LQT1 Patients Research Articles

541 Does Mutation Location Affect Severity of Phenotype in Type 1 Long QT Syndrome? Impact of Transmembrane and C-Loop Location

BACKGROUND: Examination of genotype-phenotype correlation is important for the management of patients with congenital LQTS1. Precise targeted mutation site-specific differences have correlated C-loop missense mutations with worse outcomes and increased benefit of beta blockers. Corresponding cellular expression studies have implicated the C-loop region as mechanistically important in the altered response to sympathetic stimulation that triggers events in LQT1. OBJECTIVE: Determine if there is a clinically detectable difference in KCNQ1 channel mutation site specific response to sympathetic stimulation using graded exercise stress testing (GXT). METHODS: A retrospective review of LQT1 patients undergoing GXT at a pediatric and adult regional referral center was undertaken (2002-2011). Only patients with disease-causing mutations were included. QT intervals and heart rate were recorded supine at rest, immediately upon standing, at early exercise, peak exercise, 1 minute into recovery, and 4 minutes into the recovery phase. The QTc was calculated using the Bazett formula. Results are listed as mean 95% confidence interval. RESULTS: Sixty-seven genetically characterized LQT1 patients were identified (6-67 years of age, 52% female, 16 pediatric and 51 adults patients). Mutations consisted of 3 N-terminus, 36 membrane spanning, 15 c-loop, and 13 c-terminus locations. The supine QTc was prolonged at rest (464 33 msec), and increased upon immediate standing (498 36 msec), in early exercise (504 41 msec), and at peak exercise (525 46 msec). During recovery, the QTc remained markedly prolonged at 504 51 msec at 1 minute and 500 41 msec at 4 minutes. There were no statistically significant differences in QTc between patients with c-loop mutations and patients with alternate sites of mutations in any of the recorded QTc intervals.

Triggering of cardiac arrhythmic events in long QT syndrome: lessons from funny bunnies

Triggering of cardiac arrhythmic events in long QT syndrome: lessons from funny bunnies

Differential conditions for early after‐depolarizations and triggered activity in cardiomyocytes derived from transgenic LQT1 and LQT2 rabbits

Early after-depolarization (EAD), or abnormal depolarization during the plateau phase of action potentials, is a hallmark of long-QT syndrome (LQTS). More than 13 genes have been identified as responsible for LQTS, and elevated risks for EADs may depend on genotypes, such as exercise in LQT1 vs. sudden arousal in LQT2 patients. We investigated mechanisms underlying different high-risk conditions that trigger EADs using transgenic rabbit models of LQT1 and LQT2, which lack I(Ks) and I(Kr) (slow and fast components of delayed rectifying K(+) current), respectively. Single-cell patch-clamp studies show that prolongation of action potential duration (APD) can be further enhanced by lowering extracellular potassium concentration ([K(+)](o)) from 5.4 to 3.6 mm. However, only LQT2 myocytes developed spontaneous EADs following perfusion with lower [K(+)](o), while there was no EAD formation in littermate control (LMC) or LQT1 myocytes, although APDs were also prolonged in LMC myocytes and LQT1 myocytes. Isoprenaline (ISO) prolonged APDs and triggered EADs in LQT1 myocytes in the presence of lower [K(+)](o). In contrast, continuous ISO perfusion diminished APD prolongation and reduced the incidence of EADs in LQT2 myocytes. These different effects of ISO on LQT1 and LQT2 were verified by optical mapping of the whole heart, suggesting that ISO-induced EADs are genotype specific. Further voltage-clamp studies revealed that ISO increases L-type calcium current (I(Ca)) faster than I(Ks) (time constant 9.2 s for I(Ca) and 43.6 s for I(Ks)), and computer simulation demonstrated a high-risk window of EADs in LQT2 during ISO perfusion owing to mismatch in the time courses of I(Ca) and I(Ks), which may explain why a sympathetic surge rather than high sympathetic tone can be an effective trigger of EADs in LQT2 perfused hearts. In summary, EAD formation is genotype specific, such that EADs can be elicited in LQT2 myocytes simply by lowering [K(+)](o), while LQT1 myocytes require sympathetic stimulation. Slower activation of I(Ks) than of I(Ca) by ISO may explain why different sympathetic modes, i.e. sympathetic surge vs. high sympathetic tone, are associated with polymorphic ventricular tachycardia in LQTS patients.

Variants in the 3′ untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner

AimsHeterozygous mutations in KCNQ1 cause type 1 long QT syndrome (LQT1), a disease characterized by prolonged heart rate-corrected QT interval (QTc) and life-threatening arrhythmias. It is unknown why disease penetrance and expressivity is so variable between individuals hosting identical mutations. We aimed to study whether this can be explained by single nucleotide polymorphisms (SNPs) in KCNQ1's 3′ untranslated region (3′UTR).Methods and resultsThis study was performed in 84 LQT1 patients from the Academic Medical Center in Amsterdam and validated in 84 LQT1 patients from the Mayo Clinic in Rochester. All patients were genotyped for SNPs in KCNQ1's 3′UTR, and six SNPs were found. Single nucleotide polymorphisms rs2519184, rs8234, and rs10798 were associated in an allele-specific manner with QTc and symptom occurrence. Patients with the derived SNP variants on their mutated KCNQ1 allele had shorter QTc and fewer symptoms, while the opposite was also true: patients with the derived SNP variants on their normal KCNQ1 allele had significantly longer QTc and more symptoms. Luciferase reporter assays showed that the expression of KCNQ1's 3′UTR with the derived SNP variants was lower than the expression of the 3′UTR with the ancestral SNP variants.ConclusionOur data indicate that 3′UTR SNPs potently modify disease severity in LQT1. The allele-specific effects of the SNPs on disease severity and gene expression strongly suggest that they are functional variants that directly alter the expression of the allele on which they reside, and thereby influence the balance between proteins stemming from either the normal or the mutant KCNQ1 allele.

Carvedilol, a Non-Selective β-with α1-Blocker is Effective in Long QT Syndrome Type 2

Background: β‐blockers offer the first line therapy in congenital long QT syndrome (LQTS), and are more effective to prevent the cardiac event in LQTS type 1 than in type 2 or 3. In contrast, left cardiac sympathetic denervation (LCS D) was shown to be highly effective in patients refractory to β‐blockers. Total sympathetic ablation by LCSD indicates the addititional involvement of α‐adr enoceptor‐mediated pathway. In genotyped LQT2 patients, we therefore hypothesized that blockade of α‐adrenoceptor in addition to α‐adrenoceptor by carvedilol could reduce cardiac events more efficiently than other types of β‐blockers.Methods and Results: The study population consisted of 51 genotyped LQT2 patients (18 males, 23 ± 11years old). They were divided into 2 groups (group 1: 43 patients treated with selective β‐blockers, group 2: 8 patients with carvedilol) and retrospectively analyzed the efficacy of the respective β‐blocker therapy in suppressing cardiac events. Cardiac events were observed in 11 patients of group 1 (26%) but none in group 2 during a follow‐up period of 83 ± 80 months (P = 0.098).Conclusions: Carvedilol may be a potentially beneficial therapy for genotyped LQT2 patients who are refractory to other β selective blockers.

Thinking more before deciding to implant an ICD in LQT3 patients

Thinking more before deciding to implant an ICD in LQT3 patients

Utility of treadmill testing and DCG in diagnosis of long QT syndrome

BackgroundThe hereditary long QT syndrome (LQTS) is a genetic channalopathy that is characterised by a prolonged QT interval, syncope, ventricular arrhythmias, and sudden death. The clinical diagnosis of LQTS remains...

The diagnostic utility of recovery phase QTc during treadmill exercise stress testing in the evaluation of long QT syndrome

Nearly 40% of patients with long QT syndrome (LQTS) can have a nondiagnostic QTc at rest. Treadmill and cycle exercise stress testing are used in the diagnostic evaluation of LQTS. The purpose of this study was to determine the diagnostic significance of peak exercise and recovery phase QTc values during treadmill stress testing in LQTS. An Institutional Review Board-approved, retrospective analysis was performed on the treadmill stress tests in 243 patients including 82 LQT1, 55 LQT2, 18 LQT3, and 88 genotype-negative patients dismissed as normal. Blinded to genotype, QTc was calculated at rest, peak exercise, and 1, 2, 3, 4, and 5 minutes of recovery. Compared with those dismissed as normal, the average QTc was greater at all scored stages in LQT1 and LQT3 patients and at all stages in LQT2 patients except peak exercise and 1 minute of recovery (P < .01). Either an absolute QTc ≥ 460 ms during the recovery phase or a maladaptive, paradoxical increase in QTc, defined as QTc recovery--QTc baseline ≥ 30 ms (ΔQTc), distinguished patients with either manifest or concealed LQT1 from all other subsets (P < .0001). The presence of beta-blockers did not blunt these abnormal repolarization profiles. Treadmill stress testing can unmask patients with concealed LQTS, particularly LQT1, with good diagnostic accuracy.

Index of Suspicion in the Nursery

A woman is admitted for induction of labor at 40-3/7 weeks' gestation. Prenatal care was initiated at 21 weeks' gestation. Ultrasonographic examinations at 23 and 34 weeks' gestation revealed a slightly enlarged right kidney and polyhydramnios, with amniotic fluid indices of 18.6 and 26.7, respectively. An emergency cesarean section is performed for fetal distress. Meconium-stained fluid is noted at delivery. A female infant weighing 3,140 g (10th to 25th percentile for weight) is delivered and assigned Apgar scores of 2, 5, and 9 at 1, 5, and 10 minutes, respectively. At delivery, she is flaccid and apneic but responds quickly to nasal and oral suctioning, stimulation, and bag-mask ventilation. She requires endotracheal intubation for worsening respiratory distress and desaturations. Her initial chest radiograph shows an enlarged cardiac silhouette and diffusely hazy lung fields (Fig. 1). An additional study is performed, which helps to explain the infant's presentation. Figure 1. Chest radiograph shows an enlarged cardiac silhouette and bilateral streaky opacities. Physical examination reveals a grade II/VI systolic ejection murmur along the left sternal border without radiation. Peripheral pulses are diminished in all extremities. She is having moderate respiratory distress on mechanical ventilation support. Her abdomen is soft but distended, and the liver edge is palpable 4 cm below the right costal margin and extends across the midline. No splenomegaly is noted. A palpable mass in the right flank is also detected. A three-vessel cord is present, with a prominent umbilical vein. An abdominal radiograph demonstrates a paucity of bowel gas consistent with ascites and hepatomegaly (Fig. 2). Laboratory results include a white blood cell count of 8.0×103/μL (8.0×109/L) with a normal differential count, a hematocrit of 24% (0.24), and a platelet count of 71×103/μL (71×109/L). Bacterial and viral cultures are negative. Figure 2. Abdominal radiograph of …

Holter Monitoring in the Evaluation of Congenital Long QT Syndrome

Long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy that affects one in 2,000 persons; causes syncope, seizures, and sudden death; and is both under- and overdiagnosed. LQTS diagnostic miscues have stemmed from assessment of ambulatory electrocardiographic monitoring (Holter) results. We sought to determine the prevalence of positive Holter monitor tests and its diagnostic significance in evaluating LQTS. We performed an institutional review board-approved review of patients evaluated in our LQTS clinic from 2000 to 2009 who had Holter testing during their evaluation. Included patients (N = 473) were diagnosed with LQTS or dismissed as otherwise normal. Holters classified as positive had an episode of nonsustained ventricular tachycardia, supraventricular tachycardia, ≥4 couplets/day, ≥10 premature ventricular contractions/hour, or >5-second sinus pause. Among 209 patients dismissed as normal (128 females, average age 21 ± 15 years, average QTc 424 ± 39 ms), 27 (12.9%) had a positive Holter, while among 264 patients with LQTS (149 females, average age 22 ± 16 years, average QTc 472 ± 41 ms), 30 (11.3%) had a positive Holter (P = NS). Patients with LQT3 (5/23, 21%) and genotype-negative LQTS (5/19, 26%) had a higher rate of positive Holter testing compared to LQT1 patients (7/124, 6%, P < 0.03). Among the 473 Holters, only one (0.2%) impacted clinical decision making. Routine Holter monitoring appears to be of minimal clinical utility from a diagnostic and prognostic perspective in evaluating LQTS, and may not be cost effective. Whether Holter monitoring aids in therapeutic decisions such as dosing or whether ambulatory QTc measurements, provided by some newer devices, might help in the diagnostic evaluation warrants further scrutiny.

Mutation and gender-specific risk in type 2 long QT syndrome: Implications for risk stratification for life-threatening cardiac events in patients with long QT syndrome

Men and women with type 2 long QT syndrome (LQT2) exhibit time-dependent differences in the risk for cardiac events. We hypothesized that data regarding the location of the disease-causing mutation in the KCNH2 channel may affect gender-specific risk in LQT2. This study sought to risk-stratify LQT2 patients for life-threatening cardiac events based on clinical and genetic information. The risk for life-threatening cardiac events from birth through age 40 years (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) was assessed among 1,166 LQT2 male (n = 490) and female (n = 676) patients by the location of the LQTS-causing mutation in the KCNH2 channel (prespecified in the primary analysis as pore-loop vs. non-pore-loop). During follow-up, the cumulative probability of life-threatening cardiac events years was significantly higher among LQT2 women (26%) as compared with men (14%; P <.001). Multivariate analysis showed that the risk for life-threatening cardiac events was not significantly different between women with and without pore-loop mutations (hazard ratio 1.20; P =.33). In contrast, men with pore-loop mutations displayed a significant >2-fold higher risk of a first ACA or SCD as compared with those with non-pore-loop mutations (hazard ratio 2.18; P = .01). Consistently, women experienced a high rate of life-threatening events regardless of mutation location (pore-loop: 35%, non-pore-loop: 23%), whereas in men the rate of ACA or SCD was high among those with pore-loop mutations (28%) and relatively low among those with non-pore-loop mutations (8%). Combined assessment of clinical and mutation-specific data can be used for improved risk stratification for life-threatening cardiac events in LQT2.

T-wave morphology abnormalities in benign, potent, and arrhythmogenic Ikr inhibition

There is a consensus on the limited value of the QTc interval prolongation as a surrogate marker of drug cardiotoxicity and as a risk stratifier in inherited long QT syndrome (LQTS) patients. We investigated the interest of repolarization morphology in the acquired and the inherited LQTS. We analyzed 2 retrospective electrocardiographic (ECG) datasets from healthy on/off moxifloxacin and from genotyped KCNH2 patients. We measured QT, RR, and T-peak to T-end intervals, early repolarization duration (ERD) and late repolarization duration, T-roundness, T-amplitude, left (αL) and right slopes of T-waves. We designed multivariate logistic models to predict the presence of the KCNH2 mutation or moxifloxacin while adjusting for the level of QTc prolongation and the level of heart rate in LQT2 patients. Independent learning and validation sets were used. A list of 4,874 ECGs from 411 healthy individuals, 293 from 143 LQT2 carriers and 150 noncarrier family members were analyzed. In the moxifloxacin model, ERD was associated with the presence of the drug (odds ratio = 1.15 per ms increase, confidence interval 1.04 to 1.26, P = .0001) after adjustment for QTc. The model for the LQT2 revealed that left slope was associated with the presence of the KCNH2 mutation (odds ratio = 0.38 per 1.5 μV/ms decrease, confidence interval 0.23 to 0.64, P = .0002). Only T-roundness complemented QTc in the model investigating cardiac events in LQT2. These observations demonstrate that the phenotypic expression of KCNH2 mutations and the effect of IKr-inhibitory drug on the surface electrocardiogram are specific. Future research should investigate whether this phenomenon is linked to different level/form of loss functions of Ikr channels, and whether they could result in different arrhythmogenic mechanisms.

A Spectrum of Functional Phenotypes Associated with LQT1 Mutations Identified in Patients with Early-Onset Atrial Fibrillation

Mutations in KCNQ1, the gene encoding the voltage-gated K+ channel α-subunit that underlies the slowly activating delayed rectifier K+ current (IKs) in the heart, are linked to Type I Long QT Syndrome (LQT1) and Familial Atrial Fibrillation (FAF). Compared to the background prevalence of 0.1%, early-onset atrial fibrillation (patients < 50 years) was observed in ∼2% of LQT1 patients (Johnson et al., Heart Rhythm, 2008). We expressed several LQT1 mutations (P7S, R231H, and T322A) identified in patients with early-onset AF in HEK293 to better understand their functional phenotype. Cells were transfected with cDNA for the auxiliary K+ channel subunit KCNE1 (E1) and WT-, P7S-, R231H-, or T322A-KCNQ (Q1). Whole-cell Q1E1 currents (IQ1E1) were measured using the patch-clamp technique and holding potential of −80mV. We measured I-V relations from these cells by prepulsing from a holding potential of −80 mV to 70 mV in 10-mV increments for 5 seconds, followed by a test-pulse to −50mV for 5 seconds. The peak IQ1E1 measured during the test-pulse was plotted as function of the pre-pulse and the data were described using the Boltzmann equation to calculate the maximally activated IQ1E1 (IMAX), the midpoint potential (V1/2), and slope factor (k). Each mutation generated different functional phenotypes. Compared to cells expressing WT (n=7), cells expressing P7S (n=10) did not alter IMAX (WT=99±9 pA/pF, P7S=93±17 pA/pF), V1/2 (WT=26±3mV, P7S=24±3mV), or k (WT=16±1mV/e-fold ΔI, P7S=16±1mV/e-fold ΔI ). Cells expressing R231H (n=9) generated constitutively active IQ1E1 (R231H=64.07±27.48 pA/pF) at −80 mV that was similar to previously described FAF-linked mutations, and IMAX was not altered (80.09±15.58 pA/pF). In contrast, cells expressing T322A (n=7) generated no IQ1E1. These data demonstrate there is no characteristic IQ1E1 phenotype for LQT1 mutations identified in patients with early-onset AF.

214 Gene-specific effect of beta-adrenergic blockade on QT duration in the Long QT syndrome

In the long QT syndrome (LQTS) the clinical efficacy of beta-blocker treatment differs according to the genotype. We aimed to asses the effect of beta-blocker treatment in LQT1 and LQT2 patients. 24-hour Holter ECG were recorded before and after beta-blocking therapy initiation in genotyped LQT1 (n = 30, 8 males, mean age 21 ± 17) and LQT2 patients (n = 16, 8 males, mean age 19 ± 15). QT duration was measured on consecutive 1-minute averaged QRS-T complexes leading to up to 1440 QT-RR pairs for each recording. Then, we computed subject- and condition-specific log/log QT/RR relationships which were used to calculate QT interval duration at RR = 1000 ms (QT1000 = 1000*). Before treatment, coefficients were higher in LQT2 than in LQT1 patients (0.53 ± 0.10 vs. 0.40 ± 0.11, p < 0.001) and QT1000 was longer in LQT2 than in LQT1 patients (521 ± 38 vs. 481 ± 39 ms, p < 0.01). Beta-blockers significantly prolonged the mean RR interval (RR = 827 ± 161 ms before treatment and 939 ± 197 ms on beta-blocker, p < 0.0001). The coefficients were not significantly modified by beta-blockers (0.41 ± 0.9 in LQT1 patients and 0.52 ± 0.12 LQT2 patients). Beta-blocker treatment was associated with a prolongation of the QT1000 interval (from 481 ± 39 to 498 ± 43 ms, p < 0.01) in LQT1 patients but with a shortening in LQT2 patients (from 521 ± 38 to 503 ± 32 ms, p < 0.01). Our results confirm the elevated coefficient of the QT/RR relationship in LQTS patients. LQT2 patients showed higher coefficient and longer QT1000 when compared to LQT1 patients. The effect of beta-adrenergic blockade on QT1000 duration was gene-specific. Given the demonstrated efficacy of beta-blockers in LQT1 and 2 patients, our data suggest that QT1000 might be a poor predictor of outcome under anti-adrenergic therapy.

Different Dynamic Aspects of the Repolarization Morphology between LQT1 and LQT2 Forms of Congenital Long QT Syndrome

Because of the limitation of electrocardiographic findings for diagnosis of congenital long QT syndrome (LQTS), we assessed the diagnostic value of rate-dependent dynamics of the repolarization morphology for genotyping of LQTS. Methods: CM5 lead digital Holter ECG was recorded for 24-hour in 12 patients with LQT1, 12 with LQT2 and 16 controls. The QT/RR, T-amp/RR and T-area/RR linear regression lines were analyzed. Results: The QT/RR slope was greater in both LQT1 and LQT2 patients compared to controls (0.15±0.02 and 0.2±0.02 vs 0.13±0.03, p<0.01), and was greater in LQT2 than in LQT1. QT interval (sec) at RR interval of either 0.6 or 1.2 sec was longer in LQTS than in controls. Moreover, QT at RR interval of 1.2 sec was longer in LQT2 than in LQT1. Both slopes of T-amp/RR (mV/sec) and T-area/RR (mV) regression lines were smaller (p<0.01) in LQT2 (0.36±0.14 and 0.24±0.17) compared to both LQT1 (1.23±0.31 and 0.7±0.17) and controls (1.19±0.31 and 0.69±0.18). Both T-amplitude (mV) and T-area (mV·sec) at RR interval of either 0.6 or 1.2 sec were smaller in LQT2 patients than other groups. Conclusions: Enhanced QT prolongation during bradycardia was demonstrated in both LQT1 and LQT2 patients; however, impaired rate-dependent increment of both the amplitude and the area of T-wave were characteristic of patients with LQT2.

Carvedilol, a Non-Selective β-with α1-Blocker is Effective in Long QT Syndrome Type 2

Background: β-blockers offer the first line therapy in congenital long QT syndrome (LQTS), and are more effective to prevent the cardiac event in LQTS type 1 than in type 2 or 3. In contrast, left cardiac sympathetic denervation (LCS D) was shown to be highly effective in patients refractory to β-blockers. Total sympathetic ablation by LCSD indicates the addititional involvement of α-adr enoceptor-mediated pathway. In genotyped LQT2 patients, we therefore hypothesized that blockade of α-adrenoceptor in addition to α-adrenoceptor by carvedilol could reduce cardiac events more efficiently than other types of β-blockers. Methods and Results: The study population consisted of 51 genotyped LQT2 patients (18 males, 23 ± 11years old). They were divided into 2 groups (group 1: 43 patients treated with selective β-blockers, group 2: 8 patients with carvedilol) and retrospectively analyzed the efficacy of the respective β-blocker therapy in suppressing cardiac events. Cardiac events were observed in 11 patients of group 1 (26%) but none in group 2 during a follow-up period of 83 ± 80 months (P = 0.098). Conclusions: Carvedilol may be a potentially beneficial therapy for genotyped LQT2 patients who are refractory to other β selective blockers.

Changes in Ventricular Repolarization Duration During Typical Daily Emotion in Patients With Long QT Syndrome

Intense emotions are known triggers of sudden cardiac death. However, the effect of typical daily emotion on repolarization has not been examined. We examined whether QT interval changes as a function of typical daily emotion in patients at risk for cardiac events in the context of emotion. We studied 161 patients (n = 114 females; mean age, 35 years) with the congenital form of the Long QT Syndrome during daily activities. Each day for 3 days, a 12-hour Holter recording was completed. Patients were paged ten times per day at random times and rated the intensity of 16 prespecified emotions during the preceding 5 minutes. Measurements of QT interval and interbeat intervals were synchronized with emotion ratings. Low Arousal Positive Affect was associated with significant increases in QT interval corrected for heart rate (using Fridericia's QTc) (p < .001), whereas higher arousal Activated Positive Affect (p < .001) and Activated Negative Affect (p < .01) were associated with significant decreases in QTc. Changes in QTc as a function of daily emotion ranged from 5-ms increases to 11-ms decreases. High-frequency heart rate variability (vagal tone) was positively correlated with QTc (p < .001). The effects of each positive emotion variable on QTc were greater in LQT2 than LQT1 patients (p < .001). Ventricular repolarization duration (QTc) changes dynamically as a function of daily emotion. These changes are relatively small and do not constitute a risk in themselves. In the context of other risk factors, however, they may contribute to ventricular arrhythmias in vulnerable populations.

Repolarization Dynamics During Exercise Discriminate Between LQT1 and LQT2 Genotypes

Genotype and Exercise in LQTS. Repolarization dynamics during exercise in patients with long-QT Syndrome (LQTS) may be influenced by various factors such as a patient's genotype. We sought to systematically characterize the repolarization dynamics during exercise in patients with LQTS with a particular focus on the influence of genotype. Three groups of patients were studied on the basis of clinical status and genotype: LQT1, LQT2, and normal controls. Twenty-five age- and gender-matched patients were selected for each group. The QTc was measured during bicycle exercise testing and its dynamics were compared between the 3 groups. The degree of QTc prolongation during exercise was greater in LQTS patients (LQT1 80 ± 47 ms, LQT2 64 ± 41 ms, Control 46 ± 20 ms, P = 0.02), with significant differences between LQT1 and LQT2 patients observed at heart rates ≥ 60% of the predicted maximum (P < 0.05). LQT1 patients demonstrated progressive or persistent QTc prolongation at higher heart rates, whereas LQT2 patients demonstrated maximum QTc prolongation at submaximal heart rates (50% of the predicted maximum) with subsequent QTc correction toward baseline values at higher heart rates. Importantly, these observations were consistent regardless of age, gender, or exercise type in subgroup analyses. Reduced repolarization reserve in LQTS is genotype and heart rate specific.

Who Are the Long-QT Syndrome Patients Who Receive an Implantable Cardioverter-Defibrillator and What Happens to Them?

Background— A rapidly growing number of long-QT syndrome (LQTS) patients are being treated with an implantable cardioverter-defibrillator (ICD). ICDs may pose problems, especially in the young. We sought to determine the characteristics of the LQTS patients receiving an ICD, the indications, and the aftermath. Methods and Results— The study population included 233 patients. Beginning in 2002, data were collected prospectively. Female patients (77%) and LQT3 patients (22% of genotype positive) were overrepresented; mean QTc was 516±65 milliseconds; mean age at implantation was 30±17 years; and genotype was known in 59% of patients. Unexpectedly, 9% of patients were asymptomatic before implantation. Asymptomatic patients, almost absent among LQT1 and LQT2 patients, represented 45% of LQT3 patients. Patients with cardiac symptoms made up 91% of all study participants, but only 44% had cardiac arrest before ICD implantation. In addition, 41% of patients received an ICD without having first been on LQTS therapy. During follow-up, 4.6±3.2 years, at least 1 appropriate shock was received by 28% of patients, and adverse events occurred in 25%. Appropriate ICD therapies were predicted by age &lt;20 years at implantation, a QTc &gt;500 milliseconds, prior cardiac arrest, and cardiac events despite therapy; within 7 years, appropriate shocks occurred in no patients with none of these factors and in 70% of those with all factors. Conclusions— Reflecting previous concepts, ICDs were implanted in some LQTS patients whose high risk now appears questionable. Refined criteria for implantation, reassessment of pros and cons, ICD reprogramming, and consideration for other existing therapeutic options are necessary.

Clinical Summaries

Clinical Summaries