Proteomics, Human Environmental Exposure, and Cardiometabolic Risk.

BACKGROUND: The biological mechanisms linking environmental exposures with cardiovascular disease pathobiology are incompletely understood. We sought to identify circulating proteomic signatures of environmental exposures and examine their associations with cardiometabolic and respiratory disease in observational cohort studies. METHODS: We tested the relations of >6500 circulating proteins with 29 environmental exposures across the built environment, green space, air pollution, temperature, and social vulnerability indicators in ≈3000 participants of the CARDIA study (Coronary Artery Risk Development in Young Adults) across 4 centers using penalized and ordinary linear regression. In >3500 participants from FHS (Framingham Heart Study) and JHS (Jackson Heart Study), we evaluated the prospective relations of proteomic signatures of the envirome with cardiovascular disease and mortality using Cox models. RESULTS: Proteomic signatures of the envirome identified novel/established cardiovascular disease-relevant pathways including DNA damage, fibrosis, inflammation, and mitochondrial function. The proteomic signatures of the envirome were broadly related to cardiometabolic disease and respiratory phenotypes (eg, body mass index, lipids, and left ventricular mass) in CARDIA, with replication in FHS/JHS. A proteomic signature of social vulnerability was associated with a composite of cardiovascular disease/mortality (1428 events; FHS: hazard ratio, 1.16 [95% CI, 1.08-1.24]; P=1.77×10-5; JHS: hazard ratio, 1.25 [95% CI, 1.14-1.38]; P=6.38×10-6; hazard ratio expressed as per 1 SD increase in proteomic signature), robust to adjustment for known clinical risk factors. CONCLUSIONS: Environmental exposures are related to an inflammatory-metabolic proteome, which identifies individuals with cardiometabolic disease and respiratory phenotypes and outcomes. Future work examining the dynamic impact of the environment on human cardiometabolic health is warranted.

Systemic Arterial Oxygen Levels Differentiate Pre- and Post-capillary Predominant Hemodynamic Abnormalities During Exercise in Undifferentiated Dyspnea on Exertion.

BACKGROUND: Whether systemic oxygen levels (SaO2) during exercise can provide a window into invasively derived exercise hemodynamic profiles in patients with undifferentiated dyspnea on exertion is unknown. METHODS: We performed cardiopulmonary exercise testing with invasive hemodynamic monitoring and arterial blood gas sampling in individuals referred for dyspnea on exertion. Receiver operator analysis was performed to distinguish heart failure with preserved ejection fraction from pulmonary arterial hypertension. RESULTS: Among 253 patients (mean ± SD, age 63 ± 14 years, 55% female, arterial O2 [PaO2] 87 ± 14 mmHg, SaO2 96% ± 4%, resting pulmonary capillary wedge pressure [PCWP] 18 ± 4mmHg, and pulmonary vascular resistance [PVR] 2.7 ± 1.2 Wood units), there was no exercise PCWP threshold, measured up to 49 mmHg, above which hypoxemia was consistently observed. Exercise PaO2 was not correlated with exercise PCWP (rho = 0.04; P = 0.51) but did relate to exercise PVR (rho = -0.46; P < 0.001). Exercise PaO2 and SaO2 levels distinguished left-heart-predominant dysfunction from pulmonary-vascular-predominant dysfunction with an area under the curve of 0.89 and 0.89, respectively. CONCLUSION: Systemic O2 levels during exercise distinguish relative pre- and post-capillary pulmonary hemodynamic abnormalities in patients with undifferentiated dyspnea. Hypoxemia during upright exercise should not be attributed to isolated elevation in left heart filling pressures and should prompt consideration of pulmonary vascular dysfunction.

Blood Pressure Responses During Exercise: Physiological Correlates and Clinical Implications.

BACKGROUND: Abnormal blood pressure (BP) responses to exercise can predict adverse cardiovascular outcomes, but their optimal measurement and definitions are poorly understood. We combined frequently sampled BP during cardiopulmonary exercise testing with vascular stiffness assessment to parse cardiac and vascular components of exercise BP. METHODS: Cardiopulmonary exercise testing with BP measured every two minutes and resting vascular tonometry were performed in 2858 Framingham Heart Study participants. Linear regression was used to analyze sex-specific exercise BP patterns as a function of arterial stiffness (carotid-femoral pulse wave velocity) and cardiac-peripheral performance (defined by peak O2 pulse). RESULTS: Our sample was balanced by sex (52% women) with mean age 54±9 years and 47% with hypertension. We observed variability in carotid-femoral pulse wave velocity and peak O2 pulse across individuals with clinically defined exercise hypertension (peak systolic BP [SBP] in men ≥210 mm Hg; in women ≥190 mm Hg). Despite similar resting SBP and cardiometabolic profiles, individuals with higher peak O2 pulse displayed higher peak SBP (P≤0.017) alongside higher fitness levels (P<0.001), suggesting that high peak exercise SBP in the context of high peak O2 pulse may in fact be favorable. Although both higher (favorable) O2 pulse and higher (adverse) arterial stiffness were associated with greater peak SBP (P<0.0001 for both), the magnitude of association of carotid-femoral pulse wave velocity with peak SBP was higher in women (sex-carotid-femoral pulse wave velocity interaction P<0.0001). In sex-specific models, exercise SBP measures accounting for workload (eg, SBP during unloaded exercise, SBP at 75 watts, and SBP/workload slope) were directly associated with the adverse features of greater arterial stiffness and lower peak O2 pulse. CONCLUSIONS: Higher peak exercise SBP reflects a complex trade-off between arterial stiffness and cardiac-peripheral performance that differs by sex. Studies of BP responses to exercise accounting for vascular and cardiac physiology may illuminate mechanisms of hypertension and clarify clinical interpretation of exercise BP.

Association of Smartwatch-Based Heart Rate and Physical Activity With Cardiorespiratory Fitness Measures in the Community: Cohort Study.

BACKGROUND: Resting heart rate (HR) and routine physical activity are associated with cardiorespiratory fitness levels. Commercial smartwatches permit remote HR monitoring and step count recording in real-world settings over long periods of time, but the relationship between smartwatch-measured HR and daily steps to cardiorespiratory fitness remains incompletely characterized in the community. OBJECTIVE: This study aimed to examine the association of nonactive HR and daily steps measured by a smartwatch with a multidimensional fitness assessment via cardiopulmonary exercise testing (CPET) among participants in the electronic Framingham Heart Study. METHODS: Electronic Framingham Heart Study participants were enrolled in a research examination (2016-2019) and provided with a study smartwatch that collected longitudinal HR and physical activity data for up to 3 years. At the same examination, the participants underwent CPET on a cycle ergometer. Multivariable linear models were used to test the association of CPET indices with nonactive HR and daily steps from the smartwatch. RESULTS: We included 662 participants (mean age 53, SD 9 years; n=391, 59% women, n=599, 91% White; mean nonactive HR 73, SD 6 beats per minute) with a median of 1836 (IQR 889-3559) HR records and a median of 128 (IQR 65-227) watch-wearing days for each individual. In multivariable-adjusted models, lower nonactive HR and higher daily steps were associated with higher peak oxygen uptake (VO2), % predicted peak VO2, and VO2 at the ventilatory anaerobic threshold, with false discovery rate (FDR)-adjusted P values <.001 for all. Reductions of 2.4 beats per minute in nonactive HR, or increases of nearly 1000 daily steps, corresponded to a 1.3 mL/kg/min higher peak VO2. In addition, ventilatory efficiency (VE/VCO2; FDR-adjusted P=.009), % predicted maximum HR (FDR-adjusted P<.001), and systolic blood pressure-to-workload slope (FDR-adjusted P=.01) were associated with nonactive HR but not associated with daily steps. CONCLUSIONS: Our findings suggest that smartwatch-based assessments are associated with a broad array of cardiorespiratory fitness responses in the community, including measures of global fitness (peak VO2), ventilatory efficiency, and blood pressure response to exercise. Metrics captured by wearable devices offer a valuable opportunity to use extensive data on health factors and behaviors to provide a window into individual cardiovascular fitness levels.

Dietary metabolic signatures and cardiometabolic risk.

AIMS: Observational studies of diet in cardiometabolic-cardiovascular disease (CM-CVD) focus on self-reported consumption of food or dietary pattern, with limited information on individual metabolic responses to dietary intake linked to CM-CVD. Here, machine learning approaches were used to identify individual metabolic patterns related to diet and relation to long-term CM-CVD in early adulthood. METHODS AND RESULTS: In 2259 White and Black adults (age 32.1 ± 3.6 years, 45% women, 44% Black) in the Coronary Artery Risk Development in Young Adults (CARDIA) study, multivariate models were employed to identify metabolite signatures of food group and composite dietary intake across 17 food groups, 2 nutrient groups, and healthy eating index-2015 (HEI2015) diet quality score. A broad array of metabolites associated with diet were uncovered, reflecting food-related components/catabolites (e.g. fish and long-chain unsaturated triacylglycerols), interactions with host features (microbiome), or pathways broadly implicated in CM-CVD (e.g. ceramide/sphingomyelin lipid metabolism). To integrate diet with metabolism, penalized machine learning models were used to define a metabolite signature linked to a putative CM-CVD-adverse diet (e.g. high in red/processed meat, refined grains), which was subsequently associated with long-term diabetes and CVD risk numerically more strongly than HEI2015 in CARDIA [e.g. diabetes: standardized hazard ratio (HR): 1.62, 95% confidence interval (CI): 1.32-1.97, P < 0.0001; CVD: HR: 1.55, 95% CI: 1.12-2.14, P = 0.008], with associations replicated for diabetes (P < 0.0001) in the Framingham Heart Study. CONCLUSION: Metabolic signatures of diet are associated with long-term CM-CVD independent of lifestyle and traditional risk factors. Metabolomics improves precision to identify adverse consequences and pathways of diet-related CM-CVD.

Circulating metabolites may illustrate relationship of alcohol consumption with cardiovascular disease.

BACKGROUND: Metabolite signatures of long-term alcohol consumption are lacking. To better understand the molecular basis linking alcohol drinking and cardiovascular disease (CVD), we investigated circulating metabolites associated with long-term alcohol consumption and examined whether these metabolites were associated with incident CVD. METHODS: Cumulative average alcohol consumption (g/day) was derived from the total consumption of beer, wine, and liquor on average of 19 years in 2428 Framingham Heart Study Offspring participants (mean age 56 years, 52% women). We used linear mixed models to investigate the associations of alcohol consumption with 211 log-transformed plasma metabolites, adjusting for age, sex, batch, smoking, diet, physical activity, BMI, and familial relationship. Cox models were used to test the association of alcohol-related metabolite scores with fatal and nonfatal incident CVD (myocardial infarction, coronary heart disease, stroke, and heart failure). RESULTS: We identified 60 metabolites associated with cumulative average alcohol consumption (p < 0.05/211 ≈ 0.00024). For example, 1 g/day increase of alcohol consumption was associated with higher levels of cholesteryl esters (e.g., CE 16:1, beta = 0.023 ± 0.002, p = 6.3e - 45) and phosphatidylcholine (e.g., PC 32:1, beta = 0.021 ± 0.002, p = 3.1e - 38). Survival analysis identified that 10 alcohol-associated metabolites were also associated with a differential CVD risk after adjusting for age, sex, and batch. Further, we built two alcohol consumption weighted metabolite scores using these 10 metabolites and showed that, with adjustment age, sex, batch, and common CVD risk factors, the two scores had comparable but opposite associations with incident CVD, hazard ratio 1.11 (95% CI = [1.02, 1.21], p = 0.02) vs 0.88 (95% CI = [0.78, 0.98], p = 0.02). CONCLUSIONS: We identified 60 long-term alcohol consumption-associated metabolites. The association analysis with incident CVD suggests a complex metabolic basis between alcohol consumption and CVD.

The Molecular Basis of Predicting Atherosclerotic Cardiovascular Disease Risk.

Atherosclerotic cardiovascular disease (ASCVD) proceeds through a series of stages: initiation, progression (or regression), and complications. By integrating known biology regarding molecular signatures of each stage with recent advances in high-dimensional molecular data acquisition platforms (to assay the genome, epigenome, transcriptome, proteome, metabolome, and gut microbiome), snapshots of each phase of atherosclerotic cardiovascular disease development can be captured. In this review, we will summarize emerging approaches for assessment of atherosclerotic cardiovascular disease risk in humans using peripheral blood molecular signatures and molecular imaging approaches. We will then discuss the potential (and challenges) for these snapshots to be integrated into a personalized movie providing dynamic readouts of an individual's atherosclerotic cardiovascular disease risk status throughout the life course.

Circulating metabolite profile in young adulthood identifies long-term diabetes susceptibility: the Coronary Artery Risk Development in Young Adults (CARDIA) study.

AIMS/HYPOTHESIS: The aim of this work was to define metabolic correlates and pathways of diabetes pathogenesis in young adults during a subclinical latent phase of diabetes development. METHODS: We studied 2083 young adults of Black and White ethnicity in the prospective observational cohort Coronary Artery Risk Development in Young Adults (CARDIA) study (mean ± SD age 32.1 ± 3.6 years; 43.9% women; 42.7% Black; mean ± SD BMI 25.6 ± 4.9 kg/m2) and 1797 Framingham Heart Study (FHS) participants (mean ± SD age 54.7 ± 9.7 years; 52.1% women; mean ± SD BMI 27.4 ± 4.8 kg/m2), examining the association of comprehensive metabolite profiles with endophenotypes of diabetes susceptibility (adipose and muscle tissue phenotypes and systemic inflammation). Statistical learning techniques and Cox regression were used to identify metabolite signatures of incident diabetes over a median of nearly two decades of follow-up across both cohorts. RESULTS: We identified known and novel metabolites associated with endophenotypes that delineate the complex pathophysiological architecture of diabetes, spanning mechanisms of muscle insulin resistance, inflammatory lipid signalling and beta cell metabolism (e.g. bioactive lipids, amino acids and microbe- and diet-derived metabolites). Integrating endophenotypes of diabetes susceptibility with the metabolome generated two multi-parametric metabolite scores, one of which (a proinflammatory adiposity score) was associated with incident diabetes across the life course in participants from both the CARDIA study (young adults; HR in a fully adjusted model 2.10 [95% CI 1.72, 2.55], p<0.0001) and FHS (middle-aged and older adults; HR 1.33 [95% CI 1.14, 1.56], p=0.0004). A metabolite score based on the outcome of diabetes was strongly related to diabetes in CARDIA study participants (fully adjusted HR 3.41 [95% CI 2.85, 4.07], p<0.0001) but not in the older FHS population (HR 1.15 [95% CI 0.99, 1.33], p=0.07). CONCLUSIONS/INTERPRETATION: Selected metabolic abnormalities in young adulthood identify individuals with heightened diabetes risk independent of race, sex and traditional diabetes risk factors. These signatures replicate across the life course.

The association of lung function and pulmonary vasculature volume with cardiorespiratory fitness in the community.

BACKGROUND: Cardiorespiratory fitness is not limited by pulmonary mechanical reasons in the majority of adults. However, the degree to which lung function contributes to exercise response patterns among ostensibly healthy individuals remains unclear. METHODS: We examined 2314 Framingham Heart Study participants who underwent cardiopulmonary exercise testing (CPET) and pulmonary function testing. We investigated the association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC and diffusing capacity of the lung for carbon monoxide (D LCO) with the primary outcome of peak oxygen uptake (V'O2 ) along with other CPET parameters using multivariable linear regression. Finally, we investigated the association of total and peripheral pulmonary blood vessel volume with peak V'O2 . RESULTS: We found lower FEV1, FVC and D LCO were associated with lower peak V'O2 . For example, a 1 L lower FEV1 and FVC was associated with a 7.1% (95% CI 5.1-9.1%) and 6.0% (95% CI 4.3-7.7%) lower peak V'O2 , respectively. By contrast, FEV1/FVC was not associated with peak V'O2 . Lower lung function was associated with lower oxygen uptake efficiency slope, oxygen pulse slope, V'O2 at anaerobic threshold (AT), minute ventilation (V'E) at AT and breathing reserve. In addition, lower total and peripheral pulmonary blood vessel volume were associated with lower peak V'O2 . CONCLUSIONS: In a large, community-based cohort of adults, we found lower FEV1, FVC and D LCO were associated with lower exercise capacity, as well as oxygen uptake efficiency slope and ventilatory efficiency. In addition, lower total and peripheral pulmonary blood vessel volume were associated with lower peak V'O2 . These findings underscore the importance of lung function and blood vessel volume as contributors to overall exercise capacity.

Arterial Stiffness and Vascular Load in HFpEF: Differences Among Women and Men.

BACKGROUND: Mechanisms underlying sex differences in heart failure with preserved ejection fraction (HFpEF) are poorly understood. We sought to examine sex differences in measures of arterial stiffness and the association of arterial stiffness measures with left ventricular hemodynamic responses to exercise in men and women. METHODS: We studied 83 men (mean age 62 years) and 107 women (mean age 59 years) with HFpEF who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and arterial stiffness measurement (augmentation pressure [AP], augmentation index [AIx], and aortic pulse pressure [AoPP]). Sex differences were compared using multivariable linear regression. We examined the association of arterial stiffness with abnormal left ventricular diastolic response to exercise, defined as a rise in pulmonary capillary wedge pressure relative to cardiac output (∆PCWP/∆CO) ≥ 2 mmHg/L/min by using logistic regression models. RESULTS: Women with HFpEF had increased arterial stiffness compared with men. AP was nearly 10 mmHg higher, and AIx was more than 10% higher in women compared with men (P < 0.0001 for both). Arterial stiffness measures were associated with a greater pulmonary capillary wedge pressure response to exercise, particularly among women. A 1-standard deviation higher AP was associated with > 3-fold increased odds of abnormal diastolic exercise response (AP: OR 3.16, 95% CI 1.34-7.42; P = 0.008 [women] vs OR 2.07, 95% CI 0.95-5.49; P = 0.15 [men]) with similar findings for AIx and AoPP. CONCLUSIONS: Arterial stiffness measures are significantly higher in women with HFpEF than in men and are associated with abnormally steep increases in pulmonary capillary wedge pressure with exercise, particularly in women. Arterial stiffness may preferentially contribute to abnormal diastolic function during exercise in women with HFpEF compared with men.

Response of circulating metabolites to an oral glucose challenge and risk of cardiovascular disease and mortality in the community.

BACKGROUND: New biomarkers to identify cardiovascular disease (CVD) risk earlier in its course are needed to enable targeted approaches for primordial prevention. We evaluated whether intraindividual changes in blood metabolites in response to an oral glucose tolerance test (OGTT) may provide incremental information regarding the risk of future CVD and mortality in the community. METHODS: An OGTT (75 g glucose) was administered to a subsample of Framingham Heart Study participants free from diabetes (n = 361). Profiling of 211 plasma metabolites was performed from blood samples drawn before and 2 h after OGTT. The log2(post/pre) metabolite levels (Δmetabolites) were related to incident CVD and mortality in Cox regression models adjusted for age, sex, baseline metabolite level, systolic blood pressure, hypertension treatment, body mass index, smoking, and total/high-density lipoprotein cholesterol. Select metabolites were related to subclinical cardiometabolic phenotypes using Spearman correlations adjusted for age, sex, and fasting metabolite level. RESULTS: Our sample included 42% women, with a mean age of 56 ± 9 years and a body mass index of 30.2 ± 5.3 kg/m2. The pre- to post-OGTT changes (Δmetabolite) were non-zero for 168 metabolites (at FDR ≤ 5%). A total of 132 CVD events and 144 deaths occurred during median follow-up of 24.9 years. In Cox models adjusted for clinical risk factors, four Δmetabolites were associated with incident CVD (higher glutamate and deoxycholate, lower inosine and lysophosphatidylcholine 18:2) and six Δmetabolites (higher hydroxyphenylacetate, triacylglycerol 56:5, alpha-ketogluturate, and lower phosphatidylcholine 32:0, glucuronate, N-monomethyl-arginine) were associated with death (P < 0.05). Notably, baseline metabolite levels were not associated with either outcome in models excluding Δmetabolites. The Δmetabolites exhibited varying cross-sectional correlation with subclinical risk factors such as visceral adiposity, insulin resistance, and vascular stiffness, but overall relations were modest. Significant Δmetabolites included those with established roles in cardiometabolic disease (e.g., glutamate, alpha-ketoglutarate) and metabolites with less defined roles (e.g., glucuronate, lipid species). CONCLUSIONS: Dynamic changes in metabolite levels with an OGTT are associated with incident CVD and mortality and have potential relevance for identifying CVD risk earlier in its development and for discovering new potential therapeutic targets.

Metabolomics of Type 1 and Type 2 Diabetes: Insights into Risk Prediction and Mechanisms.

PURPOSE OF REVIEW: Metabolomics enables rapid interrogation of widespread metabolic processes making it well suited for studying diabetes. Here, we review the current status of metabolomic investigation in diabetes, highlighting its applications for improving risk prediction and mechanistic understanding. RECENT FINDINGS: Findings of metabolite associations with type 2 diabetes risk have confirmed experimental observations (e.g., branched-chain amino acids) and also pinpointed novel pathways of diabetes risk (e.g., dimethylguanidino valeric acid). In type 1 diabetes, abnormal metabolite patterns are observed prior to the development of autoantibodies and hyperglycemia. Diabetes complications display specific metabolite signatures that are distinct from the metabolic derangements of diabetes and differ across vascular beds. Lastly, metabolites respond acutely to pharmacologic treatment, providing opportunities to understand inter-individual treatment responses. Metabolomic studies have elucidated biological mechanisms underlying diabetes development, complications, and therapeutic response. While not yet ready for clinical translation, metabolomics is a powerful and promising precision medicine tool.

Physical activity and fitness in the community: the Framingham Heart Study.

AIMS: While greater physical activity (PA) is associated with improved health outcomes, the direct links between distinct components of PA, their changes over time, and cardiorespiratory fitness are incompletely understood. METHODS AND RESULTS: Maximum effort cardiopulmonary exercise testing (CPET) and objective PA measures [sedentary time (SED), steps/day, and moderate-vigorous PA (MVPA)] via accelerometers worn for 1 week concurrent with CPET and 7.8 years prior were obtained in 2070 Framingham Heart Study participants [age 54 ± 9 years, 51% women, SED 810 ± 83 min/day, steps/day 7737 ± 3520, MVPA 22.3 ± 20.3 min/day, peak oxygen uptake (VO2) 23.6 ± 6.9 mL/kg/min]. Adjusted for clinical risk factors, increases in steps/day and MVPA and reduced SED between the two assessments were associated with distinct aspects of cardiorespiratory fitness (measured by VO2) during initiation, early-moderate level, peak exercise, and recovery, with the highest effect estimates for MVPA (false discovery rate <5% for all). Findings were largely consistent across categories of age, sex, obesity, and cardiovascular risk. Increases of 17 min of MVPA/day [95% confidence interval (CI) 14-21] or 4312 steps/day (95% CI 3439-5781; ≈54 min at 80 steps/min), or reductions of 249 min of SED per day (95% CI 149-777) between the two exam cycles corresponded to a 5% (1.2 mL/kg/min) higher peak VO2. Individuals with high (above-mean) steps or MVPA demonstrated above average peak VO2 values regardless of whether they had high or low SED. CONCLUSIONS: Our findings provide a detailed assessment of relations of different types of PA with multidimensional cardiorespiratory fitness measures and suggest favourable longitudinal changes in PA (and MVPA in particular) are associated with greater objective fitness.

Comprehensive Metabolic Phenotyping Refines Cardiovascular Risk in Young Adults.

BACKGROUND: Whereas cardiovascular disease (CVD) metrics define risk in individuals >40 years of age, the earliest lesions of CVD appear well before this age. Despite the role of metabolism in CVD antecedents, studies in younger, biracial populations to define precise metabolic risk phenotypes are lacking. METHODS: We studied 2330 White and Black young adults (mean age, 32 years; 45% Black) in the CARDIA study (Coronary Artery Risk Development in Young Adults) to identify metabolite profiles associated with an adverse CVD phenome (myocardial structure/function, fitness, vascular calcification), mechanisms, and outcomes over 2 decades. Statistical learning methods (elastic nets/principal components analysis) and Cox regression generated parsimonious, metabolite-based risk scores validated in >1800 individuals in the Framingham Heart Study. RESULTS: In the CARDIA study, metabolite profiles quantified in early adulthood were associated with subclinical CVD development over 20 years, specifying known and novel pathways of CVD (eg, transcriptional regulation, brain-derived neurotrophic factor, nitric oxide, renin-angiotensin). We found 2 multiparametric, metabolite-based scores linked independently to vascular and myocardial health, with metabolites included in each score specifying microbial metabolism, hepatic steatosis, oxidative stress, nitric oxide modulation, and collagen metabolism. The metabolite-based vascular scores were lower in men, and myocardial scores were lower in Black participants. Over a nearly 25-year median follow-up in CARDIA, the metabolite-based vascular score (hazard ratio, 0.68 per SD [95% CI, 0.50-0.92]; P=0.01) and myocardial score (hazard ratio, 0.60 per SD [95% CI, 0.45-0.80]; P=0.0005) in the third and fourth decades of life were associated with clinical CVD with a synergistic association with outcome (Pinteraction=0.009). We replicated these findings in 1898 individuals in the Framingham Heart Study over 2 decades, with a similar association with outcome (including interaction), reclassification, and discrimination. In the Framingham Heart Study, the metabolite scores exhibited an age interaction (P=0.0004 for a combined myocardial-vascular score with incident CVD), such that young adults with poorer metabolite-based health scores had highest hazard of future CVD. CONCLUSIONS: Metabolic signatures of myocardial and vascular health in young adulthood specify known/novel pathways of metabolic dysfunction relevant to CVD, associated with outcome in 2 independent cohorts. Efforts to include precision measures of metabolic health in risk stratification to interrupt CVD at its earliest stage are warranted.

Metabolic Architecture of Acute Exercise Response in Middle-Aged Adults in the Community.

BACKGROUND: Whereas regular exercise is associated with lower risk of cardiovascular disease and mortality, mechanisms of exercise-mediated health benefits remain less clear. We used metabolite profiling before and after acute exercise to delineate the metabolic architecture of exercise response patterns in humans. METHODS: Cardiopulmonary exercise testing and metabolite profiling was performed on Framingham Heart Study participants (age 53±8 years, 63% women) with blood drawn at rest (n=471) and at peak exercise (n=411). RESULTS: We observed changes in circulating levels for 502 of 588 measured metabolites from rest to peak exercise (exercise duration 11.9±2.1 minutes) at a 5% false discovery rate. Changes included reductions in metabolites implicated in insulin resistance (glutamate, -29%; P=1.5×10-55; dimethylguanidino valeric acid [DMGV], -18%; P=5.8×10-18) and increases in metabolites associated with lipolysis (1-methylnicotinamide, +33%; P=6.1×10-67), nitric oxide bioavailability (arginine/ornithine + citrulline, +29%; P=2.8×10-169), and adipose browning (12,13-dihydroxy-9Z-octadecenoic acid +26%; P=7.4×10-38), among other pathways relevant to cardiometabolic risk. We assayed 177 metabolites in a separate Framingham Heart Study replication sample (n=783, age 54±8 years, 51% women) and observed concordant changes in 164 metabolites (92.6%) at 5% false discovery rate. Exercise-induced metabolite changes were variably related to the amount of exercise performed (peak workload), sex, and body mass index. There was attenuation of favorable excursions in some metabolites in individuals with higher body mass index and greater excursions in select cardioprotective metabolites in women despite less exercise performed. Distinct preexercise metabolite levels were associated with different physiologic dimensions of fitness (eg, ventilatory efficiency, exercise blood pressure, peak Vo2). We identified 4 metabolite signatures of exercise response patterns that were then analyzed in a separate cohort (Framingham Offspring Study; n=2045, age 55±10 years, 51% women), 2 of which were associated with overall mortality over median follow-up of 23.1 years (P≤0.003 for both). CONCLUSIONS: In a large sample of community-dwelling individuals, acute exercise elicits widespread changes in the circulating metabolome. Metabolic changes identify pathways central to cardiometabolic health, cardiovascular disease, and long-term outcome. These findings provide a detailed map of the metabolic response to acute exercise in humans and identify potential mechanisms responsible for the beneficial cardiometabolic effects of exercise for future study.

Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Arterial Stiffness and Aabnormal Left Ventricular Hemodynamic Responses During Exercise.

BACKGROUND: Arterial stiffness is thought to contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF). We sought to examine arterial stiffness in HFpEF and hypertension and investigate associations of arterial and left ventricular hemodynamic responses to exercise. METHODS AND RESULTS: A total of 385 symptomatic individuals with an EF of ≥50% underwent upright cardiopulmonary exercise testing with invasive hemodynamic assessment of arterial stiffness and load (aortic augmentation pressure, augmentation index, systemic vascular resistance index, total arterial compliance index, effective arterial elastance index, and pulse pressure amplification) at rest and during incremental exercise. An abnormal hemodynamic response to exercise was defined as a steep increase in pulmonary capillary wedge pressure relative to cardiac output (∆PCWP/∆CO > 2 mm Hg/L/min). We compared rest and exercise measures between HFpEF and hypertension in multivariable analyses. Among 188 participants with HFpEF (mean age 61 ± 13 years, 56% women), resting arterial stiffness parameters were worse compared with 94 hypertensive participants (mean age 55 ± 15 years, 52% women); these differences were accentuated during exercise in HFpEF (all P ≤ .0001). Among all participants, exercise measures of arterial stiffness correlated with worse ∆PCWP/∆CO. Specifically, a 1 standard deviation higher exercise augmentation pressure was associated with 2.15-fold greater odds of abnormal LV hemodynamic response (95% confidence interval 1.52-3.05; P < .001). Further, exercise measures of systemic vascular resistance index, elastance index, and pulse pressure amplification correlated with a lower peak oxygen consumption. CONCLUSIONS: Exercise accentuates the increased arterial stiffness found in HFpEF, which in turn correlates with left ventricular hemodynamic responses. Unfavorable ventricular-vascular interactions during exercise in HFpEF may contribute to exertional intolerance and inform future therapeutic interventions.

Differential Clinical Profiles, Exercise Responses, and Outcomes Associated With Existing HFpEF Definitions.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is common, yet there is currently no consensus on how to define HFpEF according to various society and clinical trial criteria. How clinical and hemodynamic profiles of patients vary across definitions is unclear. We sought to determine clinical characteristics, as well as physiologic and prognostic implications of applying various criteria to define HFpEF. METHODS: We examined consecutive patients with chronic exertional dyspnea (New York Heart Association class II to IV) and ejection fraction ≥50% referred for comprehensive cardiopulmonary exercise testing with invasive hemodynamic monitoring. We applied societal and clinical trial HFpEF definitions and compared clinical profiles, exercise responses, and cardiovascular outcomes. RESULTS: Of 461 patients (age 58±15 years, 62% women), 416 met American College of Cardiology/American Heart Association (ACC/AHA), 205 met European Society of Cardiology (ESC), and 55 met Heart Failure Society of America (HFSA) criteria for HFpEF. Clinical profiles and exercise capacity varied across definitions, with peak oxygen uptake of 16.2±5.2 (ACC/AHA), 14.1±4.2 (ESC), and 12.7±3.1 mL·kg-1·min-1 (HFSA). A total of 243 patients had hemodynamic evidence of HFpEF (abnormal rest or exercise filling pressures), of whom 222 met ACC/AHA, 161 met ESC, and 41 met HFSA criteria. Over a mean follow-up of 3.8 years, the incidence of cardiovascular outcomes ranged from 75 (ACC/AHA) to 298 events per 1000 person-years (HFSA). Application of clinical trial definitions of HFpEF similarly resulted in distinct patient classification and prognostication. CONCLUSIONS: Use of different HFpEF classifications variably enriches for future cardiovascular events, but at the expense of not including up to 85% of individuals with physiologic evidence of HFpEF. Comprehensive phenotyping of patients with suspected heart failure highlights the limitations and heterogeneity of current HFpEF definitions and may help to refine HFpEF subgrouping to test therapeutic interventions.

Recent Update to the US Cholesterol Treatment Guidelines: A Comparison With International Guidelines.

The 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guideline advocated several changes from the previous Adult Treatment Panel III guidelines. Assuming full implementation, the 2013 ACC/AHA guideline would identify ≈13 million Americans as newly eligible for consideration of statin therapy. Three features of the 2013 ACC/AHA guideline primarily responsible for these differences are the specific risk assessment tool endorsed, the risk threshold considered sufficient to warrant primary prevention statin therapy, and the decision not to include cholesterol treatment targets. There is no consensus among international guidelines on the optimal approach to these 3 components. The 2013 ACC/AHA guideline recommends assessing absolute risk with the Pooled Cohort equations, which were developed to improve on previous risk assessment models by including stroke as an outcome and by broadening racial and geographic diversity. Each of the leading international guidelines recommends a different equation for absolute risk assessment. The 2013 ACC/AHA guideline advises consideration of statin therapy for an estimated 10-year risk of atherosclerotic vascular disease of ≥7.5%, which is lower than the thresholds recommended by other leading international guidelines. Lastly, the 2013 ACC/AHA guideline does not endorse a treat-to-target strategy but instead specifies the appropriate intensity of statin for each risk category. This approach is shared by the National Institute for Health and Care Excellence guidelines but differs from other international guidelines. In this review, we summarize the 2013 ACC/AHA cholesterol guideline recommendations and compare them with recommendations from Adult Treatment Panel III and other leading international guidelines.