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European Journal of Heart Failure 2003 5(1):13-21; doi:10.1016/S1388-9842(02)00118-6
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© 2002 European Society of Cardiology

Pharmacotherapeutic approaches for decompensated heart failure: a role for the calcium sensitiser, levosimendan?

Barry Greenberga,*, Claudio Borghib and Sergio Perronec

a Department of Medicine, University of California School of Medicine San Diego, CA, USA
b Department of Internal Medicine Policlinico S Orsola, Bologna, Italy
c Fundacion Favaloro—Sector Transplantes Buenos Aires, Argentina

* Corresponding author. Cardiology Division, University of California School of Medicine, 200 West Arbor St, San Diego, CA, 92103-8411, USA. Tel.: +1-619-543-7751; fax: +1-619-543-7870 E-mail address: bgreenberg{at}ucsd.edu


   Abstract
Top
 Abstract
1. Introduction
 2. Current therapeutic...
 3. Managing decompensated heart...
 4. Conclusions
 References
 
Although no universal definition exists, decompensated heart failure may be regarded as either a worsening of chronic heart failure or new-onset heart failure precipitated by an acute incident. Haemodynamic management of patients hospitalised with decompensated heart failure may include the administration of diuretics, vasodilators and positive inotropic agents. Until recently, these latter agents constituted the only drug class to produce a direct increase in stroke volume via enhanced myocardial contractility. However, despite their short-term benefits, the clinical utility of inotropic agents is compromised by their potentially deleterious effects on calcium handling and oxygen consumption, resulting in an increased risk of serious ventricular arrhythmias and death. In contrast, calcium sensitisers enhance cardiac performance without affecting calcium movement and, therefore, are potentially associated with a reduced risk of rhythmic disturbances. These agents constitute a heterogeneous group of compounds with different affinities for calcium sensitisation. Levosimendan is a potent calcium sensitiser with vasodilating properties that has been shown to provide symptomatic and haemodynamic improvement with no increase in oxygen consumption. Calcium sensitisation is therefore emerging as a promising treatment approach in this challenging therapeutic area.

Key Words: Levosimendan • Calcium sensitisers • Decompensated heart failure • Haemodynamics

Received June 4, 2001; Revised January 17, 2002; Accepted April 10, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Current therapeutic...
 3. Managing decompensated heart...
 4. Conclusions
 References
 
Although no universally accepted definition exists, decompensated heart failure may be regarded as either a consequence of worsening of chronic heart failure or new-onset heart failure precipitated by an acute incident. Examples of such precipitating events include myocardial infarction, cardiac arrhythmias, sepsis and cardiac surgery (Table 1). Most cases occurring in the developed world are caused by left ventricular dysfunction as a consequence of ischaemic heart disease [1]. Diastolic dysfunction should be considered as a direct or contributory cause in patients with acute heart failure and severe, uncontrolled hypertension, or in patients with ischaemic heart disease who develop acute pulmonary oedema [2]. Predominant diastolic dysfunction increases with age; however, most patients with heart failure and impaired diastolic function also have reduced systolic function [3]. Decompensated heart failure may be subdivided clinically into acute cardiogenic pulmonary oedema, cardiogenic shock and acute decompensation of chronic heart failure. The clinical presentation ranges from the sudden occurrence of dyspnoea to cardiogenic shock, and patients generally require hospitalisation, often in the intensive care unit (ICU) with the use of intravenous drug therapy. The prognosis is highly dependent on both the underlying cause and the clinical severity of the disease, with associated mortality rates of approximately 40% for severe pulmonary oedema and 80–90% for cardiogenic shock (Table 2) [4,5].


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  		Table 1 Common events that precipitate an acute episode of decompensated heart failure

 


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  		Table 2 The Killip classification of heart failure and the mortality rates associated with the different classes

 
Heart failure has become an increasingly common clinical condition over recent decades due, at least in part, to the escalating growth of the ageing population. It has a reported prevalence of 0.4–0.8% in the UK population, rising to 2.8% in those aged 65 years or over [6,7]. The condition is responsible for approximately 5% of all adult admissions to district general hospitals [8]. A study from Finland estimated an annual incidence rate of 0.4% for males and 0.1% for females [9], and the prevalence in the USA has been estimated to be approximately 1% [10]. A prospective audit survey of hospital admissions to the City Hospital, Birmingham, UK, which serves a multiracial population of 300 000, found that 4.7% of admissions were due to acute heart failure [11]. Following admission, 19.2% of these heart failure patients died while in hospital [11]. Other studies of patients with heart failure requiring hospital admission have shown an annual mortality rate of 10–20% for those with mild-to-moderate symptoms and 40–60% for those with severe heart failure [12,13]. In the Framingham Heart Study, median survival after the onset of heart failure was 1.7 years in men and 3.2 years in women [14].

A number of guidelines for the management of heart failure have been published, including the recently updated diagnostic and treatment guidelines compiled by the European Society of Cardiology [3], US guidelines developed under the auspices of the Agency for Health Care Policy and Research [15], US guidelines prepared by a joint task force of the American College of Cardiology and the American Heart Association (ACC/AHA) [16], and those of the World Health Organisation [17]. A further set of US guidelines issued by the Advisory Council to Improve Outcomes Nationwide in Heart Failure was published in 1999 [18]. However, most of these guidelines focus on the treatment of chronic heart failure, with recommendations for the management of decompensated heart failure of acute or chronic origins remaining largely insufficient.

Traditional short-term goals for the treatment of decompensated heart failure include stabilisation of the patient, restoration of haemodynamic function and the provision of symptomatic relief. Additional longer-term treatment objectives include reducing the progression of the disease, decreasing the number of hospital re-admissions, and improving survival. Current pharmacological treatment options for decompensated heart failure include diuretics, vasodilators, and inotropic agents. Although both diuretics and vasodilators can effectively bring about symptomatic relief, there is little evidence to suggest sustained long-term benefits. Inotrope administration can greatly help to stabilise the patient and provides considerable symptomatic and haemodynamic benefit in the short term. However, there is evidence that prolonged use of both β-adrenergic agonists and phosphodiesterase inhibitors may have adverse effects on mortality in the longer term [19–22]. As these limitations suggest, there is a clear need for novel therapeutic options for decompensated heart failure that confer symptomatic and haemodynamic improvement without adversely affecting long-term survival.


   2. Current therapeutic approaches
Top
 Abstract
 1. Introduction
 2. Current therapeutic...
3. Managing decompensated heart...
 4. Conclusions
 References
 
The reader is referred to the aforementioned guidelines [3,15–18] for more detailed information on how to assess and manage decompensated heart failure, but a brief description is given below.

Common manifestations include dyspnoea, anxiety and tachycardia, often with profound fatigue. Pallor, hypotension and cool under-perfused extremities are present in more severe cases. The presence of hypotension (systolic blood pressure <90 mmHg), oliguria and a severely depressed cardiac output constitutes a diagnosis of cardiogenic shock [3]. Severe decompensated heart failure is a typical medical emergency, effective management of which requires adequate assessment and treatment of the underlying cause, improvement of the haemodynamic status, relief of pulmonary congestion, improved tissue oxygenation, and symptomatic treatment of anxiety and/or pain.

Clinical and radiographic assessments can provide a guide to the severity and prognosis of the condition, though other diagnostic tests should be limited to those necessary to identify optimal therapy and to exclude underlying causes that require any special therapeutic procedures. An ECG should be obtained to assess the presence of cardiac disease, continuous ECG monitoring instituted, an intravenous catheter inserted and blood obtained for essential laboratory evaluations. Furthermore, placement of a urinary catheter may assist in monitoring the restoration of adequate tissue perfusion. Echocardiography is an additional, valuable procedure that provides an objective assessment of cardiac function [3]. It is ideally performed prior to any clinical decision making, particularly if a clinical diagnosis is equivocal.

The Killip classification has been developed to grade the severity of acute heart failure. Table 2 describes the Killip classification and the mortality rates associated with the different classes [4,5]. Although it is generally accepted that heart failure is associated with high morbidity and mortality rates, acute clinical management to stabilise the patient has traditionally been regarded as the treatment priority in decompensated heart failure with lesser importance placed on longer-term outcomes, such as survival rates. Clinical trial data, however, suggest that clinical manifestations and life expectancy are determined independently, and may respond differently to therapeutic interventions [20].

Therapeutic approaches for decompensated heart failure include pharmacological treatment, mechanical devices and surgical intervention. However, the use of each of these strategies may be precluded in certain patients and, furthermore, the chosen approach may have to be revised should rapid clinical deterioration occur.

In the majority of cases, pharmacological treatment is adopted as the first-line approach. The standard classes of drug used in the haemodynamic management of hospitalised patients with decompensated heart failure are diuretics, vasodilators and positive inotropes. Table 3 summarises the principal clinical effects of these agents.


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  		Table 3 Overview of standard pharmacotherapies for heart failure patients requiring hospitalisation

 
2.1. Acute cardiogenic pulmonary oedema
Treatment recommendations for the initial stabilisation of patients presenting with acute cardiogenic pulmonary oedema include administration of oxygen, diuretics, vasodilators, morphine and cardiovascular support drugs [16]. In refractory cases, invasive procedures, such as intraaortic balloon counterpulsation or ventricular assist devices, may be required.

2.2. Cardiogenic shock
The mortality rate associated with cardiogenic shock that has no reversible underlying cause is at least 85% [16]. Cardiogenic shock complicates 7–10% of cases of acute myocardial infarction and, as it constitutes the leading cause of death in this hospitalised patient group [23], aggressive diagnostic and therapeutic intervention is mandatory. Therapy must be directed at improving cardiac output, and invasive monitoring is needed to assess the patient's condition and manage the administered therapy. Oxygen and diuretics are frequently administered to this patient population. Inotropic therapy may be given in the presence of intravascular fluid overload, or once adequate intravenous fluid volume has been administered to support a systolic blood pressure that will maintain adequate tissue perfusion. In cases of low cardiac filling pressures (e.g. excessive diuresis or volume loss, or right ventricular infarction), intravenous normal saline is administered as a bolus followed by an infusion to improve intravascular volume and hence cardiac output. If the above steps fail to result in clinical and haemodynamic improvement and stabilisation of the patient, use of intraaortic balloon counterpulsation or ventricular assist devices may be considered.

2.3. Acute decompensation of chronic heart failure
Patients with previously diagnosed chronic congestive heart failure are usually receiving long-term oral treatments, including diuretics, with or without angiotensin-converting enzyme inhibitors, digoxin and—increasingly—beta-blockers. Episodes of acute decompensation occur in response to stresses such as worsening myocardial ischaemia, fluid overload, increased blood pressure or cardiac output demands, or poor compliance with the treatment and/or dietary regimen. Clinical signs and symptoms are a consequence of volume overload, elevated ventricular filling pressures and decreased cardiac output. Treatment of the patient requiring hospitalisation for decompensation of chronic heart failure includes the administration of oxygen, diuretics, vasodilators and inotropic agents. Reversion to long-term oral therapy is recommended once clinical and haemodynamic stability is achieved for 24 h.

2.4. Alternative therapeutic approaches
Tailored therapy, by which dose titration of a drug is guided by a surrogate endpoint, has been proposed as an alternative approach to the intensive clinically guided treatment of heart failure [24]. For example, brain natriuretic peptide (BNP)-guided treatment has been shown to reduce the cardiovascular adverse event rate, and delay the time to first event in patients with symptomatic heart failure (NYHA class II–IV) [25]. However, the benefits of such an approach remain contentious, and evidence to date suggests that tailored therapy should not replace a treatment regimen based on clinical trial data that show clear reductions in morbidity and mortality [26]. In addition to its proposed use as a diagnostic serum marker, infusion of BNP has been shown to improve haemodynamic effects and clinical status in patients with decompensated congestive heart failure through its vasodilatory actions [27].

Low-dose dopamine (1–3 µg kg–1 min–1) is sometimes used in patients receiving aggressive diuretic therapy who exhibit renal dysfunction despite volume overload and high ventricular filling pressures. This controversial approach is based on the rationale that these doses augment renal blood flow and glomerular filtration rate via stimulation of renal dopaminergic receptors [28].


   3. Managing decompensated heart failure via enhanced contractility
Top
 Abstract
 1. Introduction
 2. Current therapeutic...
 3. Managing decompensated heart...
4. Conclusions
 References
 
Enhancing the myocardial contractile force is an important mechanism by which cardiac output can be increased in the management of decompensated heart failure. To date, the positive inotropes and the more recently introduced calcium sensitisers constitute the only drug classes with a direct effect on stroke volume.

3.1. Positive inotropic therapy
Positive inotropes—most commonly β-adrenergic agonists and phosphodiesterase inhibitors—are widely used in the management of decompensated heart failure to correct haemodynamic disturbances and as a bridge to heart transplantation in end-stage heart failure. Inotropic agents increase cardiac output via an increase in stroke volume. Both drug groups enhance calcium entry into the myocytes by increasing levels of cyclic adenosine monophosphate (cAMP), either via an increase in production (β-adrenoceptor agonists) or by inhibiting its degradation (phosphodiesterase inhibitors) [29]. This rise in intracellular calcium levels results in increased binding of calcium ions to troponin-C, with subsequent conformational changes in the thin filament regulatory proteins that facilitate crossbridge attachment between actin and myosin and culminate in the contraction of the cardiac muscle [30].

Although these agents confer short-term benefits, they have a number of potentially deleterious effects that limit their long-term usefulness. For example, chronic administration of β-adrenergic agonists frequently leads to tachyphylaxis in the form of haemodynamic tolerance, a possible consequence of progressive receptor down-regulation [29]. Conversely, the pharmacological efficacy of the phosphodiesterase inhibitors is generally maintained over long-term therapy, though tolerance has been observed in some studies [29]. However, any long-term haemodynamic improvement may be inapparent due to progression of left ventricular dysfunction in patients with decompensation of chronic heart failure, and the occurrence of adverse effects frequently limits the drug dose that can be administered [29].

The clinical effects of these drugs are relatively non-specific as both cAMP and calcium mediate numerous biological and physiological actions [31]. The enhanced cellular calcium handling induced by these agents is associated with an increased energy demand, hence an increase in myocardial oxygen consumption [32,33]. Furthermore, increased intracellular concentrations of cAMP and the resultant increase in intracellular calcium turnover have been shown to be cardiotoxic and to enhance electrophysiological mechanisms that lead to rhythm disturbances [34–37]. Indeed, a number of studies have suggested that cAMP-enhancing agents may accelerate the progression of the underlying disease and provoke the development of serious ventricular arrhythmias [29,38–40]. This risk of arrhythmogenic stimulation limits dosing and may result in increased myocardial ischaemia and sudden death [32].

3.1.1. Effects of positive inotropic treatment on mortality
Although short-term haemodynamic variables are improved, clinical data demonstrate that the long-term oral use of positive inotropes may be associated with an adverse effect on mortality rates [19,41,42]. For example, in the PROMISE study (Prospective Randomised Milrinone Survival Evaluation)—a large randomised, placebo-controlled trial of 1088 patients with severe chronic heart failure [New York Heart Association (NYHA) class III or IV]—oral milrinone, 40 mg daily, was associated with a 28% increased mortality from all causes (P=0.038) and a 34% increase in cardiovascular mortality (P=0.016) over a median follow-up period of 6.1 months [19]. The authors of this study concluded that the impairment of cAMP production in the failing heart should no longer be viewed as a biochemical failure to be corrected. Increased mortality has also been reported in small studies with the partial β-adrenergic agonist xamoterol [41] and with the phosphodiesterase inhibitor enoximone [42]. Another phosphodiesterase inhibitor, imazodan, was shown not to have a beneficial effect on mortality in patients with congestive heart failure [43].

The β-adrenergic agonist dobutamine has also been shown to increase mortality in a number of trials [21,44,45]. A multicentre, randomised controlled trial of intermittent dobutamine vs. placebo infusion was terminated prematurely after 8 weeks of treatment because of excessive mortality in the dobutamine-treated group [20]. Of 60 patients with refractory NYHA class III/IV heart failure, 31 received dobutamine (mean dose 8.1±3.3 µg kg–1 min–1) and 29 received placebo. At 8 weeks, 20 patients had died, 5 in the placebo group, 13 in the dobutamine group and 2 who crossed over from placebo to dobutamine during the trial. In the FIRST (Flolan International Randomised Survival Trial) study of 417 patients with class IIIb/IV heart failure, continuous intravenous dobutamine was associated with both a higher occurrence of first event and a higher 6-month mortality rate compared with patients who were not administered dobutamine [44]. After adjusting for baseline differences, intravenous continuous dobutamine was found to be an independent risk factor for death [44]. Furthermore, in a comparison of chronic intravenous dobutamine (mean dose, 7±3 µg kg–1 min–1 for 12 h day–1) with nitroprusside (0.76±0.99 µg kg–1 min–1) in 113 patients with class III/IV refractory heart failure, the overall mortality was 58% vs. 28%, respectively (P<0.006) [45]. However, there is some evidence that the intermittent infusion of low doses of dobutamine (2.5 µg kg–1 min–1 for 48 h per week) is associated with lower mortality rates [46].

Vesnarinone is an inotropic drug with multiple mechanisms that appears to enhance contractility through ion-channel effects that augment sodium–calcium exchange and also through phosphodiesterase inhibition [47]. Despite early promise, however, the long-term effects of this agent have not been favourable. In a large randomised, placebo-controlled study that enrolled 3833 patients with symptoms of NYHA class III or IV heart failure, vesnarinone, 60 mg day–1, was associated with a significantly shorter time to death than placebo (P=0.02) [20]. The increase in mortality with vesnarinone was attributed to an increase in sudden death presumed to be due to arrhythmias.

The OPTIME CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) [48] is the largest randomised trial conducted to date in the setting of hospitalised chronic heart failure. Patients with known systolic heart failure requiring hospital admission for an exacerbation were randomly assigned within 48 h of admission to receive a 48-h infusion of either intravenous milrinone or placebo. Preliminary results presented at the American College of Cardiology annual meeting in 2000 did not show any reduction in mortality in patients receiving milrinone compared with those receiving placebo. Milrinone was, however, associated with a significant increase in the incidence of sustained hypotension [49].

Given the increased mortality rates seen in patients treated with inotropic agents that act through cAMP mechanisms, these drugs should be limited to short-term intravenous use in those patients with decompensated heart failure that is unresponsive to other treatment.

3.2. Calcium sensitisers—a new therapeutic option
Calcium sensitisation has been proposed as a novel therapeutic approach by which cardiac performance may be enhanced without predisposition to calcium-induced arrhythmias or an increase in myocardial oxygen demand [33]. It was hypothesised that, via their interaction with cardiac contractile proteins, ‘calcium sensitisers’ would increase the contractile force generated for a given amount of cytoplasmic free calcium compared with agents that do not possess this activity. Furthermore, by increasing the sensitivity of the contractile proteins to calcium without enhancing calcium influx into myocytes, these agents preclude the intracellular calcium overload and increased calcium turnover associated with positive inotropic treatment, thus reducing the risk of rhythmic disturbances [50].

3.2.1. Mode of action of calcium sensitisers
Compounds with calcium sensitising activity include levosimendan, pimobendan, MCI-154, EMD-53998 and its enantiomer, EMD-57033 (Fig. 1). These agents exert their calcium sensitising action via a variety of mechanisms, including increasing the affinity of troponin-C for calcium, directly stabilising the calcium-induced conformation of troponin-C, or acting distal to the troponin-C molecule [33]. Despite their demonstrated calcium sensitising activity, however, phosphodiesterase inhibition appears to be a component of the mode of action of therapeutic doses of several of these compounds, notably pimobendan, EMD 53998 and MCI-154 [51].


Figure 1
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  		Fig. 1 Calcium sensitisers constitute a structurally heterogeneous class of compounds.

 
Any agent that alters the calcium sensitivity of the cardiac contractile apparatus may potentially impair diastolic function [33,52]. Sustained increased affinity of the contractile protein for binding calcium during both systole and diastole, as manifested by some of these agents, could adversely affect the contraction–relaxation cycle of the heart. For example, pimobendan and MCI-154 appear to enhance the affinity of cardiac troponin-C for calcium, which is a more effective mechanism at lower calcium concentrations [33,53,54]. Given the association of diastole with lower calcium concentrations, these agents might be expected to impair cardiac relaxation [33]. Indeed, this postulated effect appears to be borne out in practice as prolonged relaxation has been observed in human cardiac muscle strips treated with pimobendan [55,56]. Furthermore, calcium sensitisers such as EMD 53998 and EMD 50773, that do not directly affect calcium, but rather alter the myosin–actin interaction would be expected to be equally active during the entire contraction–relaxation cycle and thus prolong diastole [57].

3.2.2. The dual mechanism of action of levosimendan
Levosimendan is the most potent of the aforementioned calcium sensitisers in skinned fibres. It appears to bind in a calcium-dependent manner to the N-terminal domain of troponin-C [33], thus magnifying the extent of the contraction produced by troponin-C when it is calcium activated [50]. As levosimendan binds only to the calcium-bound conformation of troponin-C, its maximum calcium-sensitising effect coincides with peak intracellular calcium levels with minimal effects observed during cardiac relaxation. Thus, in contrast to some other calcium sensitisers, the enhanced cardiac performance mediated by levosimendan appears to be unassociated with altered relaxation times; normal diastolic ventricular relaxation remains unaffected and, thus, diastolic function is unimpaired [58,33]. Indeed, levosimendan was shown to have no clinically relevant influence on diastolic function in 16 patients who underwent percutaneous transluminal coronary angioplasty and, in a further study, had no effect on Tau (the time constant of left ventricular isovolumic relaxation) [59,60]. Although levosimendan also selectively inhibits phosphodiesterase III activity in vitro [50], this action is only apparent at levels in excess of the recommended therapeutic doses [61,62]. At clinically relevant doses, therefore, its predominant mechanism of action is via calcium sensitisation.

Levosimendan not only increases cardiac performance, but has also been shown in both animal models and clinical studies to induce vasodilation [63–65]. This effect is mediated through a novel mechanism that involves ATP-dependent potassium (K) channels [66]. Indeed, levosimendan has been demonstrated to act as a KATP channel opener [67], and the associated increase in potassium handling produces vascular relaxation thereby reducing the preload and afterload of the myocardium. A study of the electrophysiological effects of intravenous levosimendan in patients with normal cardiac function has shown that it facilitates impulse formation and conduction in cardiac slow-response tissue, enhances recovery of excitability in the myocardium and potentially delays repolarisation [68]. The effects on the ventricle were not substantial and the likelihood of provoking serious cardiac arrhythmias was very low. By virtue of its ATP-sparing and KATP opening properties, and its dissociation with elevated cytosolic calcium levels, levosimendan has been postulated to be a cardioprotective agent [69]. This hypothesis is supported by animal studies that have shown levosimendan, to improve reperfusion function without promoting arrhythmias [70], though the clinical significance of this remains to be determined.

A comprehensive review of the clinical studies of levosimendan is beyond the scope of this article. However, increasing clinical data indicate that levosimendan produces symptomatic and haemodynamic improvement in patients with decompensated heart failure of both ischaemic and non-ischaemic origin [31,71]. Furthermore, its effects appear to be associated with no increase in myocardial oxygen consumption [72–74]. Mortality associated with decompensated heart failure precipitated by acute myocardial infarction was reduced significantly at 14 days following administration of levosimendan [75]. Furthermore, in a comparative study with dobutamine, levosimendan was associated with a significantly lower relative risk of death at 6-month follow up (RR 0.57; 95% CI: 0.34–0.95; P=0.029) [76]. However, as mortality has not constituted a primary endpoint in any clinical studies of levosimendan to date, these data remain to be confirmed in formal clinical trials.

3.2.3. Current status
To date, levosimendan and pimobendan are the only calcium sensitisers that have been introduced into clinical practice. Pimobendan is launched in Japan; however, its future elsewhere is under evaluation following results of the PICO (Pimobendan in Congestive Heart Failure) study suggesting a non-arrhythmogenic increase in the risk of death compared with placebo (hazard ratio, 1.8) over a mean follow up of 11 months [77]. Levosimendan was first launched in Sweden in 2000. Through the Mutual Recognition Process, it subsequently received final marketing authorisation in a number of other European countries, where launch has since occurred or is anticipated shortly. The product has also been launched in Latin America. Negotiations are ongoing regarding requirements for marketing authorisation in additional European markets—including France, Germany and the UK—and further trials are underway in order to obtain US approval of levosimendan.


   4. Conclusions
Top
 Abstract
 1. Introduction
 2. Current therapeutic...
 3. Managing decompensated heart...
 4. Conclusions
References
 
The treatment objectives of decompensated heart failure should include the short-term goals of stabilising the patient, improving haemodynamic function and conferring symptomatic improvement, as well as the longer-term goals of limiting disease progression, decreasing hospital readmission rates and improving survival. Currently used treatment strategies only partially fulfil these criteria, and pharmacotherapy is frequently administered to achieve short-term benefits at the expense of longer-term considerations. Most notably, the positive inotropes have been demonstrated to have a negative effect on survival rates [19,41,44,45].

Calcium sensitisers comprise a new class of drug that offer haemodynamic and symptomatic benefits without increasing cAMP and intracellular calcium concentrations. These agents enhance cardiac performance without concomitantly increasing the arrhythmic risk, and thus offer clinical benefits over traditional inotropic agents. This drug class constitutes a heterogeneous group of compounds that exhibits multiple mechanisms of action and different affinities for calcium sensitisation. The most potent calcium sensitiser to date, levosimendan, exhibits a dual mechanism of action of enhanced cardiac performance via calcium sensitisation combined with vasodilation via ATP-dependent potassium channels. Calcium sensitisation with levosimendan is therefore emerging as a promising treatment approach in this challenging therapeutic area.


   Acknowledgements
 
Supported by an educational grant from Abbott Laboratories.


   References
Top
 Abstract
 1. Introduction
 2. Current therapeutic...
 3. Managing decompensated heart...
 4. Conclusions
 References
 

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M. Adamcova, M. Sterba, T. Simunek, A. Potacova, O. Popelova, and V. Gersl
Myocardial regulatory proteins and heart failure
Eur J Heart Fail, June 1, 2006; 8(4): 333 - 342.
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