Integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failure.

Pressure overload initiates a series of alterations in the human heart that predate macroscopic organ-level remodeling and downstream heart failure. We study aortic stenosis through integrated proteomic, tissue transcriptomic, and genetic methods to prioritize targets causal in human heart failure. First, we identify the circulating proteome of cardiac remodeling in aortic stenosis, specifying known and previously-unknown mediators of fibrosis, hypertrophy, and oxidative stress, several associated with interstitial fibrosis in a separate cohort (N = 145).

Epidemiology and Cardiovascular Benefits of Physical Activity and Exercise.

While humans evolved to perform routine endurance activity, recent secular trends in the United States and globally have resulted in a dramatic rise in the amount of time spent inactive in both occupational and leisure-time settings. The high burden of physical inactivity is responsible for a high risk of preventable noncommunicable disease including cardiovascular disease, cancer, and premature death. In this review, we focus on the beneficial effects of routine physical activity (PA) on the cardiovascular system, the different ways we can achieve and measure PA, and the evidence supporting key public health guidance on optimal PA goals for promoting health.

Association of life's essential 8 score with incidence of atrial fibrillation: The Framingham heart study.

Background: Atrial fibrillation (AF) burden can be reduced by targeting modifiable risk factors. Limited data exist on the association between American Heart Association's Life's Essential 8 (LE8) score (higher scores healthier) and AF incidence.

Methods: We studied AF-free Framingham Heart Study Offspring and Omni 1 participants aged ≥45 years who attended ≥1 index exam in which LE8 components were assessed.

Blood Pressure Responses During Exercise Were Associated With Average Home Blood Pressure and Home Blood Pressure Variability: The Electronic Framingham Heart Study.

Background: Abnormal exercise blood pressure (BP) responses are associated with hypertension and cardiovascular disease, but their relationship with home BP over a mid- to long-term time span is unknown.

Methods: At an FHS (Framingham Heart Study) research examination (2016-2019), participants underwent maximum incremental ramp cycle ergometry cardiopulmonary exercise testing with BP measured every 2 minutes. At the same exam, English-speaking participants enrolled in the electronic FHS with an iPhone were provided with a digital BP cuff to measure home BP weekly for 1 year.

Circulating Proteomics Identifies a Dynamic Profile of Hepatic Steatosis During Metabolic Intervention.

Background: Weight reduction through lifestyle, activity, and dietary interventions are the mainstay of initial therapy for metabolic dysfunction associated steatotic liver disease. Data on the relative effectiveness and metabolic pathways linking weight loss and decreased hepatic steatosis are lacking. We sought to identify coordinated changes between the circulating proteome and hepatic steatosis within a randomized clinical trial of alternate day fasting and exercise and prioritize proteins relevant to hepatic steatosis within a broader context using a community cohort.

Molecular architecture of human atherosclerosis revealed through integrative human genetics.

Current genetic discovery methods are largely restricted to profiling circulating molecules or genetic architecture, limited in use of tissue-based molecular genetics to identify pathogenic and therapeutic targets. Here, we leverage a multi-level genetic discovery platform integrating population-level proteomics with functional genomic analyses based on human coronary artery tissue to reveal determinants of coronary disease susceptibility. Using aptamer-based proteomics (~7,000 aptamers) across ~3,000 individuals, we first identified the circulating proteome of prevalent and incident coronary artery calcium (CAC), a sensitive marker of subclinical coronary artery disease (CAD), with causal implication in calcified plaque formation or disease phenotypes via parallel genetic approaches (Mendelian randomization, MR) and proteome-wide association (PWAS).

Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants.

Background: Genome-wide association studies have identified several hundred susceptibility single nucleotide variants for coronary artery disease (CAD). Despite single nucleotide variant-based genome-wide association studies improving our understanding of the genetics of CAD, the contribution of structural variants (SVs) to the risk of CAD remains largely unclear.

Method And Results: We leveraged SVs detected from high-coverage whole genome sequencing data in a diverse group of participants from the National Heart Lung and Blood Institute's Trans-Omics for Precision Medicine program.

Association of Systemic Thromboxane Generation With Risk of Developing Heart Failure.

Background: Systemic thromboxane A generation, which is readily assessed by quantifying thromboxane B metabolites (TXB-M) in the urine, is associated with impaired cardiac performance and mortality in aspirin (ASA) users with heart failure (HF).

Objectives: This study sought to determine the association of urinary TXB-M with the risk of developing HF in individuals without prior history of HF and with normal left ventricular function irrespective of ASA use.

Methods: Urine TXB-M were measured by immunoassay and adjusted to urine concentration and renal function (TXB-M) in 2,611 Framingham Heart Study participants (54.

Hepatic Steatosis and Fibrosis, Cardiorespiratory Fitness, and Metabolic Mediators in the Community.

Background And Aims: Individuals with steatotic liver disease (SLD) are at high cardiovascular disease (CVD) risk, but approaches to characterise and mitigate this risk are limited. By investigating relations, and shared metabolic pathways, of hepatic steatosis/fibrosis and cardiorespiratory fitness (CRF), we sought to identify new avenues for CVD risk reduction in SLD.

Methods: In Framingham Heart Study (FHS) participants (N = 2722, age 54 ± 9 years, 53% women), vibration-controlled transient elastography (VCTE) was performed between 2016-2019 to assess hepatic steatosis (continuous attenuation parameter [CAP]) and fibrosis (liver fibrosis measure [LSM]).

A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver.

Hepatic steatosis is a central phenotype in multi-system metabolic dysfunction and is increasing in parallel with the obesity pandemic. We use a translational approach integrating clinical phenotyping and outcomes, circulating proteomics, and tissue transcriptomics to identify dynamic, functional biomarkers of hepatic steatosis. Using multi-modality imaging and broad proteomic profiling, we identify proteins implicated in the progression of hepatic steatosis that are largely encoded by genes enriched at the transcriptional level in the human liver.

Latent class analysis of cardiac structure and function and association with premature cardiovascular disease: The Coronary Artery Risk Development in Young Adults (CARDIA) study.

Objective: To generate data-driven phenogroups of cardiac structure and function based on echocardiographic measures assessed in asymptomatic middle-aged adults free of CVD, and examine associations between these newly defined phenogroups and incident premature cardiovascular disease (CVD).

Methods: Data were analyzed from participants in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study free of CVD who underwent an echocardiogram at the Year 25 (2010-2011) in-person examination. Continuous echocardiographic measures of left heart structure, left ventricular systolic function (including strain) and diastolic function, right ventricular systolic function, and hemodynamic measures were included in latent class analysis to generate novel phenogroups.

The association of exhaled carbon monoxide with atrial fibrillation and left atrial size in the Framingham Heart Study.

Background: Exhaled carbon monoxide (eCO) is associated with subclinical and overt cardiovascular disease and stroke. The association between eCO with left atrial size, prevalent, or incident atrial fibrillation (AF) are uncertain.

Methods: eCO was measured using an Ecolyzer instrument among Framingham Heart Study Offspring and Omni participants who attended an examination from 1994 to 1998.

Prediagnostic Amino Acid Metabolites and Risk of Gout, Accounting for Serum Urate: Prospective Cohort Study and Mendelian Randomization.

Objective: Our objective was to prospectively investigate prediagnostic population-based metabolome for risk of hospitalized gout (ie, most accurate, severe, and costly cases), accounting for serum urate.

Methods: We conducted prediagnostic metabolome-wide analyses among 249,677 UK Biobank participants with nuclear magnetic resonance metabolomic profiling (N = 168 metabolites, including eight amino acids) from baseline blood samples (2006-2010) without a history of gout. We calculated multivariable hazard ratios (HRs) for hospitalized incident gout, before and after adjusting for serum urate levels; we included patients with nonhospitalized incident gout in a sensitivity analysis.

Percent Predicted Peak Exercise Oxygen Pulse Provides Insights Into Ventricular-Vascular Response and Prognosticates HFpEF.

Background: Peak oxygen consumption and oxygen pulse along with their respective percent predicted measures are gold standards of exercise capacity. To date, no studies have investigated the relationship between percent predicted peak oxygen pulse (%PredOP) and ventricular-vascular response (VVR) and the association of %PredOP with all-cause mortality in heart failure with preserved ejection fraction (HFpEF) patients.

Objectives: The authors investigated the association between: 1) CPET measures of %PredOP and VVR; and 2) %PredOP and all-cause mortality in HFpEF patients.

Clusters of multidimensional exercise response patterns and estimated heart failure risk in the Framingham Heart Study.

Aims: New tools are needed to identify heart failure (HF) risk earlier in its course. We evaluated the association of multidimensional cardiopulmonary exercise testing (CPET) phenotypes with subclinical risk markers and predicted long-term HF risk in a large community-based cohort.

Methods And Results: We studied 2532 Framingham Heart Study participants [age 53 ± 9 years, 52% women, body mass index (BMI) 28.

Proteomic analysis of cardiorespiratory fitness for prediction of mortality and multisystem disease risks.

Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.

Uncovering Unrecognized Heart Failure With Preserved Ejection Fraction Among Individuals With Obesity and Dyspnea.

Background: Although heart failure with preserved ejection fraction (HFpEF) has become the predominant heart failure subtype, it remains clinically under-recognized. HFpEF diagnosis is particularly challenging in the setting of obesity given the limitations of natriuretic peptides and resting echocardiography. We examined invasive and noninvasive HFpEF diagnostic criteria among individuals with obesity and dyspnea without known cardiovascular disease to determine the prevalence of hemodynamic HFpEF in the community.

Life's Essential 8 Cardiovascular Health Score and Cardiorespiratory Fitness in the Community.

Background: 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.

Methods And Results: Framingham Heart Study (FHS) participants underwent maximum effort cardiopulmonary exercise testing for direct quantification of peak oxygen uptake (V̇O).

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.

Human metabolic chambers reveal a coordinated metabolic-physiologic response to nutrition.

The emerging field of precision nutrition is based on the notion that inter-individual responses across diets of different calorie-macronutrient content may contribute to inter-individual differences in metabolism, adiposity, and weight gain. Free-living diet studies have been traditionally challenged by difficulties in controlling adherence to prescribed calories and macronutrient content and rarely allow a period of metabolic stability prior to metabolic measures (to minimize influences of weight changes). In this context, key physiologic measures central to precision nutrition responses may be most precisely quantified via whole room indirect calorimetry over 24-h, in which precise control of activity and nutrition can be achieved.