interquartile range, 3.9-11.6) years, 92 patients (13.5%) experienced a major adverse cardiovascular event. At 10 years, freedom from major adverse cardiovascular event was 85.1% (95% CI, 81.3-88.2) and was lower in men compared with women (76.1% [95% CI, 68.9-81.9] versus 91.3% [95% CI, 87.0-94.2]; log-rank χ2=26.9; P<0.001). On multivariable analysis, age (hazard ratio, 1.04 [95% CI, 1.01-1.06] per 1 year; P<0.001), estimated glomerular filtration rate (hazard ratio, 0.99 [95% CI, 0.98-0.99] per 1 mL/min per 1.73 m2; P<0.001), QRS interval (hazard ratio, 1.02 [95% CI, 1.01-1.03] per 1 ms; P=0.002), and left ventricular mass index (hazard ratio, 1.01 [95% CI, 1.00-1.01] per 1 g/m2; P=0.032) were independent predictors of major adverse cardiovascular events during follow-up. CONCLUSIONS:This study shows that the prevention and treatment of cardiovascular disease remain an unmet need for patients with Fabry disease.
BACKGROUND:Heart failure (HF) and its main subtypes, heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF), impose an enormous health burden on elders. Assessment of the circulating proteome to illuminate pathogenesis could open new opportunities for treatment.METHODS:We conducted a plasma proteomics screen of incident HF and its subtypes in 2 older population-based cohorts, the CHS (Cardiovascular Health Study) and the AGES-RS (Aging, Gene/Environment Susceptibility-Reykjavik Study). The 2 studies used SomaLogic platforms, with 4404 aptamers in common. Multivariable Cox models were fit to evaluate individual-protein associations with HF, HFpEF, and HFrEF separately in each cohort, and study-specific associations were combined by fixed-effects meta-analysis. Replication was performed in the ARIC (Atherosclerosis Risk in Communities) cohort. Two-sample Mendelian randomization of HF and its subtypes, along with colocalization analysis, was performed to support causal inference.RESULTS:Among 8599 participants, 1590 experienced incident HF (536 HFpEF, 471 HFrEF). There were 119 proteins associated with HF, 15 proteins with HFpEF, and 11 proteins with HFrEF, at Bonferroni-corrected significance. Among these, 9 have never previously been identified for cardiovascular diseases, and another 61 represent new associations with incident HF or its subtypes. Of these 70 proteins, 55 of the 66 available replicated externally. Mendelian randomization analysis revealed 7 proteins genetically associated with HF at nominal significance; 2 were separately associated with HFpEF, and another 2 with HFrEF. Seven of these 9 proteins (NPDC1 [neural proliferation differentiation and control protein 1], APOF [apolipoprotein F], LMAN2 [lectin, mannose-binding 2], ADIPOQ [adiponectin], CD14 [cluster of differentiation 14], ARHGAP1 [Rho GTPase-activating protein 1], C9 [complement 9]) showed new, possibly causal associations, although we did not detect evidence for colocalization.CONCLUSIONS:In this large-scale proteomic study involving 3 longitudinal cohorts of older adults, we identified and replicated 55 novel protein markers of HF or its subtypes, and 7 new, possibly causal proteins. These proteins may enhance risk prediction, improve understanding of pathobiology, and help prioritize targets for therapeutic development of these foremost disorders in elders.
BACKGROUND:Spontaneous coronary artery dissection (SCAD) is an uncommon cause of myocardial infarction that disproportionately affects women, particularly during pregnancy and the peripartum period. Limited understanding of its underlying pathophysiology hinders the development of effective preventive and therapeutic strategies. METHODS:This study investigated associations between genetically predicted circulating proteins and tissue-specific RNA levels with genetically predicted SCAD risk using Mendelian randomization and Bayesian colocalization. Genetic scores for >1500 circulating proteins were derived from the UK Biobank (N=34 557) and deCODE (N=35 559). Scores for 13 848 gene transcripts in arterial and fibroblast tissues were generated from Genotype-Tissue Expression data. Associations between these scores and SCAD were assessed in a genome-wide association study meta-analysis of 1917 individuals with SCAD and 9292 controls. Findings were validated in vitro using mass spectrometry-based proteomic analysis of extracellular vesicles from 50 patients with SCAD and 50 healthy controls. RESULTS:Genetic associations of 4 circulating proteins with SCAD (AFAP1 [actin filament-associated protein 1], ECM1 [extracellular matrix protein 1], SPON1 [spondin 1], and STAT6 [signal transducer and activator of transcription 6]) were identified. Two were supported by gene expression data (AFAP1 and ECM1), and one by tissue-specific Bayesian colocalization analyses (ECM1). Protein interaction mapping identified potential shared pathways through the JAK-STAT (Janus kinases and signal transducers and activators of transcription) signaling pathway and inflammatory regulation. Mass spectrometry-based proteomic analysis demonstrated that ECM1 was significantly upregulated in SCAD cases versus controls. CONCLUSIONS:Integrative analysis of proteomic, transcriptomic, and experimental data revealed 4 circulating proteins genetically associated with SCAD risk, with ECM1 emerging as a key protein with a likely causal role in SCAD pathogenesis. These findings highlight biological pathways for mechanistic studies and protein targets for potential therapeutic interventions.
BACKGROUND:TRPC6 (transient receptor potential canonical 6) channels, encoded by the TRPC6 gene, are widely expressed in cardiomyocytes and play a critical role in maintaining intracellular Ca2+ homeostasis. Variants in TRPC6 are associated with chemotherapy-related cardiomyopathy. Specifically, the TRPC6 A404V polymorphism, with a minor (404 V) allele frequency of 12% in the general population, has been identified in patients undergoing anthracycline therapy. However, the underlying mechanisms remain largely unexplored. METHODS:Using patch-clamp recordings, Ca2+ imaging, computational analysis, and molecular biology techniques, we assessed the effects of doxorubicin and its metabolite, doxorubicinol, on regulating TRPC6 alanine (A) at position 404 replaced by valine (V; A404V) channel expression and function in a heterologous expression system and native cardiac cells. RESULTS:Both additive and recessive models demonstrated a significant association between the TRPC6 A404V variant and doxorubicin-related cardiomyopathy. The TRPC6 A404V channel exhibited higher membrane expression levels compared with the wild type (WT) control. Patch-clamp recordings showed that both TRPC6 WT and A404V channels remained mostly inactive at baseline. Application of 50 μmol/L 1-oleoyl acetyl-sn-glycerol (OAG), a TRPC6 activator, significantly increased the inward- and outward-current densities of WT and A404V channels. Furthermore, a 24-hour treatment with 0.5 μmol/L doxorubicin enhanced TRPC6 mRNA expression and potentiated the OAG effects on both WT and A404V channels, with a more pronounced response in A404V channels. Treatment with 0.5 μmol/L doxorubicinol had no effect on OAG-induced current densities in either WT or A404V channels. Doxorubicin effects on intracellular Ca2+ levels were confirmed by Ca2+ imaging in native cardiac cells. Computational modeling revealed that the A404V mutation induces a conformational change in the OAG-binding pocket, enhancing its interaction with OAG in the A404V protein compared with the WT control. CONCLUSIONS:The TRPC6 A404V is a gain-of-function variant that exhibits enhanced activity in the presence of doxorubicin. Therefore, the TRPC6 A404V variant represents a risk factor for anthracycline-induced cardiotoxicity in patients with cancer.
BACKGROUND:NPs (natriuretic peptides) are bioactive hormones crucial for regulating blood pressure, glucose homeostasis, and lipid metabolism. Despite the high heritability of circulating NP levels, the genetic determinants of NP regulation, particularly across ancestries and sexes, remain poorly understood. The objective of the current study was to identify genetic variants associated with NT-proBNP (N-terminal pro-B-type NP) levels in a multiancestry study population. METHODS:Whole genome sequencing and array-based data from 81 213 individuals without heart failure were analyzed from the Trans-Omics for Precision Medicine cohorts, UK Biobank, All of Us Research Program, and REGARDS (Reasons for Geographic and Racial Differences in Stroke) study to identify common, rare, and structural variants associated with NT-proBNP levels. The main outcome of the study was rank-based inverse normal and standardized NT-proBNP levels. Genetic associations with NT-proBNP were examined, followed by gene prioritization, transcriptome-wide association studies, colocalization, and rare variant analyses. RESULTS:Nine novel loci and 3 previously reported loci were identified to be associated with NT-proBNP levels. Novel structural variants were detected across 12 loci. Similar effect sizes were observed for both common and rare variants. Key genes such as BAG3 (10q26.11) and SLC39A8 (4q24) were identified through gene prioritization, with prior animal models supporting their therapeutic relevance. Rare variant analysis identified 6 masks with significant associations, specifically non-coding masks, suggesting regulatory modulation of NT-proBNP. CONCLUSIONS:This study identifies novel common, rare, and structural variants associated with NT-proBNP levels, highlighting the contribution of both coding and regulatory non-coding variation. These findings advance our understanding of the genetic architecture of NT-proBNP and may inform future cardiometabolic therapeutic strategies.
BACKGROUND:ACTA2 pathogenic variants predispose to thoracic aortic disease, and a subset of variants lead to early onset atherosclerotic cardiovascular disease (ASCVD). The molecular pathway linking misfolded SMA (α-smooth muscle actin) monomers to augmented atherosclerosis-associated smooth muscle cell phenotypic modulation can be modeled in vitro by stably expressing the ACTA2 p.R149C variant in Acta2-/- smooth muscle cells. METHODS:The Montalcino Aortic Consortium patient registry was used to identify cases with ACTA2 pathogenic/likely pathogenic missense variants. These patients were surveyed, and medical records were reviewed, to identify cases with early onset ASCVD. The variants for these cases, as well as other recurrent ACTA2 missense variants, were individually expressed in Acta2-/- smooth muscle cells, and transcript and protein levels, HSF1 (heat shock factor 1) activation, HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) expression and activity, cholesteryl ester levels, and downstream smooth muscle cell phenotypic modulation were assessed. RESULTS:Early onset ASCVD included coronary artery disease, peripheral vascular disease, and atherosclerotic plaques identified by imaging in the arch, descending, or abdominal aorta, along with the celiac, iliac, renal, or vertebral arteries. Twelve ACTA2 variants were identified to be associated with early onset ASCVD. Early onset ASCVD was correlated with HSF1 activation (P=0.035), cellular cholesteryl ester levels (P=0.0031), and having one family member with the specific ACTA2 pathogenic variant who had early onset ASCVD (P=0.0001). CONCLUSIONS:Assays assessing the molecular mechanism that leads to early onset ASCVD can identify which ACTA2 pathogenic variants will trigger this condition. Ultimately, this information informs precision medical care for individuals with ACTA2 pathogenic variants, with the ultimate goal of preventing thoracic aortic disease and ASCVD.
BACKGROUND:Mavacamten has been shown to improve cardiac function and symptoms in patients with symptomatic (New York Heart Association class II-III) obstructive hypertrophic cardiomyopathy (HCM). Clinical studies suggest that mavacamten monotherapy is efficacious and has a favorable safety profile, but limited evidence exists regarding monotherapy in real-world studies. This analysis aimed to describe the effectiveness and safety outcomes of mavacamten monotherapy in the real-world COLLIGO-HCM study (Mavacamten ObservationaL Evidence Global Consortium in Hypertrophic Cardiomyopathy). METHODS:Patient-level data recorded between April 2022 and February 2025 at 7 sites across 5 countries were extracted. Adult patients with a diagnosis of HCM from 2018 onwards were eligible for inclusion if they had ≥1 mavacamten prescription after the date of diagnosis. Patients were categorized based on background therapy status during mavacamten treatment: mavacamten monotherapy or mavacamten with background therapy (down-titration or no dose modification). RESULTS:Overall, 278 patients were included and received mavacamten (mavacamten monotherapy, n=88; mavacamten with background therapy, n=190). At month 9, most patients achieved ≥1 New York Heart Association class improvement from baseline (mavacamten monotherapy, 60.0%; mavacamten with background therapy, 61.0%). Improvements in resting and Valsalva left ventricular outflow tract gradients from baseline to month 9 were observed in both subgroups; mean left ventricular ejection fraction through month 9 remained ≥62.0% with mavacamten monotherapy and ≥61.4% with mavacamten with background therapy. Two patients in the mavacamten monotherapy subgroup and 1 patient in the mavacamten with background therapy subgroup permanently discontinued treatment owing to left ventricular ejection fraction <50%. CONCLUSIONS:Mavacamten monotherapy was associated with improvements in cardiac function and symptoms, and positive benefits to the risk profile over a 9-month follow-up period; this was consistent with improvements observed in patients treated with mavacamten with background therapy. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT06372457.
