Skin Inflammatory Phenotypes as Biomarkers of Myocardial and Vascular Remodeling

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 DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is a major cause of death among elderly individuals with obesity and diabetes. Systemic inflammation is a common pathophysiologic hallmark of aging, diabetes, and cardiovascular illness, with animal and human data suggesting that pro-inflammatory cytokines concomitantly perturb vascular and myocardial function and lead to insulin resistance and oxidative stress. Current clinical markers of inflammation (e.g., high-sensitivity C-reactive protein), oxidative stress, and obesity (e.g., body mass index; BMI) are not sufficiently sensitive in elderly individuals to identify those at high CV and metabolic risk. Indeed, systemic markers of inflammation may rise with aging in a CVD risk- or diabetes-independent fashion. Furthermore, elderly individuals with low BMI may be at paradoxically higher CVD and mortality risk, specifically those with diabetes. Establishing biomarkers that directly reflect tissue-level inflammatory processes may therefore identify elderly individuals at greatest risk for timely therapy. Our group has recently described specific histologic and molecular dermal phenotypes in diabetes that are strongly linked to microvascular function, wound healing, and systemic inflammation. Our preliminary data suggests that macrophage polarization (M1) within skin and mast cell degranulation are strongly associated with obesity- and diabetes-related phenotypes and mark diabetes-related microvascular disease (e.g., poor wound healing). In addition, we have demonstrated microcirculatory dysfunction in older diabetics using advanced cardiovascular imaging, with associations between obesity, inflammation and myocardial dysfunction. Given the overarching role of inflammation and oxidative stress in systemic vascular and metabolic dysfunction, and aging, we hypothesize that inflammatory phenotypes in the skin may provide a critical marker of systemic inflammation and its effects on CVD and metabolic risk in an elderly population. In this application, we address the central hypothesis that dermal macrophage infiltration/polarization and mast cell activation are associated with systemic inflammation, oxidative stress, and cardiovascular remodeling, and are reversible with therapies targeting improved fitness in the elderly. We therefore propose (a) to determine the association of dermal inflammatory phenotypes with cardiovascular disease (CVD) and metabolic risk in elderly individuals with and without diabetes, (b) to quantify the relationship between dermal inflammation, skin microcirculatory dysfunction, and abnormal cardiovascular structure in elderly individuals with and without obesity and (c) to determine whether a lifestyle intervention proven to reduce systemic inflammation will impact biochemical and imaging-based markers of CVD and metabolic risk in elderly individuals with diabetes. Successful completion of the application will (1) establish skin phenotypes as a novel, minimally invasive, and reversible biomarker that directly measures ongoing CVD in the elderly and (2) further understanding of the biology of inflammation and CVD risk in an emerging elderly population.