Approach Considerations
Routinely check serum levels of potassium (and sometimes magnesium) and thyroid function in patients who present with QT prolongation after arrhythmic events, to eliminate secondary reasons for repolarization abnormalities.
Analysis of repolarization duration (QTc) and morphology on a patient's ECG and on ECGs of the patient's relatives frequently leads to an accurate diagnosis.
Imaging studies
Imaging studies (eg, echocardiography, magnetic resonance imaging [MRI]) may help only in excluding other potential reasons for arrhythmic events (eg, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy) or associated congenital heart diseases in a small subset of patients with LQTS, such as persons with LQT8.
Diagnostic criteria
A presentation with syncope or sudden cardiac death, in combination with a long QT on an ECG, typically suggests long QT syndrome (LQTS) and leads to genetic testing to diagnose the disease. In many patients, however, the presentation may not be typical. Therefore, other tests may be indicated.
In 1993, Schwartz et al suggested diagnostic criteria that still serve as the best criteria for clinicians.[7] In their model, the criteria are divided to 3 main categories, as shown in Table 2, below. The maximum score is 9, with a score of greater than 3 indicating a high probability of LQTS.
Table 2. Diagnostic Criteria for LQTS (Open Table in a new window)
| Criterion | Points | |
| ECG findings * | ||
| QTc, ms† | >480 | 3 |
| 460-469 | 2 | |
| 450-459 in male patient | 1 | |
| Torsade de pointes‡ | 2 | |
| T-wave alternans | 1 | |
| Notched T wave in 3 leads | 1 | |
| Low heart rate for age§ | 0.5 | |
| Clinical history | ||
| Syncope║ | With stress | 2 |
| Without stress | 1 | |
| Congenital deafness | 0.5 | |
| Family history ¶ | ||
| A. Family members with definite LQTS# | 1 | |
| B. Unexplained sudden cardiac death < 30y in an immediate family member | 0.5 | |
| *In the absence of medications or disorders known to affect these electrocardiographic features. †QTc calculated by Bazett's formula ‡Mutually exclusive §Resting heart rate below the second percentile for the age. ||Mutually exclusive ¶The same family member cannot be counted in A and B. #Definite LQTS is defined by an LQTS score of more than 3 (≥4). | ||
Electrocardiography
As the aforementioned criteria by Schwartz et al suggest, the most helpful ECG findings are prolongation of the QT interval, torsade de pointes, T-wave alternans, and certain morphology of the T waves (wide-based T wave, and notched T wave in 3 leads).
Correlation between the type of mutation and T-wave morphology has been suggested. Wide-based T waves are most frequently seen in LQT1, and notched T waves are most commonly seen in LQT2. In LQT3, T waves may appear normal, with a long, isoelectric ST segment.
Prolongation of the QTc interval is defined on the basis of age- and sex-specific criteria (see Table 3, below). QTc is calculated by dividing the measured QT by the square root of the R-R interval, both of which are measured in seconds. QTc prolongation of greater than 0.46 second indicates an increased likelihood of long QT syndrome (LQTS). (See the image below.)
Marked prolongation of QT interval in a 15-year-old male adolescent with long QT syndrome (LQTS) (R-R = 1.00 s, QT interval = 0.56 s, QT interval corrected for heart rate [QTc] = 0.56 s). Abnormal morphology of repolarization can be observed in almost every lead (ie, peaked T waves, bowing ST segment). Bradycardia is a common feature in patients with LQTS. However, approximately 10-15% of gene-positive patients with LQTS present with a QTc duration in the reference range. (See the image below.)
Genetically confirmed long QT syndrome (LQTS) with borderline values of QT corrected for heart rate (QTc) duration (R-R = 0.68 s, QT interval = 0.36 s, QT interval corrected for heart rate [QTc] = 0.44 s) in a 12-year-old girl. Note the abnormal morphology of the T wave (notches) in leads V2-V4. Table 3. Definition of QTc Based on Age- and Sex-Specific Criteria (Open Table in a new window)
| Group | Prolonged QTc, s | Borderline QTc, s | Reference Range, s |
| Children and adolescents (< 15 y) | >0.46 | 0.44-0.46 | < 0.44 |
| Men | >0.45 | 0.43-0.45 | < 0.43 |
| Women | >0.46 | 0.45-0.46 | < 0.45 |
In patients with suspected LQTS with borderline QTc values (or even values in the reference range) on standard ECGs or in patients with a score of 2-3 based on the 1993 diagnostic criteria, an analysis of the dynamic behavior of QTc duration during exercise ECG or long-term Holter monitoring may reveal maladaptation of the QT interval to a changing heart rate. QTc prolongation may be evident at a fast heart rate. Ventricular arrhythmias are rarely observed during exercise testing or Holter recording in patients with LQTS.
No evidence indicates that invasive electrophysiology with attempts to induce ventricular tachycardia facilitates diagnosis.
Bradycardia and tachycardia
Bradycardia and tachycardia each need special attention. Bradycardia is included in the diagnostic criteria and adds 0.5 point to the score. Tachycardia needs special attention, too, because the QTc may be overcorrected in a tachycardic situation (eg, in infants).
T-wave alternans
Visible T-wave alternans in patients with LQTS indicates an increased risk of cardiac arrhythmias (ie, torsade de pointes and ventricular fibrillation).
Detection of microvolt T-wave alternans has low sensitivity and high specificity in diagnosing LQTS. The prognostic value of microvolt T-wave alternans has not been studied systematically.
Pharmacologic provocation
Pharmacologic provocation with epinephrine or isoproterenol helps in diagnosing LQTS in patients with a borderline presentation. It may also provide information regarding the type of mutation present.
Testing family members
It is important to review the ECGs of family members of a patient with LQTS, to obtain detailed histories, and to perform physical examinations. However, an absence of ECG findings of LQTS in family members does not exclude LQTS. In the ideal setting, all family members should be tested for mutations to help limit the small, but definite, risk of arrhythmia and sudden cardiac death. Testing is especially relevant if the patient was exposed to a drug that prolongs the QT interval.
Genetic Testing
Patients with a clinical or ECG presentation of long QT syndrome (LQTS) need genetic testing to identify the mutation. Genetic testing for known mutations in deoxyribonucleic acid (DNA) samples from patients is becoming accessible in specialized centers, although such tests can entail considerable expense, and insurance coverage for genetic testing often requires specific physician intervention.
Identification of a long QT syndrome (LQTS) genetic mutation confirms the diagnosis. However, a negative result on genetic testing is of limited diagnostic value because only approximately 50% of patients with LQTS have known mutations. The remaining half of patients with LQTS may have mutations of yet unknown genes. Therefore, genetic testing has high specificity but low sensitivity.
Response to Standing
A 2010 study Viskin and colleagues demonstrated that the expected shortening of QT interval in response to sinus tachycardia induced by standing from a supine position is impaired in patients with LQTS. In fact, the QTc interval in patients with LQTS increased with standing position, and more PVCs were detected during standing in these patients. Thus, the increased QTc interval in response to standing up, which is associated with increased sympathetic tone, can provide more diagnostic information in patients with LQTS.[8]
In addition, this study may reveal that standing up in patients with LQTS may be associated with more focal activities (perhaps due to early afterdepolarization that contributes to APD and, therefore, to QT prolongation) and ventricular arrhythmias. Therefore, syncope while standing up in a patient with LQTS may not be simply a vasovagal syncope but may represent a more dangerous condition.
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| Type of LQTS | Chromosomal Locus | Mutated Gene | Ion Current Affected |
| LQT1 | 11p15.5 | KVLQT1 or KCNQ1 (heterozygotes) | Potassium (IKs) |
| LQT2 | 7q35-36 | HERG, KCNH2 | Potassium (IKr) |
| LQT3 | 3p21-24 | SCN5A | Sodium (INa) |
| LQT4 | 4q25-27 | ANK2, ANKB | Sodium, potassium and calcium |
| LQT5 | 21q22.1-22.2 | KCNE1 (heterozygotes) | Potassium (IKs) |
| LQT6 | 21q22.1-22.2 | MiRP1, KNCE2 | Potassium (IKr) |
| LQT7 (Anderson syndrome) | 17q23.1-q24.2 | KCNJ2 | Potassium (IK1) |
| LQT8 (Timothy syndrome) | 12q13.3 | CACNA1C | Calcium (ICa-Lalpha) |
| LQT9 | 3p25.3 | CAV3 | Sodium (INa) |
| LQT10 | 11q23.3 | SCN4B | Sodium (INa) |
| LQT11 | 7q21-q22 | AKAP9 | Potassium (IKs) |
| LQT12 | SNTAI | Sodium (INa) | |
| JLN1 | 11p15.5 | KVLQT1 or KCNQ1 (homozygotes) | Potassium (IKs) |
| JLN2 | 21q22.1-22.2 | KCNE1 (homozygotes) | Potassium (IKs) |
| Criterion | Points | |
| ECG findings * | ||
| QTc, ms† | >480 | 3 |
| 460-469 | 2 | |
| 450-459 in male patient | 1 | |
| Torsade de pointes‡ | 2 | |
| T-wave alternans | 1 | |
| Notched T wave in 3 leads | 1 | |
| Low heart rate for age§ | 0.5 | |
| Clinical history | ||
| Syncope║ | With stress | 2 |
| Without stress | 1 | |
| Congenital deafness | 0.5 | |
| Family history ¶ | ||
| A. Family members with definite LQTS# | 1 | |
| B. Unexplained sudden cardiac death < 30y in an immediate family member | 0.5 | |
| *In the absence of medications or disorders known to affect these electrocardiographic features. †QTc calculated by Bazett's formula ‡Mutually exclusive §Resting heart rate below the second percentile for the age. ||Mutually exclusive ¶The same family member cannot be counted in A and B. #Definite LQTS is defined by an LQTS score of more than 3 (≥4). | ||
| Group | Prolonged QTc, s | Borderline QTc, s | Reference Range, s |
| Children and adolescents (< 15 y) | >0.46 | 0.44-0.46 | < 0.44 |
| Men | >0.45 | 0.43-0.45 | < 0.43 |
| Women | >0.46 | 0.45-0.46 | < 0.45 |
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