Major alterations in relaxation during cardiac hypertrophy induced by aortic stenosis in guinea pig.

Abstract

Left ventricular hypertrophy (LVH) was produced in guinea pigs after aortic stenosis (AS). The percentage of LVH in AS was determined by normalizing left ventricular (LY) weight by the mean LV weight of sham-operated controls (n = 12). After 3 weeks of cardiac overload, a mild LVH (30 ± 3%) was induced in 17 animals and a relatively severe LVH (56 ±3%) was induced in 7 animals. LV papillary muscles were rapidly excised for mechanical studies. No significant differences were observed between control and mild hypertrophy groups. In contrast, a marked decrease in myocardial performance was seen in the more severe cardiac hypertrophy group and was expressed as a percentage of sham-operated levels (Vmax, 22%; active isometric force/mm 2 ,23%; + dF/dt max/mm 2 ,26%). Relaxation in this group was still more impaired than contraction (peak lengthening velocity, 14%; -dF/dt max/mm 2 , 19%). Moreover, the load sensitivity of relaxation was present in both shamoperated controls and mild hypertrophy but almost disappeared in more severe hypertrophy. Isometric relaxation was delayed in the latter group, as shown by the 15% increase of the half-time of the decline of isometric relaxation (t w ). On the other hand, acute hypoxia (95% N 2 -5% CO 2 for 20 minutes) also induced a fall in contractility and the disappearance of the load sensitivity of relaxation but with a 67% decrease of ti.. Thus, the mechanical analysis of relaxation allows the effects of chronic overload in relatively severe cardiac hypertrophy to be separated from those of acute hypoxia. Moreover, in severe cardiac hypertrophy, the impairment of the load sensitivity of relaxation with increased ti/, strongly suggests alterations of the sarcoplasmic reticulum. especially since the moderate decrease in the myofibrillar ATPase activity, which has been observed previously in guinea pig pressure overload, cannot account completely for the marked fall in myocardial performance. (Circulation Research 1987;61:I07-116) C hronic cardiac overload appears to modify the myocyte homeostasis in a complex manner, as shown by numerous biochemical, metabolic, or mechanical alterations described in the literature, These changes observed during cardiac hypertrophy are, in part, species specific. Thus, the rat myocardium adapts to chronic overload by changing the fast V, isomyosin to the slow V,, 1 and this isomyosin shift is related linearly to alterations in contractility 21 Also, it has been shown that relaxation in the hypertrophied rat myocardium remains sensitive to the loading conditions, a mechanical property that generally seems to be present when the sarcoplasmic reticulum is normally functional and that, in the rat, is never impaired, whatever the degree or type of cardiac overload.

Severe aortic stenosis with preserved ejection fraction and evidence of impairment in structure, myocardial strain and ventricular function: A new contribution to clinical decision making

“…All groups had impaired myocardial relaxation, as assessed by tau 50 ; these changes seen in AS have been previously described in animal models [29], as well as in clinical studies [30], and are related (among other processes) to intracellular movement of calcium, thus it could be part of the mechanisms resulting in progressive failure of the hypertrophic myocardium [31].…”

ATPase activity of the cross-linked complex between cardiac myosin subfragment 1 and actin in several models of chronic overloading. A new approach to the biochemistry of contractility.

“…The V,/V 3 V,,,,,, ratio was around 3 in studies with papillary muscles, 15 but it is considerably lower (1.6) for glycerinated or skinned fibers, 42 -43 for the Ca 2+ -ATPase of myosin SI (1.9 in Table 2), for the maximal non-cross-linked actinactivated myosin SI ATPase activity (1.7; see "Results"), and for the cross-linked myosin SI ATPase activity (1.6 in Table 2). The same is true for guinea pig.…”

“…The same correlation was also reported in our laboratory for the hearts from different species. 2 In Figure 5, in contrast with previous papers, 12 the values of V^, came from the same investigator, Lecarpentier et al, 15 using the same animal strains and the same models as those used in the present study. This probably explains why the correlation coefficients between V,™, and both the myosin SI and the cross-linked actomyosin SI ATPase were so high (r=0.99 in both cases, p<0.001).…”

“…The ventricular wt/body wt (mg/g) ratios were 2.9±0.1 and 4.2±0.1, respectively, as previously shown. 15 Also, a significant drop in both myosin SI ATPase activity and in cross-linked myosin SI ATPase was observed while the amplitude of the early phosphate burst remained unchanged (0.60 mol ATP per myosin active site for the control and 0.65 for the hypertrophied heart). In both normal and hypertrophied hearts, the time course of the activating process and the electrophoretic mobility of the products were the same as those described for skeletal muscle and rat heart (Figure 3).…”

Mechanical and energetic changes in short-term volume and pressure overload of rabbit heart

“…Three types of myosin ATPases are found in mammalian ventricular muscle: Vb V2, and V3, listed in order of decreasing ATPase activity, according to the nomenclature of Hoti et al [14]. It is clear from the literature, however, that changes in myosin ATPase activity cannot account for the prolongation of the contraction seen in hypertrophied heart muscle preparations obtained from many species (e.g., guinea pig [15]). …”