Long QT Syndrome Mutation Carriers Research Articles

Reversed apico-basal myocardial relaxation sequence during exercise in related to impaired diastolic function and attenuated stroke volume response in LQTS mutations carriers

Abstract Background Speckle-tracking echocardiography studies in inherited long QT syndrome (LQTS) have recently shown myocardial relaxation disturbances at rest in the form of delayed onset of relaxation as a result of prolonged and dispersed mechanical contraction. The aim of this study was to assess disturbances in left ventricular regional myocardial relaxation sequence during exercise. Methods Forty seven (age 45±15 years, 25 female, LVEF: 65±6%, 36 LQT1 and 11 LQT2 whereof 20 symptomatic) patients underwent cardiac exercise test using Bruce protocol. ECG and echo parameters were recorded at rest, during peak exercise (p.e.) and at were compared with 35 healthy individuals. All time intervals were calculated from onset of R wave on superimposed ECG and were corrected to R-R interval. Results LQTS patients had longer QTc interval than controls at all the three exercise phases. LV longitudinal tESR, a reflector of relaxation delay was examined separately in the LV basal, mid and apical segments. At rest, no significant differences were noted between the two groups at the basal (490±59 vs. 486±36, p=0.6) and mid LV cavity regions (488±45 vs. 498±39, p=0.3); whereas in patients were seen more prolonged tESR in the apical regions (467±52 vs. 512±44, p<0.0001). At peak exercise, patients had longer tESR at all three LV segments; basal (394±67 vs. 316±30, p<0.0001), mid cavity (363±64 vs. 340±32, p=0.03) and apical (348±60 vs. 368±28, p=0.03). The apico-basal relaxation dispersion (Δt ESRbase-apex) was significantly more pronounced in patients than in controls both at rest (49±43 vs. −29±19, p<0.0001) and at p.e. (46±38 vs. −40±22, p<0.0001). Moreover, the longitudinal relaxation sequence was reversed in patients (positive values for Δt ESRbase-apex); the early relaxation phase at the base was more delayed than at the apex, opposite to controls in whom the early relaxation onset occurred earlier in LV base than at apex. The magnitude of this apico-basal relaxation dispersion (Δt ESRbase-apex) correlated with longer QTc interval (r=0.9, p<0.0001), lower ESR (r=−0.8, p<0.0001) and attenuated LV stroke volume (r=−0.9, p<0.0001). This difference in Δt ESRbase-apex was more pronounced in symptomatic patients at p.e. than in asymptomatic (69±44 vs. 32±26, p<0.0007). Conclusion Our results showed reversed longitudinal relaxation sequence with more delayed early relaxation contraction phase at LV base than at LV apex in LQTS mutation carriers opposite to controls. These disturbances worsened at peak exercise and were related to longer QTc intervals and symptomatic patients. Funding Acknowledgement Type of funding sources: None.

Generation of the human induced pluripotent stem cell (hiPSC) line PSMi007-A from a Long QT Syndrome type 1 patient carrier of two common variants in the NOS1AP gene

We generated human induced pluripotent stem cells (hiPSCs) from a symptomatic Long QT Syndrome (LQTS) type 1 patient, belonging to a South African (SA) founder population segregating the heterozygous mutation c.1022C > T p.A341V on the KCNQ1 gene. The patient is also homozygous for the two minor variants rs4657139 and rs16847548 on the NOS1AP gene, associated with greater risk for cardiac arrest and sudden death in LQTS mutation carriers of the founder population. hiPSCs, obtained using four retroviruses encoding the reprogramming factors OCT4, SOX2, cMYC and KLF4, display pluripotent stem cell characteristics, and can be differentiated into spontaneously beating cardiomyocytes (hiPSC-CMs).

Abstract 11828: Follow-up of Genetically Confirmed Adult Long QT Syndrome Type 1 and 2 Patients: Clinical Course and Tools for Mutation-specific Risk Stratification

Introduction: Long QT syndrome (LQTS) is an inherited cardiac disorder predisposing to sudden cardiac death (SCD). Research has been scarce on its clinical course in genetically confirmed patients not receiving β-blocker therapy. Also, applicability of specific mutations as a part of risk stratification calls for further investigation. Methods: The study population was drawn from the Finnish Inherited Cardiac Disorder Research Registry comprising 4000 molecularly tested subjects. The inclusion criteria were 1) genetically confirmed KCNQ1 or KCNH2 mutation, or non-carrier status of the family-specific LQTS mutation, and 2) the age of 18-40 years during the follow-up. A questionnaire was sent to the study subjects. Data of all deaths were obtained from Statistics Finland, and data of ICD and pacemaker implantations were acquired from Hospital discharge register (HDR). Results: A total of 2723 subjects fulfilled the inclusion criteria. Of them 14 died during the follow-up, 1495 (55%) responded to the inquiry, and additional 12 subjects with device therapy were drawn from the HDR. The final study population (n=1521) consisted of 867 LQTS mutation carriers (617 with KCNQ1 , 242 with KCNH2 , and seven with ≥1 mutation), and 654 non-carrier relatives. The total follow-up time including retrospectively collected data was 18.3±6.3 years. In mutation carriers, risk factors for cardiac events before initiation of β-blocker included LQT2 genotype (hazard ratio [HR]=2.1, p=0.002), female gender (HR=3.2, p<0.001), a cardiac event before the age of 18 years (HR=5.9, p<0.001), and QTc ≥500 ms (vs <470 ms, HR=2.7, p=0.01). LQT1 patients carrying the KCNQ1 D317N mutation were at higher risk (HR=3.0-3.9, p<0.001-0.03) compared to G589D, c.1129-2A>G and other KCNQ1 mutation carriers after adjusting for gender and QTc duration. KCNH2 c.453delC, L552S and R176W mutations associated with lower risk (HR=0.12-0.24, p<0.001) than other KCNH2 mutations. Of the seven SCDs four, and of the 14 aborted cardiac arrests three involved QT-prolonging drug. Conclusions: Specific mutations modulate the risk independently of gender and QTc duration. The avoidance of QT-prolonging drugs is fundamental in the prevention of potentially life-threatening cardiac events.

Is Symptomatic Long QT Syndrome Associated with Depression in Women and Men?

We examined whether long QT syndrome (LQTS) mutation carrier status or symptomatic LQTS are associated with depression, and whether there are sex differences in these potential relationships. The sample comprised 782 participants (252 men). Of the 369 genetically defined LQTS mutation carriers, 169 were symptomatic and 200 were asymptomatic. The control group consisted of 413 unaffected relatives. Depression was assessed using the Beck Depression Inventory-II (BDI-II). No association was found for LQTS mutation carrier status with depression. The multinomial logistic regression showed that LQTS mutation carrier men with arrhythmic events scored higher on depression compared with the control group, even when adjusting for age, β-blockers, antidepressants, and social support (OR=1.09, 95% CI [1.02, 1.15], p=.007). The binary logistic regression comparing symptomatic and asymptomatic LQTS mutation carriers showed that symptomatic LQTS was associated with depression in men (OR=1.10, 95% CI [1.03, 1.19], p=.009). The results were unchanged when additionally adjusted for education. These findings suggest that symptomatic LQTS is associated with depression in men but not in women. Overall, however, depression is more frequent in women than men. Thus, regular screening for depression in LQTS mutation carriers and their unaffected family members can be important.

Follow-up of 316 molecularly defined pediatric long-QT syndrome patients: clinical course, treatments, and side effects.

Inherited long-QT syndrome (LQTS) is associated with risk of sudden death. We assessed the clinical course and the fulfillment of current treatment strategies in molecularly defined pediatric LQTS type 1 and (LQT1) and type 2 (LQT2) patients. Follow-up data covering a mean of 12 years were collected for 316 genotyped LQT1 and LQT2 patients aged 0 to 18 years. No arrhythmic deaths occurred during the follow-up. Finnish KCNQ1 and KCNH2 founder mutations were associated with fewer cardiac events than other KCNQ1 and KCNH2 mutations (hazard ratio [HR], 0.33; P=0.03 and HR, 0.16; P=0.01, respectively). QTc interval ≥500 ms increased the risk of cardiac events compared with QTc <470 ms (HR, 3.32; P=0.001). Treatment with β-blocker medication was associated with reduced risk of first cardiac event (HR, 0.23; P=0.001). Noncompliant LQT2 patients were more often symptomatic than compliant LQT2 patients (18% and 0%, respectively; P=0.03). Treatment with implantable cardioverter defibrillator was rare (3%) and resulted in reinterventions in 44% of cases. Severe cardiac events are uncommon in molecularly defined and appropriately treated pediatric LQTS mutation carriers. β-Blocker medication reduces the risk of cardiac events and is generally well tolerated in this age group of LQTS patients.

Work Stress and the Long QT Syndrome

To examine whether work stress is associated with a symptomatic status of the long QT syndrome (LQTS). The sample comprised 173 KCNQ1, KCNH2, or SCN5A gene mutation carriers (70 symptomatic) and control groups of 203 relatives without the family mutation, and of 1209 population-based young Finns control subjects. Work stress was assessed using the Job Content Questionnaire and Occupational Stress Questionnaire. We found an association between the occurrence of symptoms in the LQTS and high work stress, higher job demands/effort, lower job control, and lower rewards compared with control subjects. We also found that symptomatic LQTS mutation carriers had higher work stress than asymptomatic LQTS mutation carriers. Higher work stress is related to arrhythmic risk in the LQTS. It may be useful to incorporate assessment of work conditions and stress interventions into management of high-risk patients.

Stress Proneness in Molecularly Defined Long QT Syndrome: A Study Using Temperament Assessment by Behavioural Inhibition System Scale

The long QT syndrome (LQTS) is an inherited cardiac disorder that predisposes the mutation carrier to ventricular arrhythmias that can lead to sudden death. The objective of the present study was to replicate the previous finding in terms of stress-related temperament trait, i.e. behavioural inhibition system (BIS). The study subjects included 583 LQTS mutation carriers (256 symptomatic and 327 asymptomatic) from the Finnish LQTS registry and 79 healthy subjects randomly derived from the population-based sample of the Young Finns Study. Symptomatic and asymptomatic LQTS mutation carriers did not differ from each other on BIS (3.27 versus 3.24, p > 0.05), whereas LQTS mutation carriers scored higher on BIS than the comparison group derived from the representative population-based sample (3.25 versus 2.99, p = 0.003, η² = 0.014). BIS was significantly higher in women than in men (3.32 versus 3.06, p < 0.001, η² = 0.017). The results confirm our previous finding of higher stress proneness of LQTS mutation carriers. Their innate stress proneness may have relevance because it increases our understanding on the role of stress in the manifestation of symptoms.

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Stressful Work Involvement and Inherited Long QT-Syndrome

Aims: The long QT syndrome (LQTS) is an inherited cardiac disorder which predisposes the mutation carrier to ventricular arrhythmias that can lead to sudden death. The objective of the study was to study whether stressful work involvement (i.e. worrying about work and job dissatisfaction) is related to arrhythmic risk in LQTS. Study design: Cross-sectional study. Place and Duration of Study: The study took place in Finland in 2006 for the LQTS mutation carriers and 2007 for the general Finnish population. Methodology: The study subjects included 164 symptomatic and 229 asymptomatic LQTS mutation carriers from the Finnish LQTS registry and 1368 comparison subjects randomly derived from the population-based sample, Young Finns Study (YFS). Stressful work involvement was measured with questions derived from the Framingham type A scale. Results: Upon assessment of the stressful work involvement, symptomatic LQTS Research Article British Journal of Medicine & Medical Research, 2(1): 31-38, 2012 32 mutation carriers scored higher than asymptomatic LQTS mutation carriers (1.51 vs. 1.40, p=0.003, η2=0.022) and the general Finnish population (1.51 vs. 1.39, p<0.001, η2=0.012), while asymptomatic LQTS mutation carriers did not differ from the general Finnish population in the corresponding scores (1.40 vs. 1.39, p=0.374, η2<0.001). Conclusion: The results confirm the suggestion that perceived stress, in terms of stressful work involvement, may increase the likelihood of arrhythmic events in LQTS mutation carriers. Thus, individual stress proneness may be a risk factor for LQT symptoms, which should be taken into account in counseling LQTS patients. There is previous evidence that stress proneness can be modified by behavioral therapy.

Prevalence of Significant Genetic Variants in Congenital Long QT Syndrome is Largely Underestimated

Congenital long QT syndrome (LQTS) is clinically characterized by the occurrence of syncope due to polymorphic ventricular tachycardia (torsades de pointes), associated to delayed cardiac repolarization that is reflected by a prolongation of the QT interval on the ECG (Webster and Berul, 2008). Thus far, 13 genes coding for ion channel subunits and ion channel regulatory proteins have been found mutated in patients and families with LQTS (Schwartz et al., 2009). The estimated prevalence of LQTS in the general population is reported to be in the range of 1:7000–1:2000 (0.01–0.05%), without any significant ethnical disparity (Roden and Spooner, 1999; Tester et al., 2006; Schwartz et al., 2009). Different research groups from many countries have reported similar data or cited the same sources (Roden and Spooner, 1999; Tester et al., 2006; Schwartz et al., 2009). Recently, two original studies reported a high prevalence of LQTS founder mutations in the Finnish and Norwegian population (Berge et al., 2008; Marjamaa et al., 2009). In Finland, it was concluded that 1 out of 250 individuals (0.4%) carry a LQTS founder mutation (Marjamaa et al., 2009). In Norway, the prevalence of LQTS mutation carriers was estimated to be close to 1%, which is a prevalence that is the highest documented worldwide (Berge et al., 2008). These findings are of clear interest to researchers and clinicians since they may not be only relevant for the Finnish and Norwegian populations, but may also give some important clues about the actual worldwide distribution of genetic variants predisposing to cardiac arrhythmias. In a study looking at variants in KCNQ1 in a subgroup with the longest QTc interval (403–443 ms) from French general population of 100 non-related and non-treated individuals from the DESIR cohort, two new mutations in KCNQ1 were found (Gouas et al., 2004). This study suggests that such low-penetrant variants might be found with 2% frequency within one “healthy” cohort after screening of one only one gene of interest. As it can be seen, there are clear discrepancies in estimations of LQTS mutation prevalence depending on the sources. Long QT syndrome is considered as a Mendelian arrhythmic disorder which is transmitted mainly in an autosomal dominant mode of inheritance (Priori et al., 2008). Thus, one should be able to apply the basic concepts of genetics such as Mendel’s law for families and Hardy–Weinberg equation for population in equilibrium. Hereafter, we analyze and interpret published data and our own results to estimate the prevalence of LQTS using different approaches.

Cloninger's temperament traits and inherited long QT syndrome

Objective The long QT syndrome (LQTS) is an inherited cardiac disorder which predisposes the mutation carrier to ventricular arrhythmias that can lead to sudden death. The objective of the present study was to examine the association between the symptom status of congenital long QT syndrome mutation carriers and their temperament. Methods The study subjects included 587 LQTS mutation carriers from the Finnish LQTS registry, and 2056 individuals from a database study, the Young Finns Study (YFS), representing general population and serving as control subjects. The LQTS subjects were divided into symptomatic (n=259) and asymptomatic (n=328) groups, according to their history of arrhythmic events. Temperament was assessed using the Cloninger's Temperament and Character Inventory (TCI), assessing novelty seeking, harm avoidance and reward dependence. Results Congenital long QT syndrome mutation carriers had a higher harm avoidance (HA) than those representing the general population (2.77 vs. 2.61, p<.001, η²=0.011). Symptomatic and asymptomatic LQTS mutation carriers did not differ from one another in any of the three Cloninger's temperament traits. HA was significantly higher in women (2.72 vs. 2.54, p<0.001 η²=0.017). Conclusions LQTS mutation carriers may have higher stress proneness because of their high HA, which in turn may predispose them to the effects of environmental loading and thus increase the risk of arrhythmias.

Transmural Differences in Myocardial Contraction in Long-QT Syndrome

Background— Long-QT syndrome (LQTS) is characterized by prolonged myocardial action potential duration. The longest action potential duration is reported in the endomyocardium and midmyocardium. Prolonged action potential duration in LQTS may cause prolonged cardiac contraction, which can be assessed by strain echocardiography. We hypothesized that myocardial contraction is most prolonged in subendocardial myofibers in LQTS patients and that inhomogeneous transmural contraction is related to the risk of spontaneous arrhythmia. Methods and Results— We included 101 genotyped LQTS mutation carriers and 35 healthy individuals. A history of cardiac arrhythmias was present in 48 mutations carriers, and 53 were asymptomatic. Myocardial contraction duration was assessed by strain echocardiography as time from the ECG Q wave to peak strain in 16 LV segments. Strain was assessed along the longitudinal axis, predominantly representing subendocardial fibers, and along the circumferential axis, representing midmyocardial fibers. Mean contraction duration was longer in LQTS mutation carriers compared with healthy individuals (445±45 versus 390±40 milliseconds; P &lt;0.001) and longer in symptomatic compared with asymptomatic LQTS mutation carriers (460±40 versus 425±45 milliseconds; P &lt;0.001). Contraction duration by longitudinal strain was longer than by circumferential strain in symptomatic LQTS patients (460±45 versus 445±45 milliseconds; P =0.008) but not in asymptomatic patients and healthy individuals, indicating transmural mechanical dispersion. This time difference was present in a majority of LV segments and was most evident in patients with LQT2 and the Jervell and Lange-Nielsen syndrome. Conclusion— Contraction duration in symptomatic LQTS mutation carriers was longer in the subendocardium than in the midmyocardium, indicating transmural mechanical dispersion, which was not present in asymptomatic and healthy individuals.

Clinical Summaries

Clinical Summaries

Opioid maintenance patients with QTc prolongation: Congenital long QT syndrome mutation may be a contributing risk factor

Objectives This study investigates opioid maintenance treatment (OMT) patients found to have corrected QT (QTc) interval above 500 ms, with particular focus on past medical history, genetic testing and cardiac investigations. Methods Detailed medical and cardiac history was obtained, with particular focus upon risk factors. Cardiac investigations, including genetic testing for the five most common long QT syndrome (LQTS) mutations, exercise electrocardiography (ECG) and 24-h ECG recordings, were performed. Results Of 200 OMT patients assessed with ECG, seven methadone maintained patients identified with QTc interval above 500 ms participated in this study. Two were identified as heterozygous LQTS mutation carriers. Both had experienced cardiac symptoms prior to and during OMT. No other risk factors for QTc prolongation were detected among the seven patients. Six of the seven patients underwent further cardiac investigations. QTc intervals fluctuated widely over 24 h and during exercise for all patients. Only one of the LQTS mutation carriers switched to buprenorphine and started on a beta-blocker. Despite strong medical advice and information, none of the other patients wanted to switch to buprenorphine or take other cardiac protective measures. Conclusion Findings indicate the importance of recording a thorough past medical history, focusing specifically on previous cardiac symptoms, and on other known risk factors for QTc prolongation, prior to initiating patients on methadone.

A history of stressful life events, prolonged mental stress and arrhythmic events in inherited long QT syndrome

ObjectiveTo examine whether a history of stressful life events and prolonged mental stress are associated with arrhythmic events in inherited long QT syndrome (LQTS).MethodsParticipants who had a molecularly established mutation...

Abnormal repolarization dynamics revealed in exercise test in long QT syndrome mutation carriers with normal resting QT interval

The identification of affected family members with long QT syndrome (LQTS) is often difficult due to their normal-or only marginally lengthened-QT interval duration. We examined whether physical exercise test could increase the ability to detect the mutation carrier status in phenotypically normal LQTS family members. Sixty-six subjects were included: 15 were carriers of KCNQ1 (LQT1); 15 of KCNH(2) (LQT2); and 9 of SCN5A (LQT3) gene mutations with no, or borderline, QT lengthening; and 27 were healthy controls. Multiple electrograms over the precordial area were recorded during workload and recovery phases of exercise test. QT intervals and T peak to T end intervals (Tpe intervals) were determined using an automatic algorithm at specified heart rates (HR).The LQT1 mutation carriers had QT interval most prolonged during exercise and recovery, whereas the LQT2 carriers had QT interval longest at low exercise HR. The LQT3 carriers had QT interval longest at rest. The Tpe interval remained nearly unchanged during exercise in LQT1, but shortened in LQT2 and in LQT3 carriers. The Tpe interval was longest in LQT2 carriers at the end of the recovery phase. Tentative dichotomizing values of QT and Tpe intervals improved sensitivity and specificity in distinguishing LQTS subtypes, compared with the QT interval duration alone. LQTS mutation carriers lacking diagnostic QT interval prolongation exhibit abnormal QT and Tpe interval adaptations during physical exercise test. Looking for subtype-specific adaptations might facilitate the identification of LQTS mutation carriers when molecular genetic analysis is not available.

Abnormal left ventricular relaxation in patients with long QT syndrome

We read with great interest the recent report by Haugaa et al. 1 and the accompanying editorial by De Ferrari and Schwartz2 on the association between abnormal ventricular repolarization and mechanical dysfunction (prolonged contraction and/or impaired diastolic function) in patients with long QT syndrome (LQTS). We were particularly interested by the statement of Haugaa et al. 1 that 'these findings imply an impairment of diastolic function in a number of symptomatic LQTS mutation carriers'. In keeping with this view, Moss et al. 3 also linked the prolonged ventricular repolarization in LQT3 patients ( SCN5A- ΔKPQ mutation) with slowed left ventricular (LV) relaxation.3 In these patients, the …

Long QT syndrome and associated gene mutation carriers in Japanese children: results from ECG screening examinations

LQTS (long QT syndrome) is caused by mutations in cardiac ion channel genes; however, the prevalence of LQTS in the general population is not well known. In the present study, we prospectively estimated the prevalence of LQTS and analysed the associated mutation carriers in Japanese children. ECGs were recorded from 7961 Japanese school children (4044 males; mean age, 9.9+/-3.0 years). ECGs were examined again for children who had prolonged QTc (corrected QT) intervals in the initial ECGs, and their QT intervals were measured manually. An LQTS score was determined according to Schwartz's criteria, and ion channel genes were analysed. In vitro characterization of the identified mutants was performed by heterologous expression experiments. Three subjects were assigned to a high probability of LQTS (3.5< or = LQTS score), and eight subjects to an intermediate probability (1.0< LQTS score < or =3.0). Genetic analysis of these II subjects identified three KCNH2 mutations (M124T, 547-553 del GGCGGCG and 2311-2332 del/ins TC). In contrast, no mutations were identified in the 15 subjects with a low probability of LQTS. Electrophysiological studies showed that both the M124T and the 547-553 del GGCGGCG KCNH2 did not suppress the wild-type KCNH2 channel in a dominant-negative manner. These results demonstrate that, in a random sample of healthy Japanese children, the prevalence of a high probability of LQTS is 0.038% (three in 7961), and that LQTS mutation carriers can be identified in at least 0.038% (one in 2653). Furthermore, large-scale genetic studies will be needed to clarify the real prevalence of LQTS by gene-carrier status, as it may have been underestimated in the present study.

Depressive symptoms in the congenital long QT syndrome

Background. A proportion of patients with congenital long QT syndrome (LQTS) experience potentially life-threatening cardiac arrhythmias.Aim. To examine whether depressive symptoms are related to arrhythmic events among symptomatic and asymptomatic LQTS patients, and syncope events among their relatives not carrying the family's LQTS-causing mutation.Methods. The participants were 569 molecularly defined LQTS mutation carriers and 622 non-carrier relatives from the Finnish LQTS registry. Depressive symptoms were self-rated with a revised version of the Beck Depression Inventory.Results. LQTS patients with arrhythmic events scored higher on depressive symptoms than those without (P=0.011) or the control group (P=0.005). In addition, in the binary logistic regression analysis including symptomatic and asymptomatic LQTS mutation carriers, depressive symptoms showed an age- and sex-adjusted association of odds ratio (OR) 1.40 (95% confidence interval (CI) 1.12–1.74) with symptomatic status of LQTS. In similar analysis including non-carriers of the LQTS mutation, there was no association between depressive symptoms and history of syncope events OR 1.23 (95% CI 0.99–1.53).Conclusion. Our results from this relatively large genotyped LQTS patient cohort indicate that depressive symptoms are associated with arrhythmic events in LQTS patients. Whether depressive symptoms are causally related to arrhythmias in LQTS remains uncertain.

Electrocardiographic risk stratification in families with congenital long QT syndrome

The QT interval in the surface ECG is one of the most often used risk stratifiers in families with congenital long QT syndrome (LQTS). The best ECG lead for clinical management of LQTS families remains unclear. The predictive power of the QTc interval in all ECG leads was studied in 200 consecutive genotyped LQTS family members to identify mutation carriers (n = 103; age: 35+/-19 years) and high-risk LQTS patients (n = 16 with survived sudden cardiac arrest) using receiver operating curve (ROC) analysis (ROC = area under curve). Additionally, the risk for events (syncope and sudden cardiac arrest) was calculated for QTc decile in all individuals. The predictive power was highest in lead II and lead V5 for identifying carriers in LQTS families. These ECG leads were optimal for risk stratification (ROC range 0.83-0.87). In these leads, positive predictive value (PPV) and negative predictive value (NPV) were highest for suggested QTc cut-offs (440 and 500 ms) for identification of LQTS mutation carriers and high-risk patients (PPV between 78-81 and 73-80%, respectively). The risk for events in QTc deciles increased exponentially from 10 to 80% and was 40% for QTc > 500 ms. On the basis of these data, QTc is the best diagnostic and prognostic ECG parameter in LQTS families. A single measurement should be obtained in lead II if measurable and then in left precordial leads (preferably V5) as a second choice.