Heart failure (HF) continues to be a leading cause of morbidity and mortality, and one form of HF that is increasing to near epidemic proportions is that which arises from a sustained pressure overload (LVPO). LVPO is invariably associated with increased extracellular matrix (ECM) remodeling, causing increased myocardial stiffness, impaired diastolic function, and the signs and symptoms of HF. One unifying observation is that with LVPO and the progression to HF, a shift in the relative balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) occur. More specifically, it is now recognized that a large diversity exists with respect to TIMP expression and function. TIMP-4 has been shown to alter fibroblast proliferation, survival, and collagen expression, and we have now identified that in contrast to that of TIMP-1, increased myocardial levels of TIMP-4 may actually prevent abnormal ECM remodeling and dysfunction with LVPO. This project will test the central hypothesis that HF progression with LVPO is due to inadequate TIMP-4 induction, thereby causing a shift in the TIMP stoichiometric balance favoring fibroblast transformation, ECM accumulation, increased myocardial stiffness, and thus drives the HF process forward. There are 3 aims of this project.
Specific Aim 1 will establish that a transition to HF with LVPO can be predicted by a shift in TIMP-1/TIMP-4 balance and that this represents a tipping point whereby a shift in fibroblast transformation and proliferation occurs, accompanied by increased transforming growth factor (TGF) signaling and ECM accumulation, causing a rapid rise in regional myocardial stiffness.
Specific Aim 2 will demonstrate that in a progressive model of LVPO in pigs, regional augmentation of recombinant TIMP-4 (rTIMP-4) through a novel hydrogel delivery system will prevent fibroblast transformation, ECM accumulation, and myocardial stiffness. Moreover, we will demonstrate that localized release of rTIMP-4 following the development of LVPO will reverse this ECM phenotype and thereby reduce myocardial stiffness.
In Specific Aim 3, we will advance our delivery of rTIMP-4 to an intracoronary approach and demonstrate an interruption in the progression to HF with LVPO. Through an integrated set of translational studies, the outcomes from this project will define a new insight into how TIMPs, such as TIMP-4, contribute to the development of HF secondary to LVPO, provide a readily translatable approach in terms of a new diagnostic that can be used to predict the progression of this HF process, and finally establish a novel therapeutic direction for this significant cause of HF.
to public health: One of the most common causes of death and disability in this country is from the failure of the heart muscle to fill and pump blood throughout the body, causing a syndrome called heart failure. Heart failure is also a major cause of repeated and prolonged hospital admissions, as well being a major load upon health care resource burden in this country. An underlying cause of heart failure is when the muscle thickens and becomes fibrotic, and thereby does not allow adequate filling. There are no proven treatments, and this disease is difficult to diagnose. This project will advance an entirely new direction towards our understanding of this form of heart failure, as well as advance preclinical diagnostic and treatment strategies for this fatal disease.
| Zhou, Boran; Prim, David A; Romito, Eva J et al. (2018) Contractile Smooth Muscle and Active Stress Generation in Porcine Common Carotids. J Biomech Eng 140: |
| Barlow, Shayne C; Doviak, Heather; Jacobs, Julia et al. (2017) Intracoronary delivery of recombinant TIMP-3 after myocardial infarction: effects on myocardial remodeling and function. Am J Physiol Heart Circ Physiol 313:H690-H699 |
| Spinale, Francis G; Frangogiannis, Nikolaos G; Hinz, Boris et al. (2016) Crossing Into the Next Frontier of Cardiac Extracellular Matrix Research. Circ Res 119:1040-1045 |
