Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients

Sudhir S. Kushwaha, Eugenia Raichlin, Yuri Sheinin, Walter K. Kremers, Krishnaswamy Chandrasekaran, Gregory J. Brunn, Jeffrey L. Platt

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

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 Methods and results: Fifty-eight cardiac transplant recipients were withdrawn from treatment with calcineurin inhibitors (CNIs) and treated with sirolimus.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.

Original languageEnglish (US)
Pages (from-to)2742-2750
Number of pages9
JournalEuropean Heart Journal
Volume29
Issue number22
DOIs
StatePublished - Nov 1 2008
Externally publishedYes

Keywords

  • Cardiac transplantation
  • Left ventricular hypertrophy
  • Remodeling
  • Sirolimus

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Kushwaha, S. S., Raichlin, E., Sheinin, Y., Kremers, W. K., Chandrasekaran, K., Brunn, G. J., & Platt, J. L. (2008). Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients. European Heart Journal, 29(22), 2742-2750. https://doi.org/10.1093/eurheartj/ehn407