The development of myocardial remodeling and abnormal diastolic function are critical events that impact both functional capacity and the rates of morbid and mortal events in our Veteran population with chronic heart failure (CHF). CHF has a designated Quality Enhancement Research Initiative (QUERI) in the VA system to address ways to improve cardiovascular healthcare for Veteran?s suffering from CHF. Chronic pressure- overload (PO), produced by systemic hypertension, represents the most frequent cause of myocardial hypertrophy and diastolic dysfunction, and the most important risk factor for the development of heart failure, particularly heart failure with a preserved ejection fraction (HFpEF). Our recent clinical studies in Veterans showed that the transition from compensated hypertensive heart disease (HHD) to decompensated HFpEF is associated with significant changes in diastolic properties including an increase in passive diastolic stiffness. Our translational studies in Veterans showed that one pivotal determinant of this increase in stiffness is an increase in interstitial collagen. Our studies in murine models of PO-induced fibrosis showed that one mechanism that controls changes in collagen accumulation is the time dependent production of the matricellular protein SPARC (secreted protein acidic and rich in cysteine) and its regulation of post-synthetic collagen processing. Preliminary studies presented in this application support the hypothesis that myocardial macrophages serve a fundamental role in affecting the time-dependent increase in matricellular proteins that increases post synthetic collagen processing, collagen content, and myocardial stiffness in PO and contributes to the development of heart failure. This hypothesis will be tested with 3 Specific Aims.
In Aim 1, the use of clinically relevant murine models of PO-induced fibrosis will be used to 1) determine whether increases in myocardial macrophages plays a causal role in driving post-synthetic collagen processing that results in myocardial fibrosis and diastolic dysfunction and 2) whether there is a time-dependent increase in myocardial macrophages after imposition of PO. Experiments in Aim 2 will determine whether cell-specific inhibition of SPARC expression in monocyte/macrophages versus targeted inhibition of SPARC in fibroblasts reduces and/or reverses PO-induced myocardial fibrosis and diastolic dysfunction.
In Aim 3, studies to determine whether macrophage-dependent mechanisms driving diastolic dysfunction and myocardial fibrosis defined in vivo in Aims 1&2 play a causal role in fibroblasts isolated from PO hearts and in fibroblasts isolated from Veterans with and without HHD-induced fibrosis. The completion of these Specific Aims will lead to a better understanding of the molecular and cellular mechanisms that contribute to the development of diastolic dysfunction in PO and that lead to the transition to HFpEF. Elucidation of mechanistic factors that contribute to HFpEF are critical for improved methods of diagnosis and the development of better therapies to treat our Veterans with CHF, a significant unmet need.

Public Health Relevance

to Veterans Health Care: Strategies to improve treatments for chronic heart failure (CHF) is of significant value to our Veterans population. CHF has a designated Quality Enhancement Research Initiative (QUERI) in the VA system to address ways to improve cardiovascular healthcare for Veterans suffering from CHF. If we can more completely determine the cellular mechanisms that cause changes in functional capacity and substrate vulnerability, more effective and comprehensive patient care management programs can be developed to limit the effects of aging and other co-morbidities, such as hypertension, on heart structure and function. Elucidation of cellular mechanisms that govern increases in cardiac collagen has the potential to improve strategies in this regard. These issues are especially important in our Veterans who are older, have a high incidence of hypertension, and have a disproportionately greater level of age-dependent functional limitations.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Cardiovascular Studies A (CARA)
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Ralph H Johnson VA Medical Center
United States
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McDonald, Lindsay T; Zile, Michael R; Zhang, Yuhua et al. (2018) Increased macrophage-derived SPARC precedes collagen deposition in myocardial fibrosis. Am J Physiol Heart Circ Physiol 315:H92-H100