Haglund, Carla M.

Background: Long QT syndrome (LQTS) is a potentially lethal yet highly treatable channelopathy underscored by marked heterogeneity that necessitates evidence-based and individualized therapeutic approaches. One such therapy is the implantable cardioverter defibrillator (ICD). Here, we sought to determine the percentage of patients (pts) with LQTS that received an ICD in our LQTS clinic and its short term outcomes. Methods: An IRB-approved, retrospective analysis of the electronic medical records of 167 LQT1, 113 LQT2, and 29 LQT3 pts evaluated in our LQTS Clinic with subset analysis of those implanted with an ICD in our institution from January 2000 to June 2007. Results: Forty-eight pts (15% of total, 33 females, 14 LQT1, 20 LQT2, and 14 LQT3) received an ICD. The average age at implant was 30 ± 12 years (range 8 – 52 years). Nearly two-thirds received an ICD as primary prevention. The QTc exceeded 500 ms in 18 (37.5%). With an average follow-up of 42 ± 32 months, 9 (19%) have had an appropriate, VF-terminating therapy including 3 with LQT1 and 6 with LQT2. Notably, 5 of the 6 LQT2 females have already received an appropriate ICD therapy whereas none of the LQT3 pts have received one. Secondary prevention indications (p = 0.006), LQT2 genotype (p = 0.03), QTc > 500 ms (p = 0.001), and surprisingly a negative family history (p = 0.0005) predicted those ICD pts most likely to receive an appropriate therapy. Importantly, none of the non-ICD treated pts (> 250) have died a LQT-related death during the same follow-up. Conversely, 9 pts have experienced an inappropriate shock including 6 with LQT3 and males were more likely to receive inappropriate therapies (p = 0.002). Conclusions: The majority of pts with LQTS can be treated effectively without an ICD. In this study, potentially life-saving therapies have been rendered so far at a 5– 6%/year rate. Inappropriate shocks occurred with similar frequency. Secondary prevention, genotype, and QTc predicted those ICD recipients most likely to receive appropriate therapy. Although LQT3 status is commonly associated with an ICD recommendation, so far none of the LQT3 positive ICD recipients have needed their device. Instead, the greatest “save” rate has occurred among the LQT2 positive females deemed at high risk.

Long QT syndrome (LQTS) is a heterogeneous group of channelopathies characterized by increased risk of potentially lethal ventricular arrhythmias. LQT1, LQT2, and LQT3 comprise 95% of genetically proven cases and exhibit a number of established genotype-phenotype correlations. The study aimed at examining the phenotypes of genotype-negative LQTS, accounting for ~25% of LQTS cases. An IRB-approved retrospective analysis was conducted on 56 patients (39 female, 25 ± 17 years) who, after genetic testing either in our sudden death genomics laboratory or with the commercially available Familion test, were negative for mutations in the 3 principal LQTS-susceptibility genes ( KCNQ1, KCNH2, and SCN5A), and the minor genes underlying LQT5 and LQT6. All had been diagnosed with LQTS, with a clinical diagnostic score of ≥ 3.5 or QTc ≥ 480 ms. The mean diagnostic score was 4.4 (95% CI 4.2 – 4.7); mean QTc was 525 ms (95% CI 508 – 543 ms). Two-thirds were symptomatic (syncope, cardiac arrest, and/or seizures) with exercise-triggered events in 10 (26%). Twenty-one (38%) had a family history of sudden cardiac arrest. ECG showed a T wave pattern suggestive of LQT1 in 32%, LQT2 in 43%, and LQT3 in 18%. In those with exercise-induced symptoms, the ECG was LQT2-like in 50% and LQT1-like in 30%. One patient had post-partum syncope with an LQT2-like ECG. None had an auditory trigger, but 3 patients, all with an LQT2-like ECG, had a family history of auditory-triggered events. One-third of the patients had received an ICD, 58% as secondary prevention. Over 2/3 were on beta-blockers. Among the 45 patients so far tested for mutations in minor LQTS-susceptibility genes, 2 had LQTS-causing mutations in ANKB (LQT4), 1 in SCN4B (LQT10), 1 in AKAP9 (LQT11) and 2 in SNTA1 (LQT12). Genotype-negative patients with a firm LQTS diagnosis show marked phenotypic heterogeneity, suggesting multiple underlying pathogenic pathways. Only a few patients have LQTS-causing mutations in minor genes after complete LQT1–12 genetic testing. Classifying genotype negative patients into LQT1-, LQT2-, or LQT3-like profiles may guide the discovery of novel genes encoding channel interacting proteins corresponding to those specific signaling pathways.

Background— Long-QT syndrome (LQTS) is a potentially lethal cardiac channelopathy that can be mistaken for palpitations, neurocardiogenic syncope, and epilepsy. Because of increased physician and public awareness of warning signs suggestive of LQTS, there is the potential for LQTS to be overdiagnosed. We sought to determine the agreement between the dismissal diagnosis from an LQTS subspecialty clinic and the original referral diagnosis. Methods and Results— Data from the medical record were compared with data from the outside evaluation for 176 consecutive patients (121 females, median age 16 years, average referral corrected QT interval [QTc] of 481 ms) referred with a diagnosis of LQTS. After evaluation at Mayo Clinic’s LQTS Clinic, patients were categorized as having definite LQTS (D-LQTS), possible LQTS (P-LQTS), or no LQTS (No-LQTS). Seventy-three patients (41%) were categorized as No-LQTS, 56 (32%) as P-LQTS, and only 47 (27%) as D-LQTS. The yield of genetic testing among D-LQTS patients was 78% compared with 34% for P-LQTS and 0% among No-LQTS patients ( P <0.0001). The average QTc was greater in either D-LQTS or P-LQTS than in No-LQTS (461 versus 424 ms, P <0.0001). Vasovagal syncope was more common among the No-LQTS subset (28%) than the P-LQTS/D-LQTS group (8%; P =0.04). Determinants for discordance (ie, positive outside diagnosis versus No-LQTS) included overestimation of QTc, diagnosing LQTS on the basis of “borderline” QTc values, and interpretation of a vasovagal fainting episode as an LQTS-precipitated cardiac event. Conclusions— Diagnostic concordance was present for less than one third of the patients who sought a second opinion. Two of every 5 patients referred with the diagnosis of LQTS departed without such a diagnosis. Miscalculation of the QTc, misinterpretation of the normal distribution of QTc values, and misinterpretation of symptoms appear to be responsible for most of the diagnostic miscues.

Background— Swimming is a relatively genotype-specific arrhythmogenic trigger for type 1 long-QT syndrome (LQT1). We hypothesize that mimickers of concealed LQT1, namely catecholaminergic polymorphic ventricular tachycardia (CPVT), may also underlie swimming-triggered cardiac events. Methods and Results— Between August 1997 and May 2003, 388 consecutive, unrelated patients were referred specifically for LQTS genetic testing. The presence of a personal and/or family history of a near-drowning or drowning was determined by review of the medical records and/or phone interviews and was blinded to genetic test results. Comprehensive mutational analysis of the 5 LQTS-causing channel genes, KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6), along with KCNJ2 (Andersen-Tawil syndrome) and targeted analysis of 18 CPVT1-associated exons in RyR2 , was performed with the use of denaturing high-performance liquid chromatography and direct DNA sequencing. Approximately 11% (43 of 388) of the index cases had a positive swimming phenotype. Thirty-three of these 43 index cases had a “Schwartz” score (≥4) suggesting high clinical probability of LQTS. Among this subset, 28 patients (85%) were LQT1, 2 patients (6%) were LQT2, and 3 were genotype negative. Among the 10 cases with low clinical probability for LQTS, 9 had novel, putative CPVT1-causing RyR2 mutations. Conclusions— In contrast to previous studies that suggested universal LQT1 specificity, genetic heterogeneity underlies channelopathies that are suspected chiefly because of a near-drowning or drowning. CPVT1 and strategic genotyping of RyR2 should be considered when LQT1 is excluded in the pathogenesis of a swimming-triggered arrhythmia syndrome.