PROJECT SUMMARY Symptom burden continues to be a significant problem for millions of adults living with heart failure (HF), the fastest growing cardiovascular condition in the U.S. Symptoms, which often co-occur or cluster together, are of utmost importance in HF because they predict quality of life and clinical events. There is considerable heterogeneity in symptoms in HF, however, that is particularly evident in the vulnerable transition period after a hospitalization for acute decompensated HF. While symptoms improve for some patients and they have longer periods of relative stability, others are plagued by enduring symptoms leading to poor outcomes, including rehospitalization. Given little-to-no association between hemodynamic markers (e.g. ejection fraction) and symptoms in HF, our clinical efforts to optimize hemodynamic stability during a hospitalization may not translate to improvement in symptoms post-hospitalization. Many studies have shown that HF is not just a hemodynamic, “pump failure” problem, but that it is a multifactorial, systemic condition involving processes such as inflammation, sympathetic dysregulation, and endothelial dysfunction. Based on research by our group and others, we propose that a multi-biomarker panel and the physical frailty phenotype that capture the multifaceted nature of HF might tell us more about symptoms in HF than our current objective markers. Therefore, the purpose of the proposed research is to 1) identify clusters of change in symptoms after a HF hospitalization and 2) quantify longitudinal associations between symptoms, biomarkers, and physical frailty. We will address the following aims through a gender- and age-balanced longitudinal study of 240 adults during the 6 month transition period after a hospitalization for acute decompensated HF: 1) identify clusters of change in physical symptoms among adults with heart failure, 2) quantify longitudinal associations between biomarkers and physical symptoms among adults with heart failure, and 3) quantify longitudinal associations between physical frailty and physical symptoms among adults with heart failure. We will use advanced quantitative modeling, including growth mixture modeling and longitudinal mediation modeling, to examine changes in symptoms, biomarkers, and physical frailty post-HF hospitalization and associations therein. This innovative study will advance HF symptom science by utilizing a multi-biomarker panel and the physical frailty phenotype that capture the multifaceted nature of HF, coupled with advanced quantitative modeling, to characterize heterogeneity and identify potential mechanisms of symptoms in HF. As a result, this research will inform the next phase of this program of research by pinpointing amenable targets for intervention to provide better, individualized treatment to improve symptom burden in HF.