Rare variant genetics have been associated with peripartum cardiomyopathy (PPCM), but the role of genetics remains unsettled. The study sought to compare dilated cardiomyopathy (DCM) genetic risk in first-degree relatives (FDRs) of female patients (probands) with DCM or PPCM to gain causal inference, and to assess DCM-relevant rare variant prevalence in DCM/PPCM probands and population controls. Clinical and genetic data were analyzed from the DCM Precision Medicine Study. Risk of DCM or partial DCM, where partial DCM was defined as left ventricular enlargement or a left ventricular ejection fraction of <50%, was estimated in 665 FDRs from 452 female probands, all of whom had been pregnant; 67 had PPCM and 385 had DCM; prevalence of pathogenic, likely pathogenic, or uncertain significance variants was estimated among probands. The risk of DCM/partial DCM for FDRs of PPCM probands was similar to that for FDRs of DCM probands (hazard ratio, 0.77 [95% CI, 0.47-1.28]). Estimated DCM prevalence among the lowest-risk FDRs of non-Hispanic European ancestry probands with PPCM (7.0% [95% CI, 0%-14.1%] females, 9.0% [95% CI, 1.6%-16.3%] males) exceeded population estimates from a UK Biobank study (0.30% females, 0.63% males). Estimated prevalences of a pathogenic, likely pathogenic, or uncertain significance variant among African ancestry and European ancestry probands with PPCM were 55.4% (95% CI, 33.1%-77.7%) and 66.0% (95% CI, 38.6%-93.3%), respectively. The estimated prevalence of pathogenic/likely pathogenic variants among European ancestry PPCM probands (26.6% [95% CI, 12.6%-40.6%]) exceeded a population estimate from a UK Biobank study (0.6%). The risk of DCM/partial DCM among FDRs was similar regardless of whether their probands had PPCM or DCM. Also, DCM-relevant rare variant findings for females with PPCM or DCM were similar and greater than in population controls, suggesting a similar causal basis for PPCM and DCM. These findings underscore the need for genetic evaluations in all patients with PPCM. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037632.
Despite accounting for a substantial proportion of the global population and disease burden, African countries are underrepresented in randomized controlled trials (RCTs), including those informing cardiovascular (CV) care. In this study, we sought to quantify African representation in RCTs published from 2019 to 2024 in: 1) 5 leading general medical journals; and 2) 3 leading CV journals. We conducted a systematic review of RCTs published from 2019 to 2024 in the British Medical Journal, the Journal of the American Medical Association, The Lancet, Nature Medicine, and the New England Journal of Medicine, and in Circulation, the European Heart Journal, and the Journal of the American College of Cardiology. Eligible studies included traditional, pragmatic, cluster, and stepped-wedge RCTs. African representation was assessed by trial scope (Africa-only vs multicontinental), country and regional participation, disease category, and African authorship. Among 2,138 RCTs published in leading general medical journals, only 83 (3.9%) were conducted exclusively in Africa, and 195 (9.1%) were multicontinental studies including at least 1 African site. In the CV journals, 2 out of 334 RCTs (0.6%) were conducted exclusively in Africa, and African sites were included in only 9 multicontinental trials (2.7%). South Africa accounted for the majority of Africa-based RCTs across both journal categories. Regionally, southern Africa predominated and central Africa was minimally represented. Trials published in general medical journals and conducted exclusively in Africa largely focused on infectious diseases (n = 63; 75.9%), with only 3 addressing cardiovascular disease (CVD). In contrast, Africa-including multicontinental trials more frequently investigated noncommunicable diseases, including CVD. African leadership was common in Africa-only trials but rare in multicontinental studies. African countries are profoundly underrepresented in RCTs published in the world's most influential medical and CV journals. Addressing this imbalance requires expanding African participation in global trials, investing in local research capacity, and promoting equitable leadership to strengthen the relevance and validity of clinical evidence. (Underrepresentation of African Countries in Randomized Controlled Trials: A Systematic Review of Leading General Medical and Cardiovascular Journals; CRD42024603157).
While GWAS (genome-wide association studies) have identified over 1000 obesity-associated loci, their functional impact on gene expression remains unclear. Moreover, many studies have not fully captured the genetic architecture of obesity in high-risk populations or considered the complexity of adiposity beyond traditional measures. To address these gaps, this study explores the genetic and transcriptomic pathways of obesity using diverse obesity phenotypes in a high-risk population. We analyzed genomic and whole-blood transcriptomic data from the CCHC (Cameron County Hispanic Cohort), performing GWAS on 13 obesity-related traits. Differential expression analysis was conducted for genes near GWAS-identified single nucleotide polymorphisms (P<5×10-6) followed by expression quantitative trait loci mapping and GWAS-expression quantitative trait loci colocalization. GWAS identified 486 trait associations, including 6 genome-wide significant (P<5×10-8) loci, with 3 novel signals linked to abdominal subcutaneous adipose tissue, body fat percentage, and waist circumference. Among 3024 genes near these loci, 60 showed differential expression. Further expression quantitative trait loci analysis suggested 2 single nucleotide polymorphism-gene-trait relationships: rs543314376-MAPK11, associated with subcutaneous adipose tissue volume in females, and rs963018484-PER1, linked to body mass index in females. Both genes play key roles in obesity-related pathways, including inflammation and circadian rhythm regulation. This integrative genomic-transcriptomic analysis uncovers 2 novel candidate genes for obesity and underscores the critical need for involving all populations and comprehensive adiposity measures in obesity research. By expanding beyond body mass index in a Hispanic/Latino population, we move closer to a deeper and more inclusive understanding of obesity's genetic architecture.
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. 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. 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. 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.
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. 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. 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. 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.
Coronary artery disease remains the leading cause of death worldwide. One of the greatest developments in preventive cardiology has been the identification and treatment of standard modifiable risk factors associated with coronary artery disease. However, despite advances in the management of standard modifiable risk factors, there is an escalating number of patients who continue to present with acute coronary syndromes, a trend that is particularly concerning given the decreasing age-adjusted incidence rates of these conditions. This persistent clinical challenge underscores the urgency to explore alternative approaches for early detection and improved risk stratification. In recent years, the emergence of proteomics technologies has brought forth promising avenues for the discovery of novel biomarkers that hold the potential to revolutionize the timely detection and management of coronary artery disease. Proteomics enables the high throughput and often unbiased analysis of protein abundance, modifications, and interactions within pathways relevant to cardiovascular disease pathogenesis. Of particular importance is the capability to detect low-abundance proteins including those with currently unknown functions. While the functional assessment of these proteins aligns more with mechanistic studies, their role in biomarker discovery is equally important. Such detection may provide new insights into cardiac pathophysiology, including potential new markers for early disease detection and risk assessment. Although the latest proteomics technology and bioinformatic approaches do provide the opportunity for novel discoveries, understanding the limitations of each technology platform is important. This review provides an updated overview of major proteomic platforms and discusses their methodological strengths, constraints, and applications, using recent coronary artery disease studies as illustrative examples. By integrating proteomics data with clinical information, including advanced noninvasive imaging techniques and other omics disciplines, such as genomics and metabolomics, we can deepen our understanding of disease mechanisms and improve risk stratification. Although the discovery of novel biomarkers represents a significant step forward in the field, their true clinical value is contingent upon their rigorous validation in clinical trials and implementation studies. With our current capabilities and emerging advancements, we are well-positioned to advance proteomics-guided precision medicine in cardiovascular care over the coming decade.
The analysis of the circulating proteome can identify translational modifiers and biomarkers of disease expressivity and severity at a given time point. Here, we explore the relationships between protein measures implicated in cardiovascular disease and whether they mediate causal relationships between cardiovascular risk factors and disease development. To understand the relationships between circulating biomarkers and genetic variants, medications, anthropometric traits, lifestyle factors, imaging-derived measures, and diagnoses of cardiovascular disease, we undertook in-depth analyses of measures of 9 plasma proteins with a priori roles in genetic and structural cardiovascular disease or treatment pathways (ACE2 [angiotensin-converting enzyme 2], ACTA2 [actin alpha 2], ACTN4 [actinin alpha 4], BAG3 [BAG cochaperone 3], BNP [B-type natriuretic peptide], CDKN1A [cyclin-dependent kinase inhibitor 1A], NOTCH1 [neurogenic locus notch homolog protein 1], NT-proBNP [N-terminal pro-B-type natriuretic peptide], and TNNI3 [troponin I]) from the Pharma Proteomics Project of the UK Biobank cohort (over 45 000 participants sampled at recruitment). We identified significant variability in circulating proteins with age, sex, ancestry, alcohol intake, smoking, and medication intake. Phenome-wide association studies highlighted the range of cardiovascular clinical features with relationships to protein levels. Genome-wide genetic association studies identified variants near GCKR, APOE, and SERPINA1, that modified multiple circulating protein levels (BAG3, CDKN1A, and NOTCH1). NT-proBNP and BNP levels associated with variants in BAG3. ACE2 levels were increased with a diagnosis of hypertension or diabetes, particularly in females, and were influenced by variants in genes associated with diabetes (HNF1A and HNF4A). Two-sample Mendelian randomization identified ACE2 as protective for systolic blood pressure and type-2 diabetes. From a panel of circulating proteins, the results from this observational study provide evidence that ACE2 is causally protective for hypertension and diabetes. This suggests that ACE2 treatment may provide additional protection from these cardiovascular diseases. This study provides an improved understanding of the circulating pathways depicting cardiovascular disease dynamics.
Myotonic dystrophy type 1 (DM1) is caused by a (CTG)n trinucleotide repeat expansion in the 3'UTR of the DMPK gene. Once expressed, repeat RNA forms toxic hairpins that sequester the MBNL (muscle blind-like) family of splicing factors. This disrupts the tissue alternative splicing landscape, triggering multisystemic manifestations-myotonia, muscle weakness, cardiac contractile defects, arrhythmia, and neurological disturbances. Although impaired mitochondrial function has been reported in the brain, skeletal muscle, and fibroblasts of patients with DM1, they have not been reported in the heart, nor have their contribution to the DM1 cardiac pathogenesis been explored. Here, we probed the bioenergetic profile of DM1-afflicted heart tissues and explored the mechanistic basis of DM1-induced cardiac bioenergetic defects. Using an inducible, heart-specific DM1 mouse model, we performed extracellular flux analyses, measured total ATP and NAD(H) concentrations, and performed immunofluorescence staining and transmission electron microscopy to characterize DM1-induced cardiac bioenergetics and mitochondrial structural defects. We analyzed eCLIP-Seq data to identify mitochondria-related missplicing events, which we validated in human and mouse DM1 heart tissues. Finally, we used antisense oligonucleotides to replicate these events and to test the recapitulation of DM1-like bioenergetic and structural defects in vitro. DM1 induced a multistate decrease in oxygen consumption rate with a corresponding reduction in ATP and NAD(H) concentrations, indicating impaired oxidative phosphorylation in DM1-afflicted mouse hearts. We also found significant cardiac mitochondria fragmentation, which correlated with the missplicing of transcripts encoding mitochondria fission factor (Mff, encodes MFF protein) and dynamin related protein 1 (Dnm1l, encodes DRP1 protein) in DM1-afflicted human and mouse hearts. Antisense oligonucleotides-mediated redirection of Dnm1l alternative splicing reproduced DM1-like impairment in cardiac bioenergetics and mitochondrial dynamics in wild-type HL-1 cardiomyocytes. Together, these findings reveal that expanded (CUG)n RNA toxicity in DM1 disrupts cardiac bioenergetics through the missplicing of critical mitochondrial fission transcripts. These misspliced transcripts represent potential therapeutic targets for improving mitochondrial function and cardiac symptoms of DM1.
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. 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. 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. 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.
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. 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. 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. 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.
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. 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. 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. Postmortem genetic testing identifies pathogenic or likely pathogenic variants in a significant subset of SADS cases, supporting its utility in postmortem evaluation.
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. 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. 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. 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.
Risk prediction has been used in the primary prevention of cardiovascular disease for >3 decades. Contemporary cardiovascular risk assessment relies on multivariable models, which integrate established cardiovascular risk factors and have evolved over time from the Framingham Risk Model to the pooled cohort equations to the PREVENT (Predicting Risk of CVD Events) equations. Recent scientific (ie, genomics, proteomics, metabolomics) and methodologic (ie, artificial intelligence) advances have led to a proliferation of novel models, biomarkers, and tools for potential use in risk prediction. In parallel, the growing armamentarium of preventive therapies, some with considerable cost, underscores the need for more accurate and precise risk assessment to prioritize those at highest risk who will derive the greatest absolute benefit. Accompanying the considerable enthusiasm for the potential of newer approaches to improve risk prediction is the need for rigorous evaluation and assessment of their performance (ie, accuracy, precision, incremental performance when added to contemporary multivariable risk models or established risk factors) and clinical utility (ie, actionability, scalability, generalizability) before adoption in clinical practice. Additional considerations in risk tool evaluation include reproducibility, cost-value considerations (including impact on downstream health care costs), and implications for health equity. This scientific statement defines a standardized framework for general considerations in risk prediction, statistical assessment of predictive utility, and critical appraisal of clinical utility and readiness. This scientific statement is intended to support clinicians, researchers, and policymakers in how best to evaluate current and emerging risk prediction tools and ultimately improve the prevention of cardiovascular disease in diverse populations.
Until December 2024, China had identified and named 66 new HIV-1 recombinant genotypes. Among them, CRF85-BC is showing a rapidly growing trend in popularity in southwestern China, especially in Sichuan and Yunnan. This genotype was first discovered and reported in Sichuan and is believed to have originated in Yunnan. However, there are relatively few reports on the comprehensive systematic transmission data in Yunnan. This study will further elucidate the accurate evolutionary origin time and epidemic transmission dynamics of CRF85-BC. We obtained 496 partial pol and 47 near full-length genomic sequences of HIV-1 CRF85_BC from 28,384 individuals with treatment failure in Yunnan, 2009-2023. Bayesian coalescent phylogeny analysis was performed to investigate the origin and timeline of CRF85_BC. A molecular transmission network was constructed using the genetic distance method to evaluate the transmission pattern. Spatial analysis was used to reveal the geographic patterns of phylogenetic clustering rates. The number of CRF85_BC sample cases increased significantly between 2009 and 2023, and showed resistance to reverse transcriptase inhibitors (M184V/I and K103N/S). Bayesian phylogeny of nearly full-length sequences indicated that the emergence time in Yunnan was between January 1989 (95% confidence interval [CI]: 1984.9-1992.8) and February 1992 (95% CI: 1986.1-1996.6). Molecular networks resolved 87 transmission clusters, and the differences in transmission patterns were mainly manifested in the high aggregation rate (63.29%; 95% CI: 55.69%-70.89%) and cluster size (average size: 8.3) in Sichuan, which were higher than those in Yunnan (40.33%; 95% CI: 36.19%-44.47%; average size: 2.5). And all of them were heterosexual people, with a predominance of 77.81% (256/329). Spatiotemporal analysis revealed that Yunnan significantly transmitted to Sichuan, with Zhaotong and Yibin serving as key transmission hubs in both provinces. The CRF85_BC genotype from Yunnan has a growing transmission network, with the potential for further expansion.
SGLT2 (sodium-glucose cotransporter-2) inhibitors and GLP-1R (glucagon-like peptide-1 receptor) agonists reduce the risk of major adverse cardiovascular and kidney events in individuals with various cardiometabolic conditions. The long-term efficacy and safety of these therapies, especially in low- and moderate-risk populations, remain uncertain. We conducted a biobank-scale analysis using genetic instruments derived from naturally occurring genetic variations in the genes encoding the targets of SGLT2 inhibitors (SLC5A2) and GLP-1R agonists (GLP1R) that are associated with glycated hemoglobin levels. This Mendelian randomization study utilized data from the All of Us Research Program, which includes whole genome sequencing and electronic health records of 633 547 participants. Higher SGLT2 inhibitor genetic instrument scores were associated with a lower risk of heart failure (odds ratio [OR], 0.97 [95% CI, 0.96-0.99]) and chronic kidney disease (OR, 0.98 [95% CI, 0.96-0.99]). Higher GLP-1R agonist genetic instrument scores were linked to reduced risks of heart failure (OR, 0.97 [95% CI, 0.96-0.99]), chronic kidney disease (OR, 0.96 [95% CI, 0.95-0.98]), and coronary artery disease (OR, 0.98 [95% CI, 0.96-0.99]). We did not detect associations between the GLP-1R agonist instrument and multiple endocrine neoplasia or medullary thyroid carcinoma. PheWAS (Phenome-Wide Association Study) identified associations between the SGLT2 inhibitor and GLP-1R agonist genetic instruments and a lower risk of diabetes, but no other phenotypes. This study demonstrates the utility of biobank-scale health data for pharmacology research and suggests that, if feasible to implement in routine practice, long-term, primary prevention with an SGLT2 inhibitor or GLP-1R agonist would safely lower the risk of major adverse cardiovascular and kidney events in low- to moderate-risk adults.
Proteins linked to heritable coronary heart disease (CHD) could uncover new pathophysiological mechanisms of atherosclerosis. We report on the protein profile associated with a family history of early-onset CHD and whether the relation between proteins and coronary atherosclerotic burden differs according to family history status, as well as inferences from Mendelian randomization. Data on coronary atherosclerotic burden from computed tomography angiography and Olink proteomics were retrieved for 4521 subjects, free of known CHD, from SCAPIS (the Swedish Cardiopulmonary Bioimage Study). Records of myocardial infarction and coronary revascularization therapies in any parent or sibling of subjects were retrieved from national registers. Linear associations between family history and proteins were adjusted for age, sex, and study site. Statistical interactions between proteins and family history for the association between proteins and the coronary atherosclerotic burden were also studied. Mendelian randomization for causal associations between proteins and CHD was performed with genome-wide association study summary data from UKB-PPP (UK Biobank Pharma Proteomics Project), CARDIoGRAMplusC4D, and FinnGen. Of 4251 subjects, family history of early-onset CHD was present in 9.5%. Thirty-eight proteins, with biological features of inflammation, lipid metabolism, and vascular function, were associated with family history using a false discovery rate of 0.05. The strongest associations were observed with cathepsin D, paraoxonase 3, renin andfollistatin, neither of which was attenuated by adjusting for cardiovascular risk factors. Eighteen proteins were statistical interactors with family history in the association between each protein and the coronary atherosclerotic burden, most notably the LDL (low-density lipoprotein) receptor, transferrin receptor protein 1, and PECAM1 (platelet endothelial cell adhesion molecule 1). In 2-sample Mendelian randomization, a novel association was found for follistatin and myocardial infarction, and previous associations for PCSK9 (proprotein convertase subtilisin/kexin type 9) and PECAM1 were repeated. These findings highlight new potential mechanisms for heritable and general atherosclerosis.
The Helix Research Network program is a large population genomics initiative that screens an all-comers population of patients for Centers for Disease Control and Prevention Tier 1 genetic conditions, including familial hypercholesterolemia (FH). We evaluated changes in clinical management and low-density lipoprotein cholesterol (LDL-C) levels among patients we identified to have FH. Participants across 9 US health systems provided samples that underwent clinical-grade exome sequencing. Individuals with a positive screening result for a Tier 1 condition were offered no-cost genetic counseling through their health system. Using medication and laboratory testing records, we evaluated changes in patients' lipid-lowering therapies and LDL-C levels. Among 228 602 adults enrolled between 2017 to 2025, 1155 (≈1/198) had a pathogenic FH variant in LDLR (74%), APOB (25%), or PCSK9 (1%). Of the 622 with retrospective and prospective electronic health record data available (mean of 11.8 and 2.1 years, respectively), 84% lacked a prior clinical FH diagnosis. Overall, 33% received new/modified lipid-lowering therapy within the first year, but this proportion was higher in those with a newly documented FH diagnosis code (57% versus 17% for those without documentation; P<0.001). Patients with new/modified therapies had a mean LDL-C reduction of 52 mg/dL, compared with 20 mg/dL in patients with no therapeutic change (difference=32 mg/dL; P<0.001). Following genetic screening, many patients with a pathogenic FH variant experienced improvements in clinical management and LDL-C levels. Electronic health record documentation of the diagnosis code was associated with a greater likelihood of therapeutic modifications, which, in turn, were associated with larger LDL-C reductions. Findings underscore the powerful potential of population genomic screening for supporting optimal lipid management in individuals with FH.
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. 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. 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. 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.
RBM20 (RNA binding motif protein 20) is a cardiac splicing factor responsible for the splicing of several cardiac genes such as titin (TTN), triadin (TRDN), ryanodine receptor 2 (RYR2), PDZ and LIM domain protein 1 (PDLIM1), and calcium/calmodulin-dependent protein kinase II (CAMK2D). Pathogenic variants in RBM20 are a major cause of familial dilated cardiomyopathy, and lead to missplicing of RBM20 target genes. We identified a patient with a novel RBM20 variant, and expressed the human and mouse-equivalent variant in neonatal rat cardiomyocytes and HEK293 cells. We performed splicing assays, and assessed protein expression and stability. Furthermore, we generated heterozygous RBM20-c.1222DupC human induced pluripotent stem cells, differentiated these into human induced pluripotent stem cell-derived cardiomyocytes, and evaluated splicing changes and calcium handling. We describe a novel heterozygous truncating variant, RBM20-c.1222DupC, identified in a patient with mitral valve prolapse and late-onset familial dilated cardiomyopathy. The variant introduces a premature termination codon and generates a truncated protein of ≈55 kDa in vitro. Splicing assays demonstrated complete loss of activity and no dominant-negative effect on wild-type RBM20. The truncated protein localized to both the cytoplasm and nucleus, partially colocalizing with wild-type RBM20, despite lacking the RS and RRM domains. Western blot analysis of endogenous RBM20 in human induced pluripotent stem cell-derived cardiomyocytes carrying the variant revealed a strong reduction in RBM20 protein levels. Reverse transcriptase-polymerase chain reaction revealed splicing defects in canonical RBM20 targets, and RNA sequencing identified widespread splicing abnormalities, including in established RBM20 targets (TTN, RYR2, CAMK2D, and CACNA1G). Finally, we observed increased calcium transients. Together, these findings establish RBM20 c.1222DupC as a truncating variant that causes dilated cardiomyopathy likely through haploinsufficiency.
Pathogenic variants in ALPK3 (α-protein kinase 3), an atypical α‑kinase acting as a sarcomeric M-band scaffold, cause cardiomyopathy with severity linked to zygosity. We present a comprehensive review with systematic curation of peer-reviewed clinical and experimental reports through June 9, 2025, encompassing 156 patient-level variants and all published preclinical models. Biallelic loss-of-function variants lead to severe, often lethal cardiomyopathy with prenatal or early onset presentation and extracardiac involvement. Heterozygous protein-truncating variants, defined as nonsense or frameshift (resulting from insertion/deletion events or splicing mutations), explain ≈1% to 4% of adult hypertrophic cardiomyopathy, often with apical/septal hypertrophy, right ventricular involvement, fibrosis, and risk of progression. ALPK3 lacks catalytic activity and maintains sarcomeric proteostasis by scaffolding MYOMs (myomesins), MuRF (muscle ring-finger protein) E3 ligases, and SQSTM1 (sequestosome-1)/p62. Loss of this scaffolding function displaces MYOMs, drives thick‑filament protein aggregation, and precipitates severe contractile dysfunction in human induced pluripotent stem cell-derived cardiomyocytes and multiple mouse models. Therapeutic proof‑of‑concept has now been achieved on 2 fronts: (1) pharmacological correction of sarcomeric hypercontractility with the myosin inhibitor mavacamten and (2) durable phenotypic rescue in global knockout mice using an adeno-associated virus-delivered miniALPK3 gene‑replacement construct. Together, these data position ALPK3 cardiomyopathy as a compelling target for precision medicine. Early genetic diagnosis, genotype-tailored surveillance, and focused development of gene-replacement or editing strategies, potentially combined with modulators of the ALPK3-MuRF proteostatic axis, offer a realistic path to disease-modifying therapy for this once enigmatic condition.