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.

Genetics of hypertrophic cardiomyopathy: A review of current state

“…Since 2012, when Herman et al identified a high frequency of variants in TTN in dilated and HCM populations, a significant percentage of TTN radical variants in affected patients and in control populations have been identified. TTN has become the most prevalent mutation gene in patients with DCM, being numerous the related reports published; in contrast, the reports about defect in TTN as a cause of HCM are practically non‐existent.…”

Dilated Cardiomyopathy

“…A mouse models with an in frame deletion in the PEVK region of TTN develops diastolic dysfunction, consistent with the complex role of titin for both systolic and diastolic dysfunction 82 . In both rats and mice with heterozygous TTN truncation mutations, additional stressors like transaortic constriction are used to promote the development of DCM 71, 83 .…”

Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure

“…Metabolic stress is generated by abnormal mRNA transcripts from the truncation variant leading to increased non-sense mRNA decay (NMD). This leads to long term compensatory changes and development of a common DCM phenotype that is independent of TTN mutation location [ 31 , 32 , 33 ] ( Figure 3 ). Rat models with A-band and I-band TTNtv do not alter the amount of TTN expressed, but there is increased NMD and a shift in cardiac metabolism to preference branched chain amino acids and glycolytic intermediates instead of fatty acids that are typically utilized in healthy cardiomyocytes [ 34 , 35 ].…”