ABSTRACT Chronic lung disease and heart failure (HF) are highly prevalent, commonly co-occur, and are associated with significant morbidity and mortality. Work from our group and others has demonstrated an independent relationship between chronic lung disease and incident HF that may be driven in part by inflammation. We have also documented that even in the absence of symptomatic lung disease, impaired lung function defined by spirometry is associated with adverse cardiac remodeling on echocardiography and incident HF events. While symptomatic lung disease and HF often occur in the elderly, many younger adults have relatively asymptomatic impairment in lung health and cardiac structure and function. These subclinical cardiopulmonary abnormalities develop during the key modifiable period from young adulthood to midlife. However, data are sparse on the timing and associated mechanisms of the transition from health to disease spanning young adulthood to midlife, and related race-sex differences. Without identifying these unique patterns of change, it will not be possible to screen for subclinical changes and employ prevention strategies prior to irreversible damage in the lung and heart. This requires upstream identification at the earliest detectable change. While spirometry is the gold standard for lung disease detection, it is a relatively crude and insensitive measure of impaired lung health. In contrast, lung injury (quantified using a novel local histogram analysis developed and validated by our group) from computed tomography (CT) scans is a more sensitive and earlier indicator of impaired lung health (e.g. due to tobacco, air pollution, and respiratory viral infection). Therefore, we now propose to take advantage of the Coronary Artery Risk Development in Young Adults (CARDIA) study’s unique platform to study the temporal relationship of and mechanisms underlying the transition from lung and heart health to disease. To-date, our group has investigated the predictors and consequences of impaired lung health and HF, separately, in CARDIA. In this project, we will build upon our prior work by analyzing CT scans to determine the concurrent evolution of lung injury and adverse cardiac remodeling and identify mechanisms by assaying a multitude of blood-based biomarkers (using a multiplexed array) and performing 4-dimensional flow cardiovascular magnetic resonance imaging (cMRI). We will test the hypothesis that detailed imaging and blood-based markers can inform clinically relevant endotypes reflecting dynamic changes in lung injury and adverse cardiac remodeling during a key vulnerable period of life through the following specific aims: (1) Determine the longitudinal association between lung injury and left ventricular end-diastolic volume (LVEDV); (2) Determine the risk of subclinical and clinical HF among joint lung injury and LVEDV trajectory groups; and (3) Determine the hemodynamic mediators of the association between lung injury and adverse cardiac remodeling. This study will investigate factors associated with transitions from cardiopulmonary health to disease and associated mechanisms, and in doing so, will identify screening strategies and contribute novel pathways for targeted disease interception of lung and heart disease.

PUBLIC HEALTH SIGNIFICANCE This research is relevant to public health because it examines patterns in how lung and heart health change over time. We will use repeated imaging studies to identify the earliest, pre-symptomatic changes from young adulthood to midlife to identify susceptible individuals, track transitions from subclinical to clinical disease, and ultimately design prevention strategies for lung and heart disease.