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Abstract Whether, and how, cardioprotective effects of antiretroviral treatment (ART) in adolescents with perinatal HIV infection (APHIV) vary with age at treatment initiation is unknown. We used magnetic resonance imaging to compare cardiac status between APHIV initiated on ART at

Background Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA‐HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). Methods and Results A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5–20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site‐interpreted Valsalva left ventricular outflow tract gradient

Abstract Heart failure (HF) causes substantial morbidity and mortality but its pathobiology is incompletely understood. The proteome is a promising intermediate phenotype for discovery of novel mechanisms. We measured 4877 plasma proteins in 13,900 HF-free individuals across three analysis sets with diverse age, geography, and HF ascertainment to identify circulating proteins and protein networks associated with HF development. Parallel analyses in Atherosclerosis Risk in Communities study participants in mid-life and late-life and in Trøndelag Health Study participants identified 37 proteins consistently associated with incident HF independent of traditional risk factors. Mendelian randomization supported causal effects of 10 on HF, HF risk factors, or left ventricular size and function, including matricellular (e.g. SPON1, MFAP4), senescence-associated (FSTL3, IGFBP7), and inflammatory (SVEP1, CCL15, ITIH3) proteins. Protein co-regulation network analyses identified 5 modules associated with HF risk, two of which were influenced by genetic variants that implicated trans hotspots within the VTN and CFH genes.

Background Studies demonstrated sex differences in outcomes following acute myocardial infarction, with women more likely to develop heart failure (HF). Sacubitril/valsartan has been shown to reduce cardiovascular death and HF hospitalizations in patients with HF with reduced ejection fraction. Methods and Results A total of 5661 patients (1363 women [24%]) with acute myocardial infarction complicated by reduced left ventricular ejection fraction (≤40%), pulmonary congestion, or both and ≥1 of 8 risk‐augmenting factors were randomized to receive sacubitril/valsartan or ramipril. The primary outcome was cardiovascular death or incident HF. Baseline characteristics, clinical outcomes, and safety events were compared according to sex, a prespecified subgroup. Female participants were older and had more comorbidities. After multivariable adjustment, women and men were at similar risks for cardiovascular death or all‐cause death. Women were more likely to have first HF hospitalization (hazard ratio [HR], 1.34 [95% CI, 1.05–1.70]; P=0.02) and total HF hospitalizations (HR, 1.39 [95% CI, 1.05–1.84]; P=0.02). Sex did not significantly modify the treatment effect of sacubitril/valsartan compared with ramipril on the primary outcome (P for interaction=0.11). Conclusions In contemporary patients who presented with reduced left ventricular ejection fraction, pulmonary congestion, or both, following acute myocardial infarction, women had a higher incidence of HF during follow‐up. Sex did not modify the treatment effect of sacubitril/valsartan relative to ramipril. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02924727.

Background Frailty and heart failure frequently coexist in late life. Limited data exist regarding the longitudinal associations of frailty and subclinical cardiac dysfunction. We aim to quantify the association of frailty with longitudinal changes in cardiac function and of cardiac function with progression in frailty status in older adults. Methods and Results Participants in the Atherosclerosis Risk in Communities cohort underwent frailty assessments at Visit 5 (V5; 2011–2013), V6 (2016–2017), and V7 (2018–2019), and echocardiographic assessments at V5 and V7. We assessed the association between frailty status at V5 and changes in frailty status from V5 to V7 and changes in cardiac function over 6 years. We then evaluated the association of cardiac function measured at Visit 5 with progression in frailty status over 4 years. Multivariable regression models adjusted for demographics and comorbidities. Among 2574 participants free of heart failure at V5 and V7 (age 74±4 years at V5 and 81±4 years at V7), 3% (n=83) were frail. Frailty at V5 was associated with greater left atrial volume index and E/e' ratio at V5 and 7. Participants who transitioned from robust at V5 to frail at V7 demonstrated greater increases in left ventricular mass index, left atrial volume index, and E/e' over the same period. Among 1648 robust participants at Visit 5, greater left ventricular mass index and mean wall thickness, lower tissue Doppler imaging e', and higher E/e' ratio at Visit 5 were associated with progression in frailty status. Conclusions Among robust, older adults free of heart failure, progression in frailty and subclinical left ventricular remodeling and diastolic dysfunction are interrelated.

Abstract Background Compared with enalapril, sacubitril/valsartan lowered HbA1c and reduced new insulin therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes in the PARADIGM-HF trial. We sought to assess the glycemic effects of sacubitril/valsartan in heart failure with preserved ejection fraction (HFpEF) and diabetes, and across the spectrum of left ventricular ejection fraction (LVEF) in heart failure and diabetes. Methods We compared the effect of sacubitril/valsartan, relative to valsartan, on HbA1c, new insulin therapy and hypoglycemia in the randomized controlled trial PARAGON-HF, and performed pooled analyses of PARAGON-HF and PARADIGM-HF. Results Among 2395 patients with HFpEF and diabetes in PARAGON-HF, sacubitril/valsartan compared with valsartan reduced HbA1c (baseline-adjusted between-group difference in HbA1c change at 48 weeks: − 0.24%, 95% CI − 0.33 to − 0.16%, P

Abstract Aims Despite adequate treatment, recent studies have hypothesized that malaria may affect long‐term cardiovascular function. We aimed to investigate the long‐term risk of cardiovascular events and death in individuals with a history of imported malaria in Denmark. Methods Using nationwide Danish registries, we followed individuals with a history of malaria for the risk of incident heart failure (HF), myocardial infarction (MI), cardiovascular death and all‐cause death (1 January 1994 to 1 January 2017). The population was age‐ and sex‐matched with individuals without a history of malaria from the Danish population (ratio 1:9). We excluded patients with known HF and ischaemic heart disease at inclusion. Results We identified 3912 cases with a history of malaria (mean age 33 ± 17 years, 57% male, 41% Plasmodium falciparum infections). The median follow‐up was 9.8 years (interquartile range 3.9–16.4 years). Event rates per 1000 person‐years for individuals with a history vs. no history of malaria were HF: 1.84 vs. 1.32; MI: 1.28 vs. 1.30; cardiovascular death: 1.40 vs. 1.77; and all‐cause death: 5.04 vs. 5.28. In Cox proportional hazards models adjusted for cardiovascular risk factors, concomitant pharmacotherapy, region of origin, household income and educational level, malaria was associated with HF (HR: 1.59 [1.21–2.09], P = 0.001), but not MI (HR: 1.00 [0.72–1.39], P = 1.00), cardiovascular death (HR: 1.00 [0.74–1.35], P = 0.98) or all‐cause death (HR 1.11 [0.94–1.30], P = 0.21). Specifically, P. falciparum infection was associated with increased risk of HF (HR: 1.64 [1.14–2.36], P = 0.008). Conclusion Individuals with a history of imported malaria, specifically P. falciparum, may have an increased risk of incident HF.

Background Whether coronary artery disease (CAD) is a significant risk factor for heart failure (HF) with preserved ejection fraction (HFpEF) is unclear. Methods and Results Among 9902 participants in the ARIC (Atherosclerosis Risk in Communities) study, we assessed the association of incident CAD with subsequent incident HFpEF (left ventricular ejection fraction [≥50%]) and HF with reduced ejection fraction (HFrEF; left ventricular ejection fraction 1 year post‐CAD event, adjusted incidence of HFrEF and HFpEF were similar (7.2 [95% CI, 5.2–10.0] and 6.7 [4.8–9.2] per 1000 person‐years, respectively) and CAD remained predictive of both (HFrEF: hazard ratio, 2.76 [95% CI, 1.99–3.84]; HFpEF: 1.85 [1.35–2.54]) after adjusting for demographics and common comorbidities. Among 4779 HF‐free participants at Visit 5 (2011–2013), the 490 with prevalent CAD had lower left ventricular ejection fraction and higher left ventricular mass index, E/e’, and left atrial volume index (all P

Abstract Aims We sought to examine sex differences in congestion in patients hospitalized for acute heart failure (AHF). Understanding congestive patterns in women and men with AHF may provide insights into sex differences in the presentation and prognosis of AHF patients. Methods and results In a prospective, two‐site study in adults hospitalized for AHF, four‐zone lung ultrasound (LUS) was performed at the time of echocardiography at baseline (LUS1) and, in a subset, pre‐discharge (LUS2). B‐lines on LUS and echocardiographic images were analysed offline, blinded to clinical information and outcomes. Among 349 patients with LUS1 data (median age 74, 59% male, and 87% White), women had higher left ventricular ejection fraction (mean 43% vs. 36%, P

Background Age‐related left atrial (LA) structural and functional abnormalities may be related to subclinical cerebral infarcts (SCIs) and stroke. We evaluated the association of 3‐dimensional echocardiographic LA contractility parameters with SCIs and stroke across the spectrum of tertiles of age increment in elderly patients with sinus rhythm, normal ejection fraction, and no history of atrial fibrillation. Methods and Results We enrolled 407 participants (mean age, 76±8 years; 40% men) from ARIC‐NCS (Atherosclerosis Risk in Communities Neurocognitive Study) undergoing a brain magnetic resonance imaging and 3‐dimensional echocardiographic examinations in 2011 to 2013. The sample was analyzed among age tertiles and subgroups: no cerebral magnetic resonance imaging–detectable infarcts (n=315), magnetic resonance imaging–diagnosed SCIs (n=58), and clinically diagnosed stroke (n=34). The frequency of SCIs significantly increased over age tertiles (P trend 0.023). LA global longitudinal strain—a 3‐dimensional echocardiographic index of LA reservoir function—and E/e’ divided by LA global longitudinal strain—an index of LA stiffness—worsened across age tertiles (P trend 0.014 and 0.001, respectively), and only in the categories of SCIs (P trend

Objectives We sought to understand the demographic and clinical factors associated with variations in longitudinal antibody response following completion of two-dose regiment of BNT162b2 vaccination.Design This study is a 10-month longitudinal cohort study of healthcare workers and serially measured anti-spike protein IgG (IgG-S) antibody levels using mixed linear models to examine their associations with participant characteristics.Setting A large, multisite academic medical centre in Southern California, USA.Participants A total of 843 healthcare workers met inclusion criteria including completion of an initial two-dose course of BNT162b2 vaccination, complete clinical history and at least two blood samples for analysis. Patients had an average age of 45±13 years, were 70% female and 7% with prior SARS-CoV-2 infection.Results Vaccine-induced IgG-S levels remained in the positive range for 99.6% of individuals up to 10 months after initial two-dose vaccination. Prior SARS-CoV-2 infection was the primary correlate of sustained higher postvaccination IgG-S levels (partial R2=0.133), with a 1.74±0.11 SD higher IgG-S response (p

Background Baseline and temporal changes in natriuretic peptide (NP) concentrations have strong prognostic value with regard to long‐term cardiovascular risk stratification. To increase the clinical utility of NP sampling for patient management, we wanted to assess the incremental predictive value of 2 serial NP measurements compared with a single measurement and provide absolute risk estimates for cardiovascular death or heart failure hospitalization (HFH) within 6 months based on 2 serial NP measurements. Methods and Results Consecutive NP samples obtained from 5393 patients with a recent coronary event and type 2 diabetes enrolled in the ELIXA (Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With Lixisenatide) trial were used to construct best logistic regression models with outcome of cardiovascular death or HFH (136 events). Absolute risk estimates of cardiovascular death or HFH within 6 months using either BNP (B‐type natriuretic peptide) or NT‐proBNP (N‐terminal pro‐BNP) serial measurements were depicted based on the concentrations of 2 serial NP measurements. During the 6‐month follow‐up periods, the incidence rate (±95% CIs) of cardiovascular death or HFH for patients was 14.0 (11.8‒16.6) per 1000 patient‐years. Risk prediction depended on NP concentrations from both prior and current sampling. NP sampling 6 months apart improved the predictive value and reclassification of patients compared with a single sample (AUROC [Area Under the Receiver Operating Characteristic curve]: BNP, P=0.003. NT‐proBNP, P

Background Whether cardiac structure and function abnormalities associated with dysglycemia are sufficient to explain the increased risk of death or heart failure (HF) remains unclear. Methods and Results We analyzed 6059 participants (mean age, 75±5 years; 58% women; and 22% Black individuals) who attended the ARIC (Atherosclerosis Risk in Communities) study visit 5 examination (2011–2013). Participants were categorized as no diabetes, pre‐diabetes, and diabetes (on the basis of medical history and glycated hemoglobin values). We assessed whether diabetes modified the association between echocardiographic measures of cardiac structure and function and the composite of all‐cause death or HF hospitalization and then estimated the extent to which the increased risk of the composite outcome associated with diabetes was explained by cardiac structure and function. Diabetes was prevalent in 33.5% of the subjects. Death or HF occurred in 1111 (18%) at a rate of 3.6 per 100 person‐years. Both measures of cardiac structure and function and diabetes status were significantly associated with worse prognosis after accounting for clinical confounders. While diabetes was consistently associated with a higher risk of events, it did not significantly modify the association between cardiac abnormalities and the risk of death or HF, except for subjects with higher left atrial volume who showed higher relative risk of events (P for interaction

Background Influenza infection may increase the risk of stroke and acute myocardial infarction (AMI). Whether influenza vaccination may reduce mortality in patients with hypertension is currently unknown. Methods and Results We performed a nationwide cohort study including all patients with hypertension in Denmark during 9 consecutive influenza seasons in the period 2007 to 2016 who were prescribed at least 2 different classes of antihypertensive medication (renin‐angiotensin system inhibitors, diuretics, calcium antagonists, or beta‐blockers). We excluded patients who were aged 100 years, had ischemic heart disease, heart failure, chronic obstructive lung disease, cancer, or cerebrovascular disease. The exposure to influenza vaccination was assessed before each influenza season. The end points were defined as death from all‐causes, from cardiovascular causes, or from stroke or AMI. For each influenza season, patients were followed from December 1 until April 1 the next year. We included a total of 608 452 patients. The median follow‐up was 5 seasons (interquartile range, 2–8 seasons) resulting in a total follow‐up time of 975 902 person‐years. Vaccine coverage ranged from 26% to 36% during the study seasons. During follow‐up 21 571 patients died of all‐causes (3.5%), 12 270 patients died of cardiovascular causes (2.0%), and 3846 patients died of AMI/stroke (0.6%). After adjusting for confounders, vaccination was significantly associated with reduced risks of all‐cause death (HR, 0.82; P

Abstract Background The relationship between blood pressure and mortality in type 2 diabetes (T2DM) is controversial, with concern for increased risk associated with excessively lowered blood pressure. Methods We evaluated whether prior cardiovascular disease (CVD) altered the relationship between baseline blood pressure and all-cause mortality in 5852 patients with T2DM and a recent acute coronary syndrome (ACS) who participated in the ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) trial. Risk of death was assessed in Cox models adjusted for age, sex, race, heart rate, BMI, smoking, diabetes duration, insulin use, HbA1c, eGFR, brain natriuretic peptide (BNP), urine albumin/creatinine ratio, treatment allocation and prior coronary revascularization. Results Although overall there was no significant association between systolic blood pressure (SBP) and mortality (hazard ratio per 10 mmHg lower SBP 1.05 (95% CI 0.99–1.12) P = 0.10), lower SBP was significantly associated with higher risk of death (hazard ratio per 10 mmHg lower SBP 1.13 (95% CI 1.04–1.22) P = 0.002) in 2325 patients with additional CVD (index ACS+ at least one of the following prior to randomization: myocardial infarction other than the index ACS, stroke or heart failure). In 3527 patients with only the index ACS no significant association was observed (hazard ratio per 10 mmHg lower SBP 0.95 (0.86–1.04) P = 0.26; P for interaction 0.005). Conclusions The association between blood pressure and mortality was modified by additional CVD history in patients with type 2 diabetes and a recent coronary event. When blood pressures measured after an acute coronary event are used to assess the risk of death in patients with type 2 diabetes, the cardiovascular history needs to be taken into consideration. Trial registration ClinicalTrials.gov number NCT01147250, first posted June 22, 2010

Abstract Aims Increased body mass index (BMI) is common in heart failure (HF) patients and is associated with lower levels of N‐terminal pro‐brain natriuretic peptide (NT‐proBNP). We evaluated the influence of BMI on lung ultrasonography (LUS) findings indicative of pulmonary congestion (i.e. B‐lines) in patients with chronic and acute HF (AHF). Methods and results We analysed ambulatory chronic HF (n = 118) and hospitalized AHF (n = 177) patients (mean age 70 years, 64% men, mean BMI 29 kg/m2, mean ejection fraction 42%) undergoing echocardiography and LUS in eight chest zones. B‐lines and chest wall thickness (skin to pleura) on ultrasound were quantified offline and blinded to clinical findings. NT‐proBNP was available in AHF patients (n = 167). In chronic HF, B‐line number decreased by 18% per 5 unit increase in BMI [95% confidence interval (CI) −35% to +5%, P = 0.11]. In AHF, the number of B‐lines decreased by 12% per 5 unit increase in BMI (95% CI −19% to −5%, P = 0.001), whereas NT‐proBNP concentration decreased by 28% per 5 unit increase in BMI (95% CI −40% to −16%, P 6 B‐lines were observed in half of AHF patients with severe obesity. There was an inverse relationship between B‐line number and chest wall thickness, and this association varied by chest region. Conclusions Despite an inverse relationship between B‐lines and BMI, B‐lines declined to a lesser degree than NT‐proBNP with increasing BMI. These data suggest that LUS may be useful in patients with HF despite obesity.

Background Maximal left atrial (LA) volume is reported by most echocardiography laboratories and is associated with clinical outcomes in patients with heart failure (HF). Recent studies suggest that minimal LA volume may better reflect left ventricular filling pressure and may be more prognostic than maximal LA volume. This study assessed the prognostic value of indexed minimal LA volume (LAVImin) in patients with HF with preserved ejection fraction. Methods and Results We assessed the relationship of LAVImin with a primary composite end point of cardiovascular death, aborted cardiac death, or HF hospitalization in 347 patients with HF with preserved ejection fraction enrolled from the Americas region in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). We compared LAVImin with indexed maximal LA volume with respect to their prognostic values. In addition, we assessed if LA functional parameters provide additional prognostic information over LAVImin. During a median follow‐up of 2.5 years, 107 patients (31%) experienced a primary composite end point. LAVImin was associated with increased risk of a primary composite outcome (hazard ratio [HR], 1.35; 95% CI, 1.12–1.61) and HF hospitalization alone (HR, 1.42; 95% CI, 1.17–1.71) after adjusting for clinical confounders and ejection fraction. In contrast, indexed maximal LA volume was not related to the primary composite outcome, but related to HF alone (HR, 1.25; 95% CI, 1.02–1.54). In comparison with indexed maximal LA volume, LAVImin was significantly more prognostic for primary composite outcome (P for comparison=0.032). Both LA emptying fraction and LA strain were prognostic of primary outcome independent of LAVImin (all P

BackgroundHeart failure (HF) risk is highest in late life, and impaired pulmonary vascular function is a risk factor for HF development. However, data regarding the contributors to and prognostic importance of pulmonary vascular dysfunction among HF-free elders in the community are limited and largely restricted to pulmonary hypertension. Our objective was to define the prevalence and correlates of abnormal pulmonary pressure, resistance, and compliance and their association with incident HF and HF phenotype (left ventricular [LV] ejection fraction [LVEF] ≥ or < 50%) independent of LV structure and function.Methods and findingsWe performed cross-sectional and time-to-event analyses in a prospective epidemiologic cohort study, the Atherosclerosis Risk in Communities study. This is an ongoing, observational study that recruited 15,792 persons aged 45-64 years between 1987 and 1989 (visit 1) from four representative communities in the United States: Minneapolis, Minnesota; Jackson, Mississippi; Hagerstown, Maryland; and Forsyth County, North Carolina. The current analysis included 2,810 individuals aged 66-90 years, free of HF, who underwent echocardiography at the fifth study visit (June 8, 2011, to August 28, 2013) and had measurable tricuspid regurgitation by spectral Doppler. Echocardiography-derived pulmonary artery systolic pressure (PASP), pulmonary vascular resistance (PVR), and pulmonary arterial compliance (PAC) were measured. The main outcome was incident HF after visit 5, and key secondary end points were incident HF with preserved LVEF (HFpEF) and incident HF with reduced LVEF (HFrEF). The mean ± SD age was 76 ± 5 years, 66% were female, and 21% were black. Mean values of PASP, PVR, and PAC were 28 ± 5 mm Hg, 1.7 ± 0.4 Wood unit, and 3.4 ± 1.0 mL/mm Hg, respectively, and were abnormal in 18%, 12%, and 14%, respectively, using limits defined from the 10th and 90th percentile limits in 253 low-risk participants free of cardiovascular disease or risk factors. Left heart dysfunction was associated with abnormal PASP and PAC, whereas a restrictive ventilatory deficit was associated with abnormalities of PASP, PVR, and PAC. PASP, PVR, and PAC were each predictive of incident HF or death (hazard ratio per SD 1.3 [95% CI 1.1-1.4], p < 0.001; 1.1 [1.0-1.2], p = 0.04; 1.2 [1.1-1.4], p = 0.001, respectively) independent of LV measures. Elevated pulmonary pressure was predictive of incident HFpEF (HFpEF: 2.4 [1.4-4.0, p = 0.001]) but not HFrEF (1.4 [0.8-2.5, p = 0.31]). Abnormal PAC predicted HFrEF (HFpEF: 2.0 [1.0-4.0, p = 0.05], HFrEF: 2.8 [1.4-5.5, p = 0.003]), whereas abnormal PVR was not predictive of either (HFpEF: 0.9 [0.4-2.0, p = 0.85], HFrEF: 0.7 [0.3-1.4, p = 0.30],). A greater number of abnormal pulmonary vascular measures was associated with greater risk of incident HF. Major limitations include the use of echo Doppler to estimate pulmonary hemodynamic measures, which may lead to misclassification; inclusions bias related to detectable tricuspid regurgitation, which may limit generalizability of our findings; and survivor bias related to the cohort age, which may result in underestimation of the described associations.ConclusionsIn this study, we observed abnormalities of PASP, PVR, and PAC in 12%-18% of elders in the community. Higher PASP and lower PAC were independently predictive of incident HF. Abnormally high PASP predicted incident HFpEF but not HFrEF. These findings suggest that impairments in pulmonary vascular function may precede clinical HF and that a comprehensive pulmonary hemodynamic evaluation may identify pulmonary vascular phenotypes that differentially predict HF phenotypes.

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.

Aim: An inverse relationship between coffee consumption and mortality has been reported in the general population. However, the effect of coffee consumption in diabetes remains unclear. We aimed to evaluate the association of caffeine consumption and caffeine source with mortality among patients with diabetes.Methods: We examined the association of caffeine consumption with mortality among 1974 women and 1974 men with diabetes, using the National Health and Nutrition Examination Survey (NHANES) 1999–2010. Caffeine consumption was assessed at baseline using 24 h dietary recalls. Cox proportional hazard models were fitted to estimate hazard ratios (HR) for all-cause, cardiovascular, and cancer-related mortality according to caffeine consumption and its source, adjusting for potential confounders.Results: A dose-dependent inverse association between caffeine and all-cause mortality was observed in women with diabetes. Adjusted HR for death among women who consumed caffeine, as compared with non-consumers, were: 0.57 (95% CI, 0.40–0.82) for

Introduction. We investigated the association of diabetic retinopathy and neuropathy with increased risk of recurrent cardiovascular (CV) events in 6068 patients with type 2 diabetes mellitus (T2DM) and recent acute coronary syndrome (ACS) enrolled in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA). Methods. History of retinopathy and neuropathy as well as duration of T2DM were self-reported at screening. Proportional hazards regression models were used to assess relationships between retinopathy, neuropathy, and recurrent CV events. Results. At screening, retinopathy and neuropathy were reported in 10.7% and 17.5% of patients, respectively, while 5.7% reported both. When adjusted for randomized treatment only, both retinopathy and neuropathy were associated with a primary composite outcome (CV death, nonfatal MI, stroke, or hospitalization for unstable angina) (retinopathy: HR 1.44, 95% CI 1.19–1.75; neuropathy: HR 1.33, 95% CI 1.12–1.57), CV composite (CV death, nonfatal MI, stroke, hospitalization for heart failure (HF)) (retinopathy: HR 1.57, 95% CI 1.31–1.88; neuropathy: HR 1.38, 95% CI 1.19–1.62), myocardial infarction (retinopathy: HR 1.38, 95% CI 1.08–1.76; neuropathy: HR 1.26, 95% CI 1.02–1.54), HF hospitalization (retinopathy: HR 2.03, 95% CI 1.48–2.78; neuropathy: HR 1.71, 95% CI 1.30–2.27), and all-cause mortality (retinopathy: HR 1.65, 95% CI 1.28–2.12; neuropathy: HR 1.43, 95% CI 1.14–1.78). When included in the same model, and adjusted for T2DM duration, there were no independent associations of either with CV outcomes, while T2DM duration remained strongly associated with all outcomes. Addition of demographic characteristics and CV risk factors did not further alter these relationships. Conclusions. In patients with T2DM and recent ACS, a history of retinopathy and/or neuropathy and longer T2DM duration could be considered clinical markers for high risk of recurrent CV events. This trial is registered with the ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome), ClinicalTrials.gov registration number NCT01147250.

BackgroundNatriuretic peptides are recognized as important predictors of cardiovascular events in patients with heart failure, but less is known about their prognostic importance in patients with acute coronary syndrome. We sought to determine whether B‐type natriuretic peptide (BNP) and N‐terminal prohormone B‐type natriuretic peptide (NT‐proBNP) could enhance risk prediction of a broad range of cardiovascular outcomes in patients with acute coronary syndrome and type 2 diabetes mellitus. Methods and ResultsPatients with a recent acute coronary syndrome and type 2 diabetes mellitus were prospectively enrolled in the ELIXA trial (n=5525, follow‐up time 26 months). Best risk models were constructed from relevant baseline variables with and without BNP/NT‐proBNP. C statistics, Net Reclassification Index, and Integrated Discrimination Index were analyzed to estimate the value of adding BNP or NT‐proBNP to best risk models. Overall, BNP and NT‐proBNP were the most important predictors of all outcomes examined, irrespective of history of heart failure or any prior cardiovascular disease. BNP significantly improved C statistics when added to risk models for each outcome examined, the strongest increments being in death (0.77–0.82, P

BackgroundThis study aimed to compare the independent and incremental prognostic value of peak oxygen consumption (VO2) and minute ventilation/carbon dioxide production (VE/VCO2) in heart failure (HF) with preserved (HFpEF), midrange (HFmEF), and reduced (HFrEF) ejection fraction (LVEF). Methods and ResultsIn 195 HFpEF (LVEF ≥50%), 144 HFmEF (LVEF 40–49%), and 630 HFrEF (LVEF

BackgroundElevated 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‐proBNP) levels and outcomes. Methods and ResultsA 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‐proBNP 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‐proBNP compared with the AA genotype (frequency 34%), with intermediate values observed in AGs (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 AGs. 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 AAs. ConclusionsThe rs198389 G allele in the NPPB promoter is associated with elevated levels of NT‐proBNP throughout adult life, reduced blood pressure, hypertension and cardiovascular mortality, and increased lifespan.

BackgroundAlthough clear evidence shows that chronic kidney disease is a predictor of cardiovascular events, death, and accelerated coronary artery disease (CAD) progression, it remains unknown whether CAD is a predictor of progression of chronic kidney disease to end‐stage renal disease. We sought to assess whether CAD adds prognostic information to established predictors of progression to dialysis in patients with chronic kidney disease, diabetes, and anemia. Methods and ResultsUsing the previously described Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) population, we compared baseline characteristics of patients with and without CAD. Cox proportional hazards models were used to assess the association between CAD and the outcomes of end‐stage renal disease and the composite of death or end‐stage renal disease. Of the 4038 patients, 1791 had a history of known CAD. These patients were older (mean age 70 versus 65 years, P

Background Natriuretic peptides promote natriuresis, diuresis, and vasodilation. Experimental deficiency of natriuretic peptides leads to hypertension (HTN) and cardiac hypertrophy, conditions more common among African Americans. Hospital‐based studies suggest that African Americans may have reduced circulating natriuretic peptides, as compared to Caucasians, but definitive data from community‐based cohorts are lacking. Methods and Results We examined plasma N‐terminal pro B‐type natriuretic peptide (NTproBNP) levels according to race in 9137 Atherosclerosis Risk in Communities (ARIC) Study participants (22% African American) without prevalent cardiovascular disease at visit 4 (1996–1998). Multivariable linear and logistic regression analyses were performed adjusting for clinical covariates. Among African Americans, percent European ancestry was determined from genetic ancestry informative markers and then examined in relation to NTproBNP levels in multivariable linear regression analysis. NTproBNP levels were significantly lower in African Americans (median, 43 pg/mL; interquartile range [IQR], 18, 88) than Caucasians (median, 68 pg/mL; IQR, 36, 124; P

Placebo treatments and healing rituals have been used to treat pain throughout history. The present within-subject crossover study examines the variability in individual responses to placebo treatment with verbal suggestion and visual cue conditioning by investigating whether responses to different types of placebo treatment, as well as conditioning responses, correlate with one another. Secondarily, this study also examines whether responses to sham acupuncture correlate with responses to genuine acupuncture. Healthy subjects were recruited to participate in two sequential experiments. Experiment one is a five-session crossover study. In each session, subjects received one of four treatments: placebo pills (described as Tylenol), sham acupuncture, genuine acupuncture, or no treatment rest control condition. Before and after each treatment, paired with a verbal suggestion of positive effect, each subject's pain threshold, pain tolerance, and pain ratings to calibrated heat pain were measured. At least 14 days after completing experiment one, all subjects were invited to participate in experiment two, during which their analgesic responses to conditioned visual cues were tested. Forty-eight healthy subjects completed experiment one, and 45 completed experiment two. The results showed significantly different effects of genuine acupuncture, placebo pill and rest control on pain threshold. There was no significant association between placebo pills, sham acupuncture and cue conditioning effects, indicating that individuals may respond to unique healing rituals in different ways. This outcome suggests that placebo response may be a complex behavioral phenomenon that has properties that comprise a state, rather than a trait characteristic. This could explain the difficulty of detecting a signature for "placebo responders." However, a significant association was found between the genuine and sham acupuncture treatments, implying that the non-specific effects of acupuncture may contribute to the analgesic effect observed in genuine acupuncture analgesia.

Introduction Early reports highlighted racial/ethnic disparities in the severity of COVID-19 seen across the USA; the extent to which these disparities have persisted over time remains unclear. Our research objective was to understand temporal trends in racial/ethnic variation in severity of COVID-19 illness presenting over time.Methods We conducted a retrospective cohort analysis using longitudinal data from Cedars-Sinai Medical Center, a high-volume health system in Southern California. We studied patients admitted to the hospital with COVID-19 illness from 4 March 2020 through 5 December 2020. Our primary outcome was COVID-19 severity of illness among hospitalised patients, assessed by racial/ethnic group status. We defined overall illness severity as an ordinal outcome: hospitalisation but no intensive care unit (ICU) admission; admission to the ICU but no intubation; and intubation or death.Results A total of 1584 patients with COVID-19 with available demographic and clinical data were included. Hispanic/Latinx compared with non-Hispanic white patients had higher odds of experiencing more severe illness among hospitalised patients (OR 2.28, 95% CI 1.62 to 3.22) and this disparity persisted over time. During the initial 2 months of the pandemic, non-Hispanic blacks were more likely to suffer severe illness than non-Hispanic whites (OR 2.02, 95% CI 1.07 to 3.78); this disparity improved by May, only to return later in the pandemic.Conclusion In our patient sample, the severity of observed COVID-19 illness declined steadily over time, but these clinical improvements were not seen evenly across racial/ethnic groups; greater illness severity continues to be experienced among Hispanic/Latinx patients.