Epidemiologic studies in humans show hypertension to be the most frequent concomitant of congestive heart failure; however, the transition from compensated hypertrophy to heart failure still remains largely a mystery. Currently there is no genetic animal model which has hypertension and heart failure. This research proposal deals with the development of an unique strain of rats the SHR/N-cp, a substrain of the Okamoto spontaneous hypertensive rat, that are hypertensive and develop cardiomyopathy-congestive heart failure (CM-CHF) - 75% males at 11 months or older, 30% females at 24 months or older. This grant is in response to the RFA on Development of Genetic Hypertensive Animal Models. Although SHR rats have been extensively used for research in hypertension area, the high incidence of heart failure has not been observed in other SHR colonies. This proposal does not deal with the de novo development of a new model but to the refinement of a new existing model so that its research value can be enhanced.
The specific aims of this research proposal are: (1) to establish the genetics of the CM-CHF in this new animal model; (2) to study developmentally structural and ultrastructural changes in the heart and various organs of these rats and (3) to identify physical or biochemical markers that would predict which animals will develop the syndrome at the earliest possible age. In order to achieve these aims specific matings will be done to determine if the CM-CHF is a new dominant gene with reduced penetrance or if the expression of the CM-CHF is the result of the obesity gene on a hypertension background. In offspring from the various matings, a number of parameters will be followed over the course of their lives - body weight, blood pressure and blood and urine samples will be taken from each animal to determine if there are consistent alterations in any of these parameters in animals that develop CM-CHF. Clinical and pathological examinations will be done. The results will be examined for possible parallels with the natural history of human CM-CHF to determine how closely this animal model mimics human heart failure. The long term goal of this research is to maintain and establish the reliability of this new animal model as an analogue of human CM-CHF which then could be used for research leading to a better understanding of the roles played by genetics, sex, age, hypertension and obesity in spontaneous cardiovascular diseases in general and in CM-CHF in particular.
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