Recent large clinical trials have demonstrated the beneficial effects of angiotensin converting enzyme (ACE) inhibitor therapy in both symptomatic and asymptomatic heart failure patients that cannot be explained by a lowering of the blood pressure. The applicant proposes to test the hypotheses that local expression of renin- angiotensin system (RAS) components and Chymase are turned on by diastolic stretch and severity of heart failure in a dog model of volume overload hypertrophy.
Specific Aim 1 relates cardiac angiotensin II (ANGII), ACE and Chymase activity, and steady state mRNA of Chymase and RAS components to matched regional stress estimates of the left ventricle derived from a validated finite element model that is applied to magnetic resonance images and high-fidelity pressures. Because Chymase and ACE activity are increased in this model, studies using selective inhibitors will be performed to establish an etiologic relationship between increased ANGII and left ventricular remodeling.
Specific Aims 2 and 3 examine the effect of ACE inhibitor therapy and angiotensin 1 receptor (AT1) antagonists on mechanical, biochemical, and molecular indices as well as geometric changes in isolated myocytes and interstitial collagen. These results will be related to heart tissue levels and the source(s) of the ACE, Chymase, and angiotensinogen steady state mRNA levels (i.e., myocyte vs endothelial cell vs fibroblast) using the technique of in situ hybridization.
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|Gladden, James D; Zelickson, Blake R; Guichard, Jason L et al. (2013) Xanthine oxidase inhibition preserves left ventricular systolic but not diastolic function in cardiac volume overload. Am J Physiol Heart Circ Physiol 305:H1440-50|
|Chen, Yuan-Wen; Pat, Betty; Gladden, James D et al. (2011) Dynamic molecular and histopathological changes in the extracellular matrix and inflammation in the transition to heart failure in isolated volume overload. Am J Physiol Heart Circ Physiol 300:H2251-60|
|Ulasova, Elena; Gladden, James D; Chen, Yuanwen et al. (2011) Loss of interstitial collagen causes structural and functional alterations of cardiomyocyte subsarcolemmal mitochondria in acute volume overload. J Mol Cell Cardiol 50:147-56|
|Gladden, James D; Zelickson, Blake R; Wei, Chih-Chang et al. (2011) Novel insights into interactions between mitochondria and xanthine oxidase in acute cardiac volume overload. Free Radic Biol Med 51:1975-84|
|Chen, Yuanwen; Pat, Betty; Zheng, Junying et al. (2010) Tumor necrosis factor-alpha produced in cardiomyocytes mediates a predominant myocardial inflammatory response to stretch in early volume overload. J Mol Cell Cardiol 49:70-8|
|Wei, Chih-Chang; Hase, Naoki; Inoue, Yukiko et al. (2010) Mast cell chymase limits the cardiac efficacy of Ang I-converting enzyme inhibitor therapy in rodents. J Clin Invest 120:1229-39|
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|Biederman, Robert W W; Doyle, Mark; Young, Alistair A et al. (2008) Marked regional left ventricular heterogeneity in hypertensive left ventricular hypertrophy patients: a losartan intervention for endpoint reduction in hypertension (LIFE) cardiovascular magnetic resonance and echocardiographic substudy. Hypertension 52:279-86|
|Pat, Betty; Killingsworth, Cheryl; Denney, Thomas et al. (2008) Dissociation between cardiomyocyte function and remodeling with beta-adrenergic receptor blockade in isolated canine mitral regurgitation. Am J Physiol Heart Circ Physiol 295:H2321-7|
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