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Cardiovascular Research 1997 35(1):6-12; doi:10.1016/S0008-6363(97)00076-X
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Copyright © 1997, European Society of Cardiology

Cardiac hypertrophy, arrhythmogenicity and the new myocardial phenotype. II. The cellular adaptational process

Bernard Swynghedauwa,*, Brigitte Chevaliera, Daniéle Charlemagnea, Pascale Mansiera and François Carréb

aU127-INSERM, Hôpital Lariboisière, 41 Bd de la Chapelle, 75475, Paris CEDEX, France
bDépartement de Physiologie, Faculté de Médecine, Rennes, France

* Corresponding author. Tel.: +33 (1) 42858065; fax: +33 (1) 48742315.

Received 5 June 1996; accepted 20 February 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Action potential, QT...
 3 Tolerance to calcium,...
 4 Automaticity and calcium...
 5 The adrenergic and...
 References
 
Ventricular fibrosis is not the only structural determinant of arrhythmias in left ventricular hypertrophy. In an experimental model of compensatory cardiac hypertrophy (CCH) the degree of cardiac hypertrophy is also independently linked to ventricular arrhythmias. Cardiac hypertrophy reflects the level of adaptation, and matches the adaptational modifications of the myocardial phenotype. We suggest that these modifications have detrimental aspects. The increased action potential (AP) and QT duration and the prolonged calcium transient both favour spontaneous calcium oscillations, and both are potentially arrhythmogenic and linked to phenotypic changes in membrane proteins. To date, only two ionic currents have been studied in detail: Ito is depressed (likely the main determinant in AP duration), and If, the pacemaker current, is induced in the overloaded ventricular myocytes. In rat CCH, the two components of the sarcoplasmic reticulum, namely Ca2+-ATPase and ryanodine receptors, are down-regulated in parallel. Nevertheless, while the inward calcium current is unchanged, the functionally linked duo composed of the Na+/Ca2+ exchanger and (Na+, K+)-ATPase, is less active. Such an imbalance may explain the prolonged calcium transient. The changes in heart rate variability provide information about the state of the autonomic nervous system and has prognostic value even in CCH. Transgenic studies have demonstrated that the myocardial adrenergic and muscarinic receptor content is also a determining factor. During CCH, several phenotypic membrane changes participate in the slowing of contraction velocity and are thus adaptational. They also have a detrimental counterpart and, together with fibrosis, favour arrhythmias.

KEYWORDS Arrhythmias; Heart rate, variability; Cardiac hypertrophy, compensatory; Calcium transients; Na+/Ca2+ exchange; Phenotype


   1 Introduction
Top
 Abstract
 1 Introduction
2 Action potential, QT...
 3 Tolerance to calcium,...
 4 Automaticity and calcium...
 5 The adrenergic and...
 References
 
Ventricular fibrosis is not the only structural determinant of arrhythmias in left ventricular hypertrophy (LVH) [1]. In fact, heart weight is also linked to ventricular arrhythmias in an experimental model of compensatory cardiac hypertrophy (CCH) [2]. LVH, in spontaneously hypertensive rats (SHR), is proportional to afterload and linked to blood pressure. Cardiac hypertrophy reflects the level of adaptation and matches the various qualitative modifications of the myocardial phenotype. The isomyosin shift and the diminished density of the Ca2+-ATPase of the sarcoplasmic reticulum (SR), for example, are proportional to the degree of cardiac hypertrophy [3].

Our aim is to link the incidence of arrhythmias and both changes in heart rate variability (HRV) and modifications of the myocardial phenotype (calcium movements, ionic channels and autonomic nervous system activity). We therefore review the biological arguments that arrhythmias in CCH are favoured not only by fibrosis but also by the detrimental aspects of mechanogenic transduction. This review is restricted to CCH of mechanical origin.


   2 Action potential, QT duration and ionic currents
Top
 Abstract
 1 Introduction
 2 Action potential, QT...
3 Tolerance to calcium,...
 4 Automaticity and calcium...
 5 The adrenergic and...
 References
 
In mammalian hearts, the most consistent change linked to chronic mechanical overload is the lengthening of the action potential (AP) duration [reviewed in [4, 5]] which, in part, explains the increase in QT interval on the ECG. The AP prolongation favours after-depolarisations and triggered arrhythmias, and has prognostic value. Clinical studies have also demonstrated that the lengthening of the QT interval has a prognostic significance [6]. AP lengthening is the first event in excitation–contraction coupling, and, as such, participates in the slowing of the shortening velocity and the subsequent improvement in the economy of the contractile machinery [1]. Such a phenomenon has to be clearly distinguished from the mechano-electrical feedback related to the immediate electrophysiological changes due to acute ventricular dilatation or stretch of the myocardial tissue [reviewed in [7]]. We will now present arguments which favour the adaptational nature of changes in the expression of genes encoding the ionic channel subunits (Table 1).


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  		Table 1 Permanent changes in genetic expression in rat CCH

 
2.1 Ionic channels
AP duration itself depends on the activity of several ionic channels and increases both when an outward current is depressed and when an inward current is enhanced [4]. Its determinants are likely to be both species- and tissue-specific. In rats, for example, It0 plays a major role, whereas other K+ currents are more important in other species. The electrophysiological pattern observed during cardiac hypertrophy and failure has recently been reviewed [5].

1. Voltage-sensitive calcium channels, which are responsible for the slow inward current (ICaL), contribute to the plateau phase and could be involved in lengthening the AP provided that the corresponding current density is increased. In contrast, both the current density [8, 9]and the number of dihydropyridine-binding sites (which represent the overall channels) [10]are unchanged, at least in our model of CCH. This regulation is likely to be species-specific.

2. Potassium currents are outward currents which accelerate repolarisation. The major defect in CCH is a pronounced depression of the early transient outward current (Ito) [9, 11]. The delayed rectifier outward current (IK) is also reduced in feline models of cardiac hypertrophy, while the background inward rectifier current (IK1) is increased [4]. For the moment, the relative contribution of the cloned channels to cardiac function has only partly been elucidated [12].

3. Sodium–calcium exchange creates an inward depolarisation current. Its activation could create a long-lasting slow inward current and contribute to the lengthening of the action potential [4]. This point is controversial, however [13, 14].

4. At least 3 currents or proteins specific for the sinus node have been found in overloaded ventricles: (i) Cerbai et al. [15]have recently shown the spontaneous occurrence of If, the main current responsible for the spontaneous depolarisation of the pacemaker, in isolated ventricular myocytes from senescent SHRs, with a good correlation between the duration of the pressure overload and the number of cells in which this current is found. (ii) Re-expression of ICaT, a calcium channel specific for the sinus node, has been demonstrated in the hypertrophied ventricle [16], although there is indirect evidence that this channel is not functional [17]. (iii) More recently, we found that the {alpha}3-isoform of the sodium pump, which is likely to be a marker of the conductive system [18], was re-expressed in the overloaded rat ventricle [19].

2.2 Functional modification or change in genetic expression?
The diminished density of Ito, the unchanged density of ICaL and the rise in If can either result from hundreds of functional changes, involving various effectors, mediators or ionic changes, or contribute to the adaptational process as a result of modifications in the expression of the genes encoding ionic channel subunits. Such a genetic explanation is supported by the following data: (i) As far as the calcium channels are concerned, the current changes run parallel to the density of the dihydropyridine-binding sites, suggesting that the expression of the corresponding genes is sensitive to mechanical stress, and is activated in proportion to the degree of hypertrophy [8, 9]. (ii) With regard to K+ channels, we have no information on protein density, but recent investigations published in abstract form [20]showed modifications in the expression of Kv1.4, the gene encoding It0, and Kv1.5. The topic is far from clear [12]. (iii) The reappearance of If, ICaT, and the {alpha}3-isoform of (Na+,K+)-ATPase is suggestive of the induction of a foetal programme (such a programme is also expressed in the adult conductive tissue). Such re-expression may favour automaticity. It is important to note that a diastolic depolarization has been observed in hypertrophied cardiocytes [15]. In addition, an increased susceptibility to pacemaker-like activity has been demonstrated in human trabeculae from failing hearts during superfusion with a modified Tyrode solution [21]. Attempts to trigger automaticity in pure models of CCH by increasing the external calcium concentration were unsuccessful, however [15, 17]. (iv) The long QT syndrome, which is an inherited monogenic multiallelic disease, is associated with several mutations. Two loci, at least, have been isolated and characterised. One is on a subunit of the sodium channel, and the other is on HERG, which encodes the {alpha}-subunits of a potassium channel; it has been demonstrated that both mutations lengthen the QT interval [22–24]. Although there are no arguments in favour of a sodium channel deficiency in acquired disease like cardiac mechanical overload, this genetic finding raises the possibility that the inability of an ionic channel to function adequately may be detectable on the ECG and have clinical consequences.


   3 Tolerance to calcium, anoxia, and ischaemia in CCH
Top
 Abstract
 1 Introduction
 2 Action potential, QT...
 3 Tolerance to calcium,...
4 Automaticity and calcium...
 5 The adrenergic and...
 References
 
When the hypertrophied heart is submitted to brief episodes of anoxia or ischaemia, or a sudden increase in calcium load, its capacity to buffer acute stress is hampered relative to normal hearts, suggesting that its calcium or energy metabolism is modified.

3.1 Calcium sensitivity of the hypertrophied heart
The normal rat heart becomes stiffer when perfused for 5–10 min in anoxic conditions. This phenomenon is exaggerated in CCH, regardless of the model used [25, 26]. It has been demonstrated that this exaggeration is unrelated to high energy phosphate availability and is likely to reflect an attenuated capacity of the hypertrophied heart to buffer sudden changes in intracellular calcium (Cai) [26].

The senescent rat heart is frequently considered as a model of pressure overload. LVH occurs in this model through enhanced aortic impedance. Most of the biological characteristics of the senescent myocardium result from the senescence of the large arteries. An elevation in diastolic pressure was observed in response to stepwise increases in perfusate calcium concentration. Ventricular fibrillation and spontaneous calcium oscillations were not observed in young animals at a calcium concentration of 10 mM. In contrast, ventricular arrhythmias and calcium oscillations were observed in the senescent myocardium at calcium concentrations of 6–8 mM, suggesting that the capacity to buffer sudden changes in calcium concentration is hampered in the hypertrophied senescent cardiocyte [27]. The same threshold is also lower in the Syrian cardiomyopathic hamster, even in the pre-hypertrophic stage [28].

3.2 The sensitivity to ischaemia of the hypertrophied heart
Several experimental studies have shown that the electrophysiologic response to ischaemia is altered in failing and hypertrophied myocardium with a predisposition to ventricular arrhythmias [29, 30].

The response to coronary occlusion was studied in dogs with chronic renal hypertension and cardiac hypertrophy (+28%). Ischaemia induced short episodes of polymorphic ventricular tachycardia in half of the controls. In contrast, sustained monomorphic ventricular tachycardia was induced in nearly all the animals with cardiac hypertrophy [31].

Taylor [32]used the same model of cardiac hypertrophy. Dogs were pretreated with lidocaine, and a 15 min period of coronary occlusion was followed by 24 h of reperfusion. Reperfusion-associated ventricular fibrillation occurred in seven out of 17 dogs with cardiac hypertrophy versus one of the 18 dogs with normal heart weight.

Eighteen-week-old SHRs have a pronounced left ventricular hypertrophy. The incidence of ischaemia-induced ventricular tachycardia and fibrillation was examined on a Langendorff apparatus after coronary ligation. VPBs and non-sustained ventricular tachycardia sometimes occurred in control Wistar rats while the same regional ischaemia induced severe arrhythmias in 63% of the SHRs in conjunction with a greater dispersion of AP duration [33].


   4 Automaticity and calcium movements in cardiac hypertrophy
Top
 Abstract
 1 Introduction
 2 Action potential, QT...
 3 Tolerance to calcium,...
 4 Automaticity and calcium...
5 The adrenergic and...
 References
 
4.1 Automaticity and intracellular calcium (Cai)
High [Cai] generates oscillating electrical currents strong enough to cause recurrent APs. The normal quiescent cardiocyte is therefore able to behave as a pacemaker. The SR can generate spontaneous calcium oscillations (oscillations not triggered by the AP) at frequencies ranging from less than 0.1 Hz to several hertz [27]. Such oscillations create heterogeneous AP repolarisation times and the amplitude of ICaL, and favour after-depolarisations. Aronson [34]showed that the hypertrophied rat heart has a greater propensity to develop both delayed and early after depolarisations. Such a scheme, when applied to chronic cardiac overload, requires a real substrate with regard to the changes in genetic expression of the membrane proteins.

A rather large number of clinical conditions which can trigger automaticity are associated with the development of electrical instability and abnormalities of calcium metabolism, including therapy with agents able to modify [Cai] such as digitalis and catecholamines, hypokalaemia, stress, ischaemia and anoxia. Fibrosis and/or necrosis play an additional role by creating electrical heterogeneity in the tissue.

4.2 Calcium movements and concentration in cardiac hypertrophy
The calcium transient is profoundly altered in heart failure in both clinical and experimental settings. Two studies have addressed this question in models of CCH. In both studies, basal [Cai] values were unchanged [35, 36]. In renovascular hypertensive rats, calcium dynamics during the contraction–relaxation cycle are affected, peak calcium is significantly depressed and the calcium removal phase is prolonged [35]. These results differ slightly from those obtained in a model of pressure overload in the ferret in which the peak calcium was unchanged and the only abnormality was a prolongation of the calcium transient [36].

An increasing body of evidence from molecular biological experiments suggests that the prolongation of the calcium transient results from phenotypic modifications of membrane proteins (Table 1). Nevertheless, the puzzle is still incomplete, and sound studies have yielded conflicting data. Calcium homeostasis in any cell depends upon two compartments—internal SR stores and the extracellular space. The calcium concentration in these two compartments is much higher than in cytoplasm and the determinants of calcium homeostasis are voltage-gated calcium channels and energy-dependent calcium transporters such as the calcium ATPases. (Na+,K+)-ATPase (the sodium pump) is not, of course, directly involved in the calcium movements but plays an important role as an indirect energy source for the Na+/Ca2+ exchanger (Fig. 1).


Figure 1
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  		Fig. 1 Calcium metabolism in a rat cardiocyte. Our working hypothesis (in black) is that the cause of the prolongation of the calcium transient is impaired activity of the functional duo consisting of the Na+/Ca2+ exchanger and (Na+,K+)-ATPase. Calcium release in the external space is hampered, while the calcium inward current is normal. On the SR, Ca2+-ATPase and Ca2+-induced Ca2+ release are down-regulated in parallel, and calcium homeostasis is maintained at this level. This hypothesis is supported by data from rat CCH models. The topic is controversial: human data, even within our own laboratory, are different, especially regarding the ryanodine receptor. Our findings on the Na+/Ca2+ exchanger have not so far been confirmed.

 
4.3 Membrane proteins and calcium movements
4.3.1 Sarcoplasmic reticulum
One of the most interesting events in this field of investigation during the past few years was the simultaneous publication of converging reports on SR Ca2+-ATPase (reviewed in [3, 37]). During chronic cardiac overload, in both experimental models and clinical settings, the SR is less capable of pumping calcium against the SR-cytoplasmic calcium gradient because the density per cell or per surface area of Ca2+-ATPase is lower. The corresponding gene is not activated by the mechanical stress, meaning that the products of the gene, namely the mRNA and the protein, are diluted in the hypertrophied myocyte [37]. This family of genes now includes several other members (see below).

In the heart, calcium release is autocatalytic and triggered by the calcium inward current. The density of ryanodine receptors, the calcium channels responsible for the calcium release, is diminished in CCH, and runs parallel to that of Ca2+-ATPase [38]. Therefore, we can predict that calcium homeostasis has to be maintained in the SR of CCH since the density of the protein responsible for the calcium release is the same as that of the ATPase in charge of the calcium uptake. Whether such phenotypic changes explain the prolongation of the calcium transient is debatable (Fig. 1).

4.3.2 External membrane
As explained above, the calcium inward current density is not modified in CCH, suggesting that calcium entry from the extracellular space is normal. The calcium output is regulated by a functional duo composed of the Na+/Ca2+ exchanger and (Na+,K+)-ATPase, the first being responsible for the release of calcium, while the second provides energy to the exchanger. Both are modified in CCH, suggesting that calcium homeostasis is unbalanced at this level. The precise nature of the changes is still controversial.

Kinetic studies of normal rat heart showed two affinity sites for ouabain which correspond in adults to two different {alpha}-subunit isoforms, {alpha}1 ({alpha}1β) and {alpha}2 ({alpha}2β). A third isoform ({alpha}3) is mainly embryonic and, as explained above, specific for the conductive system. In normal rat heart, {alpha}1 and {alpha}2 are present in approximately equal proportions; {alpha}2 has the lowest affinity for Na+ and is mainly responsible for the therapeutic effect of digitalis, while {alpha}1, which has a higher affinity for sodium, is responsible for toxicity. Studies of CCH in the rat have shown a complex pattern which combines unchanged specific activity, an increased density at the high-affinity sites, and a slowing of the dissociation rate constant for ouabain. These modifications are likely to reflect an isoenzymic shift from the adult form of the {alpha}-subunit ({alpha}2) to the foetal isoform ({alpha}3) which finally results in a lower affinity of the overall enzyme for sodium [39]. Basically it would mean that the sodium pump should be less active in cardiac hypertrophy, at least in the rat. The situation is species-specific and is, for example, different in human who possess an {alpha}3-subunit with a high affinity for sodium. The sodium pump is modified in CCH, the changes varying from one animal species to another depending on basal conditions (calcium metabolism). As a result, the genetic expression of this key enzyme acts as a mirror from the overall ionic exchanges in the cell.

We found that the activity of the Na+/Ca2+ exchanger is depressed in CCH in rats [14]. Opposite results were published by Studer et al. [13]regarding end-stage human heart failure, with a major increase in both the mRNA and protein level of the Na+/Ca2+ exchanger. Such discrepancies could have several explanations including the fact that our membrane preparation was composed of inside-out vesicles. In such preparations the fluxes of radioactive calcium or sodium—the tools used to measure the activity of the exchanger—also depend on the sodium pump. The sodium pump is altered in CCH, and this could compensate for augmented specific activity.

4.3.3 Calcium homeostasis
The calcium transient is prolonged in human cardiac hypertrophy as well as in rats and rabbits. We proposed a scheme linking this prolongation of the calcium transient to membrane protein changes (Fig. 1). Calcium homeostasis in the hypertrophied myocyte is thought to be fragile. The balance between calcium influx and efflux is unstable and renders the cell incapable of controlling any abnormal influx of calcium, due for example to ischaemia, inotropic agents or various types of stress. This might represent a basis for explaining the arrhythmogenicity of the hypertrophied heart.


   5 The adrenergic and muscarinic system
Top
 Abstract
 1 Introduction
 2 Action potential, QT...
 3 Tolerance to calcium,...
 4 Automaticity and calcium...
 5 The adrenergic and...
References
 
5.1 The β-adrenergic/muscarinic myocardial system
The β-adrenergic system has been extensively explored following human cardiac hypertrophy and failure, as well as in animal models, and two situations have to be distinguished: (i) In failing hearts, even in humans, the elevated circulating catecholamine level down-regulates β1-adrenergic receptor density and is responsible for the transcriptionally regulated elevation of G{alpha}i2. This is clearly a homologous down-regulation which mainly involves β1-adrenergic receptors. (ii) Studies on CCH have shown that, in spite of a normal plasma level and myocardial catecholamine content, β1-adrenergic receptor density is depressed by 30% [40]. We have recently shown a parallel fall in the corresponding mRNAs [41], suggesting that the changes in receptor density are regulated pretranslationally, and that the corresponding gene belongs to the same family as the SR Ca2+-ATPase and is not activated by mechanical stress (Table 1).

Muscarinic receptors are also modified in CCH [40]. Their density is diminished and, at least in the rat, the muscarinic/β1-adrenergic receptor ratio remains unchanged suggesting that they reflect a compensatory mechanism more than a homologous down-regulation in reaction to circulating hormones.

5.2 Physiological consequences
The diminished β1-adrenergic receptor density protects the heart against acute stress and, in CCH, participates in the overall process of cardiac adaptation by attenuating the inotropic effects of catecholamines. As such, non-induction of the genes encoding this system has the same significance as non-induction of SR Ca2+-ATPase or the isomyosin shift to the slow V3 isoform (discussed in [3]).

The heart rate reflects a balance between the two components of the autonomic nervous system. The heart rate fluctuations are composed of two groups of oscillations—the low (LF) and the high frequency (HF) oscillations. The LF/HF ratio indicates the respective influence of each component of the system [42]. The spectral power of these oscillations is modified in the case of an imbalance between sympathetic and parasympathetic drive which can be due either to a deficit or to a saturation of the system. The biological determinants of the autonomic system include numerous neural pathways, but also the myocardial phenotype (β-adrenergic/muscarinic receptor ratio).

During CCH in rats, the β1-adrenergic and muscarinic receptors are down-regulated in parallel. The balance between the two systems is unchanged and the HRV is only slightly modified. Ten months later, the changes in HRV become more evident as do changes in the myocardial phenotype. Thyroxine up-regulates the β-adrenergic receptor density and down-regulates the muscarinic receptors. The result is a spectacular attenuation of HRV [42].

It is difficult to implicate the myocardial phenotype on the basis of experimental models of heart disease, as they all have additional effects on the reflex arcs. Experiments are needed in which the changes in receptor density are not accompanied by haemodynamic changes. Transgenic mice have been designed with a targeted atrial overexpression of β1-adrenergic receptors. The transgenic manipulation resulted in a decreased HRV without arrhythmias and an unaltered lifespan, showing that the myocardial phenotype is indeed one of the determinants of the HRV, but that an additional substrate is required to produce arrhythmias [43].

No doubt neural reflex disorders and the plasma catecholamine content are partly responsible for HRV abnormalities in pathological states, but experiments with transgenic mice have suggested that myocardial receptor down-regulation may also be of importance.

In conclusion, adaptation to the new environmental requirements during mechanical overload involves several phenotypic changes at the membrane or sarcomere levels which both slow down the contraction velocity and participate in the improved economy. The membrane modifications also have a detrimental counterpart and, together with fibrosis, favour arrhythmias.

Time for primary review 41 days.


   References
Top
 Abstract
 1 Introduction
 2 Action potential, QT...
 3 Tolerance to calcium,...
 4 Automaticity and calcium...
 5 The adrenergic and...
 References
 

  1. Assayag P, Carré F, Chevalier B, Delcayre C, Mansier P, Swynghedauw B. Compensated cardiac hypertrophy: arrhythmogenicity and the new myocardial phenotype. I. Fibrosis. Cardiovasc Res 1997;34:439–444.
  2. Chevalier B., Heudes D., Heymes C., et al. Trandolapril decreases prevalence of ventricular ectopic activity in middle-aged SHR. Circulation (1995) 92:1947–1953.[Abstract/Free Full Text]
  3. Swynghedauw B. Molecular cardiology for the cardiologist. Boston: Kluwer Academic Publishers, 1995.
  4. Swynghedauw B, Coraboeuf E. Basic aspects of myocardial function, growth, and development. Cardiac hypertrophy and failure. In: Willerson JT, Cohn JN, editos. Cardiovascular medicine. New York: Churchill Livingstone, 1994:771–790.
  5. Hart G. Cellular electrophysiology in cardiac hypertrophy and failure. Cardiovasc Res (1994) 28:933–946.[Free Full Text]
  6. Higham P.D., Campbell R.W.F. QT dispersion. Br Heart J (1994) 71:508–510.[Free Full Text]
  7. Franz M.R. Mechano-electrical feedback in ventricular myocardium. Cardiovasc Res (1996) 32:15–24.[Free Full Text]
  8. Scamps F., Mayoux E., Charlemagne D., Vassort G. Ca current in single isolated cells from normal and hypertrophied rat heart. Effect of β-adrenergic stimulation. Circ Res (1990) 67:199–208.[Abstract/Free Full Text]
  9. Cerbai E., Barbieri M., Li Q., Mugelli A. Ionic basis of action potential prolongation of hypertrohied cardiac myocytes isolated from hypertensive rats of different ages. Cardiovasc Res (1994) 28:1180–1187.[Abstract/Free Full Text]
  10. Mayoux E., Callens F., Swynghedauw B., Charlemagne D. Adaptional process of the cardiac Ca2+ channels to pressure overload: biochemical and physiological properties of the dihydropyridine receptors in normal and hypertrophied rat hearts. J Cardiovasc Pharmacol (1988) 12:390–396.[ISI][Medline]
  11. Coulombe A., Montaza A., Richer P., Swynghedauw B., Coraboeuf E. Reduction of calcium-independent transient outward current density in DOCA-salt hypertrophied rat ventricular myocytes. Pflügers Arch (1994) 427:47–55.[CrossRef][ISI][Medline]
  12. Deal K.K., England S.K., Tamkun M.M. Molecular physiology of cardiac potassium channels. Physiol Rev (1996) 76:49–67.[Abstract/Free Full Text]
  13. Hasenfuss G, Holubarsch C, Just H, Alpert NR, editors. Cellular and molecular alterations in the failing human heart. Darmstadt: Steinkopff Verlag, 1992.
  14. Hanf R., Drubaix I., Lelièvre L. Rat cardiac hypertrophy: altered sodium–calcium exchange activity in sarcolemmal vesicles. FEBS Lett (1988) 236:145–149.[CrossRef][ISI][Medline]
  15. Cerbai E., Barbieri M., Mugelli A. Characterization of the hyperpolarisation-activated current If in ventricular myocytes isolated from hypertensive rats. J Physiol (London) (1994) 481:585–591.[Abstract/Free Full Text]
  16. Nuss H.B., Houser S.R. T-type Ca2+ current is expressed in hypertrophied adult feline left ventricular myocytes. Circ Res (1993) 73:777–782.[Abstract/Free Full Text]
  17. Aronson R.S. Characteristics of action potentials of hypertrophied myocardium from rats with renal hypertension. Circ Res (1980) 47:443–454.[Free Full Text]
  18. Zahler R., Sun W., Ardito T., Zhang Z.-T., Korsis J.D., Kashgarian M. The {alpha}3 isoform protein of the Na+, K+-ATPase is associated with the sites of cardiac and neuromuscular impulse transmission. Circ Res (1996) 78:870–879.[Abstract/Free Full Text]
  19. Charlemagne D., Orlowski J., Oliviero P., et al. Alteration of Na+, K+-ATPase subunit mRNA and protein levels in hypertrophied heart. J Biol Chem (1994) 269:1541–1547.[Abstract/Free Full Text]
  20. Matsubara H., Suzuki J., Murasawa S., Inada M. Kv1.4 mRNA regulation in cultured rat heart myocytes and differential expression of Kv1.4 and 1.5 genes in myocardial development and hypertrophy (Abstract). Circulation (1993) 88:I–86.
  21. Vermeulen J.T., McGuire M.A., Opthof T., et al. Triggered activity and automaticity in ventricular trabeculae of failing human and rabbit hearts. Cardiovasc Res (1994) 28:1547–1554.[Abstract/Free Full Text]
  22. Bennett P.B., Yazawa K., Makita N., George A.L. Jr. Molecular mechanisms for an inherited cardiac arrhythmia. Nature (1995) 376:683–685.[CrossRef][Medline]
  23. Keating M.T., Sanguinetti M.C. Molecular genetic insights into cardiovascular disease. Science (1996) 272:681–685.[Abstract]
  24. Kass R.S., Davies M.P. The roles of ionic channels in an inherited heart disease: molecular genetic of the long QT syndrome. Cardiovasc Res (1996) 32:443–454.[Free Full Text]
  25. Callens-El Amrani F., Snoeckx L., Swynghedauw B. Anoxia-induced changes in ventricular diastolic compliance in two models of hypertension in rats. J Hypertens (1992) 10:229–236.[CrossRef][ISI][Medline]
  26. Wexler L.F., Lorell B.H., Momomura S.-i., Weinberg E.O., Ingwall J.S., Apstein C.S. Enhanced sensitivity to hypoxia-induced diastolic dysfunction in pressure-overload left ventricular hypertrophy in the rat: role of high-energy phosphate depletion. Circ Res (1988) 62:766–775.[Abstract/Free Full Text]
  27. Hano O., Bogdanov K.Y., Sakai M., et al. Reduced threshod for myocardial cell calcium intolerance in the rat with aging. Am J Physiol (1995) 269:H1607–H1612.[ISI][Medline]
  28. Hano O., Lakatta E.G. Diminished tolerance of prehypertrophic, cardiomyopathic Syrian hamster hearts to Ca2+ stresses. Circ Res (1991) 69:123–133.[Abstract/Free Full Text]
  29. Winterton S.J., Turner M.A., O'Gorman D.J., Flores N.A., Sheridan D.J. Hypertrophy causes delayed conduction in human and guinea pig myocardium: accentuation during ischaemic perfusion. Cardiovasc Res (1994) 28:47–54.[Abstract/Free Full Text]
  30. Vermeulen J.T., Tan H.L., Rademaker H., et al. Electrophysiologic and extracellular ionic chages during acute ischemia in failing and normal rabbit myocardium. J Mol Cell Cardiol (1996) 28:123–131.[CrossRef][ISI][Medline]
  31. Martins J.B., Kim W., Marcus M.L. Chronic hypertension and left ventricular hypertrophy facilitate induction of sustained ventricular tachycardia in dogs 3 hours after left circumflex coronary occlusion. J Am Coll Cardiol (1989) 14:1365–1373.[Abstract]
  32. Taylor A.L., Winter R., Thandroyen F., et al. Potentiation of reperfusion-associated ventricular fibrillation by left ventricular hypertrophy. Circ Res (1990) 67:501–509.[Abstract/Free Full Text]
  33. Kohya T., Yokoshiki H., Tohse N., et al. Regression of left ventricular hypertrophy prevents ischemia-induced lethal arrhythmias. Beneficial effect of angiotensin II blockade. Circ Res (1995) 76:892–899.[Abstract/Free Full Text]
  34. Aronson R.S. Mechanisms of arrhythmias in ventricular hypertrophy. J Cardiovasc Electrophysiol (1991) 2:249–261.[CrossRef]
  35. Moore R.L., Yelemarty R.V., Misawa H., et al. Altered Ca2+ dynamics in single cardiac myocytes from renovascular hypertensive rats. Am J Physiol (1991) 260:C324–C327.
  36. Gwathmey J.K., Morgan J.P. Altered calcium handling in experimental pressure-overload hypertrophy in the ferret. Circ Res (1985) 57:836–843.[Abstract/Free Full Text]
  37. de la Bastie D., Levitsky D., Rappaport L., et al. Function of the sarcoplasmic reticulum and expression of its Ca2+ ATPase gene in pressure overload-induced cardiac hypertrophy in the rat. Circ Res (1990) 66:554–564.[Abstract/Free Full Text]
  38. Naudin V., Oliviero P., Rannou F., Sainte-Beuve C., Primot I., Charlemagne D. Ryanodine receptors in pressure-overload induced cardiac hypertrophy in the rat. FEBS Lett (1991) 285:135–138.[CrossRef][ISI][Medline]
  39. Charlemagne D., Orlowski J., Oliviero P., et al. Alteration of Na+, K+-ATPase subunit mRNA and protein levels in hypertrophied heart. J Biol Chem (1994) 269:1541–1547.[Abstract/Free Full Text]
  40. Mansier P., Chevalier B., Barnett D.B., Swynghedauw B. Beta1-adrenergic and muscarinic receptor densities in compensatory cardiac hypertrophy of the adult rat. Pflügers Arch (1993) 424:354–360.[CrossRef][ISI][Medline]
  41. Mondry A., Bourgeois F., Carré F., Swynghedauw B., Moalic J.M. Decrease in β1-adrenergic and M2-muscarinic receptor mRNA levels and unchanged accumulation of mRNAs coding for G{alpha}1-2 and G{alpha}s proteins in rat cardiac hypertrophy. J Mol Cell Cardiol (1995) 27:2287–2294.[CrossRef][ISI][Medline]
  42. Carré F., Maison-Blanche P., Ollivier L., et al. Heart rate variability in cardiac hypertrophy in rats. Relationships with β-adrenergic and muscarinic receptor density. Am J Physiol (1994) 266:H1872–H1878.[ISI][Medline]
  43. Mansier P., Médigue C., Charlotte N., et al. Decreased heart rate variability in transgenic mice overexpressing atrial β1-adrenoceptors. Am J Physiol (1996) 271:H1465–H1472.[ISI][Medline]

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