In the heart, increased Ang II activity from intracellular or interstitial formation is a cause of cardiac remodeling, arrhythmias, and fibrosis. In humans, Ang-(-12), an extended form of Ang I, accounts for nonrenin dependent synthesis of Ang II in cardiac myocytes. Further demonstration of substantial Ang-(1-12) expression in atrial myocytes obtained from patients undergoing cardiac surgery for control of atrial fibrillation (AF) and the associated discovery that cardiac chymase converted Ang-(1-12) into Ang II in both human atrial and left ventricular myocytes generates the hypothesis that stretch-related increased cardiac chymase expression and Ang- (1-12) conversion to Ang II promotes the occurrence of AF through activation of matrix metalloproteinases (MMP) and disruption of connexins (Cx), gap junctions proteins important in cell-cell communication and electrical stability.
Aim 1 will test the hypothesis that activation of chymase contributes to elevated Ang-(1-12)/Ang II/MMP-9 axis and gap junction remodeling in left atrial tissue from patients undergoing valve repair for mitral valve regurgitation (MR) vs. normal left atria from hearts rejected for transplantation;
Aim 2 will show how atrial tissue expression and release of chymase Ang-(1-12)/Ang II/MMP-9 components, assessed in pericardial fluid obtained before cardiopulmonary bypass and at 4, 12, 24 and 48 hour time points, are related to a) atrial remodeling and function from cine-magnetic resonance imaging with 3-dimensional analysis performed before and after surgery and b) the occurrence of AF postsurgery. And in Aim 3 will test the hypothesis that stretch and/or hypoxia-reoxygenation of atrial myocytes increases chymase and Cx disruption and electrical instability in HL1 cells which reproduce human atrial myocytes. Achievement of these aims will provide impetus for a clinical trial testing the efficacy of chymase inhibition in the treatment/prevention of AF.

Public Health Relevance

Heart disease is the number one cause of death in Americans including veterans. Every aspect of medical care in the VA medical system is affected by its common presence. A condition in which the heart is no longer in regular rhythm, atrial fibrillation, occurs frequently (4% of thoseof 60 years old and 9% in those over 80);it is the most common arrhythmia in the United States, including veterans. Atrial fibrillation is associated with high risks of stroke and death, yet causs of this widespread problem are not well understood. This study aims to find a connection between common factors which are associated with high blood pressure and heart disease (angiotensin and renin), and a newly related factor (chymase) with the common arrhythmia atrial fibrillation. Furthermore, the function of the heart will be evaluated by magnetic resonance imaging (MRI) to show the effects that chymase has on contractility and ejection of both the upper and lower chambers of the heart. This will allow for directed treatments to facilitate alleviation of atrial fibrillation.

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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Birmingham VA Medical Center
United States
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Dell'Italia, Louis J; Collawn, James F; Ferrario, Carlos M (2018) Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling. Circ Res 122:319-336
Butts, Brittany; Goeddel, Lee A; George, David J et al. (2017) Increased Inflammation in Pericardial Fluid Persists 48 Hours After Cardiac Surgery. Circulation 136:2284-2286
Fu, Lianwu; Wei, Chih-Chang; Powell, Pamela C et al. (2016) Increased fibroblast chymase production mediates procollagen autophagic digestion in volume overload. J Mol Cell Cardiol 92:1-9
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Fu, Lianwu; Wei, Chih-Chang; Powell, Pamela C et al. (2015) Volume overload induces autophagic degradation of procollagen in cardiac fibroblasts. J Mol Cell Cardiol 89:241-250