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The electrocardiogram, commonly known as “EKG” or “ECG” is a measure of the electrical activities in the body that are generated by the heart. Recording electrodes are placed on the skin surfaces at specific positions on the chest, arms and legs in order to measure these signals.

A Dutch physician, Willem Einthoven (1860-1927) introduced the ECG ‘PQRST’

designations. The different waves and intervals on the ECG are P, PQ, QRS, QT and ST.

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Figure 2: Schematic representation of normal ECG trace (sinus rhythm) with waves and intervals labeled.

33 2.5.1 QT Interval:

The QT interval comprises of the QRS complex, ST segment and the T wave. It is measured from the start of the QRS complex to the end of the T wave and averaged over 3 to 5 beats or cycles for each lead. The end of the T wave is defined as the point of return to the isoelectic baseline. When a U wave is present, the QT interval is measured to the nadir of the curve between the T and U waves.

The QT interval on the surface ECG indicates the time from the onset of the electrical wave in the heart to when the entire heart has reset and is ready for next beat. Thus, it is the electrocardiographic manifestation of ventricular depolarization and repolarization. The QT interval has been known since 1887 to represent ventricular electrical activities. This electrical activity of the heart is mediated through channels, complex molecular structures within the myocardial cell membrane that regulate the flow of ions in and out of cardiac cells, the rapid inflow of positively charged ions (sodium and calcium) results in normal myocardial depolarization. When this inflow is exceeded by outflow of potassium ions, myocardial repolarization occurs. Malfunction of ion channels leads to an intracellular excess of positively charged ions by way of an inadequate outflow of potassium ions or excess inflow of sodium ions. This intracellular excess of positively charged ions extends ventricular repolarization and results in QT interval prolongation⁴³.

The QT interval (on the ECG) has gained clinical importance, primarily because prolongation of this interval can predispose to a potentially fatal ventricular arrhythmia known as Torsades de Pointes. In pathological prolonged QT interval, it takes longer than the normal period for the myocardial cells to be ready for a new cycle. There is a possibility that some cells are not yet repolarized, but that a new cycle is already initiated. These cells are then at risk for uncontrolled depolarization, induction of Torsades de Pointes and subsequent ventricular

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fibrillation. The QT interval can also be a screening instrument for hypertensive with increased risk of sudden cardiac death⁴⁴.

In clinical setting, it is now widely recognized that typical measurement of the QT interval is subject to substantial variability, which can cloud interpretation. This variability in QT interval measurement results from biological factors such as diurnal effects, differences in autonomic tone, electrolytes and drugs; technical factors and the environment, the processing of the recording, and the acquisition of the ECG recording; and intra-observer and inter-observer variability resulting from variation in T wave morphology, noisy baseline and presence of U waves⁴⁵.

There are major problems with defining the normal QT interval:

1. Variations on gender, heart rate and age bias. QT is longer in female, old age and with slow heart rate.

2. Difficulties in determining the end of the T wave

3. Lack of consensus as to the best way to correct for the normal variation in the QT interval based on heart rate and because unified opinion as to which lead or leads should be used to measure the QT interval.

4. Potential fusion of the U wave with the T wave

On modern ECG machines, the QT interval is usually given but their values are unreliable particularly for patients with a prolonged QT interval because these machines are not always capable of making the correct determination of the end of the T wave. Machine reading of QT interval has been shown in a case ziprasidone overdosage where the automatically measured QT on the standard bedside ECG machine did not identify a prolonged QT compared with both automated 12 lead Holter and manual measurements which found a prolonged QT interval⁴⁶. Hence, it is important to also check the QT interval manually. This manual approach has the advantage of more accurately determining the end of the QT but it is

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time consuming. Automatic approaches allow the rapid measurement of large number of QT intervals but even the best algorithm may be inaccurate in determining the end of the QT interval.⁴⁷. It has been suggested that the most accurate way to measure the QT interval is to use high resolution digital 12 lead ECGs extracted from continuous 12 lead ECG displayed on-screen in a magnified view where the six limb leads and the six chest leads are separately overlapped. On-screen calipers can then be adjusted by a manual operator to confirm the automatic QT measurement and correct it if necessary. This technology is unlikely to be available outside of pharmaceutical development and has only been used in a limited number of studies.^{46.48, 49}

A major problem with measurement of QT interval is defining the end of the T wave.

QT interval in an ECG complex can be measured manually by at least 3 methods;

1. Visual method – is the simplest method. It identifies the point where the T wave returns to the isoelectric baseline.⁵⁰

2. Threshold method – in this method, the end of the T wave is determined as a point where the descending limb of the T wave meets the isoelectric baseline⁵¹ as shown in figure 3 below.

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Figure 3: QT interval measurement by threshold method.

(Adapted from Salvi V, Karnad D, Panicker G, Kothari S. Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development. Br J Pharmacol 2010; 159: 36.)

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3. Tangent method - in which the end of T wave is determined by the intersection of a line extrapolated from isoelectric baseline and the tangent line, which touches the terminal part of the T wave at the point of maximum downslope⁵². A line is drawn through the baseline (preferably the PR segment), then the tangent is drawn against the steepest part of the end of the T wave. If the T wave has 2 deflections, the taller deflection should be chosen, if the T wave is biphasic, the end of the taller deflection should be chosen. The QT interval measurement therefore measured from the beginning of the QRS interval to the point where the tangent and the baseline cross (figure 4).The tangent method has been shown to have less inter reader variability, it gives a shorter measurement of the QT compared with other methods and may be more inaccurate with unusual T wave morphology⁵⁰.

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Figure 4: QT interval measurement by Tangent method

(Adapted from Salvi V, Karnad D, Panicker G, Kothari S. Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development. Br J Pharmacol 2010; 159: 36.)

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With the increased availability of digital ECGs with simultaneous 12 channel recording, QT interval measurement may also be done by the ‘superimposed median beat’ method⁵³. In this method, a median ECG complex is constructed for each of the 12 leads. The 12 median beats are superimposed on each other and the QT interval is measured either from the earliest onset of the Q wave to the latest offset of the T wave or from the point of maximum convergence for the Q wave onset to the T wave offset (Figure 5).

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Figure 5: QT interval measurement by superimposed median beat method

(Adapted from Salvi V, Karnad D, Panicker G, Kothari S. Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development. Br J Pharmacol 2010; 159: 36.)

41 2.5.2 Corrected QT interval (QTc)

This is the QT interval that has been corrected for Heart Rate (HR).The single most important parameter that affects the QT interval is the heart rate. The QT interval is dependent on the HR in an obvious way (the faster the HR, the shorter the QT interval and vice versa) and may be adjusted to improve the detection of patients at high risk of ventricular arrhythmias.

There are number of different correction formulae but the standard clinical correction use mostly is the Bazett’s formula, named after physiologist Bazett⁵⁴.

Bazett’s formula is as follows:

QTc = QT/√𝑅𝑅 (ms) RR = 60/HR X 1000 (ms)

Where RR is the interval from the onset of one QRS complex to the onset of the next QRS. Here the QT is measured in milliseconds.

However, this non-linear formula, obtained from data in only 39 young men, is not accurate, and overcorrects at high heart rate and under-corrects at low heart rate⁵⁵.

Fridericia⁵⁶ published an alternative correction formula using the cube root of RR interval where

QTc = QT/∛𝑅𝑅

There are several other methods as well, which include the linear regression equation called the Framingham formula as well as Hodges formula.

Framingham formula⁵⁷: QTc = QT+ 0.154(1-RR) QTc = QT +0.154{1-(60/HR)}

Hodges formula⁵⁸:

QTc = QT +1.75(HR – 60)

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The Framingham formula performs better during ventricular pacing, but still overestimates the QTc in sinus rhythm by about 37- 43ms⁵⁹.

The application of heart rate correction formulae such as Bazett’s, Friedricia, Hodges, and Framingham is problematic and has not completely remove the dependence of the QT interval on the heart rate and therefore does not allow comparisons of QT interval for different heart rates⁶⁰. This is most problematic with Bazett’s which will over-correct and under-correct outside a narrow physiological range of heart rate⁶¹.

Davey⁶² provides reasons why Bazett’s and other correction formulae fail to correct the QT interval:

The first reason is that the formulae do not remove the dependence of the QT interval on the heart rate which is worst in the case of Bazett’s formula which over corrects for heart rate as indicated by the correlation between heart rate and corrected QT. This has been confirmed for Bazett’s formula in a number of studies^{63, 64}. Friedricia and Hodges perform better at high heart rate (>100bpm) ^{65, 66}.

The second reason is that these universal correction formulae correct for heart rate at population level. These formulae assume that the relationship between QT interval and heart rate is fixed for different individuals. Numerous studies have demonstrated that the QT/ heart rate relationship is stable within an individual but varies significantly between individuals.

Therefore, accurate heart rate correction of the QT interval can only occur if the relationship between heart rate and QT is known at individual level.

To circumvent the problems with heart rate correction and what QTc cut-off to use, the QT nomogram (Figure 6) was developed.⁶⁷ This QT nomogram is based on the ‘cloud’ which is a plot of QT versus the RR interval for a population. The QT-RR plots in an individual form a unique cloud which shows the variability in the QT- heart rate relationship, usually over a 24 hour period. Individual clouds can then be superimposed and the inter-individual differences

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form a population cloud. Fossa et al ⁶⁸ also suggested that any QT-RR pairs outside this population ‘cloud’, which is 95% ‘normal’ range, are associated with an increased risk of arrhythmia. To make the QT-RR ‘cloud’ more practical for clinical use, the QT nomogram plots the QT versus heart rate but retains the same normal and ‘at risk’ formulae and can be potentially used for single individual.

QT nomogram :

QTc = QT + 0.116 X (1000 – RR), if RR > 1000

QTc = QT + 0.156 X (1000 – RR), if RR 600> RR< 1000 QTc = QT + 0.384 X (1000 – RR), if RR < 600

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Figure 6: QT Nomogram: The nomogram line separates HR, QT pairs above the line associated with increased risk of Torsade de Pointes compared with the below line.

(Adapted from Chan A, Isbister GK, Kirkpatrick CM, Dufful SB. Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram. QJM.2007;

100(10):611.)

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The QT nomogram had a sensitivity of 97% and specificity of 99% compared with Bazett’s formula with a sensitivity of 99% and specificity of 67% (QTc =440ms) and sensitivity of 94% and specificity of 97% (QTc = 500ms)⁶⁷.

A subsequent study has independently demonstrated that the QT nomogram is better than QTc criteria, with a lower positive false rate⁶⁹. This QT nomogram has been used in numerous studies as a risk assessment tool for ventricular tachyarrhythmias and Torsades de Pointes^70-75.

The definitions of normal ‘QTc’ vary across publications being ≤ 400ms - 440ms in most publications. The normal value for QTc is below 450ms for men and below 460ms for women as agreed upon by the ACC/HRS⁷⁶.

In a recent ACC consensus document, an expert writing group suggests that in an hospital setting the upper limit be raised to the 99^th percentile of normal: 470ms in males and 480ms in females, as approximately 10 to 20% of the general population have a QTc >440ms

For both men and women QTc > 500ms is considered abnormal. If QTc is <340ms, short QT syndrome can be considered⁷⁷.

Causes of prolonged QT 1. Hereditary syndromes

2. Electrolyte / metabolic abnormalities including hypocalcemia, hypokalemia, hypomagnessemia, hypothyroidism, hypothermia

3. Intrinsic cardiac disease

4. Medications including antiarrhythmics, antimalarials, antibiotics, anticholinergics drugs, antihistamines, tricyclic antidepressants, antipsychotics and antifungals

5. CNS disorders 6. Systemic illnesses 7. Myocardial infarction

46 Causes of short QTc

1. Digitalis effect 2. Hyperthermia 3. Vagal stimulation 4. Hypercalcemia 5. Short QT syndrome

2.6 QT dispersion (QTd) and the corrected QTd (QTcd)

2.6.1 QT dispersion (QTd)

QT dispersion is simply defined as the difference between the longest (QTmax) and the shortest (QTmin) QT interval on 12 lead ECG.

For clinical purposes, ECG based assessment of ventricular repolarization has traditionally been limited to the measurement of the QT interval and to the description of the polarity and the shape of T wave often using vague terms such as “ non-specific ST segment and T wave changes”. QT dispersion is a crude and approximate measure of a general abnormality of repolarization.

In 1990, a report by Campbell et al⁷⁸ revived an old idea of the inter-lead differences in the QT interval duration. The range of the durations, termed “QT dispersion” was proposed as an index of the spatial dispersion of the ventricular recovery times. It was proposed that the different ECG leads magnify the ECG signal of different myocardial regions and that consequently QT dispersion is an almost direct measure of the heterogeneity of myocardial repolarization.

Recent studies have defined QT dispersion as interlead QT variability on the surface ECG and it may reflect regional variations in myocardial recovery of excitability. The finding of a

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decreased QTd in patient with heart diseases treated with class III agents (sotalol, amiodarone) further support the concept⁷⁹.

Pathophysiology of QT dispersion

There has been much concern about the validity of the concept and methodology of QT measurement. The initial concept that QTd is an index of inhomogeneity was supported by the link between the dispersion of the ventricular recovery times and genesis of arrhythmias.

It is generally believed that the standard 12 lead ECG contained information about regional ventricular repolarization. The validity of the concept is further consolidated by studies correlating intra cardiac monophasic action potentials (MAPs) with various QT dispersion indices⁸⁰.

Zabel et al⁸¹ showed that the dispersion of the QT and JT intervals were significantly correlated with the dispersion of 90% duration of the action potential duration (APD90) and with the dispersion of recovery times. This study was generally interpreted as a proof of QT dispersion representing regional variation in the duration of the ventricular action potentials Kors et al⁸² further contributed to the understanding of the interlead differences. They found that QTd was significantly different between patients with narrow (54.2±27.1ms) and wide T loops (69.5±33.5ms, P< 0.001). They also showed that in each of the six limb leads as well as the six precordial leads, the difference between the QT interval in a lead and the maximum QT interval was dependent on the angle between the axis of the lead and axis of the terminal part of the T- loop.

It is reasonable to conclude that the dispersion of the ventricular recovery times measured with MAPs and QTd are direct and indirect expression of repolarization abnormalities that are likely to correlate even without any mechanistic link⁸³.

As far as possible each of the 12 QT intervals should be individually measured to determine the values of these two extreme indices.

QTd = QTmax – QTmin

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A dilemma arises when the QT intervals are not measurable in all the 12 leads, and it is not possible to tell whether any of the omitted leads contain the extreme QT values necessary for the QTd calculation. It is possible to correct for the missing leads but this has not gained wide acceptance. Further studies are required to settle the need for missing lead correction.

The current consensus is to use only ECGs with at least 8 measurable leads, bearing in mind that only two limb leads are necessary to mathematically derive the other four limb⁸⁴.

What constitutes a normal QTd is still being debated. A population based study involving over 3000 adults and children suggested that QTd≤ 50ms indicated normality; age or gender having no impact on this definition.^{85, 86}

2.6.2 Corrected QT dispersion (QTcd)

The QT interval can on its own vary according to the heart rate, it may be corrected using the Bazett’s formula to give rise to the corrected QT interval (QTc), and the difference between maximum QTc (QTcmax) and the minimum QTc(QTcmin) is the corrected QT dispersion (QTcd). QTcd is simply QT dispersion (QTd) that has been corrected for heart rate.

QTcd = QTcmax - QTcmin

It can be shown that if there is a shortest T – wave in one of the extremity leads, the other 5 extremity leads must have the same end of T.

QTc dispersion can accurately be defined as the difference between the maximum and the minimum QTc in 8 leads that is the 6 precordial leads, the shortest extremity lead and the median of the 5 other extremity leads.

The Rotterdam study has shown that increased QTc dispersion is a strong and independent risk factor for cardiac mortality in older men and women⁸⁷.

The Strong Heart Study also assessed the predictive value of the corrected QT dispersion in 1839 American Indians who were followed up for 3.7± 0.9yrs. Heart rate corrected QT

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interval assessed as a continuous variable remained a significant independent predictor of cardiovascular risk in both univariate and multivariate cox proportional hazard models, with 34% increase of cardiovascular mortality for each 17ms increase in QTcd. In multivariate analysis QTcd > 58ms (the upper 95^th percentile in a separate population of normal subjects) was associated with a 3.2 fold increase of cardiovascular mortality (95%CI 1.8 – 5.7)⁸⁸.