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 well as lung hyperinflation during the acute event and after recovery. The results of our study will potentially identify a novel mechanism of exacerbations by defining a congestive phenotype. I will utilize this proposal to acquire additional skills in advanced echocardiographic techniques to further study the complex heart-lung interrelationships in COPD; gain a fundamental understanding of the most up-to-date mass spectrometry techniques and their applications to proteomics of the lung in COPD; as well as obtain a Master?s degree in Clinical and Translational Sciences to foster an independent career in translational research and clinical trial design.
The aims of this research proposal and career development plan are possible through the active collaboration of Dr. Edwin Blalock, a leader in neutrophilic inflammation in COPD and Dr. Mark Dransfield, a leading investigator in COPD with a special focus on exacerbations and cardiovascular comorbidity. The opportunities created by this Career Development Award will provide me with a clearly delineated path to acquire expertise and develop a research niche, compete successfully for independent funding for translational and clinical research in the field of COPD and cardiovascular disease, especially as it pertains to acute exacerbations. My ultimate goal is to identify novel etio-pathogenic mechanisms and new therapies for acute exacerbations, with a special focus on the complex heart-lung interactions in this disease.

Public Health Relevance

Acute exacerbations account for the majority of morbidity and mortality associated with chronic obstructive pulmonary disease (COPD). A significant number of acute exacerbations occur without a known precipitating cause and are associated with a distinct lack of pulmonary inflammation. Given the close interrelationship between the lungs and the heart, some of these exacerbations may have a cardiac etiology, and exploring new risk factors and pathways for acute exacerbations may lead to novel interventions for acute exacerbations of COPD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL133438-03
Application #
9539564
Study Section
NHLBI Mentored Patient-Oriented Research Review Committee (MPOR)
Program Officer
Tigno, Xenia
Project Start
2016-09-01
Project End
2021-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Bhatt, Surya P; Kim, Young-Il; Harrington, Kathy F et al. (2018) Smoking duration alone provides stronger risk estimates of chronic obstructive pulmonary disease than pack-years. Thorax 73:414-421
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Copeland, Carla R; Nath, Hrudaya; Terry, Nina L J et al. (2018) Paratracheal Paraseptal Emphysema and Expiratory Central Airway Collapse in Smokers. Ann Am Thorac Soc 15:479-484
Bhatt, Surya P (2018) Early Chronic Obstructive Pulmonary Disease or Early Detection of Mild Disease? Am J Respir Crit Care Med 198:411-412
Bhatt, Surya P (2018) Generic Respiratory Symptoms and Branded Lung Diseases. Same Difference? Am J Respir Crit Care Med 197:1521-1523
Bodduluri, Sandeep; Reinhardt, Joseph M; Hoffman, Eric A et al. (2018) Recent Advances in Computed Tomography Imaging in Chronic Obstructive Pulmonary Disease. Ann Am Thorac Soc 15:281-289
Bhatt, Surya P; Kazerooni, Ella A; Newell Jr, John D et al. (2018) Visual Estimate of Coronary Artery Calcium Predicts Cardiovascular Disease in COPD. Chest 154:579-587
Bhatt, Surya P (2018) Diagnosis of Chronic Obstructive Pulmonary Disease: Breathing New Life into an Old Debate. Ann Am Thorac Soc 15:163-165
Bhatt, Surya P; Vegas-Sánchez-Ferrero, Gonzalo; Rahaghi, Farbod N et al. (2017) Cardiac Morphometry on Computed Tomography and Exacerbation Reduction with ?-Blocker Therapy in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 196:1484-1488

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