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

CLINICAL RESEARCH Europace (2010) 12, 1296–1301 doi:10.1093/europace/euq184 Channelopathies Abnormal repolarization dynamics revealed in exercise test in long QT syndrome mutation carriers with normal resting QT interval Anna-Mari Hekkala 1*, Matti Viitasalo 1, Heikki Väänänen 2, Heikki Swan 1, and Lauri Toivonen 1 1 Department of Cardiology, Helsinki University Hospital, PL 340, 00029 Helsinki, Finland; and 2Department of Biomedical Engineering and Computational Science, Aalto University, Espoo, PL 12200, 00076 AALTO, Finland Received 22 March 2010; accepted after revision 24 May 2010; online publish-ahead-of-print 20 June 2010 Aims 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. ..................................................................................................................................................................................... Methods Sixty-six subjects were included: 15 were carriers of KCNQ1 (LQT1); 15 of KCNH2 (LQT2); and 9 of SCN5A and results (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. ..................................................................................................................................................................................... Conclusions 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. ----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords Exercise test † LQTS † QT interval † Tpe interval † Ventricular repolarization Introduction Congenital long QT syndrome (LQTS) is a familial disorder caused by mutations in different genes coding sarcolemmal ion channels. The most common subtypes LQT1 and LQT2 are caused by loss of function mutations in slow (IKs) and fast (IKr) cardiac potassium channels, whereas subtype LQT3, present in about 10% of patients, is caused by gain of function mutations in cardiac sodium channel (INa).1 The clinical outcome is prolonged and nonhomogenous ventricular repolarization, exposing the patient to torsades de pointes ventricular tachycardia, leading to abrupt loss of consciousness and sudden cardiac death.2 – 4 Molecular screening has become an important tool for diagnosing LQTS. However, 30– 40% of mutation carriers still escape molecular genetic diagnosis,4,5 and screening tests are not readily available. In the absence of molecular genetic testing the diagnosis is based on clinical characteristics.6 A considerable proportion of mutation carriers—and even symptomatic patients—present with normal (QTc ,440 ms) or borderline (QTc ,470 ms) QT intervals. T wave morphology and gene-specific T wave patterns5,7 and dynamic changes in ventricular repolarization8 have been looked for facilitating the diagnosis. Exercise tolerance test has been used for identifying LQTS2 and its subtypes.9,10 We characterized subtype-specific features in ventricular repolarization using * Corresponding author. Anna-Mari Hekkala, Haartman Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland. Tel: +358 403 347 362; fax: +358 931 034 389, Email: anna-mari. Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010. For permissions please email: . 1297 Abnormal repolarization dynamics Table 1 Basic characteristics of study subjects Controls (n 5 27) LQT1 carriers (n 5 15) LQT2 carriers (n 5 15) LQT3 carriers (n 5 9) ............................................................................................................................................................................... Age (years) 34 + 7 34 + 11 41 + 10 35 + 15 BMI (kg/m2) Peak exercise level (W) 23 + 3 254 + 74 24 + 4 221 + 76 26 + 3 228 + 59 25 + 3 181 + 33* Resting heart rate (bpm) 60 + 7 61 + 9 65 + 9 66 + 12 Achieved heart rate (bpm) QTc at rest (ms) 184 + 9 378 + 22 164 + 11† 420 + 24* 177 + 11 438 + 30* 174 + 17 440 + 29* Tpe at rest (ms) 78 + 10 83 + 11 114 + 25‡ 83 + 17 Values are presented as mean + SD. BMI, body mass index; bpm, beats per minute; QTc, QT interval at rest, adjusted for heart rate by Bazett’s formula; Tpe, T wave peak to T wave end interval at rest. *P , 0.05, compared with controls; †P , 0.05, compared with controls and LQT2 mutation carriers; ‡P , 0.001, compared with other groups. automatic algorithms during maximal exercise test in LQTS mutation carriers with normal appearing QT intervals. Methods Subjects The study population consisted of asymptomatic LQTS mutation carriers and healthy controls. We selected randomly from our national LQTS register mutation carriers who had normal—or nondiagnostic—QT interval duration. None of them had had beta-blocker therapy prior to, or during, the study. Fifteen subjects had LQTS type 1, 15 LQTS type 2, and 9 LQTS type 3 mutations. The mutations were KCNQ1 G589D mutation in 15, KCNH2 del453C in 8, L552S in 5, R176W in 1, and G584S in 1, and SCN5A V1667I in 4, I239V in 2, A691T in 2, and E1784K in 1. All these mutations are known to cause clinical disease.11,12 Twenty-seven healthy volunteers without any history of syncope or clinical evidence of cardiovascular disease, and with normal baseline QT intervals (QTc ,440 ms) served as controls. Ages are presented in Table 1. None took any regular medication during the study. Exercise testing and analysis of electrocardiograms Exercise was performed with bicycle ergometer starting with a load of 30 W followed by increments of 15 W for females and 20 W for males every minute until exhaustion. Blood pressure was measured at rest and subsequently every 3 min (...truncated)