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.

Human Physiologic Responses to Insulin in Indigenous Americans Identify a Metabolic Susceptibility Profile Linked to Diabetes.

Objective: To identify metabolic signatures of insulin action/secretion in Indigenous Americans (IAs) and their association with diabetes.

Research Design And Methods: We defined circulating metabolomic signatures of insulin action/secretion in 446 IAs, including glucose disposal rate during low-dose insulin clamp (Mlow) and endogenous glucose production (EGP) during insulin infusion (suppression of hepatic glucose production). We then determined associations of these metabolic scores with glucose tolerance (in a separate set of ∼700 IAs) and diabetes/metabolic risk in ∼2,000 individuals (from Coronary Artery Risk Development in Young Adults [CARDIA] study).

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).

The Primacy of Adipose Tissue Gene Expression and Plasma Lipidome in Cardiometabolic Disease in Persons With HIV.

Background: Persons with HIV (PWH) on contemporary antiretroviral therapy (ART) are at elevated risk for developing age-related cardiometabolic diseases. We hypothesized that integrative analysis of cross-tissue, multimodal data from PWH could provide insight into molecular programming that defines cardiometabolic phenotypes in this high-risk group.

Methods: We enrolled 93 PWH without diabetes who were virologically suppressed on contemporary ART and obtained measures of insulin resistance, glucose intolerance, and adiposity.

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.

Left Ventricular Wall Stress and Incident Heart Failure in Elderly Community-Dwelling Individuals.

Background: Greater left ventricular (LV) wall stress is associated with adverse outcomes among patients with prevalent heart failure (HF). Less is known about the association between LV wall stress and incident HF.

Objectives: The purpose of the study was to identify clinical factors associated with wall stress and test the association between wall stress and incident HF.

Proteomic Risk Score of Increased Respiratory Susceptibility: A Multi-Cohort Study.

Rationale: Accelerated decline in lung function is associated with incident COPD, hospitalizations and death. However, identifying this trajectory with longitudinal spirometry measurements is challenging in clinical practice.

Objective: To determine whether a proteomic risk score trained on accelerated decline in lung function can assess risk of future respiratory disease and mortality.

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.

Capillary blood self-collection for high-throughput proteomics.

In this study, we sought to compare protein concentrations obtained from a high-throughput proteomics platform (Olink) on samples collected using capillary blood self-collection (with the Tasso+ device) versus standard venipuncture (control). Blood collection was performed on 20 volunteers, including one sample obtained via venipuncture and two via capillary blood using the Tasso+ device. Tasso+ samples were stored at 2°C-8°C for 24-hs (Tasso-24) or 48-h (Tasso-48) prior to processing to simulate shipping times from a study participant's home.

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.

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

Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is increasing in parallel with an obesity pandemic, calling for novel strategies for prevention and treatment. We defined a circulating proteome of human MASLD across ≈7000 proteins in ≈5000 individuals from diverse, at-risk populations across the metabolic health spectrum, demonstrating reproducible diagnostic performance and specifying both known and novel metabolic pathways relevant to MASLD (central carbon and amino acid metabolism, hepatocyte regeneration, inflammation, fibrosis, insulin sensitivity). A parsimonious proteomic signature of MASLD was associated with a protection from MASLD and its related multi-system metabolic consequences in >26000 free-living individuals, with an additive effect to polygenic risk.

Targeted Proteomics Reveals Functional Targets for Early Diabetes Susceptibility in Young Adults.

Background: The circulating proteome may encode early pathways of diabetes susceptibility in young adults for surveillance and intervention. Here, we define proteomic correlates of tissue phenotypes and diabetes in young adults.

Methods: We used penalized models and principal components analysis to generate parsimonious proteomic signatures of diabetes susceptibility based on phenotypes and on diabetes diagnosis across 184 proteins in >2000 young adults in the CARDIA (Coronary Artery Risk Development in Young Adults study; mean age, 32 years; 44% women; 43% Black; mean body mass index, 25.

Implications of metabolism on multi-systems healthy aging across the lifespan.

Aging is increasingly thought to involve dysregulation of metabolism in multiple organ systems that culminate in decreased functional capacity and morbidity. Here, we seek to understand complex interactions among metabolism, aging, and systems-wide phenotypes across the lifespan. Among 2469 adults (mean age 74.

Proteomic architecture of frailty across the spectrum of cardiovascular disease.

While frailty is a prominent risk factor in an aging population, the underlying biology of frailty is incompletely described. Here, we integrate 979 circulating proteins across a wide range of physiologies with 12 measures of frailty in a prospective discovery cohort of 809 individuals with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation. Our aim was to characterize the proteomic architecture of frailty in a highly susceptible population and study its relation to clinical outcome and systems-wide phenotypes to define potential novel, clinically relevant frailty biology.

Physical Activity Over the Lifecourse and Cardiovascular Disease.

Despite improvements in cardiovascular care in recent decades, cardiovascular disease (CVD) remains a leading cause of death worldwide. At its core, CVD is a largely preventable disease with diligent risk factor management and early detection. As highlighted in the American Heart Association's , physical activity plays a central role in CVD prevention at an individual and population level.

Beta-blocker use and mortality among patients with systolic heart failure and pacemaker rhythm.

Aims: Beta-blockers are proven to improve survival among patients with heart failure with reduced ejection fraction. Their efficacy in patients with heart failure with reduced ejection fraction and pacemaker devices has not been demonstrated. Our aim was to test the hypothesis that beta-blocker therapy is associated with improved survival in patients with chronic heart failure and a pacemaker rhythm on electrocardiogram (ECG).