Interplay of Inflammation, Angiogenesis, and Coronary Microvascular Perfusion in Advanced Kidney Disease - PROJECT SUMMARY/ABSTRACT Chronic kidney disease (CKD) is associated with accelerated cardiovascular (CV) aging including maladaptive myocardial and vascular remodeling, ultimately increasing cardiovascular risk independent of traditional risk factors. Microcirculatory dysfunction plays a key role in the early stages of myocardial injury and dysfunction. Specifically, a decline in myocardial flow reserve (MFR) - a well-validated quantitative marker of vascular health assessed using positron emission tomography (PET) – is linked to maladaptive myocardial remodeling and adverse outcomes. Chronic systemic and vascular inflammation, which is highly prevalent in CKD, is linked to endothelial dysfunction, dysregulated angiogenesis, atherosclerosis, myocardial dysfunction, and abnormalities in the coronary microcirculation. Kidney transplantation offers a unique observational model to examine the impact of reducing CKD-related inflammation on CV outcomes, including coronary microvascular function and myocardial mechanics. The goal of the proposal, based on the observational study RESTORE (Impact of Renal Transplant on Coronary Microvascular Function in Patients with Advanced Chronic Kidney Disease), is to mechanistically explore cardiovascular health before and after transplant, focusing on the interplay between inflammation, angiogenesis, myocardial perfusion and myocardial function. We hypothesize that systemic inflammation and dysregulated angiogenesis contribute to abnormal myocardial blood flow, measured by PET, and abnormal myocardial mechanics, assessed by echocardiography, in patients with advanced CKD on the transplant waitlist (Specific Aim 1). Leveraging transplantation as an observational intervention, we further hypothesize that kidney transplant will be associated with improved myocardial blood flow and myocardial mechanics (Specific Aim 2), and that reductions in inflammation and dysregulated angiogenesis after transplant will be associated with improved myocardial blood flow and function (Specific Aim 3). By gaining a mechanistic understanding of how CKD, its associated inflammation and dysregulated angiogenesis, and kidney transplant influence myocardial blood flow and function, this study may lead to targeted preventive therapies in the future, such as immunomodulatory treatments, including IL-6 inhibitors. The proposal will be accomplished within a comprehensive career development plan designed to provide the award applicant Dr. Huck, who is a cardiovascular imaging specialist and early career investigator, the skills to become an independent R01-funded clinical-translational investigator and academic leader performing mechanistic and therapeutic clinical trials with imaging endpoints in people with kidney disease. Dr. Huck has an expert mentorship team of multidisciplinary researchers in coronary microvascular dysfunction, kidney transplant, clinical trials and state-of-the-art cardiovascular imaging and a superb environment for early career development at Brigham and Women’s Hospital and Harvard Medical School. He is ideally supported for a transition to scientific independence over the course of the award period.
