European Heart Journal Advance Access published online on September 11, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn407
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Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients
1 Division of Cardiovascular Diseases, Mayo Clinic, Go 5-469, Rochester, MN 55905, USA
2 Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
3 Division of Experimental Surgery, Mayo Clinic, Rochester, MN 55905, USA
Received 4 April 2008; revised 23 July 2008; accepted 21 August 2008.
* Corresponding author. Tel: +1 507 284 0294, Fax: +1 507 284 0228, Email: kushwaha.sudhir{at}mayo.edu
Aims: 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.
Methods and results: Fifty-eight cardiac transplant recipients were withdrawn from treatment with calcineurin inhibitors (CNIs) and treated with sirolimus.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/m2 (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/m2 (P = 0.008) and increased from 52.07 ± 19.45 to 57.03 ± 19.93 cc/m2 (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.
Conclusion: 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.
Key Words: Cardiac transplantation • Remodeling • Sirolimus • Left ventricular hypertrophy
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