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 Citations (Scopus)

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 Methods and results: Fifty-eight cardiac transplant recipients were withdrawn from treatment with calcineurin inhibitors (CNIs) and treated with sirolimus.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 2008

Fingerprint

Sirolimus
Cardiac Myocytes
Cardiomegaly
TOR Serine-Threonine Kinases
Cyclin-Dependent Kinase Inhibitor p27
Ventricular Remodeling
Heart Transplantation
Immunosuppressive Agents
Transplant Recipients
Cell Division
Cell Differentiation
Myocardium
Cell Count
Blood Pressure
Biopsy
Therapeutics
Growth

Keywords

  • Cardiac transplantation
  • Left ventricular hypertrophy
  • Remodeling
  • Sirolimus

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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

Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients. / Kushwaha, Sudhir S.; Raichlin, Eugenia; Sheinin, Yuri; Kremers, Walter K; Chandrasekaran, Krishnaswamy; Brunn, Gregory J.; Platt, Jeffrey L.

In: European Heart Journal, Vol. 29, No. 22, 11.2008, p. 2742-2750.

Research output: Contribution to journalArticle

Kushwaha, SS, Raichlin, E, Sheinin, Y, Kremers, WK, Chandrasekaran, K, Brunn, GJ & Platt, JL 2008, 'Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients', European Heart Journal, vol. 29, no. 22, pp. 2742-2750. https://doi.org/10.1093/eurheartj/ehn407
Kushwaha, Sudhir S. ; Raichlin, Eugenia ; Sheinin, Yuri ; Kremers, Walter K ; Chandrasekaran, Krishnaswamy ; Brunn, Gregory J. ; Platt, Jeffrey L. / Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients. In: European Heart Journal. 2008 ; Vol. 29, No. 22. pp. 2742-2750.
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