A renaissance of positive inotropic interventions to treat heart failure?

̈ See article by Kogler et al. [1] (pages 582–592) in tion for terminal heart failure, the protein expression of XO this issue. was increased compared to control samples [3]. In isolated cardiac muscles from rat, allopurinol and oxypurinol 21 Heart failure has a high and increasing prevalence due to increased developed tension at constant intracellular Ca the aging population and the better survival rates in other levels when given acutely [6]. This indicates a direct 21 heart diseases (e.g. acute myocardial infarction) in the positive inotropic effect due to increased Ca sensitivity Western world. Myocardial oxidative stress due to inof the myofilaments, at least in intact rat tissue. Al21 creased production of reactive oxygen free radicals may lopurinol and oxypurinol apparently are the first Ca play an important role in the development and progression sensitizers that purely increase maximum force without 21 of heart failure. shifting the range of contractile activation to lower [Ca ]. 21 ̈ In this issue of Cardiovascular Research, Kogler et al. This should be advantageous because other Ca sensitiz[1] report on a positive inotropic effect of oxypurinol in a ers impair diastolic relaxation [7]. The blunted b-adrenrat model of heart failure. Oxypurinol (plasma half life ergic response in a canine heart failure model could be in about 14 h) is the active metabolite of allopurinol (plasma part restored by allopurinol treatment [8]. It will be half life about 40 min); both are xanthine oxidase (XO) worthwhile to study whether this improvement by oxyinhibitors. XO forms free oxygen radicals as it catalyzes purinol of the effect of inotropic support is present in the degradation of purines like hypoxanthine and xanthine humans as well. to uric acid. Increased plasma levels of uric acid lead to Previous findings are being extended by the paper of ̈ gout. Inhibition of XO activity reduces the plasma levels of Kogler et al. [1]. They show that the myocardial activity of uric acid as its precursors are eliminated by the kidney. XO is increased in a well-characterized rat model of Therefore, allopurinol has long been used in the treatment cardiac hypertrophy/ failure, that myocardial XO activity is of gout. XO also converts allopurinol to oxypurinol. greatly reduced by application of oxypurinol, and that Oxypurinol is not available as a commercial drug. Inoxypurinol exerts a positive inotropic effect that is larger creased XO activity may lead to reperfusion injury by in isolated failing than in nonfailing rat hearts. This 21 modifying contractile proteins and thereby reducing Ca indicates (but does not prove) a causal link between heart sensitivity of the myofilaments [2]. In previous reports, failure and increased XO activity, as well as between XO allopurinol improved cardiac performance, hastened postinhibition and positive inotropy. The cellular source of operative recovery of cardiac output, and reduced the need increased XO activity in a canine heart failure model is, at for inotropic support or mechanical postoperative support least in part, the cardiomyocyte [9]. It should be considin patients undergoing coronary bypass therapy [3,4]. ered, however, that allopurinol and oxypurinol themselves Intracoronary infusion of allopurinol in patients suffering have hydroxyl radical scavenging properties, with no from idiopathic cardiomyopathy (who were otherwise on requirement of any enzyme activity [10]. standard drug treatment) decreased myocardial oxygen From a mechanistical point of view, these data support a consumption at constant dP/dt indicating improved causal link between free radical formation and the developmax efficiency of cardiac contraction [5]. In contrast, classical ment of heart failure. However, one could argue that free positive inotropic compounds like b-adrenoceptor agonists radical formation is only an aggravating factor of inor phosphodiesterase inhibitors usually decrease myocaradequate relative or absolute oxygen supply. Moreover, dial efficiency. In patients undergoing cardiac transplantahow inhibition of free radical formation should increase 21 the Ca sensitivity of the myofilaments remains unclear. Perhaps tonic levels of free radical species in normal hearts *Tel.: 149-251-835-502; fax: 149-251-835-5501. 21 E-mail address: [email protected] (J. Neumann). decrease Ca sensitivity of the myofilaments and this