Valvular heart disease represents a major public health problem worldwide. The incidence of valvular heart
disease increases with age, and it is estimated that about 15% of the population above the age of 75 years
suffer from some form of significant valvular disorder. Mitral regurgitation (MR) is the most frequent form of
valvular heart diseases, where it is estimated that moderate and severe MR occurs at a frequency of 1.7% as
adjusted to the US adult population, and up to 5% of the population in Europe have significant mitral valve
disease. The natural history of chronic MR is characterized by a compensated hemodynamic state in its early
phases, followed by a gradual progressive left ventricular (LV) remodeling and eccentric hypertrophy resulting
in heart failure. MR patients with depressed systolic function can present a difficult management dilemma;
corrective valve surgery is not recommended, and medical therapy is ineffective in preventing LV dysfunction.
It should perhaps be not surprising that medical therapy for MR has repeatedly failed, since very little is known
about the molecular mechanisms of myocardial dysfunction associated with primary severe MR, perhaps
owing to the paucity of research tools.
One of the major limitations in understanding the molecular mechanisms of myocardial response to severe MR
lies in the lack of mouse models. Although several elegant large animal studies, and even a rat MR model
have been published, the mechanism of eccentric hypertrophy and myocardial dysfunction secondary to
severe MR is not known. Therefore, the overall goal of this project is to understand the mechanistic basis of LV
systolic dysfunction secondary to severe MR that can guide the development of new therapeutic strategies. In
the current proposal, we developed the first mouse model of MR. Valvular damage was achieved by severing
the MV leaflets and chords using iridectomy scissors, and severe MR was confirmed by echocardiography. We
found that this model recapitulates the effect of severe MR on the human myocardium with eccentric
hypertrophy, systolic dysfunction, and activation of canonical hypertrophy pathways. In addition, we found
evidence of activation of directional cell growth as a possible mechanism of longitudinal cardiomyocyte growth
in response to MR. Therefore, we hypothesize that MR-induced eccentric cardiomyocyte hypertrophy is
mediated by activation of canonical hypertrophy pathways in conjunction with directional cell growth. There are
three aims: Determine the role of oxidative DNA damage in regulating eccentric cardiomyocyte hypertrophy in
response to severe MR. To determine the role of Crb2 in regulation of cardiomyocyte shape during postnatal
development and in response to hypertrophic stimuli. Finally, we aim to identify the spatial pattern of
sarcomeric mRNA translation during cardiomyocyte hypertrophy in response to MR.