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G. L. Brown Prize Lecture |
1 Institute of Biomedical and Life Sciences2 BHF Cardiovascular Centre, University of Glasgow, Glasgow G12 8QQ, UK
Abstract
Heart failure as a result of a myocardial infarction (MI) is a common condition with a poor prognosis. The adaptive changes in the surviving myocardium appear to be insufficient in terms of both mechanical/contractile performance and electrical stability. The modification of the underlying myocardial physiology is complex, varying across the different layers within the wall of the ventricle and within one layer. Two therapeutic strategies are briefly discussed, as outlined here. (i) Enhancing contractility by alteration of the expression of a single protein (e.g. sarco-endoplasmic reticulum Ca2+ ATPase, SERCA) could potentially reverse both mechanical and electrical abnormalities. However, experimental data involving the upregulation of SERCA suggest that the therapeutic range of this approach is narrow. (ii) The use of regular exercise training to improve cardiac performance in heart failure. This appears to act by normalizing a number of aspects of myocardial physiology.
(Received 18 May 2007;
accepted after revision 14 August 2007; first published online 14 September 2007)
Corresponding author G. Smith: Institute of Biomedical and Life Sciences IBLS, University of Glasgow, Glasgow G12 8QQ, UK. Email: g.smith{at}bio.gla.ac.uk
The failing heart
Heart failure (HF) is a clinical syndrome characterized by a reduced pump efficiency of the heart resulting in haemodynamic disturbances and a cascade of local and systemic changes (Poole-Wilson, 1993). Unlike other cardiovascular diseases, the prevalence and incidence of congestive heart failure are rising and the disease imposes a substantial burden on hospital services as well as being a major cause of disability and death (McMurray et al. 1993). Results from the MRC Clinical Research Initiative in North Glasgow indicate that the prevalence of left ventricular dysfunction in men and women over the age of 65 years is 6.8 and 4.9%, respectively (McDonagh et al. 1997). The quality of life of these individuals is substantially impaired; they suffer symptoms of dyspnoea, oedema and fatigue and typically demonstrate impairment of left ventricular systolic and diastolic function. Functional testing reveals a significant reduction in effort capacity, peak oxygen uptake and peak cardiac output (Cowley et al. 1991). Not only is there impairment of myocardial contraction and relaxation under resting conditions (Grossman, 1990) but also of the normal mechanisms responsible for adaptive increases in cardiac output. These include flattening of the Starling curve (Pye et al. 1996; Ng et al. 2002), reduced inotropic effect of β-adrenoreceptor agonists (Brown & Harding, 1992) and a depressed or negative force–frequency relationship (Pieske et al. 1997).
Cause of death in heart failure. The prognosis of patients with advanced heart failure (New York Health Association Class III or IV) is poor, with 5 year mortality rates around 50% (Yusuf, 1991; Goldman et al. 1993; Narang et al. 1996). The immediate mechanisms leading to death in heart failure are often difficult to establish (Narang et al. 1996). Patients may die from progressive haemodynamic deterioration, or as a result of a new ischaemic event such as recurrent myocardial infarction (MI; Luu et al. 1989). However, up to 40% of patients with heart failure die suddenly and unexpectedly (Goldman et al. 1993; Narang et al. 1996). Sudden unexpected death in patients with mild to moderate heart failure is most likely to be due to ventricular fibrillation (VF), while in advanced failure a significant proportion of sudden deaths are due to bradyarrhythmias or asystole (Luu et al. 1989). Sudden cardiac death is proportionately more common in patients with mild to moderate heart failure than in those with end-stage disease, although the absolute risk of either sudden or non-sudden death is greater in advanced heart failure (Narang et al. 1996). Even among patients whose death is preceded by an episode of haemodynamic deterioration, the terminal event may be arrhythmic (Goldman et al. 1993). Prevention of arrhythmic death in such patients may permit stabilization of the haemodynamic status and significant further survival with a reasonable quality of life.
Treatment of heart failure. Although superficially logical, strategies directed at increasing myocardial contractile function in heart failure have been disappointing. The traditional mainstay of positive inotropic therapy, digoxin, reduces the risk of death or hospital admission for progressive heart failure. However, digoxin had no significant effect on ‘all-cause mortality’ and caused a slight excess in sudden deaths (Perry et al. 1997). Other positive inotropic interventions based on elevation of intracellular cyclic AMP levels have all been abandoned as a result of clinical trials indicating an increase in mortality (Packer et al. 1991; Reddy et al. 1997). These trials are salutary in indicating that acute increases in inotropic function may be associated with an increased risk of arrhythmia in the failing heart.
Conversely, studies of antiarrhythmic drugs to reduce the risk of sudden death in left ventricular dysfunction or heart failure have either increased the risk of death (Echt et al. 1991), or at best have failed to demonstrate a significant reduction in mortality (Moller, 1996; Connolly et al. 1997). These disappointing results have been attributed to a pro-arrhythmic or negative inotropic effect of antiarrhythmic drugs in certain clinical circumstances. The risk of a pro-arrhythmic response is increased in advanced left ventricular dysfunction, acute ischaemia or in the presence of catecholamine stimulation, all conditions seen commonly in advanced heart failure. Effective prevention of sudden death is hampered by an imperfect knowledge of the events that trigger and/or sustain arrhythmias in heart failure. Therapeutic advances must await a deeper understanding of the mechanisms responsible for arrhythmogenesis and progression of contractile dysfunction in heart failure.
Animal models of heart failure
There are several models of cardiac hypertrophy employed in experimental animals to generate the features of a failing heart, these have been reviewed elsewhere (Hasenfuss, 1998). A common approach is to simulate a myocardial infarction by ligation of a coronary artery via an operative procedure. The infarct is allowed to heal and the remaining myocardium hypertrophies to compensate for the loss. The myocardial infarction model in the rabbit has been extensively characterized. This model demonstrates many features of clinical heart failure, including impairment of left ventricular ejection fraction (Pye et al. 1996), compensatory hypertrophy (Ng et al. 1998) and neuroendocrine activation (Maurice et al. 1997). The survival curve for this model shows a non-linear relationship over a period of 8 weeks post-MI, with an overall mortality of 
10% after 8 weeks (Fig. 1B).
This has similar characteristics to data from human studies (Pitt et al. 2003; Fig. 1A). In vivo and postmortem measurements indicate that 8 weeks post-MI, the heart is enlarged and contractility is reduced. Signs of congestive heart failure are evident in terms of congestion in the lungs and liver (Table 1).
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Adult cardiac myocytes are incapable of mitosis, so the adaptive response to myocyte loss or mechanical stress in chronic heart failure is hypertrophy of the surviving cells. Prolongation of action potential duration (APD) is a characteristic of hypertrophied myocardium. Voltage clamp studies of myocytes with prolonged APD in human heart failure (Beuckelmann et al. 1993) and in animal models (McIntosh et al. 1998) have identified reductions in the inward rectifier, transient outward or sustained outward K+ currents. The electrophysiological characteristics of the cells studied in these reports suggest that they may have been derived from the subepicardium and mid-myocardium. These cells also display reduced intracellular [Ca2+], which may contribute to the alterations in repolarization via Ca2+-sensitive currents (Ca2+-sensitive K+ currents, Barrett et al. 1987; Cl– current, Hiraoka & Kawano, 1989; delayed rectifier, Nitta et al. 1994; Na+–Ca2+ exchanger, Diaz et al. 1996; and inward rectifier, Mazzanti & DiFrancesco, 1998). Recent work indicates that subendocardial myocytes display a decreased APD in volume-overload hypertrophy (McIntosh et al. 1996; Shipsey et al. 1997; McIntosh et al. 2000; Fig. 3). The electrophysiological basis of this effect and its possible role in the generation of arrhythmias are unknown.
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Mechanisms of arrhythmogenesis in heart failure
Postulated mechanisms for arrhythmogenesis in heart failure have focused either on single cell arrhythmic mechanisms, particularly triggered activity due to early or delayed after-depolarizations (Han & Moe, 1964; Damiano & Rosen, 1984; Aronson & Ming, 1993), or on heterogeneity of electrophysiological properties between cells, e.g. conduction velocity or refractoriness (Han & Moe, 1964; Kuo et al. 1983), predisposing to re-entry.
Early after-depolarizations (EADs). Early after-depolari-zations are defined as depolarizing potentials that occur before the action potential repolarizes completely. Early after-depolarizations are facilitated by prolonging action potential duration (Damiano & Rosen, 1984), whether by delayed inactivation of either Na+ (Boutjdir & El-Sherif, 1991) or Ca2+ currents (January & Riddle, 1989) or by reduction in outward current (e.g. class III antiarrhythmic drugs, caesium). Physiological interventions, such as adrenergic stimulation, bradycardia, lowered extracellular K+ and Mg2+, promote EAD activity (Priori & Corr, 1990; Drouin et al. 1996). Early EADs may be caused by a depolarizing current generated by slow inactivation of Na+ channels (Marban & Robinson, 1986), by recovery from inactivation and re-activation of L-type Ca2+ channels (Boutjdir & El-Sherif, 1991) or by isoprenaline-activated Cl– current (Yamazaki et al. 1992). However, there is no consensus as to whether these are triggered by spontaneous sarcoplasmic reticulum (SR) Ca2+ release. Isoprenaline-induced EADs in guinea-pig myocytes were accompanied by a simultaneous and uniform increase of intracellular [Ca2+] throughout the cell; in contrast, spontaneous release from cardiac SR is non-uniform, originating in one discrete area of the cell (Deferrari et al. 1995). Oscillatory changes in intracellular Ca2+ coincide with these EADs. They occur on the descending phase of the primary Ca2+ transient, a period when spontaneous SR Ca2+ release is unusual (Allen et al. 1985). However, the threshold for spontaneous SR Ca2+ release may be affected by membrane potential and cytosolic [Ca2+].
Late EADs occur during phase 3 of the action potential. They are thought to be due to Ca2+-activated inward currents; Na+–Ca2+ exchange (Diaz et al. 1996), non-selective current or Ca2+-activated Cl– current (Trafford et al. 1998) generated by spontaneous Ca2+ SR release (Szabo et al. 1994) in a similar fashion to delayed after-depolarizations (DADs).
Delayed after-depolarizations. Delayed after-depolari-zations are caused by spontaneous Ca2+ release from local regions of the SR which give rise to a transient inward current during the diastolic period. Conditions of intracellular Ca2+ overload such as are produced by catecholamine administration or digitalis toxicity predispose to DADs. While early EADs are common during bradycardia, the amplitude and frequency of DADs increase with increasing heart rate (Aronson & Ming, 1993).
On the basis of the known downregulation of the SR in heart failure, the likelihood of SR Ca2+ overload and spontaneous Ca2+ release from the SR would appear to be lower in failing than in normal myocardium. However, recent work suggests that intracellular [Ca2+] is increased in subendocardial myocytes, in contrast to the reduced Ca2+ transients seen in cells from subepicardium and mid-myocardium (McIntosh et al. 2000). These novel observations are supported by reports indicating that DADs in surface cells from rabbit papillary muscles (i.e. endocardium) and pronounced after-contractions in rat papillary muscles were more frequent in failing hearts (Heller, 1979; Vermeulen et al. 1994). Thus the subendocardium may be an important site for DADs, which may be the cause of arrhythmogenic events in failing myocardium. Shortened APDs observed in subendocardial cells in heart failure would indicate that EADs should be less likely in this region. In heart failure, M-cells may act as a depolarizing current source for adjacent subendocardial cells, if more widespread electrotonic equalization of action potential duration in the subendocardium is disrupted by reduced connexin expression (Anyukhovsky et al. 1996) or by interstitial fibrosis.
Recent work using animal models has focused on the link between calcium cycling within cardiomyocytes and the production of arrhythmias, in particular, aberrant Ca2+ leak via the ryanodine receptor (RyR2) during diastole and triggered arrhythmias (Lehnart et al. 2004). Abnormal Ca2+ leak via the RyR2 in heart failure is thought to be associated with the depletion of the accessory protein FKBP12.6 from the channel (Marx et al. 2000). This dissociation occurs during chronically elevated catecholamine levels (a common feature of heart failure patients) leading to persistent activation of cAMP-dependent signalling (Marx et al. 2000). One laboratory using FKBP12.6 knockout mice has correlated greater RyR2 Ca2+ leak with the increased incidence of exercise-induced arrhythmias and sudden cardiac death; however, a cellular mechanism linking these two observations is far from clear (Lehnart et al. 2004). The links between the phosphorylation of RyR2 and abnormal SR Ca2+ release and arrhythmias have been challenged by several studies (Jiang et al. 2000; Stange et al. 2003; Xiao et al. 2004), so the underlying molecular defects responsible for arrhythmic behaviour remain controversial.
Conditions for maintaining re-entry. Triggered activity may be responsible for initiating premature beats in the failing heart. However, a substrate for re-entry is essential for the development of sustained ventricular tachycardia or fibrillation. A number of clinical studies in patients with lower left ventricular ejection fraction have shown that the risk of sudden death is greater (Wilber et al. 1988; Goldman et al. 1993) and the ability of antiarrhythmic drugs to suppress arrhythmias is reduced (Meissner et al. 1988). In a rabbit model, ventricular tachycardia (VT) and fibrillation (VF) were more easily induced by extrastimuli in failing hearts (Pye & Cobbe, 1996) and VF threshold was reduced (Burton & Cobbe, 2001), suggesting that failing myocardium is a more favourable substrate for the development of arrhythmias than normal myocardium. The mechanisms responsible for these observations are not fully understood. The ‘wavelength theory’ of re-entry (Rensma et al. 1988) suggests that the likelihood of re-entry in tissue of given size is determined by the product of the conduction velocity and the refractory period of the tissue. Thus, areas of slowed conduction and shortened refractoriness may interact to increase the probability of re-entry. Abnormal connexin expression has been identified in animal models (Peters et al. 1997) and failing human heart (Peters et al. 1993), resulting in slowed intercellular conduction velocity.
Re-entry: dispersion of repolarization and refractoriness. The probability of re-entry may be enhanced by dispersion of action potential duration and effective refractory period. Previous work has shown that increased dispersion of repolarization, measured as an increase in the QT dispersion in the electrocardiogram, is a predictor of ventricular arrhythmias (Dani et al. 1979) and sudden death in patients in heart failure (Barr et al. 1994). An increased heterogeneity in duration of monophasic action potentials was recorded from the epicardial surface of the Langendorff-perfused failing heart during regular atrial pacing at 300 ms (Ng et al. 1997). While these discrepancies would be insufficient alone to sustain re-entry, they may facilitate the persistence of the arrhythmia. Electrical heterogeneity may be enhanced by abnormal connexin expression, resulting in a reduction in electrotonic current flow, which would otherwise tend to equalize action potential duration (Anyukhovsky et al. 1996).
Depressed and prolonged intracellular Ca2+ transients in failing hearts. Both amplitude and time course of the intracellular Ca2+ transient in isolated cells or muscle preparations are altered in animal models of heart failure and failing human myocardium (Gwathmey et al. 1987; Bing et al. 1991; Siri et al. 1991; Beuckelmann et al. 1992). In general, systolic [Ca2+] is lower than normal, and the duration of the Ca2+ transient is prolonged. These changes have been considered to be the basis of the mechanical abnormalities observed in heart failure (Morgan et al. 1990) and may also be linked to electrophysiological abnormalities. Prolonged Ca2+ transients on the epicardial surface of failing whole heart preparations at physiological stimulation rates were demonstrated (Ng et al. 1998). Furthermore, Ca2+ transient configuration changes were not homogeneous. By examining 15 sites sequentially on the epicardial surface of failing rabbit hearts, regions of abnormally long Ca2+ transient were shown to exist adjacent to regions with normal characteristics (Fig. 4). This inhomogeneity may contribute to the impairment of diastolic function in heart failure. There was a weak but statistically significant correlation between the Ca2+ transient duration and epicardial monophasic action potential duration measured at the same site at different times (Ng et al. 1998).
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The principal basis for reduced intracellular Ca2+ and contractile dysfunction observed in human heart failure and in most animal models is thought to be depressed SR function (Hasenfuss et al. 1997). Abnormalities in SR Ca2+ release and uptake lead to reduction in peak systolic [Ca2+] and lengthening of the duration of the Ca2+ transient, respectively. These changes will impair both the inotropic and the lusitropic properties of the myocardium. Although a variety of Ca2+ handling proteins are known to be affected, severe heart failure is associated with reduced RNA and protein levels of sarcoplasmic reticulum Ca2+ ATPase (SERCA2) and phospholamban (PLB) in the majority of animal models (Arai et al. 1994). An additional feature of these changes is an increase in the relative ratio of PLB to SERCA2 (Arai et al. 1994; Koss & Kranias, 1996). This change in stoichiometry would enhance the inhibitory effect of PLB on the remaining SERCA2, further depressing SR Ca2+ uptake. Reductions in SERCA2 (by 60%) and PLB (by 40%) in the left ventricular free wall in the rabbit infarct model were recently demonstrated by Currie et al. (1999). In the same paper, the phosphorylation state of the regulatory protein PLB was higher in failing myocardium compared with sham hearts, a feature that would stimulate the residual activity of SERCA2. The effect of the reduced abundance of SERCA2 and increase in PLB:SERCA2 ratio outweighed the stimulatory effect of PLB phosphorylation as reflected in the reduced Ca2+ uptake capacity of SR from failing rabbit heart. However, as suggested by a recent study, reduced SERCA2 activity may be pro-arrhythmic, since in these conditions the propagation of spontaneous intracellular Ca2+ waves (the cause of DADs) is more likely (O'Neill et al. 2004).
Region-specific changes of intracellular Ca2+ in heart failure
Work on isolated cells from a heart failure model has revealed a marked difference in the Ca2+ transient characteristics of subendocardial myocytes compared with M-cells and subepicardial myocytes. The shortened action potential duration described above (Fig. 3) is accompanied by a Ca2+ transient of shorter duration and a higher peak systolic [Ca2+] than normal (McIntosh et al. 2000). This behaviour would not be expected to have significant effects on global mechanical function, since depressed Ca2+ transients were observed in M-cell and subepicardial myocytes, which make up 85–90% of the ventricular myocardium. In contrast, this abnormality of subendocardial myocytes may have significant pro-arrhythmic effects. In support of this, Pogwizd (1995) showed that the subendocardial region was the site of premature ventricular complexes in a rabbit model of heart failure; separately (Vermeulen et al. 1994) demonstrated DADs in surface cells of papillary muscles from failing hearts. The larger than normal Ca2+ transients suggest an increased SR Ca2+ content in subendocardial cells, supported by reports in the literature on permeabilized (endocardial) trabeculae (Afzal & Dhalla, 1992; Denvir et al. 1996). The link between increased Ca2+ uptake by the SR and arrhythmic DADs has been made by a number of authors, but the link to EADs has yet to be established. Furthermore, the increased intracellular [Ca2+] may also contribute to the shortened APD in these cells via Ca2+-activated repolarizing currents.
Manipulation of sarcoplasmic reticulum proteins by adenoviral gene transfer
The importance of downregulation of SERCA2 expression in the genesis of the abnormalities of SR function in heart failure has been discussed above. If SERCA2 downregulation plays a key role in the mechanical and electrophysiological changes in heart failure, then specific restoration of SERCA2 levels to normal would be expected to correct the abnormalities in the Ca2+ transient, leading to improved systolic and diastolic function. For this reason, there is a worldwide interest in the SR as a target for therapeutic intervention in heart failure (Koss & Kranias, 1996). Hajjar et al. (1998) reported that PLB levels in the normal rat heart could be increased using specific adenoviral vectors. Overexpression of PLB resulted in reduced systolic pressure and rate of relaxation 2–7 days post-transfection. Earlier work using isolated myocytes showed that depressed function due to adenovirus-mediated PLB overexpression could be reversed by concomitant overexpression of SERCA2. This work illustrates the feasibility of the adenoviral transfection technique to specifically manipulate SR protein abundance and alter cardiac contractility. However, the experimental practicality of achieving high-efficiency myocardial gene expression in vivo by introduction of adenovirus constructs is controversial. Even allowing for its shortcomings, gene transfer remains an attractive tool to test the specific hypothesis that SERCA2 downregulation is a key molecular defect in heart failure and it may in the long term be of therapeutic use.
The contribution that SR Ca2+ release and uptake processes make to the overall cycling of Ca2+ of the myocyte is similar in human and rabbit heart (60%), whereas rat heart is dominated by SR Ca2+ processes. The general view is that upregulation of the Na+–Ca2+ exchanger occurs in rabbits and humans in heart failure (Studer et al. 1994; Litwin & Bridge, 1997). This may limit the ability of the restoration of SR function to improve contractile function. Furthermore, while myocardial upregulation of SERCA2 function may restore cardiac contractility, it might also result in supernormal SR function in areas (e.g. subendocardium) where it was already normal or even upregulated. Transgenic mice overexpressing SERCA type 2a exhibited improved cardiac function and Ca2+ handling (Sullivan et al. 1988; He et al. 1997; Baker et al. 1998; Goebbels et al. 1998). In neonatal rat cardiomyocytes with normal and depressed SERCA2a expression, adenovirus-mediated overexpression of SERCA2a resulted in enhanced SR Ca2+ uptake and accelerated decay of Ca2+ transients (Giannuzzi et al. 1993; Hajjar et al. 1997; Giordano et al. 1997). Furthermore, catheter-based transfection with an adenovirus encoding SERCA2a restored cardiac function in rats in transition to HF (Schmidt et al. 2000) and improved survival (Del Monte et al. 2001). In human cardiomyocytes isolated from end-stage failing hearts, adenovirus-mediated augmented expression of SERCA2a resulted in enhanced contractility and Ca2+ handling and increased survival (Del Monte et al. 1999; Chen et al. 2004), supposedly through an antiarrhythmic mechanism. A recent study used adenovirus-mediated gene transfer of SERCA1a into isolated rabbit ventricular cardiomyocytes. SERCA1a is a splice transcript of the SERCA1 gene (expressed in adult fast-twitch skeletal muscle; Teucher et al. 2004). This SERCA isoform has faster Ca2+ transport kinetics than SERCA2a (Sumbilla et al. 1999) and might achieve higher levels of SERCA activity than equivalent upregulation of SERCA2a (Loukianov et al. 1998). Therefore, SERCA1a may be a more suitable candidate for gene therapy. Teucher et al. (2004) demonstrated that dissociation between SR Ca2+ content and myocyte contractility occurs at high levels of SERCA overexpression (Fig. 5).
Myocytes expressing low levels of SERCA1a (MOI-10) showed enhanced shortening and intracellular Ca2+ transients and SR Ca2+ content. As shown in Fig. 5, with higher SERCA1a expression levels (MOI-50), myocytes exhibited further increases in SR Ca2+ uptake, relaxation rate and SR Ca2+ content, but showed depressed contraction amplitude and no Ca2+ transient enhancement versus control myocytes (Teucher et al. 2004).
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20% (Li et al. 1997). A second means by which increased SERCA expression can limit intracellular [Ca2+] ([Ca2+]i) is that it adds to cytosolic Ca2+ buffering. After troponin C (70 µmol l–1), the SR Ca2+ pump is the most prominent cytosolic Ca2+ buffer (50 µmol l–1), with equally high affinity (Pogwizd et al. 2001; Wisloff et al. 2002). Thus, a 50% increase in SR Ca2+ pump expression would compete for Ca2+ binding to troponin C, which is essential for contractile activation, and also limit the amplitude of the Ca2+ transient. Also, more SR Ca2+ pumps can increase the rate of SR Ca2+ uptake, but may not increase maximal SR Ca2+ load for a given [Ca2+]i (Shannon & Bers, 1997; Ginsburg et al. 1998; Shannon et al. 2002). This is because the SR Ca2+ ATPase can only build a [Ca2+] gradient (or potential energy) related to 
GATP (e.g. GSR-Pump
= 2RT ln([Ca2+]SR/[Ca2+]i) or [Ca2+]SR/[Ca2+]i
7000). This limiting gradient is only reached when Ca2+ leak is small compared with the forward pump rate (Slack et al. 1997) Thus, higher SR Ca2+ pump expression may allow closer approach towards this limit. It is notable that the diastolic [Ca2+]i was significantly lower and SR Ca2+ load significantly higher in SERCA versus Ad-LacZ and this may represent approach to this limiting [Ca2+]SR/[Ca2+]i gradient. Thus, at high SERCA levels, one may approach a maximal SR Ca2+ load, which more SERCA cannot further improve. Teucher et al. (2004) concluded that the dose of SERCA overexpression is critical for improved myocardial function. While increased SR Ca2+ pump expression can enhance SR Ca2+ content, Ca2+ transient amplitude and diastolic function, there may be an optimum, above which limiting factors prevent further increase in Ca2+ transients and can even reduce contraction. This illustrates physiological tuning where too much SERCA can limit Ca2+ transients and contraction by both buffering and removal of some cytosolic Ca2+ before adequate myofilament response (and contractility) is achieved. The optimal dose of SERCA overexpression may depend on endogenous levels of SERCA. Increasing SR Ca2+ pump function in failing hearts (with low functional SERCA expression) may be beneficial, but the same SERCA expression in myocardium with normal SERCA levels could be detrimental; one can add too much of a good thing. Therefore, use of SERCA for gene therapy in HF requires careful control of transfection efficiency and induced expression levels.
How does exercise modify the response of a heart to a myocardial infarction?
The effects of exercise training on left ventricle (LV) remodelling post-MI are controversial. In an early study of patients with extended anterior myocardial infarction Jugdutt (1985) found increased LV dilatation and decreased regional and global cardiac function following exercise. In contrast, recent studies suggest that physical training increases endurance capacity, attenuates LV dilatation, improves cardiac function and quality of life and reduces mortality in patients with heart failure (Sullivan et al. 1988; Goebbels et al. 1998). Similar disparity exists in data from animal models. Exercise after MI in rats has caused ventricular enlargement in three studies (Hammerman et al. 1983; Oh et al. 1993; Gaudron et al. 1994), with two studies describing a decrease in LV dilatation (Orenstein et al. 1995; Wisloff et al. 2002). The reason for this lack of consensus is unknown; one possible variable is the form of exercise training undertaken. Treadmill running generally increases SERCA2 activity (Tate et al. 1996) and NCX (Tibbits et al. 1989; Wisloff et al. 2002), in conjunction with improvements in myocyte contractility (Wisloff et al. 2002). Zhang and co-workers reported that in post-MI rats, myocytes were larger and had a depressed Ca2+ transient along with decreased SERCA2 and PLB expression. Intense anaerobic training post-MI significantly restored cell length (Zhang et al. 1998) and systolic [Ca2+] but further decreased SERCA2 and PLB levels (Zhang et al. 2000). Recently, Wisloff et al. (2002) have examined the effects of aerobic endurance training in normal animals and in animals with a healed infarct scar (Wisloff et al. 2002). This study used a treadmill training regimen analogous to that used in human exercise training protocols. In line with other studies, the MI caused reduced Ca2+ transient size and reduced contractility. A standardized 8 week training regimen was applied to animals with a MI and clear signs of heart failure. At the end of the training period, the cardiac performance had been restored to normal across the full range of parameters examined in the study, including increased cardiomyocyte contractility, SERCA2 and NCX protein content (Fig. 6B) and improved myofilament sensitivity. Interestingly, the cellular hypertrophy observed as a result of the MI was partly reversed by exercise training (Fig. 6A). This suggests that the improved cardiac performance induced by exercise causes ‘reverse remodelling’. While exercise clearly restored cardiac mechanical performance, these studies did not examine whether the pro-arrhythmic status of the heart had been altered. This awaits further investigation.
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Heart failure as a result of a MI is a common condition with a poor prognosis. The adaptive changes in the surviving myocardium appear to be insufficient in terms of both mechanical/contractile performance and electrical stability. The modifications of the underlying myocardial physiology are complex, varying across the different layers within the wall of the ventricle. Two therapeutic strategies are briefly discussed, as outlined here. (i) Attempting to restore contractility by alteration of the expression of a single protein (e.g. SERCA) could potentially reverse both mechanical and electrical abnormalities. However, experimental data involving the upregulation of SERCA suggest that the therapeutic range of this approach is narrow. (ii) Alternatively, exercise appears to improve cardiac performance in heart failure by normalizing a number of aspects of myocardial physiology. This approach deserves further investigation, both in terms of the details of the effects on myocardial physiology and the underlying mechanisms.
Footnotes
This is the 2005/2006 G. L. Brown Prize Lecture, which was given by Professor G. L. Smith at the Universities of Bristol, Birmingham, Cardiff, King's College London, University College Cork, Manchester and Dundee.
References
Afzal N & Dhalla NS (1992). Differential changes in left ventricular and right ventricular SR calcium transport in congestive heart failure. Am J Physiol Heart Circ Physiol 262, H868–H874.
Allen DG, Eisner DA, Pirolo JS & Smith GL (1985). The relationship between intracellular calcium and contraction in calcium overloaded ferret papillary muscles. J Physiol 364, 169–182.
Antzelevitch C, Sicouri S, Litovsky SH, Lukas A, Krishnan SC, Di Diego JM, Gintant GA & Liu DW (1991). Heterogeneity within the ventricular wall. Electrophysiology and pharmacology of epicardial, endocardial, and M cells. Circ Res 69, 1427–1449.
Anyukhovsky EP, Sosunov EA & Rosen MR (1996). Regional differences in electrophysiological properties of epicardium, midmyocardium, and endocardium. In vitro and in vivo correlations. Circulation 94, 1981–1988.
Arai M, Matsui H & Periasamy M (1994). Sarcoplasmic reticulum gene expression in cardiac hypertrophy and heart failure. Circ Res 74, 555–563.
Aronson R & Ming Z (1993). Cellular mechanisms of arrhythmias in hypertrophied and failing myocardium. Circulation 87, 76–83.
Baker LC, Choi BR, Koren G & Salama G (1998). Optical mapping of reentrant VT in transgenic mice. Circulation 98, (Suppl DI 744 Abstract).
Barr CS, Naas A, Freeman M, Lang CC & Struthers AD (1994). QT dispersion and sudden unexpected death in chronic heart failure. Lancet 343, 327–329. [See comments in Lancet 343, 742.][CrossRef][Medline]
Barrett JN, Magleby KL & Pallotta BS (1987). Properties of single calcium-activated potassium channels in cultured rat muscle. J Physiol 331, 211–230.
Beuckelmann DJ, Nabauer M & Erdmann E (1992). Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure. Circulation 85, 1046–1055.
Beuckelmann DJ, Nabauer M & Erdmann E (1993). Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ Res 73, 379–385.
Bing OHL, Brooks WW, Conrad CH, Sen S, Perreault CL & Morgan JP (1991). Intracellular calcium transients in myocardium from spontaneously hypertensive rats during the transition to heart failure. Circ Res 68, 1390–1400.
Boutjdir M & El-Sherif N (1991). Pharmacological evaluation of early afterdepolarisations induced by sea anemone toxin (ATXII) in dog heart. Cardiovasc Res 25, 815–819.[Medline]
Brown LA & Harding SE (1992). The effect of pertussis toxin on β-adrenoceptor responses in isolated cardiac myocytes from noradrenaline-treated guinea-pigs and patients with cardiac failure. Br J Pharmacol 106, 115–122.[Medline]
Burton FL & Cobbe SM (2001). Dispersion of ventricular repolarization and refractory period. Cardiovasc Res 50, 10–23.
Burton FL, McPhaden AR & Cobbe SM (2000). Ventricular fibrillation threshold and local dispersion of refractoriness in isolated rabbit hearts with left ventricular dysfunction. Basic Res Cardiol 95, 359–367.[CrossRef][Medline]
Chen Y, Escoubet B, Prunier F, Amour J, Simonides WS, Vivien B, Lenoir C, Heimburger M, Choqueux C, Gellen B, Riou B, Michel JB, Franz WM & Mercadier JJ (2004). Constitutive cardiac overexpression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase delays myocardial failure after myocardial infarction in rats at a cost of increased acute arrhythmias. Circulation 109, 1898–1903.
Connolly SJ, Cairns J, Gent M, Roberts R, Yusuf S, Julian DG, Camm AJ, Frangin G, Janse MJ, Munoz A, Schwartz PJ, Simon P, Rosenbaum MB, Elizari MV, Cagide A, Girotti LA, Martinez JM, Carbajalles J, Scapin O & Garguichevich J (1997). Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet 350, 1417–1424.[CrossRef][Medline]
Coronel R, Opthof T, Taggart P, Tytgat J & Veldkamp M (1998). Differential electrophysiology of repolarisation from clone to clinic. Cardiovasc Res 33, 503–517.
Cowley AJ, Fullwood LJ, Muller AF, Stainer K, Skene AM & Hampton JR (1991). Exercise capability in heart failure: is cardiac output important after all? Lancet 337, 771–773.[CrossRef][Medline]
Currie S & Smith GL (1999). Enhanced phosphorylation of phospholamban and downregulation of SERCA2 in cardiac sarcoplasmic reticulum from rabbits with heart failure. Cardiovasc Res 41, 135–146.
Damiano BP & Rosen MR (1984). Effects of pacing on triggered activity induced by early afterdepolarisations. Circulation 69, 1013–1025.
Dani AM, Cittadini A & Inesi G (1979). Calcium transport and contractile activity in dissociated mammalian heart cells. Am J Physiol Cell Physiol 237, C147–C155.
Deferrari GM, Viola MC, Damato E, Antolini R & Forti S (1995). Distinct patterns of calcium transients during early and delayed afterdepolarizations induced by isoproterenol in ventricular myocytes. Circulation 91, 2510–2515.
Del Monte F, Harding SE, Schmidt U, Matsui T, Kang ZB, Dec GW, Gwathmey JK, Rosenzweig A & Hajjar RJ (1999). Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. Circulation 100, 2308–2311.
Del Monte F, Williams E, Lebeche D, Schmidt U, Rosenzweig A, Gwathmey JK, Lewandowski ED & Hajjar RJ (2001). Improvement in survival and cardiac metabolism after gene transfer of sarcoplasmic reticulum Ca2+-ATPase in a rat model of heart failure. Circulation 104, 1424–1429.
Denvir MA, MacFarlane NG, Miller DJ & Cobbe SM (1996). Enhanced SR function in saponin-treated ventricular trabeculae from rabbits with heart failure. Am J Physiol Heart Circ Physiol 271, H850–H859.
Diaz ME, Cook SJ, Chamunorwa JP, Trafford AW, Lancaster MK, O'Neill SC & Eisner DA (1996). Variability of spontaneous Ca2+ release between different rat ventricular myocytes is correlated with Na+-Ca2+ exchange and [Na+]i. Circ Res 78, 857–862.
Drouin E, Charpentier F & Gauthier C (1996). 
-Adrenergic stimulation induces early afterdepolarisations in ferret Purkinje fibres. J Cardiovasc Pharmacol 27, 320–326.[CrossRef][Medline]
Echt DS, Liebson PR, Mitchell LB, Peters RW, Obiasmanno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, Huther ML & Richardson DW (1991). Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 324, 781–788.[Abstract]
Gaudron P, Hu K, Schamberger R, Budin M, Walter B & Ertl G (1994). Effect of endurance training early or late after coronary artery occlusion on left ventricular remodeling, hemodynamics, and survival in rats with chronic transmural myocardial infarction. Circulation 89, 402–412.
Giannuzzi P, Tavazzi L, Temporelli PL, Corra U, Imparato A, Gattone M, Giordano A, Sala L, Schweiger C & Malinverni C (1993). Long-term physical training and left ventricular remodeling after anterior myocardial infarction: results of the Exercise in Anterior Myocardial Infarction (EAMI) trial. EAMI Study Group. J Am Coll Cardiol 22, 1821–1829.[Abstract]
Ginsburg KS, Weber CR & Bers DM (1998). Control of maximum sarcoplasmic reticulum Ca load in intact ferret ventricular myocytes. Effects of thapsigargin and isoproterenol. J Gen Physiol 111, 491–504.
Giordano FJ, He H, McDonough P, Meyer M, Sayen MR & Dillmann WH (1997). Adenovirus-mediated gene transfer reconstitutes depressed sarcoplasmic reticulum Ca2+-ATPase levels and shortens prolonged cardiac myocyte Ca2+ transients. Circulation 96, 400–403.
Goebbels U, Myers J, Dziekan G, Muller P, Kuhn M, Ratte R & Dubach P (1998). A randomized comparison of exercise training in patients with normal vs reduced ventricular function. Chest 113, 1387–1393.[CrossRef][Medline]
Goldman S, Johnson G, Cohn JN, Cintron G, Smith R & Francis G (1993). Mechanism of death in heart failure: the vasodilator-heart failure trials. Circ 87, 24–31.
Grossman W (1990). Diastolic dysfunction and congestive heart failure. Circulation 81, III1–III7.[Medline]
Gwathmey JK, Copelas L, MacKinnon R, Schoen FJ, Feldman MD, Grossman W & Morgan JP (1987). Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ Res 61, 70–76.
Hajjar RJ, Kang JX, Gwathmey JK & Rosenzweig A (1997). Physiological effects of adenoviral gene transfer of sarcoplasmic reticulum calcium ATPase in isolated rat myocytes. Circulation 95, 423–429.
Hajjar RJ, Schmidt U, Matsui T, Guerrero L, Lee K-H, Judith K & Gwathmey JK (1998). Modulation of ventricular function through gene transfer in vivo. Proc Nat Acad Sci U S A 95, 5251–5256.
Hammerman H, Schoen FJ & Kloner RA (1983). Short-term exercise has a prolonged effect on scar formation after experimental acute myocardial infarction. J Am Coll Cardiol 2, 979–982.[Abstract]
Han J & Moe GK (1964). Nonuniform recovery of excitability in ventricular muscle. Circ Res 14, 44–60.
Hasenfuss G (1998). Animal models of human cardiovascular disease, heart failure and hypertrophy. Cardiovasc Res 39, 60–76.
Hasenfuss G, Meyer M, Schillinger W, Preuss M, Pieske B & Just H (1997). Calcium handling proteins in the failing human heart. Basic Res Cardiol 92, 87–93.[CrossRef][Medline]
He H, Giordano FJ, Hilal-Dandan R, Choi D-J, Rockman HA, McDonough P, Bluhm WF, Meyer M, Sayen MR, Swanson E & Dillmann WH (1997). Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation. J Clin Invest 100, 380–389.[Medline]
Heller LJ (1979). Augmented aftercontractions in papillary muscles from rats with cardiac hypertrophy. Am J Physiol Heart Circ Physiol 237, H649–H654.
Hiraoka M & Kawano S (1989). Calcium-sensitive and insensitive transient outward current in rabbit ventricular myocytes. J Physiol 410, 187–212.
January CT & Riddle JM (1989). Early afterdepolarisations: mechanism of induction and block: a role for L-type Ca2+ current. Circ Res 64, 977–990.
Jiang M, Lokuta AJ, Wolff MR, Haworth RA & Valdivia HH (2000). Depression of ryanodine receptor density, but not function, may decrease calcium release in heart failure (HF). Biophys J 78, 376A.
Jugdutt B (1985). Delayed effects of early infarct-limiting therapies on healing after myocardial infarction. Circulation 72, 907–914.
Koss KL & Kranias EG (1996). Phospholamban: a prominent regulator of myocardial contractility. Circ Res 79, 1059–1063.
Kuo CS, Munakata K, Reddy CP & Surawicz B (1983). Characteristics and possible mechanism of ventricular arrhythmia dependent on the dispersion of action potential durations. Circulation 67, 1356–1367.
Lehnart SE, Wehrens XH, Laitinen PJ, Reiken SR, Deng SX, Cheng Z, Landry DW, Kontula K, Swan H & Marks AR (2004). Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak. Circulation 109, 3208–3214.
Li P, Hofmann PA, Li B, Malhotra A, Cheng W, Sonnenblick EH, Meggs LG & Anversa P (1997). Myocardial infarction alters myofilament calcium sensitivity and mechanical behavior of myocytes. Am J Physiol Heart Circ Physiol 272, H360–H370.
Litwin SE & Bridge JHB (1997). Enhanced Na+-Ca2+ exchange in the infarcted heart: implications for excitation-contraction coupling. Circ Res 81, 1083–1093.
Loukianov E, Ji Y, Grupp IL, Kirkpatrick DL, Baker DL, Loukianova T, Grupp G, Lytton J, Walsh RA & Periasamy M (1998). Enhanced myocardial contractility and increased Ca2+ transport function in transgenic hearts expressing the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+-ATPase. Circ Res 83, 889–897.
Luu M, Stevenson WG, Stevenson LW, Baron K & Walden J (1989). Diverse mechanisms of unexpected cardiac arrest in advanced heart failure. Circulation 80, 1675–1680.
McDonagh TA, Morrison CE, Lawrence A, Ford I, Tunstall-Pedoe H, McMurray JJ & Dargie HJ (1997). Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet 350, 829–833.[CrossRef][Medline]
McIntosh MA, Cobbe SM, Kane KA & Rankin AC (1998). Action potential prolongation and potassium currents in left ventricular myocytes isolated from hypertrophied rabbit hearts. J Mol Cell Cardiol 30, 43–53.[CrossRef][Medline]
McIntosh MA, Cobbe SM & Smith GL (2000). Heterogeneous changes in action potential duration and intracellular Ca2+ in left ventricular myocyte sub-types from rabbits with heart failure. Cardiovasc Res 45, 397–409.
McIntosh MA, Rankin AC & Cobbe SM (1996). Comparison of cardiac action potential characteristics in two models of left ventricular hypertrophy. J Mol Cell Cardiol 28, P36.
McMurray JJV, McDonagh TA, Morrison CE & Dargie HJ (1993). Trends in hospitalization for heart failure in Scotland 1980–90. Eur Heart J 14, 1158–1162.
Marban E & Robinson SW (1986). Mechanisms of arrhythmogenic delayed and early after depolarizations in ferret ventricular muscle. J Clin Invest 78, 1185–1192.[Medline]
Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N & Marks AR (2000). PKA phosphorylation dissociates FKB12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101, 365–376.[CrossRef][Medline]
Maurice JP, Kypson AP, Skaer CA & Koch WJ (1997). β-Adrenergic signaling characteristics in an infarct heart failure model. Circulation 96, A2024.
Mazzanti M & DiFrancesco D (1998). Intracellular Ca modulates K-inward rectification in cardiac myocytes. Pflugers Arch 413, 322–324.[CrossRef]
Meissner MD, Kay HR, Horowitz LN, Spielman SR, Greenspan AM & Kutalek SP (1988). Relation of acute antiarrhythmic drug efficacy to left ventricular function in coronary artery disease. Am J Cardiol 61, 1050–1055.[CrossRef][Medline]
Moller M (1996). DIAMOND antiarrhythmic trials. Danish Investigations of Arrhythmia and Mortality on Dofetilide. Lancet 348, 1597–1598.[Medline]
Morgan JP, Erny RE, Allen PD, Grossman W & Gwathmey JK (1990). Abnormal intracellular calcium handling, a major cause of systolic and diastolic dysfunction in ventricular myocardium from patients with heart faillure. Circulation 81 (suppl. II), 21–32.
Narang R, Cleland JGF, Erhardt L, Ball SG, Coats AJS, Cowley AJ, Dargie HJ, Hall AS, Hampton JR & Poolewilson PA (1996). Mode of death in chronic heart failure: a request and proposition for more accurate classification. Eur Heart J 17, 1390–1403.
Ng GA, Cobbe SM & Smith GL (1997). Asynchronous ventricular activation contributes toward the contractile dysfunction in heart failure. Eur Heart J 18, P2931.
Ng GA, Cobbe SM & Smith GL (1998). Non-uniform prolongation of intracellular Ca2+ transients recorded from the epicardial surface of isolated hearts from rabbits with heart failure. Cardiovasc Res 37, 489–502.
Ng GA, Hicks MN, Cobbe SM & Smith GL (2002). Depressed inotropic response to increased preload in rabbit hearts with left-ventricular dysfunction induced by chronic myocardial infarction. Pflugers Arch 444, 513–522.[CrossRef][Medline]
Nitta J, Furukawa T, Marumo F, Sawanobori T & Hiraoka M (1994). Subcellular mechanism for Ca2+-dependent enhancement of delayed rectifier K+ current in isolated membrane patches of guinea pig ventricular myocytes. Circ Res 74, 96–104.
Oh BH, Ono S, Rockman HA & Ross J Jr (1993). Myocardial hypertrophy in the ischemic zone induced by exercise in rats after coronary reperfusion. Circulation 87, 598–607.
O'Neill SC, Miller L, Hinch R & Eisner DA (2004). Interplay between SERCA and sarcolemmal Ca2+ efflux pathways controls spontaneous release of Ca2+ from the sarcoplasmic reticulum in rat ventricular myocytes. J Physiol 559, 121–128.
Orenstein TL, Parker TG, Butany JW, Goodman JM, Dawood F, Wen WH, Wee L, Martino T, McLaughlin PR & Liu PP (1995). Favorable left ventricular remodeling following large myocardial infarction by exercise training. Effect on ventricular morphology and gene expression. J Clin Invest 96, 858–866.[Medline]
Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, Dibianco R, Zeldis SM et al. (1991). Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group [see comments]. N Engl J Med 325, 1468–1475.[Abstract]
Perry G, Brown E, Thornton R, Shiva T, Hubbard J, Reddy KR et al. (1997). The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med 336, 525–533.
Peters NS (1996). New insights into myocardial arrhythmogenesis: distribution of gap-junctional coupling in normal, ischaemic and hypertrophied human hearts. Clin Sci (Lond) 90, 447–452.[Medline]
Peters NS, Coromilas J, Severs NJ & Wit AL (1997). Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation 95, 988–996.
Peters NS, Green CR, Poole-Wilson PA & Severs NJ (1993). Reduced content of connexin43 gap junctions in ventricular myocardium from hypertrophied and ischemic human hearts. Circulation 88, 864–875.
Pieske B, Schlotthauer K, Schattmann J, Beyersdorf F, Martin J, Just H & Hasenfuss G (1997). Ca2+-dependent and Ca2+-independent regulation of contractility in isolated human myocardium. Basic Res Cardiol 92, 75–86.[Medline]
Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J & Gatlin M (2003). Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 348, 1309–1321.
Pogwizd SM (1995). Nonreentrant mechanisms underlying spontaneous ventricular arrhythmias in a model of nonischemic heart-failure in rabbits. Circulation 92, 1034–1048.
Pogwizd SM, Schlotthauer K, Li L, Yuan W & Bers DM (2001). Arrhythmogenesis and contractile dysfunction in heart failure: roles of sodium-calcium exchange, inward rectifier potassium current, and residual β-adrenergic responsiveness. Circ Res 88, 1159–1167.
Poole-Wilson PA (1993). Relation of pathophysiologic mechanisms to outcome in heart failure. J Am Coll Cardiol 22, 22A–29A.[Medline]
Priori SG & Corr PB (1990). Mechanisms underlying early and delayed afterdepolarisations induced by catecholamines. Am J Physiol Heart Circ Physiol 258, H1796–H1805.
Pye MP, Black M & Cobbe SM (1996). Comparison of in vivo and in vitro haemodynamic function in experimental heart failure: use of echocardiography. Cardiovasc Res 31, 873–881.[CrossRef][Medline]
Pye MP & Cobbe SM (1996). Arrhythmogenesis in experimental models of heart failure: the role of increased load. Cardiovasc Res 32, 248–257.
Reddy S, Benatar D & Gheorghiade M (1997). Update on digoxin and other oral positive inotropic agents for chronic heart failure. Curr Opin Cardiol 12, 233–241.[Medline]
Rensma PL, Allessie MA, Lammers WJEP, Bonke FIM & Schalij MJ (1988). Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs. Circ Res 62, 395–410.
Schmidt U, Del Monte F, Miyamoto MI, Matsui T, Gwathmey JK, Rosenzweig A & Hajjar RJ (2000). Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca2+-ATPase. Circulation 101, 790–796.
Shannon TR & Bers DM (1997). Assessment of intra-SR free [Ca] and buffering in rat heart. Biophys J 73, 1524–1531.
Shannon TR, Ginsburg KS & Bers DM (2002). Quantative assessment of the SR Ca2+ leak-load relationship. Circ Res 91, 594–600.
Shipsey SJ, Bryant SM & Hart G (1997). Effects of hypertrophy on regional action potential characteristics in the rat left ventricle: a cellular basis for T-wave inversion? Circulation 96, 2061–2068.
Siri FM, Krueger J, Nordin C, Ming Z & Aronson RS (1991). Depressed intracellular calcium transients and contraction in myocytes from hypertrophied and failing guinea-pig hearts. Am J Physiol Heart Circ Physiol 261, H514–H530.
Slack JP, Grupp IL, Luo W & Kranias EG (1997). Phospholamban ablation enhances relaxation in the murine soleus. Am J Physiol Cell Physiol 273, C1–C6.
Stange M, Xu L, Balshaw D, Yamaguchi N & Meissner G (2003). Characterization of recombinant skeletal muscle (Ser-2843) and cardiac muscle (Ser-2809) ryanodine receptor phosphorylation mutants. J Biol Chem 278, 51693–51702.
Studer R, Reinecke H, Bilger J, Eschenhagen T, Bohm M & Hasenfuss G (1994). Gene expression of the Na+-Ca2+ exchanger in end-stage human heart failure. Circ Res 75, 443–453.
Sullivan MJ, Higginbotham MB & Cobb FR (1988). Exercise training in patients with severe left ventricular dysfunction. Hemodynamic and metabolic effects. Circulation 78, 506–515.
Sumbilla C, Cavagna M, Zhong L, Ma H, Lewis D, Farrance I & Inesi G (1999). Comparison of SERCA1 and SERCA2a expressed in COS-1 cells and cardiac myocytes. Am J Physiol Heart Circ Physiol 277, H2381–H2391.
Szabo G, Sweidan R, Rajagopalan CV & Lazzara R (1994). Role of Na2+:Ca2+ exchange current in Cs+-induced early afterdepolarisations in Purkinje fibres. J Cardiovasc Electrophysiol 5, 933–944.[Medline]
Tate CA, Helgason T, Hyek MF, McBride RP, Chen M, Richardson MA & Taffet GE (1996). SERCA2a and mitochondrial cytochrome oxidase expression are increased in hearts of exercise-trained old rats. Am J Physiol Heart Circ Physiol 271, H68–H72.
Teucher N, Prestle J, Seidler T, Currie S, Elliott EB, Reynolds DF, Schott P, Wagner S, Kogler H, Inesi G, Bers DM, Hasenfuss G & Smith GL (2004). Excessive sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression causes increased sarcoplasmic reticulum Ca2+ uptake but decreases myocyte shortening. Circulation 110, 3553–3559.
Tibbits GF, Kashihara H & O'Reilly K (1989). Na+-Ca2+ exchange in cardiac sarcolemma: modulation of Ca2+ affinity by exercise. Am J Physiol Cell Physiol 256, C638–C643.
Trafford AW, Diaz ME & Eisner DA (1998). Ca-activated chloride current and Na-Ca exchange have different timecourses during sarcoplasmic reticulum Ca release in ferret ventricular myocytes. Pflugers Arch 435, 743–745.[CrossRef][Medline]
) and after (•) inflation of an intraventricular balloon to 40 mmHg. Median, quartiles and range for each group are indicated. The VF threshold was significantly lower at 0 mmHg (P < 0.05) in the HF group (ejection fraction < 45%) compared with sham hearts. The VF threshold in control hearts fell significantly (P < 0.01) postinflation. The VF threshold was measured as the minimal current (in mA) of a pulse train of stimuli (10 constant current pulses, 4 ms duration, 10 ms apart) applied to the left ventricle via an epicardial electrode that induces VF. Adapted from 
