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1.
Nat Commun ; 14(1): 266, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36650173

RESUMO

For any given body mass index (BMI), individuals vary substantially in fat distribution, and this variation may have important implications for cardiometabolic risk. Here, we study disease associations with BMI-independent variation in visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) fat depots in 40,032 individuals of the UK Biobank with body MRI. We apply deep learning models based on two-dimensional body MRI projections to enable near-perfect estimation of fat depot volumes (R2 in heldout dataset = 0.978-0.991 for VAT, ASAT, and GFAT). Next, we derive BMI-adjusted metrics for each fat depot (e.g. VAT adjusted for BMI, VATadjBMI) to quantify local adiposity burden. VATadjBMI is associated with increased risk of type 2 diabetes and coronary artery disease, ASATadjBMI is largely neutral, and GFATadjBMI is associated with reduced risk. These results - describing three metabolically distinct fat depots at scale - clarify the cardiometabolic impact of BMI-independent differences in body fat distribution.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Índice de Massa Corporal , Fatores de Risco , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/metabolismo , Adiposidade , Tecido Adiposo/diagnóstico por imagem , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/metabolismo
2.
Neth Heart J ; 31(1): 1-2, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36538263
3.
Circ Genom Precis Med ; : e003676, 2022 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-36580284

RESUMO

BACKGROUND: Absence of a dicrotic notch on finger photoplethysmography is an easily ascertainable and inexpensive trait that has been associated with age and prevalent cardiovascular disease. However, the trait exists along a continuum, and little is known about its genetic underpinnings or prognostic value for incident cardiovascular disease. METHODS: In 169 787 participants in the UK Biobank, we identified absent dicrotic notch on photoplethysmography and created a novel continuous trait reflecting notch smoothness using machine learning. Next, we determined the heritability, genetic basis, polygenic risk, and clinical relations for the binary absent notch trait and the newly derived continuous notch smoothness trait. RESULTS: Heritability of the continuous notch smoothness trait was 7.5%, compared with 5.6% for the binary absent notch trait. A genome-wide association study of notch smoothness identified 15 significant loci, implicating genes including NT5C2 (P=1.2×10-26), IGFBP3 (P=4.8×10-18), and PHACTR1 (P=1.4×10-13), compared with 6 loci for the binary absent notch trait. Notch smoothness stratified risk of incident myocardial infarction or coronary artery disease, stroke, heart failure, and aortic stenosis. A polygenic risk score for notch smoothness was associated with incident cardiovascular disease and all-cause death in UK Biobank participants without available photoplethysmography data. CONCLUSIONS: We found that a machine learning derived continuous trait reflecting dicrotic notch smoothness on photoplethysmography was heritable and associated with genes involved in vascular stiffness. Greater notch smoothness was associated with greater risk of incident cardiovascular disease. Raw digital phenotyping may identify individuals at risk for disease via specific genetic pathways.

4.
JAMA Cardiol ; 2022 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-36576811

RESUMO

Importance: The clinical utility of polygenic risk scores (PRS) for coronary artery disease (CAD) has not yet been established. Objective: To investigate the ability of a CAD PRS to potentially guide statin initiation in primary prevention after accounting for age and clinical risk. Design, Setting, and Participants: This was a longitudinal cohort study with enrollment starting on January 1, 2006, and ending on December 31, 2010, with data updated to mid-2021, using data from the UK Biobank, a long-term population study of UK citizens. A replication analysis was performed in Biobank Japan. The analysis included all patients without a history of CAD and who were not taking lipid-lowering therapy. Data were analyzed from January 1 to June 30, 2022. Exposures: Polygenic risk for CAD was defined as low (bottom 20%), intermediate, and high (top 20%) using a CAD PRS including 241 genome-wide significant single-nucleotide variations (SNVs). The pooled cohort equations were used to estimate 10-year atherosclerotic cardiovascular disease (ASCVD) risk and classify individuals as low (<5%), borderline (5-<7.5%), intermediate (7.5-<20%), or high risk (≥20%). Main Outcomes and Measures: Myocardial infarction (MI) and ASCVD events (defined as incident clinical CAD [including MI], stroke, or CV death). Results: A total of 330 201 patients (median [IQR] age, 57 [40-74] years; 189 107 female individuals [57%]) were included from the UK Biobank. Over the 10-year follow-up, 4454 individuals had an MI. The CAD PRS was significantly associated with the risk of MI in all age groups but had significantly stronger risk prediction at younger ages (age <50 years: hazard ratio [HR] per 1 SD of PRS, 1.72; 95% CI, 1.56-1.89; age 50-60 years: HR, 1.46; 95% CI, 1.38-1.53; age >60 years: HR, 1.42; 95% CI, 1.37-1.48; P for interaction <.001). In patients younger than 50 years, those with high PRS had a 3- to 4-fold increased associated risk of MI compared with those in the low PRS category. A significant interaction between CAD PRS and age was replicated in Biobank Japan. When CAD PRS testing was added to the clinical ASCVD risk score in individuals younger than 50 years, 591 of 4373 patients (20%) with borderline risk were risk stratified into intermediate risk, warranting initiation of statin therapy and 3198 of 7477 patients (20%) with both borderline or intermediate risk were stratified as low risk, thus not warranting therapy. Conclusions and Relevance: Results of this cohort study suggest that the predictive ability of a CAD PRS was greater in younger individuals and can be used to better identify patients with borderline and intermediate clinical risk who should initiate statin therapy.

5.
JAMA ; 328(19): 1935-1944, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36378208

RESUMO

Importance: Ascending thoracic aortic disease is an important cause of sudden death in the US, yet most aortic aneurysms are identified incidentally. Objective: To develop and validate a clinical score to estimate ascending aortic diameter. Design, Setting, and Participants: Using an ongoing magnetic resonance imaging substudy of the UK Biobank cohort study, which had enrolled participants from 2006 through 2010, score derivation was performed in 30 018 participants and internal validation in an additional 6681. External validation was performed in 1367 participants from the Framingham Heart Study (FHS) offspring cohort who had undergone computed tomography from 2002 through 2005, and in 50 768 individuals who had undergone transthoracic echocardiography in the Community Care Cohort Project, a retrospective hospital-based cohort of longitudinal primary care patients in the Mass General Brigham (MGB) network between 2001-2018. Exposures: Demographic and clinical variables (11 covariates that would not independently prompt thoracic imaging). Main Outcomes and Measures: Ascending aortic diameter was modeled with hierarchical group least absolute shrinkage and selection operator (LASSO) regression. Correlation between estimated and measured diameter and performance for identifying diameter 4.0 cm or greater were assessed. Results: The 30 018-participant training cohort (52% women), were a median age of 65.1 years (IQR, 58.6-70.6 years). The mean (SD) ascending aortic diameter was 3.04 (0.31) cm for women and 3.32 (0.34) cm for men. A score to estimate ascending aortic diameter explained 28.2% of the variance in aortic diameter in the UK Biobank validation cohort (95% CI, 26.4%-30.0%), 30.8% in the FHS cohort (95% CI, 26.8%-34.9%), and 32.6% in the MGB cohort (95% CI, 31.9%-33.2%). For detecting individuals with an ascending aortic diameter of 4 cm or greater, the score had an area under the receiver operator characteristic curve of 0.770 (95% CI, 0.737-0.803) in the UK Biobank, 0.813 (95% CI, 0.772-0.854) in the FHS, and 0.766 (95% CI, 0.757-0.774) in the MGB cohorts, although the model significantly overestimated or underestimated aortic diameter in external validation. Using a fixed-score threshold of 3.537, 9.7 people in UK Biobank, 1.8 in the FHS, and 4.6 in the MGB cohorts would need imaging to confirm 1 individual with an ascending aortic diameter of 4 cm or greater. The sensitivity at that threshold was 8.9% in the UK Biobank, 11.3% in the FHS, and 18.8% in the MGB cohorts, with specificities of 98.1%, 99.2%, and 96.2%, respectively. Conclusions and Relevance: A prediction model based on common clinically available data was derived and validated to predict ascending aortic diameter. Further research is needed to optimize the prediction model and to determine whether its use is associated with improved outcomes.


Assuntos
Aorta , Aneurisma Aórtico , Modelos Cardiovasculares , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aorta/diagnóstico por imagem , Aneurisma Aórtico/diagnóstico por imagem , Ecocardiografia , Estudos Retrospectivos , Valor Preditivo dos Testes , Aneurisma da Aorta Torácica/diagnóstico por imagem , Imageamento por Ressonância Magnética , Pesos e Medidas Corporais , Tomografia Computadorizada por Raios X , Estudos Longitudinais
6.
Nat Commun ; 13(1): 6914, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36376295

RESUMO

Heart failure is a leading cause of cardiovascular morbidity and mortality. However, the contribution of common genetic variation to heart failure risk has not been fully elucidated, particularly in comparison to other common cardiometabolic traits. We report a multi-ancestry genome-wide association study meta-analysis of all-cause heart failure including up to 115,150 cases and 1,550,331 controls of diverse genetic ancestry, identifying 47 risk loci. We also perform multivariate genome-wide association studies that integrate heart failure with related cardiac magnetic resonance imaging endophenotypes, identifying 61 risk loci. Gene-prioritization analyses including colocalization and transcriptome-wide association studies identify known and previously unreported candidate cardiomyopathy genes and cellular processes, which we validate in gene-expression profiling of failing and healthy human hearts. Colocalization, gene expression profiling, and Mendelian randomization provide convergent evidence for the roles of BCKDHA and circulating branch-chain amino acids in heart failure and cardiac structure. Finally, proteome-wide Mendelian randomization identifies 9 circulating proteins associated with heart failure or quantitative imaging traits. These analyses highlight similarities and differences among heart failure and associated cardiovascular imaging endophenotypes, implicate common genetic variation in the pathogenesis of heart failure, and identify circulating proteins that may represent cardiomyopathy treatment targets.


Assuntos
Estudo de Associação Genômica Ampla , Insuficiência Cardíaca , Humanos , Estudo de Associação Genômica Ampla/métodos , Fenótipo , Insuficiência Cardíaca/genética , Coração , Perfilação da Expressão Gênica , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença
7.
JACC Adv ; 1(3)2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36147540

RESUMO

BACKGROUND: State-of-the-art genetic risk interpretation for a common complex disease such as coronary artery disease (CAD) requires assessment for both monogenic variants-such as those related to familial hypercholesterolemia-as well as the cumulative impact of many common variants, as quantified by a polygenic score. OBJECTIVES: The objective of the study was to describe a combined monogenic and polygenic CAD risk assessment program and examine its impact on patient understanding and changes to clinical management. METHODS: Study participants attended an initial visit in a preventive genomics clinic and a disclosure visit to discuss results and recommendations, primarily via telemedicine. Digital postdisclosure surveys and chart review evaluated the impact of disclosure. RESULTS: There were 60 participants (mean age 51 years, 37% women, 72% with no known CAD), including 30 (50%) referred by their cardiologists and 30 (50%) self-referred. Two (3%) participants had a monogenic variant pathogenic for familial hypercholesterolemia, and 19 (32%) had a high polygenic score in the top quintile of the population distribution. In a postdisclosure survey, both the genetic test report (in 80% of participants) and the discussion with the clinician (in 89% of participants) were ranked as very or extremely helpful in understanding the result. Of the 42 participants without CAD, 17 or 40% had a change in management, including statin initiation, statin intensification, or coronary imaging. CONCLUSIONS: Combined monogenic and polygenic assessments for CAD risk provided by preventive genomics clinics are beneficial for patients and result in changes in management in a significant portion of patients.

8.
Nat Rev Cardiol ; 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36131050

RESUMO

Aortic disease has many forms including aortic aneurysm and dissection, aortic coarctation or abnormalities in aortic function, such as loss of aortic distensibility. Genetic analysis in humans is one of the most important experimental approaches in uncovering disease mechanisms, but the relative infrequency of thoracic aortic disease compared with other cardiovascular conditions such as coronary artery disease has hindered large-scale identification of genetic associations. In the past decade, advances in machine learning technology coupled with large imaging datasets from biobank repositories have facilitated a rapid expansion in our capacity to measure and genotype aortic traits, resulting in the identification of dozens of genetic associations. In this Review, we describe the history of technological advances in genetic discovery and explain how newer technologies such as deep learning can rapidly define aortic traits at scale. Furthermore, we integrate novel genetic observations provided by these advances into our current biological understanding of thoracic aortic disease and describe how these new findings can contribute to strategies to prevent and treat aortic disease.

9.
NPJ Digit Med ; 5(1): 131, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36056190

RESUMO

Physical activity is regarded as favorable to health but effects across the spectrum of human disease are poorly quantified. In contrast to self-reported measures, wearable accelerometers can provide more precise and reproducible activity quantification. Using wrist-worn accelerometry data from the UK Biobank prospective cohort study, we test associations between moderate-to-vigorous physical activity (MVPA) - both total MVPA minutes and whether MVPA is above a guideline-based threshold of ≥150 min/week-and incidence of 697 diseases using Cox proportional hazards models adjusted for age, sex, body mass index, smoking, Townsend Deprivation Index, educational attainment, diet quality, alcohol use, blood pressure, anti-hypertensive use. We correct for multiplicity at a false discovery rate of 1%. We perform analogous testing using self-reported MVPA. Among 96,244 adults wearing accelerometers for one week (age 62 ± 8 years), MVPA is associated with 373 (54%) tested diseases over a median 6.3 years of follow-up. Greater MVPA is overwhelmingly associated with lower disease risk (98% of associations) with hazard ratios (HRs) ranging 0.70-0.98 per 150 min increase in weekly MVPA, and associations spanning all 16 disease categories tested. Overall, associations with lower disease risk are enriched for cardiac (16%), digestive (14%), endocrine/metabolic (10%), and respiratory conditions (8%) (chi-square p < 0.01). Similar patterns are observed using the guideline-based threshold of ≥150 MVPA min/week. Some of the strongest associations with guideline-adherent activity include lower risks of incident heart failure (HR 0.65, 95% CI 0.55-0.77), type 2 diabetes (HR 0.64, 95% CI 0.58-0.71), cholelithiasis (HR 0.61, 95% CI 0.54-0.70), and chronic bronchitis (HR 0.42, 95% CI 0.33-0.54). When assessed within 456,374 individuals providing self-reported MVPA, effect sizes for guideline-adherent activity are substantially smaller (e.g., heart failure HR 0.84, 95% CI 0.80-0.88). Greater wearable device-based physical activity is robustly associated with lower disease incidence. Future studies are warranted to identify potential mechanisms linking physical activity and disease, and assess whether optimization of measured activity can reduce disease risk.

10.
Arterioscler Thromb Vasc Biol ; 42(11): 1355-1374, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36172868

RESUMO

BACKGROUND: Mural cells in ascending aortic aneurysms undergo phenotypic changes that promote extracellular matrix destruction and structural weakening. To explore this biology, we analyzed the transcriptional features of thoracic aortic tissue. METHODS: Single-nuclear RNA sequencing was performed on 13 samples from human donors, 6 with thoracic aortic aneurysm, and 7 without aneurysm. Individual transcriptomes were then clustered based on transcriptional profiles. Clusters were used for between-disease differential gene expression analyses, subcluster analysis, and analyzed for intersection with genetic aortic trait data. RESULTS: We sequenced 71 689 nuclei from human thoracic aortas and identified 14 clusters, aligning with 11 cell types, predominantly vascular smooth muscle cells (VSMCs) consistent with aortic histology. With unbiased methodology, we found 7 vascular smooth muscle cell and 6 fibroblast subclusters. Differentially expressed genes analysis revealed a vascular smooth muscle cell group accounting for the majority of differential gene expression. Fibroblast populations in aneurysm exhibit distinct behavior with almost complete disappearance of quiescent fibroblasts. Differentially expressed genes were used to prioritize genes at aortic diameter and distensibility genome-wide association study loci highlighting the genes JUN, LTBP4 (latent transforming growth factor beta-binding protein 1), and IL34 (interleukin 34) in fibroblasts, ENTPD1, PDLIM5 (PDZ and LIM domain 5), ACTN4 (alpha-actinin-4), and GLRX in vascular smooth muscle cells, as well as LRP1 in macrophage populations. CONCLUSIONS: Using nuclear RNA sequencing, we describe the cellular diversity of healthy and aneurysmal human ascending aorta. Sporadic aortic aneurysm is characterized by differential gene expression within known cellular classes rather than by the appearance of novel cellular forms. Single-nuclear RNA sequencing of aortic tissue can be used to prioritize genes at aortic trait loci.


Assuntos
Aneurisma da Aorta Torácica , Aneurisma Aórtico , Humanos , Estudo de Associação Genômica Ampla , Músculo Liso Vascular/metabolismo , Actinina/genética , RNA Nuclear/metabolismo , Aorta/patologia , Miócitos de Músculo Liso/metabolismo , Aneurisma da Aorta Torácica/patologia , Aneurisma Aórtico/metabolismo , Análise de Sequência de RNA , Fator de Crescimento Transformador beta/metabolismo
12.
Cardiovasc Digit Health J ; 3(4): 161-170, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36046430

RESUMO

Background and Objective: Postexercise heart rate recovery (HRR) is an important indicator of cardiac autonomic function and abnormal HRR is associated with adverse outcomes. We hypothesized that deep learning on resting electrocardiogram (ECG) tracings may identify individuals with impaired HRR. Methods: We trained a deep learning model (convolutional neural network) to infer HRR based on resting ECG waveforms (HRRpred) among UK Biobank participants who had undergone exercise testing. We examined the association of HRRpred with incident cardiovascular disease using Cox models, and investigated the genetic architecture of HRRpred in genome-wide association analysis. Results: Among 56,793 individuals (mean age 57 years, 51% women), the HRRpred model was moderately correlated with actual HRR (r = 0.48, 95% confidence interval [CI] 0.47-0.48). Over a median follow-up of 10 years, we observed 2060 incident diabetes mellitus (DM) events, 862 heart failure events, and 2065 deaths. Higher HRRpred was associated with lower risk of DM (hazard ratio [HR] 0.79 per 1 standard deviation change, 95% CI 0.76-0.83), heart failure (HR 0.89, 95% CI 0.83-0.95), and death (HR 0.83, 95% CI 0.79-0.86). After accounting for resting heart rate, the association of HRRpred with incident DM and all-cause mortality were similar. Genetic determinants of HRRpred included known heart rate, cardiac conduction system, cardiomyopathy, and metabolic trait loci. Conclusion: Deep learning-derived estimates of HRR using resting ECG independently associated with future clinical outcomes, including new-onset DM and all-cause mortality. Inferring postexercise heart rate response from a resting ECG may have potential clinical implications and impact on preventive strategies warrants future study.

13.
Nat Commun ; 13(1): 5106, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-36042188

RESUMO

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.


Assuntos
Endofenótipos , Síndrome do QT Longo , Suscetibilidade a Doenças , Humanos , Virulência
14.
J Am Coll Cardiol ; 80(9): 873-883, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-36007985

RESUMO

BACKGROUND: A familial predisposition to sudden and/or arrhythmic death (SAD) in the setting of coronary artery disease (CAD) exists; however, the genetic basis is poorly understood. OBJECTIVES: The purpose of this study was to determine whether a genome-wide polygenic score for coronary artery disease (GPSCAD) might have utility in SAD risk stratification in CAD patients without severe systolic dysfunction. METHODS: A previously validated GPSCAD was generated utilizing genome-wide genotyping in 4,698 PRE-DETERMINE participants of European ancestry with CAD and left ventricular ejection fraction >30%-35%. The population was dichotomized according to top GPSCAD decile as defined by the general population, and absolute, proportional, and relative risks for SAD and non-SAD were estimated using competing risk analyses. RESULTS: Over a median follow-up of 8.0 years, participants in the top GPSCAD decile were at elevated absolute SAD risk (8.0%; 95% CI: 5.1%-12.4% vs 4.8%; 95% CI: 3.3%-7.0%; P = 0.005) and proportional SAD risk (29% vs 16%; P = 0.0003) compared with the remainder. After controlling for left ventricular ejection fraction, clinical factors, and electrocardiogram parameters, the top GPSCAD decile was associated with SAD (subdistribution HR: 1.77; 95% CI: 1.23-2.54; P = 0.002) but not non-SAD (subdistribution HR: 1.00; 95% CI: 0.80-1.25; P = 0.98) (P for Δ = 0.003). The addition of the top GPSCAD decile to the multivariable model significantly improved net reclassification indexes (NRIs) (continuous NRI: 14.0%; P = 0.024; and categorical NRI: 6.6%; P = 0.005) but not the C-index (difference in C-index: 0.007; P = 0.143). CONCLUSIONS: Among CAD patients without severe systolic dysfunction, high GPSCAD specifically predicted SAD and enriched for both absolute and proportional SAD risk, identifying a population who might benefit from defibrillator therapy.


Assuntos
Doença da Artéria Coronariana , Doença da Artéria Coronariana/genética , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/etiologia , Humanos , Medição de Risco , Fatores de Risco , Volume Sistólico , Função Ventricular Esquerda
15.
JCI Insight ; 7(19)2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-35998035

RESUMO

Obesity is an important risk factor for atrial fibrillation (AF), but a better mechanistic understanding of obesity-related atrial fibrillation is required. Serum glucocorticoid kinase 1 (SGK1) is a kinase positioned within multiple obesity-related pathways, and prior work has shown a pathologic role of SGK1 signaling in ventricular arrhythmias. We validated a mouse model of obesity-related AF using wild-type mice fed a high-fat diet. RNA sequencing of atrial tissue demonstrated substantial differences in gene expression, with enrichment of multiple SGK1-related pathways, and we showed upregulated of SGK1 transcription, activation, and signaling in obese atria. Mice expressing a cardiac specific dominant-negative SGK1 were protected from obesity-related AF, through effects on atrial electrophysiology, action potential characteristics, structural remodeling, inflammation, and sodium current. Overall, this study demonstrates the promise of targeting SGK1 in a mouse model of obesity-related AF.


Assuntos
Fibrilação Atrial , Animais , Fibrilação Atrial/genética , Fibrilação Atrial/prevenção & controle , Modelos Animais de Doenças , Glucocorticoides/metabolismo , Átrios do Coração , Camundongos , Obesidade/complicações , Obesidade/genética , Obesidade/metabolismo , Sódio/metabolismo
16.
Nat Cardiovasc Res ; 1(7): 649-664, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36034743

RESUMO

Sudden cardiac death, arising from abnormal electrical conduction, occurs frequently in patients with coronary heart disease. Myocardial ischemia simultaneously induces arrhythmia and massive myocardial leukocyte changes. In this study, we optimized a mouse model in which hypokalemia combined with myocardial infarction triggered spontaneous ventricular tachycardia in ambulatory mice, and we showed that major leukocyte subsets have opposing effects on cardiac conduction. Neutrophils increased ventricular tachycardia via lipocalin-2 in mice, whereas neutrophilia associated with ventricular tachycardia in patients. In contrast, macrophages protected against arrhythmia. Depleting recruited macrophages in Ccr2 -/- mice or all macrophage subsets with Csf1 receptor inhibition increased both ventricular tachycardia and fibrillation. Higher arrhythmia burden and mortality in Cd36 -/- and Mertk -/- mice, viewed together with reduced mitochondrial integrity and accelerated cardiomyocyte death in the absence of macrophages, indicated that receptor-mediated phagocytosis protects against lethal electrical storm. Thus, modulation of leukocyte function provides a potential therapeutic pathway for reducing the risk of sudden cardiac death.

17.
JAMA Health Forum ; 3(8): e222419, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-36003419

RESUMO

Importance: Undiagnosed atrial fibrillation (AF) is an important cause of stroke. Screening for AF using wrist-worn wearable devices may prevent strokes, but their cost-effectiveness is unknown. Objective: To evaluate the cost-effectiveness of contemporary AF screening strategies, particularly wrist-worn wearable devices. Design Setting and Participants: This economic evaluation used a microsimulation decision-analytic model and was conducted from September 8, 2020, to May 23, 2022, comprising 30 million simulated individuals with an age, sex, and comorbidity profile matching the US population aged 65 years or older. Interventions: Eight AF screening strategies, with 6 using wrist-worn wearable devices (watch or band photoplethysmography, with or without watch or band electrocardiography) and 2 using traditional modalities (ie, pulse palpation and 12-lead electrocardiogram) vs no screening. Main Outcomes and Measures: The primary outcome was the incremental cost-effectiveness ratio, defined as US dollars per quality-adjusted life-year (QALY). Secondary measures included rates of stroke and major bleeding. Results: In the base case analysis of this model, the mean (SD) age was 72.5 (7.5) years, and 50% of the individuals were women. All 6 screening strategies using wrist-worn wearable devices were estimated to be more effective than no screening (range of QALYs gained vs no screening, 226-957 per 100 000 individuals) and were associated with greater relative benefit than screening using traditional modalities (range of QALYs gained vs no screening, -116 to 93 per 100 000 individuals). Compared with no screening, screening using wrist-worn wearable devices was associated with a reduction in stroke incidence by 20 to 23 per 100 000 person-years but an increase in major bleeding by 20 to 44 per 100 000 person-years. The overall preferred strategy was wearable photoplethysmography, followed conditionally by wearable electrocardiography with patch monitor confirmation, which had an incremental cost-effectiveness ratio of $57 894 per QALY, meeting the acceptability threshold of $100 000 per QALY. The cost-effectiveness of screening was consistent across multiple scenarios, including strata of sex, screening at earlier ages (eg, ≥50 years), and with variation in the association of anticoagulation with risk of stroke in the setting of screening-detected AF. Conclusions and Relevance: This economic evaluation of AF screening using a microsimulation decision-analytic model suggests that screening using wearable devices is cost-effective compared with either no screening or AF screening using traditional methods.


Assuntos
Fibrilação Atrial , Acidente Vascular Cerebral , Dispositivos Eletrônicos Vestíveis , Idoso , Fibrilação Atrial/diagnóstico , Análise Custo-Benefício , Feminino , Hemorragia/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/diagnóstico
18.
Eur Heart J ; 2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-35980763

RESUMO

AIMS: Interest in targeted screening programmes for atrial fibrillation (AF) has increased, yet the role of genetics in identifying patients at highest risk of developing AF is unclear. METHODS AND RESULTS: A total of 36,662 subjects without prior AF were analyzed from four TIMI trials. Subjects were divided into quintiles using a validated polygenic risk score (PRS) for AF. Clinical risk for AF was calculated using the CHARGE-AF model. Kaplan-Meier event rates, adjusted hazard ratios (HRs), C-indices, and net reclassification improvement were used to determine if the addition of the PRS improved prediction compared with clinical risk and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Over 2.3 years, 1018 new AF cases developed. AF PRS predicted a significant risk gradient for AF with a 40% increased risk per 1-SD increase in PRS [HR: 1.40 (1.32-1.49); P < 0.001]. Those with high AF PRS (top 20%) were more than two-fold more likely to develop AF [HR 2.45 (1.99-3.03), P < 0.001] compared with low PRS (bottom 20%). Furthermore, PRS provided an additional gradient of risk stratification on top of the CHARGE-AF clinical risk score, ranging from a 3-year incidence of 1.3% in patients with low clinical and genetic risk to 8.7% in patients with high clinical and genetic risk. The subgroup of patients with high clinical risk, high PRS, and elevated NT-proBNP had an AF risk of 16.7% over 3 years. The C-index with the CHARGE-AF clinical risk score alone was 0.65, which improved to 0.67 (P < 0.001) with the addition of NT-proBNP, and increased further to 0.70 (P < 0.001) with the addition of the PRS. CONCLUSION: In patients with cardiovascular conditions, AF PRS is a strong independent predictor of incident AF that provides complementary predictive value when added to a validated clinical risk score and NT-proBNP.

19.
Nature ; 608(7922): 353-359, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35922509

RESUMO

Regulation of transcript structure generates transcript diversity and plays an important role in human disease1-7. The advent of long-read sequencing technologies offers the opportunity to study the role of genetic variation in transcript structure8-16. In this Article, we present a large human long-read RNA-seq dataset using the Oxford Nanopore Technologies platform from 88 samples from Genotype-Tissue Expression (GTEx) tissues and cell lines, complementing the GTEx resource. We identified just over 70,000 novel transcripts for annotated genes, and validated the protein expression of 10% of novel transcripts. We developed a new computational package, LORALS, to analyse the genetic effects of rare and common variants on the transcriptome by allele-specific analysis of long reads. We characterized allele-specific expression and transcript structure events, providing new insights into the specific transcript alterations caused by common and rare genetic variants and highlighting the resolution gained from long-read data. We were able to perturb the transcript structure upon knockdown of PTBP1, an RNA binding protein that mediates splicing, thereby finding genetic regulatory effects that are modified by the cellular environment. Finally, we used this dataset to enhance variant interpretation and study rare variants leading to aberrant splicing patterns.


Assuntos
Alelos , Perfilação da Expressão Gênica , Especificidade de Órgãos , RNA-Seq , Transcriptoma , Processamento Alternativo/genética , Linhagem Celular , Conjuntos de Dados como Assunto , Genótipo , Ribonucleoproteínas Nucleares Heterogêneas/deficiência , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Especificidade de Órgãos/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/deficiência , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Reprodutibilidade dos Testes , Transcriptoma/genética
20.
J Am Coll Cardiol ; 80(5): 486-497, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35902171

RESUMO

BACKGROUND: The left ventricular outflow tract (LVOT) and ascending aorta are spatially complex, with distinct pathologies and embryologic origins. Prior work examined the genetics of thoracic aortic diameter in a single plane. OBJECTIVES: We sought to elucidate the genetic basis for the diameter of the LVOT, aortic root, and ascending aorta. METHODS: Using deep learning, we analyzed 2.3 million cardiac magnetic resonance images from 43,317 UK Biobank participants. We computed the diameters of the LVOT, the aortic root, and at 6 locations of ascending aorta. For each diameter, we conducted a genome-wide association study and generated a polygenic score. Finally, we investigated associations between these scores and disease incidence. RESULTS: A total of 79 loci were significantly associated with at least 1 diameter. Of these, 35 were novel, and most were associated with 1 or 2 diameters. A polygenic score of aortic diameter approximately 13 mm from the sinotubular junction most strongly predicted thoracic aortic aneurysm (n = 427,016; mean HR: 1.42 per SD; 95% CI: 1.34-1.50; P = 6.67 × 10-21). A polygenic score predicting a smaller aortic root was predictive of aortic stenosis (n = 426,502; mean HR: 1.08 per SD; 95% CI: 1.03-1.12; P = 5 × 10-6). CONCLUSIONS: We detected distinct genetic loci underpinning the diameters of the LVOT, aortic root, and at several segments of ascending aorta. We spatially defined a region of aorta whose genetics may be most relevant to predicting thoracic aortic aneurysm. We further described a genetic signature that may predispose to aortic stenosis. Understanding genetic contributions to proximal aortic diameter may enable identification of individuals at risk for aortic disease and facilitate prioritization of therapeutic targets.


Assuntos
Aneurisma , Aneurisma da Aorta Torácica , Estenose da Valva Aórtica , Aorta/diagnóstico por imagem , Aorta/patologia , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/epidemiologia , Aneurisma da Aorta Torácica/genética , Estenose da Valva Aórtica/genética , Constrição Patológica , Estudo de Associação Genômica Ampla , Humanos
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