Background:Most polygenic risk scores (PRS) are derived and validated using genetic data from European populations. However, European-based PRS perform poorly in individuals of non-European ancestry, and their transferability to the admixed Brazilian population remains unknown. Methods:PRS derived from the United Kingdom Biobank (UKB) were selected from the PGS Catalog, including 33 scores for body mass index (BMI), 36 for systolic blood pressure (SBP), and 33 for diastolic blood pressure (DBP). PRS were applied to 4,758 participants from two geographically distinct Brazilian cohorts (São Paulo and North Minas Gerais) and a UKB sample. Performance was evaluated across self-identified racial subgroups and in Brazilian individuals genetically similar to the UK sample, as determined by genomic clustering techniques (Uniform Manifold Approximation and Projection, UMAP; and Principal Component Analysis, PCA). Effect sizes were compared using multivariable mixed-effects models. Results:Most BMI PRS were validated in São Paulo (96.7%) and North Minas Gerais (90.9%), whereas blood pressure PRS showed lower validation rates (SBP: 66.7 and 38.9%; DBP: 69.7 and 54.5%, respectively). Validated PRS consistently exhibited lower effect sizes in Brazilian cohorts compared to the UKB (p < 0.001). PRS calibration for obesity and hypertension using cohort-specific quintiles and precision-recall F1 scores did not improve performance. BMI PRS effects were slightly higher in São Paulo than in North Minas Gerais (+0.39 kg/m2 per SD, p < 0.001), whereas SBP and DBP effects did not differ significantly between regions. BMI PRS effects were higher in Brazilian Whites than Non-Whites (+0.60 kg/m2 per SD, p < 0.001), but blood pressure PRS effects were similar in the racial subgroups. Across all traits, PRS effects were higher in the UKB than in Brazilian individuals clustering with the British by UMAP/PCA (p < 0.001), and no differences were observed between Brazilian UMAP/PCA subgroups. Conclusion:European-derived PRS are not directly transferable to the Brazilian population without prior empirical validation. Regional origin, self-identified race, and genetic similarity to the UKB do not reliably identify Brazilian subgroups with differential PRS performance. These findings highlight the urgent need for polygenic scores derived and trained on Brazilian genomic data.

Genetic predisposition and alcohol consumption are risk factors for increased blood pressure (BP), but their interactions influencing BP remain understudied. We conducted population-specific and cross-population meta-analyses of genome-wide gene-alcohol (GxAlc) interactions affecting BP in >1.1M individuals from multiple populations. We identified 46 GxAlc interaction loci for BP, including 21 from one-degree-of-freedom interaction tests (PGxAlc<5×10-8; or <0.05/Meff, Meff independent BP associations at P<10-5), and 25 from two-degree-of-freedom tests of main and interaction effects (PGxAlc<0.05/M2df, M2df independent 2df-associations at P2df<5×10-8), including 7 novel and 39 known BP loci. The 12q24 locus highlights the genetic effect of BRAP-rs11066001 on BP, being ~6 times larger in current drinkers than in non-drinkers. Gene prioritization with 46 GxAlc loci identified 15 genes with ≥3 lines of evidence (location, literature, druggability, functional/regulatory annotation, or pathway analyses). Several loci showed sex- and population-specific effects and revealed biological pathways of alcohol's influence on BP, suggesting mechanisms underlying alcohol-induced hypertension.

Abstract Rapid identification and localization of an acute coronary occlusion are vital to prevent myocardial damage, yet reliance on ST-segment ECG criteria misses many acute occlusion myocardial infarctions (OMI) and triggers unnecessary acute angiographies. Here, we present a trained and validated deep learning model using 540,372 emergency ECGs paired with definitive catheterization outcomes. The model has a C-statistic of ≥0.95 for OMI and ≥0.87 for non-OMI infarctions and can localize culprit lesions in the three main coronary branches, which can guide the angiographer. Performance is similar across age, sex, and ECG hardware subgroups. Obviating dependence on ST-elevations and troponins, this model for the identification and localization of OMI has the potential to shorten the time to reperfusion of an acute coronary occlusion and save resources. Because human oversight of OMI detection on the ECG is limited, randomized clinical trials with patient-relevant outcomes are warranted.

Resumo A doença de Danon é uma doença rara ligada ao cromossomo X, causada por variantes patogênicas ou provavelmente patogênicas no gene da proteína 2 da membrana associada ao lisossomo (LAMP2). Manifesta-se principalmente como cardiomiopatia hipertrófica, miopatia, deficiência intelectual e retinopatia, sendo que os homens geralmente apresentam um fenótipo mais grave e de início precoce. A fisiopatologia da doença de Danon está ligada à autofagia defeituosa devido à deficiência de LAMP2, levando ao acúmulo de vacúolos cheios de glicogênio dentro dos cardiomiócitos e outros tecidos. Isso resulta em hipertrofia cardíaca progressiva, anormalidades de condução e eventual insuficiência cardíaca, frequentemente necessitando de transplante cardíaco. O envolvimento da musculatura esquelética é comum em homens, enquanto o comprometimento cognitivo é observado em ambos os sexos, embora mais prevalente em homens. O diagnóstico é desafiador devido à raridade da doença e à apresentação variável, o que destaca a necessidade de uma abordagem multidisciplinar, incluindo testes genéticos para um diagnóstico definitivo. Os testes genéticos devem ser realizados somente após aconselhamento genético adequado. O diagnóstico diferencial deve ser considerado quando há suspeita de doença de Danon, dependendo dos sinais e sintomas, incluindo doenças como a doença de Fabry, a síndrome PRKAG2, a doença de Pompe, entre outras. As estratégias de tratamento atuais focam no alívio dos sintomas, sendo o transplante cardíaco uma intervenção crucial para casos avançados. Terapias emergentes, como a terapia gênica direcionada ao gene LAMP2, podem auxiliar na alteração da progressão da doença. Esta revisão oferece uma visão abrangente da doença de Danon, abordando suas manifestações clínicas, mecanismos subjacentes, desafios diagnósticos e potenciais abordagens terapêuticas para melhorar os resultados. Nosso objetivo é aumentar o reconhecimento da doença de Danon para que a prevenção de possíveis complicações e o diagnóstico precoce se tornem viáveis, levando, em última análise, a desfechos mais favoráveis para os pacientes.

Background Heart failure (HF) has multiple etiologies, but genetic testing remains mainly recommended for selected subgroups with suspected inherited cardiomyopathy. Objectives This study identified and classified genetic variants in patients within a HF cohort with reduced ejection fraction or mildly reduced ejection fraction from diverse etiologies in an admixed population. Methods The authors analyzed whole-genome sequencing data from 1,013 unrelated individuals in the GENIUS-HF (Genetic and ElectroNic medIcal records to predict oUtcomeS in Heart Failure patients) cohort. Rare variants in 123 ClinGen-curated cardiovascular genes were classified according to American College of Medical Genetics and Genomics (ACMG) criteria. Local ancestry inference evaluated associations with variant distribution. Results Overall, 6.5% of individuals carried at least one pathogenic/likely pathogenic variant considered causal (no significant difference between HF cohort with reduced ejection fraction and HF with mildly reduced ejection fraction, P = 0.500), 77.7% had at least 1 variant of uncertain significance, and 15.8% had only benign/likely benign variants observed. TTN variants accounted for nearly half of the causal findings, including 13 novel variants, with additional causal variants in MYBPC3, FLNC, BAG3, and DSP. Idiopathic dilated cardiomyopathy showed the highest yield (9.9%), but pathogenic variants were also detected in ischemic (4.6%), Chagasic HF (4.9%), and hypertensive (3.8%). Local ancestry analyses showed that variant of uncertain significance were significantly more frequent in regions with African and Native American ancestry. Conclusions These findings replicate a significant diagnostic yield of molecular genetic testing in individuals with dilated cardiomyopathy but extend the relevance of genetic testing beyond traditionally selected HF subgroups. They also underscore the importance of including non-European and admixed populations in cardiovascular genomics to reduce interpretation bias and improve equity in precision medicine.

Danon disease (DD) is a rare X-linked disorder caused by pathogenic or likely pathogenic variants in the lysosome-associated membrane protein 2 (LAMP2) gene. It primarily manifests as hypertrophic cardiomyopathy, myopathy, intellectual disability, and retinopathy, with males typically experiencing a more severe and early-onset phenotype. The pathophysiology of DD is linked to defective autophagy due to LAMP2 deficiency, leading to the accumulation of glycogen-filled vacuoles within cardiomyocytes and other tissues. This results in progressive cardiac hypertrophy, conduction abnormalities, and eventual heart failure, often necessitating heart transplantation. Skeletal muscle involvement is common in males, while cognitive impairments are observed in both genders, though more prevalent in males. Diagnosis is challenging due to the condition's rarity and variable presentation, highlighting the need for a multidisciplinary approach, including genetic testing for definitive diagnosis. Genetic testing must be performed only after proper genetic counseling is done. Differential diagnosis must be considered when DD is suspected, depending on the signs and symptoms, such as Fabry disease, PRKAG2, Pompe disease, and others. Management strategies currently focus on symptomatic treatment, with cardiac transplantation as a critical intervention for advanced cases. Emerging therapies, such as gene therapy targeting LAMP2, could help in altering disease progression. This review provides a comprehensive overview of DD, discussing its clinical manifestations, underlying mechanisms, diagnostic challenges, and potential therapeutic approaches in improving outcomes. Our goal is to increase the recognition of DD so that the prevention of possible complications and early diagnosis becomes feasible, ultimately leading to more favorable patient outcomes.

Cardiac complications are common and clinically significant in COVID-19, yet their underlying molecular drivers remain poorly understood. Here, we integrate post-mortem histopathology with transcriptomic and microRNA (miRNA) analyses to delineate the regulatory architecture of SARS-CoV-2-induced myocardial injury. Histological examination of cardiac tissue from 29 deceased COVID-19 patients revealed pronounced immune infiltration, cardiomyocyte necrosis, and fibrotic remodeling. To gain new insights into these pathological processes, we first analyzed 42 transcriptomes from SARS-CoV-2-infected cardiomyocytes, including primary human, iPSC, and hESC-derived cells. We identified 871 differentially expressed genes (DEGs) in infected cardiomyocytes associated with immune activation, extracellular matrix (ECM) remodeling, and impaired contractile function. Based on these dysregulated genes, we then inferred miRNA–mRNA regulatory networks and, through miRTarBase analysis, we uncovered 331 miRNAs as putative regulators of these DEGs, including miR-29a, miR-145, and miR-199a, known to modulate fibrosis, ECM composition, and cardiomyocyte survival. Finally, selected candidates were evaluated in blood samples from COVID-19 patients. We profiled circulating miRNAs in plasma from COVID-19 patients and detected 32 dysregulated miRNAs, 11 of which overlapped with the predicted set. Notably, downregulation of miR-29a correlated with profibrotic signatures, while immune-regulatory miR-21 was upregulated in mild disease. Together, our multi-modal analysis reveals a miRNA-mRNA regulatory program orchestrating inflammation, fibrosis, and contractile dysfunction in the SARS-CoV-2-infected heart. These findings highlight molecular candidates for risk stratification and therapeutic targeting in COVID-19-associated cardiomyopathy.

IntroductionObesity and related metabolic disorders represent a major global health burden, yet their genetic determinants remain incompletely characterized, particularly in non-European populations. We aimed to identify body mass index (BMI)–associated loci in an admixed Brazilian population and to functionally characterize ancestry-enriched variants contributing to obesity risk.MethodsWe conducted a genome-wide association study (GWAS) of BMI in 1,079 admixed Brazilian individuals. Significant and suggestive loci were evaluated using integrative analysis, including epigenomic annotation and chromatin conformation data. Regulatory activity was assessed using allele-specific luciferase reporter assays and electrophoretic mobility shift assays. The functional role of the prioritized gene was examined using pharmacological inhibition in human preadipocytes and genetic deletion in mice.ResultsWe identified three BMI-associated loci reaching genome-wide significance (p ≤ 5 × 10-8) and 49 additional loci previously implicated in obesity-related traits at suggestive significance. Integrative analyses prioritized a non-coding variant at chromosome 20 (rs149309426), located within an active enhancer that physically interacts with the KCNB1 promoter during preadipocyte differentiation. The BMI risk allele (C) increased enhancer activity in luciferase assays and showed enhanced transcription factor binding. Pharmacological inhibition of KCNB1 impaired adipocyte differentiation and lipid accumulation in human preadipocytes. Consistently, Kcnb1 knockout mice exhibited reduced fat mass and increased lean mass. The rs149309426 risk allele was rare in European populations but enriched in individuals with African ancestry.DiscussionOur findings identify KCNB1 as a regulator of adipogenesis and body composition and highlight the importance of studying admixed populations to uncover ancestry-specific genetic mechanisms underlying obesity.

Abstract The aorta shows significant regional variation in geometry and composition. This complexity makes numerical modelling challenging, as it requires the identification of material parameters. Typically, the Holzapfel–Gasser–Ogden model is used. However, it suffers from nonuniqueness and sensitivity to outliers, which can obscure biological variation. In addition, standard compressible formulations with a volumetric-isochoric split fail to couple volumetric and anisotropic responses. To address these issues, a regularized dual-estimation framework was introduced. This framework combines a global baseline estimator with local refinement while maintaining structural material continuity. Furthermore, it uses a modified anisotropic model to improve the representation of compressibility physics. For biological corroboration, the approach combined uniaxial extension tests with regional protein quantification in fresh rings of the ascending/aortic arch, descending and abdominal aorta of Wistar rats. The results show that the proximal ascending/aortic-arch segment is most compliant at low stretch, whereas the abdominal aorta stiffens earlier and becomes fibre-dominated at lower stretch levels. Notably, these trends align directionally with regional composition. However, the fitted stress components are model-based descriptors rather than direct measurements of individual constituents.

Deep neural networks (DNNs) have demonstrated excellent performance in classifying arrhythmias from electrocardiogram (ECG) signals. However, their black-box nature pose challenges to interpretability, limiting clinical trust and raising concerns about potential bias. This study aims to evaluate the interpretability of DNN models for atrial fibrillation (AFib) classification using ECG image representations. We compared two convolutional neural networks (CNNs) architectures, a ResNet-50 and a previously developed model, trained on DII-long lead images from the private InCor-DB dataset. To enhance interpretability, we applied two widely adopted Explainable AI (XAI) techniques: LIME And SHAP. In addition, we also employed pixel-flipping, a perturbation-based method, to quantitatively assess the contribution of highlighted image regions to model predictions. For external validation, the proposed approach was tested on the publicly available CPSC dataset, from which 1D ECG signals were converted into images. Both models achieved high classification performance, with accuracies of 96.9

Aim: The aim of the study was to describe the design, the neuroimaging protocol as well as the baseline characteristics of the participants from Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), which will be part of an extensive investigation of the determinants of brain aging based on high-resolution neuroimaging 3T and 7T magnetic resonance imaging (MRI) conceptualized by the Ageing and Brain Working Study Group from ELSA-Brasil. Methods: A representative sample of 2,165 participants (mean age = 60.3 [9.9] years, 55.5% female) for further neuroimaging and study with the protocol described here was selected from ELSA-Brasil. The criteria used for selection into this protocol were cognitive status and age in wave 3 (2017–2019), and participants were split into two subsamples: (1) a randomized sample of participants with <70 years at wave 3 (2017–2019) categorized in three groups based on their global cognitive trajectories from wave 1 to wave 3 – (1) below the average (z-score <−1, n = 620), (2) average (z-score = −1 to +1, n = 835), and (3) above-average performance (z-score >+1, n = 215); and (2) all participants with ≥70 years at wave 3 were classified as SuperAgers cases (n = 171) and their matched controls (n = 324) based on delayed memory (wave 3). Both samples will be scanned using a 3T MRI, and an additional 7T MRI exam will be conducted in the SuperAgers study to further evaluate brain connectivity. An extensive dataset of sociodemographic, lifestyle, cognitive, mental health, frailty, and other laboratory and clinical exams collected since the baseline of the main study will be considered as predictors of structural and functional patterns of brain aging. The main characteristics of participants and the MRI protocol are described here. Results: Among those under 70 years, the above-average group for cognition showed better cognitive and mental health scores than the other groups (most p values <0.001). Considering the elderly who were 70 years or older, SuperAgers showed higher scores for delayed recall memory, better global cognition, and verbal fluency than controls at wave 3 (all p values <0.001). Conclusion: The ELSA-Brasil study will be a unique opportunity to unravel the determinants of brain aging in an admixed sample in Latin America.

A Filamina C (FLNC) desempenha um papel crítico na manutenção da integridade estrutural das células musculares, particularmente dentro do sarcômero cardíaco. Variantes patogênicas no gene FLNC são cada vez mais reconhecidas como contribuintes significativos para uma gama diversificada de cardiomiopatias, incluindo cardiomiopatia dilatada (CMD), hipertrófica (CMH), arritmogênica (CMA) e restritiva (CMR). Esta revisão explora as correlações genótipo-fenótipo em cardiomiopatias relacionadas ao gene FLNC, enfatizando como o tipo e a localização das variantes genéticas influenciam a apresentação clínica. Variantes truncadas são principalmente associadas a CMD e CMA, caracterizadas por um alto risco de eventos arrítmicos e resultados graves, enquanto variantes missense frequentemente levam a CMH e CMR, com características fenotípicas únicas. A revisão também discute os padrões de herança, mecanismos moleculares e fenótipos clínicos de miopatias associadas à FLNC, destacando a necessidade de testes genéticos na estratificação e gestão de risco. Perspectivas futuras enfatizam a importância de expandir a pesquisa sobre os mecanismos subjacentes das variantes em filamina C e suas interações com outros fatores genéticos e ambientais. Essa compreensão integrada é crítica para melhorar o gerenciamento clínico de pacientes com cardiomiopatias relacionadas a FLNC.

Artificial intelligence is increasingly used to extract health insights from 12-lead (12L) electrocardiograms (ECG). Here, we propose a deeplearning model to predict sex and age from 12L and reduced-lead ECGs (6L–1L) and assess their impact on mortality risk. Using a ResNeXt-based model trained on the CODE15 dataset, our best models achieved an F1-score of 0.800 for sex classification (12L) and a mean absolute error of 8.961 for age estimation (4L). We found that overestimated age predictions and incorrect sex classifications were associated with higher mortality risk, whereas underestimated age predictions correlated with lower risk. These findings highlight the potential of reduced-lead ECGs for risk assessment, expanding their clinical utility.

O gene MYH7, que codifica a cadeia pesada da beta-miosina, é um componente crítico na integridade estrutural e funcional das células musculares cardíacas e esqueléticas. Variantes no MYH7 estão entre as causas genéticas mais comuns de cardiomiopatias, particularmente cardiomiopatia hipertrófica (CMH) e cardiomiopatia dilatada (CMD), e também foram implicadas na cardiomiopatia restritiva (CMR) e com hipertrabeculação do ventrículo esquerdo (HTVE). Esta revisão explora os mecanismos moleculares pelos quais as variantes do MYH7 levam a esses fenótipos diversos, com foco nas correlações genótipo-fenótipo que fundamentam as manifestações clínicas de cada condição. As variantes do MYH7 são principalmente do tipo missense concentradas no domínio da cabeça da miosina, afetando a função contrátil da proteína. Essas variantes levam a um amplo espectro de anormalidades cardíacas, desde o espessamento das paredes miocárdicas até a dilatação das câmaras cardíacas. A revisão também aborda as implicações mais amplas das mutações do MYH7, incluindo seu papel nas miopatias esqueléticas e possíveis associações com o câncer. Compreender os mecanismos patogênicos das variantes do MYH7 não apenas aumenta a precisão do diagnóstico, mas também embasa o desenvolvimento de terapias-alvo. À medida que a integração de conhecimentos genéticos na prática clínica continua a evoluir, o gene MYH7 permanece um ponto crucial para o avanço na gestão e no tratamento das cardiomiopatias, oferecendo aos pacientes esperança de melhores desfechos clínicos por meio da medicina de precisão.

As variantes do gene ALPK3 (proteína alfa-quinase 3), em especial as variantes truncadas (ALPK3tv), têm sido associadas à cardiomiopatia hipertrófica (CMH) e à cardiomiopatia dilatada (CMD), contribuindo para a variabilidade fenotípica e para resultados clínicos graves. A CMH é caracterizada por uma hipertrofia ventricular esquerda não atribuível a outras causas, sendo uma condição genética comum, ligada frequentemente a variantes patogênicas em genes de sarcômeros. No entanto, em aproximadamente 40% dos casos, os testes genéticos não são capazes de identificar uma variante causal, o que sugere o envolvimento de genes não sarcoméricos, como o ALPK3. Estudos recentes revelam que a ALPK3tv bialélica está associada à cardiomiopatia grave de início precoce. Os pacientes podem apresentar uma progressão clínica da CMD na infância para a CMH, com função sistólica prejudicada na vida adulta. Nesses indivíduos, o fenótipo da CMH é caracterizado, em geral, por fibrose miocárdica extensa, padrões apicais ou concêntricos de hipertrofia ventricular esquerda e baixa prevalência de obstrução do trato de saída do ventrículo esquerdo. Os portadores de ALPK3tv também correm o risco de desenvolver disfunção miocárdica progressiva, insuficiência cardíaca e, em alguns casos, morte cardíaca súbita. Os mecanismos moleculares subjacentes à cardiomiopatia relacionada ao ALPK3 envolvem a interrupção de proteínas estruturais e regulatórias, como as miomesinas, essenciais para a integridade do sarcômero e o controle da força dos cardiomiócitos. A descoberta das variantes do gene ALPK3 em populações sub-representadas destaca a importância da pesquisa genética em diversas coortes. A compreensão das consequências clínicas e moleculares das variantes do gene ALPK3 pode resultar em abordagens diagnósticas e terapêuticas mais precisas para cardiomiopatias associadas a esse gene.