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.
