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Investigational Positive Inotropic Agents for Acute Heart Failure

Juan Tamargo*, Ricardo Caballero, Ricardo Gmez, Adriana Barana, Irene Amors and Eva Delpn
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain
Abstract: Acute heart failure (AHF) represents a major public health problem due to its high prevalence, high rates of mortality and readmissions and significant healthcare costs. Patients with AHF and low cardiac output represent a small subgroup of patients with very high mortality rates that require inotropic support to improve cardiac systolic function. Classical inotropic agents, such as 1-adrenergic agonists (dobutamine, dopamine) and phosphodiesterase III inhibitors (milrinone, enoximone) improve symptoms and hemodynamics by increasing free intracellular Ca2+ levels, but also increase myocardial O2 demands and exert arrhythmogenic effects. These actions explain why these drugs increase both short- and long-term mortality, particularly in patients with AHF and coronary artery disease. Thus, we need new inotropic agents that do not increase cytosolic Ca2+ or myocardial oxygen demands or produce arrhythmogenesis for the treatment of high-risk patients with (AHF) and low cardiac output. This review describes three new classes of investigational agents: levosimendan, a calcium sensitizer and potassium channel opener, istaroxime, the first new luso-inotropic agent and cardiac myosin activators.

Key Words: Inotropic drugs, acute heart failure, levosimendan, istaroxime, CK-1827452. INTRODUCTION The term acute heart failure (AHF) includes a group of related clinical syndromes defined as gradual or rapid change in heart failure signs and symptoms that require urgent therapy [1-4]. The recent European Guidelines for the diagnosis and treatment of acute and chronic heart failure (ECS 2008) state that the final common denominator in AHF syndromes is a critical inability of the myocardium to maintain a cardiac output sufficient to meet the demands of the peripheral circulation [4]. AHF may be either new heart failure or worsening of pre-existing chronic heart failure. The cardiac dysfunction can be related to ischemia, increased filling pressures, increased systemic resistances, abnormalities in cardiac rhythm and valvular or pericardial diseases. AHF represents a major public health problem due to its high prevalence, high rates of in-hospital and postdischarge mortality and readmissions and significant healthcare costs [1-4]. AHF is the leading cause of hospitalization in patients older than 65 years and, the rate of hospitalization is increasing due to progressive aging of the population and the better management of acute myocardial infarction. Moreover, almost 50% of patients hospitalized with AHF will be rehospitalized within 6 months of discharge from their first admission. The in-hospital mortality of AHF is approximately 5% [5, 6] and the risk of death/rehospitalization within 2-3 months ranges from 20% to 60%, depending on the population studied [5, 7-9]. The management of heart failure represents between 1 and 2% of all healthcare expenditures and is mainly related to hospitalization [6, 10]. Furthermore, patients with AHF often present other comorbidities and cardiovascular risk factors, including coronary artery disease (40-68% of patients), abnormalities
*Address correspondence to this author at the Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain; Tel: 91-3941472; Fax: 91-3941470; E-mail: jtamargo@med.ucm.es

in cardiac rhythm (mainly atrial fibrillation in ~30% of patients), arterial hypertension (53-73%), diabetes mellitus (2740%), renal insufficiency (17-30%), chronic obstructive pulmonary disease (30%) and valvular dysfunction [1-4]. These comorbidities cause and/or contribute to the pathogenesis of AHF and, therefore, they should be identified and incorporated into the treatment strategy. CLASSIFICATION AHF is not an homogenoeus entity but includes a broad spectrum of clinical syndromes with different clinical presentations, history, pathophysiology, prognosis and treatment [1-4, 11]. It is difficult to differentiate among these conditions because they frequently overlap. Therefore, we need a classification that can be easily used by any physician and that can be accompanied by appropriate treatment algorithms. Data from several large multicenter registries (Acute decompensated heart failure national registry-ADHERE [12], Organized program to initiate lifesaving treatment in hospitalized patients with heart failure-OPTIMIZE-HF [13] and EuroHeart Failure Survey II-EHFS II [14]), and the National surveys of France [10], Italy [15] and Finland [16] have recognized that systolic blood pressure levels at the time of admission, a readily accesible vital sign, identify three groups of patients with different risk for subsequent morbidity and mortality that require a different therapeutic approach: 1) the hypertensive group. More than 50% of patients with AHF, mainly females, have preserved left ventricular (LV) ejection fraction, high systolic blood pressure (> 140 mm Hg) and increased pulmonary capillary wedge pressure usually without signs of peripheral edema at admission. They present low in-hospital mortality (2%), and 5% mortality and 30% readmission rates within 6090 days of discharge. 2) The normotensive group. These patients have a low LV ejection fraction and signs and symptoms of pulmonary/systemic congestion (edema) at the time of admission.
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Their in-hospital mortality rate is approximately 3%, and 7% within 6090 days of discharge. 3) The hypotensive group. A minority of patients (2-8%) present low LV ejection fraction and symptoms of poor end-organ perfusion (systolic blood pressure 120 mm Hg, cold skin, renal dysfunction, impaired mentation) on admission (AHF/LO). This subgroup of patients presents high inhospital and postdischarge mortality rates (7% and 14%, respectively) and readmission rates (30%) within 6090 days of discharge. GENERAL THERAPEUTIC APPROACH In patients with AHF, symptoms, clinical course and prognosis are critically dependent on the hemodynamics. Thus, the general goals of the treatment are [1]: a) relieve symptoms (dyspnea and/or fatigue) and signs; b) stabilize the hemodynamics (increase stroke volume and cardiac output and decrease pulmonary capillary wedge pressure and LV filling pressures); 3) exert favourable effects on outcomes, reducing the duration of intravenous vasoactive therapy, patients stay in-hospital and intensive care unit, rehospitalizations and both short- and long-term mortality; and 4) preserve or improve renal function, prevent myocardial damage and manage other comorbidities that may cause/contribute to the pathogenesis of AHF. Early management in patients with AHF and high or normal systolic blood pressure is directed to reduce systemic and/or pulmonary congestion and correct the high LV filling pressure and/or afterload using intravenous vasodilators (eg, nitroglycerin, nitroprusside, nesiritide) and loop diuretics. According to the ESC Guidelines, intravenous inotropic drugs are indicated in AHF/LO patients characterized by peripheral hypoperfusion with or without congestion or pul-

monary edema despite the use of diuretics and/or vasodilators at optimal doses [4]. In these patients, a short-term treatment with inotropic agents relieves congestive symptoms, increases LV function (stroke volume and cardiac output), normalizes systolic blood pressure, improves peripheral hypoperfusion and restores end-organ function. Inotropes can also be used to stabilize patients at risk of progressive hemodynamic collapse or as a life-sustaining bridge until other life-saving therapy (mechanical circulatory support, ventricular assist devices, or cardiac revascularization or transplantation) can be undertaken [3,4,17]. Finally, in a small number of end-stage patients in whom other therapies are not appropriate, chronic IV inotropics may be considered as a palliative option of end-of-life care. CARDIAC EXCITATIONCONTRACTION COUPLING (E-C)

Ca ions (Ca2+) play a key role in the cardiac E-C coupling (Fig. 1). During the plateau phase of the cardiac action potential Ca2+ enters into the cell through voltage-activated L-type Ca2+ channels which, in turn, binds to ryanodine receptors (RyRs) of the sarcoplasmic reticulum (SR) and triggers a larger release of Ca2+ via SR Ca2+ release channels [18,19]. During the diastole, the [Ca2+]i returns to diastolic levels mainly by activation of the SR Ca2+ ATPase isoform 2a (SERCA2a) and sarcolemmal Na+/Ca2+ exchanger, and partly, by the sarcolemmal Ca2+ ATPase (Fig. 1). During the contractile process a molecular interaction takes place between the thin (actin) and thick (myosin) filament of the sarcomeres, which is triggered by the rise in [Ca2+]i and driven by the energy derived from adenosine-5'triphosphate (ATP) hydrolysis. The thin filaments are com-

Fig. (1). Cardiac excitation-contraction coupling. Ca2+ entry via L-type Ca2+ channels activates sarcoplasmic reticulum (SR) Ca2+ release via the ryanodine receptor (RyR), resulting in an increase in intracelular Ca2+ concentration and the activation of contraction. SR Ca2+ uptake via the SR Ca2+-ATPase (SERCA2a) and extrusion via Na+/Ca2+ exchange (NCX) and sarcolemma Ca2+-ATPase (PMCA) allows relaxation. Istaroxime inhibits Na+-K+ ATPase activity at the sarcolemma and stimulates SERCA2a activity. CICR: calcium-induced calcium release. PBL: phospholamban. TnC: troponin C.

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posed of actin, tropomyosin, and the troponin (Tn) complex [20]. This complex includes: TnC, the Ca2+-binding subunit, TnT, which attaches the troponin complex to tropomyosin, and Tn-I, which in concert with tropomyosin regulates the interactions between actin and myosin. At low [Ca2+]i (during the diastole) TnI binds tightly to actin and with tropomyosin inhibiting the actin-myosin interaction (Fig. 2). During the systole, Ca2+ binds to the N-terminus of TnC and induces a conformational change in the Tn complex, so that TnI and tropomyosin move away from the myosin binding sites on actin, making them accessible to the myosin globular heads. Molecular events begin during the diastole (Fig. 3), after the binding of ATP to the globular head of myosin, which rapidly detaches myosin from actin producing muscle relaxation [19]. Next, myosin ATPase hydrolyses myosin-bound ATP into ADP and Pi, which forms a myosin-ADP-Pi complex that increases the affinity for actin. During this step the myosin head is cocked and placed in line with its binding site on the actin filament. When the [Ca2+]i increases the actin binding site becomes available, the myosin head weakly binds to actin and a cross-bridge is formed. The release of Pi is associated to a strong binding between myosin and actin, and the myosin head flexes pulling the actin filaments towards the center of the sarcommere (power stroke). Finally, the release of ADP dissociates from myosin occurs, which causes it dissociation from actin and prepares the cycle to repeat. POSITIVE INOTROPIC AGENTS Conventional intravenous inotropic agents, including sympathomimetics (dopamine, dobutamine) and phosphodiesterase III inhibitors (milrinone, enoximone) increase Ca2+

transients and cardiac contractility in a concentration-dependent manner by increasing cellular levels of 3-5-cyclic adenosine monophosphate (cAMP) in cardiac myocytes, leading to the activation of cAMP-dependent protein kinase A (PKA) [1,4,17,19]. Dobutamine increases cAMP production via activation of 1-adrenergic-mediated stimulation of adenylate cyclase, whereas, phosphodiesterase III inhibitors increase cAMP levels by blocking the enzyme that breaks down cAMP. PKA produces the phosphorylation of: a) Ltype Ca2+ channels, increasing extracellular Ca2+ entry during the plateau phase of the cardiac action potential, and b) ryanodine receptors located in the SR, which induces a further release of Ca2+ at this level. As a result of both mechanisms the [Ca2+]i and the contractile force increase. c) Phospholamban, so that its ability to inhibit Ca2+ transport via the SERCA2a is lost, enhancing Ca2+ uptake by the SR, and d) TnI, which decreases the Ca2+ affinity of the contactile proteins; both effects result in an acceleration of cardiac relaxation. Thus, inotropic agents that increase cAMP levels produce both inotropic and lusitropic effects. In patients with AHF/LO, intravenous inotropic agents improve clinical signs, symptoms and hemodynamics (increase stroke volume and cardiac output and reduce pulmonary capillary wedge pressure and LV filling pressures). Phosphodiesterase III inhibitors increase cardiac contractility and produce arterial and venous dilation, decreasing pulmonary and systemic vascular. Due to their greater vasodilator activity, phosphodiesterase inhibitors may be preferred in patients with elevated filling pressures, in particular, in those with elevated pulmonary artery pressures. Moreover, because the mechanism of action of these drugs is independent of -adrenergic receptor activation, their hemodynamic ef-

Fig. (2). Ca2+-induced conformational changes in the troponin complex. The major proteins involved in contractile activation and regulation are shown in diastole (left panel) and systole (right panel). The thin filament is composed of actin, tropomyosin (Tm), and the troponin (Tn) complex, formed by TnT, TnC, and TnI. During the systole, Ca2+ binding to Tn-C induces a conformational rearrangement in Tn-C, and the movement of Tm exposes a myosin binding site on actin (dashed line) allowing cross-bridge formation to take place. Levosimendan binds to the N-terminal domain of TnC, stabilizes the conformation of the Ca2+-TnC complex and increases the binding affinity of TnC for intracellular Ca2+.

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Fig. (3). The myosin cross-bridge cycle including the mechanism of action of cardiac myosin activators. See text for discussion. A: actin. ADP: adenosine diphosphate. ATP adenosine-5'-triphosphate. M: myosin. Pi: inorganic phosphate.

fects are maintained in patients receiving -blockers, being an alternative to dobutamine under these circumstances [1, 17, 21]. Dobutamine stimulates 1-adrenergic receptors and produces both positive inotropic and chronotropic effects. Dopamine is a catecholamine with multiple actions. At low doses (< 2 g/kg/min), it stimulates peripheral dopaminergic receptors, producing vasodilatation (renal, coronary and esplachnic) and diuresis in patients with AHFS/LO and low urine outflow; at doses between 2 and 5 g/kg/min, dopamine stimulates -adrenergic receptors and increases cardiac contractility, while at high doses, it stimulates -adrenergic receptors producing a peripheral vasoconstriction which can be used to maintain systolic blood pressure, but at an increased risk of proarrhythmia [1]. Advantages and Disadvantages of Inotropic Agents An ideal inotropic agent for treating AHF/LO patients should reduce signs and symptoms, improve LV function, reduce systemic and pulmonary vascular resistances and exert a favorable or neutral effect on mortality, without increasing heart rate or myocardial O2 consumption, decreasing blood pressure and coronary perfusion (particularly in patients with coronary artery disease), worsening cardiac metabolism or renal function and producing cardiac arrhythmias or myocardial damage (apoptosis, necrosis) [17]. However, the beneficial effects of conventional inotropes may be counteracted by several serious adverse effects, including neurohumoral activation, proarrhythmia, intracellu-

lar Ca2+ overload (which increases myocardial O2 consumption and induces delayed afterdepolarizations and triggered lethal arrhythmias and myocyte cell death) and hypotension, especially at high doses, which reduces coronary perfusion. Thus, exogenous cardiac stimulation when the myocardium is energy-depleted may result in further ischemic or apoptotic damage, promoting and/or accelerating the progression of the heart failure and explain why in several randomized clinical trials inotropic drugs may increase in-hospital and post-discharge mortality [22-26]. The Flolan international randomized survival trial (FIRST) randomized 471 patients with AHF [New York Heart Association (NYHA) functional class IIIb to IV] to dobutamine or placebo [27]. Dobutamine increased the occurrence of heart failure worsening, need for vasoactive medications, resuscitated cardiac arrest, myocardial infarction, and total mortality (85.3% vs 64.5%; P = 0.0006) and 6month mortality rate (70.5% vs 37.1%; P=0.0001) compared with the placebo group. Moreover, intravenous continuous dobutamine was an independent risk factor for death after adjusting for baseline differences. The OPTIME-CHF (Outcomes of a prospective trial of intravenous milrinone for exacerbations of chronic heart failure) trial randomized 951 patients admitted with AHF not requiring intravenous inotropic support (NYHA class III-IV; mean LV ejection fraction 23%) to the intravenous infusion of milrinone or placebo [21]. During the first 60 days after randomization the milrinone and placebo groups did not differ in the total

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number of days hospitalized for cardiovascular causes within 60 days (primary end-point) or in other important secondary end points, such as in-hospital mortality, 60-day mortality, or 60-day rates of death or rehospitalization. However, milrinone was associated with a higher incidence of hypotension and atrial fibrillation or flutter. Additionally, in the Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness (ESCAPE) trial, the short-term use of intravenous inotropes, but not of vasodilators and their combination, was associated with a significantly increased risk of all-cause mortality and all-cause mortality plus rehospitalizations [28]. Furthermore, a review of 21 trials (632 patients) with worsening heart failure receiving intravenous inotropics acting via the activation of the cAMP pathway found that compared to placebo, inotropic agents tended to increase mortality [22]. In another meta-analysis of 21 randomised controlled trials (8,408 patients), as compared to placebo, treatment with phosphodiesterase III inhibitors improved symptoms and hemodynamics but produced a significant increase in mortality rate in patients suffering from chronic heart failure [29]. In addition, phosphodiesterase III inhibitors significantly increase cardiac death, sudden death, arrhythmias and vertigos. Thus, the chronic use of these drugs should be avoided in heart failure patients. The underlying etiology of AHF has important implications not only for the prognosis but also for the long-term outcome. A hibernating myocardium is present in 40%65% of patients with AHF and coronary artery disease [1, 2, 30, 31] and they present a worse prognosis than patients with nonischemic etiology [32]. The hibernating myocardium is at risk for injury because of increased LV filling pressures, hypotension and neurohormonal activation [33]. In experimental models and in patients with hibernating myocardium inotropic stimulation without a previous restoration of coronary blood flow increases myocardial O2 consumption, myocyte apoptosis and infarct size, accelerates the progression of HF [34, 35] and increases the incidence of ventricular arrhythmias [34-36]. In a post hoc secondary analysis of the OPTIME-CHF trial, milrinone-treated patients with coronary artery disease tended to have significanttly worse outcomes (days hospitalized from cardiovascular causes within 60 days and the composite of death or rehospitalization), particularly in those who develop drug-related hypotension [21]. In contrast, outcomes in nonischemic patients treated with milrinone tended to be improved in terms of the primary end point. Therefore, on the basis of the available evidence, the routine use of conventional inotropes is not indicated in AHF patients without evidence of impaired end-organ perfusion [2]. In the ADHERE registry approximately 10% of patients hospitalized for AHF in the United States receive an intravenous inotrope (milrinone or dobutamine) and in general, these patients have higher blood urea nitrogen levels, lower systolic blood pressure, greater QRS duration, and lower LV ejection fraction [26]. In AHF patients, when needed, intravenous inotropes should be administered as early as possible

and withdrawn as soon as possible as adequate organ perfusion is restored and/or congestion reduced [1-4, 24, 26, 30]. Concerns about the efficacy and safety of presently available inotropics have stimulated the development of new agents that improve cardiac output and symptoms without increasing morbidity and mortality of patients with AHFS/ LO (Table 1). This review describes three new classes of investigational agents: a) levosimendan, a calcium sensitizer and potassium channel opener, b) istaroxime, a new lusoinotropic agent and 3) the cardiac myosin activators. The characteristics of the randomized clinical trials with these drugs are summarized in Table 2 .
Table 1. Inotropic Drugs for the Treatment of Patients with AHF and Low Blood Pressure with or Without Congestion
A. o o o Conventional inotropic drugs Catecholamines: dopamine, epinephrine, norephinephrine. Beta1-receptor agonists: dobutamine, denopamine Phosphodiesterase III inhibitors: amrinone, milrinone, olprinone, vesnarinone, enoximone, piroximone Novel inotropic agents Calcium sensitizing agents: ED-57033, EMD-53998, Levosimendan, MCI-154, Pimobendan, Senazodan, sulmazole, Istaroxime (PST-2744) Cardiac myosin activators: 116CK-112253, CK-1122534, CK1827452, CK-0689705, CK-121329, CK-1316719

B. o o o

INVESTIGATIONAL AGENTS Levosimendan

POSITIVE

INOTROPIC

Levosimendan, the R enantiomer of [4-(1,4,5,6-tetrahydro4-methyl-6-oxo-3-pyridazinyl) phenyl] hydrazono} propanedinitrile, is a drug with multiple mechanisms of action. First, it acts as a Ca2+ sensitizer, so that it increases contractile without altering the time course of Ca2+ transients. Levosimendan binds to the N-terminal domain of TnC (Fig. 2), stabilizes the conformation of the Ca2+-TnC complex and increases the binding affinity of TnC for intracellular Ca2+; thereby, it accelerates the cross-bridge association rate and decelerates the dissociation rate, thus improving contractility without increasing [Ca2+]i or myocardial O2 consumption [37-39]. Binding of levosimendan to TnC is dependent on the [Ca2+]i, i.e., it increases during systole but is significantly weaker (causing a minimum Ca2+ sensitization) during diastole, when the [Ca2+]i is low [37]. This may explain why levosimendan exerts a positive inotropic effect without impairing (and sometimes improving) diastolic relaxation or producing cytosolic Ca2+ overload. In fact, levosimendan improves LV relaxation and diastolic filling in conscious dogs with pacing-induced heart failure [40] and LV function of stunned myocardium in patients with acute myocardial ischemia and after coronary angioplasty [38,39,41,42]. It has been proposed that levosimendan may improve the function of stunned myocardium because it improves LV systolic

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Table 2.

Major Randomized Clinical Trials with New Developing Drugs in AHFS

Acronyms [Reference] CASINO [59]

Patients (n)

Study Design Phase III, R, DB, PG, DD

Treatment/ Comparator

Primary End Points

Outcomes

299* AHF/LO

Levosimendan: 16 g bolus + 0.2 g/kg/min for 24 h Dobutamine: placebo bolus + 5-10 g/kg/min for 24 h Placebo.

Death and rehospitalization due to HF deterioration

Levosimendan improved 6month survival

HORIZON-HF [69] LIDO [54]

120 Chronic HF 203 DHF

Phase II, R, PC, DB, PA, DE Phase II, R, DB, DD, PA

Istaroxime 0.5, 1 and 1.5 g/kg/min Placebo Levosimendan: 24 g/kg bolus + 0.1 g/kg/min for 24 h Dobutamine: 5 g/kg/min for 24 h The infusion rate was doubled if the response was inadequate at 2h

Changes in PCWP after 6 h of continuous infusion Hemodynamic improvement

Istaroxime improved PCWP and possibly diastolic function Levosimendan improves hemodynamics and reduces mortality at 180 days as compared to dobutamine

OPTIME-CHF [21]

949 DHF

R, P, DB, PC

Milrinone: 0.5 g/kg/min for 48 to 72 h Placebo

Days hospitalized from cardiovascular causes within 60 days of study drug infusion Symptoms and clinical status

Milrinone-treated patients with ischemic etiology have worse outcomes

REVIVE 1 [60,61]

100 DHF

Phase III, R, DB, PC, PA

Levosimendan: 6-12 g/kg for 50 min + 0.1-0.2 g/kg/h for 23 h Placebo

Levosimendan produces an early improvement (at 1 and 5 days) more frequent than with placebo. Levosimendan decreases BNP, improves primary endpoints and length of stay. Neutral effects on mortality at 90 days No differences among groups. Levosimendan reduces mortality at 14 and 180 days No differences on clinical outcome or all-cause mortality at 180 days. Greater reduction of BNP with levosimendan.

REVIVE 2 [49,62]

600 DHF

Phase III, R, M, DB, PC, PA

Levosimendan: 6-12 g/kg bolus + 0.1-0.2 g/kg/h for 24 h Placebo

Signs and symtoms of actute DHF and major clinical events over 5 days

RUSSLAND [58]

504 Post-MI HF

Phase II, R, DB, PC

Levosimendan: 6, 12 or 24 g/kg + 0.1, 0.2 or 0.4 g/kg/min over 6 h Placebo

Hypotension or myocardial ischemia at 6 h

SURVIVE [48,49]

1327 DHF

Phase III, R, DB, PG

Levosimendan: 12 g/kg bolus + 0.1 g/kg/min for 50 min for 24 h Dobutamine: 5 g/kg/min for 24 h

Survival at 5, 15, 30 and 180 days

* Originally 600 patients were planned to be enrolled. AHF/LO: acute heart failure syndrome/low output. d: days. BNP: B-type natriuretic peptide. CHF: chronic heart failure. DB: double-blind. DD: double-dummy. DE: dose-escalation. DHF: decompensated heart failure. h: hours. IV: intravenously. MI: myocardial infarction. P: prospective. PA: Parallel-assignment. PC: placebo-controlled. PCWP: pulmonary capillary wedge pressure. PG: parallel-group. R: randomized. SB: single-blind.

function and coronary blood supply to ischemic myocardial areas with a neutral effect on the energy balance after ischemia/reperfusion [38, 39, 41, 43]. In vascular smooth muscle cells, levosimendan opens both mitochondrial and sarcolemmal ATP-dependent K + (K ATP) channels in resistance vessels and Ca2+-activated (KCa) and voltage-dependent K+ channels (KV) in large conductance vessels [39, 44] (Fig. 4). Activation of K+ channels leads to membrane hyperpolarization and lowers [Ca2+]i by

decreasing the open probability of L-type Ca2+ channels and promoting the forward mode of Na+-Ca2+ exchanger. These two mechanisms lead to a decrease in [Ca2+]i, producing systemic, pulmonary and coronary vasodilatation, and antiischemic and anti-stunning effects on the myocardium [38, 39,41]. In addition, membrane hyperpolarization can indirectly decrease Ca2+ sensitivity of contractile proteins [44]. Furthermore, opening of mitochondrial K ATP channels protect the myocardium against ischemia/reper-fusion, myocardial infarction, and perioperative ischemia [45]. Levosimen-

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ferase-2, which is responsible for the metabolism of OR1855 to OR-1896, is polymorphically distributed in the population. OR-1896 has similar pharmacologic properties to levosimendan. It reaches peak plasma concentrations around 2 days after stopping a 24-h infusion, binds to plasma proteins (40%) and presents an elimination half-life of 70-80 h, which explains why the effects of levosimendan persist for 1 week following a 24-h intravenous infusion. Renal dysfunction prolongs the elimination half-life of OR-1896, but it has little effect on levosimendan plasma concentrations, while the pharmacokinetics of levosimendan is unaltered in patients with moderate hepatic impairment. Clinical Studies In patients with AHF, levosimendan improves heart failure signs and symptoms (dyspnea and fatigue), increases stroke volume and cardiac output and reduces pulmonary capillary wedge pressure and systemic and pulmonary vascular resistances [38, 42, 48-50]. These effects persist in patients treated with -blockers, which represents an important advantage against dobutamine [38, 39, 51]. Moreover, in contrast to other inotropics, levosimendan does not have significant effects on myocardial O2 consumption [52] and exerts favourable effects on echocardiographic markers of LV diastolic dysfunction in AHF patients on optimal standard treatment [17]. Levosimendan also reduces plasma concentrations of brain natriuretic peptide (BNP) and endothelin-1 (but not noradrenaline levels), proinflammatory cytokines (interleukin-6) and soluble apoptosis mediators (soluble Fas and Fas ligand) in patients with decompensated heart failure [17, 49, 53, 54]. The effects of levosimendan persist even after infusions lasting for as long as 7 days and no rebound decline in haemodynamic variables is observed after drug withdrawal. In patients with normal cardiac function levosimendan increases heart rate, shortens the sinus node recovery time and the effective refractory periods in atrium, ventricle and atrioventricular node, decreases atrioventricular nodal conduction interval and prolongs the rate-corrected QT interval (QTc) [39,55]. Moreover, in patients with stable ischemic cardiomyopathy high doses of levosimendan increase the frequency of ventricular arrhythmias [49], suggesting that caution should be exerted under these circumstances. These effects may explain the higher incidence of cardiac arrhythmias reported in the SURVIVE and REVIVE-II studies compared with placebo and dobutamine [56, 57]. The long-term effects of levosimendan were studied in several randomized trials (Table 2). The Levosimendan Infusion Versus Dobutamine (LIDO) study compared levosimendan and dobutamine in patients with AHF/LO (LV ejection fraction <35% and pulmonary capillary wedge pressure >15 mmHg) who were believed to require inotropic therapy [51]. A significantly greater proportion of patients in the levosimendan group achieved the primary endpoint (defined as 30% increase in cardiac output and 25% decrease in pulmonary capillary wedge pressure and LV filling pressures at the end of the 24-h infusion) than in the dobutamine group

Fig. (4). The vasodilator effect of levosimendan results from different mechanisms. a) It opens both mitochondrial and sarcolemmal ATP-dependent K+ (K ATP) channels in resistance vessels and Ca2+activated (KCa) and voltage-dependent K+ channels (KV) in large conductance vessels. Activation of K+ channels leads to membrane hyperpolarization and lowers [Ca2+]i by decreasing the open probability of L-type Ca2+ channels and promoting the forward mode of Na+-Ca2+ exchanger (NCX). b) Levosimendan also decreases Ca2+ sensitivity of contractile proteins. (+): activation. (-): inhibition. Modified from Yokoshiki and Sperelakis [44].

dan protects cardiac myocytes from oxidant stressinduced apoptosis via activation of adenosine triphosphatedependent potassium (K ATP) channels, this being a potential mechanism by which this agent might protect cardiac myocytes during episodes of AHF [46]. Other calcium sensitizers (Table 1) may also act as phosphodiesterase inhibitors, increasing cardiac intracellular cAMP levels. In vitro , at high concentrations, levosimendan may act as phosphodiesterase III inhibitor, but whether this effect plays a role at therapeutic concentrations is uncertain [17, 39]. Pharmacokinetics The pharmacokinetics of levosimendan are linear at the therapeutic dose range of 0.05-0.2 g/kg/minute [39, 47]. Levosimendan has high oral bioavailability, but in clinical practice it has only been developed for intravenous administration, reaching steady-state within 5 h of a constant dose infusion. It binds to plasma proteins (95-98%), has an elimination half-life of ~ 1 h, a volume of distribution of 20 L and a total body clearance of approximately 200360 mL/min. Levosimendan is excreted into the small intestine and reduced by intestinal bacteria to an amino phenolpyridazinone metabolite (OR-1855), that by acetylation leads to a Nacetylated conjugate (OR-1896) [39, 47, 48]. The hemodynamic effects of levosimendan are similar in fast and slow acetylators despite the fact that the enzyme N-acetyltrans-

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(28% vs 15%). In a post-hoc analysis, levosimendan significantly reduced mortality (26% vs 38%) and the median number of days alive out of hospital through the first 180 days (157 days vs 133 days) as compared to dobutamine. In this study levosimendan was well tolerated, but headaches or migraines were more frequent in the levosimendan group, while adverse cardiac effects (rhythm disorders and myocardial ischemia) were more common with dobutamine. The Randomized Study on Safety and Effectiveness of Levosimendan in Patients with Left Ventricular Failure Due to an Acute Myocardial Infarct (RUSSLAND) trial randomized patients with acute myocardial infarction to levosimendan or placebo [58]. Levosimendan did not affect the incidence of hypotension or myocardial ischemia during the 6-h infusion (primary end points), but significantly reduced mortality and worsening HF as compared to placebo (2.0% vs 5.9%) and over 24 hours (4.0% vs 8.8%). Mortality was also significantly lower with levosimendan at 14 days (11.7% vs 19.6%) and 180 days post-randomization (22.6% vs 31.4%). The Calcium Sensitizer or Inotrope or None in Low-Output Heart Failure (CASINO) trial compared the 24-h intravenous infusion of levosimendan, dobutamine and placebo in patients hospitalized with HF (NYHA class IV and LV ejection fraction 35%). The study was terminated prematurely because of a clear mortality benefit at 6 months of levosimendan over both placebo and dobutamine (15.3% vs 39.6% and 24.7%) [59]. However, in another two trials no differences were found in mortality between levosimendan and dobutamine or placebo. The Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) study compared the effects of levosimendan and dobutamine in patients hospitalized with AHF (LV ejection fraction 30%, oliguria and/or dyspnea at rest), who required intravenous inotropic therapy [56]. Levosimendan decreased plasma BNP levels at 24 h, but there were no differences in all-cause mortality at 180 days (the primary end point) between levosimendan (26%) and dobutamine (28%) or at 31 days, number of days alive out of the hospital, patient global assessment, and cardiovascular mortality at 180 days. In this study, a higher incidence of atrial fibrillation, hypokalemia, and headache in the levosimendan group and of heart failure in the dobutamine group. The randomized multicenter evaluation of intravenous levosimendan efficacy vs. placebo in the short-term treatment of decompensated HF (REVIVE) study randomized patients with AHF (LV ejection fraction 35%) and dyspnea at rest requiring intravenous diuretics to levosimendan or placebo, in addition to standard care. The end point was patient status: improved (self-reported), worsened (death or required intravenous treatment for HF during the 5-day trial duration) or unchanged. In the pilot REVIVE1 study during the 5 days of the study, a clinical improvement was observed more frequently with levosimendan than placebo (49% vs 33%) [60]. Levosimendan decreased plasma levels of BNP and creatinine at 24 h and 5 days and shortened the lengths of hospitalization (5.7 vs 6.8 days) and stay in the intensive care units (4.4 vs 5.1 days) [61]. The

REVIVE-2 trial randomized the next 600 patients (mean LV ejection fraction 23%). The primary end point was the proportion of patients classified as improved at 5 days. By day 5, significantly 33% more patients in the levosimendan group improved (19.4% vs 14.6%) and 30% fewer worsened (19.4% vs 27.2%) compared with the control group. Levosimendan also decreased BNP levels at 24 h and at 5 days and shortened hospital stay as compared to placebo (7.0 vs 8.9 days) [62]. However, a higher incidence of headache, hypotension, ventricular extrasystoles, ventricular tachycardia and atrial fibrillation, and a trend toward increased all-cause mortality at 90 days (15.1% vs. 11.6% for placebo) was observed in the levosimendan group. Thus, the SURVIVE and REVIVE trials demonstrated that in patients with AHF and a clinical indication for inotropic therapy, levosimendan improves symptoms and hemodynamics more than placebo, but produces a greater incidence of adverse events, and similar mortality rates, than dobutamine and placebo. Side Effects Levosimendan is generally well tolerated. The most common side effects are related to its vasodilator properties (headache, dizziness, nausea and hypotension) [39, 51, 54, 58-60]. Hypotension which may cause myocardial ischemia, cardiac arrhythmias, and hypoxemia [49, 56, 62] is uncommon when the treatment remains within the recommended doses [49, 58]. Mild hypokalemia occurs in 5% of patients. Levosimendan does not present serious interactions with other drugs commonly prescribed to heart failure patients, including angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers, diuretics, nitrates, amiodarone, -blockers and digoxin [49,56,62]. The combination of levosimendan with ACEI produces only minor decreases in mean arterial blood pressure when levosimendan is administered at the recommended dose range [39, 49]. Future Developments At the present time, levosimendan is indicated in patients with AHFS/LO secondary to cardiac systolic dysfunction without severe hypotension [4]. However, and because of the contradictory results observed on mortality rates in randomized clinical trials, further studies are needed in order to define the safest dosing and timing of infusion in the daily clinical practice, the subset of patients who may benefit more from levosimendan and whether levosimendan induces cardiac arrhythmias in AHF patients compared with conventional inotropics. Istaroxime (PST-2744) This agent [(EZ)-3-((2-aminoethoxy)imino)androstane-6, 17-dione hydrochloride] exhibits a dual mecanism of action (Fig. 1). It inhibits Na+-K+ ATPase activity at the sarcolemma, producing an increase in [Ca2+]i during the systole and an inotropic response, and stimulates SERCA2a activity, leading to rapid sequestration of cytosolic Ca2+ into the SR during diastole, which promotes myocardial relaxation [63, 64]. Thus, istaroxime exerts both positive inotropic and lusitropic effects.

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In cardiac muscle strips from patients undergoing cardiac transplantation, istaroxime increases the developed tension and the maximum and minimum first derivative of tension and improves SERCA2a activity in SR microsomes at physiologic free Ca2+ concentrations [64]. In dogs with chronic ischemic heart failure, intravenous infusion of istaroxime (0.5-5 g/kg for 1 h) increases LV ejection fraction in a dose-dependent manner, decreases LV end-diastolic and endsystolic volumes and improves myocardial relaxation, without increasing myocardial O2 consumption [65-67]. In this model, istaroxime has no effect on heart rate and produces only a modest reduction in blood pressure at high doses, but does not produce proarrhythmic or ischemic effects, changes in intracardiac conduction velocity or PR and QT intervals [65, 66]. Clinical Trials In a phase I-II trial, 18 patients with chronic stable heart failure and LV dysfunction (NYHA class II or III, LV ejection fraction 27% and pulmonary capillary wedge pressure 25 mm Hg) were exposed to 4 sequentially increasing 1-h infusions of istaroxime (0.005-5 g/kg/min for 6 h) or placebo [68]. The hemodynamic activity of the drug appeared at a dose of 1.01.67 g/kg/min administered over 1 h. At doses 1 g/kg/min, istaroxime lowered pulmonary capillary wedge pressure (the primary end point) and increased cardiac contractility and cardiac index. A lusitropic effect, as assessed by increased mitral deceleration time, was observed only at the highest dose compared with placebo. During the infusion of 0.5 and 5 g/kg/min peak plasma concentrations (14.46 and 90.9 ng/mL, respectively) were obtained after 37.5-45.0 minutes, suggesting that plasma concentration reached the plateau near the end of 1-h infusion. The mean half-life was 6 and 18.3 minutes at 1.67 and 5 g/kg/min, respectively, but the half-life of its weakly active metabolite PST2915 was longer (207.4 and 273.4 minutes, respectively). Istaroxime was well tolerated at doses up to 3.33 g/kg/min. Side effects (constipation, headache, nausea and infusion site pain) disappeared within minutes after the infusion ended. No changes in laboratory parameters, heart rate and blood pressure or cardiac arrhythmias were observed. The phase II HORIZON-HF (Hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: a randomized control trial in patients hospitalized with heart failure) trial compared the effects of istaroxime and placebo, in patients with AHF symptoms requiring hospitalization (LV ejection fraction 35%, NYHA II-III, pulmonary capillary wedge pressure > 20 mm Hg and systolic/diastolic blood pressure < 150/90 mm Hg) [69]. At all doses, istaroxime decreased pulmonary capillary wedge pressure (the primary end point), right atrial pressure, heart rate (and QTc interval) and serum Na+ and increased cardiac index and systolic blood pressure. At 1.5 g/kg/min, istaroxime decreased LV end-diastolic volume and exerted a favorable lusitropic effect, as assessed by increased mitral deceleration time, but no changes in neurohormones, renal function or troponin I were observed.

However, no data were provided on symptomatic improvement or diuresis. During the infusion, plasma istaroxime levels increased rapidly, reaching steady state levels after 4 to 5 h. The drug had a short half-life (< 1 h), probably due to the high systemic clearance (3.5-3.9 L/kg) despite a large Vd (2 L/kg). Istaroxime is not excreted by the kidney and is converted into 3 metabolites less active than the parent compound. The main side effects were nausea, vomiting and pain at the infusion site, and no major adverse events occurred during the trial. Even when these results suggest that istaroxime may represent a novel, effective and safe inotropic agent for the treatment of AHF/LO patients, there are several limitations with this trial. This was a very short-term (6 h) dose ranging study performed in patients with mild to moderate symptoms and no evidence for hypotension or end-organ dysfunction and the decreases in pulmonary capillary wedge pressure were quite modest, and the improvement in cardiac output and lusitropic function occurred only at the highest dose studied. Thus, the future of istaroxime will depend on its effects on in-hospital and post-discharge clinical outcomes in patients, especially in patientswith AHF/LO. A phase II trial is ongoing to assess the safety and efficacy of istaroxime in patients hospitalized for acute decompensated heart failure not requiring inotropic therapy (ClinicalTrials.gov. Identifier: NCT00838253). Cardiac Myosin Activators Both -adrenergic receptor agonists and phosphodiesterase III inhibitors increase the [Ca2+]i, which indirectly activates cardiac myosin and the velocity of cardiac contractility and shortens systolic ejection time. In contrast, cardiac myosin activators are a novel class of inotropic agents that directly activate the ATPase activity of cardiac myosin by accelerating the rate of actin-dependent phosphate release of the crossbridge (step heighlighted in Fig. 3), and thus, the entry into the force producing state [70-73]. In rat isolated cardiac myocytes, CK-1827452 (CK-452), a selective cardiac myosin activator without phosphodiesterase III inhibitor activity, increases fractional shortening and the time to peak parameter cycle without direct effects on [Ca2+]i, SR Ca2+ content or the Na+ - Ca2+ exchanger [74, 75]. In anesthetized rats, CK-452 (0.25-2.5 mg/kg/h) significantly increases fractional shortening without significant changes in heart rate and blood pressure. Similar results are observed in anesthetized dogs (0.03-1 mg/kg/h) and in rats with heart failure induced by ligation of the left coronary artery [75]. In a dog model of heart failure induced by myocardial infarction combined with rapid ventricular pacing, CK-1827452 (0.5 mg/kg bolus, then 0.5 mg/kg/min for 6-8 h) significantly increases LV systolic function by lengthening LV systolic ejection time without affecting the velocity of cardiac contraction, myocardial oxygen consumption, arterial blood presure, coronary blood flow or diastolic function [70,73,76]. In conscious dogs with congestive heart failure or with heart failure and severe LV hypertophy, CK-1827452 increases LV systolic ejection time, systolic wall thickening,

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fractional shortening and stroke volume and decreases LV end-diastolic pressure, mean left atrial pressure, and heart rate [77]. However, CK-1827452 does not modify the endo/ epi myocardial blood flow ratio or arterial and coronary sinus O2 content. In a Phase I dose-ranging study 34 healthy volunteers were enrolled in 4 ascending dose cohorts. An intravenous infusion of CK-1827452 (0.005-1 mg/kg/h) or placebo was administered over a 6-h period, on 4 separate days 1 week apart [78]. Each subject received 3 ascending CK-1827452 doses with a placebo infusion randomized into the treatment sequence. CK-1827452 dose-dependently increased LV ejection fraction and fractional shortening and this increase was associated with a prolongation of systolic ejection time versus placebo. The lowest concentration at which a significant mean increase in systolic ejection time occurred was 51-100 ng/mL and for LV ejection fraction and fractional shortening 151-200 ng/mL [79]. Unlike Ca2+-dependent inotropes, CK827452 did not decrease isovolumic contraction time or increase systolic tissue velocity. At the end of the 6-h infusion at the maximum tolerated dose (0.5 mg/kg/h), mean standing systolic/diastolic blood pressure decreased 11/7.4 mm Hg versus placebo, but no changes were observed in the PR, QT, or QTc intervals. CK-1827452 exhibited linear, doseproportional pharmacokinetics across the range of doses studied and was well-tolerated [74, 75]. Side effects (postural dizziness, headache, chest tightness, palpitations and light-headedness) resolved promptly after discontinuation of drug infusion. A phase IIa double-blind, randomized, placebo-controlled study evaluated the safety and tolerability of CK-1827452 administered as an intravenous infusion in 28 patients with LV ejection fraction <40% treated with an ACE inhibitors (or angiotensin receptor blockers) and a -blocker, diuretics [80, 81]. In cohorts 1-4 patients received 3 infusions of escalating active doses and 1 placebo treatment randomized into the dose escalation sequence to maintain blinding. Each of the four infusions was at least 1 week apart. Duration of infusion was 2 h in cohorts 1 (loading dose of 0.125-0.5 mg/kg for 1 hour followed by 1 hour of 0.0625-0.25 mg/kg) and 2 (0.5-1 mg/kg/h followed by 0.25-0.5 mg/kg/h), and 24 h in cohorts 3 and 4 (0.25-1 mg/kg for 1 hour, followed by 22 hours at 0.125-0.5 mg/kg or 0.025-0.1 mg/kg/min, respectively). CK-1827452 significantly increased systolic ejection time and fractional shortening at plasma concentrations greater than 100 ng/mL, stroke volume at concentrations greater than 200 ng/mL and cardiac output at greater than 300 ng/mL. At plasma levels greater than 400 ng/mL, increases in stroke volume and cardiac output appeared to plateau in association with a concentration-dependent decline in heart rate. Statistically significant correlation concentration dependence was observed for increases in systolic ejection time, stroke volume, fractional shortening and ejection fraction and for decreases in heart rate and LV end systolic volume. Three serious adverse events were reported, but only one of which was deemed related to CK-1827452. Five

patients were discontinued from the trial; two of them had signs and symptoms associated with clinical intolerance due to excessive concentrations of CK-1827452 and 1 patient with severe hypertension had an asymptomatic increase in troponin levels following completion of the CK-1827452 infusion. An oral liquid and capsule formulation of CK-1827452 is also under development for the treatment of chronic heart failure. A phase 1 clinical trial found that oral bioavailability approaches 100%; food did not affect bioavailability but delayed drug absorption [82]. CK-1827452 in both oral and intravenous formulations reached peak plasma concentrations (57-72 and 93 ng/mL, respectively) after 1-3 h. The half-life was 18 h after intravenous infusion and 20-25 h after oral administration. Because of the novelty of the mechanism of action, the absence of phase III clinical trials and the lack of long-term safety data, at the present time, it is difficult to predict whether cardiac myosin activators can be a safe and effective therapy in the treatment of AHFS. Three ongoing phase II randomized, double blind, placebo controlled trials analyze the pharmacokinetics, efficacy and safety of intravenous and oral CK-1827452 in patients with ischemic cardiomyopathy (NCT00682565), and of intravenous CK-1827452 in patients with stable heart failure (NCT00624442 and NCT00748579). CONCLUSIONS AHF is a complex condition associated with substantial morbidity and mortality and a leading health care cost. For the majority of patients with AHF, who present high or normal systemic blood pressure and no clinical evidence of hypoperfusion, there are no data to support the use of inotropic therapy. However, inotropics have a role in the short-term stabilization of patients with evidence of AHF/LO who present a high morbidity and mortality. In these patients, positive inotropic drugs improve clinical status, cardiac output, blood pressure and end-organ perfusion. However, their use is associated with increased myocardial O2 consumption, cardiac arrhythmias and even an increased mortality, particularly in patients with coronary artery disease. Thus, there is an unmet need of novel inotropic agents that increase cardiac contractility without increasing [Ca2+]i and myocardial O 2 consumption or producing cardiac arrhythmias. There are three main groups of drugs under development: Ca2+ sensitizers (levosimendan), luso-inotropic agents (istaroxime) and cardiac myosin activators (CK-1827452). Phase III trials with levosimendan led to contradictory results on its effects on mortality risk as compared with dobutamine and placebo, while istaroxime and cardiac myosin activators are being presently studied in phase II trials. Thus, until now, any new agent has demonstrated a clear benefit in terms of long-term clinical outcomes compared to placebo or conventional therapies. Thus, large-scale, randomized, placebo-controlled trials with outcome-driven data, including prevention of rehospitalizations and improvement of survival, are needed to fully define their role in the treatment of AHF/LO patients.

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ACKNOWLEDGEMENTS This work was supported by CICYT (SAF2005-04609, SAF2008-04903, PI080665), Red HERACLES (RD06/0009) and Lilly Foundation Grants. REFERENCES
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Received: 02 February, 2009

Revised: 23 April, 2009

Accepted: 19 May, 2009