Impaired myocardial relaxation (diastolic dysfunction) is an important component of the pathophysiology of heart disease. This Program Project will study the modulation and regulation of myocardial diastolic function in selected pathologic states. """"""""Modulation"""""""" (the alteration of diastolic myocardial properties as assessed in the intact ventricle) will be studied during hypoxia, ischemia, reoxygenation, and reperfusion in intact normal and hypertrophied hearts. """"""""Regulation"""""""" (the subcellular events which determine the rate and extent of myocardial relaxation) will be studied in intact hearts by nuclear magnetic resonance (NMR) spectroscopy and in isolated myocytes and myocardial samples by means of patch clamping (to measure sarcolemmal electrical events), and aequorin light emission (to assess intracellular calcium transients and levels). Six projects, a Metabolism Core, and a Morphology Core will provide a spectrum of experimental approaches. Project I will use multivessel coronary stenoses in the pig to study regional diastolic dysfunction during demand ischemia. Project II will use isolated blood perfused rabbit hearts to study diastolic dysfunction during simulated clinical syndromes of """"""""demand"""""""" and """"""""supply"""""""" ischemia. Project III will study diastolic dysfunction during demand ischemia in hypertrophied isolated blood perfused rabbit hearts to simulate clinical states where coronary stenoses and hypertrophy are both present. Project IV will use isolated perfused rat hearts with three types of hypertrophy: pathologic pressure or volume overload hypertrophy, and physiologic hypertrophy due to exercise conditioning. In Projects IIIV NMR spectroscopy will measure critical intracellular metabolites and cations during hypoxia and ischemia, to identify basic mechanisms of abnormal relaxation, differences relating to the type of hypertrophy, and to provide simultaneous metabolic and mechanical data when interventions are used to modulate diastolic dysfunction. Project V will study diastolic relaxation in isolated cardiac myocytes from animals and man. Project VI will study relaxation in isolated working myocardium from patients with severe hypertrophy and/or heart failure. The research program will provide new information important to the basic understanding of myocardial relaxation and for the clinical care of patients with diastolic dysfunction.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Research Review Committee A (HLBA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Schools of Medicine
United States
Zip Code
Yan, Xinhua; Schuldt, Adam J T; Price, Robert L et al. (2008) Pressure overload-induced hypertrophy in transgenic mice selectively overexpressing AT2 receptors in ventricular myocytes. Am J Physiol Heart Circ Physiol 294:H1274-81
Nakayama, Masaharu; Yan, Xinhua; Price, Robert L et al. (2005) Chronic ventricular myocyte-specific overexpression of angiotensin II type 2 receptor results in intrinsic myocyte contractile dysfunction. Am J Physiol Heart Circ Physiol 288:H317-27
Ito, Kenta; Nakayama, Masaharu; Hasan, Faisal et al. (2003) Contractile reserve and calcium regulation are depressed in myocytes from chronically unloaded hearts. Circulation 107:1176-82
Yan, Xinhua; Price, Robert L; Nakayama, Masaharu et al. (2003) Ventricular-specific expression of angiotensin II type 2 receptors causes dilated cardiomyopathy and heart failure in transgenic mice. Am J Physiol Heart Circ Physiol 285:H2179-87
Goldsmith, Edie C; Carver, Wayne; McFadden, Alex et al. (2003) Integrin shedding as a mechanism of cellular adaptation during cardiac growth. Am J Physiol Heart Circ Physiol 284:H2227-34
Ito, K; Yan, X; Feng, X et al. (2001) Transgenic expression of sarcoplasmic reticulum Ca(2+) atpase modifies the transition from hypertrophy to early heart failure. Circ Res 89:422-9
Ding, B; Price, R L; Goldsmith, E C et al. (2000) Left ventricular hypertrophy in ascending aortic stenosis mice: anoikis and the progression to early failure. Circulation 101:2854-62
Ito, K; Yan, X; Tajima, M et al. (2000) Contractile reserve and intracellular calcium regulation in mouse myocytes from normal and hypertrophied failing hearts. Circ Res 87:588-95
Bartunek, J; Weinberg, E O; Tajima, M et al. (2000) Chronic N(G)-nitro-L-arginine methyl ester-induced hypertension : novel molecular adaptation to systolic load in absence of hypertrophy. Circulation 101:423-9
Bartunek, J; Weinberg, E O; Tajima, M et al. (1999) Angiotensin II type 2 receptor blockade amplifies the early signals of cardiac growth response to angiotensin II in hypertrophied hearts. Circulation 99:22-5

Showing the most recent 10 out of 53 publications