Anti-Meg3 therapy supports reverse remodeling in a mouse model resembling aortic stenosis and TAVI

Aortic stenosis (AS), characterized by aortic valve narrowing resulting in reduced blood flow from the heart to the body represents one of the most common valve diseases. Thereby, the. It is accompanied by progressive left ventricular remodeling and fibrosis transitioning towards heart failure (HF) which largely contributes to disease-related mortality. Transcatheter aortic valve implantation (TAVI) represents the common treatment strategy whereby fibrosis in patients with severe AS is associated with worse outcome. Unfortunately, there are still no therapeutic options to stop or reverse cardiac fibrosis in those patients, underlining the need for new anti-fibrotic therapeutic strategies. However, for testing such therapies, we first needed to establish an in vivo model recapitulating TAVI in diseased hearts. For proof-of-concept, we then combined this model with an adjuvant therapy inhibiting long noncoding RNA Meg3 which is already described as promising anti-fibrotic therapeutic candidate.

To establish an in vivo model, we performed an 8-weeks and 12-weeks in vivo experiment in which first pressure-overload induced cardiac hypertrophy was induced by transverse aortic constriction (TAC) surgery. After 4-weeks or 6-weeks the previously performed TAC was removed to simulate TAVI procedure (referred to as debanding, DeTAC) in one experimental group, while in the control group the banding was kept. Both experiments were assessed echocardiographically and histologically whereby the 12-weeks approach was proven to be an appropriate model since the heart failed to completely recover LV mass, LV wall thickness and ejection fraction. In line, cardiomyocyte hypertrophy and increased heart weight was still present in the DeTAC group. Based on these results we conclude that in the 12-weeks experiment reverse remodeling is incomplete suggesting this debanding approach as an appropriate tool for the investigation of new adjuvants supporting cardiac recovery.

Since we previously demonstrated that preventive antisense oligonucleotide (ASO)-mediated Meg3 inhibition decreases cardiac hypertrophy and fibrosis in the TAC mouse model, we here investigated whether Meg3 inhibition can aid in reverse remodeling after debanding. We therefore, combined the 12-weeks debanding approach with an anti-Meg3 therapy performed by weekly injections of a Meg3 specific ASO. Promisingly, anti-Meg3 therapy indeed enhanced cardiac recovery as indicated by a significantly increased stroke volume compared to the untreated DeTAC control group. Furthermore, we could show that inhibition of human MEG3 elicits anti-fibrotic response in human living myocardial slices and human cardiac fibroblasts, which we further validated by mRNA sequencing and KEGG pathway analysis.

In summary, our results highlight anti-Meg3 therapy as an effective anti-fibrotic treatment and as a promising adjuvant treatment strategy in the context of cardiac unloading therapy, which will be further investigated in future experiments.