7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Congenital long QT syndrome: Diagnosis : Peter J Schwartz, MD, Michael J Ackerman, MD, PhD : John K Triedman, MD, Samuel Asirvatham, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 13, 2019. INTRODUCTION Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death (SCD) [1]. The primary symptoms in patients with LQTS include syncope, seizures, cardiac arrest, and SCD. LQTS is associated with an increased risk of a characteristic life-threatening cardiac arrhythmia known as torsades de pointes or "twisting of the points" ( waveform 2) [2]. LQTS may be congenital or acquired [1,3-7]. Pathogenic variants in up to 17 genes have been identified thus far in patients with congenital LQTS; the three major genetic subtypes are designated LQT1 through LQT3 while the minor LQTS-susceptibility genes are designated by their genetic substrate (eg, CALM1-LQTS) ( table 1) [7]. Acquired LQTS usually results from undesired QT prolongation and potential for QT-triggered arrhythmias by either QT-prolonging disease states, QT-prolonging medications ( www.crediblemeds.org), or QT-prolonging electrolyte disturbances ( table 2). (See "Congenital long QT syndrome: Pathophysiology and genetics".) The ECG features and diagnostic approach to persons with suspected congenital LQTS will be reviewed here [1]. The epidemiology, clinical features, and management of congenital LQTS in children and adults and the acquired LQTS are discussed separately. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Congenital long QT syndrome: Treatment" and "Acquired long QT syndrome: Definitions, pathophysiology, and causes" and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 1/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate DIAGNOSTIC EVALUATION Our approach Our approach to evaluating the patient with suspected congenital LQTS involves multiple steps [1]: For all patients, the initial evaluation of suspected congenital LQTS should include obtaining a comprehensive personal and family history, performance of a physical examination, and review of an ECG (examination of serial ECGs is extremely helpful). The ECGs are examined to determine both the length of repolarization (the QTc) and the look of repolarization (T wave morphology). When available, ECGs are also obtained from immediate family members to determine if any first-degree relatives (parents, siblings, and/or children) exhibit QT prolongation or other associated abnormalities. Secondary causes of QT prolongation and the acquired LQTS should be excluded ( table 2). Besides the resting ECG, 24-hour ambulatory ECG monitoring (full 12-lead monitoring, if available) is performed as well, looking for arrhythmias as well as any dynamic T wave changes including (rarely) macroscopic T wave alternans, especially at nighttime. If the patient is old enough and able to perform a bicycle or treadmill stress test, we perform an exercise stress test looking for exercise-associated arrhythmias, changes in T wave morphology, and the presence of a maladaptive QT response during the recovery phase. A QTc >470 milliseconds at two through five minutes of recovery is highly suggestive of LQT1. (See 'Exercise testing' below.) Calculation of the LQTS diagnostic score, also known as the "Schwartz Score." (See 'Diagnosis' below.) Clinical and family history Obtaining a detailed personal medical history and a multi- generation family history is crucial in determining the pretest likelihood of congenital LQTS. The personal clinical history should focus on signs and symptoms suggestive of tachyarrhythmia, particularly ventricular tachyarrhythmias, as many LQTS families have pre-sudden death warning signs including: Syncope suggestive of cardiac/arrhythmic origin (ie, not vasovagal syncope) Syncope followed by generalized seizures Resuscitated sudden cardiac arrest https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 2/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Additionally, obtaining a multi-generation family history, and utilizing a genetic counsellor when available, is also crucial to establishing the clinical likelihood of congenital LQTS. Key family history items that increase the likelihood of congenital LQTS include: Premature sudden deaths (<40 years of age and autopsy negative) Unexplained motor vehicle accidents Unexplained drownings Generalized seizures (frequently, patients with LQTS have been misdiagnosed with, and treated for, epilepsy) After obtaining the clinical and family history and reviewing the results of the resting, ambulatory, and stress ECGs, the LQTS diagnostic score can be calculated. (See '12-lead ECG' below and 'Ambulatory ECG monitoring' below and 'Diagnosis' below.) 12-lead ECG All patients being evaluated for congenital LQTS should have multiple 12-lead ECGs performed. The QT interval should be measured manually on serial ECGs using multiple leads (preferably leads II and V5) and then corrected for heart rate. Once consistent QTc prolongation has been shown on two ECGs (on occasion even one ECG is sufficient), serial ECG testing may be discontinued altogether or at least the interval of surveillance lengthened. The point at which serial ECG testing can be discontinued is highly variable, depending upon the patient s age, growth patterns, and the significance of previous ECG findings. Even after the diagnosis of LQTS is established, most pediatric patients with LQTS will have a 12-lead ECG and 12-lead ambulatory ECG monitoring performed every one to two years. In Europe there is a preference for yearly (rather than every two years) follow-up, including an exercise stress test. If low-risk and asymptomatic, most adults with LQTS will continue to have periodic cardiac re- evaluations every one to five years. Sometimes, the ECG itself is used to monitor satisfaction with the LQTS-directed treatment program such as when mexiletine is used to attenuate the QTc. If so, a follow-up ECG may be obtained even more frequently than annually. While yearly ECGs in general are most appropriate, obtaining an ECG more frequently (eg, every one to two months) is usually unnecessary and unacceptable. In addition, beat-to-beat variability and respiratory sinus arrhythmia affect formulas used to correct for heart rate. As a result, several successive beats may on occasion need to be measured and averaged for each ECG. (See 'QT rate correction' below and 'Special circumstances' below.) Prolongation of the QTc is an essential component of the diagnosis of LQTS. However, the QTc varies in response to a number of factors, such as autonomic state, electrolyte imbalance, drugs, and diurnal changes [8,9]. https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 3/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Other ECG features, such as T wave morphology and bradycardia, may be useful in the evaluation of the patient with suspected LQTS, but the QTc appears to be the most useful diagnostic and prognostic parameter [10]. General ECG principles The QT interval reflects the time required for both depolarization (the QRS complex) and repolarization (the T wave) of the ventricles. Repolarization is a larger component of the entire QT interval, and QT prolongation is generally considered to reflect abnormalities of repolarization. The QT interval varies inversely with the heart rate; therefore, the QT measurement is adjusted for the heart rate, resulting in the corrected QT interval, or QTc. (See 'QT rate correction' below.) Measuring the QT interval The computer-derived QTc should always be confirmed or corrected manually. The QT interval is measured from the onset of the QRS complex to the point at which the T wave ends ( waveform 1). Accurate measurements can be technically challenging, largely due to difficulties in determining the precise termination of the T wave. The QT interval should be measured in different beats and in several leads. The technique of measuring the QT interval is discussed separately. (See "ECG tutorial: ST and T wave changes", section on 'Prolonged QT interval'.) Impact of U waves Identifying the termination of the T wave can be particularly difficult when a U wave is present. The U wave should not be included if it is distinct from and smaller than the T wave (generally excluded if the T wave has returned completely to the isoelectric line and then a U wave that is <one-half the amplitude of the preceding T wave is inscribed). Erroneous inclusion of the U wave in the QT interval measurement can lead to overdiagnosis of LQTS [11]. Which lead should be used? QT intervals vary significantly among leads [12]. Most normal reference ranges are based upon measurements from lead II, and lead V5 is often favored because of the clarity of T wave termination [13,14]. Additionally, some experts find leads V2 and V3 to be very useful, since QT measurements are typically the longest in these leads [12,14]. Other experts, however, avoid measuring the QT interval in leads V2 and V3, particularly in adolescents and children in whom a U wave is frequently present, making it more difficult to precisely determine the point of T wave termination. QT rate correction Under normal circumstances, the duration of repolarization depends upon the heart rate. The QT interval is longer at slower rates and shorter at faster rates. For this reason, formulas have been developed to "correct" the QT interval for heart rate (or the duration of the RR interval), although none is ideal (calculator 1) [8,15-17]. The most commonly used rate correction formula was developed by Bazett [18]: https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 4/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate QTc = QT interval RR interval (in sec) Although this approach is simple and generally accurate, it is less accurate at heart rate extremes and results in overcorrecting at high heart rates and undercorrecting at low heart rates [8]. Normative values are available for newborns and older children, which are standardized by age [19-21]. Normal QTc ranges Overall, the average QTc in healthy persons after puberty is 420 20 milliseconds, while during infancy the average QTc is 400 20 milliseconds. By contrast, the average QTc among patients with genetically confirmed LQTS is approximately 470 milliseconds, although patients with confirmed LQTS can exhibit a wide range of QTc values (360 to >800 milliseconds in our experts practices). In general, the 99th percentile QTc values are 460 milliseconds (prepuberty), 470 milliseconds in postpubertal males, and 480 milliseconds in postpubertal females. Asymptomatic patients who incidentally exceed these values on serial ECGs, and do not have any acquired QT-prolonging factors, should be evaluated further for the possibility of congenital LQTS as they now have a 10 percent chance of having LQTS (rather than the 1 in 2000 chance that they had prior to getting an ECG). Further, for asymptomatic children with an otherwise idiopathic QTc >480 milliseconds and asymptomatic adults with an otherwise idiopathic QTc >500 milliseconds, LQTS genetic testing is recommended since at these thresholds, LQTS is now more likely for that patient than merely being an extreme QTc outlier. Further, patients with a QTc >500 milliseconds are at increased risk of SCD. (See 'Genetic testing' below.) Special circumstances In addition to the methodologic and technical challenges discussed above, QT measurement and interpretation is complicated in the following situations: Atrial fibrillation (AF) Due to the irregular changes in the RR interval, the QT interval can vary on a beat-to-beat basis during AF. To accommodate this variability, some clinicians recommend averaging the measurements over 10 beats. Others advise measuring the QT intervals that follow the longest and shortest RR intervals in the ECG, then dividing each by the square root of the preceding RR interval [15]. The average of these two values is then used as the corrected QT interval. Still others find the measurement of QT and QTc in AF to be completely unreliable and instead focus on the look of repolarization (T wave morphology characteristics) rather than trying to measure the length of repolarization in AF. https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 5/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Sinus arrhythmia Similarly, in cases with marked RR variability, the QT rate correction formulas may not be as accurate, and taking an average of multiple beats can reduce the variation due to respiratory sinus arrhythmia. Another approach in such patients is to attempt to identify beats which are further away from any longer pauses and measure the QT in those beats. QRS prolongation QT prolongation usually reflects abnormal repolarization, but when depolarization (the QRS complex) is abnormal and prolonged, the significance of mild QT prolongation is uncertain. It has been suggested that measurement of the JT interval (defined as the QT interval minus the QRS duration) may be a more appropriate way to identify abnormalities in repolarization in such patients [22]. The normal JTc is less than 360 milliseconds in children without LQTS and is typically greater than 360 milliseconds in children with LQTS [22]. However, the validity of using the JT interval in this manner has been questioned. An alternative approach is to adjust the QT interval as a linear function to account for QRS duration and heart rate in the setting of ventricular conduction delay [23]. Another approach is to use a threshold of 500 milliseconds for a prolonged QTc in the setting of a wide QRS complex [15]. However, this threshold will result in an overdiagnosis of LQTS. Importantly, patients with congenital LQTS almost never have concomitantly prolonged QRS values. Recalling JT interval norms is also problematic. Instead, a simple wide QRS adjustment formula can be used: Wide QRS adjusted QTc = QTc [QRS 100] Other ECG features The T waves of patients with congenital LQTS are frequently abnormal with a biphasic contour or a prominent notched component (particularly in LQT2). However, this finding is fairly insensitive, and the absence of an abnormal T wave morphology does not exclude patients from having congenital LQTS. In one report, notched or biphasic T waves were present in 62 percent of patients with LQTS compared with 15 percent of control subjects [24]. A variety of other atypical T wave shapes have also been described in LQTS [25]. In experienced hands, T wave morphology, when coupled with knowledge about arrhythmia triggers, may suggest a particular genotype (such as notched T waves plus auditory triggers during the postpartum period equating with LQT2), but the presence or absence of T wave abnormalities does not alter the diagnostic evaluation in any notable way. Exercise testing In nearly all patients (ie, those who are old enough to cooperate and are capable of performing an exercise protocol) with known or suspected congenital LQTS, we perform an exercise (treadmill or bicycle) ECG stress test as part of the initial diagnostic evaluation. Additionally, for patients diagnosed with congenital LQTS, we repeat an exercise ECG https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 6/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate stress test every one to five years (annually for previously symptomatic patients, less frequently for asymptomatic, low-risk adults) as part of the ongoing follow-up. The response to ECG testing in patients with suspected congenital LQTS is frequently subtle and complex, requiring a high degree of aptitude to correctly interpret and diagnose the findings. If doubt exists surrounding the interpretation or implication of ECG findings post-exercise, the patient should be referred to a clinician with specific expertise and experience with congenital LQTS. ECG stress testing in patients with suspected congenital LQTS is performed to assess for exercise-associated arrhythmias, changes in T wave morphology, and the presence of a maladaptive QT response during the recovery phase. Physiologically, the QT interval shortens with exercise and with increased heart rate. By contrast, in individuals with LQT1, the QT interval may fail to shorten or may lengthen with exertion and at higher heart rates, and may be prolonged during the recovery phase after exercise. At least part of the variability in the response to exercise in LQTS patients results from different responses among the major types of congenital LQTS: Patients with LQT1 have diminished shortening of the QT interval and a reduced chronotropic response during exercise followed by exaggerated lengthening of the QT interval as the heart rate declines during early and late (eg, one and four minutes) recovery after exercise [26-28]. This is due to the fact that their pathogenic variants impair the function of the Kv7.1 outward-rectifying potassium channels, which contributes to shortening the action potential during activation of the sympathetic nervous system. Many patients with LQT2 have marked QT interval shortening and a normal chronotropic response during exercise, although there are exceptions [26,29]. There is exaggerated lengthening of the QT interval as the heart rate declines during late recovery (eg, > four minutes) after exercise [26,28]. These characteristics may explain the observation that many cardiac events occur during exercise in LQT1 ( figure 1) [30]. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Triggers of arrhythmia'.) Accentuated heart rate recovery following standard exercise testing, a marker of vagal activity, appears to be a marker of increased risk of cardiac events (syncope or aborted SCD) in patients with LQT1. Among 169 patients identified as LQT1 genotype positive who underwent standard exercise testing and achieved similar maximal heart rate and workloads, those with prior cardiac events had a significantly greater heart rate recovery during the first minute following exercise compared with those without prior events (19 versus 13 beats per minute in a 47 patient South African cohort; 27 versus 20 beats per minute in a 122 patient Italian cohort) [31]. Greater heart https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 7/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate rate reductions immediately following exercise in persons positive for the LQT1 genotype appear to risk stratify them at a higher risk of arrhythmic events. The response of QTc during exercise recovery may be helpful in identifying LQTS in asymptomatic relatives of individuals with LQTS as well as in identifying probands [28]. Supine QTc at rest: If 470 milliseconds in males or 480 milliseconds in females with personal or family history suspicious for LQTS, then the patient has high probability LQTS (estimated at >90 percent likelihood). However, if the patient exceeds these QTc thresholds but is <500 milliseconds AND has no personal or family history to suggest LQTS, then although the patient is graded as intermediate probability LQTS by the Schwartz score, this should not be viewed as definite LQTS. Instead, the patient has a small but definite chance (5 to 20 percent) of having congenital LQTS. If normal or borderline normal Check the QTc during the recovery phase of the stress test. Recovery QTc at two, three, or four minutes into recovery after peak exercise: If QTc 470 milliseconds, then there is an estimated 70 percent positive predictive value (PPV) for unmasking LQT1 [32]. If the QTc at five minutes of recovery is 470 milliseconds and is 40 to 50 milliseconds greater than the QTc at one minute of recovery (ie, QTc latency), then LQT2 is possible (approximately 70 percent PPV). The QTc values shorten during exercise and in recovery in patients with LQT3, and therefore stress testing is not helpful in LQT3. However, if the patient exhibits QT prolongation at rest and then the QTc shortens at peak exercise and in recovery, then LQT3 emerges as the possible underlying genotype. In addition, the stress test is often used to assess the adequacy of beta blockade by noting a measurable reduction in maximum heart rate. However, there is no particular threshold of peak heart rate reduction (ie, 20, 25, 30 percent, etc) that guarantees protection from ventricular arrhythmias and SCD. Instead, this assessment at least confirms that reasonable levels of beta blocker have been achieved in the patient. Ambulatory ECG monitoring In patients with known or suspected congenital LQTS, we perform ambulatory ECG monitoring to help establish the diagnosis of LQTS and to add https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 8/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate corroborative information in borderline cases [33-36]. The QT interval and other ECG features of LQTS may vary with activity and time of day. Holter monitoring can detect intermittent QT prolongation, bradyarrhythmia, macroscopic T wave alternans, and T wave notching [33,35,36]. A 12-lead ambulatory ECG monitor can be helpful to detect abnormal changes in T wave morphology, especially at night. The results of ambulatory monitoring should be interpreted with caution, however, since patients without congenital LQTS can have QT intervals over the normal limits at times, reducing the specificity of Holter monitor QTc results [37]. However, this usually happens with rapid heart rate increases, and the expert observer is not misled. Discrepancies in measurements may occur when Holter recordings are compared with standard ECGs. Given the limitations of Holter monitoring for establishing the diagnosis of LQTS, we do not recommend making the diagnosis of LQTS based solely on the QTc measurement during ambulatory recordings. The results of such testing should be used only as ancillary information. Provocative testing In some patients, the diagnosis of congenital LQTS may be uncertain after application of the diagnostic criteria outlined above. Additional testing, including serial cardiologic testing of the index case and appropriate relatives and provocative electrocardiographic testing with catecholamines (the epinephrine QT stress test), facial immersion, abrupt supine-to-standing ECG, or mental stress test [38], may be helpful in such patients. However, these tests must be interpreted with great caution as the positive predictive values are generally 70 percent or less. Genetic testing Our recommendations for genetic testing in the evaluation of suspected congenital LQTS are generally in accord with those of professional societies [39-41]. We proceed with genetic testing in the following instances: Patients with a high clinical suspicion of congenital LQTS based on history, family history, ECG findings, and results of any additional testing, such as a high Schwartz score 3.5 (Class I recommendation). Patients with an intermediate clinical suspicion of congenital LQTS based on history, family history, ECG findings, and results of any additional testing, such as an intermediate Schwartz score of 1.5 to 3 (Class II recommendation). Asymptomatic patients without a family history of congenital LQTS but who have serial ECGs with QTc 480 milliseconds before puberty or 500 milliseconds post-puberty (Class I recommendation). https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 9/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Asymptomatic patients without a family history of congenital LQTS but who have serial ECGs with QTc 460 milliseconds before puberty or 480 milliseconds post-puberty (Class II recommendation). Cascade/variant-specific testing of all appropriate relatives when the disease-causative variant has been identified in the proband (Class I recommendation). This generally proceeds in concentric circles of relatedness. For example, if the LQTS- causative variant was inherited paternally, then the paternal aunts and uncles are tested first rather than testing them and the cousins at the same time. If an aunt, for example, tests negative, then there is generally no need to perform cascade testing on that aunt's children. Among families with genetically proven/confirmed LQTS, it is unacceptable to tell family members/relatives that they do or do not have LQTS based solely on their ECG. Only a negative variant-specific genetic test result and a normal ECG in that relative can prompt the conclusion that the relative does not have LQTS and can be dismissed from follow-up. Genetic testing will identify a specific LQTS-causative variant in approximately 80 percent of patients with a high probability LQTS diagnosis (ie, Schwartz score >3.5). It may establish the diagnosis when it is uncertain, allow for efficient identification of affected family members, and have prognostic and therapeutic utility by determining which gene is involved. (See "Congenital long QT syndrome: Pathophysiology and genetics".) Genetic testing to identify the patient's LQTS-causative variant is now more readily available for clinical use [4,7,42-44]. As a result, genotyping has become more frequently utilized as part of the diagnostic and prognostic evaluation of patients with congenital LQTS. However, congenital LQTS is a complex and genetically heterogeneous condition, so a negative test does not exclude disease. Nevertheless, when a negative genetic test is obtained (which by itself rules out approximately 80 percent of congenital LQTS), it is very reasonable to reassess the veracity of the clinical diagnosis of congenital LQTS. If the diagnosis is robust, then the patient belongs to the 20 percent subset of genotype negative congenital LQTS patients, and the patient and their family should be connected to research laboratories to search for their genetic cause of LQTS. On the other hand, if the strength of the evidence was weak/inconclusive in the first place, then a negative genetic test can help begin the subsequent reevaluation efforts to move away from and rescind the previously rendered diagnosis of congenital LQTS, which can involve the removal of previously implanted defibrillators as well [45,46]. This is yet another reason why consideration for referral to LQTS specialty centers should be given. In one dedicated LQTS clinic, 40 percent of the patients who came with the diagnosis of LQTS were dismissed without the diagnosis of LQTS, with the vast majority of those being reclassified as otherwise healthy without any evidence of important heart disease [45]. https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 10/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Genetic testing in LQTS is discussed in detail separately. (See "Congenital long QT syndrome: Pathophysiology and genetics".) DIAGNOSIS For all patients in whom congenital LQTS is suspected following the initial evaluation, we calculate the Schwartz score to better estimate the clinical likelihood of a congenital LQTS diagnosis and proceed directly to phenotype-directed genetic testing (ie, the genetic test panel that comprises the established LQTS-susceptibility genes) ( table 3). A weighted, non-genetic scoring system for the diagnosis of congenital LQTS, also called the "Schwartz score," incorporates the measured QTc and other clinical and historical factors; the score was developed in 1985 [47] and revised in 1993 [48], 2006 [49], and 2011 [50]. An algorithm was developed in which diagnostic criteria were assigned points as follows ( table 3): ECG findings (in the absence of medications or disorders known to affect these features): QTc (= QT/ RR, interpret with caution with tachycardia since QTc overcorrects at fast heart rates) - - 480 milliseconds: 3 points 460 to 479 milliseconds: 2 points 450 to 459 milliseconds (in males): 1 point QTc at fourth minute of recovery from exercise stress test 480 milliseconds: 1 point [50] (see 'Exercise testing' above) Torsades de pointes* (in the absence of drugs known to prolong QT): 2 points T wave alternans: 1 point Notched T wave in three leads: 1 point Resting heart rate below second percentile for age (restricted to children): 0.5 point Clinical findings: Syncope* (*Points for documented torsade and syncope are mutually exclusive) - With stress: 2 points Without stress: 1 point https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 11/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Family history (the same family member cannot be counted in both of these criteria): Family members with LQTS: 1 point Unexplained SCD in immediate family members <30 years of age: 0.5 point The points are added to calculate the LQTS diagnostic score ("Schwartz Score"). The 2006 and 2011 versions rate the probability of having LQTS according to the number of accrued points [49,50]: Low 1 point Intermediate 1.5 to 3 points High 3.5 points When a patient satisfies a high probability Schwartz score (ie, 3.5 points), the likelihood of a positive LQTS genetic test is approximately 80 percent. While an intermediate probability Schwartz score warrants further pursuit of the possibility of congenital LQTS (ie, genetic testing of the patient and ECG testing of his/her relatives), it does not equal a diagnosis of congenital LQTS. In this setting, the likelihood of LQTS is approximately a 5 to 20 percent chance, far higher than the 1 in 2000 background rate for this disease. In such a patient, when genetic testing is pursued, and if it comes back negative (thereby ruling out 80 percent of LQTS by itself), such a patient with an "intermediate probability" Schwartz score could be dismissed as normal eventually with insufficient evidence to merit the diagnosis of LQTS. Importantly, if the Schwartz score is low (<1 point), genetic testing should not be pursued. Do not label such individuals as borderline LQTS or possible LQTS. Instead, in most circumstances, these patients should be reclassified quickly as normal and dismissed from follow-up. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 12/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Long QT syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1), ventricular arrhythmias, and an increased risk of sudden cardiac death (SCD) caused by torsades de pointes or "twisting of the points" ( waveform 2). (See 'Introduction' above.) LQTS may be congenital or acquired. Pathogenic variants in up to 17 genes have been identified thus far in patients with genetic LQTS; the major and most important genetic subtypes are designated LQT1 through LQT3, while the minor LQTS-susceptibility genes are designated by their genetic substrate such as CALM1-LQTS, for example ( table 1). (See 'Introduction' above.) The initial diagnostic strategy includes evaluation of the presenting event (eg, syncope, seizures, sudden cardiac arrest, or SCD), obtaining a careful family history, careful evaluation of the QTc, exclusion of secondary causes of QT prolongation, ambulatory ECG monitoring (with 12-lead ECG if at all possible), exercise testing, and calculation of the LQTS diagnostic score (the "Schwartz score"). (See 'Our approach' above.) Obtaining a detailed personal medical history and multi-generation family history is crucial in determining the pretest likelihood of congenital LQTS. The personal clinical history should focus on signs and symptoms suggestive of tachyarrhythmia, particularly ventricular tachyarrhythmias, as many LQTS families have pre-sudden death warning signs including syncope suggestive of cardiac etiology, syncope followed by generalized seizures, or resuscitated sudden cardiac arrest. (See 'Clinical and family history' above.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 13/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate All patients being evaluated for congenital LQTS should have a 12-lead ECG performed. The QT interval should be measured manually on serial ECGs using multiple leads (preferably leads II and V5), and then corrected for heart rate. The heart rate corrected QT interval (QTc) is the most useful diagnostic and prognostic parameter for LQTS. The computer- derived QTc should always be confirmed or corrected manually. Since the QTc varies in response to physiologic factors and drugs, the sensitivity of a QTc from a single ECG is less than 100 percent, and serial ECG testing is required frequently. (See '12-lead ECG' above.) The average QTc values in healthy adults are 420 20 milliseconds with 99th percentile values being 460 milliseconds (prepuberty), 470 milliseconds (postpubertal males), and 480 milliseconds (postpubertal females). (See 'Normal QTc ranges' above.) Other ECG features of LQTS include abnormal T wave morphology, T wave alternans, and increased QT dispersion. (See 'Other ECG features' above.) In nearly all patients (ie, those who are old enough to cooperate and are capable of performing an exercise protocol) with known or suspected congenital LQTS, we perform an exercise (treadmill or bicycle) ECG stress test as part of the initial diagnostic evaluation to assess for exercise-associated arrhythmias, changes in T wave morphology, and the presence of maladaptive QT response during the recovery phase. (See 'Exercise testing' above.) In patients with known or suspected congenital LQTS, we perform ambulatory ECG monitoring (with 12-lead ECG if available) to help establish the diagnosis of LQTS and to add corroborative information in borderline cases. (See 'Ambulatory ECG monitoring' above.) The LQTS diagnostic score ("Schwartz score") may be helpful in evaluating individuals with suspected LQTS but is not adequate for screening of family members of affected individuals. (See 'Diagnosis' above.) Genetic testing will identify a specific LQTS-causative variant in approximately 80 percent of patients with a definite diagnosis of LQTS. Genetic testing should be viewed as standard of care in the diagnostic and prognostic evaluation of LQTS on par with the ECG itself. It may establish the diagnosis when it is uncertain, allow for efficient identification of affected family members, and have prognostic and therapeutic utility by determining which gene is involved. By all major cardiac societies throughout the world, genetic testing is indicated clinically for any patient in whom the diagnosis of LQTS is being considered or for whom the diagnosis of LQTS has been established already. (See 'Genetic testing' above.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 14/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Among families with genetically proven/confirmed LQTS, it is unacceptable to tell family members/relatives that they do or do not have LQTS based solely on their ECG. Only a negative variant-specific genetic test result and a normal ECG in that relative can prompt the conclusion that the relative does not have LQTS and can be dismissed from follow-up. (See 'Genetic testing' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013; 34:3109. 2. Roden DM. 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