New Therapeutic Targets for the Develop- ment of Positive ... · decompensated HF (ADHF) is the...

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Discovery Medicine, volume 12, Number 66, pages n-n, November 2011

Abstract: Heart failure is associated with significantmorbidity and mortality despite significantadvances in therapies developed for it. Becauseimpaired cardiac contractility plays a central role insystolic HF, drugs increasing cardiac contractility(positive inotropics) have been widely used for HFtreatment. Conventional inotropics that increasecAMP and intracellular Ca2+ levels improve symp-toms and hemodynamics, but also increase myocar-dial O2 demands, cardiac arrhythmias, and mortal-ity, which decreases their overall therapeutic bene-fit-risk ratio in HF. Thus, we need new inotropicagents with different mechanisms of action thatimprove clinical outcomes. This review describes themechanism of action and preliminary clinical resultsobtained with these new investigational positiveinotropic agents. [Discovery Medicine 12(66):381-392,November 2011]

Introduction

Heart failure (HF) comprises a heterogeneous group ofsyndromes with different clinical presentations, history,pathophysiology, prognosis, and response to specifictherapies (Dickstein et al., 2008; Hunt et al., 2009). HFrepresents a major health problem due to its high preva-lence, high rates of morbidity and mortality, and signif-icant healthcare costs (Roger et al., 2011). Acutedecompensated HF (ADHF) is the leading hospital dis-

charge diagnosis in patients older than 65 years and thistrend will continue due to the progressive aging of thepopulation, improved survival after myocardial infarc-tion, and improved prevention of sudden cardiac death(Dickstein et al., 2008; Fang et al., 2008). In the last 30years, advances in pharmacological and device-basedtreatment have improved symptoms, hemodynamics,and outcomes in patients with chronic HF (CHF).Conversely, and despite many promising new drugs,treatment of ADHF has not changed considerably overthis period as no drug has yet been shown to reducemortality in this population (Dickstein et al., 2008;Hunt et al., 2009; Gheorghiade and Pang, 2009) and thethree drugs approved (milrinone, nesiritide, and levosi-mendan) have been under further study because of con-cerns about their safety and efficacy (Gheorghiade andPang, 2009; Tamargo and López-Sendón, 2011). Giventhe lack of effective and safer new therapies, the focusof ADHF management has shifted to optimizing exist-ing therapies.

HF results from any structural or functional cardiac dis-order that impairs the ability of the ventricles to fill withor eject blood (Hunt et al., 2009). Impaired cardiac con-tractility plays a central role in systolic HF, activating aseries of maladaptive hemodynamic, structural and neu-rohormonal responses which contribute to HF progres-sion (Tamargo and López-Sendón, 2011). Based on thisparadigm, drugs increasing cardiac contractility (posi-tive inotropics) were the first developed for HF treat-ment. This article analyzes the disadvantages of con-ventional positive inotropic agents. New pharmacolog-ical strategies under early clinical development are alsodescribed (Table 1). The mechanisms of action of thesenew drugs and the most relevant clinical trials, recentlypublished or ongoing, are summarized in Figures 1 and2 and Table 2, respectively.

Cardiac Excitation-Contraction Coupling

Excitation-contraction coupling is the process by which

New Therapeutic Targets for the Develop-

ment of Positive Inotropic Agents

JuAN TAmArgo, JuAN DuArTe, rIcArDo cAbAllero, AND evA DelpóN

Juan Tamargo, M.D., Ph.D., Ricardo Caballero,

Ph.D., and Eva Delpón, Ph.D., are at the Department

of Pharmacology, School of Medicine, Universidad

Complutense, Madrid, 28040, Spain.

Juan Duarte, Ph.D., is at the Department of

Pharmacology, School of Pharmacy, University of

Granada, Granada, 18071, Spain.

Corresponding author: Professor Juan Tamargo ([email protected]).

© Discovery Medicine. All rights reserved.

Discovery Medicine®

www.discoverymedicine.comISSN: 1539-6509; eISSN: 1944-7930

http://www.discoverymedicine.com




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membrane depolarization activates cardiac contraction(Bers, 2008) (Figure 1). During the plateau phase of thecardiac action potential, Ca2+ entry via voltage-activat-ed L-type Ca2+ channels (ICa) triggers Ca2+ release afteractivation of ryanodine receptors (RyRs) of the sar-coplasmic reticulum (SR), producing a rise in [Ca2+]i

(Ca2+ transients). Ca2+ released from the SR diffusesthrough the cytosol, binds to troponin C (TnC) andinduces conformational changes in the thin (actin-TnI-TnT-tropomyosin) myofilament which allows themyosin head to attach to actin and increase contractili-ty. During relaxation, intracellular Ca2+ concentration([Ca2+]i) decreases via the SR Ca2+-ATPase(SERCA2a), which increases Ca2+ uptake into the SR,and the sarcolemmal Na+/Ca2+ (NCX) exchanger thatfacilitates Ca2+ extrusion outside the cell.

SR Ca2+ content is determined by SR Ca2+ uptake viaSERCA2, diastolic Ca2+ leak via RyRs, and bindingcapacity of intra-SR Ca2+ binding sites. SERCA2aactivity is regulated by phospholamban (PLB). PLBphosphorylation via cAMP-protein kinase A (PKA) orCa2+/calmodulin-dependent protein kinase II (CaMKII)

relieves its inhibitory effect on SERCA2 and enhancesCa2+ uptake (Bers, 2008). Diastolic SR Ca2+ leak is pre-vented by the RyR-stabilizing protein calstabin2, whichmaintains RyRs being closed, whereas PKA- andCaMKII-induced RyR2 hyperphosphorylation dissoci-ates calstabin2 from RyRs and increases open channelprobability and diastolic Ca2+ release.

Positive Inotropic Drugs: Advantages andDisadvantages

Because decreased cardiac contractility plays a centralrole in systolic HF, it seems logical to treat systolic HFwith positive inotropic agents. Short-term treatmentwith conventional intravenous inotropes that increasecardiac cAMP levels (Table 1) improves symptoms(dyspnea) and hemodynamics (increases stroke volumeand left ventricular ejection fraction-LVEF and reducesLV filling pressures) of ADHF patients. However, theirbenefits can be counteracted by serious adverse effects,including neurohumoral activation, maladaptativeremodeling, intracellular Ca2+ overload [which increas-es myocardial oxygen demands (MVO2) and induces

Discovery Medicine, volume 12, Number 66, November 2011

New Therapeutic Targets for the Development of positive Inotropic Agents

Table 1. Conventional and Developmental Positive Inotropic Agents

Conventional positive inotropic drugs

1. Na+-K+-ATPase inhibition: Digoxin2. Activation of the cAMP-PKA pathway

• Beta-adrenoceptor stimulation: Dopamine, Dobutamine• Phosphodiesterase III inhibition: Enoximone, Milrinone

3. Calcium sensitization (plus phosphodiesterase III inhibition): Levosimendan

New positive inotropic drugs under development

1. Na+-K+-ATPase inhibition and SERCA2a activation: Istaroxime2. Cardiac myosin activators: Omecamtiv mecarbil 3. Modulation of Ca2+-handling proteins:

• SERCA2a activation: AVV1/SERCA2a, Allosteric modulators (CDN1054)• SERCA2a activation plus vasodilation: Nitroxyl donors (CXL-1020)• Ryanodine receptor-stabilization: K201 (or JTV519), Rycals (CPU0213, S 107, S 44121), Ivabradine, CaMKII

inhibitors (KN-93) • Protein phosphatase (PP1/PP2) inhibition: Neuroregulin-1

4. Metabolic modulation:• Fatty acid oxidation inhibitors:

- Carnitine palmitoyl transferase type 1 inhibitors: Etoxomir, Oxfenicine, Perhexiline, Pyruvate- Long-chain 3-ketoacyl coenzyme A thiolase inhibitors: Trimetazidine- Malonyl-CoA decarboxylase inhibitors: CBM-300864- Reduction of FA plasma levels and its myocardial uptake: Nicotinic acid and analogues (Acipimox)

• Glucose uptake stimulation: Glucagon-like peptide-1 (GLP-1) - GLP-1 agonists (Exenatide, Liraglutide), DPP-IV inhibitors (Alogliptin, Linagliptin, Saxagliptin, Sitagliptin)

5. Others:• Na+-H+ exchanger activation: Apelin • Na+-K+-ATPase inhibition plus vasodilation: Crataegus extract 1442 • Ca2+ transients increase: Thyroid hormones, Growth hormone

Abbreviations: CaMKII, Ca2+/calmodulin-dependent protein kinase II; cAMP: 3’-5’-cyclic adenosine monophosphate; DPP-IV, dipep-tidyl peptidase-IV; FA, free fatty acids; PKA, protein kinase A; PLN, phospholamban; SR, sarcoplasmic reticulum.


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arrhythmias], and hypotension which decreases coro-nary perfusion (Abraham et al., 2005; Elkayam et al.,2007; Teerlink et al., 2009; Tamargo et al., 2010). Inpatients with hibernating myocardium these inotropicscan result in a supply-demand mismatch that increasesunderlying ischemia, accelerates HF progression, andincreases mortality compared with placebo (Elkayam etal., 2007; Teerlink et al., 2009). Therefore, despite theshort-term symptomatic and hemodynamic improve-ments, conventional inotropics may increase long-termmortality, which limits their usefulness in ADHFpatients.

Clinical guidelines limited the use of inotropic drugs topatients with low LVEF, peripheral hypoperfusion [sys-tolic blood pressure (SBP) <100 mmHg, cold skin,renal impairment] in the presence of signs of congestionrefractory to diuretics and/or vasodilators (Dickstein et

al., 2008; Hunt et al., 2009). These patients (2-8% ofthose hospitalized for ADHF) present higher in-hospitaland post-discharge mortality than those withnormal/high SBP (Adams et al., 2005; Gheorghiade andPang, 2009). Inotropics can also be used to stabilizepatients at risk of progressive hemodynamic collapse oras a “bridge” until other life-saving therapies (mechan-ical circulatory support, ventricular assist devices, orcardiac transplantation) can be undertaken. In a smallnumber of end-stage patients in whom other therapiesare not appropriate, inotropics may be considered as apalliative option of end-of-life care. Inotropic agentsare also indicated in outpatients with HF with persistentsevere symptoms, frequent hospitalizations caused byepisodes of fluid retention and/or peripheral hypoperfu-sion and/or signs of hepatic or renal dysfunction [classIV of the New York Heart Association (NYHA) classi-

Figure 1. Mechanisms of action of positive inotropic agents. AAV1/SERCA2, adeno-associated viral-vector (AAV1)carrying the SERCA2 gene; AC, adenylyl cyclase; AMP, adenosine monophosphate; APJ, apelin receptor; cAMP, 3’-5’-cyclic adenosine monophosphate; DAG, diacylglycerol; Gq/Gs, protein Gq and Gs; HNO, nitroxyl anion; IP3, inos-itol triphosphate; LTCC, L-type Ca2+ channel; NCX, Na+/Ca2+ exchanger; NHE, Na+-H+ exchanger; NRG-1,Neuregulin 1; PDE3, phosphodiesterase 3; PDE3Is, phosphodiesterase 3 inhibitors; PKA, protein kinase A; PKC, pro-tein kinase C; PLB, phospholamban; PMCA, sarcolemmal Ca2+-ATPase; PP1/2, protein phosphatases 1 and 2; RyR2,ryanodine receptor; SERCA2a, SR Ca2+-ATPase; SR, sarcoplasmic reticulum; TH, thyroid hormones; Tm,tropomyosin; Tn, troponin; TnC, troponin C; red lines, inhibition; blue lines, activation.


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fication, stage D of the ACCF/AHA classification].

Digoxin increases SR Ca2+ load by blocking the Na+-K+ ATPase. In patients with symptomatic HF and atrialfibrillation it can be used to slow rapid ventricular rate.In patients with HF and low LVEF in sinus rhythm,digoxin does not alter all-cause mortality but improveshemodynamics and reduces HF hospitalizations with-out negatively affecting SBP or renal function (TheDigitalis Investigation Group, 2009). However, digoxinhas not been studied in ADHF patients.

The limitations of conventional inotropes have stimu-lated the development of novel drugs that can act syn-ergistically with standard treatments to relieve HF signsand symptoms, improve cardiac output and outcomeswithout increasing cAMP levels, [Ca2+]I, or MVO2,worsening cardiac metabolism, or producing proar-rhythmia or myocardial damage.

New Positive Inotropic Agents

1. Levosimendan binds to the N-terminal domain ofTnC in a Ca2+-dependent manner and stabilizes theCa2+-TnC complex, increasing myofilament Ca2+ sen-sitivity and contractility without changes in [Ca2+]i orMVO2 (De Luca et al., 2006; Tamargo et al., 2010).Levosimendan also produces systemic and coronaryvasodilation through the opening of K+ channels [ATP-dependent (KATP) channels in resistance vessels andCa2+-activated (KCa) and voltage-dependent channels(Kv) in conductance vessels] and, at high concentra-tions, it inhibits phosphodiesterase III activity(Tamargo et al., 2010).

In ADHF, levosimendan improves symptoms andhemodynamics, but conflicting results have beenobserved on mortality; additionally, levosimendanincreases adverse effects (hypotension, arrhythmias) as

Figure 2. Cardiac metabolic modulation. AC, adenylyl cyclase; CoA, coenzyme A; CPT-1/2, carnitine palmitoyl-transferase type 1 and 2; DPPIV, dipeptidyl peptidase-IV; FATP, fatty acid transport protein 1; FFA, free fattyacids; GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor; G-6-P, glucose 6-phosphate;GLUT1/4, glucose transporters type 1 and 4; Gs, G protein Gs; IMM/OMM, inner and outer mitochondrial mem-branes; 3-KAT, 3-ketoacyl CoA thiolase; MCD, malonyl-CoA decarboxylase; MCT, monocarboxylate trans-porter; PDH, pyruvate dehydrogenase; TCA, citric acid cycle; red lines, inhibition.


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Table 2. Major Randomized, Double-blind, Placebo-controlled Clinical Trials Comparing the Effects of New Developing Drugs in

Patients with Heart Failure

Acronym

Reference (ClinicalTrial Registration)

Patients (n) Treatment Primary Endpoints Outcomes

HORIZON-HFGheorghiade et al.,2008; Shah et al.,2009

120; ADHF, NYHA II-III Istaroxime: 0.5, 1, and 1.5μg/kg/min for 6 h

Changes in PCWP after 6 h ofcontinuous i.v. infusion

Istaroxime improves PCWP andpossibly diastolic function

Omecamtiv mecarbilTeerlink et al., 2011

34, healthy men Omecamtiv mecarbil: 0.005 to 1.0mg/kg per h for 6 h

Maximum tolerated dose and drugplasma concentrations

Omecamtiv mecarbil dose-depend-ently increases systolic ejectiontime, LV stroke volume and LVEF

Omecamtiv mecarbilCleland et al., 2011

45, CHF and LV systolicdysfunction

Omecamtiv mecarbil IV over 2,24, or 72 h

Safety and efficacy of the drug Omecamtiv mecarbil improvessymptoms and hemodynamics andwas well tolerated

Omecamtiv mecarbil(NCT01300013)*

600, LV dysfunction hospi-talized for acute HF

48-h infusion of omecamtivmecarbil

Effects on dyspnea Recruiting

Japp et al., 2010 26, volunteers18, CHF (NYHA II-III)

Apelin-13: 30, 100, or 300nmol/min for 5-min

Effects of apelin on peripheral,cardiac, and systemic hemody-namics

Apelin-13 increases cardiac indexand causes peripheral and coronaryvasodilatation

INO-apelin (NCT01179061)*

24; Fase I, NYHA II-IV,LVEF <35%

Apelin IV for 6 h Cardiac output at 6 h Recruiting

NRG-1Gao et al., 2010

44, CHF NYHA II-III Rh-NRG-1 (0.3, 0.6, or 1.2μg/kg/day) for 10 days

Safety and efficacy Rh-NRG increased LVEF andreduced reducing end-diastolic andend-systolic volume

CUPIDJessup et al., 2011

39; advanced HF, NYHA III-IV, LVEF ≤35%

AAV1/SERCA2a: 10-13, 3x10-12,6x10-11 DNase-resistant particles

Safety and activity/efficacy AAV1/SERCA2a improves symp-toms and LVEF and remodeling

SERCA Gene TherapyTrial(NCT00534703)*

16, HF patients that havereceived an LV assist device

AAV1/SERCA2a: 5x10-12

DNase-resistant particlesPlacebo

Level and extent of gene expres-sion measured by PCR after 2years

Not yet open for recruiting

S 44121(ISRCTN14227980)

160, CHF at risk for ventric-ular arrhythmia

3 oral dosages of S 44121 for 12weeks

Efficacy measurements recordedon the Holter ECG

Ongoing

ERGOHolubarsch et al.,2007

347, CHF (NYHA class II-III)

Etomoxir. 40 and 80 mg for 6months

Maximal exercise tolerance testand submaximal 6-min corridorwalk test

No changes in the 6-min or walktest or in echocardiographicalparameters

Halbirk et al., 2010(NCT00549614)*

24, CHF (NYHA II-III),LVEF 26%

Acipimox: 250 mg 4 times dailyfor 28 daysPlacebo

LVEF, exercise capacity and mus-cular metabolism

Acipimox does not modify systolicor diastolic cardiac function orexercise capacity

Abozguia et al., 2010 46, symptomatic hyper-trophic cardiomyopathy

Perhexiline 100 mgPlacebo

Peak oxygen consumption (peakV̇O2)

Perhexiline ameliorates cardiacenergetic impairment, correctsdiastolic dysfunction, and increasesexercise capacity

HERB-CHFZick et al., 2008

120; CHF (NYHA II-III),LVEF <40%

WS 1442: 450 mg bid for 6months

6-min walk at six months WS 1442 provides no symptomaticor functional benefit

SPICEHolubarsch et al.,2008

2681; NYHA class II-IV,LVEF ≤35%

Crataegus extract WS 1442, 900mg/day, for 24 months

Time to first cardiac event (HFdeath, hospitalization, or sus-tained increase in diuretics)

WS 1442 does not reduce HF pro-gression, but can reduce the inci-dence of sudden cardiac death inpatients with an LVEF ≥25%

DITPAGoldman et al., 2009

86, CHF (NYHA II-IV) DITPA up to 360 mg/day Composite endpoint that classifiespatients as improved, worsened,or unchanged based on symptomchanges and cardiovascular mor-bidity/mortality

DITPA produces no symptomaticbenefit in CHF and is poorly toler-ated

CXL-1020 NCT01092325*

28, CHF Dose-Escalation Study

Intravenous infusion of one of 3active dosages of CXL-1020 for 4 h

Safety and tolerability from initialexposure to 30 days followingexposure

Completed

CXL-1020 NCT01096043*

66, systolic HF IV infusion of three doses ofCXL-1020 up-titrated over 6 h

Safety and hemodynamic effectsat 6 h following start of dosing

Recruiting

Abbreviations: ADHF, acute decompensated heart failure; CHF, chronic heart failure; FA, fatty acids; h, hours; HF, heart failure; IV, intravenously; LV, left ventric-ular; LVEF, left ventricular ejection fraction; MAP, mean arterial pressure; MI, myocardial infarction; NYHA, New York Heart Association functional classifica-tion of HF; PCR, polymerase chain reaction; PCWP, pulmonary capillary wedge pressure; *, www.clinicaltrials.gov.


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compared with placebo or dobutamine (De Luca et al.,2006; Tamargo et al., 2010). In a meta-analysis, levosi-mendan improved hemodynamics as compared toplacebo or dobutamine and reduced mortality whencompared to dobutamine (Delaney et al., 2010). Thislatter finding might result from a higher mortality asso-ciated with dobutamine, rather than a reduction in mor-tality associated with levosimendan; indeed, dobuta-mine increased mortality when compared to placebo.

2. Istaroxime inhibits Na+-K+-ATPase activity and con-sequently increases [Ca2+]i during the systole and car-diac contractility. It also stimulates SERCA2a, an effectthat increases SR Ca2+ uptake during diastole andimproves relaxation (Tamargo et al., 2010). In patientsadmitted with HF and reduced systolic function,istaroxime reduces pulmonary capillary wedge pressure(PCWP) and diastolic stiffness without changes inMVO2, neurohormones, or renal function (Gheorghiadeet al., 2008; Shah et al., 2009). Unlike conventional i.v.inotropic agents, istaroxime increases SBP and decreas-es heart rate. However, this short-term study enrolledpatients without hypotension or end-organ dysfunctionnot requiring inotropics; the decrease in PCWP wasmodest; and cardiac index increases and LV end-dias-tolic volume decreases only at the highest dose studied.

3. Omecamtiv mecarbil is a cardiac myosin activator. Itbinds to the catalytic cardiac myosin domain, acceler-ates the transition rate of myosin from a weakly to thestrongly actin-bound force-generating state, so thatmore cross-bridges are activated per unit of time andcardiac contractility increases (Malik et al., 2011).Conventional inotropics increase the rate of LV pressuredevelopment (dP/dtmax) and shorten LV systolic ejectiontime (SET). However, in healthy volunteers (Teerlink etal., 2011) and in patients with stable CHF (Cleland etal., 2011) omecamtiv mecarbil increases SET, fraction-al shortening, and LVEF, and reduces systolic/diastolicventricular volumes, without changing dP/dt, Ca2+ orcAMP levels, blood pressure, or MVO2, thus increasingmyocardial efficiency. The drug is well tolerated up to0.625 mg/kg/h without off-target adverse events; athigher concentrations symptoms of ischemia mayappear, probably due to excessive prolongation of sys-tolic ejection time. Interestingly, omecamtiv mecarbilhas no deleterious effect on exercise tolerance inpatients with ischemic cardiomyopathy, possiblybecause at high doses it decreases heart rate, so that theduration of the diastole is only slightly reduced. A phaseIIb trial evaluates its safety and efficacy in ADHFpatients and an oral formulation is under developmentfor CHF.

4. Apelin is the endogenous ligand for angiotensin-like

1 (APJ) receptors present in endothelial, vascularsmooth muscle, and cardiac cells (Japp et al., 2008;Barnes et al., 2010). Apelin markedly increases cardiaccontractility through the activation of sarcolemmal Na+-H+ exchanger (NHE) which increases [Ca2+]i via thereverse mode of the NCX (Berry et al., 2004).Stimulation of NHE leads to intracellular alkalinization,particularly in ischemic cardiac tissues, and sensitizescardiac myofilaments to intracellular Ca2+. Apelin alsoproduces arteriolar-venous vasodilation via an endothe-lium nitric oxide (NO)-dependent pathway (Tatemoto etal., 2001) and aquaretic effects by inhibiting vaso-pressin release (De Mota et al., 2004). These effects ofapelin are opposite to those produced by angiotensin IIvia AT1 receptor stimulation. Moreover, angiotensin IIdecreases cardiac apelin mRNA levels (Iwanaga et al.,2006), which suggests that apelin may counteract thedetrimental effects of AT1 activation and raise thehypothesis that the beneficial effects of renin-angiotensin-aldosterone system (RAAS) inhibitors inHF may be mediated, at least in part, through restorationof apelin-APJ system (Barnes et al., 2010).

Plasma apelin levels and APJ gene expression decreasein patients with severe CHF (Chong et al., 2006; Japp etal., 2008), but increase in patients who exhibit favorableLV remodeling after LV assist device implantation(Francia et al., 2007). However, LV apelin mRNA lev-els increase in ischemic CHF probably because cardiacapelin gene is upregulated by the hypoxia-inducible fac-tor-1 (Atruri et al., 2007). Therefore, reduced apelinexpression might contribute to the development of HF,whereas strategies increasing apelin-APJ signalingmight slow HF progression and represent an adaptivemechanism to maintain the contracting function of theischemic myocardium (Barnes et al., 2010).

In patients with CHF (NYHA II-III), intravenousapelin-13 causes peripheral and coronary vasodilatationand increases LVEF (Japp et al., 2010). Intracoronaryapelin-36 increases coronary blood flow and LV+dP/dtmax and reduces peak and end-diastolic LV pres-sures. However, further research is needed to under-stand the role of apelin-APJ pathway and the potentialof the combination of APJ-receptor agonists and RAASinhibitors to prevent/delay the decline in LV systolicfunction in patients with systolic HF. Clinical researchwith apelin is limited by its short plasma half-life (<5minutes) and lack of oral APJ agonists. The ongoingINO-apelin trial analyzes the inotropic effect of apelin.

Defects in Intracellular Ca2+ Handling

Abnormal intracellular Ca2+ handling is a hallmark ofHF characterized by (Figure 1): decreased activity of


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SERCA2a, PLB dephosphorylation and increasedexpression of protein phosphatases (PP) 1 and 2, dias-tolic Ca2+ leak through RyR2, and overexpression ofNCX that facilitates Ca2+ extrusion outside the cell(Bers, 2008; Ikeda et al., 2008; Tamargo and López-Sendón, 2011). The final effect is a decrease in SR Ca2+

content available for contraction, smaller Ca2+ tran-sients, and increased diastolic Ca2+ levels that promotesystolic/diastolic dysfunction and arrhythmias andincrease ATP consumption.

Pharmacological strategies to restore SR Ca2+ cyclingrepresent a novel therapeutic approach to increase car-diac contractility in patients with severe HF character-ized by reduced LVEF and low blood pressure.

1. Overexpression of SERCA2a activity improves sys-tolic and diastolic function, cardiac metabolism, andsurvival, and reduces LV remodeling and arrhythmiasin experimental models of HF (Lompre et al., 2010;Beeri et al., 2010). In the CUPID trial, intracoronaryadministration of adeno-associated virus type1(AAV1)/SERCA2a in patients with severe HFimproved symptoms, functional status, and LV remod-eling without untoward safety findings (Jessup et al.,2011). At 12 months, a significant reduction of cardio-vascular events (worsening HF, myocardial infarction,device implantation, transplantation, and death) andmean duration of cardiovascular hospitalizations occursin the high-dose group compared with placebo. Theseresults confirm the key role of SERCA2a in the patho-genesis of HF and strongly supports that its upregula-tion represents a novel therapeutic approach in severeHF. However, there was not a clear dose-response togene therapy for most of the variables measured, up to50% of patients presented antibodies against AAV andlong-term efficacy and the safety of gene transferremain uncertain. An ongoing trial analyzes the effectsof AAV1/SERCA2a in patients with an LV assistdevice.

2. Allosteric modulators that bind to and increaseSERCA2a activity improve cardiac contractility andLVEF in HF models and decrease relaxation time with-out increasing MVO2 or heart rate or inducing cardiacarrhythmias (Tamargo and López-Sendón, 2011).

3. RyR2-calstabin2 complex stabilizers prevent SRCa2+ leak, increase SR Ca2+ load and cardiac contractil-ity, and reduce the risk of arrhythmias (MacKrill, 2010;Lompre et al., 2010). K201 (JTV519) increases thebinding affinity of calstabin2 for RyR2, stabilizes theclosed state of the channel, and reduces diastolic SRCa2+ leak (Wehrens et al., 2005). As a consequence,K201 improves SR Ca2+ load and diastolic and systolic

function in HF models and failing human myocardium(Toischer et al., 2010) and prevents LV remodeling andcardiac arrhythmias (Wehrens et al., 2005). However,K201 also inhibits SERCA2a, α1-adrenoceptors, L-typeCa2+ and K+ channels, and possibly other transporters.

Several drugs, called “rycals,” stabilize the RyR2-cal-stabin2 interaction, inhibit SR Ca2+ leak, and preventarrhythmias in vivo (MacKrill, 2010; Tamargo andLópez-Sendón, 2011). The effects of S44121 are cur-rently evaluated in patients with CHF at risk for ventric-ular arrhythmia. Ivabradine, a specific inhibitor of thepacemaker current (If) in sinoatrial nodal cells, increas-es calstabin2 expression in cardiac myocytes.

Mice overexpressing CaMKII develop HF, associatedwith reduced SR Ca2+ load and increased SR diastolicCa2+ release (Maier et al., 2003). CaMKII inhibitors,but not PKA inhibitors, improve cardiac contractilityand decrease Ca2+ leak and increase SR Ca2+ load, sug-gesting that CaMKII is critical for RyR2 hyperphospho-rylation in HF (Bers, 2008).

4. Neuregulin (NRG)-1. This growth factor increasescardiac contractility by suppressing PP1/PP2 expres-sion, which results in activation of SERCA2a activity;additionally, rhNRG-1 activates expression of cardiac-specific myosin light chain kinase (Gao et al., 2010).Ventricular NRG-1 expression and signaling (Nrg-1/PI3K/NOS3) increase in the early stages, but decreasein late stages of CHF (Lemmens et al., 2006). rhNRG-1 improves cardiac performance and prolonged survivalin different animal models of HF (Liu et al., 2006). Inpatients with CHF, intravenous rhNRG-1 increasesLVEF and decreases LV end-systolic/diastolic volumessuggesting an improvement of cardiac function andstructure and was well tolerated (Gao et al., 2010).

Metabolic Modulators

The healthy heart derives ~70% of its energy from β-oxidation of fatty acids (FA) and the remainder fromoxidation of pyruvate, although FA utilization requires10-15% more oxygen per unit of ATP generated(Lopaschuck et al., 2010; Lionetti et al., 2011). HFswitches cardiac metabolism to FA impairing energygeneration. Furthermore, FA inhibit pyruvate dehydro-genase and glucose oxidation, impair Ca2+ handling andLV contractility, and increase the risk of arrhythmias(Lopaschuck et al., 2010). Metabolic modulators shift-ing substrate utilization from FA to glucose oxidationmay represent a novel target to preserve/improve LVfunction, without exerting negative hemodynamiceffects.


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Metabolic modulators may impair FA oxidation by(Figure 2): 1) inhibiting carnitine palmitoyl transferase-1 (CPT-1, a critical enzyme that mediates the transportof FA across the mitochondrial membrane), long-chain3-ketoacyl coenzyme A thiolase (the final enzymeinvolved in β-oxidation), or malonyl-CoA decarboxy-lase to increase malonyl-CoA, a potent inhibitor ofCPT-1; 2) decreasing FA plasma levels and its myocar-dial uptake. CPT-1 inhibitors improve LVEF and slowthe progression of HF in animal models (Lopaschuck etal., 2010; Lionetti et al., 2011). In placebo-controlledstudies the antianginal drugs perhexiline and trimetazi-dine improve symptoms, exercise tolerance, and LVEF,and reduce systolic and diastolic volumes in patientswith ischemic CHF (NYHA class II-III) (Lee et al.,2005; Fragasso et al., 2006; Tuunanen et al., 2008; Phanet al., 2009). In patients with hypertrophic cardiomy-opathy, perhexiline improves cardiac phosphocrea-tine/ATP ratio, symptoms, LVEF, and diastolic dys-function, and increases exercise capacity (Abozguia etal., 2010). Thus, metabolic modulation may represent atherapeutic target in HF of ischemic or non-ischemicetiology. However, their effects have not been analyzedin patients with AHFS. Acipimox (Halbirk et al., 2010)and etoxomir do not produce benefit in patients withCHF and a placebo-controlled trial with etoxomir wasstopped because the drug increases the level of livertransaminases (Holubarsch et al., 2007).

Conversely, metabolic modulators can stimulate car-diac glucose uptake and oxidation. Glucagon-like pep-tide-1 (GLP-1) increases glucose-stimulated pancreaticinsulin secretion and myocardial glucose uptake via thetranslocation of glucose-transporting vesicles (GLUT-1and -4) to the sarcolemma (Davidson, 2011). In patientswith HF (NYHA class II-IV) and LVEF <40% afteracute myocardial infarction, with or without diabetes,GLP-1 infusions improve LVEF, functional status, andglycemic control, and reduce the use of inotropic andvasoactive drugs (Sokos et al., 2006; Davidson, 2011).Thus, GLP-1 may overcome many adverse effects ofglucose-lowering drugs. Native GLP-1 is rapidlydegraded by dipeptidyl peptidase-IV (DPP-IV) butGLP-1 agonists and DPP-IV inhibitors might overcomethis problem.

Pyruvate exerts positive inotropic effects and decreasesdiastolic force in failing human hearts. Pyruvateincreases cytosolic ATP phosphorylation potential, SRCa2+ content, and Ca2+ transients (Hasenfuss andTeerlink, 2011), and potentiates β-adrenergic inotropicresponses (Hermann et al., 2002). It also increasesintracellular pH by enhancing mitochondrial protonuptake via the monocarboxylate-proton symporter, aneffect that increases myofilament Ca2+ sensitivity

(Hasenfuss and Teerlink, 2011). In patients with CHF,intracoronary pyruvate increases LVEF, improvesrelaxation and decreases LV end-diastolic pressure andheart rate; since pyruvate does not induce systemic orcoronary vasodilation, its effects on systolic/diastolicfunction result from direct myocardial effects and notfrom altering loading conditions (Hermann et al.,2004). In patients with cardiogenic shock refractory tocatecholamines because of acute myocardial infarction,intracoronary pyruvate increases cardiac stroke volumeindex and mean arterial blood pressure, whereas heartrate does not change (Schillinger et al., 2011).However, these effects disappear within 10 minutes andthe high plasma levels obtained by intra-arterial admin-istration can produce sodium overload and hyperosmo-larity.

Other Treatments

1. Crataegus extracts (hawthorn) have been used forcenturies for the treatment of cardiovascular diseases.The standarized Crataegus extract WS1442 blocksNa+/K+-ATPase activity and raises [Ca2+]i (Schwingeret al., 2000), prolongs the cardiac action potential dura-tion, and produces systemic and coronary vasodilationvia the phosphorylation of endothelial NO synthase(NOS3) at Ser1177 (Brixius et al., 2006). In mild CHF(NYHA class I-III), WS1442 improves symptoms andexercise capacity and is well tolerated (Daniele et al.,2006). Unfortunately, these trials are limited by lack ofmeaningful clinical outcomes, unclear severity of HF,and variations in background therapy. Furthermore, intwo recent trials WS1442 provided no benefit on eventrates and HF progression (Holubarsch et al., 2008; Zicket al., 2008). However, WS1442 reduces sudden car-diac death in patients with an LVEF ≥25% (Holubarschet al., 2008), a finding that might support furtherresearch in this population.

2. Hormones. Patients with CHF may have a low-tri-iodothyronine (T3) state accompanied by abnormalitiesin Ca2+-handling proteins similar to those found in HFand increased mortality (Saccà, 2009; Gerdes andIervasi, 2010). Thyroid hormones (TH) restore contrac-tile function and Ca2+-handling protein expression andupregulate cardioprotective (protein kinase Cδ, heatshock protein 70, and pro-survival PKB/Akt-mTOR)(Pantos et al., 2011). Additionally, TH reduce peripher-al vascular resistances (PVR) by stimulating NO pro-duction (via the activation of the PI3K/Akt pathway)(Carrillo-Sepúlveda et al., 2010) and β2-adrenoceptors.In CHF with low-T3 state, TH increase LVEF and exer-cise capacity and decrease PVR and LV end-diastolicvolume, but their effects on outcomes are unknown(Saccà, 2009; Gerdes and Iervasi, 2010). However, 5-


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diiodothyropropionic acid (DITPA) does not improvesymptoms or outcomes and is poorly tolerated(Goldman et al., 2009). The concern is that TH may beharmful by increasing heart rate and MVO2, so that,long-term efficacy and safety of TH in CHF await fur-ther evaluation.

Growth hormone (GH) increases Ca2+ transients,enhances myofilament Ca2+ sensitivity, up-regulatesSERCA2a’s function to increase cardiac contractility(Castellano et al., 2009), and produces an NO-mediatedvasodilation. However, GH has variable effects onLVEF, probably related to GH resistance and differentdosage regimens and there are concerns about long-term adverse effects (retinopathy, hypotension, hypo-glycemia) (Castellano et al., 2009; Saccà, 2009).

2. Nitroxyl anion (HNO), the 1-electron reduced formof NO, exerts inodilator properties. The inotropic effectis due to a direct interaction with specific thiols onSERCA2a (cysteine674), PLB (that relieves inhibitionof SERCA2a), and RYR2, leading to an increase in SRCa2+ uptake and release (Kohr et al., 2010). HNO alsoincreases myofilament Ca2+ sensitivity (Dai et al.,2007). HNO produces a potent vasodilation via activa-tion of soluble guanylyl cyclase, and induces release ofneuropeptide calcitonin gene-related peptide (whichstimulates endothelial NO release) and activation ofvascular smooth muscle Kv and KATP channels (Bullenet al., 2011). Additionally, HNO inhibits platelet aggre-gation and vascular smooth muscle cell proliferation.

In HF models, HNO generated by Angelis’ salt(Na2N2O3) enhances LV contractility and relaxation,reduces cardiac preload and afterload and diastolicpressure (Paolocci et al., 2007). However, since HNOpresents a short half-life (2-3 minutes), new long-actingHNO donors are needed to characterize the efficacy andsafety of HNO. Intravenous infusion of the HNO donorCXL-1020 in dogs with advanced HF (LVEF <30%)improves LV systolic and diastolic function and reducesLV end-diastolic and end-systolic volumes withoutincreasing MVO2 or inducing ventricular arrhythmias(Wang et al., 2009). Thus, HNO donors may representanother approach in the treatment of ADHF, but theirvasodilating properties may determine their clinicalutility.

Conclusions

HF is a complex syndrome associated with high mor-bidity and mortality. The limitations of conventionalinotropes stimulated the development of novel drugsthat improve symptoms, hemodynamics, and outcomeswithout increasing cAMP levels, [Ca2+]i or MVO2,

worsening cardiac metabolism, or producing proar-rhythmia or myocardial damage. Preclinical and earlyclinical data with these drugs are encouraging.However, because of the novelty of their mechanism ofaction and the preliminary clinical development, furtherstudies are needed. In particular, it is necessary todefine optimal dosing, target population, underlyingpathophysiology and HF stage and safety profile inpatients with ADHF, reduced LVEF, and evidence oforgan hypoperfusion as compared with conventionalinotropics. Furthermore, because a discrepancy is foundbetween promising results found in phase 2 trials andthe less promising results of efficacy in phase 3 trials,these new drugs must be evaluated in large-scale phase3 trials to confirm that they represent an effective andsafer alternative to conventional inotropics.

Acknowledgment

Supported by grants from the Ministerio de Ciencia eInnovación (SAF2008-04903), Instituto de SaludCarlos III (Red HERACLES RD06/0009-FEDER andPI080665), and Spanish Society of Cardiology.

Disclosure

The authors report no existing or potential conflicts ofinterest.

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