Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients.
OBJECTIVE
The cellular mechanisms underlying cardiac hypertrophy may result from changes in cardiac myocyte growth and differentiation. We tested whether sirolimus, an immunosuppressive agent that inhibits mTOR, a protein that regulates cell division and differentiation, might modify cardiac hypertrophy after cardiac transplantation.


RESULTS
Fifty-eight cardiac transplant recipients were withdrawn from treatment with calcineurin inhibitors (CNIs) and treated with sirolimus. Eighty-three control subjects were maintained on CNIs. After 12 months, left ventricular (LV) mass decreased from 196.15 +/- 48.28 to 182.21 +/- 43.56 g (P = 0.05) and LV mass index from 99.25 +/- 20.08 to 93.82 +/- 20.22 g/m(2) (P = 0.031) in sirolimus-treated subjects but did not change in controls. The left atrial volume index of sirolimus-treated subjects decreased from 52.44 +/- 17.22 to 48.40 +/- 15.14 cc/m(2) (P = 0.008) and increased from 52.07 +/- 19.45 to 57.03 +/- 19.93 cc/m(2) (P = 0.0012) in controls. The difference between the groups was independent of blood pressure. The number of cells in myocardial biopsies positive for p27Kip1, a protein induced by mTOR inhibition, increased in sirolimus-treated subjects (P = 0.0005) and did not change in controls (P = 0.54) suggesting sirolimus acted directly on myocardium.


CONCLUSIONS
Sirolimus may inhibit adverse ventricular remodelling resulting in cardiac hypertrophy and have potential in the treatment of conditions in which severe hypertrophy compromises cardiac function.
Kushwaha
Sudhir S
SS
Division of Cardiovascular Diseases, Mayo Clinic, Go 5-469, Rochester, MN 55905, USA. kushwaha.sudhir@mayo.edu
Raichlin
Eugenia
E
Sheinin
Yuri
Y
Kremers
Walter K
WK
Chandrasekaran
Krishnaswamy
K
Brunn
Gregory J
GJ
Platt
Jeffrey L
JL
D019703:Calcineurin / Q000627:therapeutic use; D005260:Female; D016027:Heart Transplantation / Q000000981:diagnostic imaging / Q000276:immunology*; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000188:drug therapy*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects*; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D012189:Retrospective Studies; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000187:drug effects
D007166:Immunosuppressive Agents; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D019703:Calcineurin; D020123:Sirolimus
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