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Cardiovascular Research 1998 37(2):300-311; doi:10.1016/S0008-6363(97)00273-3
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

Ca2+ currents in compensated hypertrophy and heart failure

Sylvain Richard*, Florence Leclercq, Stéphanie Lemaire, Christophe Piot and Joël Nargeot

Centre de Recherches de Biochimie Macromoléculaire, CNRS ERS-155, 1919, Route de Mende, BP 5051, 34033 Montpellier Cedex, France

* Corresponding author. Tel. (33) 467 61 33 55; Fax (33) 467 52 15 59; E-mail: richard@xerxes.crbm.cnrs-mop.fr

Received 18 August 1997; accepted 23 October 1997


   Abstract
Top
 Abstract
1 Calcium, myocardial...
 2 T-type Ca2+ channels
 3 L-type Ca2+ channels
 4 Ca2+ channels and...
 5 Concluding remarks and...
 References
 
Transmembrane voltage-gated Ca2+ channels play a central role in the development and control of heart contractility which is modulated by the concentration of free cytosolic calcium ions (Ca2+). Ca2+ channels are closed at the normal membrane resting potential of cardiac cells. During the fast upstroke of the action potential (AP), they are gated into an open state by membrane depolarisation and thereby transduce the electrical signal into a chemical signal. In addition to its contribution to the AP plateau, Ca2+ influx through L-type Ca2+ channels induces a release of Ca2+ ions from the sarcoplasmic reticulum (SR) which initiates contraction. Because of their central role in excitation-contraction (E-C) coupling, L-type Ca2+ channels are a key target to regulate inotropy [1]. The role of T-type Ca2+ channels is more obscure. In addition to a putative part in the rhythmic activity of the heart, they may be implicated at early stages of development and during pathology of contractile tissues [2]. Despite therapeutic advances improving exercise tolerance and survival, congestive heart failure (HF) remains a major problem in cardiovascular medicine. It is a highly lethal disease; half of the mortality being related to ventricular failure whereas sudden death of the other patients is unexpected [3]. Although HF has diverse aetiologies, common abnormalities include hypertrophy, contractile dysfunction and alteration of electrophysiological properties contributing to low cardiac output and sudden death. A significant prolongation of the AP duration with delayed repolarisation has been observed both during compensated hypertrophy (CH) and in end-stage HF caused by dilated cardiomyopathy (Fig. 1A) [4–8]. This lengthening can result from either an increase in inward currents or a decrease in outward currents or both. A reduction of K+ currents has been demonstrated [6, 9]. Prolonged Na+/Ca2+ exchange current may also be involved [9]. In contrast, there is a large variability in the results concerning Ca2+ currents (ICa). The purpose of this paper is to review results obtained in various animal models of CH and HF with special emphasis on recent studies in human cells. We focus on: (i) the pathophysiological role of T-type Ca2+ channels, present in some animal models of hypertrophy; (ii) the density and properties of L-type Ca2+ channels and alteration of major physiological regulations of these channels by heart rate and β-adrenergic receptor stimulation; and (iii) recent advances in the molecular biology of the L-type Ca2+ channel and future directions.


Figure 1
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  		Fig. 1 APs and Ca2+ transients recorded in diseased human cardiac cells. (A) Graph shows representative APs recorded in two different single ventricular cells. Stimulation frequency was 0.5 Hz. AP duration in myocytes from patients with heart failure (dilated cardiomyopathy) was significantly prolonged (AP90 1,038±223 msec; n=7) as compared to controls (649±101 msec; n=4). (B) Graph shows representative [Ca2+]i transients of two different ventricular cells loaded with Ca2+ indicator fura-2 during external stimulation at a frequency of 0.5 Hz. Resting [Ca2+]i were significantly higher in the myopathic cells compared to the control cell (165±61 nmol/l, n=31 vs. 96±47 nmol/l, n=8). In contrast, the peak [Ca2+]i was lower (367±109 nmol/l vs. 746±249 nmol/l) and the decline of [Ca2+]i was slower (t1/2 692±166 msec vs. 320±68 msec). Temperature was 35°C. (Data in panel A and panel B and numbers were taken from [7]with permission).

 

   1 Calcium, myocardial hypertrophy and heart failure
Top
 Abstract
 1 Calcium, myocardial...
2 T-type Ca2+ channels
 3 L-type Ca2+ channels
 4 Ca2+ channels and...
 5 Concluding remarks and...
 References
 
In addition to various structural, biochemical and energetic abnormalities, regulation of intracellular Ca2+ ([Ca2+]i) is defective during HF. For full information, we recommend several papers and reviews that concentrate on specific aspects of the subject [10–13]. Briefly, acute and chronic forms of HF involve mechanical dysfunction during systole, diastole, or both phases of the cardiac cycle [11, 13]. Reduced contraction and slowed relaxation can be observed in single ventricular myocytes isolated from failing human hearts [12]. The positive inotropy induced by accelerated heart rate is abolished in human HF [14]. This alteration, which is graded with the degree of ventricular dysfunction, [15]is associated with impaired [Ca2+]i handling [16]. In dilated human cardiomyopathy, there is a prolonged diastolic Ca2+ transient (Fig. 1B) resulting from a diminished capacity to restore low resting Ca2+ levels [7, 16]. Increased resting or end-diastolic [Ca2+]i therefore results in Ca2+ overload. Impaired Ca2+ removal from the cytosol is an early manifestation of pressure overload hypertrophy which precludes impairment of myocardial relaxation.

The transition from compensated hypertrophy to cardiac dysfunction and overt failure is poorly understood. Decompensated eccentric hypertrophy defines end-stage HF, whether ischemic or not. It is characterised by a large increase in cavity volume with respect to wall thickness. These alterations in cardiac size and shape reflect the ‘ventricular remodeling’ which may determine the occurrence of clinical signs of HF in dilated cardiomyopathy [17, 18]. This change is associated with abnormalities of Ca2+ transport proteins and with quantitative changes in expression of the SR Ca2+ ATP-ase, the ryanodine receptor, and the Na+/Ca2+ exchanger [13, 19, 20]. In animal models, depressed protein levels of phospholamban are also observed in overt HF but not in compensated hypertrophy [13, 19].


   2 T-type Ca2+ channels
Top
 Abstract
 1 Calcium, myocardial...
 2 T-type Ca2+ channels
3 L-type Ca2+ channels
 4 Ca2+ channels and...
 5 Concluding remarks and...
 References
 
In contrast to neurons that can express up to six types of ICa (L, N, P, Q, R and T), cardiac cells express only L- and T-type ICa. The L-type ICa (or ICaL; L for long lasting or large conductance) was first evidenced in multicellular cardiac preparations 30 years ago and initially termed ‘slow inward current’ [6, 21, 22]. The cardiac T-type ICa (ICaT; T for transient or tiny conductance) was discovered much more recently thanks to the development of the patch-clamp technique [23–26]. However, while our knowledge of the distribution, properties, functions and structure of L-type Ca2+ channels has increased extensively over this last period of time, much has still to be learnt about the T-type Ca2+ channels.

2.1 Functional properties
T-type Ca2+ channels have been found in a wide variety of excitable and non-excitable cells [27]. They probably represent an heterogeneous subgroup of Ca2+ channels with significant differences in functional properties [28, 29]. Their existence in the heart is well established [1, 2, 23–26]. The L- and T-type Ca2+ channels have distinct electrophysiological and pharmacological properties. During voltage-clamp depolarisation, ICaT is characterised by a fast decay and slow rate of deactivation whereas ICaL is more sustained and has faster deactivation. The L- and T-type Ca2+ channels are also distinguished by their threshold of activation and their voltage-dependence of availability for opening. ICaL is activated by strong depolarisations whereas ICaT is low-voltage-activated. At physiological concentration of extracellular Ca2+ ([Ca2+]o), ICaL activates at depolarisations≥–30 mV whereas ICaT begins to activate at much more negative voltages (~–60 mV). ICaL is fully available for activation at the resting membrane potentials of –50 mV whereas ICaT requires more negative voltages (<–50 mV).

In addition to different unitary conductances (6 to 8 pS versus 21 pS, respectively, when using 110 mM Ba2+ ions as the charge carrier), T- and L-type Ca2+ channels have distinct regulatory and pharmacological properties [1, 2, 23–29]. For example, ICaT is not stimulated by protein kinase A (PKA) activation which is a major regulation of ICaL. However, ICaT is stimulated by growth hormones and by various agents releasing diacylglycerol (e.g. angiotensin II, endothelin-1, phospholipase C, phorbol esters) and is blocked by low concentrations of tetramethrin, U-88779E, Ni2+ ions and amiloride [1, 2, 25, 26, 30]. In contrast to ICaL, ICaT is not the preferential target of those synthetic ligands widely referred to as ‘Ca2+ antagonists’ such as dihydropyridines (DHPs), phenylalkylamines and benzothiazepines (e.g. nifedipine, verapamil, diltiazem) despite potential blockade by these compounds [31]. The DHP agonist Bay K 8644 is probably the most selective L-type Ca2+ channel ligand (except in frog atrial cells) [2]. Of particular interest, the newly described compound Ro 40-5967 (mibefradil) is selective for ICaT versus ICaL [32]. In contrast to the L-type Ca2+ channel, the structure of the T-type Ca2+ channel family has not yet been identified.

2.2 Physiological role in adult cardiac cells
ICaT was first recorded in non-diseased cardiac cells from guinea pig ventricle and canine atrium and ventricle [23, 24]and more recently in myocytes isolated from various species and tissues including canine Purkinje fibre, frog atrium and sinus venosus, rabbit sinus arteriosus (SA) node and ventricle, chick embryonic ventricle and cat atrium [1, 2, 23–26, 33, 34]. When present, its amplitude ranges from only 10% in guinea pig ventricle to 100% of that of ICaL in chick embryonic ventricle [33]. It is worth noting that ICaT is scarce in ventricular cells from mature mammals (including rat, calf and rabbit), except perhaps in guinea pig, and that it has always been found concomitant with ICaL. Because of its higher expression in sinusal cells and its low threshold of activation, ICaT has been suggested to play a role in the setting of the firing threshold in Purkinje fibres and nodal cells (pacemaking activity) [26]and ‘latent pacemaker’ activity in feline atrium [34]. ICaT does not seem to play a role in triggering the SR Ca2+ release or in SR Ca2+ loading [1, 2].

2.3 Re-expression in diseased cardiac cells
The physiological function(s) of T-type Ca2+ channels is (are) not clearly defined. In addition to a putative contribution to automaticity in adult cardiac tissues, ICaT seems to be associated with rapid postnatal growth and hypertrophy. The presence of ICaT during early development may be associated with the relatively undifferentiated (with respect to contractility) state of these tissues which also lack a well-developed T-tubular system [35]. For example, a robust ICaT has been recorded in embryonic chick ventricular and freshly isolated neonatal rat ventricular cells [33, 36]. ICaT is apparently lost during maturation. However, mature atrial myocyte cells can re-express ICaT under stimulation with growth hormones known to play significant roles in regulating cardiac growth during postnatal development and during hypertrophy. There is an increase in ICaT in atrial myocytes from adult rats with Growth Hormone-secreting tumours [37]. A similar increase follows exposure of atrial cells to Insulin-Like Growth Factor 1 (IGF-1) in short term primary cultures of myocytes [38]. Re-expression of ICaT has also been shown in adult rat ventricular myocytes grown in vitro during primary culture [39].

There is growing evidence that T-type Ca2+ channels mediate the responses to various hypertrophic signals. The expression of ICaT, absent in myocytes isolated from normal adult feline left ventricle, is promoted by long-standing pressure-overload-induced hypertrophy [40]. Similarly, in a genetically determined cardiomyopathic Syrian hamster which develops a progressive and ultimately fatal congestive HF, ICaT had a 2 to 3 fold higher density than in normal cells and displayed abnormal activation and inactivation kinetics whereas the density and the properties of ICaL were not altered [41]. These alterations suggest a contribution of ICaT to the pathogenesis of Ca2+ overload and to arrhythmogenic activity in this cardiomyopathy. Moreover, the Ca2+ antagonist Ro 40-5967, selective for ICaT versus ICaL compared to the DHP amlodipine, improved survival in a rat model of chronic HF suggesting a possible involvement of T-type Ca2+ channels in this pathology. [42]

In contrast with feline hypertrophied left ventricular myocytes and cardiomyopathic hamster hearts, in which ICaT is overexpressed, no significant ICaT has been detected in atrial or ventricular cells isolated from human tissues with various diseases including CH and dilated cardiomyopathy [6, 43–47]. Although a low-voltage activated ICa has been detected in human atrial cells, this current is unrelated to T-type Ca2+ channels [48]. Rather, it seems to reflect the presence and activation of Na+ channels with an abnormal permeability for Ca2+ ions. In summary, the potential pathophysiological role of T-type Ca2+ channels in the development of hypertrophy and dilated cardiomyopathy has still to be demonstrated in humans. Furthermore, the presence of ICaT in human cardiomyocytes and its potential role in pacemaking activity remains speculative since the tissues that are likely to express it (based on animal models studies) are not readily available for scientific studies.


   3 L-type Ca2+ channels
Top
 Abstract
 1 Calcium, myocardial...
 2 T-type Ca2+ channels
 3 L-type Ca2+ channels
4 Ca2+ channels and...
 5 Concluding remarks and...
 References
 
3.1 Structure, functional properties and role
In contrast to ICaT, ICaL has been found in all cardiac cells that have been studied to date. ICaL is both a trigger for Ca2+ release and a route to Ca2+ for refilling the SR and then plays an important role in E-C coupling. The cardiac L-type Ca2+ channel is a multimeric protein. The pore-forming subunit {alpha}1, which bears pharmacological binding sites for Ca2+ channel modulators, is associated with a transmembrane {alpha}2-{delta} subunit and a cytoplasmic β subunit (Fig. 2). A schematic model of the {alpha}1 subunit primary structure is presented in Fig. 3. Most of the important regions for Ca2+ channel activity and selectivity, such as pore localisation, are indicated as well as the drug binding regions of Ca2+ channel antagonists. The {alpha}1 subunit of the cardiac L-type Ca2+ channel is encoded by the class C gene ({alpha}1C subunit). Heterologous expression in Xenopus oocytes or fibroblastic cell lines allows recordings of functional expression of ICaL inhibited by DHP antagonists and activated by DHP agonists. The human {alpha}1C subunit has been cloned and sequenced and alternative splicing variants have been shown to display specific pharmacological profiles [49]. A second degree of diversity is brought about by the variety of combinations with different β subunits (four genes) [50]. All β subunits increase the level of expression of {alpha}1C-directed ICa in expression systems [50]. The {alpha}1C subunit on its own induces only weak Ca2+ channel currents but when co-expressed with cardiac β subunits the current is increased several fold. Both activation and inactivation kinetics are also accelerated, as observed in animal cells [50]. Therefore, the β subunit is considered as a true endogenous modulator influencing the electrical activity as well as the pharmacological properties of Ca2+ channels [6, 50]. One type of β subunit isoform and several spliced variants have been cloned in the human heart. Studies at the mRNA level suggest that cardiac L-type Ca2+ channels contain the {alpha}1C and the β2a subunit isoforms [51, 52].


Figure 2
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  		Fig. 2 Subunit composition of the cardiac L-type Ca2+ channel.

 

Figure 3
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  		Fig. 3 General structure of the {alpha}1C subunit with the functionally important regions.

 
Biochemical studies have demonstrated that several kinases, including PKA, PKC, cGMP-dependent kinase and calmoduline kinase II, can phosphorylate cardiac Ca2+ channels [1]. The best known regulation of ICaL in cardiac cells is the regulation by β-adrenergic receptor stimulation which activates the intracellular cAMP cascade resulting in increased opening probability of Ca2+ channels [1]. Only the {alpha} and the β subunits of the Ca2+ channels possess consensus phosphorylation sites for PKA (Fig. 3) and have been reported to be phosphorylated in vitro. Despite extensive study of the pathway, the specific events that underlay protein phosphorylation in vivo are not clearly identified yet. There is controversy as to whether expressed cardiac L-type ICa can reproduce or not the expected increase following activation of the PKA pathway [53]suggesting that the phosphorylation may also involve an unidentified protein expressed in cardiac tissue [54]. Interestingly, it has been recently found that the PKA-mediated regulation of L-type Ca2+ channels is critically dependent on a functional A-Kinase anchoring protein called AKAP79 and phosphorylation of the cardiac {alpha}1C subunit at the C-terminal residue Ser1928 (Fig. 3) in native cardiomyocytes [55]. Though the β2a subunit is also an excellent substrate of PKA in vivo, its phosphorylation is apparently not sufficient to significantly modulate channel function [55].

3.2 ICaL in animal models of CH and HF
The results obtained by many groups in various animal models are heterogeneous and puzzling [4, 5, 56–70]. Table 1 summarises these results. Besides species-dependence, there are many reasons for the apparent heterogeneity generated by the disparity of models, the importance of hypertrophy, the degree of hemodynamic stress (adaptive mechanism limited to CH) and the stage of HF. The experimental procedure, in particular when isolating the cells with enzymes, may also be selective and introduce variability. There may also be various degrees of hypertrophy or failure among cells in a same tissue (heart). Nevertheless, the general trend is that the effects of CH range from no change to significant increases of ICaL (or number of DHP-receptors) density whereas the effects of HF range from no change to significant decrease. There is apparently no major effect on the electrophysiological properties of ICaL (see Table 1). Interestingly, a recent study performed using confocal microscopy and patch-clamp methods showed that, though ICaL density and SR Ca2+-release channels are normal in experimental rat models of hypertension-induced cardiac hypertrophy and HF, the defect resides in the inability of the Ca2+ channels to activate SR Ca2+ release [60]. β-adrenergic stimulation overcame this defect in hypertrophic but not in HF myocytes. β-adrenergic sensitivity of ICaL has also been shown to be decreased in some studies [58, 70]. Interestingly, re-emergence of the fetal isoform of the {alpha}1 subunit of the cardiac L-type Ca2+ channel has been reported during left ventricular remodeling in non infarcted rat myocardium [71]. It is therefore possible that the nature (isoform) of the {alpha}1 subunit or subunit composition of the cardiac L-type Ca2+ channel is modified during pathology leading to functional alteration of E-C coupling.


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  		Table 1 Ca2+ channels in various animal models of hypertrophy and HF

 
3.3 ICaL in diseased human cardiomyocytes
One important objective in cellular electrophysiology applied to human cardiac tissue is to analyse the alterations occurring during CH and overt HF. Although studies of animal models provide valuable information, studies in human cells, though still limited, have a major interest because no single animal model adequately represents the wide variety of causes and manifestations of clinical syndromes. Investigations of ICa in human cardiomyocytes started only a decade ago with the development of the patch-clamp technique, enzymatic cell dissociation procedures and surgical techniques. At present, experiments are carried out routinely on single myocytes isolated from small pieces of atrial or ventricular myocardium excised from hearts of patients undergoing corrective open heart surgery or cardiac transplantation [6]. These studies have already provided valuable information concerning the nature, biophysics, pharmacology and regulation of ionic currents in normal and diseased tissues. However, potential modifications of ICa or Ca2+ channel proteins during CH and HF are not well established in humans (see Table 2).


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  		Table 2 Ca2+ channels in human HF

 
There is a general agreement that ICaL, but not ICaT, is commonly found in both right atrial and ventricular cells [6, 36, 43–48, 72]. Human ICaL exhibit properties similar to those of other mammalian species [6, 36, 43–48, 72–74]; e.g. it begins to activate at –40 to –30 mV, is maximal at ~+10 mV with decay kinetics best described by a two exponential process (time constants {tau}1 and {tau}2 of approximately 10 to 25 and 100 to 150 ms, respectively). It is also generally agreed that there are no major functional abnormalities in the basic properties of ICaL in isolated myocytes from failing heart [45, 46, 75]. Recent data suggest that there is a decrease of ICaL in diseased human atrial myocytes [6, 43, 44]and in atrial and ventricular cells from failing hearts [75]. In agreement, a decrease (40–50%) in the number of DHP binding sites in end-stage failing hearts has been shown [76]but some results suggest that there is no effect of HF on the density of ICaL in human ventricular myocytes [7]. Therefore, as observed in animal models, the effects of HF range from no change to a substantial decrease. It is interesting to note that the apparent difference which is observed for example between dilated and non-dilated atria disappears when ICaL is submitted to maximal stimulation by β-adrenergic agents or by the DHP agonist Bay K 8644. This may indicate that dilatation reduces the basal activity of Ca2+ channels rather than the number of functional channels. However, an alteration of both the β-adrenergic (Fig. 4) and the serotoninergic potentiations of ICaL has also been shown in cardiomyocytes isolated from human hearts with end stage failure [75, 77]which may reflect a down-regulation of receptors as has been well described for β-adrenergic receptors (mainly β1) [78].


Figure 4
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  		Fig. 4 Regulation of ICaL by isoprenaline (ISO) in human ventricular myocytes. Cells were isolated from healthy hearts (that were not used for transplantation at the last moment for technical reasons; CS) and from hearts of transplanted patients (CT; with EF<40%) cardiomyocytes. (A) ICaL was evoked from –80 mV to –10 mV in CS and in CT atrial myocytes in absence (O) and presence of ISO (1 µM; bullet). (B) Mean of the effect of ISO (1 µM) on ICaL in CS and CT ventricular myocytes. The numbers indicate the number of cells. Currents were recorded using 2 mM extracellular Ca2+ in conditions optimized to eliminate other currents and using 10 mM EGTA in the patch pipette. Data in panel A and panel B and numbers were taken from [75], with permission (see this publication for further details and information).

 
3.4 Frequency-dependent regulation of ICaL in HF
Modulation of ICaL by frequency of activation is probably important for heart physiology. Heart rate has long been known as a determinant of cardiac performance in the normal heart in vivo. In many animal species, including human, it has been shown that increasing the cardiac frequency induces a positive inotropic effect [79, 80], known as the force-frequency relation or Bowditch ‘staircase’ [81]. In physiological conditions, increased reflex norepinephrine release and circulating catecholamines during exercise induce both positive inotropic and chronotropic effects, so that an increase in heart rate is always coupled with an augmentation of contractility. In addition to the direct effect on cardiac contraction, amplification of the resting force-frequency relation during β-adrenergic stimulation is an important indirect mechanism regulating myocardial contractility in vivo [82]. Recent experiments showing amplification of the force-frequency relation by β-adrenergic receptor stimulation and by exercise in vivo have re-emphasised the importance of this potent inotropic mechanism in the physiology of the normal heart [82]. Various subcellular mechanisms have been proposed to be involved in the force-frequency relation. Though a role of L-type Ca2+ channels, which constitute a major target of the β-adrenergic receptor stimulation, has been ignored or minimised, early studies suggested that an increase in the rate of cell stimulation can up-regulate Ca2+ channel activity in mammalian cardiomyocytes [36, 83]. Similar frequency-dependent regulation of ICaL can also be observed in myocytes from both right and left human atria and ventricles (Fig. 5) [36, 84]. It occurs over a range of frequencies corresponding to heart rates frequently encountered in human pathophysiology [84]. This effect, related to changes in the gating properties rather than an increase in the number of active Ca2+ channels, is augmented by β-adrenergic receptors stimulation (Fig. 5) (and by other cAMP promoting agents) [36]and is probably involved in the amplification of the force-frequency effect by β-adrenergic stimulation. This regulation of transmembrane Ca2+ influx may be crucial in the adaptation of the normal human heart to stress and exercise [36, 84].


Figure 5
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  		Fig. 5 High frequency-induced upregulation of ICaL and enhancement by isoproterenol in a human ventricular cell. The cell was isolated from the left ventricle of a transplanted heart obtained from a patient with terminal HF (ischemic cardiopathy; EF<40%) and no drug treatment. Rates of stimulation were applied as shown in inset using the whole-cell patch-clamp technique (for details see [44] and [84]). This effect was rarely observed in cells isolated from failing hearts. It was more consistent in atrial myocytes isolated from patients with EF>40% and no drug treatment (see Fig. 6). Currents were recorded as described in Fig. 4 (for further details and information see [84]).

 
Experiments in isolated myocardium from patients with moderate or end-stage HF suggest that the high rate-induced potentiation of cardiac contraction is impaired or absent [14, 85, 86]. Similar conclusions have been reached by increasing pacing rates during atrial or ventricular stimulation in patients with low left ventricular function [87]. In addition to abnormal intracellular [Ca2+]i handling [7, 16], an alteration of transarcolemmal Ca2+ signalling via L-type voltage-gated Ca2+ channels may partly explain the impaired force-frequency relation observed in the failing myocardium. In particular, the high frequency-induced upregulation of ICaL, observed in atrial cells enzymatically isolated from hearts with a high ejection fraction (EF), is significantly altered in cardiomyocytes from end-stage failing hearts with low EF (Fig. 6). Stimulation by isoprenaline can preserve or enhance this upregulation in atrial cells taken from hearts with a high EF but not in those originating from hearts with low EF (Fig. 6) [84]. Consistently, stimulation by isoprenaline preserves the positive force-frequency in healthy, but not in failing, human hearts [88]. Since cAMP-dependent phosphorylation, resulting for example from β-adrenergic receptors stimulation, is important for the frequency-dependent facilitation of ICaL in human cardiomyocytes, it is possible that alteration of this mechanism simply reflects the down regulation of β-adrenergic receptors in failing hearts [78]because no evidence for impairment of the signal transduction cascade beyond the level of GTP binding proteins has been found [45]. However, the Ca2+ channels themselves may also well be altered in terms of structure (nature or stoichiometry of associated subunits) or in terms of regulation by second messengers or phosphorylating-dephosphorylating agents. These alterations could contribute to impaired cardiac function.


Figure 6
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  		Fig. 6 Bar graphs showing the effect of HF on the potentiation of ICaL by high rates of stimulation in human atrial and ventricular cells. Atrial cells were obtained during open heart surgery from non-failing hearts (EF>40%) with various diseases such as aortic or mitral disease (stenosis or insufficiency) or coronary artery disease. These patients were not treated with Ca2+ antagonists or β-blockers. Both atrial and ventricular cells were also obtained from explanted hearts of patients with terminal HF (ischemic or dilated cardiopathy; EF<40%; no drug treatment). Experiments were performed as described in Fig. 4 (for details see [84]). Ca2+ entry was quantified by integrating ICaL during the test pulse rather than by measuring peak current (see inset). Values (means±SD) reflect comparisons between groups of patients (data for each patient were averaged from 2 to 6 cells). Currents were recorded as described in Fig. 4 (for further details and information see [84]).

 

   4 Ca2+ channels and therapy of heart failure
Top
 Abstract
 1 Calcium, myocardial...
 2 T-type Ca2+ channels
 3 L-type Ca2+ channels
 4 Ca2+ channels and...
5 Concluding remarks and...
 References
 
4.1 Agents with positive inotropic activity
The β-adrenergic receptor agonists, such as dobutamine and norepinephrine, promote increased Ca2+ influx through Ca2+ channels via increased intracellular cAMP. They have a positive inotropic effect and improve the diastolic relaxation by enhancing Ca2+ re-uptake by the SR. Dobutamine is a synthetic catecholamine which is very effective acutely and widely used for short term therapy. However, both down-regulation and desensitisation of the β-adrenergic receptors rapidly induce intolerance and inefficacy of this drug. Furthermore, long term oral therapy with catecholamines is not only ineffective but accelerates mortality, in part because of increased arrhythmogenesis but also because it causes progression of cardiac dysfunction [89–91]. The use of phosphodiesterase inhibitors is also disappointing. These drugs have favorable acute hemodynamic effects without inducing short-term tolerance but, similarly to the β-adrenergic receptor agonists, they increase mortality during chronic therapy, apparently owing to ventricular arrhythmia and accelerated progression of the left ventricular dysfunction [92]. Therefore, cAMP-promoting agents produce little clinical benefit and only during short term therapy [88, 93].

4.2 Rationale and beneficial effect of β-blocker therapy
The rationale for using β-blockers in congestive HF secondary to idiopathic dilated cardiomyopathy is based on the hypothesis that the disease is caused and/or worsened by abnormal activity of the sympathetic nervous system [90, 91]. Although the mechanisms of benefit of β-blockade in patients with HF is probably multifactorial, both ‘up-regulation’ of β-receptors and prevention of Ca2+ overload may be involved in improvement of systolic and diastolic functions observed with this therapy in cardiomyopathy [94, 95]. Furthermore, because the shape of the force-frequency relationship is inverted in human cardiac disease, reducing heart rate can improve contractility of the failing myocardium [12, 15, 16]. Numerous placebo-controlled studies have shown improvement of NYHA functional class and quality of life with β-blockers therapy in patients with idiopathic dilated cardiomyopathy. The long term hemodynamic effects include a consistent increase in ejection fraction and variable effects on exercise tolerance [94, 95]. Two large prospective studies have demonstrated a beneficial effect of metoprolol and bisoprolol, respectively [94, 95], concerning the number of readmissions to hospital due to worsening of HF but with no significant effect on survival on the total patient group. Therefore, the effect of β-blocker therapy on mortality in cardiomyopathies is uncertain. Large prospective studies are in progress (CIBIS II, Bisoprolol, BEST, Bucindolol).

4.3 Ca2+ channels blockers
By blocking the inward transmembrane ICaL and opposing the effects of increased [Ca2+]i, Ca2+ antagonists induce coronary and peripheral vascular dilatation which results in increased coronary flow, reduced afterload and, therefore, reduced myocardial oxygen consumption. However, data accumulated from clinical trials conducted over the last decade have raised serious concerns regarding the safety of Ca2+ antagonists, in particular the short-acting Ca2+ channel blocker nifedipine, whether these drugs are used for hypertension, instable angina or recent myocardial infarction [96, 97]. Concerning HF due to ischemic cardiomyopathy, the metanalysis of Furberg points out that Ca2+ channels blockers may exacerbate HF and that nifedipine provokes a dose-related increase in mortality in patients with coronary artery disease [96]. Ca2+ antagonists have a negative inotropic effect but their deleterious long term effects are mainly due to increased sympathetic activity and neurohormonal activation secondary to acute vasodilatation [96–98]. However, new Ca2+ antagonists such as amlodipine and felodipine (long-acting DHPs) are devoid of the problems linked to negative inotropy, positive chronotropy and neurohormonal activation. The PRAISE trial, a mortality and morbidity evaluation of amlodipine, showed significant benefit in patients whose heart failure was not due to coronary disease [99]. However, probably because Ca2+ antagonists lead to hemodynamic improvement without affecting other aspects of the pathophysiology of HF, they are unlikely to have an important effect on survival and progression of left ventricular dysfunction even if they do improve symptoms and exercise tolerance.


   5 Concluding remarks and perspectives
Top
 Abstract
 1 Calcium, myocardial...
 2 T-type Ca2+ channels
 3 L-type Ca2+ channels
 4 Ca2+ channels and...
 5 Concluding remarks and...
References
 
Whether there is a change in L-type Ca2+ channel proteins or activity during CH and HF is not firmly established at the moment. Concerning animals, some heterogeneity probably arises from differences among species and models (degree of hypertrophy, stage of HF). Concerning humans, age, sex, pathology and drug treatment of patients certainly introduce variability in studies. In addition, studies are hampered by difficulties relating to regular obtention of homogeneous and abundant sources of tissues and to differences between experimental protocols. For example, most patients receive medication prior to and during surgery. The interpretations may also be complicated when there is a lack of ‘normal’ tissue. However, despite the difficulties and limitations mentioned, it seems clear that L-type Ca2+ channels are not involved in the prolongation of AP duration in HF because ICaL is either decreased or unchanged. They have also probably no (or only a minor) role in CH. Nevertheless, a possible scenario could be that ICaL: (i) increases during CH to help maintain cardiac performance; and, then (ii) decreases during development of chronic hypertrophy and HF.

Impairment of Ca2+ channel function in E-C coupling and of its major physiological regulations responsible for positive inotropy are more clearly evident than dramatic changes in Ca2+ channel density and biophysical properties during HF. Increases of ICaL by high heart rates and by β-adrenergic stimulation (and other camp-promoting agents), probably crucial for adaptation of the beating heart to exercise, are altered in human (Fig. 7). In addition to possible partial electromechanical uncoupling, these alterations may also contribute to prevent Ca2+ overload, contractility and O2 consumption and, thereby, decrease metabolic expenses of the working myocardium. Future studies should provide more information at the molecular level. Much remains to be studied to precise whether the Ca2+ channel protein undergoes some change, in terms of {alpha}1 isoforms with distinct properties and/or subunit composition, that could account in part for some alterations of time- and voltage-dependent properties and of sensitivity to phosphorylation.


Figure 7
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  		Fig. 7 Hypothetical schematic of the effect of HF on the human cardiac L-type Ca2+ channel and regulation of ICaL by the β-adrenergic pathway and rate of heart beating.

 
Finally, the cardiac T-type Ca2+ channel has unique properties. Possibly involved in the pacemaker activity of the heart, its contribution and other function(s) remain to be clarified. Its expression (or re-expression) during early stages of development and during various hypertrophic states of the heart has been well established in animal models. For what role? The development of ICaT-selective Ca2+ antagonists and the expected molecular cloning should add to our understanding of the pathophysiology of T-type Ca2+ channels. These approaches are fundamental to developing new therapeutical strategies provided that ICaT is present in the human heart and involved in pathophysiology.

Although less obvious than with animal models, working with human tissue provides valuable information. However, this approach cannot be exclusive and therefore should be used in parallel with animal models. The experience gained on human cells studies can help select animal models more closely related to the human pathology studied. Future studies will probably be based on techniques combining both molecular and electrophysiological approaches and on the forthcoming use of genetically engineered mice. Transgenic mice models of cardiac hypertrophy and dilated cardiomyopathy have been created [100]. The transgenic model of hypertrophy expresses oncogenic human H-ras, known to activate several features of hypertrophy, in a ventricular-specific manner. The model of dilated cardiomyopathy and heart failure reproduces the morphological and clinical pictures of pathology including, for example, cardiac dilatation accompanied by wall thickening and eccentric hypertrophy, impairment of both contractility and relaxation, decreased sensitivity to the β-adrenergic stimulation and myocardial fibrosis. Clearly these existing models and the creation of new models will be of great help for the development of new strategies to understand more precisely the role of Ca2+ (and other ion) channels.

Time for primary review 28 days.


   Acknowledgements
 
We thank Dr. Isabel-Ann Lefèvre for her corrections on the manuscript. This work was supported by grants of the Fondation de France, the Association Française contre les Myopathies and the French MENESR (ACCSV9).


   References
Top
 Abstract
 1 Calcium, myocardial...
 2 T-type Ca2+ channels
 3 L-type Ca2+ channels
 4 Ca2+ channels and...
 5 Concluding remarks and...
 References
 

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