Hypertension, a disease that affects more than 50 million Americans, is the most common cause of left ventricular hypertrophy (LVH). Over 20 percent of patients with hypertension have LVH, and its presence is associated with a 50 percent increase in cardiovascular morbidity, and a risk of mortality from cardiovascular disease that is four to six times greater than the risk from hypertension alone. Because of this, regression of LVH with antihypertensive medication has become a goal of treatment. The precise mechanisms by which cardiac hypertrophy in arterial hypertension increases cardiac morbidity and mortality remain unknown. Although it is known that structural abnormalities of the myocardium and the microcirculation in LVH result in decreased coronary flow reserve, the relation between these and abnormalities in contractile, and metabolic function are unknown. It is also unkown whether regression of LVH induced by pharmacologic intervention decreases the risk of subsequent cardiovascular disease. Hence, understanding the mechanisms responsible for the transition from hypertrophy to heart failure, and elucidating whether reversal of LVH with antihypertensive medication results in salutary effects to the coronary circulation and cardiac function and whether it is associated with reduced morbidity and mortality from cardiovascular disease is of great importance. The working hypotheses of this proposal are: a) that hypertensive LVH is associated with decreased coronary artery reserve, and that this is associated with abnormalities in metabolic and contractile function; and b) that pharmacologic therapy with ACE inhibitors result in normalization of the left ventricular mass and improvements in myocardial blood flow reserve, myocardial metabolism, and systolic function. We propose to prove these hypotheses by use of novel approaches and methods, most of which have been developed and validated at our institution. These methods include imaging techniques that allow measurements of left ventricular mass with echocardiography, myocardial blood flow by positron emission tomography (PET) with 15 O- water, global contractile function with magnetic resonance imaging (MRI) with and without tissue-tagging by stress-strain relations, and myocardial metabolism measured by PET with 11 C-acetate and 11 C- palmitate. Measurements at baseline and after one year of treatment with ACE inhibitors will be performed in patients with LVH induced by hypertension and with either normal or decreased left ventricular function. Results of these studies are designed to determine the benefits of normalization of arterial blood pressure and left ventricular mass with antihypertensive medication. We have previously used and validated these methods and preliminary studies from our institution suggests that the cardiac imaging approach outlined in this proposal is rational and feasible.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058878-02
Application #
2901339
Study Section
Diagnostic Radiology Study Section (RNM)
Project Start
1998-04-01
Project End
2002-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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de las Fuentes, Lisa; Gu, C Charles; Mathews, Santhosh J et al. (2008) Osteopontin promoter polymorphism is associated with increased carotid intima-media thickness. J Am Soc Echocardiogr 21:954-60
Gu, C Charles; Flores, Hubert R; de las Fuentes, Lisa et al. (2008) Enhanced detection of genetic association of hypertensive heart disease by analysis of latent phenotypes. Genet Epidemiol 32:528-38
de las Fuentes, Lisa; Brown, Angela L; Mathews, Santhosh J et al. (2007) Metabolic syndrome is associated with abnormal left ventricular diastolic function independent of left ventricular mass. Eur Heart J 28:553-9
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de las Fuentes, Lisa; Soto, Pablo F; Cupps, Brian P et al. (2006) Hypertensive left ventricular hypertrophy is associated with abnormal myocardial fatty acid metabolism and myocardial efficiency. J Nucl Cardiol 13:369-77
Waggoner, Alan D; Rovner, Aleksandr; de las Fuentes, Lisa et al. (2006) Clinical outcomes after cardiac resynchronization therapy: importance of left ventricular diastolic function and origin of heart failure. J Am Soc Echocardiogr 19:307-13
Rovner, Aleksandr; de las Fuentes, Lisa; Waggoner, Alan D et al. (2006) Characterization of left ventricular diastolic function in hypertension by use of Doppler tissue imaging and color M-mode techniques. J Am Soc Echocardiogr 19:872-9
Peterson, Linda R; Waggoner, Alan D; de las Fuentes, Lisa et al. (2006) Alterations in left ventricular structure and function in type-1 diabetics: a focus on left atrial contribution to function. J Am Soc Echocardiogr 19:749-55
Narayan, Sanjiv M; Smith, Joseph M; Lindsay, Bruce D et al. (2006) Relation of T-wave alternans to regional left ventricular dysfunction and eccentric hypertrophy secondary to coronary heart disease. Am J Cardiol 97:775-80

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