Ivabradine improved left ventricular function and pressure overload-induced cardiomyocyte apoptosis in a transverse aortic constriction mouse model

Mutations in the giant sarcomeric protein titin (TTN) are a major cause for inherited forms of dilated cardiomyopathy (DCM). We have previously developed a mouse model that imitates a TTN truncation mutation we found in a large pedigree with DCM. While heterozygousTtnknock-in mice do not display signs of heart failure under sedentary conditions, they recapitulate the human phenotype when exposed to the pharmacological stressor angiotensin II or isoproterenol. In this study we investigated the effects of pressure overload by transverse aortic constriction (TAC) in heterozygous (Het)Ttnknock-in mice. Two weeks after TAC, Het mice developed marked impairment of left ventricular ejection fraction(p<0.05), while wild-type (WT) TAC mice did not. Het mice also trended toward increased ventricular end diastolic pressure and volume compared to WT littermates. We found an increase in histologically diffuse cardiac fibrosis in Het compared to WT in TAC mice. This study shows that a pattern of DCM can be induced by TAC-mediated pressure overload in a TTN-truncated mouse model. This model enlarges our arsenal of cardiac disease models, adding a valuable tool to understand cardiac pathophysiological remodeling processes and to develop therapeutic approaches to combat heart failure.

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Preservation of left ventricular function by insulin in experimental catecholamine cardiomyopathy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1980.238.2.h257 ◽

1980 ◽

Vol 238 (2) ◽

pp. H257-H262

Author(s):

J. C. Werner ◽

J. C. Lee ◽

S. E. Downing

Keyword(s):

Left Ventricular Function ◽

Ventricular Function ◽

Myocardial Injury ◽

Diastolic Pressure ◽

Left Ventricular ◽

Initial Slope ◽

Histological Findings ◽

Aortic Constriction ◽

The Mean ◽

Lv Volume

We have shown previously that insulin reduces myocardial injury associated with norepinephrine (NE) infusion in the rabbit (Am. J. Pathol. 93:399--353, 1978). In the present study, left ventricular function (LVF) was assessed from afterload curves obtained by progressive aortic constriction 2--4 days following NE infusion. The initial slope of the function curves (SFC), maximum dP/dt and left ventricular end-diastolic pressure at 120 mmHg ((LVEDP120) were used for comparison. In 4 controls, SFC averaged 23.8 mmHg/cmH2O. In 10 rabbits given NE, the mean slope was 8.4 (P less than 0.01). However, animals pretreated with insulin before being given NE did not differ from controls (SFC, 19.7 mmHg/cmH2O). These performance data were supported by measurements of LVEDP120, which were 2.8, 12.3 and 3.1 cmH2O, respectively (P less than 0.05 and less than 0.02). In spite of the higher LVEDP, max dP/dt120 was significantly lower in the NE group than in the group given insulin. Histological findings and postmortem measurements of LV volume and mass were consistent with the observed differences in LVF. It is concluded that NE damage reduces LVF and this is largely prevented by pretreatment with insulin.

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