Long QT syndrome and anaesthesia

Abstract

Long QT syndrome (LQTS) is an arrhythmogenic cardiovascular disorder resulting from mutations in cardiac ion channels. LQTS is characterized by prolonged ventricular repolarization and frequently manifests itself as QT interval prolongation on the electrocardiogram (ECG). The age at presentation varies from in utero to adulthood. The majority of symptomatic events are related to physical activity and emotional stress. Although LQTS is characterized by recurrent syncope, cardiac arrest, and seizure-like episodes, only about 60% of patients are symptomatic at the time of diagnosis.3Ackerman MJ The long QT syndrome: ion channel diseases of the heart.Mayo Clin Proc. 1998; 73: 250-269Abstract Full Text Full Text PDF PubMed Google Scholar The clinical features of LQTS result from a peculiar episodic ventricular tachyarrhythmia called ‘torsade de pointes’. ‘Twisting of the points’ describes the typical sinusoidal twisting of the QRS axis around the isoelectric line of the ECG. Usually torsade de pointes start with a premature ventricular depolarization, followed by a compensatory pause. The next sinus beat often has a markedly prolonged QT interval and abnormal T wave. This is followed by a ventricular tachycardia that is characterized by variation in the QRS morphology, and a constantly changing R-R interval (Fig. 1). The ‘short-long-short’ cycle length sequence heralding torsade de pointes is a hallmark of LQTS. Commonly, the episode of torsade de pointes is self-terminating, producing a syncopal episode or pseudo-seizure, secondary to the abrupt decrease in cerebral blood flow. The majority of episodes of sudden death in LQTS result from ventricular fibrillation triggered by torsade de pointes, although the mechanism of this deterioration is unknown. Traditionally, LQTS has been classified as either familial (inherited) or acquired. However, it is likely that many patients with previously labelled acquired LQTS carry a silent mutation in one of the genes responsible for congenital LQTS.22Chevalier P Rodriguez C Bontemps L et al.Non-invasive testing of acquired long QT syndrome: evidence for multiple arrhythmogenic substrates.Cardiovasc Res. 2001; 50: 386-398Crossref PubMed Scopus (0) Google Scholar 119Yang P Kanki H Drolet B et al.Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.Circulation. 2002; 105: 1943-1948Crossref PubMed Scopus (0) Google Scholar The evidence for this hypothesis has been gradually emerging over the past few years. It is important for anaesthetists to be aware of this concept, as it means that a much higher proportion of the general population may be affected by asymptomatic mutations in genes encoding cardiac ion channels than was thought previously. The prevalence of LQTS in developed countries may be as high as 1 per 1100–3000 of the population.32Fukushige T Yoshinaga M Shimago A et al.Effect of age and overweight on the QT interval and the prevalence of long QT syndrome in children.Am J Cardiol. 2002; 89: 395-398Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar 119Yang P Kanki H Drolet B et al.Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.Circulation. 2002; 105: 1943-1948Crossref PubMed Scopus (0) Google Scholar About 30% of congenital LQTS carriers have an apparently normal phenotype, and thus a normal QT interval, and remain undiagnosed until an initiating event.105Vincent GM Timothy K Zhang L Congenital long QT syndrome.Cardiac Electrophysiol Rev. 2002; 6: 57-60Crossref PubMed Scopus (0) Google Scholar Fatal arrhythmias associated with primary electrical disease of the heart such as the Brugada and LQTS, probably account for 19% of sudden deaths in children between 1 and 13 yr of age, and 30% of sudden deaths that occur between 14 and 21 yr of age.10Antzelevitch C Molecular biology and cellular mechanisms of Brugada and long QT syndromes in infants and young children.J Electrocardiol. 2001; 34: 177-181Abstract Full Text PDF PubMed Google Scholar Furthermore, there is a strong association between prolonged corrected QT interval (QTc) in the first week of life and risk of sudden infant death syndrome.86Schwartz PJ Stramba-Badiale M Segantini A et al.Prolongation of the QT interval and the sudden infant death syndrome.N Engl J Med. 1998; 338: 1709-1714Crossref PubMed Scopus (532) Google Scholar The QT interval normally varies with heart rate, lengthening with bradycardia and shortening at increased rates. The measured QT interval is therefore corrected for heart rate according to the formula of Bazette:15Bazette HC An analysis of the time-relations of electrocardiograms.Heart. 1920; 7: 353-370Google Scholar QTc = Measured QT/RR interval (all measured in seconds). A QTc interval of >440 ms is considered prolonged, although about 6% of patients with symptomatic LQTS have a normal QTc interval.35Garson jr, A Dick M Fournier A et al.The long QT syndrome in children. An international study of 287 patients.Circulation. 1993; 87: 1866-1872Crossref PubMed Google Scholar As the QT interval on the ECG represents the total duration of both the depolarization and repolarization phases of the ventricular action potential, a lengthening of the QT interval occurring because of a prolongation in QRS complex duration does not constitute LQTS. Hence, measurement of the JT interval, which avoids incorporation of the QRS duration, has been advocated as a more accurate reflection of ventricular repolarization.17Berul CI Sweeten TL Dubin AM Shah MJ Use of the rate-corrected JT interval for prediction of repolarization abnormalities in children.Am J Cardiol. 1994; 74: 1254-1257Abstract Full Text PDF PubMed Scopus (0) Google Scholar The QT interval is generally measured in lead II, as the T-wave ending is usually discrete, and the QT interval in lead II has a good correlation with the maximal QT measurement from the whole 12-lead ECG. In many LQTS patients, the QT interval is not only prolonged but also has increased variability in length as measured in the individual leads of the 12-lead ECG. QT dispersion (QTD) is an index of this variation and is the difference between the longest and shortest QT interval measured from all 12 leads of the standard surface ECG. QTD is significantly increased in symptomatic LQTS patients, but may not be significantly different to control values in asymptomatic LQTS patients.95Swan H Saarinen K Kontula K et al.Evaluation of QT interval duration and dispersion and proposed clinical criteria in diagnosis of long QT syndrome in patients with a genetically uniform type of LQT1.J Am Coll Cardiol. 1998; 32: 486-491Crossref PubMed Scopus (0) Google Scholar T wave and U wave abnormalities are common in LQTS. T waves may be larger, prolonged, or have a notched, bifid or biphasic appearance.32Fukushige T Yoshinaga M Shimago A et al.Effect of age and overweight on the QT interval and the prevalence of long QT syndrome in children.Am J Cardiol. 2002; 89: 395-398Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar A pathognomonic feature of LQTS is so-called T wave alternans, where there is beat-to-beat variation in T wave amplitude. This sign of enhanced electrical instability is a highly specific but very insensitive marker for LQTS.42Kaufman ES Priori SG Napolitano C et al.Electrocardiographic prediction of abnormal genotype in congenital long QT syndrome: experience in 101 related family members.J Cardiovasc Electrophysiol. 2001; 12: 455-461Crossref PubMed Google Scholar Exercise testing of patients with LQTS may provoke prolongation of the QTc. Patients with LQTS also have reduced heart rates at maximal exercise, although there is considerable overlap with the normal distribution.96Swan H Toivonen L Viitasalo M Rate adaptation of QT intervals during and after exercise in children with congenital long QT syndrome.Eur Heart J. 1998; 19: 508-513Crossref PubMed Scopus (43) Google Scholar A notched T wave during the recovery phase of exercise is highly suggestive of LQTS. Holter recordings may be helpful in establishing the diagnosis by revealing abnormal QT prolongation during bradycardias, and ventricular arrhythmias. Head up tilt testing may also provoke abnormal QT prolongation and arrhythmias. Schwartz and colleagues first proposed formal criteria to help the clinical diagnosis of LQTS in 1985;80Schwartz PJ Idiopathic long QT syndrome: progress and questions.Am Heart J. 1985; 109: 399-411Abstract Full Text PDF PubMed Scopus (465) Google Scholar these were revised in 1993.83Schwartz PJ Moss AJ Vincent GM Crampton RS Diagnostic criteria for the long QT syndrome: an update.Circulation. 1993; 88: 782-784Crossref PubMed Google Scholar The current criteria are based on clinical history, family history, and ECG findings (Table 1).Table 1Diagnostic Criteria in LQTS.83 The ECG findings, clinical history and family history are all individually scored as detailed below. If the total score is <1 point, the patient has a low probability of having the syndrome, whereas if the total score is 2–3 points, there is an intermediate probability, and a score of >4 points implies a high probability. aIn the absence of medications or disorders known to affect these ECG features. bQTc calculated from Bazette's formula, where QTc = QT/RR. cMutually exclusive. dResting heart rate below the second percentile for age. eThe same family member cannot be counted twice. fDefinite LQTS is defined by a LQTS score >4PointsECG findingsaQTcb≥480 ms3460–470 ms2450 ms (in males)1Torsades de pointesc2T wave alternans1Notched T wave in three leads1Low heart rate for aged0.5Clinical historySyncopecWith stress2Without stress1Congenital deafness0.5Family historyeFamily members with definite LQTSf1Unexplained sudden cardiac death before age 30 in immediate family members0.5 Open table in a new tab The different subtypes of LQTS may display specific ECG phenotypes. Thus, LQT1 typically has a prolonged T wave duration, the LQT2 subtype has lower amplitude T waves in the limb leads and, characteristically, LQT3 patients have a late appearing T wave preceded by a long isoelectric ST segment.120Zhang L Timothy KW Vincent GM et al.Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome.Circulation. 2000; 102: 2849-2855Crossref PubMed Google Scholar There is, however, considerable variation between patients, and the morphology varies with age. These patterns are useful in directing the search for a mutation by genetic testing, but cannot be relied upon in isolation in directing genotype-specific treatment without confirmation. Diagnosing LQTS in patients is difficult, because of variable penetrance and genetic heterogeneity. Examination of clinical and ECG features cannot always accurately identify gene carriers in affected families and genetic testing is usually recommended.42Kaufman ES Priori SG Napolitano C et al.Electrocardiographic prediction of abnormal genotype in congenital long QT syndrome: experience in 101 related family members.J Cardiovasc Electrophysiol. 2001; 12: 455-461Crossref PubMed Google Scholar However, only 60% of families diagnosed with LQTS can be genotyped to one of the known mutations. Moreover, sporadic cases occur because of spontaneous new mutations, so at present negative genetic screening cannot rule out the disease. In addition, as several mutations have been discovered in each of the known LQTS genes, diagnostic genotyping is extremely expensive, laborious, and equivalent to searching a haystack for the proverbial needle. Currently, diagnostic genotyping within a realistic time frame is not routinely available in the UK, so such a policy of perfection is not practicable, even in patients with a suggestive family history. Examination of clinical and ECG features therefore remains the mainstay of diagnosing LQTS in this country. ECGs should be obtained in all first-degree relatives of a patient with LQTS. The identification of QTc interval prolongation and T wave abnormalities in family members of a victim of sudden cardiac death is suggestive of a LQTS gene in the family. Routine genetic screening is not yet feasible, however, for all the reasons outlined above; automated analysis is required before routine screening becomes a possibility. In order to understand the underlying pathophysiology of LQTS, it is necessary to appreciate the current concepts of ion channel function in human myocardial cells. The cardiac action potential, which represents variation in the transmembrane potential of the myocyte during one cardiac cycle, is traditionally divided into five phases. These phases reflect the variation in the composition of ionic currents flowing during this time period. Ionic currents arise mainly from passive movements of ions through ion channels, which are composed of transmembrane proteins. The ionic basis of the ‘fast’ response action potential, seen in atrial and ventricular muscle cells and Purkinje fibres, is different from that of the ‘slow’ response action potential, seen in sinoatrial and atrioventricular nodal cells. However, as nodal cell function is not relevant to this review, it is not discussed further. In the resting myocyte, the potential of the cell interior is about 90 mV less than that of extracellular fluid. When the myocyte is stimulated, the cell membrane rapidly depolarizes. During depolarization, the potential difference reverses such that the potential of the cell interior exceeds that of the exterior by about 20 mV. This rapid change in potential difference is reflected by the upstroke of the action potential and is designated phase 0. The upstroke is followed immediately by a brief period of partial early repolarization (phase 1), and then by a plateau (phase 2) that persists for about 0.1–0.2 s. The membrane then further repolarizes (phase 3), until the final resting state of repolarization (phase 4) is again attained. Any stimulus that abruptly changes the resting membrane potential to a critical ‘threshold’ value results in an action potential; human ventricular myocytes have a threshold value of about –65 mV. At this potential, there is a sudden increase in sodium conductance because of opening of fast Na+ channels; the resultant influx of Na+ into the myocyte causes rapid depolarization (phase 0). The opening and closing of fast Na+ channels is controlled by voltage-dependent gating; Na+ channels, like all other ion channels, are dynamic molecules that change their structural conformation in response to changes in transmembrane potential. The Na+ channel consists of a principal α-subunit, the pore-forming component, and one or more smaller, regulatory β-subunits. There are at least three different types of β-subunit genes widely expressed in mammalian cardiac Na+ channels; they may affect the rate of channel activation and inactivation, although their precise function is uncertain.18Bezzina CR Rook MB Wilde AAM Cardiac sodium channel and inherited arrhythmia syndromes.Cardiovasc Res. 2001; 49: 257-271Crossref PubMed Scopus (0) Google Scholar, 30Fahmi AI Patel M Stevens EB et al.The sodium channel β-subunit SCN3b modulates the kinetics of SCN5a and is expressed heterogeneously in sheep heart.J Physiol. 2001; 537: 693-700Crossref PubMed Scopus (0) Google Scholar 36Grant AO Molecular biology of sodium channels and their role in cardiac arrhythmias.Am J Med. 2001; 110: 296-305Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar The α-subunit is composed of four homologous domains, each containing six transmembrane segments (S1–S6). Cytoplasmic chains of amino acids link the four domains to each other. Links between the fifth and sixth segments line the transmembrane pore, hence the term ‘P-loop’ (Fig. 2). The P-loops for each domain are different and their specific structure defines the permeation characteristics of the ion channel. Na+ channels permit selective flux of Na+ over other monovalent cations by a factor of 10:1 or more, and are not normally conductive to divalent cations such as Ca2+. However, a change in one amino acid in the domain III P-loop can convert a Na+ channel into a Ca2+ selective channel.13Balser JR Structure and function of the cardiac sodium channels.Cardiovasc Res. 1999; 42: 327-338Crossref PubMed Scopus (0) Google Scholar Cell membrane depolarization triggers activation (opening) of the Na+ channels, but if the depolarization is maintained, the channels become inactivated and non-conducting. Subsequent to complete repolarization, the channels return to a closed state capable of being activated once again. All these processes are the result of complex interactions among the structural domains of the channel protein. The fourth transmembrane segment (S4 in Fig. 2) in each domain is affected by changes in membrane potential, and is responsible for activation gating. Depolarization causes these helical segments to rotate outwards, leading to opening of the channel pore.36Grant AO Molecular biology of sodium channels and their role in cardiac arrhythmias.Am J Med. 2001; 110: 296-305Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Inactivation has an initial rapid component and one with a slower recovery time constant. The cytoplasmic linker between the third and fourth domains (DIII and DIV) mediates fast inactivation. A portion of this linker acts as a hinged lid, that docks against receptor sites surrounding the inner vestibule of the pore, thereby occluding it (Fig. 3). These receptor sites become available only when the channel is activated. Slow inactivation involves conformational changes in the outer pore that probably involve the P-loops.18Bezzina CR Rook MB Wilde AAM Cardiac sodium channel and inherited arrhythmia syndromes.Cardiovasc Res. 2001; 49: 257-271Crossref PubMed Scopus (0) Google Scholar Inactivation is coupled to activation; the rate of inactivation increases as a consequence of conformational changes in the channel protein associated with activation. This is because movement of the S4 segments that initiate activation of the channel, changes both the position of the DIII–DIV cytoplasmic linker relative to its docking sites, and the orientation of the docking sites themselves (Fig. 3). At the resting transmembrane potential of –90 mV the activation gates are all closed, the inactivation gates are open, and the conductance of the resting cell to Na+ is very low. As the transmembrane potential becomes less negative, activation gates start to open. The precise potential required to open activation gates varies from one channel to another in the cell membrane. As the transmembrane potential becomes progressively less negative, more and more gates open, and the influx of Na+ accelerates. The entry of Na+ into the cell neutralizes some of the negative charges within the cell and thereby makes the transmembrane potential still less negative, which in turn results in more gates opening and the Na+ current increasing. As the transmembrane potential approaches about –65 mV, virtually all the activation gates are open. Although Na+ ions that enter the cell during one action potential alter the transmembrane potential by more than 100 mV, the actual quantity of Na+ that enters the cell is so small that the resultant change in its intracellular concentration is tiny. Hence, the chemical force (concentration gradient) remains virtually constant, and only the electrostatic force changes throughout the action potential. As Na+ enters the cardiac cell during phase 0, the negative charges inside the cell are neutralized, and the transmembrane potential becomes progressively less negative until it reaches zero, at which point there is no electrostatic force attracting Na+ into the cell. As long as Na+ channels are open, however, Na+ continues to enter the cell because of the large concentration gradient. This continuation of the inward Na+ current causes the inside of the cell to become positively charged with respect to the exterior, resulting in the ‘overshoot’ of the cardiac action potential. As the Nernst potential equilibrium for Na+ is approached, the electrostatic force opposing Na+ influx starts to counter the chemical force generated by the concentration gradient across the cell membrane, and the rate of net inward Na+ flux starts to decrease. Nevertheless, this inward Na+ current persists during phase 1 and 2, and only finally ceases when all the inactivation gates have closed. Inactivation gates are not directly affected by the value of the transmembrane potential, and derive most of their voltage dependence from being coupled to activation. Whereas activation gates take about 0.1 ms to open, inactivation gate closure, which can occur only after activation has occurred, takes a few milliseconds. This relative delay in pore closure provides sufficient time for the Na+ influx seen in phase 0, which is terminated when all the inactivation gates have closed. Inactivation gates remain closed while activation gates are open. Once the cell has partially repolarized (phase 3), the change in transmembrane potential triggers closure of the activation gates by reversal of the conformational changes in the S4 segments, a process called deactivation. Deactivation results, after a variable interval, in reversal of the inactivation mechanism and hence, opening of the inactivation gates (Fig. 3). This phase constitutes an early brief period of limited repolarization, consequent upon activation of various types of K+ channels. K+ channel opening results in a substantial efflux of K+ from the cell, because the interior of the cell is positively charged and because the concentration of K+ inside the cell greatly exceeds that in the exterior. Phase 1 produces a notch in the action potential between the end of the upstroke and the beginning of the plateau. It is particularly prominent in Purkinje fibres and in myocytes in the epicardial and mid-myocardial regions; in endocardial myocytes it is almost undetectable. The configuration and rate of repolarization of action potentials are controlled by many types of K+ channel currents that differ with respect to their kinetics and density in the cell membrane. There are at least 20 different K+ channel proteins in the human myocardium, although all can be assigned to one of four categories based on function: transient outward, delayed rectifier, inward rectifier, and leak channels. The delayed rectifier ‘current’ is actually a composite of at least three distinct currents: the ultra-rapid (IKur), the rapid (IKr), and the slow (IKs) delayed rectifier currents. These vary in their speed of activation and in their pharmacological properties.101Tristani-Firouzi M Chen J Mitcheson JS Sanguinetti MC Molecular biology of K+ channels and their role in cardiac arrhythmias.Am J Med. 2001; 110: 50-59Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Cloning and analysis of the secondary structure of voltage-dependent Ca2+ and K+ channels have revealed that the relationship between structure and gating function is similar to that described above for Na+ channels.118Yamaguchi H Muth JN Schwartz A Varadi G Critical role of conserved proline residues in the transmembrane segment 4 voltage sensor function and in the gating of L-type calcium channels.Proc Natl Acad Sci USA. 1999; 96: 1357-1362Crossref PubMed Scopus (21) Google Scholar Recent reviews of the molecular basis of cardiac K+ currents are recommended for interested readers.60Nerbonne JM Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium.J Physiol. 2000; 525: 285-298Crossref PubMed Google Scholar, 101Tristani-Firouzi M Chen J Mitcheson JS Sanguinetti MC Molecular biology of K+ channels and their role in cardiac arrhythmias.Am J Med. 2001; 110: 50-59Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The rapid partial repolarization of phase 1 is the result of the transient outward (IKto), the IKur and leak currents.101Tristani-Firouzi M Chen J Mitcheson JS Sanguinetti MC Molecular biology of K+ channels and their role in cardiac arrhythmias.Am J Med. 2001; 110: 50-59Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar K+ channels carrying IKto activate very rapidly in response to the rapid depolarization of phase 0. A membrane-spanning helical portion of one of the K+ channel protein domains senses membrane depolarization; it is coupled to other regions of the protein that form the activation gate. When the activation gate is open, the channel conducts K+ in a direction that depends on the electrochemical gradient across the cell membrane. Within 10–500 ms after depolarization, the channels close and this state of inactivation continues until such time as the membrane is repolarized to the resting potential. Only then do these channels recover from their inactivated state and again become capable of opening in response to membrane depolarization. Channels carrying IKur activate during depolarization and stay open for most of the duration of the action potential; the magnitude of this current progressively decreases during repolarization because of the progressive decrease in electrostatic driving force (Fig. 4). Most cardiac cells also have a very small background K+ conductance through so-called leak K+ channels, which are open at all voltages; they contribute to the maintenance of the resting potential and repolarization of the action potential. The efflux of positively charged K+ ions during phase 1 results only in a brief, partial repolarization because it rapidly becomes counterbalanced by an influx of Ca2+ ions during phase 2. The voltage-regulated Ca2+ channels are activated as the transmembrane potential becomes progressively less negative during the upstroke of the action potential. But because the predominant type of Ca2+ channel, the L-type, activates and inactivates much more slowly than do the fast Na+ channels, Ca2+ conductance does not increase until after most of the Na+ channels have closed. Ca2+ ions move across the cell membrane down their concentration gradient to cause a significant increase in intracellular Ca2+ concentration, although the amount of Ca2+ that enters the cell from the interstitium is not sufficient in itself to induce myofibril contraction; rather it acts as a trigger to release Ca2+ from the sarcoplasmic reticulum. Hence, peak force development does not occur until repolarization is complete. Inactivation of L-type Ca2+ channels occurs in two phases: an initial fast phase that is dependent upon a Ca2+–calmodulin complex binding to the cytoplasmic side of the channel protein, and a slower phase that is voltage-dependent.5Adams B Tanabe T Structural regions of the cardiac Ca channel α1C subunit involved in Ca-dependent inactivation.J Gen Physiol. 1997; 110: 379-389Crossref PubMed Scopus (0) Google Scholar, 94Sun L Fan J-S Clark JW Palade PT A model of the L-type Ca++ channel in rat ventricular myocytes: ion selectivity and inactivation mechanisms.J Physiol. 2000; 529: 139-158Crossref PubMed Google Scholar Both mechanisms act to induce a conformational change in the channel protein, so resulting in pore closure; the inward Ca2+ current (ICa) is insignificant at potentials more negative than about –50 mV.14Barrère-Lemaire S Piot C Leclercq F et al.Facilitation of L-type calcium currents by diastolic depolarization in cardiac cells: impairment in heart failure.Cardiovasc Res. 2000; 47: 336-349Crossref PubMed Scopus (0) Google Scholar During the plateau of the action potential, the concentration gradient for K+ across the cell membrane is virtually the same as that during the resting state, but the transmembrane potential is positive. Therefore, both chemical and electrostatic forces favour efflux of K+ from the cell. The activation of the IKs channels by depolarization proceeds very slowly and tends to increase K+ conductance only very gradually during phase 2. In addition, IKur channels and leak channels continue to allow K+ efflux out of the cell. Towards the end of the plateau phase, as the transmembrane potential starts to become slightly more negative, IKr starts to assume significance. The amplitude of IKr increases during repolarization, reaching a peak at about –30 mV, before decreasing again as the membrane potential reaches its resting level. This increase in current occurs in spite of a decrease in electrostatic driving force, because channels recover from inactivation to an open state in a voltage-dependent manner. The action potential plateau persists as long as efflux of charge carried mainly by K+ is balanced by the influx of charge carried mainly by Ca2+, together with a small amount carried by Na+. Hence, administration of either calcium or potassium channel blockers can substantially diminish or prolong the duration of the plateau. Action potential duration, which relates to the duration of phase 2, shows considerable heterogeneity within the heart. The action potential duration is longer in mid-myocardial (M) cells than in epicardial or endocardial cells, because of a smaller IKs, and larger INa and Na+/Ca2+ exchange (INa–Ca) currents. It is the transmural differences in the time course of repolarization of the three types of myocyte that are largely responsible for T wave morphology on the ECG, and it is the duration of the M cell action potential that determines the QT interval.11Antzelevitch C Fish J Electrical heterogeneity within the ventricular wall.Basic Res Cardiol. 2001; 96: 517-527Crossref PubMed Scopus (230) Google Scholar The process of final repolarization, phase 3, begins when the efflux of K+ significantly exceeds the influx of Ca2+ and Na+. IKto takes no part in this phase, and IKur and leak currents are relatively insignificant (Fig. 4). IKs and IKr are the largest contributo