Project Summary The defining morbidity of heart failure (HF) is exercise intolerance, which reduces quality of life despite existing therapies. Currently, prescribed exercise in the form of cardiac rehabilitation can provide benefit, but is underutilized, thus there is a need to better understand the molecular transducers responsible for exercise’s benefit. Evidence suggests that cardiac-specific adaptation to exercise is muted in HF patients, thus peripheral adaptation at the level of the vasculature is hypothesized to be of increased importance in mediating exercise benefit. In support of this hypothesis, preliminary data from healthy adults using high-throughput proteomic profiling demonstrates an association between circulating levels of vascular extracellular matrix (ECM) proteins and exercise adaptation. Thus, the Research Strategy leverages Olink proteomic profiling before and after exercise training to test the hypothesis that changes in vascular ECM are associated with exercise adaptation, particularly among HF patients as compared to healthy adults. In Aim 1, the applicant Dr. Daniel Katz, will analyze Olink proteomic data from the Molecular Transducers of Physical Activity Consortium (MoTrPAC) to elucidate the relationship between vascular ECM proteins, as well as other proteins, and exercise training in healthy adults. Machine learning techniques will also differentiate molecular adaptation response subtypes. In Aim 2, 90 HF patients with non-ischemic cardiomyopathy and an ejection fraction < 35% will be randomized to 12 weeks of cardiac rehabilitation vs 12 weeks of no rehabilitation. Exercise testing and plasma samples (for proteomic profiling) will be obtained before and after the intervention period. The relationship between vascular ECM proteins, as well as other proteins, and exercise training will be determined and compared to healthy adults from MoTrPAC. In Aim 3, genetic variants which determine plasma levels for vascular ECM proteins, and other proteins identified in Aims 1 and 2, will be leveraged for Mendelian Randomization to support a causal link to cardiovascular health outcomes. Dr. Katz builds on prior proteomic training, and has produced 25 publications (13 as first or co-first author) since 2013. The career development plan will provide new training in exercise physiology and testing, clinical trials, bioinformatics, machine learning, and genetic causal analysis, through immersion and course work. Mentor Dr. Euan Ashley is an expert in exercise physiology and training, genetics, and precision medicine. Co-mentor Dr. Robert Gerszten is an expert in multi-omics, especially Olink proteomics, and both collaborate on the MoTrPAC proteomic working group. Drs. Matthew Wheeler (bioinformatics), Jon Myers (exercise testing and trials), and Michael Snyder (exercise biology) offer complimentary expertise as advisors. Together, the proposed work enhances understanding of exercise adaptation, and supports future efforts to expan...