Kr and IKs Are Involved in Acquired LQT Syndrome

Although a number of different genetic defects can give rise to LQT syndrome, in most cases the disorder is not inherited but acquired. As described above, repolarization of the cardiac action potential results from activation of IKr and IKs and mutations in the genes that encode these channels result in long QT syndrome. It is therefore not unexpected that drugs which block IKr and IKs currents prolong the cardiac action potential and induce long QT syndrome. Among these are class III antiarrthymic agents such as sotalol, dofetilide and quinidine, which selectively block IKr. Although it appears ironic that drugs used to treat cardiac arrythmias should themselves be arrythmogenic and cause significant mortality, it is worth noting that there are multiple types of cardiac arrthymia and that these may have different causes and require different therapy. The class III antiarrthymic drugs, for example, are effective against re-entrant arrythmias. Hypokalaemia and bradycardia are additional precipitating factors in drug-induced LQT syndrome.

The K+ sensitivity of HERG (IKr) may be of importance in acquired long QT syndrome. External K+ ions accumulate in the space between cardiac muscle fibres when action potential activity is high, as at rapid heart rates. This enhances HERG currents, shortening the action potential and enabling more rapid heart rates to be achieved. Modest hypokalaemia is a common clinical problem and would be expected to reduce HERG currents, thus lengthening the cardiac action potential. Class III anti-arrhythmic agents also tend to lengthen the cardiac action potential. By themselves, neither hypokalaemia, nor anti-arrhythmic agents, prolong the action potential sufficiently to trigger torsade de pointes, but in combination they can be lethal. It has been suggested that mild elevation of blood K+ levels may reduce the incidence of side-effects in anti-arrhythmic therapy (Yang and Roden, 1996). Indeed, in patients with mutations in HERG (LQT2), increasing plasma K+ concentration by ~1.5 mM caused a marked improvement of ventricular action potential repolarization, shortening the QT interval by ~25% (Compton et al, 1996).

Sudden cardiac death is also associated with the antihistamine H1-receptor antagonists terfenidine and astemizole. These drugs are very potent blockers of IKr (HERG) and cause a prolonged action cardiac potential and QT interval, early after-depolarizations and torsade de pointes (Salata et al., 1995). In most people, terfenidine does not produce cardiac problems as it is rapidly broken down in the liver and its metabolite, terfenidine carboxylate, does not block IKr : as the drug is taken orally, it will encounter the liver before it ever reaches the heart. Those individuals with liver disease, or who are deficient in the oxidative P-450 enzymes that break down terfenidine, or who are coadministered drugs which inhibit these enzymes (such as ketoconazole and macrolide antibiotics), or who take an overdose of terfenidine, are at risk of developing torsade de pointes. The drug is now only available on prescription in the United Kingdom.

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FIGURE 6.6 TEEPEE ARCHITECTURE OF THE KcsA CHANNEL Ribbon representation illustrating the inverted teepee-like structure formed by the four S2 a-helices of the bacterial KscA channel (inner helices, shown in red). The four pore helices (white) are slotted between them and line the upper part of the structure. The pictures form a stereo pair that can be used to give a 3-dimensional image of the channel structure. From Doyle et al. (1998).

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FIGURE 6.7 KcsA STRUCTURE

Two subunits of KscA are shown. The outer helices are the SI domains, and the inner helices the S2 domains. Mutations in the Shaker Kv channel that affect the pore properties have been mapped onto their equivalent positions in the KscA sequence and are shown in colour. Mutation of any of the white side chains alters the affinity of block by charybdotoxin or agitoxin2. Changing the yellow side chains affects the block by extracellular TEA+: thus, this is the external TEA+ binding site. The orange side chains form the internal TEA+ binding site. If the green side chains are mutated to cysteine they are affected by intracellular thiol reagents regardless of whether the channel is open or not, while the pink side chains are modified only when the channel is open. This suggests that the channel gate must lie somewhere between these two sets of residues. The red side chains (GYG) are essential for K+ selectivity and form part of the selectivity filter. From Doyle et al. (1998).

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