SERCA2a Activity and Arrhythmogenesis

The choice of species is particularly important for investigation of the potential arrhythmogenic effects of stimulation of SERCA2a activity through phospholamban depletion. Mouse myocardium is heavily dependent on SR Ca2+, and it is well known that mouse myocytes show a high degree of spontaneous Ca2+ release from the SR. Human or rabbit myocytes can maintain an unchanged contraction amplitude when SR function is completely inhibited pharmacologically if the stimulation frequency is not too high (28,29), whereas contraction in mouse myocytes is abolished by the same maneuver. Additionally, the action potential of the mouse is extremely short compared to human (or rabbit) and lacks the plateau related to L-type Ca2+ channel activation. Probably for these reasons, among others, little note has been made of arrhythmias in the PLB-KO mouse. Alterations in the SR Ca2+ release channel and the P-adrenoceptor number in this model also complicate interpretation of phenomena (24,30).

Investigations have been done on rabbit myocytes with adenovirus using either phospholamban antisense or SERCA2a overexpression to increase SERCA2a activity. Ca2+ levels in the SR are raised by 50-80% (31,32), and this in itself might be expected to increase the incidence of spontaneous Ca2+ release, but no such increase was observed. The greater survival of the myocytes in culture and their ability to withstand high stimulation frequencies without diastolic contracture suggested that the beneficial effect of lowering diastolic Ca2+ outweighed the influence of SR load (31).

Even if not arrhythmogenic per se, increased SR Ca2+ might be predicted to potentiate the arrhythmic effects of catecholamines. This is of particular concern because the final target of the gene transfer is failing human heart, which is prone to arrhythmias because of both changes in the myocyte (e.g., prolonged duration of action potential) and in the myocardium (e.g., areas of necrosis) and is under constant sympathetic tone. Several distinct classes of catecholamine-dependent arrhythmias can be detected in the contracting isolated myocyte, and these are thought to have parallels in the myocardium in vivo. First, P-adrenoceptor agonists produce or accentuate early aftercontractions/afterdepolarizations. These are observed at isoproterenol concentrations below maximum and do not necessarily disrupt stimulated contractions. The extra contraction is close to the main beat and can initially be observed as a second, long phase of relaxation; the associated afterdepolar-ization occurs before repolarization, often during the plateau phase of the action potential. Reactivation of the L-type Ca2+ channel during the plateau is a likely mechanism, although some reverse-mode Na+/Ca2+ exchange might be involved (33). Prolongation of the action potential potentiates aftercontractions, and this accounts for an increased incidence of torsades de pointes (their in vivo correlate [34]) in heart failure or long QT syndrome.

Strikingly, SERCA2a overexpression or phospholamban depletion not only did not exacerbate early aftercontractions, but actually reduced their incidence in rabbit or human myocytes (16,22,31) (Fig. 3). This suggests that the effect of ^-adrenoceptor stimulation to increase the open probability of the L-type Ca2+ channel is central to the development of catecholamine-induced aftercontractions. Part of the mechanism for the decrease in aftercontractions in myocytes overexpressing SERCA2a may have been a reduction in the duration of action potential (32).

In contrast to the aftercontractions, at high isoproterenol concentrations, contraction in the myocytes is frequently disrupted by arrhythmias, indicating a calcium overload state, and these arrhythmias are characterized by disorganized contraction, loss of synchronization with the stimulation pulse, and waves of contraction likely resulting from spontaneous calcium release from the SR. These arrhythmias have more in common with delayed afterdepolarizations in their occurrence and calcium dependence (33). However, even these arrhythmias were slightly reduced in phospholamban-deficient or SERCA2a-overexpressing rat myocytes (16). This indicates that the higher SR calcium load has not made the cells more sensitive to the arrhythmic effects of P-adrenoceptor stimulation.

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