Cardiac hypertrophy in response to pathological stimuli represents a common feature of maladaptive cardiac remodeling, ultimately leading to the development of contractile dysfunction, heart failure, left ventricular (LV) dysfunction and a cardiomyopathic phenotype. Cardiomyocyte cell death is a feature of pathological cardiac remodeling, and modulating the cell death pathway represents a logical strategy to prevent adverse cardiac remodeling and symptomatic heart failure. Dysregulation of a number of cytokines/growth factors including the TGF-2 superfamily of proteins contributes to the complex pathogenesis of LV systolic heart failure. The follistatin family proteins generally function by binding to and modifying the members of the TGF-2 superfamily. To date, little is known about the role of follistatin-like proteins in heart failure and cardiac remodeling. Our pilot data demonstrate that among the follistatin family of secreted proteins, transcripts of follistatin-like 1 (Fstl1) and follistatin-like 3 (Fstl3), but not follistatin, are dramatically upregulated in murine hypertrophic and ischemic hearts. More importantly, our pilot data also shows increased serum Fstl1 levels in cardiomyopathy patients with LV systolic dysfunction (depressed LV function) compared to control subjects. Additionally Fstl1 levels were decreased in subjects whose LV function normalized. Furthermore in vitro pilot data also suggests opposing actions of Fstl1 and Fstl3: Fstl1 protects against apoptosis whereas Fstl3 promotes apoptosis in cardiac myocytes that have been subjected to hypoxia/reoxygenation. The central hypothesis of this proposal is that members of the follistatin family of secreted protein, Fstl1 and Fstl3, have distinct patterns in heart failure and contribute to the pathogenesis of LV systolic heart failure and cardiac remodeling. We will explore the relationship between circulating Fstl1 and Fstl3 levels and cardiac remodeling.
In Aim 1 we will test the hypothesis that Fstl1 and Fstl3 levels are altered in LV systolic heart failure patients and are associated with cardiac remodeling. In patients with LV systolic dysfunction, cytokines and growth factors are increased and are associated with pathologic cardiac structural remodeling (by echocardiography) and a biomarker of cardiomyocyte remodeling (e.g., BNP).
In Aim 2 we will test the hypothesis that changes in Fstl1 and Fstl3 levels (between baseline and at one year) are associated with disease progression (as determined by LV mass on echocardiography) and BNP levels in LV systolic heart failure. This work may lead to the verification of the role of the cardiac secretome in adverse cardiac remodeling, and could provide new therapeutic targets for prevention or treatment of LV systolic dysfunction. Together with my colleagues, the proposed study will lead to a better understanding of the cardiac secretome in pathological cardiac remodeling and its contribution to the pathogenesis of adverse cardiac remodeling in HF

Public Health Relevance

Heart failure is the most significant public health problems in the world and in the United States alone, afflicts more than 5 million people and is the primary cause of 53,000 deaths annually. Despite the application of evidence-based therapies and the utilization of guidelines the incidence of HF has not declined for two decades while the mechanisms influencing the pathogenesis and progression of HF remain incompletely understood. Novel factors secreted by the heart likely plays an important pathophysiology role in how the heart itself responds to heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL102631-02
Application #
8062288
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Adhikari, Bishow B
Project Start
2010-04-15
Project End
2014-03-31
Budget Start
2011-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2011
Total Cost
$244,876
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Essick, Eric E; Wilson, Richard M; Pimentel, David R et al. (2013) Adiponectin modulates oxidative stress-induced autophagy in cardiomyocytes. PLoS One 8:e68697
Gopal, Deepa M; Sam, Flora (2013) New and emerging biomarkers in left ventricular systolic dysfunction--insight into dilated cardiomyopathy. J Cardiovasc Transl Res 6:516-27
Garcia, Anthony G; Wilson, Richard M; Heo, Joline et al. (2012) Interferon-γ ablation exacerbates myocardial hypertrophy in diastolic heart failure. Am J Physiol Heart Circ Physiol 303:H587-96
Essick, Eric E; Ouchi, Noriyuki; Wilson, Richard M et al. (2011) Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling. Am J Physiol Heart Circ Physiol 301:H984-93
Seldin, David C; Berk, John L; Sam, Flora et al. (2011) Amyloidotic cardiomyopathy: multidisciplinary approach to diagnosis and treatment. Heart Fail Clin 7:385-93
Greene, Michael J; Sam, Flora; Soo Hoo, Pamela T et al. (2011) Evidence for a functional role of the molecular chaperone clusterin in amyloidotic cardiomyopathy. Am J Pathol 178:61-8
El-Armouche, Ali; Ouchi, Noriyuki; Tanaka, Komei et al. (2011) Follistatin-like 1 in chronic systolic heart failure: a marker of left ventricular remodeling. Circ Heart Fail 4:621-7
Essick, Eric E; Sam, Flora (2011) Cardiac hypertrophy and fibrosis in the metabolic syndrome: a role for aldosterone and the mineralocorticoid receptor. Int J Hypertens 2011:346985