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Background The American Heart Association's framework “ideal cardiovascular health” (CVH) focuses on modifiable risk factors to reduce cardiovascular disease (CVD). Metabolomics provides important pathobiological insights into risk factors and CVD development. We hypothesized that metabolomic signatures associate with CVH status, and that metabolites, at least partially, mediate the association of CVH score with atrial fibrillation (AF) and heart failure (HF). Methods and Results We studied 3056 adults in the FHS (Framingham Heart Study) cohort to evaluate CVH score and incident outcomes of AF and HF. Metabolomics data were available in 2059 participants; mediation analysis was performed to evaluate the mediation of metabolites in the association of CVH score and incident AF and HF. In the smaller cohort (mean age, 54 years; 53% women), CVH score was associated with 144 metabolites, with 64 metabolites shared across key cardiometabolic components (body mass index, blood pressure, and fasting blood glucose) of the CVH score. In mediation analyses, 3 metabolites (glycerol, cholesterol ester 16:1, and phosphatidylcholine 32:1) mediated the association of CVH score with incident AF. Seven metabolites (glycerol, isocitrate, asparagine, glutamine, indole‐3‐proprionate, phosphatidylcholine C36:4, and lysophosphatidylcholine 18:2), partly mediated the association between CVH score and incident HF in multivariable‐adjusted models. Conclusions Most metabolites that associated with CVH score were shared the most among 3 cardiometabolic components. Three main pathways: (1) alanine, glutamine, and glutamate metabolism; (2) citric acid cycle metabolism; and (3) glycerolipid metabolism mediated CVH score with HF. Metabolomics provides insights into how ideal CVH status contributes to the development of AF and HF.

Background Systolic blood pressure increases with age after midlife, particularly in women, and contributes to development of wide pulse pressure hypertension in middle‐aged and older adults. Relative contributions of aortic stiffness and premature wave reflection to increases in pulse pressure remain controversial. Methods and Results We evaluated visit‐specific values and change in key correlates of pulse pressure, aortic characteristic impedance, forward and backward wave amplitude, and global reflection coefficient, at 3 sequential examinations of the Framingham Generation 3 (N=4082), Omni‐2 (N=410), and New Offspring Spouse (N=103) cohorts (53% women). Data were analyzed using repeated‐measures linear mixed models adjusted for age, sex, and risk factor exposures. Pulse pressure increased markedly with age after midlife (age and age‐squared terms, P

Background Deep vein thrombosis (DVT) is the primary cause of pulmonary embolism and the third most life‐threatening cardiovascular disease in North America. Post‐DVT anticoagulants, such as warfarin, heparin, and direct oral anticoagulants, reduce the incidence of subsequent venous thrombi. However, all currently used anticoagulants affect bleeding time at various degrees, and there is therefore a need for improved therapeutic regimens in DVT. It has recently been shown that mast cells play a crucial role in a DVT murine model. The underlying mechanism involved in the prothrombotic properties of mast cells, however, has yet to be identified. Methods and Results C57BL/6 mice and mouse mast cell protease‐4 (mMCP‐4) genetically depleted mice (mMCP‐4 knockout) were used in 2 mouse models of DVT, partial ligation (stenosis) and ferric chloride–endothelial injury model of the inferior vena cava. Thrombus formation and impact of genetically repressed or pharmacologically (specific inhibitor TY‐51469) inhibited mMCP‐4 were evaluated by morphometric measurements of thrombi immunochemistry (mouse and human DVT), color Doppler ultrasound, bleeding times, and enzymatic activity assays ex vivo. Recombinant chymases, mMCP‐4 (mouse) and CMA‐1 (human), were used to characterize the interaction with murine and human plasmin, respectively, by mass spectrometry and enzymatic activity assays. Inhibiting mast cell–generated mMCP‐4, genetically or pharmacologically, resolves and prevents venous thrombus formation in both DVT models. Inferior vena cava blood flow obstruction was observed in the stenosis model after 6 hours of ligation, in control‐ but not in TY‐51469–treated mice. In addition, chymase inhibition had no impact on bleeding times of healthy or DVT mice. Furthermore, endogenous chymase limits plasmin activity in thrombi ex vivo. Recombinant mouse or human chymase degrades/inactivates purified plasmin in vitro. Finally, mast cell–containing immunoreactive chymase was identified in human DVT. Conclusions This study identified a major role for mMCP‐4, a granule‐localized protease of chymase type, in DVT formation. These findings support a novel pharmacological strategy to resolve or prevent DVT without affecting the coagulation cascade through the inhibition of chymase activity.

Background Stiffness of the proximal aorta may play a critical role in adverse left ventricular (LV)–vascular interactions and associated LV diastolic dysfunction. In a community‐based sample, we sought to determine the association between proximal aortic stiffness measured by cardiovascular magnetic resonance (CMR) and several clinical measures of LV diastolic mechanics. Methods and Results Framingham Heart Study Offspring adults (n=1502 participants, mean 67±9 years, 54% women) with available 1.5T CMR and transthoracic echocardiographic measures were included. Measures included proximal descending aortic strain and aortic arch pulse wave velocity by CMR (2002–2006) and diastolic function (mitral Doppler E and A wave velocity, E wave area, and LV tissue Doppler e' velocity) by echocardiography (2005–2008). Multivariable linear regression analysis was used to relate CMR aortic stiffness measures to measures of echocardiographic LV diastolic function. All continuous variables were standardized. In multivariable‐adjusted regression analyses, aortic strain was inversely associated with E wave deceleration time (estimated β=−0.10±0.032, P=0.001), whereas aortic arch pulse wave velocity was inversely associated with E/A ratio (estimated β=−0.094±0.027, P=0.0006), E wave area (estimated β=−0.070±0.027, P=0.010), and e' (estimated β=−0.061±0.027, P=0.022), all indicating associations of higher aortic stiffness by CMR with less favorable LV diastolic function. Compared with men, women had a larger inverse relationship between pulse wave velocity and E/A ratio (interaction β=−0.085±0.031, P=0.0064). There was no significant effect modification by age or a U‐shaped (quadratic) relation between aortic stiffness and LV diastolic function measures. Conclusions Higher proximal aortic stiffness is associated with less favorable LV diastolic function. Future studies may clarify temporal relations of aortic stiffness with varying patterns and progression of LV diastolic dysfunction.

Background In a previous trial, higher 5‐year mortality was observed following treatment with biodegradable polymer Orsiro sirolimus‐eluting stents (SES). We assessed 5‐year safety and efficacy of all‐comers as well as patients with diabetes treated with SES or Synergy everolimus‐eluting stents (EES) versus durable polymer Resolute Integrity zotarolimus‐eluting stents (ZES). Methods and Results The randomized BIO‐RESORT (Comparison of Biodegradable Polymer and Durable Polymer Drug‐Eluting Stents in an All Comers Population) trial enrolled 3514 all‐comer patients at 4 Dutch cardiac centers. Patients aged ≥18 years who required percutaneous coronary intervention were eligible. Participants were stratified for diabetes and randomized to treatment with SES, EES, or ZES (1:1:1). The main end point was target vessel failure (cardiac mortality, target vessel myocardial infarction, or target vessel revascularization). Five‐year follow‐up was available in 3183 of 3514 (90.6%) patients. The main end point target vessel failure occurred in 142 of 1169 (12.7%) patients treated with SES, 130 of 1172 (11.6%) treated with EES, versus 157 of 1173 (14.1%) treated with ZES (hazard ratio [HR], 0.89 [95% CI, 0.71–1.12], Plog‐rank=0.31; and HR, 0.82 [95% CI, 0.65–1.04], Plog‐rank=0.10, respectively). Individual components of target vessel failure showed no significant between‐stent difference. Very late definite stent thrombosis rates were low and similar (SES, 1.1%; EES, 0.6%; ZES, 0.9%). In patients with diabetes, target vessel failure did not differ significantly between stent‐groups (SES, 19.8%; EES, 19.2%; versus ZES, 21.1% [Plog‐rank=0.69 and Plog‐rank=0.63]). Conclusions Orsiro SES, Synergy EES, and Resolute Integrity ZES showed similar 5‐year outcomes of safety and efficacy, including mortality. A prespecified stent comparison in patients with diabetes also revealed no significant differences in 5‐year clinical outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01674803.

Background Cardiorespiratory fitness is a powerful predictor of health outcomes that is currently underused in primary prevention, especially in young adults. We sought to develop a blood‐based biomarker of cardiorespiratory fitness that is easily translatable across populations. Methods and Results Maximal effort cardiopulmonary exercise testing for quantification of cardiorespiratory fitness (by peak oxygen uptake) and profiling of >200 metabolites at rest were performed in the FHS (Framingham Heart Study; 2016–2019). A metabolomic fitness score was derived/validated in the FHS and was associated with long‐term outcomes in the younger CARDIA (Coronary Artery Risk Development in Young Adults) study. In the FHS (derivation, N=451; validation, N=914; age 54±8 years, 53% women, body mass index 27.7±5.3 kg/m2), we used LASSO (least absolute shrinkage and selection operator) regression to develop a multimetabolite score to predict peak oxygen uptake (correlation with peak oxygen uptake r=0.77 in derivation, 0.61 in validation; both P

Abstract Aims Heart failure (HF) is associated with several metabolic changes, but it is unknown whether distinct components of the circulating metabolome may be related to cardiac structure and function, and with incident HF in the community. Methods and results We assayed 217 circulating metabolites in 2336 Framingham Study participants (mean age 55 ± 10 years, 53% women) without HF at baseline. We used linear and Cox regression to relate concentrations of metabolites to left ventricular (LV) diastolic dimension, LV wall thickness, LV ejection fraction, left atrial dimension, LV ventricular mass, and aortic root size cross‐sectionally and to incident HF prospectively. Bonferroni‐adjusted P‐values

Background We investigated preoperative referral patterns, rates of cardiovascular testing, surgical wait times, and postoperative outcomes in White versus Black, Hispanic, or other racial or ethnic groups of patients undergoing metabolic and bariatric surgery. Methods and Results This was a single center retrospective cohort analysis of 797 consecutive patients undergoing metabolic and bariatric surgery from January 2014 to December 2018; 86% (n=682) were Black, Hispanic, or other racial or ethnic groups. White versus Black, Hispanic, or other racial or ethnic groups had similar baseline comorbidities and were referred for preoperative cardiovascular evaluation in similar proportion (65% versus 68%, P=0.529). Black, Hispanic, or other racial or ethnic groups of patients were less likely to undergo preoperative cardiovascular testing (unadjusted odds ratio [OR], 0.56; 95% CI, 0.33–0.95; P=0.031; adjusted for Revised Cardiac Risk Index OR, 0.59; 95% CI, 0.35–0.996; P=0.049). White patients had a shorter wait time for surgery (unadjusted hazard ratio [HR], 0.7; 95% CI, 0.58–0.87; P=0.001; adjusted HR, 0.7; 95% CI, 0.56–0.95; P=0.018). Reduction in body mass index at 6 months was greater in White patients (12.9 kg/m2 versus 12.0 kg/m2, P=0.0289), but equivalent at 1 year (14.9 kg/m2 versus 14.3 kg/m2, P=0.330). Conclusions White versus Black, Hispanic, or other racial or ethnic groups of patients were referred for preoperative cardiovascular evaluation in similar proportion. White patients underwent more preoperative cardiac testing yet had a shorter wait time for surgery. Early weight loss was greater in White patients, but equivalent between groups at 12 months.

Abstract Recently, citizen scientist photographs led to the discovery of a new auroral form called “the dune aurora” which exhibits parallel stripes of brighter emission in the green diffuse aurora at about 100 km altitude. This discovery raised several questions, such as (i) whether the dunes are associated with particle precipitation, (ii) whether their structure arises from spatial inhomogeneities in the precipitating fluxes or in the underlying neutral atmosphere, and (iii) whether they are the auroral manifestation of an atmospheric wave called a mesospheric bore. This study investigates a large‐scale dune aurora event on 20 January 2016 above Northern Europe. The dunes were observed from Finland to Scotland, spanning over 1,500 km for at least 4 h. Spacecraft observations indicate that the dunes are associated with particle precipitation and reveal the presence of a temperature inversion layer below the mesopause during the event, creating suitable conditions for mesospheric bore formation. The analysis of a time lapse of pictures by a citizen scientist from Scotland leads to the estimate that, during this event, the dunes propagate toward the west‐southwest direction at about 200 m s−1, presumably indicating strong horizontal winds near the mesopause. These results show that citizen science and dune aurora studies can fill observational gaps and be powerful tools to investigate the least‐known region of near‐Earth space at altitudes near 100 km.

Background Epidemiological and animal studies have associated systemic inflammation with blood pressure (BP). However, the mechanistic factors linking inflammation and BP remain unknown. Fatty acid–derived eicosanoids serve as mediators of inflammation and have been suggested to regulate renal vascular tone, peripheral resistance, renin‐angiotensin system, and endothelial function. We hypothesize that specific proinflammatory and anti‐inflammatory eicosanoids are linked with BP. Methods and Results We studied a population sample of 8099 FINRISK 2002 participants randomly drawn from the Finnish population register (53% women; mean age, 48±13 years) and, for external validation, a sample of 2859 FHS (Framingham Heart Study) Offspring study participants (55% women; mean age, 66±9 years). Using nontargeted liquid chromatography–mass spectrometry, we profiled 545 distinct high‐quality eicosanoids and related oxylipin mediators in plasma. Adjusting for conventional hypertension risk factors, we observed 187 (34%) metabolites that were significantly associated with systolic BP (P

Background Reservoir‐wave approach is an alternative model of arterial hemodynamics based on the assumption that measured arterial pressure is composed of volume‐related (reservoir pressure) and wave‐related components (excess pressure). However, the clinical utility of reservoir‐wave approach remains debatable. Methods and Results In a single‐center cohort of 260 dialysis patients, we examined whether carotid and radial reservoir‐wave parameters were associated with all‐cause and cardiovascular mortality. Central pulse pressure and augmentation index at 75 beats per minute were determined by radial arterial tonometry through generalized transfer function. Carotid and radial reservoir‐wave analysis were performed to determine reservoir pressure and excess pressure integral. After a median follow‐up of 32 months, 171 (66%) deaths and 88 (34%) cardiovascular deaths occurred. In Cox regression analysis, carotid excess pressure integral was associated with a hazard ratio of 1.33 (95% CI, 1.14–1.54; P

Background Waveform parameters derived from pressure‐only Windkessel models are related to cardiovascular disease risk and could be useful for understanding arterial system function. However, prior reports varied in their adjustment for potential confounders. Methods and Results Carotid tonometry waveform data from 2539 participants (mean age 63±11 years, 58% women) of the Framingham Heart Study were used to derive Windkessel measures using pressure and assuming a linear model with fixed diastolic time constant (τdias) and variable asymptotic pressure (Pinf, median 54.5; 25th, 75th percentiles: 38.4, 64.9 mm Hg) or nonlinear model with inverse pressure‐dependent τdias and fixed Pinf (20 mm Hg). During follow‐up (median 15.1 years), 459 (18%) participants had a first cardiovascular disease event. In proportional hazards models adjusted for age, sex, total cholesterol, high‐density lipoprotein cholesterol, smoking, antihypertensive medication use, diabetes mellitus, and physician‐acquired systolic blood pressure, only the systolic time constant (τsys) derived from the nonlinear model was related to risk for cardiovascular disease events (hazard ratio=0.91 per 1 SD, 95% CI=0.84–0.99, P=0.04). When heart rate was added to the model, τsys (hazard ratio=0.92, CI=0.84–1.00, P=0.04) and reservoir pressure amplitude (hazard ratio=1.14, CI=1.01–1.28, P=0.04) were related to events. In contrast, measures derived from the linear model were not related to events in models that adjusted for risk factors including systolic blood pressure (P>0.31) and heart rate (P>0.19). Conclusions Our results suggest that pressure‐only Windkessel measures derived by using a nonlinear model may provide incremental risk stratification, although associations were modest and further validation is required.

Background Prior studies relating proteomics markers to incident AF screened for limited numbers of proteins. Methods and Results We performed proteomics assays among participants from the Framingham Heart Study Offspring attending their fifth examination. Plasma protein levels (n=1373) were measured by the SOMAscan proteomic profiling platform. We used robust inference for the Cox proportional hazards model to relate each protein level with incident AF. In addition, we examined the association between AF‐related genetic loci and levels of proteins associated with AF. Our study included 1885 participants (mean age 55±10 years, 54% women) who had proteomic profiles measured. A total of 349 participants developed AF during follow‐up (mean follow‐up 18.3 years). We observed that 8 proteins were significantly associated with incident AF after adjusting for age, sex, technical covariates, and correction for multiple testing (P

BackgroundLeft ventricular diastolic dysfunction (DD) is common, particularly in women and older individuals, and it is associated with adverse cardiovascular outcomes. We evaluated the impact of age‐ and sex‐specific diagnostic criteria on the assessment of DD in the community‐based Framingham Heart Study. Methods and ResultsWe estimated age‐ and sex‐specific reference limits for echocardiographic measures of DD in a healthy reference subsample (N=2355, mean age 44 years, 66% women). The prevalence, correlates, and association with future cardiovascular disease were compared for DD using age‐ and sex‐specific versus single cut point reference limits in a broad sample (N=6102, mean age 50 years, 56% women). Using age‐ and sex‐specific criteria, DD was present in ≈25% to 30% of individuals across age groups, and it was directly associated with a number of modifiable risk factors. In contrast, with single cut point criteria, age was the primary determinant of DD. During follow‐up (mean 7.9±2.2 years), incident cardiovascular disease occurred in 213 of 5770 individuals. Using age‐ and sex‐specific criteria, mild and moderate‐severe DD were associated with 50% (95% confidence interval, 1.09–2.05) and 65% (95% confidence interval, 1.14–2.38) higher incidences of cardiovascular disease, respectively, in age‐ and sex‐adjusted analyses. With single cut point criteria, moderate‐severe DD (hazard ratio, 1.66; 95% confidence interval, 1.05–2.61), but not mild DD (hazard ratio, 0.94; 95% confidence interval, 0.63–1.40), was associated with incident cardiovascular disease. ConclusionsAge‐ and sex‐specific reference limits may result in DD assessments that are less dependent on age, more robustly related to modifiable risk factors, and are more closely associated with incident cardiovascular disease.