RESUMEN
BACKGROUND AND AIMS: Low birth weight is a common pregnancy complication, which has been associated with higher risk of cardiometabolic disease in later life. Prior Mendelian randomization (MR) studies exploring this question do not distinguish the mechanistic contributions of variants that directly influence birth weight through the foetal genome (direct foetal effects), vs. variants influencing birth weight indirectly by causing an adverse intrauterine environment (indirect maternal effects). In this study, MR was used to assess whether birth weight, independent of intrauterine influences, is associated with cardiovascular disease risk and measures of adverse cardiac structure and function. METHODS: Uncorrelated (r2 < .001), genome-wide significant (P < 5 × 10-8) single nucleotide polymorphisms were extracted from genome-wide association studies summary statistics for birth weight overall, and after isolating direct foetal effects only. Inverse-variance weighted MR was utilized for analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischaemic stroke, and 16 measures of cardiac structure and function. Multiple comparisons were accounted for by Benjamini-Hochberg correction. RESULTS: Lower genetically-predicted birth weight, isolating direct foetal effects only, was associated with an increased risk of coronary artery disease (odds ratio 1.21, 95% confidence interval 1.06-1.37; P = .031), smaller chamber volumes, and lower stroke volume, but higher contractility. CONCLUSIONS: The results of this study support a causal role of low birth weight in cardiovascular disease, even after accounting for the influence of the intrauterine environment. This suggests that individuals with a low birth weight may benefit from early targeted cardiovascular disease prevention strategies, independent of whether this was linked to an adverse intrauterine environment during gestation.
Asunto(s)
Isquemia Encefálica , Enfermedad de la Arteria Coronaria , Accidente Cerebrovascular , Embarazo , Femenino , Humanos , Peso al Nacer/genética , Estudio de Asociación del Genoma Completo , Isquemia Encefálica/genética , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND: Observational studies suggest that electrocardiogram (ECG) indices might be influenced by obesity and other anthropometric measures, though it is difficult to infer causal relationships based on observational data due to risk of residual confounding. We utilized mendelian randomization (MR) to explore causal relevance of multiple anthropometric measures on P-wave duration (PWD), PR interval, QRS duration, and corrected QT interval (QTc). METHODS AND FINDINGS: Uncorrelated (r2 < 0.001) genome-wide significant (p < 5 × 10-8) single nucleotide polymorphisms (SNPs) were extracted from genome-wide association studies (GWAS) on body mass index (BMI, n = 806,834), waist:hip ratio adjusted for BMI (aWHR, n = 697,734), height (n = 709,594), weight (n = 360,116), fat mass (n = 354,224), and fat-free mass (n = 354,808). Genetic association estimates for the outcomes were extracted from GWAS on PR interval and QRS duration (n = 180,574), PWD (n = 44,456), and QTc (n = 84,630). Data source GWAS studies were performed between 2018 and 2022 in predominantly European ancestry individuals. Inverse-variance weighted MR was used for primary analysis; weighted median MR and MR-Egger were used as sensitivity analyses. Higher genetically predicted BMI was associated with longer PWD (ß 5.58; 95%CI [3.66,7.50]; p = < 0.001), as was higher fat mass (ß 6.62; 95%CI [4.63,8.62]; p < 0.001), fat-free mass (ß 9.16; 95%CI [6.85,11.47]; p < 0.001) height (ß 4.23; 95%CI [3.16, 5.31]; p < 0.001), and weight (ß 8.08; 95%CI [6.19,9.96]; p < 0.001). Finally, genetically predicted BMI was associated with longer QTc (ß 3.53; 95%CI [2.63,4.43]; p < 0.001), driven by both fat mass (ß 3.65; 95%CI [2.73,4.57]; p < 0.001) and fat-free mass (ß 2.08; 95%CI [0.85,3.31]; p = 0.001). Additionally, genetically predicted height (ß 0.98; 95%CI [0.46,1.50]; p < 0.001), weight (ß 3.45; 95%CI [2.54,4.36]; p < 0.001), and aWHR (ß 1.92; 95%CI [0.87,2.97]; p = < 0.001) were all associated with longer QTc. The key limitation is that due to insufficient power, we were not able to explore whether a single anthropometric measure is the primary driver of the associations observed. CONCLUSIONS: The results of this study support a causal role of BMI on multiple ECG indices that have previously been associated with atrial and ventricular arrhythmic risk. Importantly, the results identify a role of both fat mass, fat-free mass, and height in this association.
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Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Humanos , Antropometría , Índice de Masa Corporal , ElectrocardiografíaRESUMEN
Conclusions and Relevance: The findings of this study provide genetic evidence supporting an association between HDPs and higher risk of coronary artery disease and stroke, which is only partially mediated by cardiometabolic factors. This supports classification of HDPs as risk factors for cardiovascular disease. Design, Setting, and Participants: A genome-wide genetic association study using mendelian randomization (MR) was performed from February 16 to March 4, 2022. Primary analysis was conducted using inverse-variance-weighted MR. Mediation analyses were performed using a multivariable MR framework. All studies included patients predominantly of European ancestry. Female-specific summary-level data from FinnGen (sixth release). Exposures: Uncorrelated (r2<0.001) single-nucleotide variants (SNVs) were selected as instrumental variants from the FinnGen consortium summary statistics for exposures of any HDP, gestational hypertension, and preeclampsia or eclampsia. Importance: Hypertensive disorders in pregnancy (HDPs) are major causes of maternal and fetal morbidity and are observationally associated with future maternal risk of cardiovascular disease. However, observational results may be subject to residual confounding and bias. Main Outcomes and Measures: Genetic association estimates for outcomes were extracted from genome-wide association studies of 122â¯733 cases for coronary artery disease, 34â¯217 cases for ischemic stroke, 47â¯309 cases for heart failure, and 60â¯620 cases for atrial fibrillation. Objective: To investigate the association of HDPs with multiple cardiovascular diseases. Results: Genetically predicted HDPs were associated with a higher risk of coronary artery disease (odds ratio [OR], 1.24; 95% CI, 1.08-1.43; P = .002); this association was evident for both gestational hypertension (OR, 1.08; 95% CI, 1.00-1.17; P = .04) and preeclampsia/eclampsia (OR, 1.06; 95% CI, 1.01-1.12; P = .03). Genetically predicted HDPs were also associated with a higher risk of ischemic stroke (OR, 1.27; 95% CI, 1.12-1.44; P = 2.87 × 10-4). Mediation analysis revealed a partial attenuation of the effect of HDPs on coronary artery disease after adjustment for systolic blood pressure (total effect OR, 1.24; direct effect OR, 1.10; 95% CI, 1.02-1.08; P = .02) and type 2 diabetes (total effect OR, 1.24; direct effect OR, 1.16; 95% CI, 1.04-1.29; P = .008). No associations were noted between genetically predicted HDPs and heart failure (OR, 0.97; 95% CI, 0.76-1.23; P = .79) or atrial fibrillation (OR, 1.11; 95% CI, 0.65-1.88; P = .71).
Asunto(s)
Fibrilación Atrial , Enfermedades Cardiovasculares , Enfermedad de la Arteria Coronaria , Diabetes Mellitus Tipo 2 , Eclampsia , Insuficiencia Cardíaca , Hipertensión Inducida en el Embarazo , Accidente Cerebrovascular Isquémico , Preeclampsia , Femenino , Humanos , Embarazo , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , Estudio de Asociación del Genoma Completo , Hipertensión Inducida en el Embarazo/epidemiología , Hipertensión Inducida en el Embarazo/genética , Preeclampsia/epidemiología , Preeclampsia/genética , Análisis de la Aleatorización MendelianaRESUMEN
BACKGROUND: Bariatric surgery results in significant weight loss and a reduction in the incidence of cardiovascular disease in patients with obesity; however, relatively little research considers its effect on the incidence of heart failure (HF). We aimed to determine whether bariatric surgery reduces the incidence of HF in patients with obesity, compared to non-surgical management. METHODS: A propensity-score matched, retrospective cohort study using patients records from the nationwide Clinical Practice Research Database (CPRD) was conducted. 3052 patients who received bariatric surgery were matched with 3052 patients who did not, according to propensity to receive bariatric surgery, determined through a logistic regression model. Patients were eligible if >18 years old, BMI > 35 kg/m2, and no prior diagnosis of HF. The pre-defined primary endpoint was the development of new HF, and secondary endpoints were all-cause mortality and hospitalisations due to HF. RESULTS: Patients who received bariatric surgery had a significantly lower incidence of new HF (hazard ratio 0.45, 95% confidence interval 0.28-0.73, p = 0.0011) and all-cause mortality (hazard ratio 0.56, 95% confidence interval 0.38-0.83, p = 0.0036). CONCLUSIONS: This study provides evidence of lower rates of HF and all-cause mortality in patients who undergo bariatric surgery, compared to propensity-score matched controls. Future studies to understand the mechanism(s) involved in this reduction and explore the lifetime benefits in high-risk cohorts are paramount.
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Cirugía Bariátrica , Insuficiencia Cardíaca , Humanos , Adolescente , Estudios de Cohortes , Estudios Retrospectivos , Puntaje de Propensión , Obesidad/diagnóstico , Obesidad/epidemiología , Obesidad/cirugía , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/cirugíaRESUMEN
Gynecomastia is defined as a palpable enlargement of the male breast, secondary to an increase in the glandular and stromal breast tissue. Gynecomastia is encountered in up to 80% of Klinefelter syndrome cases. The pathophysiology involves testosterone/estrogen imbalance. This review article will further explore the pathophysiology of gynecomastia along with the different lines of management.