Automated QT analysis on Holter monitors in pediatric patients can differentiate long QT syndrome from controls

1 Background

Borderline QTc is a common referral to the pediatric cardiology clinic. Evaluation is challenging due to significant overlap of normal and abnormal QTc ranges. We hypothesized that automated QT analysis on Holter could differentiate between patients with long QT syndrome (LQTS) and healthy controls.

2 Methods

We conducted a retrospective review of 39 patients with known genotype‐positive, phenotype‐positive LQTS who underwent Holter monitoring between January 2010 and January 2016. They were compared 2:1 to age‐ and sex‐matched controls. Automated QT analysis data were analyzed.

3 Results

Significant differences were found in all automated QT and QTc fields, except minimum QTc interval (P = 0.57). Mean QTc interval (LQTS 479 ± 28 ms vs controls 429 ± 16 ms; P ≤ 0.001) and percent QTc intervals (%QTc) >450 ms (LQTS 80 ± 28% vs controls 14 ± 16%; P ≤ 0.001) were selected for further analysis. A receiver operating characteristic curve was generated for each variable demonstrating high area under the curve values of 0.9494 and 0.9540, respectively. Threshold values of ≥461 ms for mean QTc (sensitivity 79.49%, specificity 98.72%) and ≥65% of %QTc >450 ms (sensitivity 79.49%, specificity 98.72%) allowed highly specific discrimination between cohorts (false positive rate 1.09%). Similarly, thresholds of <434 ms (sensitivity 97.44, specificity 61.54) for mean QTc and <32% (sensitivity 89.74, specificity 87.18) for %QTc >450 ms resulted in highly sensitive discrimination (false negative rates 2.17% and 8.7%).

4 Conclusion

Holter monitor testing with automated QT analysis may be a useful tool to differentiate LQTS and control patients.     

Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome

OBJECTIVE: To determine the effect of epinephrine on the QT interval in patients with genotyped long QT syndrome (LQTS). PATIENTS AND METHODS: Between May 1999 and April 2001, 37 patients (24 females) with genotyped LQTS (19 LQT1, 15 LQT2, 3 LQT3, mean age, 27 years; range, 10-53 years) from 21 different kindreds and 27 (16 females) controls (mean age, 31 years; range, 13-45 years) were studied at baseline and during gradually increasing doses of intravenous epinephrine infusion (0.05, 0.1, 0.2, and 0.3 microg x k(-1) x min(-1)). The 12-lead electrocardiogram was monitored continuously, and heart rate, QT, and corrected QT interval (QTc) were measured during each study stage. RESULTS: There was no significant difference in resting heart rate or chronotropic response to epinephrine between LQTS patients and controls. The mean +/- SD baseline QTc was greater in LQTS patients (500+/-68 ms) than in controls (436+/-19 ms, P<.001). However, 9 (47%) of 19 KVLQT1-genotyped LQT1 patients had a nondiagnostic resting QTc (<460 milliseconds), whereas 11 (41%) of 27 controls had a resting QTc higher than 440 milliseconds. During epinephrine infusion, every LQT1 patient manifested prolongation of the QT interval (paradoxical response), whereas healthy controls and patients with either LQT2 or LQT3 tended to have shortened QT intervals (P<.001). The maximum mean +/- SD change in QT (AQT [epinephrine QT minus baseline QT]) was -5+/-47 ms (controls), +94+/-31 ms (LQT1), and -87+/-67 ms (LQT2 and LQT3 patients). Of 27 controls, 6 had lengthening of their QT intervals (AQT >30 milliseconds) during high-dose epinephrine. Low-dose epinephrine (0.05 microg x kg(-1) x min(-1)) completely discriminated LQT1 patients (AQT, +82+/-34 ms) from controls (AQT, -7+/-13 ms; P<.001). Epinephrine-triggered nonsustained ventricular tachycardia occurred in 2 patients with LQTS and in 1 control. CONCLUSIONS: Epinephrine-induced prolongation of the QT interval appears pathognomonic for LQT1. Low-dose epinephrine infusion distinguishes controls from patients with concealed LQT1 manifesting an equivocal QTc at rest. Thus, epinephrine provocation may help unmask some patients with concealed LQTS and strategically direct molecular genetic testing.     

Arrhythmia detection after atrial fibrillation ablation: value of incremental monitoring time

Background: After pulmonary vein isolation (PVI), patients need to be followed to analyze the effect of the treatment. We evaluated the influence of the duration of Holter monitoring on the detection of arrhythmia recurrences after a single PVI at 12 months. Methods: Consecutive patients with paroxysmal atrial fibrillation (AF) underwent successful PVI with phased radiofrequency and pulmonary vein ablation catheter. Follow‐up was performed with electrocardiogram at 3, 6, and 12 months and 7‐day Holter at 12 months. Symptomatic patients received additional event recording. The 7‐day Holters at 12 months were evaluated for documented left atrial tachyarrhythmia recurrences, and each individual day with AF was categorized. Results: At 12 months after the procedure, 21 of the 96 (22%) patients had AF on their 7‐day Holter. In the patients with AF recurrence, there was an increase in sensitivity from 53% of a 1‐day Holter up to 88% with 4‐day Holter, and 100% of a 7‐day Holter. Monitoring with duration of less than 4 days resulted in significantly less detection of patients with AF compared to 7‐day Holter. Conclusions: A 4‐day Holter at 12 months has an 88% sensitivity for arrhythmia detection, and appears to provide a sufficient monitoring time. Prolonging the monitoring time to 7 days does not significantly increase the yield. PACE 2012; 35:164–169)     

QT Interval Variability and Adaptation to Heart Rate Changes in Patients with Long QT Syndrome

Background: Increased QT variability (QTV) has been reported in conditions associated with ventricular arrhythmias. Data on QTV in patients with congenital long QT syndrome (LQTS) are limited.
Methods: Ambulatory electrocardiogram recordings were analyzed in 23 genotyped LQTS patients and in 16 healthy subjects (C). Short-term QTV was compared between C and LQTS. The dependence of QT duration on heart rate was evaluated with three different linear models, based either on the RR interval preceding the QT interval (RR₀), the RR interval preceding RR₀ (RR_-1), or the average RR interval in the 60-second period before QT interval (mRR).
Results: Short-term QTV was significantly higher in LQTS than in C subjects (14.94 ± 9.33 vs 7.31 ± 1.29 ms; P < 0.001). It was also higher in the non-LQT1 than in LQT1 patients (23.00 ± 9.05 vs 8.74 ± 1.56 ms; P < 0.001) and correlated positively with QTc in LQTS (r = 0.623, P < 0.002). In the C subjects, the linear model based on mRR predicted QT duration significantly better than models based on RR₀ and RR_-1. It also provided better fit than any nonlinear model based on RR₀. This was also true for LQT1 patients. For non-LQT1 patients, all models provided poor prediction of QT interval.
Conclusions: QTV is elevated in LQTS patients and is correlated with QTc in LQTS. Significant differences with respect to QTV exist among different genotypes. QT interval duration is strongly affected by noninstantaneous heart rate in both C and LQT1 subjects. These findings could improve formulas for QT interval correction and provide insight on cellular mechanisms of QT adaptation.     

Congenital Myocardial Sympathetic Dysinnervation (CMSD)—A Structural Defect of Idiopathic Long QT Syndrome

Concerning the pathogenetic mechanism of idiopathic long QT syndrome (LQTS), the hypothesis of a specific sympathetic imbalance has gained general acceptance, but its validity has never been proven. To test this hypothesis I-123-MIBG, an analogue of norepinephrine and guanethidine, was used to provide scintigraphic display of the efferent cardiac sympathetic innervation. Twelve members of four LQTS families (mean age 38.2 +/- 17.2 years, eight males) and eight healthy volunteers (mean age 48.2 +/- 13.3 years, five males) were studied by means of I-123-MIBG single photon emission computed tomography (SPECT). A quantitative analysis of all scans was performed. All scans of the healthy volunteers show a uniform tracer uptake with sometimes slightly decreased activity in the apex. (1) All patients with QTc greater than 440 msec (n = 5); (2) all, who had suffered from at least one episode of torsade de pointes, ventricular fibrillation (VF) or syncope (n = 5); and (3) all symptomatic patients with QTc prolongation (n = 4) have reduced or abolished (P less than 0.02) MIBG uptakes in the inferior and inferior septal parts of the left ventricle (congenital myocardial sympathetic dysinnervation [CMSD]). Additionally, one female without symptoms or QTc prolongation (LQT) shows an abnormal MIBG SPECT similar to the one of her daughter, who has LQT and symptoms. One male without LQT, who had suffered from VF shows CMSD similar to his father, who has LQT, but no symptoms. All members of the families with normal MIBG SPECTs have neither LQT nor symptoms. In all families CMSD fulfills the criteria of autosomal-dominant inheritance. Normal QTc-interval predicted only in 57% normal cardiac sympathetic innervation in the present LQTS families. Therefore, quantitative I-123-MIBG SPECT enables to identify myocardial sympathetic dysinnervation as structural defect in LQTS. CMSD is associated with and without LQT and presents a pattern of autosomal-dominant inheritance. LQT at rest or during exercise was specific (100%), but less sensitive (63%) in the assessment of CMSD than I-123-MIBG SPECT.     

Hotter monitoring in the evaluation and rehabilitation of post-cerebrovascular accident patients

Coronary artery disease, overt or silent, is frequently present in patients who have suffered a cerebrovascular accident (CVA). Rehabilitation therapy of CVA patients is based mostly on physical activity, which may be limited by fear of overloading the cardiovascular system. Therefore, assessment of the severity of coronary heart disease in CVA patients is of utmost importance. In this study we assessed the usefulness of 24-hour electrocardiographic Holter monitoring in the evaluation of post-CVA patients during daily activities and rehabilitation. Of the 43 post-CVA patients, 24 (55.8%) revealed pathological changes on Holter monitoring and 17 (71%) had a history of coronary artery disease prior to CVA. Holter monitoring revealed mainly ventricular and atrial arrhythmias and in three patients detected transient ischaemic episodes. Only six patients (14%) showed aggravation of arrhythmia during rehabilitation therapy, without aggravation of ST-T changes. The mean maximum heart rate during regular daily activities was 104±20 beats/min, which was significantly higher than the mean maximum heart rate during physical therapy (100±18 beats/min; p < 0.01) and during occupational therapy (87±18 beats/min; p < 0.001). These findings indicate that more vigorous physical and occupational therapy can be prescribed to these patients. The performance of Holter monitoring in post-CVA patients is a valuable substitute to exercise testing, and is useful for cardiovascular evaluation during daily activities and rehabilitation therapy.     

Detection of spatial repolarization abnormalities in patients with LQT1 and LQT2 forms of congenital long-QT syndrome

The aim of this study is to detect the spatial current dispersion that appears in the T-wave of patients with congenital long-QT syndrome (LQTS). To observe this dispersion, magnetocardiograms (MCGs)--which have a high spatial resolution--of LQT1 patients (n = 7), LQT2 patients (n = 9) and a control group (n = 33) were recorded. The dispersion was evaluated by plotting current-arrow maps (CAMs) calculated from the MCG signals. In the case of LQT1, abnormal current arrows in the CAMs appeared above the inferior part of the heart in two LQT1 patients with a long corrected QT interval (QTc) (>0.6), and the current direction was from the left (origin side) to the right ventricular muscle (110 degrees). In six out of nine LQT2 patients, abnormal current arrows with angles below 20 degrees were observed above the right inferior part or lower septum; the current direction was from the right (origin side) to the left ventricular muscle. However, in the case of the LQT2 patients, the QTc values did not correlate with the abnormal current. These findings suggest that the origin of abnormal repolarization in LQT1 is the left ventricular muscle and the origin of that in LQT2 is the right ventricular muscle or lower septum. The estimation of the origin in LQTS patients can provide important information such as the risk factor of sudden death.     

Catecholamine-induced T-wave lability in congenital long QT syndrome: a novel phenomenon associated with syncope and cardiac arrest

OBJECTIVE: To determine the effects of phenylephrine and dobutamine on repolarization lability in patients with genotyped long QT syndrome (LQTS). PATIENTS AND METHODS: Between December 1998 and August 2000, 23 patients with genotyped LQTS (13 LQT1, 7 LQT2, and 3 LQT3) and 16 controls underwent electrocardiographic stress testing at the Mayo Clinic in Rochester, Minn. Aperiodic repolarization lability was quantified from digitized electrocardiograms recorded during catecholamine stress testing with phenylephrine and dobutamine. T-wave lability was quantified as a root-mean-square of the differences between corresponding signal values of subsequent beats. The magnitude of aperiodic T-wave lability was quantified by using a newly derived T-wave lability index (TWLI). RESULTS: The TWLI was significantly greater in patients with LQTS than in controls (0.0945 +/- 0.0517 vs 0.0445 +/- 0.0123; P < .003). Marked T-wave lability (TWLI > or = 0.095) was detected in all 3 LQTS genotypes (10/23) but in no controls (P < .003). There was no correlation between the TWLI and the baseline corrected QT interval. All high-risk patients having either a history of out-of-hospital cardiac arrest or syncope had a TWLI of 0.095 or greater. CONCLUSIONS: Beat-to-beat nonalternating T-wave lability occurs in LQT1, LQT2, and LQT3 patients during catecholamine provocation and is associated with a history of prior cardiac events. The quantification of this novel phenomenon may assist in identifying LQTS patients with increased risk of sudden cardiac death.     

Perioperative Doses of Ondansetron or Dolasetron Do Not Lengthen the QT Interval

ObjectiveTo test the primary hypothesis that ondansetron or dolasetron extends the rate-corrected QT electrocardiographic interval (QTc) greater than 60 milliseconds or increases the fraction of patients with QTc greater than 500 milliseconds in patients having noncardiac surgery, and the secondary hypothesis that QTc prolongation is worse in diabetic patients.Patients and MethodsWe extracted data from the Cleveland Clinic's Perioperative Health Documentation System between March 25, 2006, and September 30, 2010, and additional perioperative medications from Cleveland Clinic pharmacy's Epic Cost of Goods Sold (COGS) system. We searched for patients who had a preoperative electrocardiogram within 1 month of surgery and postoperatively within 2 hours. We excluded patients given an antiemetic drug other than ondansetron or dolasetron perioperatively, and those given amiodarone.ResultsA total of 1429 patients given serotonin-3 receptor (5HT3R) antagonists and 1022 controls met the enrollment criteria. Seventeen percent of patients given 5HT3R antagonists (n=242) and 22% of controls (n=220) had postoperative QTc exceeding 500 milliseconds. Mean ± SD presurgical and postsurgical QTc, respectively, were 438±37 milliseconds and 464±41 milliseconds for 5HT3R antagonist patients and 443±40 milliseconds and 469±47 milliseconds for control patients. Univariable mean ± SD perioperative increases in QTc were 26±39 and 26±48 milliseconds in the 2 groups. After adjusting for confounding variables, there were no differences in the mean increase in QTc in patients who were and were not given 5HT3R antagonists: –0.1 milliseconds (97.5% CI, –5.2 to 5.0 milliseconds; multivariable P=.97). The QTc was prolonged, but not significantly, in diabetic patients given 5HT3R antagonists (P=.16).ConclusionsThe average QTc prolongation from baseline was only 6%. Perioperative use of ondansetron or dolasetron was not associated with extended QT prolongation, and these results did not vary by diabetic status. Perioperative use of 5HT3R antagonists does not produce potentially dangerous perioperative electrocardiographic changes and does not seem to warrant a drug safety warning from the Food and Drug Administration.     

Late hyperenhancement in gadolinium-enhanced magnetic resonance imaging: comparison of hypertrophic cardiomyopathy patients with and without nonsustained ventricular tachycardia

Aim To assess the extent of hyperenhancement in hypertrophic cardiomyopathy (HCM) patients with nonsustained ventricular tachycardia (NSVT) in comparison to patients without NSVT. Design In HCM patients, NSVT in Holter monitoring is a risk factor for sudden cardiac death; however, its positive predictive value is low. Varying risk of sudden death related to NSVT may be dependent on the heterogeneous extent of the arrhythmogenic substrate, which seems to be visible as hyperenhancement in gadolinium-enhanced magnetic resonance imaging (MRI). Methods Hyperenhancement was assessed in 47 HCM patients (30 males and 17 females, mean age 42 ± 12 years): 32 patients had NSVT, 15 patients had no NSVT. The extent of hyperenhancement was calculated by software and expressed as a mass. Results In HCM patients with NSVT 97% had some extent of hyperenhancement on MRI, ranging from 1 to 76 g. The mean mass of hyperenhanced myocardium was 19 ± 18 g (8.1 ± 7.6% of total left ventricular mass). In HCM patients without NSVT, a significantly lower percentage of patients (60%) had hyperenhancement (P < 0.05). However, the amount of hyperenhanced myocardium was not significantly different (13 ± 19 g, 6.3 ± 9.1% of total left ventricular mass; P < 0.05). Conclusions Hyperenhancement was visible in almost all HCM patients with NSVT (97%) and in a significantly lower percentage of patients without NSVT (60%). Whether this finding explains the increased risk of sudden death in case of NSVT is not clear, since the extent of hyperenhancement was not significantly different between the two groups.     

Effects of epinephrine on right ventricular monophasic action potentials in the LQT1 versus LQT2 form of long QT syndrome: preferential enhancement of "triangulation" in LQT1

AIMS: To explore effects of epinephrine and phenylephrine on the behavior of right ventricular monophasic action potentials (MAPs) in symptomatic LQT1 and LQT2 patients. METHODS AND RESULTS: We recorded endocardial MAPs from right interventricular septum at baseline and during epinephrine and phenylephrine infusions in six symptomatic DNA-verified LQT1 (QTc 528 +/- 83) and five LQT2 patients (QTc 527 +/- 72) and in five control patients (QTc 381 +/- 22). We measured MAP durations at 90% and at 50% levels of repolarization and their difference (MAP50 to MAP90, a measure of MAP morphologic "triangulation"), during atrial pacing to characterize rate dependence of MAPs and repolarization phase 3 durations, respectively. Restitution kinetics were determined during atrioventricular sequential pacing, using the approach of empirical restitution rate. Epinephrine prolonged MAP50-to-MAP90 duration and increased the rate dependence of MAP90 duration and increased restitution rate in type LQT1, but not in LQT2 patients nor in control subjects. Phenylephrine did not change MAP behavior. During epinephrine administration, both LQT1 and LQT2 patients had a ratio of the restitution rate of MAP to diastolic interval >1.0 at short diastolic intervals. CONCLUSION: Symptomatic LQT1 patients with prolonged baseline QTc intervals showed beta-adrenergic-induced changes in MAPs (triangulation) known to be arrhythmogenic, thus giving insight to the difference in clinical triggers of life-threatening arrhythmias between LQT1- and LQT2-affected individuals.     

Genetics,molecular mechanisms and management of long QT syndrome

Cardiac arrhythmias cause more than 300 000 sudden deaths each year in the USA alone. Long QT syndrome (LQT) is a cardiac disorder that causes sudden death from ventricular tachyarrhythmias, specifically torsade de pointes. Four LQT genes have been identified: KVLQT1 (LQT1) on chromosome llpl5.5, HERG (LQT2) on chromosome 7q35–36, SCNSA (LQT3) on chromosome 3p21–24, and MinK (LQT5) on chromosome 21q22. SCNSA encodes the cardiac sodium channel, and LQT-causing mutations in SCNSA lead to the generation of a late phase of inactivation-resistant whole-cell inward currents. Mexiletine, a sodium channel blocker, is effective in shortening the QT interval corrected for heart rate (QTc) of patients with SCNSA mutations. HERG encodes the cardiac I potassium channel. Mutations in HERG act by a dominant-negative mechanism or by a loss-of-function mechanism. Raising the serum potassium concentration can increase outward HERG potassium current and is effective in shortening the QTc of patients with HERG mutations. KVLQT1 is a cardiac potassium channel protein that interacts with another small potassium channel MinK to form the cardiac I potassium channel. Like HERG mutations, mutations in KVLQT1 and MinK can act by a dominant-negative mechanism or a loss-of-function mechanism. An effective treatment for LQT patients with KVLQT1 or MinK mutations is expected to be developed based on the functional characterization of the I_Ks potassium channel. Genetic testing is now available for some patients with LQT.     

Ranolazine reduces ventricular tachycardia burden and ICD shocks in patients with drug-refractory ICD shocks

Background: There are limited options for patients who present with antiarrhythmic‐drug (AAD)‐refractory ventricular tachycardia (VT) with recurrent implantable cardioverter defibrillator (ICD) shocks. Ranolazine is a drug that exerts antianginal and antiischemic effects and also acts as an antiarrhythmic in isolation and in combination with other class III medications. Ranolazine may be an option for recurrent AAD‐refractory ICD shocks secondary to VT, but its efficacy, outcomes, and tolerance are unknown. Methods and Results: Twelve patients (age 65 ± 9.7 years) were treated with ranolazine. Eleven (92%) were male, and 10 (83%) had ischemic heart disease with an average ejection fraction of 0.34 ± 0.13. All patients were on a class III AAD (11 amiodarone, one sotalol), with six (50%) receiving mexilitene or lidocaine. Five patients had a prior ablation and two were referred for a VT ablation at the index presentation. The QRS increased nonsignificantly from 128 ± 31 ms to 133 ± 31 ms, and the QTc increased nonsignificantly from 486 ± 32 ms to 495 ± 31 ms after ranolazine initiation. Over a follow‐up of 6 ± 6 months, 11 (92%) patients had a significant reduction in VT and no ICD shocks were observed. VT ablation was not required in those referred. In two patients, gastrointestinal side effects limited long‐term use. Of these two patients, one died due to progressive heart failure. In one patient, severe hypoglycemia limited dosing to 500 mg daily, but this was sufficient for VT control. Conclusion: Ranolazine proved effective in reducing VT burden and ICD shocks in patients with AAD‐refractory VT. Ranolazine should be further tested for this indication and considered for clinical application when other options have proven ineffective. (PACE 2011; 34:1600–1606)     

Catecholamine-provoked microvoltage T wave alternans in genotyped long QT syndrome

Macrovoltage T wave alternans (TWA) has been described in congenital long QT syndrome (LQTS). Microvoltage T wave alternans (microV-TWA) at low heart rate (HR) is a marker of arrhythmogenic risk in many conditions, but its significance in LQTS has not been established. Twenty-three genotypically heterogeneous patients with LQTS and 16 control subjects were studied at rest and during phenylephrine and dobutamine provocation. Genotyping was established by PCR amplification and DNA sequencing of the three most common LQTS genes; KCNQ1/KVLQT1 (LQT1), KCNH2/HERG (LQT2), and SCN5A (LQT3). microV-TWA was determined using Fast Fourier transform. Precluded by ectopy, microV-TWA could not be assessed in 8 of 23 patients with LQTS. In the remaining 15 patients with LQTS, microV-TWA occurred at lower HR in LQTS than in controls (117 +/- 49 vs 153 +/- 37 beats/min; P < 0.05). Patients with LQTS developed microV-TWA at HR < 150 beats/min more often than controls (10/15 vs 2/16; P = 0.003). However, microV-TWA was not detected in the 3 individuals with a history of out-of-hospital cardiac arrest including a 14-year-old male with an F339del-KVLQT1 mutation (LQT1) who had dobutamine-provoked polymorphic ventricular tachycardia requiring external defibrillation. Catecholamine-provoked microV-TWA occurs at lower HR in patients with LQTS than in healthy people but does not identify high risk subjects.     

Molecular characterization of two founder mutations causing long QT syndrome and identification of compound heterozygous patients

Background. Mutations of at least six different genes have been found to cause long QT syndrome (LQTS), an inherited arrhythmic disorder characterized by a prolonged QT interval on the electrocardiogram (ECG), ventricular arrhythmias and risk of sudden death.

Aim. The aims were to define the yet undetermined phenotypic characteristics of two founder mutations and to study clinical features in compound heterozygotes identified during the course of the study.

Methods. To maximize identification of the compound heterozygotes, we used an extended group of LQTS patients comprising 700 documented or suspected cases. Functional studies were carried out upon transient expression in COS‐7 or HEK293 cells.

Results. The KCNQ1 IVS7‐2A>G (KCNQ1‐FinB) mutation associated with a mean QTc interval of 464?ms and a complete loss‐of‐channel function. The HERG R176W (HERG‐FinB) mutation caused a reduction in current density as well as slight acceleration of the deactivation kinetics in vitro, and its carriers had a mean QTc of 448?ms. The HERG R176W mutation was also present in 3 (0.9%) out of 317 blood donors. A total of six compound heterozygotes were identified who had the HERG R176W mutation in combination with a previously reported LQTS mutation (KCNQ1 G589D or IVS7‐2A>G). When present simultaneously with an apparent LQTS‐causing mutation, the HERG R176W mutation may exert an additional in vivo phenotypic effect.

Conclusions. The HERG R176W mutation represents a population‐prevalent mutation predisposing to LQTS. Compound heterozygosity for mutant LQTS genes may modify the clinical picture in LQTS.     

Long-term outcome following ablation of atrial flutter occurring late after atrial septal defect repair

Aims: In patients with surgical atrial septal defect (ASD) repair, late atrial flutters (AFLs), including cavotricuspid isthmus (CTI)‐dependent and non‐CTI‐dependent scar‐related flutter (AFL), are common. Radiofrequency ablation (RFA) of these arrhythmias has a high acute success rate. We aimed to characterize the long‐term freedom from atrial arrhythmias in this population. Methods: Twenty consecutive patients undergoing RFA for AFL late after ASD repair were included. Electrophysiological assessment included multipolar activation, entrainment, and electroanatomic mapping. Clinical, electrocardiograph, and Holter monitoring follow‐up was conducted every 6 months. Results: Mean age was 53 ± 13 years. Time from surgical repair to RFA was 29 ± 15 years. All patients had CTI‐dependent AFL (20/20). There were 1.6 ± 0.7 arrhythmias per patient; other arrhythmias included non‐CTI‐dependent AFL (14), focal atrial tachycardia (two), and atrioventricular nodal reentry tachycardia (two) . Acute success was obtained in 100%. Five patients with recurrent AFL (three CTI dependent, two non‐CTI dependent) at 13 ± 8 months had successful repeat RFA. At 3.2 ± 1.6 years follow‐up since the last procedure, 90% of patients with successful RFA for AFL remained free of their clinical arrhythmia. However, 30% of the original 20 patients had documented atrial fibrillation (AF) 2.1 ± 1.6 years after the last procedure; five (25%) required AF intervention. One stroke (5%) occurred in the context of late AF. Conclusion: RFA of AFL occurring late after surgical ASD repair has a low long‐term risk of recurrence, although 25% of patients required two procedures. However, there is a high late incidence of AF (30%), with an additional 25% of patients requiring intervention for AF. (PACE 2011; 34:431–435)     

Reverse Electrical Remodeling of the Ventricles Following Successful Restoration of Sinus Rhythm in Patients with Persistent Atrial Fibrillation

Background: Atrial fibrillation (AF) has been shown to be associated with reduced survival and increased ventricular arrhythmogenesis. The purpose of this study was to assess the effects of AF with adequate rate control on the electrophysiologic properties of the ventricles. We hypothesized that AF results in increased ventricular arrhythmogenic risk and that reverse remodeling occurs postsuccessful cardioversion. Methods: In nine patients with persistent AF, we recorded 12‐lead electrocardiograms (ECGs) and 1‐hour high‐resolution Holter ECGs (H12+, Mortara Instrument, Inc. Milwaukee, WI, USA; recorders [1000 sps] immediately following cardioversion (Day 1) and after 30 days of maintaining sinus rhythm (Day 30). We measured QTc, QT dispersion, and calculated estimates of mean ventricular action potential duration (RT), diastolic interval (DI), T‐wave width (TW), T‐wave peak‐to‐end, and their respective scatter on Day 1 and Day 30. Maintenance of normal sinus rhythm was confirmed with a weekly trans‐telephonic ECG transmission. Results: The average QTc interval decreased from 449 ± 28 ms on Day 1 to 422 ± 36 ms on Day 30 (P = 0.04). There was no significant difference in the average QT dispersion. A significant decrease was also noted in DI and TW scatter at Day 30 when compared with Day 1 (P = 0.03 and 0.04, respectively). A decrease in RT scatter was also noted albeit not statistically significant (P = 0.07). Conclusion: Our results suggest a greater propensity to ventricular arrhythmogenesis in the immediate period following restoration of sinus rhythm and reverse electrical remodeling of the ventricles during the first month after successful maintenance of sinus rhythm. (PACE 2010; 33:1198–1202)     

Challenges of diagnosis of long-QT syndrome in children

We describe the clinical and genetic characteristics of the family, in which the diagnosis of LQT1 had been made. The electrocardiogram (ECG) characteristics of this patient indicated the likelihood of LQTS1. Polymorphic ventricular extrasystolies and episodes of polymorphic non-sustained ventricular tachycardia were confirmed by Holter ECG monitoring. On the exertional electrocardiogram polymorphic ventricular tachycardia (torsade de pointes) was recorded. Direct sequencing of both DNA strands revealed the absence of mutations or polymorphisms in the KCNQ1, HERG, and SCN5A genes.     

Molecular Biology of the Long QT Syndrome: Impact on Management

The long QT syndrome (LQTS) is a familial disease characterized by prolonged ventricular repolarization and high incidence of malignant ventricular tachyarrhythmias often occurring in conditions ofadrenergic activation. Recently, the genes for the LQTS linked to chromosomes 3 (LQT3), 7 (LQT2), and 11 (LQTl) were identified as SCN5A, the cardiac sodium channel gene and as HERG and KvLQTl potassium channel genes. These discoveries have paved the way for the development of gene-specific therapy for these three forms of LQTS. In order to test specific interventions potentially beneficial in the molecular variants of LQTS, we developed a cellular model to mimic the electrophysiological abnormalities of LQT3 and LQT2. Isolated guinea pig ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively. This model has been used to study the effect of sodium channel blockade and of rapid pacing showing a pronounced action potential shortening in response to Na⁺channel blockade with mexiletine and during rapid pacing only in anthopleurin-treated cells but not in dofetilide-treated cells. Based on these results we tested the hypothesis that QT interval would shorten more in LQT3 patients in response to mexiletine and to increases in heart rate. Mexiletine shortened significantly the QT interval among LQT3 patients but not among LQT2 patients. LQT3 patients shortened their QT interval in response to increases in heart rate much more than LQT2 patients and healthy controls. These findings suggest thatLQT3 patients are more likely to benefit from Na⁺ channel blockers and from cardiac pacing because they are at higher arrhythmic risk at slow heart rates. Conversely, LQT2 patients are at higher risk to develop syncope under stressful conditions, because of the combined arrhythmogenic effect of cate-cholamines with the insufficient adaptation of their QT interval. Along the same line of development of gene-specific therapy, recent data demonstrated that an increase in the extracellular concentration of potassium shortens the QT interval in LQT2 patients suggesting that intervention aimed at increasing potassium plasma levels may represent a specific treatment for LQT2. The molecular findings on LQTS suggest the possibility of developing therapeutic interventions targeted to specific genetic defects. Until definitive data become available, antiadrenergic therapy remains the mainstay in the management of LQTS patients, however it may be soon worth considering the addition of a Na + channel blocker such as mexiletine for LQT3 patients and of interventions such as K⁺ channel openers or increases in the extracellular concentration of potassium for LQTl and LQT2 patients.     

Holter monitoring for 24 hours in patients with thromboembolic stroke and sinus rhythm diagnosed in the emergency department

It is well known that patients with ischemic stroke show ST-T abnormalities and various rhythm abnormalities on an electrocardiogram (ECG). The most commonly encountered rhythm abnormality is atrial fibrillation. It was recently shown that paroxysmal atrial fibrillation (PAF) is an important causative factor in patients with stroke. Detection of PAF is important in identifying the cause, prognosis, and treatment in patients with thromboembolic stroke. Investigators in the present study followed patients with thromboembolic stroke who had been admitted to the emergency department in sinus rhythm; 24-h Holter monitoring was used, and patients were assessed at referral and every 6 h for 24 h with ECG, which was used to detect rhythm disturbances, especially PAF. In 26 patients with stroke who came to the emergency department, acute thromboembolic stroke was diagnosed on the basis of magnetic resonance imaging; no rhythm abnormalities were noted on Holter monitoring. Eighteen patients were male and 8 were female (mean age: 66±13 y). Arrhythmia was identified on ECG in 3 patients (11%) and on 24-h Holter monitoring in 24 patients (92%). PAF was diagnosed in 3 patients (11%) on ECG and in 11 patients (42%) on Holter monitoring. In 2 patients, nonsustained ventricular tachycardia was detected only on Holter monitoring, which was found to be significantly superior to ECG for the detection of arrhythmias (P < .001). Investigators found no significant relationship between PAF and variables such as hypertension, diabetes, coronary artery disease, history of myocardial infarction, ST-T changes, and elevations in cardiac markers. However, a significant relationship (P < .01) was seen between nonsustained ventricular tachycardia and a history of myocardial infarction. No relationship was discerned between arrhythmia and stroke localization. Study results suggested that (1) PAF is a commonly diagnosed rhythm abnormality, and (2) Holter monitoring is superior to routine ECG for the detection of arrhythmias such as PAF in patients anticipated to have thromboembolic stroke with sinus rhythm.