The Tragedy of TRIUMPH for Nitric Oxide Synthesis Inhibition in Cardiogenic Shock

Cardiogenic shock following an acute coronary syndrome (ACS) continues to be associated with significant mortality despite modern reperfusion strategies and inotropic support. There is mounting evidence that an acute inflammatory response accompanies the well documented decrement in left ventricular systolic function associated with cardiogenic shock and that this response may affect outcomes. In the past 2 decades it has also become apparent that nitric oxide (NO), a heteroatomic free radical has numerous biologic activities, among them the maintenance of vascular tone. The production of NO is mediated by three nitric oxide synthases (NOS); the transcription of one of these (NOS2 or inducible NOS [iNOS]) is induced by inflammatory stimuli. The iNOS gene product produces NO at very high and potentially pathologic levels. The up-regulation of iNOS transcription and overproduction of NO have been implicated in the pathogenesis of shock states where excess NO is thought to cause catecholamine resistant vasodilatation and reduced myocardial inotropy, resulting in hypotension and a fall in cardiac output. NO can also react with superoxide to produce peroxynitrate, a molecule directly toxic to the cells via modification of proteins and DNA. Inhibitors of NOS have long been utilized in the laboratory characterization of the NOS. More recently, attempts have been made to determine if the inhibition of NOS might have clinical utility in the setting of circulatory shock. With respect to septic shock, early animal studies and small trials in humans proved encouraging, but a larger trial was terminated early because of a trend toward harm among patients receiving the NO inhibitor. Studies have been undertaken in the setting of cardiogenic shock. Animal studies and small trials with humans again proved encouraging, but the large randomized TRIUMPH trial evaluating tilarginine (N ^G -monomethyl-L-arginine; L-NMMA) was recently terminated because of a lack of efficacy. These studies evaluated compounds with little selectivity for iNOS and their failure may have been due, in part, to the inhibition of the other NOS isoforms. In this review, we describe the biochemistry of NO synthesis, the regulation of NO production, and the clinical trials evaluating the efficacy of NOS inhibition with an eye to future trials with more selective inhibitors of iNOS.