Delayed regression of cardiac fibrosis does not impede early functional normalization after relief of pressure overload in a novel mouse model of aortic debanding

Manar Elkenani (Göttingen)1, S. Gersch (Göttingen)1, K. Vasic (Göttingen)1, K. Annamalai (Göttingen)1, W. E. Louch (Oslo)2, G. Hasenfuß (Göttingen)1, K. Toischer (Göttingen)1, B. A. Mohamed (Göttingen)1

1Universitätsmedizin Göttingen Herzzentrum, Klinik für Kardiologie und Pneumologie Göttingen, Deutschland; 2Institute for Experimental Medical Research Oslo University Hospital Oslo, Norwegen


Introduction Aortic stenosis (AS) is a common cause of pressure overload (PO) that elicits adverse cardiac remodeling, characterized by pathological cardiac hypertrophy, fibrosis and dysfunction. PO relief via aortic valve replacement allows the myocardium to undergo reverse remodeling. Although clinical data showed that cardiomyocyte hypertrophy remains mostly reversible, reversal of cardiac fibrosis is still controversial. However, clinical studies share common limitations.

Aim To address to what extent is cardiac fibrosis reversible, and how fibrosis reversibility, if any, is linked to normalization of cardiac function and regression of cardiac hypertrophy following PO relief.

Methods We established a novel mouse model of left ventricular (LV) PO relief via induction of transaortic constriction (TAC) in C57BL/6  wild type (WT) mice using absorbable sutures, which spontaneously loose its original tensile strength by ≈ 2 weeks post-op (novel TAC). As a control, we subjected another group of WT mice to conventional TAC using non-absorbable sutures (conventional TAC).

Results Initially, both TAC groups showed comparable maladaptive cardiac remodeling, characterized by concentric cardiac hypertrophy followed by dilation, LV dysfunction with lung congestion, fibrosis and apoptotic cell death, resulting in increased mortality. However, spontaneous suture disintegration in novel TAC mice resulted in gradual drop of transaortic pressure gradient reaching the sham level at ≈ 3 weeks post-OP. Echocardiography showed an early recovery of LV systolic and diastolic functions followed by normalization of LV geometry after suture disintegration, which was associated with improved mortality. Cardiac hypertrophy and lung congestion were completely regressed upon PO relief. Consistently, cardiomyocyte hypertrophy was efficiently normalized upon suture hydrolysis, associated with markedly reduced apoptotic cell death. On the molecular levels, fetal cardiac genes, Nppa and Nppb, fibrosis-related markers, Col I and Col III, and collagen cross-linking transcripts, Lox and Loxl2, were normalized upon suture hydrolysis in novel TAC group. However, regression of cardiac fibrosis did not take place until very late after suture disintegration (24 weeks post-OP).

Conclusion Our novel TAC model successfully portrayed development and reversal of pathological cardiac remodeling following PO induction and relief, respectively. While the potential for further cardiac fibrosis was markedly attenuated upon PO relief, existing cardiac fibrosis took longer time to regress although cardiac structure and function were efficiently normalized.

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