Abstract only
Introduction:
Cardiorespiratory fitness (CRF) is a powerful predictor of health outcomes, but its determinants are incompletely understood at the population level. Prior studies have ...suggested associations between dietary components and CRF, but they have generally been limited by small sample sizes, reliance on estimated CRF, variable dietary instruments, and lack of molecular interrogation to support shared biology.
Hypothesis:
Shared metabolite associations across dietary quality and CRF will prioritize metabolites potentially responsible for linking dietary quality with improved CRF in the community.
Methods:
Framingham Heart Study (FHS) participants underwent maximum effort cardiopulmonary exercise tests for quantification of CRF by peak oxygen uptake (VO
2
) and completed food frequency questionnaires at a routine study visit. Dietary quality was assessed by the Mediterranean-style Diet Score (MDS), and fasting levels of 201 metabolites were quantified.
Results:
In 2380 FHS participants (age 54 ± 9 years, 54% women, BMI 28 ± 5 kg/m
2
), a 1-SD higher MDS was associated with 4.4% (3.5% - 5.3%, p < 0.0001) greater peak VO
2
in linear models adjusted for age, sex, cardiovascular risk factors, and physical activity. In a representative subsample that had metabolite profiling (N = 1154), 80 metabolites were statistically significantly associated with MDS, 57 with peak VO
2
, and 27 with both MDS and peak VO
2
in multivariable linear models (FDR < 5% for all, Figure). These metabolites included dimethylguanidino valeric acid, medium chain acylcarnitines, and C16 ceramide, which are markers of insulin resistance and increased risk for cardiovascular disease. Metabolites with less established functions include C38:7 plasmalogens, which correlate with fish intake and may have anti-inflammatory effects.
Conclusions:
Healthy diet is associated with greater CRF in the community and may be partially explained by favorable metabolic health.
Abstract only
Background:
Obesity and adiposity are associated with risk of heart failure with preserved ejection fraction (HFpEF), yet the role of adipokines and other obesity related pathways as ...contributors to HFpEF remains unclear.
Objectives:
We sought to examine the association of obesity and obesity related biomarkers including adipokines, inflammatory markers, and insulin resistance with HFpEF and specific cardiac and extracardiac organ reserve measures among patients who underwent CPET.
Methods:
We studied 509 consecutive patients with LVEF ≥ 50% and NYHA class II - III symptoms, who underwent clinically indicated CPET with invasive hemodynamic monitoring. Fasting blood samples at the time of CPET were used to assay obesity-related biomarkers, including leptin, adiponectin, resistin, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), glucose and insulin to estimate insulin resistance (HOMA-IR). We examined the association of biomarkers with physiologic HFpEF and exercise traits using multivariable regression models.
Results:
Among 509 patients (mean age 55 years, 61% women, 38% obese), 223 met hemodynamic criteria for HFpEF. Obesity was associated with more than 2-fold higher odds of HFpEF (OR 2.08, 95% CI 1.38-3.14). We found that higher levels of leptin, hsCRP and HOMA-IR were associated with greater odds of HFpEF (P ≤ 0.01, Figure 1). By contrast, resistin and adiponectin were not associated with HFpEF (P>0.05). In secondary analyses, we observed associations of obesity related biomarkers with measures of impaired exercise capacity, such as lower peak VO
2
(P<0.05), higher blood pressure response (leptin, HOMA-IR), and impaired heart rate response (hsCRP, HOMA-IR, IL-6, resistin).
Conclusions:
Obesity related biomarkers were associated with HFpEF and impaired exercise capacity. These findings highlight potential pathways underlying the association of obesity and cardiometabolic disease with development of HFpEF.
Abstract only
Introduction:
Most individuals regain weight after medical weight loss via “metabolic adaptation,” the mechanism of which remains unclear. Here, we studied the relation of circulating ...inflammatory proteins with weight loss and regain to identify a role for inflammation in metabolic adaptation.
Methods:
We analyzed 74 proteins related to inflammation and native immune regulation (Olink) in plasma from a maximum of 490 participants serially in a trial of medical weight loss maintenance. Linear and mixed effects regression models and
t
-tests were used to measure cross-sectional and longitudinal association of proteins with weight, with replication in the Framingham Heart Study (FHS).
Results:
Subjects included (60% women, 35% African American) had initial median weight of 94 kg, with a median loss 8 kg over 6 months of supervised medical weight loss, with subsequent median regain 2 kg over 30 months. We observed broad changes in inflammatory proteins with initial weight loss, many of which also tracked with weight regain (e.g. hepatocyte growth factor, interleukin-18, colony stimulating factor 1;
Figure
). While many proteins have been implicated in weight regulation from mouse/human models, several are novel. Proteins associated with weight change involve pathways of angiogenesis, cell cycle regulation and immune response and are secreted from lung, adipose tissue, smooth muscle and others. Several proteins specifying chemotaxis and innate immune responses were associated with different rates of weight regain. Association with prevalent (but not incident) obesity was replicated for several proteins in the FHS.
Conclusions:
Broad changes in the inflammatory state track with weight (and its change during medical therapy) and may identify specific pathways that modify risk of weight regain. Further studies of innate immune activation in metabolic adaptation in humans to limit weight regain are warranted.
The American Heart Association Cardiovascular Health (CVH) score is inversely associated with cardiovascular disease, but its relations to cardiac remodeling traits and heart failure (HF) incidence ...have not been examined.
A 14-point score was constructed for each participant based on the presence of poor, intermediate, or ideal status on each of the 7 CVH metrics (ideal score=14). We related the CVH score to echocardiographic traits cross-sectionally and to HF incidence prospectively in the Framingham Offspring Study. In age- and sex-adjusted models, a higher CVH score was associated with lower left ventricular (LV) mass, LV wall thickness, LV diastolic dimension, and left atrial dimension (P<0.01 for all; n=2392; mean age, 58 years; 56% women), and with a 12% to 15% lower odds of prevalent LV concentric remodeling and concentric hypertrophy, respectively (P<0.0001 for both). On follow-up (mean, 12.3 years), 188 incident HF events were observed in 3201 participants (mean age, 59 years; 53% women). In age- and sex-adjusted Cox proportional hazard models, the CVH score was inversely associated with HF incidence (hazard ratio per 1-point higher CVH score, 0.77; 95% confidence interval, 0.72-0.83). This association was partially attenuated upon adjustment for LV mass and interim myocardial infarction (hazard ratio, 0.84; 95% confidence interval, 0.76-0.93), and it was consistent for HF with preserved and reduced ejection fractions.
In our community-based sample, comprised predominantly of middle-aged white individuals of European descent, better CVH was associated with lower HF incidence, in part due to a lower prevalence of adverse cardiac remodeling.
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.
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.
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.
This study evaluated the associations of obesity and cardiometabolic traits with incident heart failure with preserved versus reduced ejection fraction (HFpEF vs. HFrEF). Given known sex differences ...in HF subtype, we examined men and women separately.
Recent studies suggest that obesity confers greater risk of HFpEF versus HFrEF. Contributions of associated metabolic traits to HFpEF are less clear.
We studied 22,681 participants from 4 community-based cohorts followed for incident HFpEF versus HFrEF (ejection fraction ≥50% vs. <50%). We evaluated the association of body mass index (BMI) and cardiometabolic traits with incident HF subtype using Cox models.
The mean age was 60 ± 13 years, and 53% were women. Over a median follow-up of 12 years, 628 developed incident HFpEF and 835 HFrEF. Greater BMI portended higher risk of HFpEF compared with HFrEF (hazard ratio HR: 1.34 per 1-SD increase in BMI; 95% confidence interval CI: 1.24 to 1.45 vs. HR: 1.18; 95% CI: 1.10 to 1.27). Similarly, insulin resistance (homeostatic model assessment of insulin resistance) was associated with HFpEF (HR: 1.20 per 1-SD; 95% CI: 1.05 to 1.37), but not HFrEF (HR: 0.99; 95% CI: 0.88 to 1.11; p < 0.05 for difference HFpEF vs. HFrEF). We found that the differential association of BMI with HFpEF versus HFrEF was more pronounced among women (p for difference HFpEF vs. HFrEF = 0.01) when compared with men (p = 0.34).
Obesity and related cardiometabolic traits including insulin resistance are more strongly associated with risk of future HFpEF versus HFrEF. The differential risk of HFpEF with obesity seems particularly pronounced among women and may underlie sex differences in HF subtypes.
Display omitted
IntroductionCardiopulmonary exercise testing (CPET) can help identify early stages of heart failure with preserved ejection fraction (HFpEF). We sought to determine if percent predicted peak oxygen ...pulse (%PredO2P, as defined by peak oxygen uptake/heart rate), a noninvasive measure combining stroke volume and peripheral oxygen extraction, could serve as a marker of the hemodynamic response to exercise in HFpEF patients.Methods154 consecutive patients who underwent maximal CPET (RER>1.05) and were diagnosed with HFpEF (defined as LVEF>50% and PCWP/CO >2 mmHg*min/L or supine resting PCWP >15 mmHg) were included. Exclusion criteria included patients who were taking AV nodal agents, were paced, or had atrial fibrillation. Peak O2P and percent predicted were calculated using the Wasserman equation for peak VO2 in conjunction with peak predicted heart rate (220-age).ResultsTertiles of %PredO2P were determined with first tertile at 42.1-76.2%, second tertile at 76.2-94.4%, and third tertile at 94.4-139.2%. Baseline parameters differed across %PredO2P tertiles (Table 1) with BMI increasing (trend p=0.014). Peak cardiac output (110.0±3.0 L/min, 211.1±2.4, 311.5±3.5; p=0.038) and peak stroke volume (170.6±20.1 mL, 283.0±16.6, 392.7±20.1; p<0.001) were higher across tertiles, whereas peak HR (1143±23 bpm, 2135±25, 3123±26; p<0.001) and peak SVR (1959±304 dynes*s/cm, 2831±187, 3810±321; p=0.009) were lower. Exercise PAP/CO slope (14.5±2.1 mmHg*min/L, 23.6±1.6, 33.3±1.7; p=0.003) and PCWP/CO slope (13.4±1.8 mmHg*min/L, 22.9±1.4, 32.8±2.0; p=0.015) were lower across tertiles of %PredO2P.Conclusions%PredO2P is a noninvasive variable that associates with vascular responses to exercise in HFpEF patients. Higher %PredO2P was associated with improved vascular responses to exercise with lower SVR, PAP/CO and PCWP/CO slopes.
Abstract only
Introduction:
Abnormal blood pressure (BP) responses during exercise are associated with incident hypertension and cardiovascular disease, but how exercise BP responses relate to ...average home BP and home BP variability (BPV) over one-year follow-up is unknown.
Objective:
We investigated whether exercise BP was associated with average home BP and home BPV, after accounting for resting BP, in the electronic Framingham Heart Study (eFHS). We hypothesized that higher exercise BP predicts higher average home BP and home BPV over one-year follow-up.
Methods:
At a FHS research exam (2016-2019), participants underwent maximum incremental ramp cycle ergometry cardiopulmonary exercise testing (CPET) with BP measured every two minutes. Participants enrolled in the eFHS were provided with a digital BP cuff to measure home BP weekly for up to one year. Linear regression models were used to examine associations of exercise BP with average home systolic BP (SBP) and week-to-week average real variability (ARV) of home SBP over one-year follow-up, adjusting for covariates. ARV, which considers both the dispersion and order of BP readings, was quantified as the average of the absolute differences between consecutive BP readings. We used p<0.05 for significance.
Results:
The study sample included 806 participants (mean age 53 years, 58% women, 46% hypertension, median number of home BP returns 22, average home SBP 122 mmHg). Adjusting for resting SBP and other covariates, higher exercise SBP (as measured by peak SBP, SBP at 75 Watts, and SBP/workload slope) was associated with higher average home SBP (
Figure 1A
). Higher SBP/workload slope was associated with elevated ARV of home SBP in men (
Figure 1B
).
Conclusion:
Higher exercise SBP responses are associated with higher average digital home-based SBP and home-based SBP variability over one-year follow-up after accounting for resting SBP.
Abstract only
Background:
Cardiorespiratory fitness (CRF) is a powerful predictor of cardiovascular (CV) outcomes and multi-organ reserve capacity.
Hypothesis:
We hypothesize that hepatic steatosis, ...an emerging CV risk factor, is associated with lower CRF and that certain metabolites mediate this association.
Objective:
To determine if hepatic steatosis contributes to impaired CRF in community-dwelling individuals.
Methods:
Framingham Heart Study participants (n=2722) underwent vibration-controlled transient elastography for assessment of controlled attenuation parameter (CAP; a measure of hepatic steatosis) and maximal cardiopulmonary exercise testing (CPET). In individuals with available metabolomic data (n=1346), we evaluated whether blood metabolites mediate the association of CAP and peak CRF (peak oxygen uptake VO
2
).
Results:
The study sample (mean age 54±9 years, 53% women) had a peak VO
2
of 95±20% of the predicted value, and 722 participants (26.5%) had hepatic steatosis (defined as CAP≥290 dB/m). In multivariable regression models adjusted for age, sex, alcohol use, smoking, systolic blood pressure, hypertensive medication use, diabetes, and prevalent CV disease, both CAP (continuous) and hepatic steatosis were associated with lower peak VO
2
(in ml/kg/min) and VO
2
at the anaerobic threshold, and unfavorable heart rate and blood pressure responses to exercise (at Bonferroni-adjusted P<0.008 for all; Figure 1). Eighteen out of 201 measured circulating metabolites were associated with both peak VO
2
and CAP in separate multivariable models also adjusted for BMI (at FDR 5%). Of these metabolites, 16 significantly mediated the association between CAP and peak VO
2
, with dimethylguanidino valeric acid and lysophosphatidylcholine 20:1 demonstrating the highest proportion mediated.
Conclusions:
Hepatic steatosis is associated with impaired CRF in the community and this association is partially mediated by known and novel circulating metabolites.
Mutations in sarcomere protein genes can cause hypertrophic cardiomyopathy (HCM), a disorder characterized by myocyte enlargement, fibrosis, and impaired ventricular relaxation. Here, we demonstrate ...that sarcomere protein gene mutations activate proliferative and profibrotic signals in non-myocyte cells to produce pathologic remodeling in HCM. Gene expression analyses of non-myocyte cells isolated from HCM mouse hearts showed increased levels of RNAs encoding cell-cycle proteins, Tgf-β, periostin, and other profibrotic proteins. Markedly increased BrdU labeling, Ki67 antigen expression, and periostin immunohistochemistry in the fibrotic regions of HCM hearts confirmed the transcriptional profiling data. Genetic ablation of periostin in HCM mice reduced but did not extinguish non-myocyte proliferation and fibrosis. In contrast, administration of Tgf-β-neutralizing antibodies abrogated non-myocyte proliferation and fibrosis. Chronic administration of the angiotensin II type 1 receptor antagonist losartan to mutation-positive, hypertrophy-negative (prehypertrophic) mice prevented the emergence of hypertrophy, non-myocyte proliferation, and fibrosis. Losartan treatment did not reverse pathologic remodeling of established HCM but did reduce non-myocyte proliferation. These data define non-myocyte activation of Tgf-β signaling as a pivotal mechanism for increased fibrosis in HCM and a potentially important factor contributing to diastolic dysfunction and heart failure. Preemptive pharmacologic inhibition of Tgf-β signals warrants study in human patients with sarcomere gene mutations.
PDF
