Development of subclinical myocardial dysfunction and progression to overt left ventricular systolic dysfunction (LVSD) and heart failure (HF) represent a major and growing healthcare burden. Often a long-term complication of atherosclerotic heart disease, LVSD and HF may also develop in the absence of significant angiographic evidence of coronary artery disease. The underlying pathophysioplogical mechanisms contributing to development of LVSD and HF are multifactoral. Interestingly, treatment of HF with nitric oxide (NO) donors such as nitrates has shown a resurgence in use due to demonstrated added clinical efficacy on top of traditional neurohormonal antagonist therapy. There has been long-standing recognition that NO related processes play a role in the development and progression of ischemic and non-ischemic HF, though most data focuses on studies of advanced HF subjects. Little is known about the role of NO related pathways, including formation of NO-derived oxidants (aka nitrative stress) in the development of subclinical myocardial dysfunction, LVSD and HF. Our overall goal is to test the hypothesis that nitrative stress and specific NO-related processes are mechanistically linked to the development of ischemic and non-ischemic HF in order to facilitate both identification and preventive treatment efforts for subjects at risk of developing LVSD and HF. This will be achieved by employing a combination of biochemical and mass spectrometry-based analyses of human clinical specimens with extensive clinical phenotypic data. We will leverage access to a large (N>10,000) and well characterized cohort of cardiovascular subjects, GeneBank, at our institution for performance of the following specific aims:
Aim 1. To test the hypothesis that baseline levels of specific NO-mediated processes are associated with the presence of subclinical myocardial dysfunction, LVSD and HF in stable patients.
Aim 2. To test the hypothesis that baseline and interval changes in specific NO-mediated processes are associated with prospective risks for development of subclinical myocardial dysfunction, LVSD (as detected by comprehensive echocardiography), and HF amongst individuals without LVSD/HF at baseline.

Public Health Relevance

The present will help identify specific nitrative stress pathway of clinical relevance with mechanistic links to cardiovascular disease pathogenesis and adverse sequelae such as heart failure and left ventricular systolic dysfunction. Successful completion of the proposed studies will provide mechanistic and clinical insights into defining individuals at risk for the development of subclinical myocardial dysfunction, left ventricular systolic dysfunction, and heart failure, as well as additional potential therapeutic targets for reducing the risk for developing subclinical myocardial dysfunction, left ventricular systolic dysfunction, heart failure, and long-term adverse complications.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL103931-04
Application #
8472361
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Sopko, George
Project Start
2010-08-15
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$728,636
Indirect Cost
$252,775
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Grodin, Justin L; Hammadah, Muhammad; Fan, Yiying et al. (2015) Prognostic value of estimating functional capacity with the use of the duke activity status index in stable patients with chronic heart failure. J Card Fail 21:44-50
Grodin, Justin L; Neale, Sarah; Wu, Yuping et al. (2015) Prognostic comparison of different sensitivity cardiac troponin assays in stable heart failure. Am J Med 128:276-82
Kennedy, David J; Fan, Yiying; Wu, Yuping et al. (2014) Plasma ceruloplasmin, a regulator of nitric oxide activity, and incident cardiovascular risk in patients with CKD. Clin J Am Soc Nephrol 9:462-7
Chamsi-Pasha, Mohammed A R; Shao, Zhili; Tang, W H Wilson (2014) Angiotensin-converting enzyme 2 as a therapeutic target for heart failure. Curr Heart Fail Rep 11:58-63
Huang, Ying; DiDonato, Joseph A; Levison, Bruce S et al. (2014) An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat Med 20:193-203
Kumari, Meera; Tang, W H Wilson; Maroo, Anjli P (2014) Natriuretic peptide testing in high-risk pregnancy: a preventive opportunity? Curr Heart Fail Rep 11:471-6
Tang, W H Wilson; Wang, Zeneng; Fan, Yiying et al. (2014) Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol 64:1908-14
Nagatomo, Yuji; Tang, W H Wilson (2014) Autoantibodies and cardiovascular dysfunction: cause or consequence? Curr Heart Fail Rep 11:500-8
Tang, W H Wilson; Topol, Eric J; Fan, Yiying et al. (2014) Prognostic value of estimated functional capacity incremental to cardiac biomarkers in stable cardiac patients. J Am Heart Assoc 3:e000960

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