The development of myocardial remodeling and abnormal diastolic function is a critical event in patients with hypertensive heart disease (HHD). The mechanisms that contribute to the development of abnormal diastolic function and progression to heart failure with a preserved ejection fraction (HFpEF) are poorly defined. This proposal will examine the causal contribution made by changes in fibrillar collagen. We hypothesized that 1- the stoichiometric balance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs) is a primary determinant of diastolic stiffness and collagen content, 2- there is a critical change in this stoichiometric balance in HHD patients that develop HFpEF, 3- HFpEF patients have an increase in TIMP-1 that results in decreased interstitial protease activity, decreased collagen degradation, increased collagen content and increased collagen-dependent stiffness, 4- changes in TIMP-1 and interstitial MMP activity reflect a change in fibroblast function;fibroblasts shift to a more profibrotic phenotype in HHD patients that develop HFpEF, and 5- TIMP-1 deletion will prevent and reverse TIMP-1 dependent effects of pressure overload. We developed novel methods that allow, for the first time, in vivo measurements of aggregate interstitial protease activity (using microdialysis and a quenched fluorogenic peptide substrate) and measurement of collagen-dependent myocardial diastolic stiffness (myocardial stress vs. strain measured in LV biopsies treated with sequential extraction techniques). These methods will be applied to both patients with HHD and novel murine surgical and transgenic models of clinically relevant pressure-overload (transverse aortic constriction in tamoxifen-inducible, fibroblast-specific, TIMP-1 knock-out mice).
Specific Aim One : Demonstrate that in patients with hypertensive heart disease, the transition to heart failure is characterized by an increase in TIMP-1 and a decrease in in vivo interstitial protease activation leading to an increase in collagen content and an increase in collagen-dependent stiffness.
Specific Aim Two : Demonstrate in vitro, using primary fibroblast cultures, that fundamental changes in cardiac fibroblast function occur in patients with HFpEF that result from a TIMP-1 induced decrease in protease activation and decreased collagen degradation.
Specific Aim Three : Determine in vivo whether there is a cause and effect relationship between a change in TIMP-1 expression/abundance, interstitial protease activity, and the development of increased collagen- dependent stiffness in a murine model of pressure-overload induced heart failure.
The most common cause of CV morbidity and mortality is chronic heart failure (HF);>50% of HF patients have a preserved ejection fraction (HFpEF). To date, there is no effective treatment for HFpEF. This unmet health care burden will not be overcome until we have a clear understanding of the mechanisms that cause HFpEF. The goal of this proposal is to identify the interstitial collagen-dependent mechanisms that cause HFpEF and then to use these mechanisms as a target to develop novel, effective treatment.
|Novgorodov, Sergei A; Riley, Christopher L; Yu, Jin et al. (2016) Lactosylceramide contributes to mitochondrial dysfunction in diabetes. J Lipid Res 57:546-62|
|Zile, Michael R; Sharma, Vinod; Johnson, James W et al. (2016) Prediction of All-Cause Mortality Based on the Direct Measurement of Intrathoracic Impedance. Circ Heart Fail 9:e002543|
|LeWinter, Martin M; Zile, Michael R (2016) Could Modification of Titin Contribute to an Answer for Heart Failure With Preserved Ejection Fraction? Circulation 134:1100-1104|
|Renaud, Ludivine; Harris, Lillianne G; Mani, Santhosh K et al. (2015) HDACs Regulate miR-133a Expression in Pressure Overload-Induced Cardiac Fibrosis. Circ Heart Fail 8:1094-104|
|Zile, Michael R; Baicu, Catalin F; Ikonomidis, John S et al. (2015) Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation 131:1247-59|