Faculty Bibliography

INTRODUCTION/BACKGROUND:with dysglycemia, it remains unknown if reducing air pollution exposure through air filtration can affect improvements in glucose. This study aims to test the hypothesis that short-term, in-home air pollution reduction using high efficiency particulate air (HEPA) filtration will improve blood sugar in adults with prediabetes. METHODS AND ANALYSIS/METHODS:as the independent variable. ETHICS AND DISSEMINATION/BACKGROUND:This study has undergone peer review; and the work was supported by Grant 2023-0214 from the Doris Duke Foundation, who had no other role in study design or implementation. The study was registered in ClinicalTrials.gov (NCT05994937) prior to recruitment.

Cardiovascular health (CVH) across the life course requires stable, nurturing environments and a healthy planet. Increasing human demands on the earth's resources destabilize our world's ecosystems, compromising CVH. Unique research opportunities for cardiovascular researchers exist at the intersection of planetary and CVH. Using systems thinking can reveal cardiovascular and planetary health connections and mechanisms of action. For example, meeting global demands for water, food and energy threatens food, water and air quality at the local level, and with it, cardiovascular health. A refined understanding of planetary-CVH interconnections is urgently needed to guide decision making. Emerging, cutting-edge research methodologies include the use of spatial indicators and urban analytics to reveal relationships between physical environments and health outcomes; advanced causal inference methods and modeling simulations; studying human exposure patterns and the exposome - the totality of environmental exposures across the life span - in a population; advances in health informatics made possible by evolving computation methods and AI; and new ways of engaging community in research. The study of planetary health is advanced by engaging a diversity of disciplines from the fields of behavioral, medical, and social sciences to earth sciences, climate change, anthropology, Indigenous studies, and engineering. By employing a planetary health lens, systems thinking and research methodology innovations, expanded opportunities exist for CV researchers and others across a diversity of disciplines. The field will benefit from the development of a holistic research agenda, increased cross- and trans-disciplinary engagement, policy evaluation, and implementation science to support dissemination of evidence-based findings.

Chronic coronary disease (CCD) remains a leading cause of morbidity and mortality worldwide. However, current clinical assessments, including tests of inducible ischemia or coronary artery disease severity poorly discriminate risk for future cardiovascular (CV) disease events among this population with established CCD. To address this gap, our study leverages high-dimensional molecular data from the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) Trials biorepository to molecularly characterize patients with CCD. By integrating transcriptomic (N = 646) and methylomic (N = 732) data with core-lab confirmed clinical phenotyping, we describe molecular signatures associated with disease severity and identify distinct whole-blood molecular subtypes of CCD. These subtypes demonstrate differential risks of CV events, independent of traditional clinical risk scores, and have distinct molecular and immune profiles. Validation of the transcriptomic and methylomic subtypes in two independent external cohorts confirms the clinical relevance and generalizability of our findings. These findings underscore the potential of blood-based multi-omic approaches to refine risk stratification, improve personalized treatment strategies and advance secondary prevention in CCD. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT01471522; https://clinicaltrials.gov/ct2/show/NCT01471522.

BACKGROUND:Asian American (AsA) and Native Hawaiian and Pacific Islander (NHPI) populations are underrepresented in U.S. health studies. OBJECTIVES/OBJECTIVE:The MOSAAIC (Multi-ethnic Observational Study in American Asian and Pacific Islander Communities) is a cohort study designed to improve understanding of disparities in cardiovascular disease and other health conditions affecting AsA and NHPI groups. METHODS:Through broad eligibility criteria and outreach tailored to each study community, MOSAAIC will include 11,500 adults aged 18+ years living in 5 field center regions: New York, Philadelphia, Chicago, San Francisco Bay Area, and Honolulu. The protocol specifies sample-size targets to allow valid comparisons among persons having personal or family origins in 4 geographically defined regions, including East Asia (the largest groups being Chinese and Korean), South Asia (Indian), Southeast Asia (Vietnamese and Filipino) and Oceania (NHPI). Measurements to be obtained at an in-person examination include clinical laboratory tests, medical history, medication use, spirometry, cognitive and physical function, anthropometry, and electrocardiogram. Surveys in multiple languages to assess medical, behavioral, lifestyle, social and environmental influences on health were developed by a multistep process to ensure equivalency between translations and cultural appropriateness. Biospecimens are stored for future studies. Long-term follow-up will be conducted to ascertain and adjudicate major health events including myocardial infarction, stroke, heart failure, and mortality. CONCLUSIONS:The National Institutes of Health established MOSAAIC as a resource for wide-ranging epidemiologic investigation of factors related to cardiometabolic, pulmonary, or mental health in persons of diverse AsA and NHPI background.

BACKGROUND:Genetic determinants of resilience remain poorly defined beyond family studies. OBJECTIVES/OBJECTIVE:The purpose of this study was to perform an unbiased study of individuals with discordance between clinical/genetic risk and atherosclerotic burden to discover novel genetic pathways underpinning atherosclerosis. METHODS:We used 2 genotyped cohorts with well-defined coronary anatomy: PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) (discovery cohort: coronary computed tomography angiography) and CATHGEN (CATHeterization GENetics) (validation cohort: invasive angiography). Resilience was defined as high clinical and polygenic risk of coronary artery disease (CAD), yet without coronary plaque. Resilient individuals were compared to patients with obstructive CAD (oCAD) (stenosis ≥70%) using genome-wide association analyses at variant, gene, and pathway levels. RESULTS:In PROMISE (n = 605), 46 (8%) were resilient and 88 (15%) had oCAD. In CATHGEN (n = 3,236), 127 (4%) were resilient and 1,852 (57%) had oCAD. Clinical risk factors and polygenic risk scores were similar between resilient and oCAD patients in both cohorts. Variant- and gene-level analyses did not yield genome-wide significant signals. Pathway-level analyses identified 4 resilience-associated pathways in PROMISE that replicated in CATHGEN: adipocytokine signaling, fatty acid metabolism, fatty acid degradation, and vascular smooth muscle contraction. CONCLUSIONS:Resilience to CAD-defined as the absence of coronary atherosclerosis despite high clinical and polygenic risk-is present in both lower- (PROMISE) and higher-risk (CATHGEN) cohorts and is linked to protective variants in metabolic and vascular pathways. This unbiased, proof-of-concept approach reveals biologically plausible targets for replication and mechanistic studies in larger imaging-based genetics cohorts.

Despite major advances in medical therapies and prevention strategies, the risk of cardiovascular complications in patients with both type I and type II diabetes remains substantially elevated. In 2019, the American Heart Association sought applications for a Strategically Focused Research Network on Cardiometabolic Health and Type 2 Diabetes. In 2020, 4 centers were named, including Brigham and Women's Hospital, Johns Hopkins University, New York University, and the University of Iowa. These centers performed basic, translational, and clinical studies to provide insights to explain the over 2-fold risk of cardiovascular complications in diabetes. Clinical studies and studies in cells and animals aimed to uncover new mechanisms responsible for disease development. Studies using human populations sought to uncover new biomarkers to prognosticate risk. In this review, we discuss several key issues and current and developing methods to understand why diabetes drives atherosclerotic cardiovascular disease and heart failure. Both human data and experimental models are considered. We integrate a review of these topics with work from the Strategically Focused Research Network and conclude with suggestions for identifying novel risk factors and future experimental research.

BACKGROUND:The BEST-CLI (Best Endovascular Versus Best Surgical Therapy in Patients With Critical Limb Ischemia) trial tested the optimal initial revascularization strategy in patients with chronic limb-threatening ischemia. Little is known about the prognostic relevance of Lp(a) (lipoprotein[a]) and its modification by renal function in patients with chronic limb-threatening ischemia. We investigated the relationship between Lp(a) and prespecified cardiovascular outcomes. METHODS:A subgroup of patients from the BEST-CLI trial (as part of the TIDE [The Impact of Diabetes on Revascularization] study) underwent blinded, core-laboratory assessment of Lp(a) levels and were included in this analysis. The primary end point was major adverse limb events or death from any cause. Secondary end points were the components of the primary end point, major amputation, major reintervention, and major adverse cardiac events (myocardial infarction, ischemic stroke, or death from any cause). The association of Lp(a) with end points was assessed using Cox proportional hazard models adjusting for traditional risk factors and then also for renal function and statin use, which increase Lp(a) levels. RESULTS:=0.009). Results were similar regardless of peripheral revascularization strategy. CONCLUSIONS:Elevated Lp(a) level was not associated with major adverse limb events or death but was associated with all-cause death after controlling for renal function. Lp(a) may be an important therapeutic target in the patient population with high-risk chronic limb-threatening ischemia. REGISTRATION/BACKGROUND:https://clinicaltrials.gov/study/NCT03085524; Unique identifier: NCT03085524.

BACKGROUND AND AIMS/OBJECTIVE:Low functional capacity is an independent risk factor for cardiovascular (CV) events. Regular physical activity may reduce CV risk through suppression of inflammation and reduced platelet activity. We aimed to investigate the association of functional capacity quantified by the validated Duke Activity Status Index (DASI) with platelet activity and incident major adverse CV and limb events (MACLE) in individuals with peripheral artery disease (PAD) undergoing lower extremity revascularization (LER). METHODS:Light transmission aggregometry and platelet RNAseq were performed on specimens isolated from men and women prior to LER. Functional capacity was assessed using DASI. Prospective follow-up occurred at 1, 6, 12, and every 6 months following the LER. Subjects were separated into tertiles of DASI scores and incidence rates for MACLE were calculated using log-rank tests. Mediation analysis using linear regression fit with least squares was performed to test whether DASI exerted its effect on MACLE via platelet aggregation. RESULTS:281 patients completed the DASI questionnaire with scores ranging from 0.0 to 50.2 (bottom tertile: 0.0-9.95). Mean age was 74.4 ± 10.9 years and 32.4 % were female. During a median follow-up of 19 months, 163 (58.0 %) participants experienced a MACLE. After correction for demographics and CV risk factors, individuals in the lowest DASI tertile experienced significantly more MACLE than participants in other tertiles. The association between DASI and MACLE was consistent across multiple subgroups stratified by age, sex, body mass index, antiplatelet therapy, and clinical comorbidities. Mediation analyses suggested higher platelet aggregation to epinephrine in the bottom DASI tertile mediated 24.7 % [5.0 %, 103 %] of increased MACLE risk. Platelet mRNA demonstrated upregulation of inflammation pathways in the most sedentary individuals (lowest DASI tertile). CONCLUSIONS:Patients with PAD and low functional capacity have increased platelet activity and high incidence of MACLE. Our data suggest that elevated platelet aggregation mediates one-quarter of the MACLE risk in persons with low functional capacity undergoing LER. Our findings support a potential platelet-mediated mechanism for improved CV outcomes associated with regular physical activity.