Abstract Body: Introduction/Background: A major challenge in heart failure (HF) research is that it is a complex, multi-organ disease that is difficult to capture with in vitro studies. Preclinical HF models like coronary artery ligation and transverse aortic constriction are invasive and require microsurgical expertise. Mechanistic studies using genetic models of HF require time consuming and resource intensive crosses.

Research Goal: Develop a means of generating systolic HF with a single injection

Methods: Among autosomal dominant mutations that cause dilated cardiomyopathy, we sought a mutation that has both been well characterized, and that is small enough for packaging in AAVs.
We characterized functional parameters of HF in transgenic Tropomyosin1^E54K (Tg Tpm1^E54K) mice compared to wildtype (WT) littermates. We designed AAVs with FLAG tagged Tropomyosin1 E54K (AAV-Tpm^E54K) or mCherry under a cardiac promoter. Comparisons were made using linear regression, unpaired T-test and ANOVA.

Results:
Using activity cages, after 1 week of cage acclimation, we find that Tg Tpm1^E54K mice ambulate 18% less than WT littermates (p < .0001, N=9 Tpm mice and N=10 WT). Tg Tpm1^E54K mice move about more slowly and spend 23-fold less time than WT littermates in periods of high activity.

Wildtype FVB/N mice were injected with 1x10¹² genomic copies of AAV-Tpm^E54K or AAV-mCherry on post-natal day 3. By 2 months, AAV-Tpm^E54K injected mice had significant reductions in ejection fraction (EF, 31% versus 62%, adjusted p < .0001 ), and global longitudinal strain (GLS, -9% versus 19%, adjusted p = .0005), compared to AAV-mCherry injected controls. These changes were comparable to the reductions in systolic function seen between Tg Tpm1^E54K mice and WT mice: EF 33% versus 67% (adjusted p < .0001) and GLS -11% versus -23% (adjusted p < .0001). Notably, there was no difference in these parameters of systolic function between Tg Tpm1^E54K and AAV-Tpm^E54K mice. The ventricles of mice expressing mutant Tpm^E54K were markedly dilated compared to controls. Parameters of diastolic function, including E/e’, E/A, and isovolumetric relaxation were significantly altered in mice with ectopic expression of Tpm^E54K compared to WT mice and AAV-mCherry mice.

Conclusions:
With strides in preventive cardiology, non-ischemic cardiomyopathies make up an increasing proportion of heart failure (HF) admissions. Here we demonstrate the ease and feasibility of generating experimental HF with a single injection.