Citations

Background— A paradoxical increase in the uncorrected QT interval during infusion of low-dose epinephrine appears pathognomonic for type 1 long-QT syndrome (LQT1). We sought to determine the diagnostic accuracy of this response among patients referred for clinical evaluation of congenital long-QT syndrome (LQTS). Methods and Results— From 1999 to 2002, 147 genotyped patients (125 untreated and 22 undergoing β-blocker therapy) had an epinephrine QT stress test that involved a 25-minute infusion protocol (0.025 to 0.3 μg · kg −1 · min −1 ). A 12-lead ECG was monitored continuously, and repolarization parameters were measured. The sensitivity, specificity, and positive and negative predictive values for the paradoxical QT response (defined as a ≥30-ms increase in QT during infusion of ≤0.1 μg · kg −1 · min −1 epinephrine) was determined. The 125 untreated patients (44 genotype negative, 40 LQT1, 30 LQT2, and 11 LQT3) constituted the primary analysis. The median baseline corrected QT intervals (QTc) were 444 ms (gene negative), 456 ms (LQT1), 486 ms (LQT2), and 473 ms (LQT3). The median change in QT interval during low-dose epinephrine infusion was −23 ms in the gene-negative group, 78 ms in LQT1, −4 ms in LQT2, and −58 ms in LQT3. The paradoxical QT response was observed in 37 (92%) of 40 patients with LQT1 compared with 18% (gene-negative), 13% (LQT2), and 0% (LQT3; P <0.0001) of the remaining patients. Overall, the paradoxical QT response had a sensitivity of 92.5%, specificity of 86%, positive predictive value of 76%, and negative predictive value of 96% for LQT1 status. Secondary analysis of the subset undergoing β-blocker therapy indicated inferior diagnostic utility in this setting. Conclusions— The epinephrine QT stress test can unmask concealed type 1 LQTS with a high level of accuracy.

Background— The KCNH2 or human ether-a-go-go related gene ( hERG ) encodes the Kv11.1 α-subunit of the rapidly activating delayed rectifier K + current ( I Kr ) in the heart. Type 2 congenital long-QT syndrome (LQT2) results from KCNH2 mutations that cause loss of Kv11.1 channel function. Several mechanisms have been identified, including disruption of Kv11.1 channel synthesis (class 1), protein trafficking (class 2), gating (class 3), or permeation (class 4). For a few class 2 LQT2-Kv11.1 channels, it is possible to increase surface membrane expression of Kv11.1 current ( I Kv11.1 ). We tested the hypotheses that (1) most LQT2 missense mutations generate trafficking-deficient Kv11.1 channels, and (2) their trafficking-deficient phenotype can be corrected. Methods and Results— Wild-type (WT)-Kv11.1 channels and 34 missense LQT2-Kv11.1 channels were expressed in HEK293 cells. With Western blot analyses, 28 LQT2-Kv11.1 channels had a trafficking-deficient (class 2) phenotype. For the majority of these mutations, the class 2 phenotype could be corrected when cells were incubated for 24 hours at reduced temperature (27°C) or in the drugs E4031 or thapsigargin. Four of the 6 LQT2-Kv11.1 channels that had a wild-type–like trafficking phenotype did not cause loss of Kv11.1 function, which suggests that these channels are uncommon sequence variants. Conclusions— This is the first study to identify a dominant mechanism, class 2, for the loss of Kv11.1 channel function in LQT2 and to report that the class 2 phenotype for many of these mutant channels can be corrected. This suggests that if therapeutic strategies to correct protein trafficking abnormalities can be developed, it may offer clinical benefits for LQT2 patients.

Long QT syndrome is a malfunction of cardiac ion channels resulting in impaired ventricular repolarization that can lead to a characteristic polymorphic ventricular tachycardia known as torsades de pointes. Stressors, by increasing sympathetic tone, and drugs can provoke torsade de pointes, leading to syncope, seizures, or sudden cardiac death in these patients. Beta blockade, implantation of cardioverter defibrillators, and left cardiac sympathetic denervation are used in the treatment of these patients. However, these treatment modalities do not guarantee the prevention of sudden cardiac death. Certain drugs, including anesthetic agents, are known to contribute to QT prolongation. After reviewing the literature the authors give recommendations for the anesthetic management of these patients in the perioperative period.

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.

Objective. Inherited long QT syndrome (LQTS) may present with syncope, seizures, and/or sudden death as a result of ventricular tachyarrhythmias. Identification of family members who are at risk because they harbor the genetic substrate for LQTS is critical. Presently, such identification relies on the 12-lead electrocardiogram (ECG). The purpose of this study was to evaluate the efficacy of the automated ECG as a screening tool for LQTS. Method. Molecular testing of a proband and 22 additional family members for the KVLQT1 mutation and symptomatic status facilitated the classification of each family member into the following patient groups: noncarriers (13), asymptomatic carriers (5), and symptomatic carriers (5). Each individual had a standard 12-lead ECG from which the computer and manual (lead II) corrected QT interval were determined. In addition, we determined the accuracy of the computer ECG diagnostic interpretation for each patient group. Results. With the use of a corrected QT interval of ≥460 ms as a diagnostic cutoff, the positive and negative predictive values for identifying at-risk individuals were 100%. Despite this, the computer-generated ECG diagnostic interpretation erroneously classified 6 of 23 family members. Moreover, half of the family members, proved to have the ion channel defect, received the diagnostic interpretation “normal ECG.” Conclusion. Reliance on the computer-generated ECG diagnostic interpretation alone will fail to identify many at-risk family members. It is suggested that all first-degree relatives of an identified LQTS proband have a 12-lead ECG that is reviewed independently by a physician who is familiar with LQTS in an effort to improve screening for this potentially lethal syndrome.electrocardiogram, long QT syndrome, QT interval, sudden death.

Amino acid sequence variations in SCN5A are known to affect function of wild-type channels and also those with coexisting mutations; therefore, it is important to know the exact sequence and function of channels most commonly present in human myocardium. SCN5A was analyzed in control panels of human alleles, demonstrating that the existing clones (hH1, hH1a, hH1b) each contained a rare variant and thus none represented the common sequence. Confirming prior work, the H558R polymorphism was present in ≈30% of subjects. Quantitative mRNA analysis from human hearts showed that a shorter 2015 amino acid splice variant lacking glutamine at position 1077 (Q1077del) made up 65% of the transcript in every heart examined. Age, sex, race, or structural heart disease did not affect this proportion of Q1077del. Estimated population frequencies for the four common variants were 25% SCN5A, 10% [H558R], 45% [Q1077del], and 20% [H558R;Q1077del], where the reference sequence SCN5A is GenBank AC137587. When expressed in HEK-293 cells, these common variants had a more positive mid-point of the voltage dependence of inactivation than the standard clone hH1. Also, channels containing Q1077 expressed smaller currents. When H558R was present with Q1077 ([H558R]), current expression was profoundly reduced despite normal trafficking to the cell surface. Thus, four variant sequences for SCN5A are commonly present in human myocardium and they exhibit functional differences among themselves and with the previous standard clone. These results have implications for the choice of background sequence for experiments with heterologous expression systems, and possibly implications for electrophysiological function in vivo.

Background— Thin filament mutations are reported to cause ≈20% of cases of hypertrophic cardiomyopathy (HCM), and they have been associated with specific phenotypes. However, the frequency of these mutations and their associated phenotype(s) from a large tertiary referral center population are unknown. Methods and Results— DNA was obtained from 389 unrelated patients with HCM. A mutational analysis of all protein coding exons of cardiac troponin T, cardiac troponin I, α-tropomyosin, and cardiac actin was performed using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing. The clinical data were extracted from patient records and maintained independent of the patient genotype. Overall, only 18 patients (4.6%) harbored isolated thin filament mutations: 8 had troponin T mutations, 6 had troponin I mutations, 3 had α-tropomyosin mutations, and 1 had an actin mutation. Of the 12 unique missense mutations identified, 9 (75%) were novel mutations. As a group, patients with thin filament mutations were not significantly different from the rest of the cohort in age at diagnosis, left ventricular wall thickness, left ventricular outflow tract obstruction, or family history of HCM or sudden cardiac death. Conclusions— Mutations in genes encoding thin filament proteins are less prevalent in HCM than previously estimated. Patients with mutations in troponin T, troponin I, α-tropomyosin, and actin do not invariably present with any distinct clinical feature, thus limiting the utility of gene status for risk stratification or of clinical phenotype in guiding individual genetic screening at this time.

Background— Genotype-phenotype correlative studies have implicated 8 particular mutations that cause hypertrophic cardiomyopathy (HCM) as “benign defects,” associated with near-normal survival: N232S, G256E, F513C, V606M, R719Q, and L908V of β-myosin heavy chain ( MYH7 ); S179F of troponin T ( TNNT2 ); and D175N of α-tropomyosin ( TPM1 ). Routine genetic screening of HCM patients for specific mutations is anticipated to provide important diagnostic and prognostic information. The frequency and associated phenotype of these mutations in a large, unselected cohort of HCM is unknown. Methods and Results— A total of 293 unrelated HCM patients were genotyped for the presence of a benign mutation. DNA was obtained after informed consent; specific MHY7, TNNT2 , and TPM1 fragments were amplified by polymerase chain reaction; and the mutations were detected by denaturing high-performance liquid chromatography and automated DNA sequencing. Only 5 (1.7%) of the 293 patients possessed a benign mutation. Moreover, all 5 subjects with an ascribed benign mutation had already manifested clinically severe expression of HCM, with all 5 requiring surgical myectomy, 3 of the 5 having a family history of sudden cardiac death, and 1 adolescent requiring an orthotopic heart transplant. Conclusions— These findings demonstrate the rarity of specific mutations in HCM and challenge the notion of mutation-specific clinical outcomes. Fewer than 2% of the subjects harbored a benign mutation, and those patients with a benign mutation experienced a very serious clinical course.