Cardiovascular Research

Cardiovascular Research 1998 37(2):290-299; doi:10.1016/S0008-6363(97)00272-1
© 1998 by European Society of Cardiology

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Copyright © 1998, European Society of Cardiology

Alterations in calcium handling in cardiac hypertrophy and heart failure

C.William Balke^* and Stephen R. Shorofsky

Department of Physiology and Department of Medicine, Division of Cardiology, University of Maryland School of Medicine, Baltimore, MD, USA

^* Corresponding author. University of Maryland School of Medicine, Department of Physiology, Room 544, Howard Hall, 660 West Redwood Street, Baltimore, MD 21201, USA. Tel. (+1-410) 706-0515; Fax (+1-410) 706-8610; E-mail: bbalke@heart.ab.umd.edu

Received 16 September 1997; accepted 30 October 1997

	Abstract

Top Abstract 1 Introduction 2 Calcium currents in... 3 Excitation-contraction... 4 Role of Ca2+... 5 [Ca2+]i transients in... References

 
There is conflicting data concerning the effects of cardiac hypertrophy and failure on L-type Ca²⁺ channel density, the amplitude of the intracellular Ca²⁺ transients, and the characteristics of Ca²⁺ sparks. These discrepancies are probably due to multiple factors. First, the effects of cardiac hypertrophy on channel expression and cell adaptation are model dependent. Even within the same species, the mechanisms by which cardiac hypertrophy and heart failure are generated (genetic alteration, pressure overload, volume overload, high rate pacing, etc.) influence the results obtained. Second, with many animal models and diseased human hearts, the disease process is not uniformly distributed throughout the myocardium. Third, the effects on L-type Ca²⁺ channel behavior and SR function clearly depend on the extent of disease expression. Myocardial contractility increases with cardiac hypertrophy whereas it decreases with heart failure. Thus, it is difficult to compare results from different models of hypertrophy and heart failure at different stages of disease. More consistent data is likely to be obtained from longitudinal studies using a single animal model of disease. The challenge before us is to develop animal models that mimic human disease, which can be studied longitudinally during the progression of the disease process. This approach coupled with continued improvement in Ca²⁺ imaging and a greater understanding of normal E-C coupling, will enable us to identify precisely the abnormalities in E-C coupling that occur with the development of cardiac hypertrophy and heart failure and define the appropriate treatment modalities.

KEYWORDS Cardiac hypertrophy; Heart failure; Sarcoplasmic reticulum; Calcium channel

	1 Introduction

Top Abstract 1 Introduction 2 Calcium currents in... 3 Excitation-contraction... 4 Role of Ca2+... 5 [Ca2+]i transients in... References

 
Cardiac hypertrophy has a prevalence approaching 60% in patients with hypertension [1, 2]. Considering that 24% of the adult population in the US has hypertension [3, 4], it is clear that the prevalence of cardiac hypertrophy has reached epidemic proportions in the US and in most industrialized western societies. This excessive prevalence is magnified further by the very low success rate in the primary treatment of hypertension and in the secondary regression of cardiac hypertrophy [3, 4].

Cardiac hypertrophy is the single most important contributor to cardiovascular morbidity and mortality. It is associated with an increased incidence of heart failure in the absence of a myocardial infarction [5–7], and with heart failure as a consequence of myocardial infarction with the inevitable hypertrophy of the surviving portions of the heart. Consequently, the key role of cardiac hypertrophy in the pathogenesis of heart disease underscores the need to identify the cellular and molecular mechanisms responsible for both cardiac hypertrophy and its progression to heart failure. A better understanding of the primary mechanisms involved in the heart's response to chronic pressure overload may facilitate the development of new and novel therapeutic modalities, as well as the development of better guidelines for the prevention of cardiac hypertrophy.

Cardiac hypertrophy is associated with marked changes in myocardial contractility. Peak active tension increases [8–14]and the rates both of tension development and of relaxation are slowed [13, 15–20]. These contractile abnormalities are accompanied by alterations in the whole-cell calcium transient ([Ca²⁺]_i transient). Initially, the amplitude of the [Ca²⁺]_i transient increases [21]. As hypertrophy progresses to heart failure, the amplitude of the [Ca²⁺]_i transient decreases [22–25]. In several animal models of hypertrophy [20, 22–24, 26–29]and in failing human hearts [25, 30], the duration of the whole-cell [Ca²⁺]_i transient prolongs. The precise cellular mechanisms that are responsible for the observed changes in contractility and for these alterations in the whole-cell [Ca²⁺]_i transient are largely unknown.

The difficulties in identifying the cellular mechanisms that underlie altered excitation-contraction (E-C) coupling in cardiac hypertrophy and heart failure can be attributed, in large part, to several problems. (1) Many of the experimental studies on cardiac hypertrophy and heart failure have focused on the relatively narrow period of time during the transition from long-standing cardiac hypertrophy to heart failure. Consequently, these studies provide little useful information regarding the primary cellular mechanisms that underlie the initial development of cardiac hypertrophy. Considering the complex cascade of physiological, neurohumeral, and biochemical abnormalities associated with heart failure, it is not surprising that these types of studies have yielded conflicting and often contradictory results (see below). (2) The characteristics of cardiac hypertrophy and heart failure are model-dependent. Even in the same species, the experimental results are profoundly influenced by the method used to create hypertrophy and/or heart failure (e.g., volume-overload, pressure-overload, genetically altered, rapidly paced, coronary artery ligation, etc.). (3) In any individual model, the cardiac hypertrophy may be eccentric, or concentric, and the disease process may not be uniformly expressed throughout the myocardium. (4) Progress in elucidating the cellular mechanisms of cardiac hypertrophy has been hindered also by the difficulties in quantifying the individual cellular processes that determine the [Ca²⁺]_i transient, most notably, Ca²⁺ release from the sarcoplasmic reticulum (SR).

With regard to methodological limitations, the recent application of laser scanning confocal microscopy and newly developed Ca²⁺-sensitive fluorescent indicators to normal heart cells has made it possible to measure local non-propagating elevations of [Ca²⁺]_i (Ca²⁺ sparks) at the level of individual sarcomeres [31–36]. From recent work, it is now clear that Ca²⁺ sparks represent the release of Ca²⁺ from one or a cluster of SR Ca²⁺ release channels (e.g., ryanodine receptors). These studies provide direct experimental evidence for the local control hypothesis of E-C coupling in heart [37]in which macroscopic L-type Ca²⁺ currents and whole-cell [Ca²⁺]_i transients are understood in terms of the spatial and temporal summation of single L-type Ca²⁺ channel currents and Ca²⁺ sparks, respectively. The ability to measure Ca²⁺ sparks also provides the unique opportunity to evaluate experimentally the role of SR Ca²⁺ release in abnormal muscle cells from animal models of cardiac hypertrophy. In this paper, we will review the current state of knowledge concerning the cellular mechanisms of altered E-C coupling in hypertrophied and failing cardiac cells from the perspective of what is known about normal cardiac E-C coupling.

	2 Calcium currents in normal heart cells

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Cardiac cells are known to contain at least two types of voltage-activated Ca²⁺ channels [38–43]. The L-type (large or long-lasting) Ca²⁺ channels are found in all heart cells and are responsible for the ‘slow inward current’. These channels activate at potentials greater than –40 mV, generate peak inward currents at about 0 mV and inactivate relatively slowly. These channels conduct Ba²⁺ better than Ca²⁺ and are blocked by organic (dihydropyridines, phenylalkylamines, and benzothiazepines) and inorganic (Cd²⁺, La³⁺, Mn³⁺) compounds. They are inactivated by Ca²⁺ entering through the channel and display two separate modes of gating [44, 45]. The L-type Ca²⁺ channels are responsible for the majority of Ca²⁺ that enters cardiac cells during the plateau phase of the action potential.

In contrast, the T-type (tiny or transient) Ca²⁺ channels activate and inactivate at potentials more negative and have faster kinetics than the L-type Ca²⁺ current [41, 46–49]. These channels conduct Ba²⁺ and Ca²⁺ equally well. T-type Ca²⁺ channels are blocked by Ni⁺ but are relatively insensitive to both organic and inorganic blockers of L-type Ca²⁺ channels. Although T-type Ca²⁺ channels appear to exist in all types of mammalian heart cells, they are more prevalent and generate larger amplitude currents in rat and cat atrial cells [39, 50], rabbit sino-atrial nodal cells [51], and canine Purkinje cells [41, 52, 53]. The properties of these channels, along with their distribution, has led to the hypothesis that T-type Ca²⁺ channels play a role in pacemaker activity [40, 50, 51]. In addition, preliminary data suggest that Ca²⁺ entry through T-type Ca²⁺ channels can induce contraction although with much slower kinetics than is seen when Ca²⁺ enters through the L-type Ca²⁺ channels [54].

Recently, a TTX-inhibitable, voltage-gated, Ca²⁺ conducting Na⁺ channel has been described in human atrial, rat ventricular and guinea pig ventricular cells [55–57]. This channel activates at –60 mV and has faster kinetics than the L-type Ca²⁺ channel. In addition, current (I_CaTTX) through this channel is not inhibited by known blockers of T- or L-type Ca²⁺ channels (Ni⁺ or La³⁺). Although this channel also conducts Na⁺, it is distinct from the main body of Na⁺ channels. Possible functional roles for I_CaTTX include modulating rhythmic activity, and enhancing activation of the sodium current.

	3 Excitation-contraction coupling in normal hearts

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In normal cardiac muscle, the action potential initiates the sequence of events that result in contraction. During membrane depolarization, Ca²⁺ enters the cell, triggering the release of a much larger amount of Ca²⁺ from the SR (Ca²⁺-induced Ca²⁺ release, Fig. 1). This transient rise in intracellular Ca²⁺ ([Ca²⁺]_i) initiates a series of chemical events (cross-bridge formation) which result in cell shortening and/or the generation of force [58–62]. It has been demonstrated clearly that the influx of Ca²⁺ through L-type Ca²⁺ channels activates the release of Ca²⁺ from the SR [62, 63], although the exact mechanism by which intracellular Ca²⁺ controls or grades SR release is unknown [64]. Relaxation occurs when the influx of Ca²⁺ is terminated by closure of the L-type Ca²⁺ channels, the extrusion of Ca²⁺ from the cytoplasm by the sodium/calcium (Na⁺/Ca²⁺) exchanger [65], and the sequestration of Ca²⁺ by the SR Ca²⁺-ATPase [66].

View larger version (81K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Schematic representation of the major processes that control intracellular calcium in mammalian cardiac ventricular cells. See text for discussion. ADP, adenosine diphosphate; ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; CICR, calcium-induced calcium release; SR, sarcoplasmic reticulum. (Reproduced with permission from Balke and Gold, Heart Dis Stroke 1993;2:150–155.)

 
The fact that Ca²⁺ entry via L-type Ca²⁺ channels is the major trigger for SR Ca²⁺ release presents a paradox. How can SR Ca²⁺ release be prevented from initiating the uncontrolled regenerative release of further SR Ca²⁺? In other words, how is contraction graded? Wier and coworkers [67]measured the gain or ratio between the amount of Ca²⁺ entering the cytoplasm and the amount released by the SR at different voltages (the latter quantity derived by a model) and found that the gain decreased monotonically as the membrane was clamped to more positive voltages. In contrast, the amount of Ca²⁺ entering via the L-type Ca²⁺ channel had a bell-shaped curve over the same voltage range. Therefore, SR Ca²⁺ release is not determined simply by the amount of Ca²⁺ that enters the cytoplasm, but appears to be related to a property of the L-type Ca²⁺ channel that has the same voltage dependence as the gain (i.e., the single channel current amplitude).

To explain these and other data, the local control hypothesis [37]of cardiac E-C coupling proposes that there is a ‘restricted space’ where Ca²⁺ entry through the sarcolemma is coupled to the release of Ca²⁺ by the ryanodine receptors in the adjacent junctional SR. In other words, the release of Ca²⁺ from the SR is controlled by events localized to the region of the ryanodine receptors in the SR, and these events may be very different from those seen macroscopically in the whole cell. Thus, the local control model accounts for the observed graded release of Ca²⁺ from the SR. An important prediction of the local control hypothesis is that the whole cell Ca²⁺ current and whole cell [Ca²⁺]_i transient are insensitive indicators of local Ca²⁺ entry and [Ca²⁺]_i at the T tubule-SR junction.

Experimental support for the local control hypothesis comes from several recent studies. First, a close physical relationship between the sarcolemmal L-type Ca²⁺ channel, the Na⁺/Ca²⁺ exchanger, and the SR Ca²⁺ release channel has been demonstrated by detailed ultrastructural studies [68–70]. Sun and coworkers [69]identified junctional domains in the surface membrane that were involved in E-C coupling. Arrays of foot processes were associated with, but not directly coupled to these domains. Using immunohistochemical techniques, these junctional domain/foot array complexes were identified as co-clusters of dihydropyridine receptors and ryanodine receptors. Combining double-labeling immunofluorescence techniques with laser scanning confocal microscopy, Carl et al. [70]demonstrated the co-localization of the ryanodine receptors, dihydropyridine receptors and triadin (a structural protein involved in E-C coupling of skeletal muscle) at the junction between the sarcoplasmic reticulum and T-tubule or surface membrane infoldings in rabbit ventricular cells.

Further support for the local control theory comes from the recent visualization of focal non-propagating spontaneous release of Ca²⁺ (Ca²⁺ sparks) from the SR using laser-scanning confocal microscopy coupled with the intracellular fluorescent Ca²⁺ indicator, fluo-3 [31]. These spontaneous Ca²⁺ sparks (Fig. 2) occur infrequently at rest, more frequently with increasing SR Ca²⁺ load, and are inhibited by ryanodine. In addition, Ca²⁺ sparks are evoked with membrane depolarization, behave in a stochastic manner [32–34], and have a voltage- and time-dependence similar to that of the L-type Ca²⁺ channel [33]; Fig. 3). Finally, Ca²⁺ sparks are not elicited by Ca²⁺ entry via the reverse mode of the Na⁺/Ca²⁺ exchanger [33], and do not occur randomly throughout the cell but localize to the region of the T-tubule-SR junction [44]. These observations support the conclusion that Ca²⁺ sparks represent the fundamental release of Ca²⁺ from the SR by one or a cluster of ryanodine receptors. Thus, there is a preponderance of evidence that E-C coupling in cardiac muscle occurs by Ca²⁺ entering the cell into a restricted space and triggering Ca²⁺ release from a one or a number of SR release channels in close proximity. There is strong evidence that the major source of trigger Ca²⁺ comes from Ca²⁺ entry through L-type Ca²⁺ channels.

View larger version (60K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Example of the focal, non-propagating release of Ca2+ from the sarcoplasmic reticulum (i.e., Ca2+ spark) from a rat ventricular cell. The cell was imaged along a single line every 2 ms. The line scan images acquired were then stacked together to produce a time and space image of the rise in intracellular Ca2+ (lower panel). The change in intracellular Ca2+ through the center of the Ca2+ spark is shown in the upper panel. (Reproduced with permission from Wier WG, López-López JR, Shacklock PS, Balke CW, Ciba Found Symp 1994;188:146–164.)

 

View larger version (21K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 The probability of observing Ca2+ sparks depends on voltage and time. (A) Histograms of the number of Ca2+ sparks observed during 200 ms voltage clamp steps to the indicated potentials. The decline of the histograms was fit by a single exponential function as shown. (B) The peak number of Ca2+ sparks per 20-ms interval evoked at each voltage (nLCT) was plotted as a function of voltage. Note the bell-shaped curve. (C) The probability of observing a Ca2+ spark (Pi,LCT) and of opening an L-type Ca2+ channel (Po,L) versus voltage. Note the monotonic decrease of Pi,LCT with voltage which is similar to the decline in single channel conductance of the L-type Ca2+ channels with voltage (Reproduced with permission from Ref. [40]).

 
However, LeBlanc and Hume [71]have shown that Ca²⁺ entry via the reverse mode of the Na⁺/Ca²⁺ exchanger can also trigger a contraction. Under their experimental conditions in which nisoldipine was used to block the L-type Ca²⁺ channels, TTX-sensitive [Ca²⁺]_i transients were observed. From these data, the authors concluded that Na⁺ entering the cell into the restricted space rapidly increases the intracellular Na⁺ concentration, which activates the Na⁺/Ca²⁺ exchanger in the reverse direction, generating an inward Ca²⁺ current that then triggers release of Ca²⁺ from the SR. Reverse mode of the Na⁺/Ca²⁺ exchanger causing release of Ca²⁺ from the SR has been demonstrated in feline ventricular myocytes [72], and guinea pig myocytes [73–76]. The possibility that SR Ca²⁺ release can be triggered by the Na⁺/Ca²⁺ exchanger is further supported by the demonstration that the Na⁺/Ca²⁺ exchanger is localized in the T-tubules in close proximity with the L-type Ca²⁺ channel the ryanodine receptors [68]. However, several investigators have shown that the release of SR Ca²⁺, thought to be due to Na⁺ entry activating the reverse mode of the Na⁺/Ca²⁺ exchanger in rat myocytes, is likely due to the loss of voltage control either throughout the cell or in the T-tubules [77, 78]. In addition, Ca²⁺ entry through reverse mode behavior of the Na⁺/Ca²⁺ exchanger does not induce Ca²⁺ sparks but rather a slow increase in overall Ca²⁺ within the cell [33]. Finally, contractions due to Ca²⁺ entry through reverse mode of the Na⁺/Ca²⁺ exchanger are generally slow [72]and the corresponding [Ca²⁺]_i transients are delayed in onset [71]. Therefore, from the currently available experimental studies, it appears unlikely that the reverse mode of Na⁺/Ca²⁺ exchanger plays a significant role in the initiation of a contraction in normal heart cells.

In a preliminary report, Thomas et al. [79]demonstrated that Ca²⁺ entry through TTX-inhibitable Ca²⁺ conducting Na⁺ channels caused release of Ca²⁺ from the SR. As was observed with the Na⁺/Ca²⁺ exchanger, these [Ca²⁺]_i transients were delayed in onset and had a slower time course compared with the [Ca²⁺]_i transients elicited by Ca²⁺ entry via L-type Ca²⁺ channels. Thus, it is also unlikely that I_CaTTX plays a significant role in the initiation of a contraction in normal heart cells on a beat-to-beat basis.

Recently, Levi et al. [80, 81]described a component of SR Ca²⁺-release (voltage-activated Ca²⁺ release; VACR) in mammalian cardiac muscle that they have attributed to changes in membrane voltage per se. In an intriguing set of experiments, whole-cell L-type Ca²⁺ currents and [Ca²⁺]_i transients were measured at 37°C in single adult rat (also rabbit and guinea-pig) ventricular cells perfused with fura-2 via the whole-cell voltage clamp technique. Na⁺ channels were inhibited with lidocaine (300 µM) and Na⁺/Ca²⁺ exchange was prevented with Na⁺-free pipette solutions. In the absence of cAMP in the pipette solution, test depolarizations to +20 mV from a holding potential of –60 mV elicited an inward L-type Ca²⁺ current and a large [Ca²⁺]_i transient. Not surprisingly, the L-type Ca²⁺ current and [Ca²⁺]_i transients were abolished with rapid application of blockers of L-type Ca²⁺ channels including Ni²⁺ and Cd²⁺. However, when high concentrations of cAMP were included in the pipette solution (50–100 µM), test depolarizations in the presence of blockers of L-type Ca²⁺ channels evoked a large [Ca²⁺]_i transient. These results support the hypothesis that the release of Ca²⁺ from the SR in cardiac muscle is, in part, dependent directly on membrane voltage. The possible role of a putative VACR in normal cardiac E-C coupling remains to be determined.

	4 Role of Ca2+ channels in cardiac hypertrophy and heart failure

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Despite extensive investigations, the role of Ca²⁺ channels in the pathogenesis of cardiac hypertrophy and heart failure remains controversial. L-type Ca²⁺ current density is unchanged in myocytes from rats with hypertrophy due to aortic banding [82], cats with pulmonary artery banding [83], cardiomyopathic Syrian hamsters [84], and human myocytes from patients with heart failure [25, 85]. In contrast, L-type Ca²⁺ channel density is increased in hypertrophied myocytes from guinea pigs with aortic banding [86], and rats with renal artery banding [87], while it decreased in ventricular cells from cats with aortic banding [88]and ferrets with pulmonary artery banding [89]. To further confuse the issue, the effects of cardiac hypertrophy on L-type Ca²⁺ currents seems to depend on the duration of the disease. Xiao and McArdle [90]observed a significant increase in L-type Ca²⁺ current density in spontaneously hypertensive rats (SHR) at 10 weeks of age, whereas other investigators studying cells from older SHR noted no change in current density [91, 92].

Similarly, disparate results have been obtained with biochemical studies used to identify the number of L-type Ca²⁺ channels in hypertrophied myocytes. Kuo and coworkers [93]observed an increase in dihydropyridine binding sites in the myocardium of hamsters with hereditary cardiomyopathy. However, a decrease in binding sites was seen in rat hearts [94], no change in human hearts with cardiac failure [95, 96], and both an increase and decrease in dihydropyridine binding sites in avian myocytes with heart failure depending on the extent of the disease process [97]. As was seen with the L-type Ca²⁺ channel density, the number of dihydropyridine binding sites in cardiac myocytes from SHR increase as hypertrophy develops [94, 98, 99], and decrease with the development of cardiac failure [94, 100].

Therefore, from both an electrophysiological and biochemical perspective, it is unlikely that the dissimilar effects of cardiac hypertrophy and heart failure on the L-type Ca²⁺ current from different experimental models could explain the alterations in E-C coupling observed with this disease. However, the release of Ca²⁺ from the SR is not determined simply by the amount of Ca²⁺ that enters the cell through the L-type Ca²⁺ channel since markedly different contractions can be obtained by voltage-clamp steps to potentials that generate similar whole cell Ca²⁺ currents [32, 33, 67]. Instead, the release of Ca²⁺ from the SR seems to depend on a single channel property of the L-type Ca²⁺ channel that is not reflected in the magnitude of the current (i.e., the mean open time, single channel current, etc.). Therefore, the single channel properties of the L-type Ca²⁺ channel could be altered in hypertrophy, causing the abnormalities in contraction noted. This possibility is supported by the observation that L-type Ca²⁺ current is prolonged in myocytes from virtually all animal models of cardiac hypertrophy and failure [83, 87, 89–91]although no increase in duration was observed in ventricular myocytes from humans with heart failure [85]. To date, there is no data on the single channel behavior of L-type Ca²⁺ channels from any model of cardiac hypertrophy or failure.

As mentioned above, however, Ca²⁺ can enter the cell through other ion channels and transporters, which may account for the altered E-C coupling with the development of disease. Studying hypertrophied ventricular cells from aortic banded cats, Nuss and Houser [88]measured an increase in the density of T-type Ca²⁺ channels without any alteration in the L-type Ca²⁺ channel and speculated that this increase in Ca²⁺ may be responsible for the increase in myocyte contractility. Sen and Smith [84]demonstrated an increase in the density as well as a shift of the activation and inactivation kinetics to more negative potentials of the T-type Ca²⁺ channels in ventricular cells from cardiomyopathic Syrian hamsters, again implicating these channels in changes in cardiac contractility. Increases in T-type Ca²⁺ current have also been reported in hypertrophied cells due to growth hormone secreting tumors [101]and in response to endothelium 1 secretion [102]. Interestingly, mibefradil, a selective T-channel blocker, improved survival in a rat coronary ligation model of heart failure [103]. Although this is likely to be due, in part, to the vasodilatory effects of this drug, a direct effect on the compensatory hypertrophy that occurs following a myocardial infarction can not be ruled out.

There is no data concerning the role of the Na⁺/Ca²⁺ exchanger or the newly described I_CaTTX in E-C coupling from hypertrophied or failing cardiac myocytes. Finally, it is unknown whether the putative voltage dependent component of E-C coupling is altered by the development of cardiac hypertrophy or failure.

	5 [Ca2+]i transients in cardiac hypertrophy

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Gwathmey and coworkers [13, 15, 104, 105]first reported [Ca²⁺]_i transients with a markedly prolonged declining phase in failing human myocardium. Since then, other investigators have confirmed that the [Ca²⁺]_i transient is prolonged in several animal models of cardiac hypertrophy [16, 20–24, 26–29], and in cells from failing human hearts [25, 30, 106]. Since each of these studies used Ca²⁺-sensitive bioluminescent or fluorescent indicators to measure the whole-cell or averaged [Ca²⁺]_i transients, the cellular mechanisms responsible for the prolongation of these [Ca²⁺]_i transients were not identified.

The most likely explanation for this prolongation in the intracellular Ca²⁺ transient is a decrease in the reuptake of Ca²⁺ by the SR. Limas and Cohn [107]demonstrated a decrease in Ca²⁺ uptake by SR microsomes from SHR animals with hypertrophy that worsened with the progression of disease. Pieske and coworkers [106]demonstrated that Ca²⁺ uptake into a crude preparation of SR vesicles was decreased in patients with dilated cardiomyopathies. A decreased quantity of ryanodine receptors has been demonstrated in chronically paced dogs with heart failure [108], and pressure overloaded rat myocytes [109]. In addition, there is a decrease in the expression of the mRNA for the SR Ca²⁺ release channel from failing human hearts with ischemic cardiomyopathy [110]. Therefore, it is highly likely that alterations in SR function play a critical role in prolongation of the [Ca²⁺]_i transient with cardiac hypertrophy and heart failure.

Measurement of the amplitude of the [Ca²⁺]_i transients from several animal models, and in patients with cardiac hypertrophy and heart failure have also yielded varied results. Siri and coworkers [22]showed a decrease in the peak of the [Ca²⁺]_i transient in hypertrophied myocytes from aortic-banded rats, and a further decrease in the peak of the [Ca²⁺]_i transient with the development of failure. Similar results were seen in hypertrophied myocytes from aortic-banded cats [24], rats with renovascular hypertension [23], dogs with pacing-induced heart failure [28], and humans with terminal heart failure [25, 111]. In contrast, several groups have reported no change in peak [Ca²⁺]_i transients in myocytes from patients with terminal heart failure paced at relatively slow rates [104, 112], while Bing and coworkers [21]noted an increase in peak [Ca²⁺]_i transient in SHR myocytes. Furthermore, Brooks and coworkers [29]observed a change in the peak [Ca²⁺]_i transient in SHR myocytes only when the pacing rate was increased above 2 Hz. A similar rate-dependent alteration in [Ca²⁺]_i transient amplitude has been seen in myocytes from patients with dilated cardiomyopathies [106].

Although these disparate data might result, in part, from the different experimental conditions or models used, the fact that the [Ca²⁺]_i transient is an insensitive measure of the elemental events of E-C coupling (i.e., local release and uptake of Ca²⁺ by the SR) might also play a significant role. Shorofsky et al., [113, 114]noted an increase in the peak of the intracellular Ca²⁺ transient in ventricular cells from spontaneously hypertensive rats at 6 months of age when there is mild cardiac hypertrophy. In addition, Ca²⁺ sparks from these animals had increased amplitude while the L-type Ca²⁺ current was unchanged, suggesting an alteration in the relationship between the trigger for Ca²⁺ release and release of Ca²⁺ from the SR. In contrast, however, Gomez and coworkers [115]found no difference in the Ca²⁺ sparks from Dahl sensitive hypertensive rats and control animals. Confirming the observations of others, they found no change in the density of the L-type Ca²⁺ current, and the whole cell (spatially averaged) Ca²⁺ transients had decreased amplitudes and prolonged durations. From these data, the authors concluded also that there may be a change in the relation between the SR Ca²⁺ release channels and the sarcolemmal Ca²⁺ channels with cardiac hypertrophy and failure.

Time for primary review 28 days.

	References

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