The onset of left ventricular diastolic dysfunction in SHR rats is not related to hypertrophy or hypertension

Abstract

Dupont S, Maizel J, Mentaverri R, Chillon JM, Six I, Giummelly P, Brazier M, Choukroun G, Tribouilloy C, Massy ZA, Slama M. The onset of left ventricular diastolic dysfunction in SHR rats is not related to hypertrophy or hypertension. Am J Physiol Heart Circ Physiol 302: H1524 -H1532, 2012. First published January 27, 2012; doi:10.1152/ajpheart.00955.2010.-Left ventricular (LV) diastolic dysfunction, particularly relaxation abnormalities, are known to be associated with the development of LV hypertrophy (LVH). Preliminary human and animal studies suggested that early LV diastolic dysfunction may be revealed independently of LVH. However, whether LV diastolic dysfunction is compromised before the onset of hypertension and LVH remains unknown. We therefore evaluated LV diastolic function in spontaneously hypertensive rats (SHR) at different ages and tested whether LV diastolic dysfunction is associated with abnormal intracellular calcium homeostasis. LV systolic and diastolic functions were evaluated by invasive and echocardiographic methods in 3-week-old (without hypertension) and 5-week-old (with hypertension) SHR and Wistar-Kyoto control rats. Basal intracytoplasmic calcium and sarcoplasmic reticulum (SR) Ca 2ϩ contents were measured in cardiomyocytes using fura-2 AM. Sarco(endo)plasmic Ca 2ϩ -ATPase isoform 2a (SERCA 2a) and phospholamban (PLB) expressions were quantified by Western blot and quantitative RT-PCR techniques. LV relaxation dysfunction was observed in 3-week-old SHR rats before onset of hypertension and LVH. An increase in basal intracytoplasmic Ca 2ϩ and a decrease in SR Ca 2ϩ release were demonstrated in SHR. Decreased expression of SERCA 2a and Ser16 PLB (p16-PLB) protein levels was also observed in SHR rats, whereas mRNA expression was not decreased. For the first time, we have shown that LV myocardial dysfunction precedes hypertension in 3-week-old SHR rats. This LV myocardial dysfunction was associated with high diastolic [Ca 2ϩ ]i possibly due to decreased SERCA 2a and p16-PLB protein levels. Diastolic dysfunction may be a potential predictive marker of arterial hypertension in genetic hypertension syndromes.diastole; ultrasonic; calcium; spontaneously hypertensive rats LEFT VENTRICULAR (LV) DIASTOLIC dysfunction is responsible for more than one half of all hospitalizations for congestive heart failure or acute pulmonary oedema, which has been shown to be the consequence of multiple clinical factors, mostly hypertension (15). LV diastolic dysfunction, particularly relaxation abnormalities, is usually recognized to be closely associated with the development of left ventricular hypertrophy (LVH) in hypertensive humans and spontaneously hypertensive rats (SHR), a model of human genetic hypertension (35). Nevertheless, in a previous study, we demonstrated LV relaxation impairment in young SHR without LVH (37), subsequently confirmed by Aeschbacher et al (1). Di Bello et al. (13) have also demonstrated early LV diastolic dysfunction before the onset of hypertension and LVH. In view of these da...

Old spontaneously hypertensive rats gather together typical features of human chronic left-ventricular dysfunction with preserved ejection fraction

“…To explore if the alteration of the early diastole could be in relation with a diastolic reticulum calcium capture abnormality, we explored the SERCA 2a mRNA expression. We did not observe any change at the mRNA level compared with WKYs animals but, a recent study reported a decrease in SERCA 2a protein with unchanged SERCA 2a mRNA expression [18], leading to changes in intracellular calcium homeostasis, main cause of LV diastolic dysfunction. In the same work, at cellular level, SERCA 2a mRNA expression was not significantly modified in SHRs.…”

“…The modification of these parameters, that mainly evaluate the early diastole, argues in favor of a reduction of the cardiomyocytes relaxation properties. Such dysfunction could appear as early as 3 weeks old in SHRs [18]. In a recent study investigating the time course of cardiac abnormalities in aortic-banded rats, Perlini et al [19] identified that alterations of the early diastole predict the progression of compensated pressure overload hypertrophy to heart failure.…”

Ranolazine improves diastolic function in spontaneously hypertensive rats

“…Another study showed that LV relaxation dysfunction and elevated [Ca 2ϩ ] i were observed before development of hypertension and hypertrophy in SHRs (14). These data suggest that rather than being a consequence of hypertrophy, enhanced I Na,L may contribute to Ca 2ϩ overload, causing the hypertrophic response observed in the SHR.…”

Transient Neonatal High Oxygen Exposure Leads to Early Adult Cardiac Dysfunction, Remodeling, and Activation of the Renin–Angiotensin System

“…These results are similar to changes observed in other experimental models of hypertension such as the genetic spontaneously hypertensive rat, in which LV dysfunction is also verified prior the BP increase. 16, 17 Dupont et al 16 recently showed that 3-week-old spontaneously hypertensive rat developed LV systolic dysfunction with decreased FS and impaired LV diastolic function, suggesting early diastolic dysfunction. In addition, in spontaneously hypertensive rat, interstitial fibrosis and LV hypertrophy accompany BP elevation at an adult age.…”