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.
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.
|Zhu, Weifei; Gregory, Jill C; Org, Elin et al. (2016) Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell 165:111-24|
|Grodin, Justin L; Verbrugge, Frederik H; Ellis, Stephen G et al. (2016) Importance of Abnormal Chloride Homeostasis in Stable Chronic Heart Failure. Circ Heart Fail 9:e002453|
|Hartiala, Jaana A; Tang, W H Wilson; Wang, Zeneng et al. (2016) Genome-wide association study and targeted metabolomics identifies sex-specific association of CPS1 with coronary artery disease. Nat Commun 7:10558|
|Senthong, Vichai; Wu, Yuping; Hazen, Stanley L et al. (2016) Predicting long-term prognosis in stable peripheral artery disease with baseline functional capacity estimated by the Duke Activity Status Index. Am Heart J 184:17-25|
|Hammadah, Muhammad; Brennan, Marie-Luise; Wu, Yuping et al. (2016) Usefulness of Relative Hypochromia in Risk Stratification for Nonanemic Patients With Chronic Heart Failure. Am J Cardiol 117:1299-304|
|Verbrugge, Frederik H; Grodin, Justin L; Mullens, Wilfried et al. (2016) Transient Hyponatremia During Hospitalization for Acute Heart Failure. Am J Med 129:620-7|
|Senthong, Vichai; Li, Xinmin S; Hudec, Timothy et al. (2016) Plasma Trimethylamine N-Oxide, a Gut Microbe-Generated Phosphatidylcholine Metabolite, Is Associated With Atherosclerotic Burden. J Am Coll Cardiol 67:2620-8|
|Nagatomo, Yuji; Li, Daniel; Kirsop, Jennifer et al. (2016) Autoantibodies Specifically Against Î²1 Adrenergic Receptors and Adverse Clinical Outcome in Patients With Chronic Systolic Heart Failure in the Î²-Blocker Era: The Importance of Immunoglobulin G3 Subclass. J Card Fail 22:417-22|
|Hammadah, Muhammad; Georgiopoulou, Vasiliki V; Kalogeropoulos, Andreas P et al. (2016) Elevated Soluble Fms-Like Tyrosine Kinase-1 and Placental-Like Growth Factor Levels Are Associated With Development and Mortality Risk in Heart Failure. Circ Heart Fail 9:e002115|
|Kitai, Takeshi; Kirsop, Jennifer; Tang, W H Wilson (2016) Exploring the Microbiome in Heart Failure. Curr Heart Fail Rep 13:103-9|
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