The ageing spontaneously hypertensive rat as a model of the transition from stable compensated hypertrophy to heart failure

Abstract

Spontaneously hypertensive rats (SHR) of advanced age exhibit depressed myocardial contractile function and ventricular fibrosis, as stable compensated hypertrophy progresses to heart failure. Transition to heart failure in SHR aged 18-24 months was characterized by impaired left ventricular (LV) function, ventricular dilatation, and reduced ejection fraction without an increase in LV mass. Studies of papillary muscles from SHR with failing hearts (SHR-F), SHR without failure (SHR-NF), and age-matched Wistar Kyoto (WKY) rats allowed examination of changes in the mechanical properties of myocardium during the transition to heart failure. Papillary muscles of SHR-F exhibited increased fibrosis, impaired contraction, and decreased myocyte fractional area. These findings in papillary muscles were correlated with a higher concentration of hydroxyproline and increased histological evidence of fibrosis in the LV free wall. While a depression in active tension accompanied these structural alterations in papillary muscles, it was not evident when active tension was normalized to myocyte fractional area. Together, these data suggest that individual myocyte function may be preserved but that myocyte loss and replacement by extracellular matrix contribute substantially to the decrement in active tension. An absent or negative inotropic response to isoproterenol is observed in SHR-F and SHR-NF papillary muscles and may result in part from age-related alterations in beta-adrenergic receptor dynamics and a shift from alpha- to beta-myosin heavy chain (MHC) protein. During the transition to failure, ventricles of SHR exhibit a marked increase in collagen and fibronectin mRNA levels, suggesting that an increase in the expression of specific extracellular matrix genes may contribute to fibrosis, tissue stiffness, and impaired function. Transforming growth factor-beta 1 (TGF-beta 1) mRNA levels also increase in SHR-F, consistent with the concept that TGF-beta 1 plays a key regulatory role in remodelling of the extracellular matrix gene during the transition to failure. The renin-angiotensin-aldosterone system is also implicated in the transition to failure: SHR treated with the angiotensin converting enzyme inhibitor captopril starting at 12 months of age did not develop heart failure during the 18-24 month observation period. Captopril treatment that was initiated after rats were identified with evidence of failure led to a reappearance of alpha-MHC mRNA but did not improve papillary muscle function. Research opportunities include investigation of apoptosis as a mechanism of cell loss, delineation of the regulatory roles of TGF-beta 1 and the renin-angiotensin-aldosterone system in matrix accumulation, and studies of proteinase cascades that regulate matrix remodelling.

Exercise training enhanced SIRT1 longevity signaling replaces the IGF1 survival pathway to attenuate aging-induced rat heart apoptosis

“…Spontaneously hypertensive rats (SHR) of advanced age exhibit depressed myocardial contractile function and ventricular fibrosis, and as a result, stable compensatory hypertrophy progresses to heart failure. In spontaneously hypertensive rats of advanced age, the contraction ability of heart decreases (Boluyt et al 1995). The left ventricular weight increased, and the mean cardiomyocyte number increased slightly with age to cause hypertrophy.…”

Noninvasive Evaluation of the Time Course of Change in Cardiac Function in Spontaneously Hypertensive Rats by Echocardiography

“…One of these similarities, the occurrence of long-term, stable LV hypertrophy followed by a transition to heart failure, makes SHR a useful tool for studying the mechanisms of LV hypertrophy (7). While a number of studies on LV hypertrophy in SHR have already been performed, there have been only a limited number of studies on the time course of changes in LV hypertrophy and cardiac function in SHR.…”

Influência do tempo de exposição à obesidade sobre a função cardíaca de ratos

“…(28,32,35,37,38) O enchimento diastólico depende do relaxamento ativo e das propriedades passivas do músculo cardíaco; enquanto o primeiro está relacionado com o trânsito de Ca +2 , (75,172,195) o segundo depende das propriedades viscoelásticas do miocárdio. (37,76,94,203) As causas da disfunção diastólica na obesidade não estão esclarecidas, (37,204,205) A função cardíaca também foi avaliada in vitro pelo estudo do músculo papilar isolado do VE. Este tipo de preparação permite avaliar, conforme descrito anteriormente, a capacidade do músculo cardíaco de desenvolver força e encurtar independentemente de mudanças na carga, na freqüência e geometria cardíaca, as quais podem modificar a performance in vivo.…”

“…(209) A disfunção miocárdica induzida pela obesidade após 15 semanas pode ter sido decorrente de diversos fatores, como alterações no uso do substrato energético, na composição das proteínas contráteis, no trânsito de Ca +2 intracelular, na matriz extracelular, na modulação autonômica e diminuição no número de miócitos. (118,203,206) Na obesidade, os mecanismos responsáveis pela disfunção miocárdica não estão bem esclarecidos; alterações no trânsito de Ca +2 e no sistema β-adrenérgico têm sido sugeridas por vários autores. (50,52,210,211) A partir dos experimentos realizados, pode-se sugerir que a disfunção miocárdica induzida pela obesidade após 15 semanas foi decorrente de alterações relacionadas com o trânsito de Ca +2 intracelular.…”