Project Summary/ Abstract Acute exacerbations account for the majority of the chronic obstructive pulmonary disease (COPD)- related morbidity, mortality and costs. Though many exacerbations are triggered by bacterial or viral infections or exposure to airborne pollutants and result in marked lung inflammation, a significant number occur without a clear precipitating cause and in the absence of pulmonary or systemic inflammation (pauci-inflammatory), suggesting an alternative pathophysiology. This may in part explain why current therapies targeting lung inflammation have only a modest effect on the rate of exacerbations and their outcomes even when used in combination. We and others have shown significant interactions between the lung and the heart in COPD, with accelerated atherosclerosis, arrhythmias, and a high frequency of diastolic dysfunction which may each cause or contribute to the development of acute exacerbations. This may be particularly relevant for diastolic dysfunction which may not only lead to overt pulmonary edema but can also cause subtle pulmonary congestion leading to bronchial hyper-reactivity. The prevalence, risk factors, mechanisms and consequences of diastolic dysfunction in this patient population remain unknown. We hypothesize that a subset of pauci- inflammatory acute exacerbations are due to diastolic dysfunction resulting from cardiac ischemia, cardiac arrhythmias and/or lung hyperinflation. These “congestive” exacerbations have a different clinical and inflammatory profile compared with episodes triggered by airway infection or exposure to pollution, and would therefore be expected to respond to a very different treatment algorithm. It is further hypothesized that that diastolic dysfunction in acute exacerbations is caused by subclinical coronary ischemia, cardiac arrhythmias, and/or dynamic lung hyperinflation. We propose a prospective study to answer these high impact questions by determining the frequency of diastolic dysfunction in acute pauci-inflammatory exacerbations of COPD, its clinical implications and underlying mechanisms. We will prospectively enroll patients hospitalized for acute exacerbations of COPD and test our hypothesis with the following three specific aims. Aim 1 of this application will be to assess whether diastolic dysfunction is the primary cause of the pauci-inflammatory phenotype of exacerbations of COPD by evaluation of diastolic dysfunction and pulmonary and systemic inflammation during acute exacerbation, as well as in stable phase after recovery. The goal of Aim 2 is to evaluate the clinical implications of diastolic dysfunction by comparing the length of hospital stay, time to next exacerbation and overall frequency of exacerbations in patients with and without diastolic dysfunction in the year following their index admission. In Aim 3, we will evaluate potential mechanisms underlying diastolic dysfunction by assessing coronary ischemia and surrogates for cardiac arrhythmias, as w...