Project Summary/Abstract Psoriasis is highly linked to cardiovascular disease (CVD), including myocardial infarction (MI), heart failure and CV mortality. An increased prevalence of CV risk factors in these patients only partially accounts for this enhanced clinical risk. Although systemic inflammation is thought to be a key mediator of the onset and progression of these cardiometabolic abnormalities, the excess CV risk conferred by psoriatic disease remains understudied. We will use novel multi-modality cardiac imaging to quantify abnormalities in vascular health, and cardiac structure and function and assess the association with cellular immunophenotype. The central hypothesis of this study is that reducing inflammation with tildrakizumab, an FDA approved therapy for psoriasis that inhibits the IL-23 and Th17 pathway of inflammation, will quantitatively improve myocardial blood flow and coronary flow reserve (CFR) as measured by positron emission tomography (PET) over 6 months in patients with moderate-severe psoriasis disease and enhanced CV risk. In so doing, improvement in coronary vasoreactivity, endothelial function, and tissue perfusion may have beneficial effects on myocardial mechanics, and ultimately, symptoms and prognosis. We propose to use two state-of-the-art techniques, quantitative perfusion PET imaging and cellular immunophenotyping by single cell analysis [single cell RNA-seq, cellular indexing of transcriptomes and epitopes (CITE)-seq] of peripheral blood mononuclear cells, combined with echocardiography. In Specific Aim 1, we will evaluate whether tildrakizumab therapy will (1) improve coronary vascular function based on CFR, (2) improve myocardial mechanics, and (3) whether this functional improvement will be correlated with the change in CFR after 6 months of treatment. In Specific Aim 2, we will evaluate the relationship between cellular immunophenotype and coronary vasomotor dysfunction and myocardial mechanics, at baseline and after therapy with tildrakizumab for 6 months. The overarching goal of this proposal is to use physiologic imaging techniques already available as part of routine clinical care, and novel cellular immunophenotyping to investigate mechanisms linking psoriatic disease and inflammation to coronary vascular health and cardiac structure and function. This study will address an unmet and needed clinical translation in psoriatic disease. This research will be accomplished in the setting of a comprehensive career development program designed to provide the candidate, an early career investigator with training in CV medicine and CV imaging, with the skills needed to become an independent physician-scientist in CV medicine. Her long-term career goal is to be an independent scientific investigator, integrating immunology with cardiovascular imaging to better define the role of systemic inflammation in cardiovascular pathophysiology, and ultimately inform future therapeutic trials. An outstanding mentoring tea...