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Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients. Eur Heart J 2008 Nov;29(22):2742-50

Date

09/16/2008

Pubmed ID

18790727

Pubmed Central ID

PMC2721707

DOI

10.1093/eurheartj/ehn407

Scopus ID

2-s2.0-56449128027   46 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METHODS AND RESULTS: Fifty-eight cardiac transplant recipients were withdrawn from treatment with calcineurin inhibitors (CNIs) and treated with sirolimus.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/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.

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.

Author List

Kushwaha SS, Raichlin E, Sheinin Y, Kremers WK, Chandrasekaran K, Brunn GJ, Platt JL

Authors

Eugenia Raichlin MD Professor in the Medicine department at Medical College of Wisconsin
Yuri M. Sheinin MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Calcineurin
Female
Heart Transplantation
Humans
Hypertrophy, Left Ventricular
Immunosuppressive Agents
Male
Middle Aged
Myocytes, Cardiac
Protein Kinases
Retrospective Studies
Sirolimus
TOR Serine-Threonine Kinases
Treatment Outcome
Ultrasonography
Ventricular Function, Left