Pathological cardiac remodelling and subsequent heart failure (HF) largely contribute to disease-related mortality in the developed world. Despite significant advances in the medicinal treatment in recent years, especially for patients with end-stage HF current drug therapies are very limited. Aside from full heart transplantation, implantation of left ventricular assist devices (LVADs) can substantially improve patients’ survival. LVADs are surgically implanted mechanical pumps, which help the left ventricle to pump blood to the body and thereby unloading of the failing heart is induced. Unfortunately, only a small proportion of the patients show functional heart recovery during unloading therapy for so far unknown reasons. This implies the urgent need for new adjuvant therapies supporting cardiac recovery of LVAD patients. However, for testing such therapies, we first needed to establish an in vivo model which recapitulates LVAD-induced cardiac unloading in diseased hearts. For proof-of-concept, we combined this model with an adjuvant antisense oligonucleotide (ASO)-based therapy inducing the inhibition of the long noncoding RNA (lncRNA) Meg3.

To establish an in vivo model simulating LVAD-induced reverse remodeling, 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 simulating cardiac unloading (referred to as debanding, DeTAC). Both experiments were echocardiographically and histologically assessed whereby the 12-weeks approach was proven to be an appropriate model for cardiac unloading since in this setup 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. In contrast, in the 8-weeks approach all parameters normalized completely. Based on these results we conclude that in the 12-weeks experiment reverse remodelling is incomplete suggesting this debanding approach as an appropriate tool for the investigation of adjuvants supporting cardiac unloading therapy. Since we previously demonstrated that preventive ASO-mediated inhibition of lncRNA Meg3 decreases cardiac hypertrophy and fibrosis in the TAC mouse model, we here investigated whether MEG3 knockdown can aid in reverse remodeling after cardiac unloading. Indeed, anti-MEG3 therapy, enhanced the cardiac recovery as indicated by a significantly increased stroke volume. From a translational perspective, we could show that inhibition of human Meg3 elicits anti-fibrotic response in human cardiac fibroblasts (HCFs), which was further validated by mRNA-Seq analysis 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.