Pressure Overload by Transverse Aortic Constriction Induces Maladaptive Hypertrophy in a Titin-Truncated Mouse Model

Abstract

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 heterozygous Ttn knock-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) Ttn knock-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.

Figures

Figure 1

Schematic of the study design.

Figure 2

Echocardiographic and LV pressure assessments of WT and Het mice at baseline, week 1, and week 2 following TAC. (a) There is no evidence of LV dilatation in either genotype in either the presence or absence of TAC. (b) The onset of ventricular hypertrophy appears to be more rapid in the Het group demonstrating significant increases by week 1 unlike WT mice which only manifest significant thickening by week 2. (c) The reduction in EF% induced by TAC in the Het group is significant by week 2, unlike the WT TAC mice which tended to demonstrate a fall in this measure of contractile function but did not reach significance at either time point after TAC surgery. (d) Differences in EDP between groups do not reach significance although the trend is towards increase in both TAC groups. Interestingly the EDV trend although also not significant for the Het TAC group moves to the right of the Sham Het group, a change reflective of ventricular dilatation, whereas the EDV of the WT TAC mice changes little and even moves to the left more aligned to a physiological adaptation (Ŧp < 0.05). Sample sizes are also shown.

Figure 3

Myocardial histology of 4 representative heart sections from wild-type and Het animals 2 weeks after TAC, stained with Masson's trichrome. One representative Sham heart per genotype is also shown. Note the increased level of fibrosis in Het hearts (∗p < 0.01) compared to their WT littermates. Bar = 1 mm.