In response to the chronic pressure-overload caused by arterial hypertension or aortic valve stenosis, the myocardium undergoes hypertrophic remodeling that results in the development of left ventricular hypertrophy (LVH). These structural changes are associated with mild - moderate alterations in diastolic performance and increased left ventricular diastolic chamber stiffness. However, these initial compensatory changes in structure and function do not result in the development of clinical heart failure;these patients have compensatory LVH. Eventually, some patients decompensate and develop clinical heart failure. In these patients, hypertrophic remodeling is associated with severe alterations in diastolic performance and severely increased myocardial stiffness;these patients have diastolic heart failure (DHF). The mechanisms that contribute to the transition from compensated LVH to decompensated DHF in patients with chronic pressure-overload are not clearly defined. DHF is a major cause of morbidity and mortality in the Veteran population. Despite this health care burden, there are no evidence based recommendations for treatment that will reduce the mortality, morbidity or disability suffered by Veterans with DHF. In large part, these deficiencies may result from the lack of clear understanding of what basic, fundamental, underlying cellular and molecular mechanisms cause DHF. The fundamental goal of my VA Merit Review program is to identify the mechanisms that cause diastolic heart failure. Based on the preliminary clinical studies in patients with aortic valve stenosis (AS) presented in this application and studies in animal models of pressure-overload performed during my previous Merit Review grants, we hypothesized that the formation of advanced glycation end products (AGEs) and their interaction with the receptor for AGEs (RAGE) are a primary determinants of myocardial stiffness, collagen structure and fibroblast phenotype. Furthermore, we hypothesized that three AGE-dependent mechanisms contribute to the transition from compensated LVH to decompensated diastolic heart failure in patients with AS. First, chronic PO causes the formation of AGEs that increase AGE-induced collagen cross-links, modify the material properties of collagen and increase myocardial stiffness. Second, chronic AGE-ligand stimulation of the RAGE receptor results in a change in fibroblast phenotype characterized by increased RAGE and collagen synthesis. Third, the change in fibroblast phenotype is dependent upon regulation of microRNAs (miRs) that effect mRNA degradation or protein translation, specifically miRs that target AGE/RAGE dependent pathways and effect RAGE and collagen synthesis. We will test these hypotheses using three Specific Aims.
Specific Aim 1 : Demonstrate that increased AGE- induced collagen cross-links contribute to increases in stiffness in AS patients with compensated LVH and a change in fibroblast phenotype contributes to the transition in AS patients to decompensated DHF.
Specific Aim 2 : Demonstrate that an increase in AGE/RAGE interaction contributes to a change fibroblast phenotype characterized by an increase in RAGE and collagen synthesis.
Specific Aim 3 : Demonstrate that specific endogenous microRNAs that target RAGE prevent or enhance a change in fibroblast phenotype. This completely revised proposal will more directly examine three specific AGE-dependent mechanisms that contribute to the development of compensated left ventricular hypertrophy and the transition to diastolic heart failure.

Public Health Relevance

The most common cause of CV morbidity and mortality in the Veteran population is chronic heart failure (HF). LV pressure-overload (hypertension and aortic valve stenosis) is the largest risk factor for the development of HF. Over 50% of HF patients develop symptoms and signs of clinical HF despite a normal (or preserved) ejection fraction. These patients are said to have diastolic heart failure (DHF). Patients with DHF have an enormous increase in mortality, morbidity, and disability. Despite this unmet health care burden, there is no effective treatment for these Veterans with DHF. This lack of effective treatment is caused by the fact that we do not have a clear understanding of what basic, fundamental, underlying cellular and molecular mechanisms cause DHF. My goal is to identify the mechanisms that cause pressure-overload induced DHF and then to use these mechanisms as a target to develop novel, effective treatment for VA patients with heart failure.

Agency
National Institute of Health (NIH)
Type
Non-HHS Research Projects (I01)
Project #
5I01CX000415-04
Application #
8698368
Study Section
Cardiovascular Studies A (CARA)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ralph H Johnson VA Medical Center
Department
Type
DUNS #
City
Charleston
State
SC
Country
United States
Zip Code
29401