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I. II. III. Normal QT duration A. QT modifying factors 1. Normal QT decreases with increasing Heart Rate 2. QT is longer in leads V2 and v3 B. Calculation of QTc or corrected QT (Bazett's Formula) 1. QTc = QT/(sqrt RR Interval) 2. QTc is normally <0.44 C. Approximation of normal QT 1. QT interval shortens with decreasing RR Interval 2. QT = 0.5 x preceding RR Interval (if normal rate) 3. Approximate normal QT Interval a. QT <= 0.40 if Heart Rate 70 bpm or less b. Subtract 0.02 sec for every 10 bpm over 70 c. Example: Normal QT < 0.34 if Heart Rate 100 D. Heart Rate determined QT 1. 115 - 84 bpm: QT 0.30 to 0.37 seconds 2. 83 - 72 bpm: QT 0.32 to 0.40 seconds 3. 71 - 63 bpm: QT 0.34 to 0.42 seconds 4. 62 - 56 bpm: QT 0.36 to 0.43 seconds 5. 55 - 45 bpm: QT 0.39 to 0.46 seconds Prolonged QT A. Congestive Heart Failure B. Myocardial Infarction C. Hypocalcemia D. Hypomagnesemia E. Type I Antiarrhythmic drugs F. Rheumatic Fever G. Myocarditis H. Congenital Heart Disease Shortened QT A. Digoxin (Digitalis) B. Hypercalcemia C. Hyperkalemia D. Phenothiazines 5. Electrocardiograms 5.1. What is measured by an electrocardiogram? When cells depolarize, they become positively charged with respect to their non-depolarized neighbors. The positive charge can be measured as a positive voltage between points on the surface close to the affected cells and points on the surface farther away. Body-surface measurements can detect electrical activities of nerves and skeletal muscles, but when a subject is at rest and leads are appropriately placed, the body's dominant electrical activity is that of the heart. The electrocardiogram (ECG, but sometimes appearing as EKG from the German) records the change over time in surface voltages arising in the heart. 5.2. What is the electrocardiographic appearance of a typical cardiac beat? This drawing is adapted from Netter FH, The CIBA Collection of Medical Illustrations: Heart (Summit, NJ: CIBA Pharmaceutical Company, 1969), page 50: This appearance is of course specific to one set of leads. For example, if the leads were exactly reversed, the tracing would be exactly upside down. The sequence of excursions would remain the same: P wave, PR segment, QRS complex, ST segment, T wave, and U wave. The time between one beat and the next is often referred to as the RR interval. 5.3. To what action potentials do the various portions of the ECG complex correspond? When parts of the atria are depolarized and parts are not, the net voltage is detected as the P wave. At the same time and during the ensuing PR segment, depolarization is progressing through the AV node and conduction system, but these tissues have insufficient mass for their activity to be detected. Progression of depolarization through the ventricles is seen as the QRS complex. Once depolarization of the ventricles is complete, there is no net voltage across the heart, so the tracing returns to its baseline during the ST segment. As repolarization of the ventricles proceeds, however, the heterogeneities within the ventricular wall become important, and repolarization is for a while more complete in some cells (those of the endocardium and epicardium) than in others (those of the mid-myocardium). The resulting voltage gradients are manifest in the electrocardiogram as the T wave. The origin of the U wave was obscure for many years. Its normal timing corresponds to that of repolarization of the Purkinje fibers, but the Purkinje fibers are insufficiently massive to account for large lateappearing waves that are often described as U waves. These large waves are more likely to be late components of a prolonged T wave, generated as described just above. 5.4. How are the durations of the various intervals affected by heart rate? The PR interval (normally 120-200 ms) and QRS interval (normally 80-120 ms) are unaffected by changes in heart rate. The QT interval shortens as the heart rate is increased, and this phenomenon is central to the whole next section. 6. The QT Interval 6.01. How do we decide whether a biometric datum is “normal”? Some physiological measurements have a single normal range, independent of the subject's age, sex, or other variables. For example, everyone's serum sodium concentration is normally in the range 135145 mEq/L. Other measurements are more complicated, because they vary with one or more important cofactors. The question “What is the normal range of adult weight?” is not meaningless, but the answer (something like “100200 pounds”) is almost uselessly imprecise. We sometimes decide whether a measured body weight is normal by referring to tables that show a weight range for each of many combinations of sex and height. Rather than deal with the bulky tables, physicians sometimes use simple rules of thumb, like “a normal adult woman 5 feet N inches tall weighs about 110+4N pounds.” Finally, it is sometimes convenient to run rules in reverse, normalizing the measured data by deriving a metric sometimes called an index. In the case of weight, the conventional calculation is that which yields the body-mass index, BMI = weight / height2. The claim of the BMI is that once it has been computed, the normality or abnormality of the subject's weight can be assessed with no further reference to his or her height. All of these schemes must be evaluated, at least at first, in the same way. A useful scheme should be unbiased, and to be most useful it should be reasonably precise. A scheme is unbiased if it actually describes the population for whom it is a proposed standard. To say that the normal range for adult human weight is 100-200 pounds may not be terribly useful, but it is (approximately) correct. A suggested range of 300-350 pounds would be more precise, but it would be biased. A given range, table, rule, or normalization might be unbiased for one population, but biased for another. For example, the rule of thumb given earlier functions well for short women, but the only tall women it accepts as “normal” are unnaturally thin. Although a normal range can be meaningfully defined for any scheme that is not seriously biased, the range may need be uselessly imprecise if the scheme does not take account of pertinent cofactors. This was demonstrated in the example of the single normal range for adult weight. 6.02. What is meant by QT “correction”? A QT “correction” formula is a formula that combines the measured QT duration and the measured heart rate into a computed index, similar in concept to the BMI. The term “correction” is a misnomer, inasmuch as the measured QT interval is not incorrect (as a weight might be incorrect if it were measured while the subject were wearing heavy clothing). Nevertheless, the term “correction” is deeply entrenched, and the output of the calculation is usually called the “corrected QT interval,” denoted by QTc. 6.03. What formula is used for QT correction? Several dozen different formulas have been proposed over the years. The most frequent style of these formulas has been QTc = QT / RRa where a is a formula-specific parameter, and of these formulas the one most frequently seen is the formula attributed to Bazett, in which a = 0.5, and for which the published upper limit of normal is 440 ms. In what follows, the results of correction using the Bazett formula will be denoted by QTcB. 6.04. Is the Bazett correction unbiased? No. Bazett studied only a few electrocardiograms in each of a small number of subjects, and he then chose a = 0.5 by subjectively observing the fit to his data. In more recent studies, using dozens of electrocardiograms from each of hundreds of subjects, the best value of a (by formal statistical methods not known to Bazett) has varied from population to population. Values as high as 0.5 are almost never seen; the most frequent values are close to 0.32. Using an excessive value for a causes one to expect that with increasing heart rate, the QT interval will decrease more rapidly than it actually does. As a result, normal reductions of QT duration with heart rate will be perceived as insufficient, suggesting that some concomitant process is prolonging the QT interval. With decreasing heart rate, an excessive value of a will lead to acceptance as normal of QT durations that are actually abnormally long. 6.05. When the heart rate is close to 60, so that QTcB is close to QT, need I be concerned about the failings of the Bazett formula? Probably, yes. The accepted upper limit of normal for QTcB (and for QT when HR is around 60) was probably not obtained by averaging the QT intervals of subjects whose heart rates were all around 60 bpm. Instead, the normal range was probably obtained by averaging the QTcB results of subjects at various heart rates, most of them higher than 60. Because these QTcB values were mostly too high, the accepted upper limit of normal is probably too high. These matters are now (June 2002) under active investigation. 6.06. Hasn't the Bazett formula been validated by years of use? Yes, Ptolemaic astronomy has been.... What? Sorry. Yes, homeopathy has been.... Oh, sorry again. I get distracted. Please be so kind as to repeat your stupid question. 6.07. Would it be better to use a similar formula with a around 0.32? For most populations, yes, but studies have found populationspecific values of a ranging from less than 0.2 to greater than 0.6. It's better to pool your baseline data to find the a that best fits your specific population. Even if you do that (or if you choose an arbitrary value and it turns out to be a good fit), you will probably find that although bias has been minimized, precision remains mediocre. That is, individual variation in the QT/RR relationship will probably be so large that a populationspecific normal range will need to resemble the height-independent normal range for weight discussed much earlier. You may get slightly better results by considering formulas different in style (say, using Taylor series), but the intersubject variation will probably remain a problem. 6.08. Would it be better yet to obtain sufficient baseline data to fit a separate formula for each subject? Yes. With this technique, it is possible to detect abnormal QT intervals, regardless of heart rate, with high precision. 6.09. When the heart rate changes, does the QT interval change right away? No. After a change in heart rate, the QT interval takes a minute or two to reach its new steady state. Thus, for example, a QT interval measured just after an increase in heart rate may falsely appear to be abnormally long, because it is still shortening from its (normal) duration before the change in heart rate. 6.10. What is meant by "QT dispersion"? QT dispersion was at one time thought to be the electrocardiographic manifestation of important variation of AP duration in ventricular muscle. Depending on their degree of mathematical sophistication, different authors identified QT dispersion with different measures (standard deviation, maximum-minimum difference, etc.) of the range of QT duration as seen in the various electrocardiographic leads. This notion of QT dispersion was popular a few years ago, but it lost momentum when it could not be shown to be of independent prognostic significance. These measures' insensitivity should (in hindsight) have been expected, inasmuch as each of the proposed measures of QT dispersion was sensitive to differences in milieu between regions of ventricular tissue that were physically far separated from each other, and therefore unlikely to join in hosting reentrant arrhythmias. Intraventricular variation in AP duration is important, but the important kind of variation is radial rather than circumferential. That is, the important variation in AP duration is the variation seen within a localized slab of ventricular wall, among the epicardium, the midmyocardium, and the endocardium. This sort of variation is present in normal hearts (in which it generates the normal T wave) but it is also the sort of variation that is magnified by drugs that induce torsade, and not by drugs that – even if they prolong the QT interval – do not induce torsade. Unlike the circumferential variation, unfortunately, the radial ("transmyocardial") variation in AP duration is not directly evident on the surface electrocardiogram Frequently Questioned Answers (3) 7. Torsade de Pointes 7.1. Is it torsade or torsades? A small but strangely heated literature addresses this question. Here, it's torsade. 7.2. What is torsade de pointes? Torsade de pointes (from the French for “twisting of the points”) is a re-entrant arrhythmia with a distinctive electrocardiographic appearance, sometimes described as a sine wave within a sine wave. This example is from Braunwald E, Zipes DP, and Libby P (eds.), Heart Disease [6th edition] (Philadelphia: W.B. Saunders, 2001), page 868: The pattern is called "twisting" because when the peaks are at their smallest in one lead, they are generally at their largest in another, as if a vibrating string were having its plane of vibration slowly rotated about the long axis of the string. 7.3. Why is torsade de pointes important? Many episodes of torsade de pointes are asymptomatic and stop by themselves, but the mechanical activity associated with this electrical pattern is generally dysfunctional, and torsade can degenerate into other arrhythmias that are both dysfunctional and irreversible. 7.4. Who are at risk for torsade de pointes? Torsade de pointes is seen in various congenital defects known collectively as the long-QT syndromes. In addition, torsade sometimes happens to otherwise-normal people as an adverse effect of drugs. Other things being equal, the risk of torsade is increased in women, in people who are hypokalemic or hypocalcemic, and in patients with congestive heart failure. 8. Congenital Long-QT Syndromes 8.1. What are the congenital long-QT syndromes? Mutations in the genes whose products make up the major ion channels give rise to syndromes known as the long-QT syndromes (LQT syndromes). These syndromes are congenital, but not necessarily hereditary, since about XX% of the cases turn out to be new mutations. The most frequent of the long-QT syndromes are known as LQT1 (impaired opening of the (repolarizing) IKs channel), LQT2 (impaired opening of the (repolarizing) IKr channel), and LQT3 (impaired closing of the (depolarizing) INa channel). 8.2. How common are these syndromes? A few thousand patients have been identified worldwide, but they are thought to be much more common. 8.3. How important are they to people who have them? About half of the affected people sustain major arrhythmias before the age of 40. In addition, an unknown but nonzero fraction of the deaths attributed to the catchall “sudden infant death syndrome” (SIDS) are caused by LQT-syndrome-related arrhythmias. 8.4. Are similar syndromes known to occur in animals? No. 8.5. Do people with the same hereditary long-QT syndrome all have the same mutation? No. In fact, a new kindred with one of the established syndromes is likely to have a family-specific mutation. As of June 2002, cases of the LQT1, LQT2, and LQT3 syndromes have been found as the results of about 300 different mutations. 8.6. Do people with the same ion-channel mutation all have equally prolonged QT intervals? No. When a family carrying a LQTS mutation is investigated, usually about a third of the family members with the mutation have normal electrocardiograms, and the others have varying degrees of QT prolongation. 8.7. Do people with the same ion-channel mutation all have an equal likelihood of arrhythmic events? No. Those with longer QT intervals have a higher incidence of events, but even those with normal electrocardiograms have an incidence of events that is higher than that of people who do not have LQTS. 9. Drug-Induced Changes in Ion-Channel Function 9.1. How is a drug's propensity to cause changes in ion-channel function tested? TBD. 9.2. How are the results described? Drug-induced interference with channel opening is described in terms of the concentration of drug needed to impair ion flux by 50%. This measurement is denoted by IC50. For example, some extreme values for blockade of the IKr channel are that of astemizole, a very potent blocker with an IC50 of 0.9 nM, and that of ofloxacin, an extraordinarily weak blocker with an IC50 of 1.4 mM. Drug-induced interference with channel closing? 9.3. Is alteration of ion-channel function ever an intended drug effect? Yes. Because arrhythmias are usually the result of ion-channel dysfunction, a drug with no discernible effect on ion channels would be unlikely to be developed as an anti-arrhythmic. 9.4. Are some ion channels more susceptible to drug-induced interference than others? Yes. The IKr channel turns out to have a wide, funnel-shaped vestibule, so many different kinds of small molecules can approach the channel and partially block it. Other channels are generally more selective. Even so, most drugs known to interfere with one channel are known to interfere – at least to some degree – with others. 9.5. What drugs have ion-channel effects, and which channels are affected? All of the publicly-available data that I know about are tabulated here. 9.6. Do ion-channel studies provide close analogies to distortions of human electrocardiograms? No. 9.7. Do ion-channel studies provide close analogies to human torsade de pointes? No. 9.8. Has in vitro ion-channel testing been validated as a means of predicting drug-induced torsade de pointes in humans? Yes and no. A drug could not induce torsade de pointes if it did not in some way interfere with the function of ion channels, but the converse is not true. For example, verapamil is a moderately potent IKr blocker (its IC50 is about 0.14 µM), but it never induces torsade or any other tachyarrhythmia. 10. Drug-Induced Changes in the Action Potential 10.1. How is a drug's propensity to cause changes in action potentials tested? TBD. 10.2. How are the results described? TBD. 10.3. Do action-potential studies provide close analogies to distortions of human electrocardiograms? No, except insofar as a drug that never prolongs the action potential could not prolong the QT interval. 10.4. Do action-potential studies provide close analogies to human torsade de pointes? No. 10.5. Does prolongation of action potentials in vitro reliably predict druginduced torsade de pointes in humans? No. Most drugs known to induce torsade are known to prolong the action potential in at least some types of cells. Other drugs, however (e.g., pentobarbital), by prolonging the action potential in some cells more than others are known to reduce the risk of torsade. 11. The Wedge Preparation 11.1. What is the wedge preparation, and what studies are done with it? Ion-channel and action-potential studies are generally performed in single cells (or in small multicellular specimens chosen for their homogeneity), maintained by immersion in an appropriate bath. The specimen taken for wedge-preparation studies is a full-thickness slab of the canine ventricular wall, several cubic centimeters in total volume, maintained by direct perfusion of its native coronary vessels. The voltage measured between the endocardial and epicardial surfaces of the slab integrates the action potentials of all of the cells of the slab. It resembles a surface electrocardiogram not only in its means of generation, but also in its overall appearance. Electrodes floating on the raw intra-myocardial surfaces of the slab record action potentials typical of the local cells. When drugs are added to the perfusate, the various electrodes provide simultaneous views of different cell types' action potentials and of the integrated quasi-electrocardiogram. 11.2. How are the results described? The quasi-electrocardiogram and action-potential recordings are described as ECGs and APs are usually described, with the pivotal added note that they were simultaneously recorded. 11.3. Do wedge-preparation studies provide close analogies to distortions of human electrocardiograms? Yes. 11.4. Do wedge-preparation studies provide close analogies to human torsade de pointes? Yes. 11.5. Have wedge-preparation studies been validated as a means of predicting drug-induced torsade de pointes in humans? No. 12. Drug-Induced QT Prolongation in Animals 12.1. How is a drug's propensity to cause QT prolongation in animals tested? TBD. 12.2. How are the results described? TBD. 12.3. Do QT prolongation and other ECG abnormalities in animals closely resemble these phenomena in humans? TBD. 12.4. Have studies of drug-induced QT prolongation in animals been validated as a means of predicting drug-induced torsade de pointes in humans? No. 13. Drug-Induced Torsade de Pointes in Animals 13.1. How is a drug's propensity to cause torsade de pointes in animals tested? TBD. 13.2. How are the results described? TBD. 13.3. Have studies of drug-induced torsade de pointes in animals been validated as a means of predicting drug-induced torsade de pointes in humans? No. 14. Drug-Induced QT Prolongation in Humans 14.1. Is prolongation of the human QT interval ever an intended drug effect? No. 14.2. What drugs prolong the QT interval? Lists of drugs that prolong the QT interval are widely available on the Web and elsewhere, but most of the data underlying these tables were obtained using Bazett-corrected electrocardiograms, so many drugs are probably listed in error. Conversely, many older drugs were never tested for this property, so they may well have greater effects than some of the drugs listed. 14.3. If a given dose of a drug prolongs the QT interval by a certain amount, will a higher dose of the drug prolong the QT interval by the same amount or greater? Not necessarily. If the higher dose alters the function of depolarizing channels, in addition to the repolarizing channels affected at the lower dose, then the two effects may balance each other out at the higher dose. This fanciful-sounding possibility is actually observed with some drugs, notably quinidine. 14.4. Does drug-induced QT prolongation cause torsade de pointes? No. QT prolongation is evidence that the repolarization of some cardiac cells has been delayed, and this delay can lead to torsade if adjacent cells are repolarizing much sooner. On the other hand, the AP prolongation that is evident as QT prolongation may – as is seen with amiodarone, diltiazem, pentobarbital, ranolazine, and verapamil – be concurrent with AP prolongation in adjacent cells, so that local heterogeneity of repolarization has actually been reduced, together with the likelihood of torsade de pointes. 15. Drug-Induced Torsade de Pointes 15.1. What drugs are known to cause torsade de pointes? Lists of suspect drugs are widely available on the Web and elsewhere, but these lists should not be accepted uncritically. Some of the data come from FDA case reports of patients taking multiple drugs, sometimes with underlying conditions that could by themselves have been responsible for the arrhythmias reported. 15.2. Do all of the true culprit drugs interfere with the function of ion channels? Probably, yes. 15.3. Which ion channels are involved? Even though only one (LQT2) of the three most common long-QT syndromes involves IKr, and even though various non-therapeutic drugs can reliably induce torsade de pointes in animals via interference with other channels, drug-induced torsade de pointes in humans has always been attributed to interference with IKr. In some cases, this attribution is difficult to understand, and it may reflect lack of data with respect to other channels. For example, the capacity of grepafloxacin to cause torsade is attributed to its ability to block IKr, even though the IC50 of grepafloxacin for this blockade is about 50 µM. Grepafloxacin's activity at other channels has not been publicly reported. 15.4. How often will a patient with drug-induced torsade be found to have been unusually susceptible because of a subclinical congenital channel dysfunction? Not very often. A few patients have sustained torsade after what should have been low-risk drug exposure, and have later been found to have subtle ion-channel dysfunctions, but this pattern seems to be present in only 3-5% of the incident cases of drug-induced torsade. 15.5. Do all drugs that block IKr cause torsade de pointes if given in sufficient dose? No. For example, diltiazem and (especially) verapamil block IKr, but they do not cause torsade. 15.6. Do all of the drugs known to cause torsade de pointes prolong the QT interval? Yes. 15.7. Conversely, will any drug that prolongs the QT interval cause torsade de pointes if it is given in sufficient dose? No. Diltiazem and verapamil are again counterexamples. At least in models in which animals are pretreated so as to make them especially susceptible to torsade, these drugs (and others) prolong the QT interval but actually reduce the likelihood of torsade. 15.8. Are there drugs that cause torsade de pointes even though they prolong the QT interval only slightly? Inasmuch as some patients with long-QT syndromes are at heightened risk of torsade even though their QT intervals are only slightly prolonged or even normal, there probably are drugs that can induce torsade while lengthening the QT interval only minimally (or not at all). On the other hand, no such drugs are known. Certainly there are drugs that can induce torsade under some conditions but that under other conditions cause only minimal changes to the QT interval, but this is a non sequitur. For example, when a normal dose of terfenadine is given to a metabolically-competent person, the average amount of QT prolongation is said to be only 6 ms. In the circumstances in which terfenadine is known to have induced torsade, however (higher doses, metabolic inhibition, etc.), the amount of QT prolongation is much greater. 16. Drug Development and Regulation 16.1. How important are metabolic effects during human trials of drugs that might affect repolarization? Metabolism is no more important in thinking about torsade than it is in thinking about other adverse drug effects that might be clinically concentration-related. That is to say, it is very important indeed. All drug effects could be said to be concentration-related, inasmuch as they are all related to molecular interactions that follow the rules of mass action. In the clinical context, an effect is said to be concentrationrelated only if it runs through its range of incidence or severity within a range of concentrations that is of clinical interest. For example, ACEinhibitor-induced cough is said not to be concentration-related, because its incidence no longer increases once drug concentrations have reached levels well below those that are clinically useful. Morphine-induced sedation, on the other hand, is increasing throughout (and beyond) the range of therapeutic concentrations, so this effect is said to be concentration-related. Impaired drug metabolism can result in concentrations greatly exceeding those attained by timid dose-ranging, especially when a drug is dependent upon a unique metabolic pathway. For example, concentrations of simvastatin are raised by more than an order of magnitude when that drug is co-administered with ketoconazole. Returning to the repolarization arena, while such populations as women and heart-failure patients tend to have more pronounced responses to repolarization-altering drugs, these differences are small and predictable, almost negligible when compared to the differences that are sometimes produced by metabolic interference. Another set of considerations under the metabolic heading comes from the fact that the molecule directly responsible for an adverse drug effect may be different from the molecule administered. Although most metabolites are more polar than their parent compounds, and therefore less active, some exceptions are important. For example, the CNS toxicity of meperidine is caused by normeperidine, a long-lived metabolite. This toxicity could not be detected in short-term trials. 16.2. What is the goal of Phase 1 trials? As regards repolarization changes (or other adverse drug reactions), the goal of Phase 1 trials is to see how much harm the drug can be made to do. Dosing (and metabolic inhibition, if relevant) should be increased until it's not feasible to increase any more. This is the time to discover unpleasant facts that will be much more unpleasant if they are not discovered until later phases of development or – even worse – until after marketing. Because the human metabolism may not be completely understood until later, some early Phase 1 trials may need to be repeated with revised protocols. For example, if some of a drug's toxicity is attributable to a slowly-accumulating metabolite, then it may be necessary to do new, longer trials, or to do new trials in which the metabolite is administered directly. Repolarization changes are special in two ways. First, the associated risk (death or infarction as the result of malignant tachyarrhythmias) is one from which Phase 1 subjects can be totally protected. Similar arrhythmias, after all, are deliberately induced in electrophysiology laboratories as a matter of routine. When an appropriately monitored Phase 1 subject has a suspicious electrocardiogram, the investigator might reasonably be more willing to continue than he would be if the subject had had an equally-suspicious panel of hepatocellular enzymes. Second, a subject with an unusual repolarization response to a new drug is reasonably likely to have similar responses to others, and electrophysiological evaluation of the subject is a negligible-risk option that is therefore in the interest of both the drug developer and the subject. No similar statements can be made when a subject's response to a studied drug suggests hematologic or hepatic toxicity. 16.3. How important is the non-occurrence of torsade de pointes during human drug trials? Because torsade is so rare (even in LQT patients at high risk, and even in patients taking the drugs known to cause torsade most frequently), the non-occurrence of torsade in clinical trials provides little reassurance.