Calcineurin inhibition in hypertrophy: back from the dead!

Abstract

Reactive cardiac hypertrophy has long been recognized as a compensatory process that enhances ventricular function through normalization of wall stress in the face of increased hemodynamic load. For almost as long, it has also been appreciated that the natural history of a hypertrophied heart faced with unremitting hemodynamic overload is progression from a state of functional compensation to one of functional decompensation, or heart failure.1 Under these circumstances, the heart dilates and fails because hypertrophy fails, and in this manner, nature’s temporary cure for hemodynamic overload becomes part and parcel of the disease. Because a stimulus for hypertrophy is the initiator event in a reactive compensatory response leading to pathological decompensation, an obvious remedy for pathological myocardial hypertrophy is elimination of the stimulus. This is not always possible, however, owing to insufficient control of blood pressure in hypertensive patients, uncorrected valvular stenoses or insufficiencies, or hypertrophy of viable myocardium in postinfarction patients. Furthermore, genetic causes of hypertrophic cardiomyopathy are not directly addressable with current technologies. Therefore, identification of molecular and biochemical mediators of myocardial hypertrophy has been pursued to delineate hypertrophy signaling events that might be susceptible to targeted inhibition. Various candidate signaling pathways, mostly involving hormone receptors, associated G proteins, or their downstream kinase effectors, have been implicated with the use of in vitro and in vivo systems.2 Recently, protein phosphatases have also received attention in this regard. The most thoroughly investigated and controversial protein phosphatase proposed to be a hypertrophy signaling factor is calcineurin (CN). CN is a ubiquitous phosphatase best known for its effects on T cell–mediated immunity. In these cells and others, sustained elevations in intracellular calcium activate CN, resulting in dephosphorylation of a class of transcription factors, nuclear factors of activated T cells (NFATs), which then translocate to cell nuclei and regulate expression …