Peter M. Kang, M.D., Cardiovascular Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, U.S.A.

Background

Physiologic hypertrophy, such as an exercise-induced cardiac hypertrophy, represents a favorable adaptive change in the heart that accommodates to the increases in body demand, and does not lead to heart failure. In contrast, pathologic hypertrophy, such as pressure overload-induced hypertrophy, is a maladaptive response to pathologic stimuli that, if not ameliorated, usually leads to heart failure. One potential explanation for the difference between these two groups of hypertrophic responses is that they activate different hypertrophic pathways (Kinugawa K et al., 2001; Iemitsu M et al., 2001). However, the hypertrophic signaling pathways and genetic and molecular changes that characterize these types of cardiac hypertrophy is not clearly elucidated. In this study, physiologic hypertrophy (via treadmill exercise) and pathologic hypertrophy (via a high salt diet) were induced in the Dahl salt-sensitive (DS) rats. Using cDNA microarray analysis, we investigate the genetic alterations that are associated with these two distinct forms of cardiac hypertrophy, and heart failure that occurs in pathologic cardiac hypertrophy.

Experimental Design

Physiologic Cardiac Hypertrophy
DS rats were obtained from Harlan Sprague Dawley Laboratory at 5 weeks of age. At 6 weeks of age, physiologic cardiac hypertrophy was generated by a vigorous daily exercise regimen for 6 weeks (EX group). The exercise protocol is based on those described previously with modifications (Wisloff U et al., 2001; Jin H et al., 1994). Rats were exercised daily for 6 weeks on a rodent treadmill (Exer-6M; Columbus Instruments). The exercise program consisted of three weeks of progressively strenuous exercise regimens; followed by three weeks of maintenance period, during which the rats were exercised at 16 m/min at a 5o incline for 90 minutes/day. All rats completed the exercise protocol. Control rats were age matched and sedentary DS rats fed normal rat chow. Phenotypic data and echocardiographic parameters were obtained at 3 weeks and 6 weeks of exercise. After the physiological parameters were obtained, the rats were sacrificed and the hearts were used for various analysis. For the hearts used for microarray analysis, the atria and right ventricles were rapidly removed, the apex portion of the heart (~1/3) was cut and snap frozen in liquid nitrogen.

Pathologic Cardiac Hypertrophy and Heart Failure
Pathological cardiac hypertrophy was generated by feeding a 6% NaCl diet to DS rats at 6 weeks of age (HS group) (Inoko M et al., 1994). As measured by tail-cuff blood pressure (BP) monitor, the rats developed significant hypertension after a couple weeks on a high salt diet, eventually reaching over 200 mmHg after 6 weeks on high salt diet (11 weeks of age). The control rats on normal rat chow did not show significant differences in blood pressure from the baseline. When the high salt diet was continued after 11 weeks, the rats developed either stroke or progressive heart failure between 14-18 weeks or 18-21 weeks, respectively. All the HS rats died by 20-23 weeks, and only the rats that showed clinical evidence of heart failure were included in the study with an average age of 19-20 weeks. Control rats were sedentary and age matched DS rats that were fed a normal rat chow. Similar to the physiologic hypertrophy rats, the phenotypic and echocardiographic data were obtained at 3 weeks and 6 weeks of high salt diet. In addition, for heart failure rat analysis, the rats that clearly showed clinical evidence of heart failure were sacrificed and the hearts were used for analysis. The rats that showed evidence of stroke were not used for the analysis. Average age of heart failure rats were 21 weeks (15 weeks of experiments).

C = Control
E = Exercise
H = High Salt

Page last modified: 06-Aug-2003