Clinical impact of myocardial mTORC1 activation in nonischemic dilated cardiomyopathy. (February 2016)

• Record Type: Journal Article
• Authors: Yano, Toshiyuki; Shimoshige, Shinya; Miki, Takayuki; Tanno, Masaya; Mochizuki, Atsushi; Fujito, Takefumi; Yuda, Satoshi; Muranaka, Atsuko; Ogasawara, Makoto; Hashimoto, Akiyoshi; Tsuchihashi, Kazufumi; Miura, Tetsuji
• Is Part Of: Journal of molecular and cellular cardiology. Volume 91(2016:Feb.)
• Page Start: 6
• Page End: 9
• Publication Date: 2016-02
• Subjects: Endomyocardial biopsy -- mTOR -- Ribosomal protein S6 -- Heart failure -- Angiotensin -- Dilated cardiomyopathy; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.12.022
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Background: Activity of mTOR complex 1 (mTORC1) has been shown to be up-regulated in animal models of heart failure. Here, we investigated the change and role of mTORC1 in human nonischemic dilated cardiomyopathy (NICM). Methods: Endomyocardial biopsy specimens were obtained from patients with NICM (n = 52) and from Brugada syndrome patients with normal LVEF as controls (n = 10). The specimens were stained for phospho-ribosomal protein S6 (p-Rps6) and phospho-p70S6K (p-p70S6K), and the area with p-Rps6 signal was used as an index of mTORC1 activity. Using median mTORC1 activity, patients were divided into a high mTORC1 activity (H-mTOR) group and a low mTORC1 activity (L-mTOR) group. Results: The ratio of p-Rps6-positive area in biopsy samples was 10-fold larger in patients with NICM than in controls (2.0 ± 2.2% vs. 0.2 ± 0.2%, p < 0.01). p-p70S6K signal level was higher in the H-mTOR group than in the L-mTOR group. The proportion of patients with a family history of cardiomyopathy was higher and the proportion of patients on ACE inhibitors or angiotensin receptor blockers was lower in the H-mTOR group than in the L-mTOR group. The p-Rps6-positive area was correlated with extent of myocardial fibrosis (r = 0.46, p < 0.01). The 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). Conclusion: Aberrant activation of mTORC1 in cardiomyocytes was associated with myocardial fibrosis and a trend for worse prognosis in patients with NICM, indicating that persistently activated mTORC1 contributes to progression of human heart failure. Highlights: The change and role of mTORC1 in human cardiomyopathy is unknown. Myocardial mTORC1 activity was increased in non-ischemic dilated cardiomyopathy (NICM). The mTORC1 activity was correlated with extent of myocardial fibrosis. The mTORC1 activity was higher in NICM patients who later developed cardiac events.