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.
Abstract
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.
Graphical Abstract
An overview of the study design is displayed. Cardiopulmonary fitness measures were associated with omnidirectional accelerometry data concurrent with exercise testing and from ≈8 years prior to evaluate the relations of physical activity and fitness.
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; dimethylguanidino valeric acid DMGV, −18%; P=5.8×10) and increases in metabolites associated with lipolysis (1-methylnicotinamide, +33%; P=6.1×10), nitric oxide bioavailability (arginine/ornithine + citrulline, +29%; P=2.8×10), and adipose browning (12,13-dihydroxy-9Z-octadecenoic acid +26%; P=7.4×10), 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.
Systemic inflammation has been implicated in the pathobiology of heart failure with preserved ejection fraction (HFpEF). Here, we examine the association of upstream mediators of inflammation as ...ascertained by fatty-acid derived eicosanoid and eicosanoid-related metabolites with HFpEF status and exercise manifestations of HFpEF. Among 510 participants with chronic dyspnea and preserved LVEF who underwent invasive cardiopulmonary exercise testing, we find that 70 of 890 eicosanoid and related metabolites are associated with HFpEF status, including 17 named and 53 putative eicosanoids (FDR q-value < 0.1). Prostaglandin (15R-PGF2α, 11ß-dhk-PGF2α) and linoleic acid derivatives (12,13 EpOME) are associated with greater odds of HFpEF, while epoxides (8(9)-EpETE), docosanoids (13,14-DiHDPA), and oxylipins (12-OPDA) are associated with lower odds of HFpEF. Among 70 metabolites, 18 are associated with future development of heart failure in the community. Pro- and anti-inflammatory eicosanoid and related metabolites may contribute to the pathogenesis of HFpEF and serve as potential targets for intervention.
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.
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).
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).
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.
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.
Background
Left 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 Results
We 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.
Conclusions
Age‐ 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.
The relation of cardiorespiratory fitness (CRF) to lifestyle behaviors and factors linked with cardiovascular health remains unclear. We aimed to understand how the American Heart Association's ...Life's Essential 8 (LE8) score (and its changes over time) relate to CRF and complementary exercise measures in community-dwelling adults.
Framingham Heart Study (FHS) participants underwent maximum effort cardiopulmonary exercise testing for direct quantification of peak oxygen uptake (V̇O
). A 100-point LE8 score was constructed as the average across 8 factors: diet, physical activity, nicotine exposure, sleep, body mass index, lipids, blood glucose, and blood pressure. We related total LE8 score, score components, and change in LE8 score over 8 years with peak V̇O
(log-transformed) and complementary CRF measures. In age- and sex-adjusted linear models (N=1838, age 54±9 years, 54% women, LE8 score 76±12), a higher LE8 score was associated favorably with peak V̇O
, ventilatory efficiency, resting heart rate, and blood pressure response to exercise (all
<0.0001). A clinically meaningful 5-point higher LE8 score was associated with a 6.0% greater peak V̇O
(≈1.4 mL/kg per minute at sample mean). All LE8 components were significantly associated with peak V̇O
in models adjusted for age and sex, but blood lipids, diet, and sleep health were no longer statistically significant after adjustment for all LE8 components. Over an ≈8-year interval, a 5-unit increase in LE8 score was associated with a 3.7% higher peak V̇O
(
<0.0001).
Higher LE8 score and improvement in LE8 over time was associated with greater CRF, highlighting the importance of the LE8 factors in maintaining CRF.
Background During exercise, a healthy arterial system facilitates increased blood flow and distributes it effectively to essential organs. Accordingly, we sought to understand how arterial stiffening ...might impair cardiorespiratory fitness in community-dwelling individuals. Methods and Results Arterial tonometry and maximum effort cardiopulmonary exercise testing were performed on Framingham Heart Study participants (N=2898, age 54±9 years, 53% women, body mass index 28.1±5.3 kg/m
). We related 5 arterial stiffness measures (carotid-femoral pulse wave velocity CFPWV: a measure of aortic wall stiffness; central pulse pressure, forward wave amplitude, characteristic impedance: measures of pressure pulsatility; and augmentation index: a measure of relative wave reflection) to multidimensional exercise responses using linear models adjusted for age, sex, resting heart rate, habitual physical activity, and clinical risk factors. Greater CFPWV, augmentation index, and characteristic impedance were associated with lower peak oxygen uptake (VO
; all
<0.0001). We observed consistency of associations of CFPWV with peak oxygen uptake across age, sex, and cardiovascular risk profile (interaction
>0.05). However, the CFPWV-peak oxygen uptake relation was attenuated in individuals with obesity (
=0.002 for obesity*CFPWV interaction). Higher CPFWV, augmentation index, and characteristic impedance were also related to cardiopulmonary exercise testing measures reflecting adverse O
kinetics and lower stroke volume and peripheral O
extraction but not to ventilatory efficiency, a prognostic measure of right ventricular-pulmonary vascular performance. Conclusions Our findings delineate relations of arterial stiffness and cardiorespiratory fitness in community-dwelling individuals. Future studies are warranted to evaluate whether the physiological measures implicated here may represent potential targets for improving cardiorespiratory fitness in the general population.
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.
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.
Our sample included 42% women, with a mean age of 56 ± 9 years and a body mass index of 30.2 ± 5.3 kg/m
. 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).
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.
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