Levosimendan is a new positive inotropic agent with anxillary vasodilating effects. It increases heart rate, stroke volume, and cardiac output and decreases systemic, pulmonary and coronary artery vascular resistance as well as filling pressures [1]. Its mode of action is believed to involve a unique calcium sensitizing effect: it binds to Troponin C in a calcium-concentration dependent manner. The implication of this characteristic is that it does not impair diastolic relaxation like other “conventional” calcium sensitisers [2,3]. In addition, levosimendan has phosphodiesterase III-inhibitory activity. The relative contribution of calcium-sensitization vs. PDE III inhibition for hemodynamic effects of levosimendan are currently under debate, but PDE III inhibiton appears to get more prominent with higher dosages [4]. Activation of adenosine-triphosphate regulated potassium channels (KATP channels) in smooth muscle cells may underly or contribute to the vasodilatory actions of levosimendan [5]. Levosimendan has exerted beneficial hemodynamic effects (compatible with its mode of action as an inodilator) in animal models of global ischemia or heart failure [1]. It was also postulated that levosimendan exerts direct anti-ischaemic effects in animal models of myocardial infarction [6,7]. In addition, short-and intermediate-term intravenous infusion of levosimendan improved hemodynamics in patients with stable or decompensated congestive heart failure [8–10]. However, hardly any information is available as to the effects of levosimendan in models of regional myocardial ischemia. Du Toit and coworkers reported on the effects of levosimendan in an in vivo pig model of severe regional ischemia-reperfusion [11]. In this model, levosimendan improved hemodynamic parameters of global left ventricular function during ischemia and after reperfusion, but at the expense of an increased rate of ventricular arrhythmias. In their in vivo study published in the present issue of Cardiovascular Drugs and Therapy, Tassani and coworkers extend this observation to a model of local myocardial ischemia as a consequence of reduced coronary blood flow. In their model of proximal LAD constriction in pigs (tampered to induce regional contractile dysfunction) they observed an unfavorable effect of levosimendan on regional contractility and energy metabolism in the ischemic myocardium, while contractility in non-ischemic areas as well as overall pump function (as assessed by cardiac output) increased. This is the first observation of opposing functional (and metabolic) effects of levosimendan on ischemic vs. nonischemic myocardium. It raises some concerns about the use of levosimendan in situations of cardiac contractile dysfunction related to critical coronary artery stenosis. While an inotropic agent may increase global and even regional contractile function in the stunned or hibernating myocardium, the vasodilating effect of an inodilator (such as levosimendan) may be less beneficial in the presence of critical coronary artery stenosis. When subendocardial resistance vessels become near fully dilated, autoregulation fails and their perfusion becomes pressure dependent. Redistribution of blood flow away from the subendocardium to the subepicardium develops as one mechanism of “coronary steal” [12]. As previously observed with other coronarodilators, such as dipyridamole or nifedipine, blood flow to the ischemic myocardium may further decrease with levosimendan due to coronary steal, and reduced coronary perfusion pressure as a result of reduced systemic vascular resistance may aggravate this effect. Indeed, Tassani et al. reported a decline of systemic vascular resistance by 21%, and a reduction of blood flow through the stenotic LAD by 7% (while blood flow increased in the nonstenotic LCX by 15%). A decline in coronary perfusion pressure was also observed in coronary bypass patients upon infusion of levosimendan [13], and decreased perfusion pressure may have detrimental effects in myocardial areas supplied by a critically stenosed coronary artery [14]. However, another observation of Tassani et al. needs to be considered: In their model, heart rate increased by 22 beats per minute during levosimendan infusion. Obviously, an increase in heart rate is disadvantageous in acute ischemia, and increased oxygen demand may further deteriorate contractile function in ischemic myocardial areas. The positive chronotropic effect of levosimendan is consistent with studies in humans (though increases in heart rate at pharmacological effective dosing were less prononunced in heart failure patients),