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Greater adherence to plant-based diets is associated with a lower risk of incident chronic kidney disease (CKD). Metabolomics can help identify blood biomarkers of plant-based diets and enhance understanding of underlying mechanisms.Using untargeted metabolomics, we aimed to identify metabolites associated with 4 plant-based diet indices (PDIs) (overall PDI, provegetarian diet, healthful PDI, and unhealthful PDI) and incident CKD in 2 subgroups within the Atherosclerosis Risk in Communities study.We calculated 4 PDIs based on participants' responses on an FFQ. We used multivariable linear regression to examine the association between 4 PDIs and 374 individual metabolites, adjusting for confounders. We used Cox proportional hazards regression to evaluate associations between PDI-related metabolites and incident CKD. Estimates were meta-analyzed across 2 subgroups (n1 = 1762; n2 = 1960). We calculated C-statistics to assess whether metabolites improved the prediction of those in the highest quintile compared to the lower 4 quintiles of PDIs, and whether PDI- and CKD-related metabolites predicted incident CKD beyond the CKD prediction model.We identified 82 significant PDI-metabolite associations (overall PDI = 27; provegetarian = 17; healthful PDI = 20; unhealthful PDI = 18); 11 metabolites overlapped across the overall PDI, provegetarian diet, and healthful PDI. The addition of metabolites improved prediction of those in the highest quintile as opposed to the lower 4 quintiles of PDIs compared with participant characteristics alone (range of differences in C-statistics = 0.026-0.104; P value ≤ 0.001 for all tests). Six PDI-related metabolites (glycerate, 1,5-anhydroglucitol, γ-glutamylalanine, γ-glutamylglutamate, γ-glutamylleucine, γ-glutamylvaline), involved in glycolysis, gluconeogenesis, pyruvate metabolism, and γ-glutamyl peptide metabolism, were significantly associated with incident CKD and improved prediction of incident CKD beyond the CKD prediction model (difference in C-statistics for 6 metabolites = 0.005; P value = 0.006).In a community-based study of US adults, we identified metabolites that were related to plant-based diets and predicted incident CKD. These metabolites highlight pathways through which plant-based diets are associated with incident CKD.

BACKGROUND: High diet quality is associated with a lower risk of chronic diseases. Metabolomics can be used to identify objective biomarkers of diet quality. OBJECTIVES: We used metabolomics to identify serum metabolites associated with 4 diet indices and the components within these indices in 2 samples from African Americans and European Americans. METHODS: We studied cross-sectional associations between known metabolites and Healthy Eating Index (HEI)-2015, Alternative Healthy Eating Index (AHEI)-2010, the Dietary Approaches to Stop Hypertension Trial (DASH) diet, alternate Mediterranean diet (aMED), and their components using untargeted metabolomics in 2 samples (n(1) = 1,806, n(2) = 2,056) of the Atherosclerosis Risk in Communities study (aged 45–64 y at baseline). Dietary intakes were assessed using an FFQ. We used multivariable linear regression models to examine associations between diet indices and serum metabolites in each sample, adjusting for participant characteristics. Metabolites significantly associated with diet indices were meta-analyzed across 2 samples. C-statistics were calculated to examine if these candidate biomarkers improved prediction of individuals in the highest compared with lowest quintile of diet scores beyond participant characteristics. RESULTS: Seventeen unique metabolites (HEI: n = 6; AHEI: n = 5; DASH: n = 14; aMED: n = 2) were significantly associated with higher diet scores after Bonferroni correction in sample 1 and sample 2. Six of 17 significant metabolites [glycerate, N-methylproline, stachydrine, threonate, pyridoxate, 3-(4-hydroxyphenyl)lactate)] were associated with ≥1 dietary pattern. Candidate biomarkers of HEI, AHEI, and DASH distinguished individuals with highest compared with lowest quintile of diet scores beyond participant characteristics in samples 1 and 2 (P value for difference in C-statistics

Introduction: Greater adherence to plant-based diets is associated with a lower risk of incident chronic kidney disease (CKD). Metabolomics can help identify blood biomarkers of plant-based diets and understand the underlying mechanisms. Objectives: Using untargeted metabolomics, we aimed to identify metabolites associated with 4 plant-based diet indices (PDI) [overall PDI, provegetarian, healthful PDI, and unhealthful PDI] and incident CKD in 2 subgroups within the Atherosclerosis Risk in Communities Study. Methods: Participants (n 1 =1,762; n 2 =2,152) reported usual dietary intake using a food frequency questionnaire. We used linear regression models to examine the association between 4 PDIs and 374 individual metabolites. We used Cox regression models to evaluate associations between PDI-related metabolites and incident CKD. Estimates were meta-analyzed across 2 subgroups. We calculated C-statistics to assess whether metabolites improved the prediction of those in the highest quintile vs. lower 4 quintiles of PDIs, and whether PDI-related metabolites predicted incident CKD. Results: We identified 82 significant PDI-metabolite associations (overall PDI=27; provegetarian=17; healthful PDI=20; unhealthful PDI=18); 11 metabolites overlapped across the overall PDI, provegetarian, and healthful PDI. The addition of metabolites improved prediction of those in the highest quintile vs. lower 4 quintiles of PDIs compared to participant characteristics alone ( P -value ≤0.001 for all tests). Six PDI-related metabolites representing 2 pathways were significantly associated with incident CKD ( Table ) and improved prediction of incident CKD beyond traditional risk factors (difference in C-statistics for all 6 metabolites=0.005, P -value=0.006). Conclusions: In a community-based study of US adults, we identified metabolites that were related to plant-based diets that predicted incident CKD. These metabolites highlight pathways through which plant-based diets are associated with incident CKD.

Aims The ketogenic diet (KD) is standard-of-care to achieve myocardial glucose suppression (MGS) for assessing inflammation using fluorine-18 fluorodeoxyglucose–positron emission tomography (FDG-PET). As KD protocols remain highly variable between centres (including estimation of nutrient intake by dietary logs for adequacy of dietary preparation), we aimed to assess the predictive utility of nutrient intake in achieving MGS. Methods and results Nineteen healthy participants underwent short-term KD, with FDG-PET performed after 1 and 3 days of KD (goal carbohydrate intake Conclusions During highly supervised, short-term KD, approximately half of patients meet strict carbohydrate goals. Yet, in healthy volunteers, dietary review does not provide reassurance for adequacy of myocardial preparation since no clear thresholds for carbohydrate or fat intake reliably predict MGS.

Objectives This study sought to investigate the relationship between malnutrition and adverse cardiovascular (CV) events in heart failure with preserved ejection fraction (HFpEF). Background Malnutrition is associated with poor prognosis in a wide range of illnesses, however, the prognostic impact of malnutrition in HFpEF patients is not well known. Methods Baseline malnutrition risk was determined in 1,677 patients with HFpEF enrolled in the Americas regions of the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial, according to 3 categories of the geriatric nutritional risk index (GNRI) as previously validated: moderate to severe, GNRI of Results Approximately one-third of patients were at risk for malnutrition (moderate to severe: 11%; low: 25%; and absence of risk: 64%). Over a median of 2.9-years’ follow-up, compared to those with absent risk for malnutrition, moderate to severe risk was associated with significantly increased risk for the primary outcome, CV death and all-cause death (hazard ratio [HR]: 1.34; 95% confidence interval [CI]: 1.02 to 1.76; HR: 2.06; 95% CI: 1.40 to 3.03; and HR: 1.79; 95% CI: 1.33 to 2.42, respectively) after multivariate adjustment for age, sex, history of CV diseases, and laboratory biomarkers. Conclusions Patients with HFpEF are at an elevated risk for malnutrition, which was associated with an increased risk for CV events in this population.

BackgroundSeveral studies have hypothesised that dietary habits may play an important role in COVID-19 infection, severity of symptoms, and duration of illness. However, no previous studies have investigated the association between dietary patterns and COVID-19.MethodsHealthcare workers (HCWs) from six countries (France, Germany, Italy, Spain, UK, USA) with substantial exposure to COVID-19 patients completed a web-based survey from 17 July to 25 September 2020. Participants provided information on demographic characteristics, dietary information, and COVID-19 outcomes. We used multivariable logistic regression models to evaluate the association between self-reported diets and COVID-19 infection, severity, and duration.ResultsThere were 568 COVID-19 cases and 2316 controls. Among the 568 cases, 138 individuals had moderate-to-severe COVID-19 severity whereas 430 individuals had very mild to mild COVID-19 severity. After adjusting for important confounders, participants who reported following ‘plant-based diets’ and ‘plant-based diets or pescatarian diets’ had 73% (OR 0.27, 95% CI 0.10 to 0.81) and 59% (OR 0.41, 95% CI 0.17 to 0.99) lower odds of moderate-to-severe COVID-19 severity, respectively, compared with participants who did not follow these diets. Compared with participants who reported following ‘plant-based diets’, those who reported following ‘low carbohydrate, high protein diets’ had greater odds of moderate-to-severe COVID-19 (OR 3.86, 95% CI 1.13 to 13.24). No association was observed between self-reported diets and COVID-19 infection or duration.ConclusionIn six countries, plant-based diets or pescatarian diets were associated with lower odds of moderate-to-severe COVID-19. These dietary patterns may be considered for protection against severe COVID-19.

BackgroundThe ability to preferentially protect high-groups in COVID-19 is hotly debated. Here, the aim is to present simple metrics of such precision shielding of people at high-risk of death after infection by SARS-CoV-2; demonstrate how they can estimated; and examine whether precision shielding was successfully achieved in the first COVID-19 wave.MethodsThe shielding ratio, S, is defined as the ratio of prevalence of infection among people at a high-risk group versus among people in a low-risk group. The contrasted risk groups examined here are according to age (>=70 versus =70 years old. For setting-related precision shielding, data were analyzed from 10 countries where information was available on numbers of nursing home residents, proportion of nursing home residents among COVID-19 deaths, and overall population infection fatality rate.FindingsAcross 17 seroprevalence studies, the shielding ratio S for elderly versus non-elderly varied between 0.4 (substantial shielding) and 1.6 (substantial inverse protection, i.e. low-risk people being protected more than high-risk people). Five studies in USA all yielded S=0.4-0.8, consistent with some shielding being achieved, while two studies in China yielded S=1.5-1.6, consistent with inverse protection. Assuming 25% infection fatality rate among nursing home residents, S values for nursing home residents ranged from 0.07 to 3.1. The best shielding was seen in South Korea (S=0.07) and modest shielding was achieved in Israel, Slovenia, Germany, and Denmark. No shielding was achieved in Hungary and Sweden. In Belgium (S=1.9), UK (S=2.2) and Spain (S=3.1), nursing home residents were far more frequently infected that the rest of the population.InterpretationThe experience from the first wave of COVID-19 suggests that different locations and settings varied markedly in the extent to which they protected high-risk groups. Both effective precision shielding and detrimental inverse protection can happen in real-life circumstances. COVID-19 interventions should seek to achieve maximal precision shielding.

H63D has been identified as a novel locus associated with the development of hypertension. The quantitative risks for hypertension, cardiac remodeling, and adverse events are not well studied. We analyzed white participants from the ARIC study (Atherosclerosis Risk in Communities) with H63D genotyping (N=10 902). We related genotype status to prevalence of hypertension at each of 5 study visits and risk for adverse cardiovascular events. Among visit 5 participants (N=4507), we related genotype status to echocardiographic features. Frequencies of wild type (WT)/WT, H63D/WT, and H63D/H63D were 73%, 24.6%, and 2.4%. The average age at baseline was 54.9±5.7 years and 47% were men. Participants carrying the H63D variant had higher systolic blood pressure ( P =0.004), diastolic blood pressure (0.012), and more frequently had hypertension ( P 65 years. After 25 years of follow-up, there was no relationship between genotype status and any outcome ( P >0.05). H63D/WT and H63D/H63D genotypes were associated with small differences in cardiac remodeling. In conclusion, the HFE H63D variant confers an increased risk for hypertension per allele and, given its frequency, accounts for a significant number of cases of hypertension. However, there was no increased risk for adverse cardiovascular events or substantial left ventricular remodeling.

Aims Cardiac allograft vasculopathy (CAV) is a leading cause of death in orthotopic heart transplant (OHT) survivors. Effective non-invasive screening methods are needed. Our aim was to investigate the added diagnostic and prognostic value of myocardial blood flow (MBF) to standard myocardial perfusion imaging (MPI) with positron emission tomography (PET) for CAV detection. Methods and results We studied 94 OHT recipients (prognostic cohort), including 66 who underwent invasive coronary angiography and PET within 1 year (diagnostic cohort). The ISHLT classification was used as standard definition for CAV. Positron emission tomography evaluation included semiquantitative MPI, quantitative MBF (mL/min/g), and left ventricular ejection fraction (LVEF). A PET CAV severity score (on a scale of 0-3) was modelled on the ISHLT criteria. Patients were followed for a median of 2.3 years for the occurrence of major adverse events (death, re-transplantation, acute coronary syndrome, and hospitalization for heart failure). Sensitivity, specificity, positive, and negative predictive value of semiquantitative PET perfusion alone for detecting moderate-severe CAV were 83% [52-98], 82% [69-91], 50% [27-73], and 96% [85-99], respectively {receiver operating characteristic (ROC area: 0.82 [0.70-0.95])}. These values improved to 83% [52-98], 93% [82-98], 71% [42-92], and 96% [97-99], respectively, when LVEF and stress MBF were added (ROC area: 0.88 [0.76-0.99]; P = 0.01). There were 20 major adverse events during follow-up. The annualized event rate was 5%, 9%, and 25% in patients with normal, mildly, and moderate-to-severely abnormal PET CAV grading (P

Background Long QT syndrome (LQT) is a pro-arrhythmogenic condition with life-threatening complications. Fifteen genes have been associated with congenital LQT, however, the genetic causes remain unknown in more than 20% of cases. Materials and methods Eighteen patients with history of palpitations, pre-syncope, syncope and prolonged QT were referred to the Yale Cardiovascular Genetics Program. All subjects underwent whole-exome sequencing (WES) followed by confirmatory Sanger sequencing. Mutation burden analysis was carried out using WES data from 16 subjects with no identifiable cause of LQT. Results Deleterious and novel SCN10A mutations were identified in 3 of the 16 patients (19%) with idiopathic LQT. These included 2 frameshifts and 1 missense variants (p.G810fs, p.R1259Q, and p.P1877fs). Further analysis identified 2 damaging SCN10A mutations with allele frequencies of approximately 0.2% (p.R14L and p.R1268Q) in 2 independent cases. None of the SCN10A mutation carriers had mutations in known arrhythmia genes. Damaging SCN10A mutations (p.R209H and p.R485C) were also identified in the 2 subjects on QT prolonging medications. Conclusion Our findings implicate SCN10A in LQT. The presence of frameshift mutations suggests loss-of-function as the underlying disease mechanism. The common association with atrial fibrillation suggests a unique mechanism of disease for this LQT gene.

Background:\ud \ud Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), compared with the angiotensin-converting enzyme inhibitor enalapril, and improves peripheral insulin sensitivity in obese hypertensive patients. We aimed to investigate the effect of sacubitril/valsartan versus enalapril on HbA1c and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF.\ud \ud Methods:\ud \ud In a post-hoc analysis of the PARADIGM-HF trial, we included 3778 patients with known diabetes or an HbA1c ≥6·5% at screening out of 8399 patients with HFrEF who were randomly assigned to treatment with sacubitril/valsartan or enalapril. Of these patients, most (98%) had type 2 diabetes. We assessed changes in HbA1c, triglycerides, HDL cholesterol and BMI in a mixed effects longitudinal analysis model. Time to initiation of oral antihyperglycaemic drugs or insulin in subjects previously not treated with these agents were compared between treatment groups.\ud \ud Findings:\ud \ud There were no significant differences in HbA1c concentrations between randomised groups at screening. During the first year of follow-up, HbA1c concentrations decreased by 0·16% (SD 1·40) in the enalapril group and 0·26% (SD 1·25) in the sacubitril/valsartan group (between-group reduction 0·13%, 95% CI 0·05–0·22, p=0·0023). HbA1c concentrations were persistently lower in the sacubitril/valsartan group than in the enalapril group over the 3-year follow-up (between-group reduction 0·14%, 95% CI 0·06–0·23, p=0·0055). New use of insulin was 29% lower in patients receiving sacubitril/valsartan (114 [7%] patients) compared with patients receiving enalapril (153 [10%]; hazard ratio 0·71, 95% CI 0·56–0·90, p=0·0052). Similarly, fewer patients were started on oral antihyperglycaemic therapy (0·77, 0·58–1·02, p=0·073) in the sacubitril/valsartan group.\ud \ud Interpretation:\ud \ud Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA1c than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF.

Summary: Background: Low carbohydrate diets, which restrict carbohydrate in favour of increased protein or fat intake, or both, are a popular weight-loss strategy. However, the long-term effect of carbohydrate restriction on mortality is controversial and could depend on whether dietary carbohydrate is replaced by plant-based or animal-based fat and protein. We aimed to investigate the association between carbohydrate intake and mortality. Methods: We studied 15 428 adults aged 45–64 years, in four US communities, who completed a dietary questionnaire at enrolment in the Atherosclerosis Risk in Communities (ARIC) study (between 1987 and 1989), and who did not report extreme caloric intake (4200 kcal per day for men and 3600 kcal per day for women). The primary outcome was all-cause mortality. We investigated the association between the percentage of energy from carbohydrate intake and all-cause mortality, accounting for possible non-linear relationships in this cohort. We further examined this association, combining ARIC data with data for carbohydrate intake reported from seven multinational prospective studies in a meta-analysis. Finally, we assessed whether the substitution of animal or plant sources of fat and protein for carbohydrate affected mortality. Findings: During a median follow-up of 25 years there were 6283 deaths in the ARIC cohort, and there were 40 181 deaths across all cohort studies. In the ARIC cohort, after multivariable adjustment, there was a U-shaped association between the percentage of energy consumed from carbohydrate (mean 48·9%, SD 9·4) and mortality: a percentage of 50–55% energy from carbohydrate was associated with the lowest risk of mortality. In the meta-analysis of all cohorts (432 179 participants), both low carbohydrate consumption (70%) conferred greater mortality risk than did moderate intake, which was consistent with a U-shaped association (pooled hazard ratio 1·20, 95% CI 1·09–1·32 for low carbohydrate consumption; 1·23, 1·11–1·36 for high carbohydrate consumption). However, results varied by the source of macronutrients: mortality increased when carbohydrates were exchanged for animal-derived fat or protein (1·18, 1·08–1·29) and mortality decreased when the substitutions were plant-based (0·82, 0·78–0·87). Interpretation: Both high and low percentages of carbohydrate diets were associated with increased mortality, with minimal risk observed at 50–55% carbohydrate intake. Low carbohydrate dietary patterns favouring animal-derived protein and fat sources, from sources such as lamb, beef, pork, and chicken, were associated with higher mortality, whereas those that favoured plant-derived protein and fat intake, from sources such as vegetables, nuts, peanut butter, and whole-grain breads, were associated with lower mortality, suggesting that the source of food notably modifies the association between carbohydrate intake and mortality. Funding: National Institutes of Health.

AIMS Narrower retinal arterioles and wider retinal venules have been associated with macrovascular forms of cardiovascular disease (CVD). However, whether they are predictive of the development of heart failure (HF) independent of atherosclerotic CVD is unclear. We aimed to describe long-term associations of retinal vessel calibres with incident HF, in those with and without prevalent macrovascular disease, and how they relate to cardiac structure and function. METHODS AND RESULTS This analysis included Atherosclerosis Risk in Communities Study participants who underwent retinal photography between 1993 and 1995. HF outcomes were followed in these participants until the end of 2013. Returning participants underwent echocardiography between 2011 and 2013. Participants with retinal vessel measurements who were free of CVD at baseline (n = 10 692) were followed for a mean of 16 years (baseline mean age 60 ± 6 years). Wider central retinal venular equivalent (CRVE) and narrower central retinal arteriolar equivalent (CRAE), adjusted for age, gender, and race, were significantly linearly associated with incident HF; however, a non-linear association was detected with CRVE and incident HF (P-value for overall trend

Background: Narrower retinal arterioles and wider retinal venules have been associated with negative cardiovascular outcomes. We investigated whether retinal vessel calibers are associated with cardiovascular outcomes in long-term follow-up and provide incremental value over the 2013 American College of Cardiology/American Heart Association Pooled Cohort Equations in predicting atherosclerotic cardiovascular disease events. Methods: A total of 10 470 men and women without prior atherosclerotic cardiovascular disease events or heart failure in the ARIC Study (Atherosclerosis Risk in Communities) underwent retinal photography at visit 3 (1993–1995). Results: During a mean follow-up of 16 years, there were 1779 incident coronary heart disease events, 548 ischemic strokes, 1395 heart failure events, and 2793 deaths. Rates of all outcomes were higher in those with wider retinal venules and narrower retinal arterioles. Subjects with wider retinal venules (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.08–1.18; HR, 1.18; 95% CI, 1.07–1.31; and HR, 1.10; 95% CI, 1.00–1.20 per 1-SD increase) and narrower retinal arterioles (HR, 1.06; 95% CI, 1.01–1.11; HR, 1.14; 95% CI, 1.03–1.26; and HR, 1.13; 95% CI, 1.03–1.24 per 1-SD decrease) had a higher risk of death and stroke in both sexes and incident coronary heart disease in women but not men (interaction P =0.02) after adjustment for the Pooled Cohort Equations risk score variables. The association between retinal vessel caliber and heart failure was nonsignificant after adjustment for systolic blood pressure. Among women with Pooled Cohort Equations–predicted 10-year atherosclerotic cardiovascular disease event risk 5%). Conclusions: Narrower retinal arterioles and wider retinal venules conferred long-term risk of mortality and ischemic stroke in both sexes and coronary heart disease in women. These measures serve as an inexpensive, reproducible biomarker that added incremental value to current practice guidelines in atherosclerotic cardiovascular disease event risk prediction in low-risk women.

The prevalence and clinical characteristics of familial dilated cardiomyopathy (FDCM) among patients with end stage heart failure (ESHF) has yet to be elucidated. We sought to determine the prevalence of FDCM in ESHF in the United Network for Organ Sharing (UNOS) registry and compare this with center specific data from a large tertiary teaching hospital. Patients with a banked UNOS diagnosis of dilated cardiomyopathy (DCM) whose care originated at our center then underwent detailed pedigree analysis in order to determine the true prevalence of FDCM.A total of 16,091 patients with DCM from all centers were identified in the UNOS registry of whom 492 carried the diagnosis of FDCM (3.1%). Patients with the diagnosis of FDCM tended to be younger (42 versus 49 years old in idiopathic dilated cardiomyopathy (IDCM), p=0.001), were less likely to have diabetes (7.8% versus 16.5% in IDCM, p0.0001), had slightly lower creatinine (1.2 versus 1.4 in IDCM, p=0.0001) and were more likely to have a panel reactive antibody level ≥ 20% (62.1% versus 44.7% in IDCM, p0.0001). Consecutive living adult patients with ESHF were identified from the UNOS registry that had been treated at the Yale Center for Advanced Heart Failure (YCAHF). After excluding all diagnoses that did not include any form of non-ischemic DCM, 73 patients met the inclusion criteria. Center-specific UNOS data showed pre-pedigree analysis diagnosis of FDCM in 4.12% of patients (3 out of 73), consistent with that found in the UNOS database for all centers. However, after detailed family history and pedigree analysis, 19 (26%) of 73 patients were found to have FDCM, while the remaining 54 were found to have IDCM. Echocardiographic findings including mitral regurgitation, mitral valve annulus and left ventricular end diastolic dimension were not significantly different between groups when adjusting for multiple testing.The diagnosis of FDCM was missed in the majority of patients with end stage heart failure enrolled in the UNOS database, as sampled from a large, tertiary care teaching hospital in the United States. Echocardiographic findings are unlikely to aid in the differentiation between DCM and FDCM. Detailed pedigree analysis can successfully identify undiagnosed FDCM and should be encouraged prior to transplant listing as it has important implications for early detection and treatment of disease in family members.

BackgroundDespite the widespread implementation of personal protective equipment (PPE) in the COVID-19 pandemic, there are surprisingly few studies of its impact. To assess the risk, severity and duration of COVID-19 in relation to access to PPE in at-risk healthcare workers (HCWs).MethodsFrom 17 July to 25 September 2020, at-risk physicians and nurses registered as a provider in the Survey Healthcare Globus network in six countries (the UK, Germany, France, Italy, Spain and USA) were identified based on adult medical specialties with frequent and close contact with patients with COVID-19. Exposed HCWs completed a detailed questionnaire including demographics, medical, social and lifestyle factors. COVID-19 cases were defined as COVID-19 symptoms (fever, cough, fatigue, loss of taste or smell) and asymptomatic COVID-19 test positive cases.ResultsAmong 2884 exposed HCWs (94% medical doctors and 6% nurses or physician assistants), there were 514 reports of COVID-19 illness and 54 asymptomatic COVID-19 test positive cases. COVID-19 risk was significantly associated with close contact with COVID-19 cases both inside and outside the workplace, number of work shifts and hours worked per week. Limited access to PPE compared with access to a fresh mask, gown and gloves and face shield with each patient encounter was associated with a 2.2-fold to 22-fold increased risk of reporting COVID-19 symptoms (pConclusionIn six countries, less access to PPE was strongly associated with both increased risk of reporting COVID-19 illness as well as more prolonged and severe disease course in frontline HCWs.

OBJECTIVES: Healthy dietary patterns are recommended for health promotion. Metabolomics can be used to identify objective biomarkers of healthy dietary patterns, which has the potential to improve dietary assessment. We used metabolomics to identify serum metabolites associated with healthy dietary patterns and the components within these dietary patterns in middle-aged US adults. METHODS: We evaluated known metabolites associated with 4 dietary patterns [Healthy Eating Index (HEI)-2015, Alternative Healthy Eating Index (AHEI)-2010, the Dietary Approaches to Stop Hypertension (DASH) diet, Mediterranean diet (aMED)] and their components using untargeted metabolomics in two subsamples (N(1 )= 1864; N(2 )= 2091) of the Atherosclerosis Risk in Communities Study. Dietary intakes were assessed using a food frequency questionnaire. We used multivariable linear regression models to examine associations between dietary patterns and individual serum metabolites in each sample, adjusting for sociodemographic factors, health behaviors, and clinical factors. RESULTS: 21 out of 373 metabolites (HEI = 10; AHEI = 9; DASH = 15; aMED = 2) in sample 1 and 57 out of 758 metabolites (HEI = 32; AHEI = 22; DASH = 44; aMED = 22) in sample 2 were significantly associated with healthy dietary patterns after Bonferroni correction. More than half of the significant metabolites (n(1 )= 10; n(2 )= 35) were associated with more than one dietary pattern. The DASH diet had the highest number of unique metabolites (n(1 )= 7; n(2 )= 17), a majority of which were amino acids. Other diets had similar number of unique metabolites (range: 0–3), which were mostly lipids. Some of the unique metabolites were positively associated with components of every diet. For example, N-methylproline was associated with fruit and dairy intake in the DASH diet; docosahexaenoate (22:6n3) was associated with omega-3 fatty acid intake in AHEI, and 1-docosahexaenoylglycerophosphoethanolamine was associated with plant protein and saturated fat intake in HEI. CONCLUSIONS: An untargeted metabolomics approach identified many metabolites associated with healthy dietary patterns. A considerable overlap of metabolites associated with HEI, AHEI, DASH, and aMED reflects the similar food components within healthy diets. FUNDING SOURCES: NIDDK, NHLBI.

The potential link between albumin and development of amyloidosis is indeed intriguing, although speculative. We agree with Dr. Mehmood that a significant proportion of patients with heart failure with preserved ejection fraction (HFpEF) may have amyloid cardiomyopathy. Transthyretin amyloid

The causes of heart failure are diverse. Inherited causes represent an important clinical entity and can be divided into 2 major categories: familial and metabolic cardiomyopathies. The distinct features that might be present in early disease states can become broadly overlapping with other diseases, such as in the case of inherited cardiomyopathies (ie, familial hypertrophic cardiomyopathy or mitochondrial diseases). In this review article, we focus on genetic issues related to advanced heart failure. Because of the emerging importance of this topic and its breadth, we sought to focus our discussion on the known genetic forms of heart failure syndromes, genetic testing, and newer data on pharmacogenetics and therapeutics in the treatment of heart failure, to primarily encourage clinicians to place a priority on the diagnosis and treatment of these potentially treatable conditions.

BACKGROUND Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. OBJECTIVES The goat of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. METHODS Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabotic outcomes was performed. RESULTS Among 5,687 European-American subjects (mean age 54 +/- 6 years; 47% mate), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)-Asn51Ser, Ala411Thr, and His615Gln-had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (beta-coefficient: -8.0; 95% confidence interval [CI]: -12.7 to -3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (beta = -16.3; 95% CI: -36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (beta = -3.2; 95% CI: -6.4 to 0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90). CONCLUSIONS Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions. (C) 2018 Published by Elsevier on behalf of the American College of Cardiology Foundation.

Background Radiation therapy ( RT ) is a standard treatment for head and neck cancer; however, it is associated with inflammation, accelerated atherosclerosis, and cerebrovascular events ( CVEs ; stroke or transient ischemic attack). Human papillomavirus ( HPV ) is found in nearly half of head and neck cancers and is associated with inflammation and atherosclerosis. Whether HPV confers an increased risk of CVE s after RT is unknown. Methods and Results Using an institutional database, we identified all consecutive patients treated with RT from 2002 to 2012 for head and neck cancer who were tested for HPV . The outcome of interest was the composite of ischemic stroke and transient ischemic attack, and the association between HPV and CVE s was assessed using Cox proportional hazard models, competing risk analysis, and inverse probability weighting. Overall, 326 participants who underwent RT for head and neck cancer were tested for HPV (age 59±12 years, 75% were male, 9% had diabetes mellitus, 45% had hypertension, and 61% were smokers), of which 191 (59%) were tumor HPV positive. Traditional risk factors for CVEs were similar between HPV‐positive and ‐negative patients. Over a median follow‐up of 3.4 years, there were 18 ischemic strokes and 5 transient ischemic attacks (event rate of 1.8% per year). The annual event rate was higher in the HPV ‐positive patients compared with the HPV‐negative patients (2.6% versus 0.9%, P =0.002). In a multivariable model, HPV‐positive status was associated with a >4 times increased risk of CVEs (hazard ratio: 4.4; 95% confidence interval, 1.5–13.2; P =0.008). Conclusions In this study, HPV‐positive status is associated with an increased risk of stroke or transient ischemic attack following RT for head and neck cancer.

Background Elevated B‐type natriuretic peptide ( BNP ) levels are associated with heart failure and increased mortality in the general population. We investigated rs198389, a functional variant in the promoter region of the BNP gene ( NPPB ), in patients from the Atherosclerosis Risk in Communities Study to investigate associations with N‐terminal pro‐BNP (NT‐pro BNP) levels and outcomes. Methods and Results A total of 11 361 black and white patients with rs198389 genotyping attended visit 1 (aged 45–64 years; 1987–1989), with follow‐up visits occurring every 3 years (visit 2–visit 4, 1990–1999), followed by visit 5 (2011–2013). NT ‐pro BNP levels were measured at visits 2, 4, and 5. At visit 2, the GG genotype (frequency 18%) was associated with a 41% higher mean plasma level of NT ‐pro BNP compared with the AA genotype (frequency 34%), with intermediate values observed in AG s ( P =4.2×10 −52 ). The GG genotype was associated with reduced systolic blood pressure (−1.6 mm Hg, P =0.006), diastolic blood pressure (−1 mm Hg, P =0.003), antihypertension medication use (odds ratio, 0.85; 95% CI , 0.74–0.97 [ P =0.02]), and hypertension (odds ratio, 0.81; 95% CI , 0.72–0.92 [ P =0.002]) compared with the AA genotype with intermediate values in AG s. These relationships persisted throughout subsequent visits. After a median follow‐up of 23 years, there were 4031 deaths. With and without covariate adjustment, the GG genotype was associated with modestly lower mortality (hazard ratio, 0.86; 95% CI, 0.78–0.95), primarily reflective of cardiovascular death (hazard ratio, 0.75; 95% CI, 0.61–0.92), and increased residual lifespan of 8 months from 50 years of age ( P =0.02) versus AA s. Conclusions The rs198389 G allele in the NPPB promoter is associated with elevated levels of NT ‐pro BNP throughout adult life, reduced blood pressure, hypertension and cardiovascular mortality, and increased lifespan.

Arteries consist of an inner single layer of endothelial cells surrounded by layers of smooth muscle and an outer adventitia. The majority of vascular developmental studies focus on the construction of endothelial networks through the process of angiogenesis. Although many devastating vascular diseases involve abnormalities in components of the smooth muscle and adventitia (i.e., the vascular wall), the morphogenesis of these layers has received relatively less attention. Here, we briefly review key elements underlying endothelial layer formation and then focus on vascular wall development, specifically on smooth muscle cell origins and differentiation, patterning of the vascular wall, and the role of extracellular matrix and adventitial progenitor cells. Finally, we discuss select human diseases characterized by marked vascular wall abnormalities. We propose that continuing to apply approaches from developmental biology to the study of vascular disease will stimulate important advancements in elucidating disease mechanism and devising novel therapeutic strategies.

Background— With the advent of high throughput sequencing, the identification of genetic causes of cardiovascular disease (CVD) has become an integral part of medical diagnosis and management and at the forefront of personalized medicine in this field. The use of whole exome sequencing for clinical diagnosis, risk stratification, and management of inherited CVD has not been previously evaluated. Methods and Results— We analyzed the results of whole exome sequencing in first 200 adult patients with inherited CVD, who underwent genetic testing at the Yale Program for Cardiovascular Genetics. Genetic diagnosis was reached and reported with a success rate of 26.5% (53 of 200 patients). This compares to 18% (36 of 200) that would have been diagnosed using commercially available genetic panels ( P =0.04). Whole exome sequencing was particularly useful for clinical diagnosis in patients with aborted sudden cardiac death, in whom the primary insult for the presence of both depressed cardiac function and prolonged QT had remained unknown. The analysis of the remaining cases using genome annotation and disease segregation led to the discovery of novel candidate genes in another 14% of the cases. Conclusions— Whole exome sequencing is an exceptionally valuable screening tool for its capability to establish the clinical diagnosis of inherited CVDs, particularly for poorly defined cases of sudden cardiac death. By presenting novel candidate genes and their potential disease associations, we also provide evidence for the use of this genetic tool for the identification of novel CVD genes. Creation and sharing of exome databases across centers of care should facilitate the discovery of unknown CVD genes.

Plasma HDL cholesterol levels (HDL-C) are an independent predictor of coronary artery disease (CAD). We have completed a genome-wide linkage scan for HDL-C in a US cohort consisting of 388 multiplex families with premature CAD (GeneQuest). The heritability of HDL-C in GeneQuest was 0.37 with gender and age as covariates (P = 5.1 x 10(-4)). Two major quantitative trait loci (QTL) for log-transformed HDL-C adjusted for age and gender were identified onto chromosomes 7p22 and 15q25 with maximum multipoint logarithm of odds (LOD) scores of 3.76 and 6.69, respectively. Fine mapping decreased the 7p22 LOD score to a nonsignificant level of 3.09 and split the 15q25 QTL into two loci, one minor QTL on 15q22 (LOD = 2.73) that spanned the LIPC gene, and the other at 15q25 (LOD = 5.63). A family-based quantitative transmission disequilibrium test (QTDT) revealed significant association between variant rs1800588 in LIPC and HDL-C in the GeneQuest population (P = 0.0067), which may account for the minor QTL on 15q22. The 15q25 QTL is the most significant locus identified for HDL-C to date, and these results provide a framework for the ultimate identification of the underlying HDL-C variant and gene on chromosomes 15q25, which will provide insights into novel regulatory mechanisms of HDL-C metabolism.

Objective— Susceptibility to atherosclerosis is genetically complex, and modifier genes that do not operate via traditional risk factors are largely unknown. A mouse genetics approach can simplify the genetic analysis and provide tools for mechanistic studies. Methods and Results— We previously identified atherosclerosis susceptibility QTL ( Athsq1 ) on chromosome 4 acting independently of systemic risk factors. We now report confirmation of this locus in congenic strains carrying the MOLF-derived susceptibility allele in the C57BL/6J- Ldlr −/− genetic background. Homozygous congenic mice exhibited up to 4.5-fold greater lesion area compared to noncongenic littermates ( P Athsq1 congenic interval contains the mouse region homologous to a widely-replicated CHD locus on human chromosome 9p21. Conclusion— These studies confirm the proatherogenic activity of a novel gene(s) in the MOLF-derived Athsq1 locus and provide in vivo evidence for a causative role of versican in lesion development.

An increased plasma triglyceride (TG) level is associated with coronary artery disease (CAD) and myocardial infarction (MI) and is a key characteristic of the metabolic syndrome. Here, we used a genome-wide linkage scan to identify a novel genetic locus that influences the plasma TG level. We genotyped 714 persons in 388 multiplex Caucasian families with premature CAD and MI with 408 polymorphic microsatellite markers that cover the entire human genome. The genome-wide scan identified positive linkage for the quantitative TG trait to a novel locus on chromosome 1p31-32 [peak single-point logarithm of odds (LOD) = 3.57, peak multipoint LOD = 3.12]. For single-point linkage analysis, two markers, D1S1728 and D1S551, showed LOD scores of 2.42 and 3.57, respectively. For multipoint linkage analysis, three markers, D1S3736, D1S1728, and D1S551, showed LOD scores of 2.43, 3.03, and 3.12, respectively. No other chromosomal regions showed a LOD score of >2.2. This study identifies a new genetic locus for TG on chromosome 1p31-32. Future studies of the candidate genes at this locus will identify a specific gene influencing the TG, which will provide insights into novel regulatory mechanisms of TG metabolism and may be important for the development of therapies to prevent CAD.

Objective— The purpose of this study was to examine genetic factors responsible for metabolic syndrome and atherosclerosis in a setting of low-density lipoprotein (LDL) receptor deficiency in a cross between C57BL/6J (B6) and PERA/Ei (PERA) inbred mouse strains. Methods and Results— Comparison of metabolic phenotypes in B6 and PERA strains revealed the PERA genetic background to be dramatically more susceptible to hyperleptinemia, hyperglycemia, hypertriglyceridemia, elevated insulin levels, and body fat increase than the B6 background. To facilitate genetic analysis, metabolic syndrome-related traits and atherosclerotic lesion area were measured in 167 [(PERA×B6.129S7- Ldlr tm1Her )×B6.129S7- Ldlr tm1Her ]N2 male and female backcross mice that were homozygous for the Ldlr null allele. Quantitative trait locus analysis was performed using 153 polymorphic microsatellite markers spanning the genome. On chromosome 4, we identified a locus influencing plasma triglyceride, insulin, and leptin concentrations, body weight, and atherosclerosis. Several other genetic loci were identified with separate effects on plasma insulin, body weight, high-density lipoprotein cholesterol, and atherosclerosis. Conclusions— The PERA strain is highly susceptible to the development of metabolic syndrome after feeding a Western-type diet. This susceptibility is due, in part, to a locus on murine chromosome 4 in which PERA alleles predispose to adiposity, increased insulin, and accelerated atherogenesis in the absence of marked hyperlipidemia.

Background: Type 2 diabetes (T2DM) is an independent risk factor for heart failure progression. Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, improves morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF) and was shown to improve

Cardiac allograft vasculopathy (CAV) is the leading cause of death in transplant (Tx) survivors, and effective noninvasive screening methods are urged. We investigated the utility of PET imaging for CAV detection and its association with outcomes We studied 100 Tx recipients (median age 62 years)

Klippel-Trenaunay syndrome (KTS) is a severe congenital disorder characterized by capillary malformations, venous malformations or varicose veins, and hypertrophy of the affected tissues. The angiogenic factor gene AGGF1 was previously identified as a candidate susceptibility gene for KTS, but further genetic studies are needed to firmly establish the genetic relationship between AGGF1 and KTS. We analyzed HapMap data and identified two tagSNPs, rs13155212 and rs7704267 that capture information for all common variants in AGGF1. The two SNPs were genotyped in 173 Caucasian KTS patients and 477 Caucasian non-KTS controls, and both significantly associated with susceptibility for KTS (P = 0.004 and 0.013, respectively). Permutation testing also showed a significant empirical P value for the association (empirical P = 0.006 and 0.015, respectively). To control for potential confounding due to population stratification, the population structure for both cases and controls was characterized by genotyping of 38 ancestry-informative markers (AIMs) and the STRUCTURE program. The association between the AGGF1 SNPs and KTS remained significant after multivariate analysis by incorporating the inferred cluster scores as a covariate or after removal of outlier individuals identified by STRUCTURE. These results suggest that common AGGF1 variants confer risk of KTS.

BackgroundSleep habits and burnout have been shown to be associated with increase in infectious diseases, but it is unknown if these factors are associated with risk of COVID-19. We assessed whether sleep and self-reported burnout may be risk factors for COVID-19 among high-risk healthcare workers (HCWs).MethodsFrom 17 July to 25 September 2020, a web-based survey was administered to HCWs in six countries (France, Germany, Italy, Spain, UK, USA) with a high frequency of workplace exposure. Participants provided information on demographics, sleep (number of sleep hours at night, daytime napping hours, sleep problems), burnout from work and COVID-19 exposures. We used multivariable linear and logistic regression models to evaluate the associations between sleep, burnout and COVID-19.ResultsAmong 2884 exposed HCWs, there were 568 COVID-19 cases and 2316 controls. After adjusting for confounders, 1-hour longer sleep duration at night was associated with 12% lower odds of COVID-19 (p=0.003). Daytime napping hours was associated with 6% higher odds, but the association varied by countries, with a non-significant inverse association in Spain. Compared with having no sleep problems, having three sleep problems was associated with 88% greater odds of COVID-19. Reporting burnout ‘every day’ was associated with greater odds of COVID-19 (OR: 2.60, 95% CI 1.57 to 4.31, p trend across categories=0.001), longer duration (OR: 2.98, 95% CI 1.10 to 8.05, p trend=0.02) and severity (OR: 3.26, 95% CI 1.25 to 8.48, p trend=0.02) compared with reporting no burnout. These associations remained significant after adjusting for frequency of COVID-19 exposures.ConclusionsIn six countries, longer sleep duration was associated with lower odds of COVID-19, but the association with daytime nap may not be consistent across countries. Greater sleep problems and high level of burnout were robustly associated with greater odds of COVID-19. Sleep and burnout may be risk factors for COVID-19 in high-risk HCWs.