Abstract 17085: Activation of mTORC1 in Cardiomyocyte is Associated with Fibrosis and Cardiomyocyte Loss in Heart Failure with Reduced Ejection Fraction

Background: Experimental studies have demonstrated that mTOR complex 1 (mTORC1) activity was up-regulated in models of cardiac hypertrophy and heart failure. Although short-term activation of mTORC1 is protective against cell death under an acute stress condition, a detrimental consequence may be induced by its sustained activation. Objective: We examined the functional significance of myocardial mTORC1 activation in heart failure patients with reduced ejection fraction (HFrEF). Methods: Endomyocardial biopsy specimens were obtained from patients with HFrEF (LVEF<50%, n=52). Patients with coronary artery disease and histologically documented causes of reduced ejection fraction were excluded. Specimens from patients with Brugada syndrome served as controls with normal LVEF. The area stained with anti-phosphorylated ribosomal protein S6 (Rps6) was used as an index of mTORC1 activity, and fibrotic and cardiomyocyte areas were determined by Azan staining. Using median mTORC1 activity, patients were classified into a high mTORC1 activity group (H-mTOR) or low mTORC1 activity group (L-mTOR). Results: Phospho-Rps6 signals in cardiomyocytes were often detected in patients with HFrEF but were barely detected in controls, while the signal was clearly detected in capillary endothelia in either group. mTORC1 activity was 10-fold higher in patients with HFrEF than in controls (0.2±0.2 % vs. 2.0±2.2 %, p<0.01). In the H-mTOR group, the ratio of patients with a family history of cardiomyopathy was higher (35 % vs. 8 %) and the ratio of patients on ACE inhibitors or angiotensin receptor blockers at the time of endomyocardial biopsy was lower (52 % vs. 85 %) than those in the L-mTOR group. mTORC1 activity was positively correlated with extent of fibrosis (r=0.46, p<0.01) and negatively correlated with cardiomyocyte area (r=-0.40). Cardiac event-free survival rate during a 5-year follow-up period tended to be lower in the H-mTOR group than in the L-mTOR group (52.9 % vs. 81.6 %, p=0.10, n=41). Conclusions: Aberrant activation of mTORC1 was shown to be associated with cardiomyocyte loss and fibrosis in biopsy samples, indicating a role of persistently activated mTORC1 in progression of HFrEF.