Innate Reverse Remodeling Reveals Novel Treatment Option for Heart Failure

Background: Progressive fibrosis results in myocardial stiffening and dysfunction in patients with heart failure contributing to ventricular remodeling and impaired contractility. Despite high global burden and intensive research, there are no therapies available to remove excessive fibrosis and thus, induce reverse remodeling. The right (RV) and the left ventricle (LV) differ markedly in their embryonic development, anatomy and function. In this project we aimed to (1) elucidate mechanistic differences between RV and LV regeneration and (2) thus, reveal novel therapeutic targets for LV regeneration.

Method: LV and RV heart failure were induced using absorbable sutures in a murine transaortic constriction (TAC) or pulmonary artery banding (PAB) procedure. Sutures were absorbed after 2 weeks, mimicking afterload relieve. Right and left ventricular function and mass were evaluated weekly via transthoracic echocardiography during a 4-week follow-up. Hearts were analyzed for cardiomyocyte size, myocardial thickness, and myocardial fibrosis in histological sections. LV and RV were subjected to next-generation RNA sequencing. To determine the adaption of the RV upon birth, hearts of newborn mice were harvested on day 1, 3, 7, and 14. Micro-CT and histological analysis were performed for evaluation of structural changes in myocardial thickness and myocardial fibrosis upon birth.

Results: Surgical bandings resulted in an increase of the mean gradient over the aorta or the main pulmonary artery respectively. RV and LV free wall thickened for 35.81% or 31.44% due to the increased afterload within 2 weeks. Absorption of bandings resulted in a reduction of the mean gradient to base line levels. Upon afterload relieve myocardial mass of the left ventricle remained increased after 4 weeks (23%); however, the right ventricle remodeled to baseline level thickness. Next-generation RNA sequencing revealed differential gene expression profile of left and right ventricle upon afterload relieve. Within first days of life, the afterload of the RV decreases markedly due to the adaption of the circulatory system. Micro-CTs showed a significant reduction of RV thickness between day 1 and day 3 after birth without any signs of fibrosis.

Conclusion: Contrary to the left ventricle, we demonstrate a regenerative potential of the right ventricle in a murine afterload model. Data of the adaption upon birth suggest an innate mechanism behind the regenerative capacity of the RV. Learning from the RV presents a novel approach to develop regenerative therapies for the left ventricle.

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Artikel online veröffentlicht:
28. Januar 2023