Gender differences in the relationship between sleep and age in a Brazilian cohort: the Baependi Heart Study.

Gender and age are well-established determinants of health and sleep health that influence overall health, which also often varies by gender and age. Sleep architecture is an important component of sleep health. The goal of this analysis was to examine whether associations between age and sleep stages differ by gender in the absence of moderate-severe obstructive sleep apnea (OSA) in a rural setting in Brazil. This study conducted polysomnography recordings in the Baependi Heart Study, a cohort of Brazilian adults. Our sample included 584 women and 309 men whose apnea-hypopnea index was ≤15 events/h. We used splines to distinguish non-linear associations between age, total sleep time, wake after sleep onset (WASO), N2, N3, and rapid-eye-movement sleep. The mean (standard deviation; range) age was 47 (14; 18-89) years. All sleep outcomes were associated with age. Compared to men, women had more N3 sleep and less WASO after adjusting for age. Model-based comparisons between genders at specific ages showed statistically higher mean WASO for men at ages 60 (+13.6 min) and 70 years (+19.5 min) and less N3 for men at ages 50 (-13.2 min), 60 (-19.0 min), and 70 years (-19.5 min) but no differences at 20, 30, 40 or 80 years. The other sleep measures did not differ by gender at any age. Thus, even in the absence of moderate-severe OSA, sleep architecture was associated with age across adulthood, and there were gender differences in WASO and N3 at older ages in this rural community.

Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomere-related P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted. METHODS: A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up. RESULTS: In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%-63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%-40%). Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for MYBPC3 (myosin-binding protein C3), ≈60% for TNNT2 (troponin T2) and TNNI3 (troponin I3), and ≈65% for MYH7 (myosin heavy chain 7). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean of ≈16 years of age. However, short-term gene-specific phenotypic conversion varied between ≈12% for MYBPC3 and ≈23% for MYH7. CONCLUSIONS: The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM.

Altered sleep architecture in diabetes and prediabetes: findings from the Baependi Heart Study.

STUDY OBJECTIVES: People with diabetes and prediabetes are more likely to have sleep-disordered breathing (SDB), but few studies examined sleep architecture in people with diabetes or prediabetes in the absence of moderate-severe SDB, which was the aim of our cross-sectional study. METHODS: This cross-sectional sample is from the Baependi Heart Study, a family-based cohort of adults in Brazil. About 1074 participants underwent at-home polysomnography (PSG). Diabetes was defined as fasting glucose >125 mg/dL or HbA1c > 6.4 mmol/mol or taking diabetic medication, and prediabetes was defined as HbA1c ≥ 5.7 & <6.5 mmol/mol or fasting glucose ≥ 100 & ≤125 mg/dl. We excluded participants with an apnea-hypopnea index (AHI) ≥ 30 in primary analyses and ≥ 15 in secondary analysis. We compared sleep stages among the 3 diabetes groups (prediabetes, diabetes, neither). RESULTS: Compared to those without diabetes, we found shorter REM duration for participants with diabetes (-6.7 min, 95%CI -13.2, -0.1) and prediabetes (-5.9 min, 95%CI -10.5, -1.3), even after adjusting for age, gender, BMI, and AHI. Diabetes was also associated with lower total sleep time (-13.7 min, 95%CI -26.8, -0.6), longer slow-wave sleep (N3) duration (+7.6 min, 95%CI 0.6, 14.6) and higher N3 percentage (+2.4%, 95%CI 0.6, 4.2), compared to those without diabetes. Results were similar when restricting to AHI < 15. CONCLUSIONS: People with diabetes and prediabetes had less REM sleep than people without either condition. People with diabetes also had more N3 sleep. These results suggest that diabetes and prediabetes are associated with differences in sleep architecture, even in the absence of moderate-severe sleep apnea.

Relationship of blood pressure measured in the calf with arm blood pressure and arterial stiffness: a general population study.

AIM: Leg blood pressure (BP) measurement is needed when arm BP evaluation is not feasible, and calf BP, especially when measured in standing position, may have greater association with cardiovascular remodeling than arm BP. This study evaluated the relationship between calf and arm BP, and investigated whether calf BP would be superior to arm BP in predicting increased arterial stiffness [pulse wave velocity (PWV) > 10 m/s]. METHODS: We evaluated clinical and laboratory characteristics, BP measurements, and PWV in 1397 individuals resident in Baependi, Brazil, between 2017 and 2019. Arm BP was measured in the seated and supine positions while calf BP was measured in supine and standing positions using digital oscillometric devices. Carotid-femoral PWV was measured using a noninvasive mechanotransducer. RESULTS: The sample had 62.7% females, age = 48.1 ±â€Š15.4 years and 8.4% with PWV >10 m/s. Results of linear regression analysis showed that BP values of 140/90 mmHg measured in the arm in supine and seated position were equivalent to calf supine BP values of 164/81 mmHg and 166/78 mmHg and calf standing BP values of 217/137 mmHg and 221/137 mmHg, respectively. Calf-arm BP differences were associated with age, glomerular filtration rate, body mass index, smoking, low-density lipoprotein-cholesterol, diabetes and height. Furthermore, stepwise logistic regression analysis revealed that arm supine systolic BP, but not calf BP measurements, was independently associated with increased arterial stiffness. CONCLUSION: Thresholds of ≈165/80 mmHg and ≈220/135 mmHg could be used for diagnosing hypertension when only calf measurements in supine and standing positions, respectively, are available. Conversely, calf BP was not superior to arm BP in predicting increased arterial stiffness.

Carotid intima-media thickness and incident hypertension: the Brazilian Longitudinal Study of Adult Health.

BACKGROUND: High blood pressure (BP) increases carotid intima-media thickness (CIMT). On the other hand, it is not clear whether the vascular abnormalities reflected in high CIMT may predict incident hypertension. The present study aims to investigate the association between CIMT and incident hypertension after 4 years of follow-up in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), a multiethnic sample of middle-aged adults from six Brazilian cities. METHODS: We analyzed data from 6682 ELSA-Brasil participants (aged 35-74) without hypertension and with complete CIMT data at baseline. After 4 years of follow-up, we describe hypertension incidence, stratifying the sample according to age, sex, and race-specific CIMT quartiles. We also built crude and adjusted Poisson regression models to analyze the association between mean and maximal CIMT values and incident hypertension. RESULTS: We found incident hypertension in 987 (14.8%) participants. According to mean CIMT quartile groups, hypertension incidence varied from 10.2% (first quartile group) to 22.4% (fourth quartile group; P for trend <0.001). In fully adjusted models, 0.1 mm increments in mean CIMT values were associated with a 16% [relative risk (RR):1.16; 95% confidence interval (95% CI) 1.10-1.21; P  < 0.001] higher risk of incident hypertension, respectively. Results were similar when maximal CIMT values were considered instead of mean CIMT values. CONCLUSION: CIMT values at baseline strongly predicted incident hypertension after 4 years of follow-up in this large multiethnic cohort. This highlights the relationship between CIMT and BP and may provide important insights into the significance of this ultrasound measurement.

Percentiles of predicted 10-year cardiovascular disease risk by sex and age in Brazil and their association with estimated risk of long-term atherosclerotic events.

OBJECTIVE: Expressing the cardiovascular disease (CVD) risk in relation to peers may complement the estimation of absolute CVD risk. We aimed to determine 10-year CVD risk percentiles by sex and age in the Brazilian population and evaluate their association with estimated long-term atherosclerotic CVD (ASCVD) risk. METHODS: A cross-sectional analysis of baseline data from the ELSA-Brasil study was conducted in individuals aged 40-74 years without prior ASCVD. Ten-year CVD risk and long-term ASCVD risk were estimated by the WHO risk score and the Multinational Cardiovascular Risk Consortium tool, respectively. Ten-year risk percentiles were determined by ranking the calculated risks within each sex and age group. RESULTS: Ten-year CVD risk versus percentile plots were constructed for each sex and age group using data from 13,364 participants (55% females; median age, 52 [IQR, 46-59] years). Long-term ASCVD risk was calculated in 12,973 (97.1%) participants. Compared to individuals at the <25th risk percentile, those at the ≥75th percentile had a greater risk of being in the highest quartile of long-term risk (ORs [95% CIs] 6.57 [5.18-8.30] in females and 11.59 [8.42-15.96] in males) in regression models adjusted for age, race, education, and 10-year CVD risk. In both sexes, the association between risk percentile and long-term risk weakened after age 50. A tool for calculating 10-year CVD risk and the corresponding percentile is available at https://bit.ly/3CzPUi6. CONCLUSIONS: We established percentiles of predicted 10-year CVD risk by sex and age in the Brazilian population, which independently reflect the estimated long-term ASCVD risk in younger individuals.

Cardiac Remodeling in Subclinical Hypertrophic Cardiomyopathy: The VANISH Randomized Clinical Trial.

Importance: Valsartan has shown promise in attenuating cardiac remodeling in patients with early-stage sarcomeric hypertrophic cardiomyopathy (HCM). Genetic testing can identify individuals at risk of HCM in a subclinical stage who could benefit from therapies that prevent disease progression. Objective: To explore the potential for valsartan to modify disease development, and to characterize short-term phenotypic progression in subclinical HCM. Design, Setting, and Participants: The multicenter, double-blind, placebo-controlled Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) randomized clinical trial was conducted from April 2014 to July 2019 at 17 sites in 4 countries (Brazil, Canada, Denmark, and the US), with 2 years of follow-up. The prespecified exploratory VANISH cohort studied here included sarcomere variant carriers with subclinical HCM and early phenotypic manifestations (reduced E' velocity, electrocardiographic abnormalities, or an increased left ventricular [LV] wall thickness [LVWT] to cavity diameter ratio) but no LV hypertrophy (LVH). Data were analyzed between March and December 2022. Interventions: Treatment with placebo or valsartan (80 mg/d for children weighing <35 kg, 160 mg/d for children weighing ≥35 kg, or 320 mg/d for adults aged ≥18 years). Main Outcomes and Measures: The primary outcome was a composite z score incorporating changes in 9 parameters of cardiac remodeling (LV cavity volume, LVWT, and LV mass; left atrial [LA] volume; E' velocity and S' velocity; and serum troponin and N-terminal prohormone of brain natriuretic peptide levels). Results: This study included 34 participants, with a mean (SD) age of 16 (5) years (all were White). A total of 18 participants (8 female [44%] and 10 male [56%]) were randomized to valsartan and 16 (9 female [56%] and 7 male [44%]) were randomized to placebo. No statistically significant effects of valsartan on cardiac remodeling were detected (mean change in composite z score compared with placebo: -0.01 [95% CI, -0.29 to 0.26]; P = .92). Overall, 2-year phenotypic progression was modest, with only a mild increase in LA volume detected (increased by 3.5 mL/m2 [95% CI, 1.4-6.0 mL/m2]; P = .002). Nine participants (26%) had increased LVWT, including 6 (18%) who developed clinically overt HCM. Baseline LA volume index (LAVI; 35 vs 28 mL/m2; P = .01) and average interventricular septum thickness (8.5 vs 7.0 mm; P = .009) were higher in participants who developed HCM. Conclusions and Relevance: In this exploratory cohort, valsartan was not proven to slow progression of subclinical HCM. Minimal changes in markers of cardiac remodeling were observed, although nearly one-fifth of patients developed clinically overt HCM. Transition to disease was associated with greater baseline interventricular septum thickness and LAVI. These findings highlight the importance of following sarcomere variant carriers longitudinally and the critical need to improve understanding of factors that drive disease penetrance and progression. Trial Registration: ClinicalTrials.gov Identifier: NCT01912534.

Combined Association of Novel and Traditional Inflammatory Biomarkers With Carotid Artery Plaque: GlycA Versus C-Reactive Protein (ELSA-Brasil).

Elevated levels of glycoprotein acetylation (GlycA) and C-reactive protein (CRP) have been associated with carotid artery plaque (CAP). However, it is not yet established if elevations in both inflammatory biomarkers provide incremental association with CAP. This study aimed evaluate the cross-sectional association of high CRP and GlycA with CAP at baseline participants from the ELSA-Brasil adult cohort. Participants with information on CRP, GlycA, and CAP with neither previous cardiovascular disease nor CRP >10 mg/L were included. High GlycA and CRP were defined as values within upper quintile and >3 mg/L, respectively. Participants were classified into 4 groups: 1. nonelevated CRP/GlycA (reference group); 2. elevated CRP alone; 3. elevated GlycA alone; and 4. both elevated. The analysis included 4,126 participants with median age of 50 years-old, being 54.2% of women. Prevalence of CAP was 36.1%. Participants with high CRP had the highest frequency of obesity, whereas participants with high GlycA presented higher cardiovascular risk factor burden and were more likely to have CAP than the reference group (odds ratio [OR] 1.39, 95% confidence interval [CI] 1.11 to 1.73), persisting after multivariable adjustment (OR 1.37, 95% CI 1.02 to 1.83). Participants with both elevated CRP and GlycA were more likely to have CAP in crude (OR 1.35, 95% CI 1.10 to 1.65) but not in adjusted models. The findings suggest potential different biologic pathways between inflammation and carotid atherosclerosis: high GlycA was associated with CAP whereas high CRP was more associated with obesity.

Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure.

We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of heart failure.

Contribution of Previously Unrecognized RNA Splice-Altering Variants to Congenital Heart Disease.

BACKGROUND: Known genetic causes of congenital heart disease (CHD) explain <40% of CHD cases, and interpreting the clinical significance of variants with uncertain functional impact remains challenging. We aim to improve diagnostic classification of variants in patients with CHD by assessing the impact of noncanonical splice region variants on RNA splicing. METHODS: We tested de novo variants from trio studies of 2649 CHD probands and their parents, as well as rare (allele frequency, <2×10-6) variants from 4472 CHD probands in the Pediatric Cardiac Genetics Consortium through a combined computational and in vitro approach. RESULTS: We identified 53 de novo and 74 rare variants in CHD cases that alter splicing and thus are loss of function. Of these, 77 variants are in known dominant, recessive, and candidate CHD genes, including KMT2D and RBFOX2. In 1 case, we confirmed the variant's predicted impact on RNA splicing in RNA transcripts from the proband's cardiac tissue. Two probands were found to have 2 loss-of-function variants for recessive CHD genes HECTD1 and DYNC2H1. In addition, SpliceAI-a predictive algorithm for altered RNA splicing-has a positive predictive value of ≈93% in our cohort. CONCLUSIONS: Through assessment of RNA splicing, we identified a new loss-of-function variant within a CHD gene in 78 probands, of whom 69 (1.5%; n=4472) did not have a previously established genetic explanation for CHD. Identification of splice-altering variants improves diagnostic classification and genetic diagnoses for CHD. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT01196182.

Racial Inequities in the Control of Hypertension and the Explanatory Role of Residential Segregation: a Decomposition Analysis in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

The mechanisms underlying racial inequities in uncontrolled hypertension have been limited to individual factors. We investigated racial inequities in uncontrolled hypertension and the explanatory role of economic segregation in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). All 3897 baseline participants with hypertension (2008-2010) were included. Uncontrolled hypertension (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg), self-reported race (White/Brown/Black people), and neighborhood economic segregation (low/medium/high) were analyzed cross-sectionally. We used decomposition analysis, which describes how much a disparity would change (disparity reduction; explained portion) and remain (disparity residual; unexplained portion) upon removing racial differences in economic segregation (i.e., if Black people had the distribution of segregation of White people, how much we would expect uncontrolled hypertension to decrease among Black people). Age- and gender-adjusted prevalence of uncontrolled hypertension (39.0%, 52.6%, and 54.2% for White, Brown, and Black participants, respectively) remained higher for Black and Brown vs White participants, regardless of economic segregation. Uncontrolled hypertension showed a dose-response pattern with increasing segregation levels for White but not for Black and Brown participants. After adjusting for age, gender, education, and study center, unexplained portion (disparity residual) of race on uncontrolled hypertension was 18.2% (95% CI 13.4%; 22.9%) for Black vs White participants and 12.6% (8.2%; 17.1%) for Brown vs White participants. However, explained portion (disparity reduction) through economic segregation was - 2.1% (- 5.1%; 1.3%) for Black vs White and 0.5% (- 1.7%; 2.8%) for Brown vs White participants. Although uncontrolled hypertension was greater for Black and Brown vs White people, racial inequities in uncontrolled hypertension were not explained by economic segregation.

Multi-Omics Profiling of Hypertrophic Cardiomyopathy Reveals Altered Mechanisms in Mitochondrial Dynamics and Excitation-Contraction Coupling.

Hypertrophic cardiomyopathy is one of the most common inherited cardiomyopathies and a leading cause of sudden cardiac death in young adults. Despite profound insights into the genetics, there is imperfect correlation between mutation and clinical prognosis, suggesting complex molecular cascades driving pathogenesis. To investigate this, we performed an integrated quantitative multi-omics (proteomic, phosphoproteomic, and metabolomic) analysis to illuminate the early and direct consequences of mutations in myosin heavy chain in engineered human induced pluripotent stem-cell-derived cardiomyocytes relative to late-stage disease using patient myectomies. We captured hundreds of differential features, which map to distinct molecular mechanisms modulating mitochondrial homeostasis at the earliest stages of pathobiology, as well as stage-specific metabolic and excitation-coupling maladaptation. Collectively, this study fills in gaps from previous studies by expanding knowledge of the initial responses to mutations that protect cells against the early stress prior to contractile dysfunction and overt disease.

Cardiomyocyte infection by Trypanosoma cruzi promotes innate immune response and glycolysis activation.

Introduction: Chagas cardiomyopathy, a disease caused by Trypanosoma cruzi (T. cruzi) infection, is a major contributor to heart failure in Latin America. There are significant gaps in our understanding of the mechanism for infection of human cardiomyocytes, the pathways activated during the acute phase of the disease, and the molecular changes that lead to the progression of cardiomyopathy. Methods: To investigate the effects of T. cruzi on human cardiomyocytes during infection, we infected induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) with the parasite and analyzed cellular, molecular, and metabolic responses at 3 hours, 24 hours, and 48 hours post infection (hpi) using transcriptomics (RNAseq), proteomics (LC-MS), and metabolomics (GC-MS and Seahorse) analyses. Results: Analyses of multiomic data revealed that cardiomyocyte infection caused a rapid increase in genes and proteins related to activation innate and adaptive immune systems and pathways, including alpha and gamma interferons, HIF-1α signaling, and glycolysis. These responses resemble prototypic responses observed in pathogen-activated immune cells. Infection also caused an activation of glycolysis that was dependent on HIF-1α signaling. Using gene editing and pharmacological inhibitors, we found that T. cruzi uptake was mediated in part by the glucose-facilitated transporter GLUT4 and that the attenuation of glycolysis, HIF-1α activation, or GLUT4 expression decreased T. cruzi infection. In contrast, pre-activation of pro-inflammatory immune responses with LPS resulted in increased infection rates. Conclusion: These findings suggest that T. cruzi exploits a HIF-1α-dependent, cardiomyocyte-intrinsic stress-response activation of glycolysis to promote intracellular infection and replication. These chronic immuno-metabolic responses by cardiomyocytes promote dysfunction, cell death, and the emergence of cardiomyopathy.

Cardiovascular disease onset in old people with severe hypercholesterolemia.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) variants are associated with higher atherosclerotic cardiovascular disease risk (ASCVD) even when compared with other forms of severe hypercholesterolemia, especially in young people. Lipid lowering therapies (LLT) may change hypercholesterolemia natural history. This study aimed at evaluating factors associated with occurrence of ASCVD in old severe hypercholesterolemics diagnosed or not with FH and undergoing LLT. METHODS: Hypercholesterolemic individuals ≥60 years participating on a genetic cascade screening for FH were divided in 4 groups (2 × 2) according to the presence (variant+) or not (variant-) of FH genetic variants and previous ASCVD (ASCVD+ and ASCVD-). Biomarkers associated with new incident ASCVD events were tested using Cox models. Continuous data shown as medians (%25; %75). RESULTS: From 4,111 genotyped individuals, 377 (9.1%) were elderly [age 66 (63; 71) years], 28.9% males, 42.7% variant+, 32.1% with previous ASCVD, LLT duration 9 (5; 16) years, and on treatment LDL-cholesterol 144 (109; 200) mg/dL. After 4.8 (7; 3) years of follow up there were 47 incident events (12.4%, 2.7% patient/year). The annualized event rates were 0.8% (95% CI 0.36%; 1.70%), 2.3% (95% CI 1.3%; 4.1%), 5.2% (95% CI 2.8%; 9.7%) and 6.3% (95% CI 4.0%; 10.0%) respectively for groups variant-/ASCVD-, variant+/ASCVD-, variant-/ASCVD+ and, variant+/ASCVD+ (p log rank p < 0.001). Only presence of previous ASCVD was independently associated with incident ASCVD [hazard ratio 3.236 (95%CI 1.497-6.993, p = 0.003)]. No interaction was found for previous ASCVD and variants. CONCLUSIONS: In old severe hypercholesterolemic individuals undergoing long-term LLT previous ASCVD was associated with incident events while FH causing variants were not.

mTOR signaling inhibition decreases lysosome migration and impairs the success of Trypanosoma cruzi infection and replication in cardiomyocytes.

Chagas disease is caused by the parasite Trypanosoma cruzi (T. cruzi) and, among all the chronic manifestations of the disease, Chronic Chagas Cardiomyopathy (CCC) is the most severe outcome. Despite high burden and public health importance in Latin America, there is a gap in understanding the molecular mechanisms that results in CCC development. Previous studies showed that T. cruzi uses the host machinery for infection and replication, including the repurposing of the responses to intracellular infection such as mitochondrial activity, vacuolar membrane, and lysosomal activation in benefit of parasite infection and replication. One common signaling upstream to many responses to parasite infection is mTOR pathway, previous associated to several downstream cellular mechanisms including autophagy, mitophagy and lysosomal activation. Here, using human iPSC derived cardiomyocytes (hiPSCCM), we show the mTOR pathway is activated in hiPSCCM after T. cruzi infection, and the inhibition of mTOR with rapamycin reduced number of T. cruzi 48 h post infection (hpi). Rapamycin treatment also reduced lysosome migration from nuclei region to cell periphery resulting in less T. cruzi inside the parasitophorous vacuole (PV) in the first hour of infection. In addition, the number of parasites leaving the PV to the cytoplasm to replicate in later times of infection was also lower after rapamycin treatment. Altogether, our data suggest that host's mTOR activation concomitant with parasite infection modulates lysosome migration and that T. cruzi uses this mechanism to achieve infection and replication. Modulating this mechanism with rapamycin impaired the success of T. cruzi life cycle independent of mitophagy.

Erratum: Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits-The Hispanic/Latino Anthropometry Consortium.

[This corrects the article DOI: 10.1016/j.xhgg.2022.100099.].

Saúde Cardiovascular e Fibrilação ou Flutter Atrial: Um Estudo Transversal do ELSA-Brasil / Cardiovascular Health and Atrial Fibrillation or Flutter: A Cross-Sectional Study from ELSA-Brasil

Resumo Fundamento A associação entre o status de saúde cardiovascular ideal ( ideal cardiovascular health ( ICVH) e diagnóstico de fibrilação ou flutter atrial (FFA) foi menos estudado em comparação a outras doenças cardiovasculares. Objetivos Analisar a associação entre o diagnóstico de FFA e métricas e escores de ICVH no Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil). Métodos Este estudo analisou dados de 13141 participantes com dados completos. Os traçados eletrocardiográficos foram codificados de acordo com o Sistema de Minnesota, em um centro de leitura centralizado. As métricas do ICVH (dieta, atividade física, índice de massa corporal, tabagismo, glicemia de jeju, e colesterol total) e escores do ICVH foram calculados conforme proposto pela American Heart Association . Modelos de regressão logística bruta e ajustada foram construídos para analisar associações de métricas e escores do ICVH com diagnóstico de FFA. O nível de significância foi estabelecido em 0,05. Resultados A idade mediana da amostra foi de 55 anos, e 54,4% eram mulheres. Nos modelos ajustados, os escores de ICVH não apresentaram associação significativa com diagnóstico de FFA prevalente [odds ratio (OR):0,96; intervalo de confiança de 95% (IC95%):0,80-1,16; p=0,70). Perfis de pressão arterial ideal (OR:0,33; IC95%:0,1-0,74; p=0,007) e colesterol total ideal (OR:1,88; IC95%:1,19-2,98; p=0,007) foram significativamente associados com o diagnóstico de FFA. Conclusões Não foram identificadas associações significativas entre escores de ICVH global e diagnóstico de FFA após ajuste multivariado em nossas análises, devido, ao menos em parte, às associações antagônicas da FFA com métricas de pressão arterial e de colesterol total do ICVH. Nossos resultados sugerem que estimar a prevenção da FFA por meio de escore de ICVH global pode não ser adequado, e as métricas do ICVH devem ser consideradas separadamente.

Abstract Background The association between ideal cardiovascular health (ICVH) status and atrial fibrillation or flutter (AFF) diagnosis has been less studied compared to other cardiovascular diseases. Objective To analyze the association between AFF diagnosis and ICVH metrics and scores in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Methods This study analyzed data from 13,141 participants with complete data. Electrocardiographic tracings were coded according to the Minnesota Coding System, in a centralized reading center. ICVH metrics (diet, physical activity, body mass index, smoking, blood pressure, fasting plasma glucose, and total cholesterol) and scores were calculated as proposed by the American Heart Association. Crude and adjusted binary logistic regression models were built to analyze the association of ICVH metrics and scores with AFF diagnosis. Significance level was set at 0.05. Results The sample had a median age of 55 years and 54.4% were women. In adjusted models, ICVH scores were not significantly associated with prevalent AFF diagnosis (odds ratio [OR]:0.96; 95% confidence interval [95% CI]:0.80-1.16; p=0.70). Ideal blood pressure (OR:0.33; 95% CI:0.15-0.74; p=0.007) and total cholesterol (OR:1.88; 95% CI:1.19-2.98; p=0.007) profiles were significantly associated with AFF diagnosis. Conclusions No significant associations were identified between global ICVH scores and AFF diagnosis after multivariable adjustment in our analyses, at least partially due to the antagonistic associations of AFF with blood pressure and total cholesterol ICVH metrics. Our results suggest that estimating the prevention of AFF burden using global ICVH scores may not be adequate, and ICVH metrics should be considered in separate.

Genome-wide analyses identify SCN5A as a susceptibility locus for premature atrial contraction frequency.

Premature atrial contractions (PACs) are frequently observed on electrocardiograms and are associated with increased risks of atrial fibrillation (AF), stroke, and mortality. In this study, we aimed to identify genetic susceptibility loci for PAC frequency. We performed a genome-wide association study meta-analysis with PAC frequency obtained from ambulatory cardiac monitoring in 4,831 individuals of European ancestry. We identified a genome-wide significant locus at the SCN5A gene. The lead variant, rs7373862, located in an intron of SCN5A, was associated with an increase of 0.12 [95% CI 0.08-0.16] standard deviations of the normalized PAC frequency per risk allele. Among genetic variants previously associated with AF, there was a significant enrichment in concordance of effect for PAC frequency (n = 73/106, p = 5.1 × 10-5). However, several AF risk loci, including PITX2, were not associated with PAC frequency. These findings suggest the existence of both shared and distinct genetic mechanisms for PAC frequency and AF.

Genome-wide association study for Chagas Cardiomyopathy identify a new risk locus on chromosome 18 associated with an immune-related protein and transcriptional signature.

BACKGROUND: Chronic Chagas Cardiomyopathy (CCC) usually develops between 10 and 20 years after the first parasitic infection and is one of the leading causes of end-stage heart failure in Latin America. Despite the great inter-individual variability in CCC susceptibility (only 30% of infected individuals ever present CCC), there are no known predictors for disease development in those chronically infected. METHODOLOGY/PRINCIPAL FINDINGS: We describe a new susceptibility locus for CCC through a GWAS analysis in the SaMi-Trop cohort, a population-based study conducted in a Chagas endemic region from Brazil. This locus was also associated with CCC in the REDS II Study. The newly identified locus (rs34238187, OR 0.73, p-value 2.03 x 10-9) spans a haplotype of approximately 30Kb on chromosome 18 (chr18: 5028302-5057621) and is also associated with 80 different traits, most of them blood protein traits significantly enriched for immune-related biological pathways. Hi-C data show that the newly associated locus is able to interact with chromatin sites as far as 10Mb on chromosome 18 in a number of different cell types and tissues. Finally, we were able to confirm, at the tissue transcriptional level, the immune-associated blood protein signature using a multi-tissue differential gene expression and enrichment analysis. CONCLUSIONS/SIGNIFICANCE: We suggest that the newly identified locus impacts CCC risk among T cruzi infected individuals through the modulation of a downstream transcriptional and protein signature associated with host-parasite immune response. Functional characterization of the novel risk locus is warranted.