Chronic heart failure (CHF) is a systemic inflammatory disease characterized by endothelial dysfunction and neurohormonal activation. Patients with chronic heart failure (CHF) consume a large percentage of health care resources as they are frequently hospitalized for acute decompensated heart failure (ADHF) based on clinical evidence of venous congestion. Accumulating evidence suggests that (i) venous congestion is a major predictor of morbidity and mortality in ADHF;and (ii) venous congestion begins to occur weeks before symptoms worsen resulting in a need for urgent in-hospital therapy. Despite this clinical evidence suggesting a role for venous congestion in the pathophysiology of ADHF, the biomechanically-driven effects of venous congestion on the vascular endothelium (the largest endocrine/paracrine organ of the body) and on neurohormonal activation remain unexplored. Our preliminary data using a novel, safe method of venous endothelial sampling coupled with analysis of protein and gene expression, indicate that: (i) clinical congestion, in patients hospitalized for ADHF, is associated with endothelial activation of the oxidative/inflammatory programs;and, mechanistically, (ii) that experimental congestion, in normal subjects, is sufficient to promote endothelial and neurohormonal activation. The central hypothesis of the proposed research is that venous congestion, in patients with CHF, acts as an independent oxidative/inflammatory stimulus which modulates key genetic regulatory events related to endothelial and neurohormonal activation, and, thereby, to the development and the resolution of ADHF. We propose to investigate this hypothesis using a two-pronged design which will allow us to study "volume- sensitive" genes and proteins, and global gene expression in endothelial cells, as well as neurohormonal activity in plasma in response to both (i) acute experimental congestion among n=24 compensated, euvolemic CHF patients with no recent history of ADHF, as well as among n=24 compensated patients with recent history of ADHF (Aim 1);and, conversely (ii) acute therapeutic decongestion, by "high" volume vs. "standard" volume ulltrafiltration, among n=48 patients hospitalized for ADHF with clinical evidence of venous congestion (Aim 2). In 2007, the NIH identified inflammation as "a key area of public health in need of broad-based collaborative research". If successful, our studies (i) will model the biomechanically-driven pathways that initiate and sustain inflammation in veins and thereby contribute to the clinical transition from compensation to acute decompensation in CHF;and, on the other side of the equation, (ii) will uncover those anti-oxidant/anti- inflammatory cascades that contribute to the prevention and/or resolution of ADHF. Overall, our data may provide a strong rationale for future studies that will use a molecular-based approach, in the unique individual, for the prevention and treatment of ADHF.
Chronic heart failure (CHF) is a major health problem;a systemic rather than only cardiac disorder characterized by vascular and neurohormonal derangement. Patients with CHF are responsible for consuming a large percentage of the health care resources as they are frequent hospitalized for acute decompensation. The results of this study will help elucidate the vascular and neurohormonal events that sustain clinical compensation and/or promote resolution of decompensation in the unique CHF patient, thus paving the way to more predictive and personalized medicine.
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