RESUMEN
We examined the effects of thyroid hormones (THs) on left ventricular (LV) function and myocyte remodeling in rats with spontaneously hypertensive heart failure (SHHF). SHHF rats were treated with three different TH doses from 20-21 mo of age. In terminal experiments, LV function (as determined by echocardiography and catheterization) and isolated myocyte shape were examined in SHHF rat groups and age-matched Wistar-Furth control animals. Compared with Wistar-Furth rats, the ratio of alpha- to beta-myosin was reduced in untreated SHHF rats. The alpha-to-beta-myosin ratio increased in all TH groups, which suggests a reversal of the fetal gene program. Low-dose TH produced no changes in LV myocyte size or function, but high-dose TH produced signs of hyperthyroidism (e.g., increased heart weight, tachycardia). The chamber diameter-to-wall thickness ratio declined with increasing dose due to reduced chamber diameter and increased wall thickness. This resulted in a 38% reduction in LV systolic wall stress in the middle- and high-dose groups despite sustained hypertension. Isolated myocyte data indicated that chamber remodeling and reduced wall stress were due to a unique alteration in myocyte transverse shape (e.g., reduced major diameter and increased minor diameter). Based on our present understanding of ventricular remodeling and wall stress, we believe these changes are likely beneficial. Results suggest that TH may be an important regulator of myocyte transverse shape in heart disease.
Asunto(s)
Insuficiencia Cardíaca/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Hormonas Tiroideas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Femenino , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/patología , Hipertensión/fisiopatología , Contracción Miocárdica/efectos de los fármacos , Miocitos Cardíacos/fisiología , Ratas , Ratas Endogámicas WF , Ratas Mutantes , Remodelación Ventricular/efectos de los fármacosRESUMEN
BACKGROUND: A recent study showed reverse remodeling of left ventricular myocyte shape when the type 1 angiotensin II (AT1)-receptor antagonist L-158,809 was administered to spontaneously hypertensive heart failure (SHHF) rats 4 months before the onset of failure. The aim of this study was to characterize temporally early treatment-induced reverse remodeling at the organ and cellular level by echocardiography and morphometry of isolated left ventricular myocytes. METHODS AND RESULTS: L-158,809 was administered to 9-month-old SHHF rats. Blood pressure normalized shortly after initiation of treatment. Isolated myocytes were collected in terminal experiments to assess cell remodeling. L-158,809 reduced myocyte volume and cross-sectional area significantly after 1 week of treatment with maximal regression of hypertrophy, including reduced cell length, obtained by 4 weeks. Reduced wall thickness was clearly detectable by echocardiography within 4 weeks after initiation of treatment. CONCLUSIONS: Regression of left ventricular myocyte hypertrophy occurred rapidly after initiation of AT1-blocker therapy in SHHF rats and was completed within 1 month. Regression of myocyte hypertrophy was associated with reduced wall thickness, which was detected consistently by echocardiography within 1 month after initiation of treatment.