This continuation grant will attempt to identify important factors in the genesis of the ventricular hypertrophies which develop in response to exercise and systolic overload. It will employ the isolated heterotopic heart transplant model in the rat, which is devoid of neural innervation and largely independent of load to explore the role of exercise, hypertension, catecholamines, heart rate, the renin-angiotensin system, sex and other factors on the development of hypertrophy and accompanying histologic, biochemical and molecular biological alterations. The intact heart in the chest will serve as a control for each transplanted heart. Experiments will focus upon the mechanical and biochemical effects of the various interventions, and then will use molecular biological techniques to explore the earliest changes that occur after instituting a perturbation. Special attention will be paid to a newly discovered Troponin-- Tropomyosin alteration that we have observed in certain pathologic conditions. Other biochemical and molecular biological markers will be myosin heavy chain isoenzymes, mRNAs for protooncogenes, sarcoplasmic reticulum calcium ATPase, myosin heavy chain, prorenin, angiotensin I and angiotensin converting enzyme. An understanding of the mechanisms underlying the heart's responses to interventions that result in hypertrophic adaptations to physiologic or pathologic stresses can lead toward preventive and therapeutic approaches to cardiovascular health and disease.
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