title: Clinical impact of myocardial mTORC1 activation in nonischemic dilated cardiomyopathy.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yano
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Shimoshige
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Miki
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Tanno
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mochizuki
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Fujito
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Infection Control and Laboratory Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yuda
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Muranaka
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ogasawara
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan; Division of Health Care Administration and Management, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Hashimoto
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan; Division of Health Care Administration and Management, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Tsuchihashi
authors.affiliation: Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan. Electronic address: miura@sapmed.ac.jp.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Miura
mesh_terms: D000328:Adult; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001706:Biopsy; D053840:Brugada Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D004699:Endocardium / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D005355:Fibrosis; D015870:Gene Expression; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D046912:Multiprotein Complexes; D010750:Phosphoproteins; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases
keywords: Angiotensin; Dilated cardiomyopathy; Endomyocardial biopsy; Heart failure; Ribosomal protein S6; mTOR