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European Journal of Heart Failure 2006 8(4):333-342; doi:10.1016/j.ejheart.2005.09.007
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© 2006 European Society of Cardiology

Myocardial regulatory proteins and heart failure

Michaela Adamcováa,*, Martin Sterbab, Tomás Simunekc, Anna Potácováa, Olga Popelováb and Vladimír Gerslb

a Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University in Prague Simkova 870, 500 38 Hradec Králové, Czech Republic
b Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague Simkova 870, 500 38 Hradec Králové, Czech Republic
c Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague Heyrovského 1203, 500 05 Hradec Králové, Czech Republic

* Corresponding author. Tel.: +420 49 5816180; fax: +420 49 5436054 E-mail address: adamcova{at}lfhk.cuni.cz


   Abstract
Top
 Abstract
1. Introduction
 2. Conclusions
 References
 
Cardiac troponin T (cTnT) and cardiac troponin I (cTnI) are considered to be the most specific and sensitive biochemical markers of myocardial damage. Troponins have been studied in a wide range of clinical settings, including heart failure; however, there are few data on the role of regulatory proteins in the pathogenesis of heart failure, although a few interesting hypotheses have been proposed. A considerable body of evidence favours the view that alteration of the myocardial thin filament is the primary event leading to defective contractility of the failing myocardium, while the changes in Ca2+ handling are a compensatory response. A better understanding of the role of regulatory proteins under different physiological and pathological conditions could lead to new therapeutic approaches in heart failure. Recently, calcium sensitisation has been proposed as a novel method by which cardiac performance may be enhanced via an increase in the affinity of troponin C for calcium but without affecting intracellular calcium concentration. To date, the only calcium sensitizer used in clinical practice is levosimendan.

Key Words: Heart failure • Regulatory proteins • Cardiac troponin • Cardiac marker • Calcium sensitizers • Myocardial stunning

Received November 9, 2004; Revised July 1, 2005; Accepted September 22, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Conclusions
 References
 
Heart failure represents the final stage of cardiac disease. Today coronary artery disease is the most common cause of heart failure. Improved treatment of acute myocardial infarction means that more people survive; however, cardiac function is frequently impaired and in many of these patients heart failure develops over time. On the other hand, valvular disease-another major cause of heart failure-is becoming less prevalent. The recently published Rotterdam Study (prospective population-based cohort study with 7983 participants aged ≥55 years; heart failure defined according to European Society of Cardiology criteria) revealed that heart failure prevalence increases with age from 0.9% in subjects aged 55-64 to 17.4% in those aged ≥85. Furthermore, heart failure continues to be a fatal disease, with only 35% of patients surviving 5 years after the first diagnosis [1]. The high incidence and the increasing cost of treatment confirm the importance of heart failure as a major public health problem. Recently, there has been much interest in the relationship between heart failure and myocardial regulatory proteins. Troponins can play a significant role in the pathogenesis, diagnosis, and also the treatment of heart failure. This review aims to summarize the available data and to identify possible areas for further investigation.

1.1. Regulatory proteins of the myocardium
The myocardium consists of three basic categories of proteins. (1) Myofibrillar proteins which transform the chemical energy of ATP to the mechanical work of the heart. (2) Metabolic proteins, located both in the cytosol and in the mitochondrial compartments, which provide energy for cardiac contraction. The interstitial space between the myocytes is occupied by (3) extracellular proteins (collagens, glycoproteins, glycosaminoglycans, elastins). The majority of myofibrillar proteins (about 80%) are involved in contraction (actin and myosin), while about 10% are involved in regulation (troponin, tropomyosin, and tropomodulin) and 10% maintain the myofibrilar structure (C-, M-, H-proteins, myomesin, nebulette, P-actinin, titin, CapZ protein) [2]. The properties of the myofibrillar proteins are summarized in Table 1.


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  		Table 1 Properties of myofibrillar proteins (data from reference [2])

 
The first report on troponin appeared in 1969 [3]. Subsequently, this regulatory protein was found to contain three subunits and the nomenclature proposed by Greaser et al. [4] was adopted: troponin T (TnT—37 kDa) binds troponin subunits to tropomyosin, troponin C (TnC—18 kDa) binds divalent covalent ions, and troponin I (TnI—24 kDa) affects the myosin-actin interaction.

Recently, it has been shown that the effects of each troponin subunit are much more complicated than previously thought. Mutual co-ordination of all myofibrillar proteins and their many different covalent and non-covalent bonds is required for the control of actin-myosin formation. It has been suggested that an important role of TnT is to change the TnC/TnI complex from a calcium insensitive to a calcium sensitive form in the Mg2+-ATPase system, probably by the reduction of the binding constant for the TnI/TnC complex in the absence of calcium [5]. Furthermore, the inhibition of actin-myosin crossbridges is not arranged by TnT but seems to be mediated directly by tropomyosin [6,7]. The most significant property of TnI is the ability to induce different conformational changes in each of the proteins with which it interacts (i.e. actin, tropomyosin, TnC and TnT) in order to facilitate their function. This means that TnI does not have an inhibitory effect but rather the opposite, including the ability to increase the affinity of TnC for calcium ions [5].

Troponin C belongs to the so called "EF-hand proteins" [8]. The key to the ability of these proteins to bind calcium lies in the arrangement of the oxygen-containing amino acids that form the vertices of an octahedral "pocket" for which calcium ions have a very high affinity. Cardiac troponin C originally contained four calcium binding regions, but site I has lost the ability to bind divalent cations, and sites III and IV can bind either calcium or magnesium ions. Under physiological conditions, when the concentration of intracellular magnesium is much higher than intracellular calcium, binding sites III and IV are fully saturated with magnesium ions and are not primary involved in the regulation of cardiac contractility. However, these sites participate in the stabilization of the troponin-tropomyosin bond in the I-zone of the sarcomere. Therefore, the only calcium-specific site is the site II [8].

TnT and TnI exist in three different isoforms with a unique structure, one for the slow-twitch skeletal muscle, one for the fast-twitch skeletal muscle, and one for cardiac muscle [9,10]. The three isoforms are encoded by three different genes. TnC has only two isoforms coded by two genes—one specific for the fast-twitch skeletal muscle and another one that is coexpressed both in the myocardium and in the slow-twitch skeletal muscle [11]. The genes encoding TnI and TnT isoforms are organised in pairs (Table 2). This situation differs from all other sarcomeric genes where the members of the same gene family are clustered. A close linkage of the cardiac TnI gene with the slow-skeletal TnT gene and of the slow-skeletal TnI gene with the cardiac TnT gene have been demonstrated. This linkage of genes contrasts with their pattern of expression which is cardiac-specific and skeletal-muscle specific, respectively. Further studies are needed to decipher the mechanisms regulating the overall transcription of this locus resulting in independent expression of troponin isoforms [12].


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  		Table 2 Location of the genes coding the different troponin isoforms (data from reference [12])

 
Furthermore, cardiac troponin T displays several molecular variations and both subunits of cardiac troponin T and I may undergo different changes of phosphorylation in response to stimulation by protein kinases, which can significantly influence the contractility of the myocardium. These issues are currently under intensive investigation both during the ontogenetic development and under many pathological states [13-19].

The tropomyosin molecule can be a homodimer or a heterodimer containing either one or both isoforms, called P-tropomyosin and β-tropomyosin, with molecular weights of 34000 and 36000, respectively [20,21]. In the adult myocardium, the β-isoform is estimated to represent about 10-15% of total tropomyosin, but in certain pathological states, e.g. during hypertrophy resulting from pressure overload, synthesis of the β-isoform is increased [17,22,23]. It has been demonstrated that the bonds between TnT and P-tropomyosin are less effective than the bonds between TnT and β-isoform of tropomyosin, which may result directly in changes in Ca2+ sensitivity. Unfortunately, very little is known about tropomyosin alterations which may play either an adaptive or maladaptive role in some pathological states in humans [24].

Tropomodulin is a recently discovered regulatory protein which caps the free pointed ends of the thin actin filaments to prevent excess elongation during growth [25]. The microinjection of antibodies that inhibit tropomodulin's activity in vitro results in a marked elongation of actin filaments from their pointed ends and more than an 80% reduction in the percentage of beating cells [26]. Conversely, tropomodulin overexpression in transgenic mice has been shown to induce shortening and degeneration of actin fibres, resulting in dilated cardiomyopathy [27].

1.2. Troponins and pathogenesis of heart failure
Can proteolysis of troponin I trigger the development of cardiac hypertrophy and heart failure?

One of the most exciting recent hypotheses states that proteolysis of cTnI may be a trigger which initiates the hypertrophic process [28,29]. Increased intracellular Ca2+ concentration due to alterations in Ca2+ homeostasis in the ischaemic or otherwise stressed heart, activates cysteine protease-calpain I, which results in degradation of its target proteins, such as troponin I and troponin T. If the synthesis of new troponins cannot keep pace with their destruction by calpain, the regulatory function of the troponins is disturbed, leading to impairment of contraction and relaxation. Calpain has been demonstrated immunohistochemically to be predominantly located in the nucleus, at the intercalated discs, and also in the cytosol [30].

Two major isoforms of calpain have been identified so far: (1) µ-calpain (calpain I) is activated by a micromolar concentration of [Ca2+]i, whereas (2) m-calpain (calpain II) requires a concentration of [Ca2+]i in the millimolar range [31]. Both calpain I and calpain II can be blocked by the specific endogenous inhibitor protein calpastatin. It has been postulated that the calpain-calpastatin system regulates various physiological and pathological [Ca2+]i-dependent phenomena in mammalian cells. Both the in vitro incubation of tissue with calpastatin and the overexpression of calpastatin gene transfer were shown to prevent myocardial TnI degradation [32,33].

In agreement with an earlier report suggesting that the proteolysis of cTnI occurred between residues 188 and 199, McDonough et al. [34] have demonstrated that during moderate ischaemia/reperfusion, cTnI is degraded at its C-terminal end by the removal of 17 amino acids generating cTnI1-193. With longer durations of ischaemia and moderate ischaemia/reperfusion, there is also N-terminal truncation, generating two other degraded forms of the protein (cTnI63-193 and cTnI73-193). Further studies have shown that cTnI1-193 forms a covalent complex with the N-terminus of cTnC, a region that contains the single regulatory Ca2+ domain, and with the C-terminal residues of cTnT, which are important for the transduction of the Ca2+ binding signal to tropomyosin. McDonough et al. [34] proposed that this complex formation is caused by the activity of transglutaminase. The proteolysis or loss of cTnI would lead to depressed diastolic and systolic function, ultimately resulting in a sustained elevation of end-diastolic pressure and volume as well as an altered amplitude and dynamics of the intracellular Ca2+ transient. Alterations in Ca2+ dynamics (triggering differential activation of transcription) and stretch (releasing hypertrophic factors such as endothelin and angiotensin) are two prominent mechanisms leading to the development of hypertrophy [29]. The confirmation or rejection of this hypothesis needs further studies.

Is the alteration in troponin isoform expression or phosphorylation a cause or consequence of heart failure?

Whereas the cTnC [35] and cTnI [36,37] are expressed in the adult heart as single isoforms, multiple cTnT isoforms are present [38-40]. Based on the existence of a single cTnT gene, the various isoforms with individual functional significance are the products of alternative splicing of a primary RNA transcript. Four variable regions in human cTnT were detected on the exon 4, 5, 10, and 13: the first variable domain at the 5' end of the cDNA is composed of two joined cassettes of 15 and 30 base pairs (bp), the latter being potentially excised at the first codon, the second is a single codon at amino-acid 45, and the third is a box of 9 bp [41]. The fourth variable domain is in the central region of cDNA. Although the definite number of protein isoforms is not yet known, some authors have hypothesised that these 4 variable regions can generate 36 different cardiac TnT isoforms [42].

The most cited papers [43,44] have shown four human cTnT isoforms at the protein level (Fig. 1). It has been determined that these four isoforms (cTnT1 through cTnT4 numbered in the order of decreasing molecular weight) are generated by combinatorial alternative splicing of two 15 and 30 base pairs at the first variable domain at the 5' end of the cDNA [44]. Both exons encode highly acidic peptides; the inclusion of either peptide would add an overall negative charge to the cTnT protein. The isoforms cTnT1 and cTnT2, are expressed in the foetal heart, with cTnT2 being expressed at a very low level. The third isoform, cTnT3 is the dominant isoform in the adult heart. Furthermore, TnT4 is expressed in the foetal heart. It has been demonstrated that the 5-residue peptide alters the sensitivity of ATPase activity to calcium [45]. Studies by Nassar et al. [46] and McAuliffe et al. [47] suggest that the presence of isoforms containing the 10-residue peptide increases the myofilament calcium sensitivity, which may be functionally important for the immature myocardium, where the peak cytosolic calcium concentration transient is significantly lower than that of the adult. Furthermore, Anderson et al. [43] reported that TnT4 may also be expressed in the failing heart, where expression inversely correlates with the peak of myofibrillar ATPase activity. It has been suggested that alterations in TnT isoforms may underlie the depressed myofibrillar ATPase activity which is a characteristic of the failing myocardium and is thought to be one of the major pathophysiological abnormalities in this condition.


Figure 1
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  		Fig. 1 The isoforms of cardiac troponin T. Human cardiac troponin T (TnT) 5' heterogeneity. Presenting or missing 15 base pairs and 30 base pairs sequences of TnT1-TnT4 are shown schematically (data from reference [44]).

 
Our results in an experimental model of heart failure in rabbits, also demonstrate that daunorubicin-induced cardiomyopathy was accompanied by changes in cTnT isoform expression, when compared with both the control group and the group receiving daunorubicin combined with the cardioprotective agent dexrazoxane [48]. Similar shifts of TnT isoform expression in experimental models, mainly in rabbits, have also been described by other authors [49-51]. However, taking into account that TnT isoform expression is variable between species, whether data from animal models is relevant to humans is uncertain.

The presence of the TnT isoform with higher mobility (presumably the cTnT4 isoform) has been reported in failing hearts by some authors, but was not observed at either protein or mRNA levels by others [16,41,52]. However, these latter studies also reported a decreased maximum-activated myofibrillar ATPase activity, unloaded shortening or sliding speed, and increased Ca2+-sensitivity in the failing heart muscle, independent of the presence of the TnT4 isoform [53,54]. This is why the authors postulated that these functional differences between non-failing and failing heart are not due to altered expression of troponin T but due to the level of phosphorylation mediated by protein kinase. Indeed, current opinion favours alterations in troponin phosphorylation as the likely cause of the defective contractility of the failing myocardium [24].

The phosphorylation state of troponin via protein kinase C (PKC) or protein kinase A (PKA) modulates cardiac performance by affecting both the Ca2+-stimulated contraction function and the myofibrillar ATPase activity of the heart. Two phoshorylated sites have been detected in bovine cardiac TnT: the first site is on N-terminal serine, the second is on C-terminal in the cyanogen bromide fragment CN 4 [55]. Phosphorylation of TnT led to a lower affinity for binding of tropomyosin to F actin [56].

Phosphorylation of cTnI at N-terminal, containing two serine residues in positions 23 and 24 via the cAMP-dependent protein kinase A, has been shown to reduce the Ca2+ affinity of the single Ca2+-specific regulatory site of cTnC and to increase the rate of Ca2+ dissociation from this site [55]. The study of Zhang et al. [57] suggests that Ser23 may be constitutively phosphorylated and Ser24 may be functionally more important. It is possible that increased PKA phosphorylation of TnI could affect the TnT isoform switching [58], but this hypothesis remains to be tested. In addition, protein kinase C (PKC) and/or Ca-calmodulin dependent protein kinase can phosphorylate the cardiac troponin I at Ser43, Ser45, Thr144, and this phosphorylation appears to reduce the affinity of crossbridges for the thin filament. The interaction between myosin and actin seems to be more likely when the TnI is in its dephosphorylated form [59].

Some studies have demonstrated that the failing myocardium contains significantly larger amounts of dephosphorylated cTnI than seen in control tissue [53,60]. The extent of phosphorylation of TnI can be responsible for greater myofibrillar calcium sensitivity of the failing myocardium. The functional consequence of this finding may be an adaptive or maladaptive response enhancing force development or producing ventricular diastolic dysfunction.

These differences in results for the heart failure-related alteration in troponin isoform expression and phosphorylation are probably caused by sampling problems, by the relatively limited number of studies in humans and by the limited number of samples in these studies. Recently, it has been reported that all cardiac diseases, whether due to acute or chronic injury, produce specific changes in the protein profile of cardiomyocytes [61,62]. Disease-induced protein alterations may result from posttranslational modifications (including proteolysis, covalent cross-linking, phosphorylation, oxidation, and glycosylation) or through altered gene expression (including up- or down-regulation and/or isoform switching). Unfortunately, the ventricular tissue samples used in these studies were obtained from patients with a variety of different diagnoses: mainly cardiomyopathy (dilated, idiopathic, alcoholic), ischemic heart disease, or congenital heart disease and the number of samples was very limited [41,42,53,54]. Although it is clear that heart failure is a final process resulting from diverse aetiologies, to our knowledge, there are no relevant data on how these different heart diseases affect the structure and function of troponins. The application of proteomics and modern techniques evaluating complex protein interaction is likely to bring new insight into this topic.

Another important question, which as yet has not been conclusively answered, is whether the alterations in the myocardial thin filament are the primary events in heart failure, or is it the alteration in Ca2+ handling? Recent papers by Perez et al. [63] and Ruf et al. [64] have suggested that it is in fact the alterations of the myocardial thin filament which are the primary event and that the changes in Ca2+ handling are a compensatory response.

1.2.1. The significance of mutation in the troponin gene for the development of cardiomyopathy
Regarding the key role of troponins in the contractility of the myocardium, it is not surprising that mutation of these genes can lead to cardiomyopathy, which can result in heart failure. To date, genetic analysis has revealed that mutations in the following nine different genes encoding sarcomeric proteins can cause hypertrophic cardiomyopathy (HCM): the β-myosin heavy chain, the cardiac myosin essential light chain, cardiac myosin, the cardiac myosin regulatory light chain, P-actin, P-tropomyosin, cTnT, cTnI, titin and cardiac myosin-binding protein C genes [65-67]. Within each of these genes a variety of individual mutations have been found, and it appears that most families have their "private" mutations.

The incidence of myocardial troponin T gene abnormality is high (approximately 15% of all cases of familial HCM), and affected patients sometimes die suddenly [68]. To our knowledge, about 30 mutations in human cardiac TnT gene (missense, deletion, splice variant) have been linked to HCM [69]. Each TnT mutation has different effects on myofilament properties (increased myofilament Ca2+ sensitivity, decreased maximal force, decreased binding affinity to the thin filament, impaired pH-regulation). But when the in vitro data are correlated with the results from the transgenic models, essentially all mutations can be predicted to result in: (1) impaired relaxation, (2) reduced diastolic compliance, (3) reduced contractile reserve, (4) preserved systolic function under baseline conditions, and (5) cardiac dysfunction under inotropic stimulation [67,70]. Thus, any situation with increased heart rate, decreased preload and decreased afterload could acutely result in haemodynamic collapse and sudden death. Chronically, cellular Ca2+ homeostasis, altered as a result of the changes in myofilament Ca2+ sensitivity, may be responsible for cardiac hypertrophy [70-72].

Abnormalities in the genes of other regulatory proteins are not very common. The P-tropomyosin HCM-associated mutants do not appear to cause a depression of maximum force; instead, these proteins cause an increase in the Ca2+ sensitivity of force production and hence give an increase in force at submaximal Ca2+ concentrations. It has been postulated that mutations in this gene may cause hypertrophy by a more direct "hypercontractile" mechanism. In addition, increased Ca2+-sensitivity might be expected to produce deficits in diastolic relaxation [66,73].

The cTnI HCM mutations are among the most recently reported and at this time there is a very little data on their effect on TnI function. Van Eyk et al. [74] found that mutation of any of the basic amino acids to glycine in the inhibitory peptide, including the equivalent of the Arg145 residue, had a severe effect on the peptide ability to inhibit the actomyosin ATPase.

Mutations in the three subunits of the troponin complex are also associated with dilated cardiomyopathy (DCM) [75-78], their overall frequency is estimated to be 6% [79]. The identified mutations were all localized in conserved and functionally important domains of the proteins involved in the interaction with other troponin subunits and/or tropomyosin [80-83]. The disease expression is characterized by high penetrance and severe prognosis. Previous functional studies of one of the DCM mutations (TNNT2, {delta}K210) showed that mutated protein reduced the Ca2+ sensitivity of actomyosin ATPase activity, which resulted in decreased maximum speed of muscle contraction [72]. Thus, DCM mutations in the troponin complex may induce a profound reduction in force generation leading to impaired systolic function and cardiac dilation. In addition, it is possible that the myocardium of mutation carriers may be more susceptible to environmental influences such as viruses and toxic agents.

Genetic linkage of sarcomeric protein mutations with hypertrophic and dilated cardiomyopathy is perhaps the strongest stimulus for investigation of cardiac hypertrophy and failure, not only to understand the signalling cascades engaged in this process, but also to determine structural and functional alterations in cardiomyocytes associated with hypertrophy and with transition to heart failure [19].

In addition, these genetic studies raise the following question: could a post-translation modification arising from an extrinsic stress lead to a dominant negative effect that triggers the decompensation? The previously presented data provide evidence that such a dominant negative effect exists in the form of troponin alteration in human failing hearts [19].

1.3. Troponins and the diagnosis of heart failure
Could troponins be a predictive marker of heart failure?

Determination of both cardiac TnT and cardiac TnI in plasma/serum is considered to be the most specific and sensitive method for the diagnosis of myocardial damage [84-86]. Missov et al. [87,88] assessed these cardiac markers in patients with congestive heart failure of both ischaemic and non-ischaemic origin. Increased cardiac troponin levels correlated with the severity of CHF (evaluated by NYHA and functional examination of the left ventricle) and were associated with worse prognosis. Possible mechanisms for the release of cTnT and cTnI in advanced CHF may include ventricular remodelling, effects of neurohumoral factors on the myocyte, presence of coronary artery disease in CHF, abnormalities of coronary microcirculation, and reduced coronary reserve [88]. Troponins may identify patients with latent and progressive myocardial damage and those who are at increased risk of cardiac events [89].

Ricchiuti et al. [90] showed that surviving left ventricular myocardium from infarcted porcine hearts, when undergoing overload-induced remodelling, contained substantially less cTnI and cTnT compared to control left ventricular myocardium. Thus, overloaded viable myocardium may release troponin (or its degradation products) into the circulation and, if the rate of release of troponins exceeds the rate of synthesis, the myocardium will become troponin-depleted [91]. This hypothesis implies that release of troponin and/or troponin degradation products is not specific for the necrotic myocardium but may also occur from the viable myocardium [91]. If this hypothesis is not rejected in the near future, the concept that the presence of cardiac troponins in plasma reflects "even microscopic zones of myocardial necrosis," as used by the joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction, should be withdrawn [92]. However, unfortunately there is a shortage of evidence to either support or refute this hypothesis. Though further studies are needed, we can still conclude that (1) there will be likely a continuum from a reversible to an irreversible release; (2) prognosis seems to be related to the presence of elevation, regardless of the mechanism of cellular injury [93] and (3) plasma/serum levels of cardiac troponins are becoming very useful markers of heart failure.

1.4. Troponins and heart failure therapy
How is it possible to increase the force of the cardiac contraction—a new concept of stretch activation?

Do calcium sensitizers represent a new therapeutic approach in patients with heart failure?

According to classical opinions, the force of cardiac contraction can be affected by (1) the extent of ventricular filling by means of the length-tension relationship and (2) by sympathetic stimulation which increases the stroke volume at a given end-diastolic volume via an increased cytosolic Ca2+ concentration [94]. Nowadays it has been demonstrated that the steeply ascending tension-length relationship of the myocardium cannot be readily explained by changes in the extent of actin-myosin overlap. Unlike with the skeletal muscle, the currently proposed mechanism is the length-dependent activation, where the myofilaments become more sensitive to calcium. In intact papillary muscles, stretching causes a large increase in force, whereas the amplitude of the intracellular free calcium transient does not increase [2]. Although the mechanism for this increase in calcium sensitivity in response to stretching is probably multifactorial, two favoured proposals are (1) that the stretch increases the calcium affinity of troponin C by, as yet, unknown mechanism [95] and/or that (2) the stretch thins the sarcomere to facilitate the number of interactions between actin and myosin [96,97].

In other words, this hypothesis states that decreasing the lateral distance between actin and myosin lessens the interfilament lattice spacing and thereby increases the likelihood of actin-myosin interaction [98]. Then, it is proposed that more crossbridges could be recruited into action and the myosin ATPase activity also increases [98]. Therefore, according to current concepts, the length-dependent force changes and inotropic alterations of contractile activity may have ultimate similarities in the changes they induce.

Recently, calcium sensitisation has been proposed as a novel therapeutic approach by which cardiac performance may be enhanced without increasing cAMP and intracellular calcium concentrations, associated with predisposition to arrhythmias or an increase in myocardial oxygen demand. Calcium sensitizers constitute a structurally heterogenous class of compounds including levosimendan, pimobendan, MCI-154, EMD-53998 and EMD-57033 [99]. These agents exert their calcium sensitising action via a variety of mechanisms, including an increase in the affinity of troponin C for calcium, directly stabilising the calcium induced conformation of troponin C, or acting distal to the troponin C molecule [100]. To date, the only calcium sensitizer used in clinical practice is levosimendan, a pyridazinone-dinitrile derivative. Many of the other calcium sensitizers are associated with a high incidence of side effects or are non-specific and therefore unsuitable for clinical practice. Several of these compounds inhibit phosphodiesterase [100,101], which is associated with a positive lusitropic effect. However, from the standpoint of mortality, the phosphodiesterase inhibition might not be beneficial [102].

Levosimendan exhibits a dual mechanism of action. The enhanced cardiac performance is likely to be mediated via (1) calcium sensitisation by binding to the N-terminal domain of troponin C when it is calcium activated and (2) via vasodilatation by ATP-dependent potassium channels [99,100,103]. As levosimendan binds only to the calcium-bound conformation of TnC, 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 sensitizers, 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 [104,105].

The other calcium sensitizers, however, appear to act mainly by decreasing the dissociation rate of crossbridges.

In the treatment of acute congestive heart failure, at therapeutic doses, levosimendan significantly increases cardiac output and cardiac index and decreases the filling pressure [106-111]. Levosimendan also causes coronary and systemic vasodilation [112] and produces anti-stunning effects without increasing myocardial intracellular calcium concentrations [113,114]. The haemodynamic effects of levosimendan are sustained during a long-term infusion and maintained even after the discontinuation of drug infusion [115,116].

The most important clinical study to date, RUSSLAN (Randomized Study on Safety and Effectiveness of Levosimendan in patients with left Ventricular Failure after an Acute Myocardial Infarction) assessed the safety and effectiveness of levosimendan in 504 patients who developed heart failure after AMI. Levosimendan-treated patients (doses 0.1-0.2 µg/kg/min experienced lower risk of death and worsening heart failure than patients receiving placebo, during both the 6 h infusion (2.0% vs. 5.9%) and over 24 h (4.0% vs. 88%). Mortality was lower with levosimendan compared with placebo at 14 days (11.7% vs. 19.6%; hazard ratio 0.56) and the reduction was maintained at the 180-day retrospective follow-up (22.6% vs. 31.4%; 0.67). The authors confirmed that levosimendan could be used safely in patients with post-infarction heart failure in the absence of severe hypotension and it improves both symptoms and survival [106].

As compared with dobutamine, in large controlled trials in patients with decompensated heart failure, intravenous levosimendan was significantly more effective than placebo or dobutamine for overall haemodynamic response rate (primary endpoint). Significant benefits were also seen for mortality (versus placebo or dobutamine) as well as for the combined risk of worsening heart failure or death (versus dobutamine). Improvements in key symptoms (dyspnoea and fatigue) have not been consistently demonstrated. Hospitalisation costs were similar for levosimendan and dobutamine; the total incremental (hospitalisation plus drug) cost per life-year saved (extrapolated to 3 years) for levosimendan relative to dobutamine was estimated at {euro}3205 (year of costing 2000) [117,118].

Levosimendan is usually well tolerated, the most common adverse events (headache, hypotension, nausea) are secondary to vasodilatation. It has not been shown to be arrhythmogenic. Furthermore, levosimendan has shown no clinically important pharmacokinetic interactions with captopril, felodipine, β-blockers, digoxin, warfarin, isosorbide-5-mononitrate, carvedilol, ethanol or itraconazole [119].

To sum up, levosimendan seems to be very promising and unique among intravenous inotropic agents. However, it is important to note that levosimendan has the capacity to reduce blood pressure and thereby it may not be safe or effective in patients with cardiogenic shock and very low arterial pressure [120]. The results of clinical trials encourage further investigation in this area, including the search for new calcium sensitizers, which could be very useful in clinical practice.


   2. Conclusions
Top
 Abstract
 1. Introduction
 2. Conclusions
References
 
The incidence of heart failure will probably continue to increase in coming years, the control of risk factors for hypertension and ischaemic heart disease appears to be the only option to halt this increase. On the other hand, numerous papers report that myocardial regulatory proteins, mainly cardiac troponin T and cardiac troponin I, can play an essential role in the pathogenesis, diagnosis and importantly also the therapy of heart failure. However, studies to date have produced discrepant results, and further research is therefore required. A better understanding of the sequence of events leading to heart failure should result in the implementation of new diagnostic and therapeutic approaches.


   Acknowledgements
 
The authors' own work has been supported by the Charles University Grant Agency (Grant 86/2005) and the Czech Science Foundation (Grants 305/03/1511 and 305/05/P156), and the Czech Ministry of Education (Research Project MSM 0021620820).


   References
Top
 Abstract
 1. Introduction
 2. Conclusions
 References
 

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