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European Journal of Heart Failure 2008 10(10):990-996; doi:10.1016/j.ejheart.2008.07.007
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© 2008 European Society of Cardiology

Sympathomimetic inefficiency in restoring contractility in the acute or chronic β-blocker-treated ischaemic heart: Comparison with a new agent

Giovan Giuseppe Matteraa,*, Emilio Vanolib, Jean-Pierre Gagnolc, Francesca Maria Paola Loia, Franco Borsinia and Paolo Carminatia

a Research & Development Sigma-Tau S.p.A. Pomezia Italy
b Cardiology Department, Universita di Pavia, IRCCS Policlinico S. Matteo Pavia Italy
c Universite de Montpellier 1 et CRNS UPIR5232 France

* Corresponding author. R & D-General Pharmacology Department, Sigma-Tau S.p.A., Via Pontina km 30.400, 00040 Pomezia, Roma, Italy. Tel. +39 0691393882; fax: +39 0691393988. E-mail address: giovanni.mattera{at}sigma-tau.it (G.G. Mattera).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Background: Adequate pharmacologic cardiac support in acute myocardial infarction (MI), as well as in chronic MI patients under β-blocker therapy, is problematic due to the impaired cardiac response to β-adrenergic agonists. New therapeutic approaches could resolve this problem. Istaroxime (ISTA) is a new Na+,K+-ATPase inhibitor and SERCA2 agonist.

Aims: To evaluate: 1) the effects of dobutamine (DOB) on left ventricular function in early (48–72 h) and late (14 days) phases of a post-MI canine model, compared to ISTA, and 2) the efficacy of DOB in chronic left ventricular dysfunction (6 months post-MI) in dogs pre-treated or not with a β-blocker, compared with ISTA and milrinone (MIL).

Results: When compared to the effects in healthy animals, DOB increased contractility only slightly in the first 48–72 h post-MI, whereas its efficacy recovered partially by day 14 and fully by 6 months after MI. ISTA had a greater effect on contractility than DOB and improved relaxation, while DOB did not. Moreover, β-adrenergic blockade inhibited the inotropic action of DOB, without altering the effect of ISTA. Surprisingly, ß-adrenergic blockade blunted the effects of MIL.

Conclusion: ISTA may represent a novel strategy for enhancing left ventricular performance even in the context of acute MI and/or concomitant β-adrenergic blockade.

Key Words: Acute myocardial infarction • β-blockers • Contractility • Dobutamine • Milrinone • Istaroxime

Received January 22, 2008; Revised May 21, 2008; Accepted July 14, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
The occurrence of heart failure (HF) in patients with acute myocardial infarction (AMI) has been consistently recognized as a strong predictor of increased morbidity and mortality since the 1960s [1]. The extensive use of β-adrenergic blockers in ischaemic heart disease patients, with or without left ventricular dysfunction and/or overt clinical heart failure, dramatically improves their short- and mid-term prognoses [2,3]. On the other hand, haemodynamic deterioration and overt acute decompensation are frequent events in post-MI patients and require effective therapies. In this clinical setting, increased sympathetic activity and/or impaired neuronal function, as well as a decrease in β-receptor density after MI, could cause an impairment of cardiac response to β-adrenergic stimulation [4-6]. Recent experimental data suggest that changes in β-receptor density occur very early after MI, and this may impair cardiac response to β-adrenergic stimulation [7]. Thus, β-adrenergic receptor downregulation and/or treatment with β-blockers severely limit(s) the positive haemodynamic effects of adrenergic agonists such as dobutamine. Alternatives to adrenergic agonists are phosphodiesterase inhibitors (i.e. milrinone). These compounds were extensively used to treat acute and chronic cardiac decompensation but outcomes have been disappointing, with in an increase in mid- and long-term morbidity and mortality [8,9]. This, combined with the progressive loss of enthusiasm for the use of digitalis, means that there is little if anything left to effectively and safely treat acute heart failure, specifically in ischaemic heart disease patients.

Recent studies show that combining Na+,K+-ATPase inhibition with SERCA2 activation results in an effective positive inotropic activity without the typical proarrhythmic consequences observed with digitalis, i.e. with sole action on Na+,K+-ATPase [10]. This is possibly because, while Na+,K+-ATPase inhibition produces an increase in the intracellular Ca++ concentration available to boost contractility, the sequential activation of SERCA2 allows a rapid clearance of cytosolic Ca++ with two favourable consequences. First, it facilitates the lusitropic process, improving relaxation and second, it prevents the proarrhythmic consequences of intracellular Ca++ overload.

Istaroxime (ISTA) is a new compound that concomitantly inhibits Na+,K+-ATPase and stimulates SERCA2, it is currently in phase IIb clinical evaluation. ISTA has been shown to increase cardiac compliance in different animal species under various experimental conditions, including normal hearts, acute myocardial ischaemia and chronic myocardial infarction, complicated by chronic left ventricular systolic/diastolic dysfunction [10-13].

The aim of this study was to compare the efficacy of improving cardiac contractility in the ischaemic heart using classical β-adrenergic stimulation vs a new pharmacological approach using Na+,K+-ATPase inhibition and SERCA2 stimulation. Responses were evaluated under two experimental conditions: during the acute and subacute phases of myocardial ischaemia and in chronic mild left ventricular dysfunction 6 months after induction of a myocardial infarction. The latter was investigated under baseline conditions and in β-blocker pre-treated animals.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
A total of 19 male Beagle dogs bred for research (10 to 12 kg body weight upon arrival, Morini, San Paolo d'Enza, Italy) were used for the study. All aspects of animal care were performed under the control of Sigma-Tau veterinarians, in compliance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication 85-23, revised 1985) and the Italian regulatory system (D.L.vo 116, Art. 6 of 27 Jan 1992).

2.1. Surgical preparation
All dogs underwent a pressure transducer implant (Konigsberg, USA) and left anterior coronary artery ligation surgery under plain anaesthesia and sterile conditions.

The dogs were fasted for 18 h and pre-anaesthetized with an initial injection of Zoletil 100® (a mixture of tiletamine hydrochloride and zolazepam hydrochloride at 10 mg/kg i.m.). After endotracheal intubation, a surgical level of anaesthesia was obtained and maintained by ventilation with isoflurane (1-2%) in an oxygen-nitrous oxide mixture.

A left thoracotomy was performed in the 4th intercostal space. A solid state pressure transducer (mod P2, Konigsberg, USA) was inserted into the aortic arch to monitor systemic blood pressure. The pericardium was then opened and the heart suspended in a pericardial cradle. A second solid state pressure transducer (mod. P4, Konigsberg, USA) was placed, through a small apical incision, into the left ventricle to monitor ventricular pressure. Next, the left anterior descending coronary artery (LAD) was isolated from the surrounding tissue and sham-ligated in four and tied in the other 15 dogs, using a two-stage procedure, proximally to the first diagonal branch, to produce an anteroapical myocardial infarction. Complete LAD closure was confirmed by profound ECG changes, immediate dark blue discoloration of the affected myocardium, accompanied by dyskinesis of the infarcted area. Finally, the pericardium was approximated, the transducer leads exteriorized at the dorsal aspect of the neck, the chest closed and the animals allowed to recover. As animals recovered from anaesthesia, Spectrum® (1 g per day) and Contramal® (50 mg b.i.d.) were administered as antibiotic and analgesic therapy, respectively, for one week after surgery. The four dogs that received only a sham LAD ligature were used as controls.

2.2. Experimental protocol
Data were collected consecutively at three scheduled times:

1) Forty-eight hours 2) fourteen days and 3) six months after coronary artery ligation.

At times 1 and 2, comparative tests were performed between DOB (5 µg/kg/min) and ISTA (50 µg/kg bolus+5 µg/kg/min infusion) under basal conditions.

At time 3, dogs were pre-treated with placebo (gelatin capsules) or the β-blocker, bisoprolol, (Concor®, Bracco) 5 mg/dog on day 1 followed by 10 mg/dog from days 2 to 4. Effective β-adrenergic receptor blockade was assessed from dose-response curves to the β-adrenergic agonist, isoproterenol (0.01-3 µg/kg, Sigma Chem, USA.). Curves were assessed at baseline and on day 4, 1 h after the last oral pre-treatment and 1 h before drug administration. ISTA was administered as an i.v bolus of 50 µg/kg followed by an infusion of 5 µg/kg/min. DOB was administered i.v. at 5 µg/kg/min after placebo pre-treatment, and at 5 and 7.5 µg/kg/min after β-blockade. Milrinone (MIL) was administered as an i.v. bolus of 50 µg/kg followed by an infusion at 1 µg/kg/min. DOB, ISTA and MIL infusions were maintained for a total of 20 min. In 3 of 5 animals, the 1 µg/kg/min infusion dose of MIL was followed by administration of a dose of 2 µg/kg/min for another 20 min. The doses of DOB, MIL and ISTA were chosen as they had relatively equivalent effects on cardiac contractility in a previous pilot study (data not shown). A minimum 24-h washout period was allowed between drug tests. There was a washout period of at least one week between the placebo and bisoprolol pre-treatment phases.

2.3. Data collection and statistical analyses
The following parameters were monitored and recorded in real time by a computerized acquisition system (V. 1.6.5, EMKA Tech., France) starting 20 min before drug administration (equilibration and basal periods), throughout infusion and during recovery: ECG, intraventricular (LVP), end diastolic (LVEDP) and aortic pressures (MBP). Positive and negative dP/dtmax and Tau were derived online from left ventricular pressure signals. Heart rate (HR) was computed from the LVP signal. All acquired data were analyzed by specific analysis software (IOX V. 1.6.5, EMKA Tech., Fr). The monitored parameters were measured or calculated and averaged every 10 s, then recorded and stored on a hard disk in appropriate files for later review.

Data, expressed as actual and/or delta values, with respect to basal values, are reported as mean±SEM or mean±SD. Statistical analysis was performed using paired Student's t-test or one-way ANOVA for repeated measures, followed by Bonferroni's multiple comparison test. A value of p<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
3.1. Sham-ligated healthy dogs (control)
DOB increased contractility in the control dogs (n=4) without producing significant changes in heart rate (Table 1). In the same control animals, ISTA (n=4) increased cardiac contractility (+dP/dtmax), and relaxation (–dP/dtmax). Along the same lines, Tau showed a significant decrease (Table 1). The maximal effect on contractility exerted by DOB infusion was slight, but significantly higher, than ISTA (Fig. 1). On the other hand, ISTA, but not DOB, had a positive action on relaxation.


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  		Table 1 Treatment-induced effects in healthy or post-MI conscious dogs

 


Figure 01
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  		Fig. 1 Time course of dobutamine and istaroxime effect on cardiac contractility (dP/dtmax) in infarcted (IMA) dogs (n=4 to 7).

 
3.2. Acute post-myocardial infarction phase
Two of the fifteen dogs which underwent LAD ligature developed untreatable VF and died. The 13 surviving animals showed low values of +dP/dtmax and –dP/dtmax (Table 1), compared to values recorded in sham animals (Table 1), confirming impaired cardiac muscle contractility after LAD ligature. Subsequently, dogs were randomly assigned to the DOB (n=6) or ISTA (n=7) administration group.

3.2.1. Dobutamine administration
DOB at 5.0 µg/kg/min significantly increased +dP/dtmax, and slightly but significantly decreased LVEDP and Tau. All other haemodynamic parameters remained unchanged (Table 1).

3.2.2. Istaroxime administration
ISTA administration increased contractility (+dP/dtmax) and had a beneficial effect on relaxation, as documented by a significant decrease of LVEDP, heart relaxation constant (Tau) and –dP/dtmax (Table 1). Overall, ISTA produced a significantly greater effect than DOB on both +dP/dtmax and –dP/dtmax (Table 1).

3.3. Subacute post-MI phase
Fourteen days after MI, there was an overall improvement of contractility with respect to the profile observed after 48 h (Table 1).

3.3.1. Dobutamine administration
DOB induced a more potent effect on contractility, with respect to that exerted after 48 h: it produced a significant increase in +dP/dtmax. However, the inotropic effect remained significantly lower, with respect to sham animals, and occurred at the cost of impairment of diastolic function, as LVEDP increased. HR and MBP did not show significant changes from basal values (Table 1).

3.3.2. ISTA administration
Administration of ISTA produced a significant increase in contractility and relaxation compared to DOB, as documented by a significant decrease in LVEDP and Tau, and by a –dP/dtmax increase. MBP increased slightly, while HR remained unaffected (Table 1). Thus, as in the early post-MI phase, ISTA had a greater effect on contractility than DOB and, notably, concomitantly improved relaxation, while DOB did not.

3.4. The chronic post-MI phase
Four dogs died during the 6-month period following LAD ligature. Of the nine survivors, only five maintained a fully functional implanted instrumentation. These dogs showed general improvement of contractility, despite the maintained impairment of LVEDP (Table 2).


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  		Table 2 Basal values±SEM of the recorded parameters before drug administration, 48 h, 14 days and 6 months after AMI

 
3.4.1. Effects on placebo pre-treated conditions
DOB significantly increased +dP/dtmax. However, its inotropic effect remained significantly lower, with respect to sham animals (Fig. 1). However, –dP/dtmax (–109±101 {Delta}mm Hg/s), LVEDP (–1.6±9.2 {Delta}mm Hg) and Tau (–2.2±2.9 {Delta}ms) were only modestly and insignificantly affected, with respect to basal values by DOB (Table 2). Under the same conditions, MIL produced haemodynamic effects similar to, or greater than, those observed with DOB, as it increased +dP/dtmax (Fig. 2) and reduced LVEDP (–8.9±3.1 {Delta}mm Hg; p<0.05) and Tau (–5.1±3.5 {Delta}ms, p<0.05), with respect to basal values (Table 2).


Figure 02
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  		Fig. 2 Effect of dobutamine (DOB; 7.5 µg/kg/min), milrinone (MIL; 50 µg/kg+1 µg/kg/min) and istaroxime (ISTA; 50 µg/kg+1 µg/kg/min) acute infusion on cardiac contractility (dP/dtmax) in chronic infarcted, β-blocking agent (bisoprolol)-treated dogs (n=4-5).

 
ISTA increased contractility (Fig. 1), slightly reduced HR (–7.6±10 {Delta}bpm, not significant) and Tau (–3.4±1.2 {Delta}ms, p<0.05), with respect to basal values (Table 2). Whereas, compared to the early phases, –dP/dtmax and LVEDP were not significantly changed.

3.4.2. Effects of pre-treatment with bisoprolol
Effective blockade of β-adrenoreceptors was documented by a significant right shift of one log unit of the isoproterenol dose-response curve of HR (data not shown). Moreover, in comparison with placebo, bisoprolol (Table 3) decreased basal values of MBP, HR and, consequently, double product (DP, from 14,420±3396 to 8692±1693 bpm mm Hg, p<0.05). Contractility indexes were also affected, as +dP/dtmax decreased and –dP/dtmax increased. Thus, all of the expected effects of β-adrenergic blockade were observed.


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  		Table 3 Basal values±SD of the recorded parameters before and after bisoprolol administration, 6 months after AMI

 
3.4.3. Haemodynamic responses to DOB, MIL and ISTA under β-adrenoceptor blockade conditions
All the haemodynamic effects induced by DOB under placebo-treated conditions were abolished by bisoprolol pre-treatment. Even the higher doses (up to 7.5 µg/kg/min) of DOB failed to induce any effect (Fig. 2; lower dose not shown). Under the same conditions, MIL was also less effective than under placebo conditions. In fact, bisoprolol pre-treatment significantly blunted the effect of MIL on dP/dtmax (Figs. 2 and 3), as well as on LVEDP (–1.8±3.5 vs –8.9±3.1 {Delta}mm Hg of placebo, p<0.05) and MBP (–7.0±11 vs –1.3±9.3 {Delta}mm Hg of placebo, p<0.05). Tau was the only parameter which responded to MIL, in the same way as under placebo pre-treatment conditions (–4.8±4.6 vs –4.5±2.8 {Delta}ms of placebo). In contrast to DOB and MIL, ISTA increased +dP/dtmax (Fig. 2), –dP/dtmax (from –2760±195 to –3071±182 mm Hg/s; p<0.01), and decreased Tau (from 19.4±3.6 to 14.0±2.8 ms; p<0.01) as much as under placebo conditions. HR, LVEDP and DP remained unchanged (data not shown).


Figure 03
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  		Fig. 3 Time course of milrinone (MIL 50 µg/kg+1 µg/kg/min+2 µg/kg/min) acute infusion on cardiac contractility (dP/dtmax) in chronic infarcted, placebo or β-blocker (bisoprolol)-treated dogs (n=3-5).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
The present study shows that adrenergic agonists do not provide adequate inotropic support in impaired left ventricular function following acute myocardial ischaemia. In the same setting, Na+,K+-ATPase inhibition, combined with SERCA2 activation, resulted in a significant improvement of LV function. The healing process following acute coronary occlusion is associated with progressive recovery of the cardiac response to adrenergic agonists. At this point, β-adrenergic blockade inhibits the inotropic action of dobutamine, but does not affect the positive action of istaroxime. A surprising result of the present study, was the fact that β-adrenergic blockade also blunted the effect of phosphodiesterase inhibitors.

4.1. Potential mechanisms underlying the observed findings
Adrenoceptor stimulation by catecholamines regulates diverse physiological processes, including heart rate and contraction strength. β1 and β2 adrenoceptors are the predominant subtypes expressed in the heart. They act through coupling to different G proteins, thereby activating an intracellular cascade of events, exerting effects that modulate intracellular Ca++. Different cardiac pathologies interfere with receptor expression and/or intracellular cascade [14]. For instance, high plasma and interstitial catecholamine levels, as occur in chronic heart failure, result in an internalization of beta-adrenergic receptors [15]. The present study did not analyze any receptor effects in the infarcted heart. However, recent experimental data show a significant reduction in β-adrenoreceptor function in dogs with a healed MI but with no sign of LV dysfunction at rest [7]. Thus, the well-known β1/β2 adrenergic receptor density imbalance, observed in advanced HF [15-17], may actually be present much earlier during the time course of ischaemic damage, evolving toward chronic LV dysfunction. Recent data in a chronic post-MI model of sudden death, suggest a specific loss of β1 adrenergic signalling after MI, which was associated with higher arrhythmogenic sensitivity to β2 adrenergic signalling [7]. In contrast, the progressive recovery of the contractile response to dobutamine observed in our study suggests transient acute, rather than chronic, downregulation or uncoupling of β1-receptors. This uncoupling might be due to high circulatory catecholamine levels. Although catecholamine levels were not measured in our study, the higher heart rate observed in the early post-MI is consistent with a condition of high sympathetic drive. Alternatively, the lack of an adequate response to dobutamine might be due to the extensive ischaemic damage which limits the contractile response to the adrenergic stimulus. In this context, it is important for new therapeutic agents, to have a dual mechanism of action to modulate the intracellular Ca2+ fluxes. The combined rapid increase of the latter by inhibition of Na+,K+-ATPase and its rapid clearance, via SERCA2 activation, explain the major effects of ISTA on LV function.

4.2. The β1-receptor blockade
This experimental investigation describes the consequences of standard post-MI chronic β-adrenoceptor blockade therapy on the haemodynamic effects of traditional (DOB and MIL) and novel (ISTA) inotropic agents.

β-receptor agonists, with their ability to increase cellular cAMP levels, lead to PK-A activation, which in turn phosphorylates a variety of target proteins involved in regulating intracellular calcium, such as L-type calcium channels and phospholamban. The former are responsible for increased cardiomyocyte calcium levels, which enhance contractility. Phospholamban phosphorylation causes its own dissociation from SERCA. The removal of its inhibitory effect allows calcium reuptake into the sarcoplasmatic reticulum, thus facilitating cardiomyocyte relaxation.

Based on current knowledge, the blunting effect of β-adrenoceptor blockade on DOB action is expected, however, it is surprising to observe that the inotropic response to MIL is also depressed. In fact, these novel data suggest a strong interdependence of phosphodiesterase inhibitor activity, with functional βvrecto-receptors able to respond to basal sympathetic tone. On the other hand, the results obtained in the present study underscore the independence of ISTA's mechanism of action from cAMP function. Indeed, ISTA increases cardiomyocyte calcium levels via Na+,K+-ATPase blockade. This block increases intracellular Na+ levels and provokes reverse Na+-Ca2+ exchanger function, augmenting intracellular Ca2+ availability for contraction. At the same time, the direct interaction of ISTA with the phospholamban-SERCA complex causes their dissociation and thus allows cardiomyocyte relaxation.

4.3. Clinical implications
The in-hospital mortality associated with HF is almost 5% [1]. Approximately one third of patients with HF die within a year of their first hospitalisation and 50% of patients with HF will require subsequent hospitalisation within 6 months of discharge after first admission [1]. The growing population of patients with HF and the associated increase in hospitalisations, pose an onerous challenge to the cardiological community in obtaining effective pharmacologic interventions for the management of acute decompensation in ischaemic heart disease patients. This is particularly true for LV failure complicating an acute MI. In this setting, only emergency coronary angioplasty (PTCA) seems to deal effectively with this issue. However, primary PTCA is neither extensively nor immediately available in many instances and the current pharmacologic armamentarium is far from satisfactory. Additionally, the extensive use of β-adrenoceptor blockers profoundly limits the beneficial effects of adrenergic agonists. Alternative interventions, like digitalis and PDA inhibitors, are contraindicated because of their side effects, including proarrhythmicity. The novel finding of the negative interaction between β-adrenoceptor blockade and milrinone observed in this study further limits the dependability of PDA inhibitors in the infarcted heart.

By combining Na+,K+-ATPase blockade and SERCA2 activation, ISTA may represent a novel strategy for enhancing LV performance, even in the context of acute myocardial ischaemia and/or concomitant β-adrenergic blockade which are both associated with a loss of cardiac sensitivity to adrenergic stimulation. A phase III study aimed at assessing the efficacy of ISTA on cardiac performance and prognosis in patients with acute cardiac decompensation, is currently ongoing.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
We gratefully acknowledge the expert technical assistance of Mses. Mirna Botarelli and Laura Alivernini in performing the experiments, and that of Mses. Marlene Deutsch and Daria Di Giulio in the preparation of the manuscript.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 

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