D u ring the past year there has been a running debate in basic-science journals on whether the immunosuppressive agent, cy clospo rin A (CsA), can prevent the deve lopment of cardiac hy pe rt rop hy. Since cardiac hy pe rt rop hy is a major risk factor for cardiac death and commonly precedes the development of heart fa ilure, the answer to this question may have far-reaching implications for the tre atment of hy pe rtension and heart fa ilure, and for the pre vention of remodelling after myocardial infa rction. The fully differentiated adult cardiac myo cyte cannot undergo cellular division. A decrease in ve nt ricular systolic function, induced either by injury to myo cytes (eg, from ischaemia or pressure/volume overload) or by loss of myo cytes (eg, after myocardial infarction or myo carditis), results in hy pe rt rop hy of surviving myo cy te s. I nitially, myo cyte hy pe rt rop hy has beneficial effects on leftve nt ricular function, since hy pe rt rop hy restores towa rds no rmal the increased wall stress found in hearts exposed to increased systolic pressure and in hearts that are dilat ed after myocardial infa rction. H ype rt rop hy not only invo l ve s an increase in cell size, but also results in a reprogr amming of the pat te rn of gene expression. L engt hy stimulation of the hy pe rtrophic response leads to detri mental modific ations of gene expression, which result in contractile dysfunction. Thus starts the inexorable pro gression to heart fa ilure.

The possibility that CsA is useful as an antihy pe rt rophic agent was raised by Molkentin and colleagues, 1 who found th at transgenic mice expressing a gene encoding a constituti vely active mutant of the target of CsA, calcineu ri n, de veloped massive cardiac hy pe rt rop hy, and th at treatment of the animals with CsA preve nted hy pe rt rop hy. Most strat e gies designed to block cardiac hy pe rt rop hy or to induce its regression have relied upon blockage of the activation of va rious cell-surface receptors, specifically the angiotensin II (Ang II) and endothelin-1 (E T-1 receptors). 2 Molkentin and colleagues’ finding wa s the first demonstration that hy pe rt rop hy could be inhibited by blockage of the activity of an intracellular pat h way. C alcineu rin is a calcium-dependent and calmodulindependent protein phosphat ase, which means that it rem oves phosphate residues from other proteins when cytosolic calcium concentration ri se s. R em oval of phosph ates from one major target of calcineuri n, nuclear factor of activated T cells (NF-AT s), enables a group of previously hidden aminoacids to be exposed. T hese aminoacids direct translocation of NF-ATs from the cytoplasm to the nucleus, where the NF-ATs activate the transc ription of a host of genes invo l ved in the immune response. 3 Inhibition of calcineurin-induced dephospho ry l ation of NF-ATs accounts in large part for the immunosuppressi ve effects of CsA. Molkentin et al also showed that expression in transgenic mice of a form of NF-AT3 (one of two cardiac