Mechanism of Eccentric Cardiomyocyte Hypertrophy Secondary to Severe Mitral Regurgitation

Abstract

Background: Primary valvular heart disease is a prevalent cause of morbidity and mortality in both industrialized and developing countries. Although the primary consequence of valvular heart disease is myocardial dysfunction, treatment of valvular heart diseases centers around valve repair or replacement, rather than prevention or reversal of myocardial dysfunction. This is particularly evident in primary mitral regurgitation (MR), which invariably results in eccentric hypertrophy and left ventricular (LV) failure in the absence of timely valve repair or replacement. Interestingly, the mechanism of LV dysfunction in primary severe MR is entirely unknown. Methods: Here we developed the first mouse model of severe MR. Valvular damage was achieved by severing the MV leaflets and chords using iridectomy scissors, and MR was confirmed by echocardiography. Serial echocardiography was performed to follow-up LV morphology and systolic function. Analysis of cardiac tissues was subsequently performed to evaluate valve deformation, cardiomyocytes morphology, LV fibrosis and cell death. Finally, assessment of dysregulated pathways was done by RNA-seq analysis and immunofluorescence. Results: In the ensuing 15 weeks following induction of MR, gradual LV dilatation and dysfunction occurred resulting in severe systolic dysfunction. Further analysis revealed that severe MR resulted in a marked increase in cardiac mass, and increased cardiomyocyte length, but not width, with EM evidence of sarcomere disarray and the development of sarcomere disruption. From a mechanistic standpoint, severe MR resulted in activation of multiple components of both the mTOR and calcineurin pathways. Intriguingly, inhibition of mTOR signaling preserved sarcomeric structure and prevented LV remodeling and systolic dysfunction. Immunohistochemical analysis uncovered a differential pattern of expression of the cell polarity regulator Crb2 along the longitudinal axis of cardiomyocytes and close to the intercalated disks in the MR hearts. Interestingly, EM images demonstrated a significant increase in polysome localization in close proximity to the intercalated disks and some areas along the longitudinal axis in the MR hearts. Conclusions: These results indicate that LV dysfunction in response to severe MR is a form of maladaptive eccentric cardiomyocyte hypertrophy and outline the link between cell polarity regulation and spatial localization protein synthesis as a pathway for directional cardiomyocyte growth.