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.     

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.     

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.     

Influence of posture and handgrip on the QT interval in left ventricular hypertrophy and in chronic heart failure

In certain disease states prolongation of the QT interval has been shown to be arrhythmogenic. Whether QTc interval changes with position and thus whether certain positions are more arrhythmogenic than others is not known for different diseases that predispose to arrhythmias, and was therefore studied. Patients with left ventricular hypertrophy and heart failure, and the appropriate matched controls, were recruited. Subjects were studied in the lying, sitting, standing and squatting positions and had QT intervals determined by computer algorithm 2 min after each position change. After resting, QT interval was determined while the subjects performed maximum handgrip exercise with their dominant hand. QT intervals were rate-corrected using Bazett's method. QTc interval is prolonged in heart failure patients compared with either left ventricular hypertrophy or control subjects in the lying and sitting position, but not in the standing or squatting position. The QTc intervals for heart failure and control subjects were, respectively, 443+/-7 ms versus 421+/-6 ms when lying (P<0.05), 451+/-10 ms versus 419+/-6 ms when sitting (P<0.05), 429+/-10 versus 414+/-7 ms when standing (P not significant) and 437+/-10 versus 419+/-8 ms when squatting (P not significant). The values for patients with hypertrophy did not differ from control values. Maximum handgrip does not affect the QTc interval in heart failure, but prolongs it in both the hypertrophy and control groups. Position and static exercise are important modifiers of QTc interval and their effect depends on the condition of the left ventricle.     

Effects of Sotalol on the Circadian Rhythmicity of Heart Rate and QT Intervals With a Noninvasive Index of Reverse-Use Dependency

BACKGROUND: The effects of sotalol on the 24-hour profile of the QT interval relative to that of the heart rate (HR) may be helpful in determining the time course of the drug's action in controlling cardiac arhythmias. This has not been previously determined. Thus, the objective of the current study was to evaluate the influence of the drug on the circadian rhythmicity of HR and QT intervals from Holter recordings in ambulatory patients. Reverse-use dependency (RUD) of sotalol was also studied noninvasively from Holter recordings. METHODS AND RESULTS: Holter recordings of 18 patients with ventricular arrhythmias were analyzed before and after 3-7 days of treatment with sotalol. We developed and used a signal processing system. A new noninvasive index to evaluate RUD was defined and applied to sotalol as a test agent. Sotalol significantly reduced HR from 76.9 +/- 3.2 to 60.0 +/- 1.1 (P <.001). The mean QT interval increased from 393 +/- 11 ms to 489 +/- 9 ms, whereas the mean normalized QT (QTc) interval increased from 415 +/- 5 ms to 487 +/- 5 ms (P <.001) during the drug treatment. Circadian rhythmicity of RR interval was abolished, but the circadian rhythms of the QT and QTc intervals were maintained during continuous treatment with sotalol. This finding is in contrast to amiodarone, which abolished the circadian rhythmicity of QTc interval while maintaining that of RR interval. RUD index was increased from 0.13 +/- 0.08 to 0.24 +/- 0.10 (P <.001) after sotalol, consistent with increased RUD with sotalol. CONCLUSIONS: The effects of sotalol on the circadian rhythmicity of HR and QTc interval are dissociated. They are in direct contrast to those reported for amiodarone, a difference that may be of clinical significance. The RUD index introduced here provides a noninvasive parameter for comparing short-term as well as long-term effects of class III antiarrhythmic drugs on RUD.     

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.     

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.     

Effect of epirubicin-based chemotherapy and dexrazoxane supplementation on QT dispersion in non-Hodgkin lymphoma patients

BACKGROUND AND OBJECTIVE: Aim of the present study was to assess the effect of epirubicin-based chemotherapy on QT interval dispersion in patients with aggressive non-Hodgkin lymphoma (NHL), and the effect of dexrazoxane supplementation. Prolongation of QT dispersion may not only represent a sensitive tool in identifying the first sign of anthracycline-induced cardiotoxicity, but it may serve also in identifying patients who are at risk of arrhythmic events. METHODS: Twenty untreated patients, 相似文献   

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.     

Temporary disturbances of the QT interval precede the onset of ventricular tachyarrhythmias in patients with structural heart diseases

An increase in sinus rate prior to ventricular tachyarrhythmias has been demonstrated in previous studies. There is no clear data available concerning changes in ventricular de- and repolarization prior to ventricular tachyarrhythmias, especially in patients with structural heart disease. Therefore, the aim of this study was to analyze the QT and QTc interval (Bazett's formula immediately before the onset of ventricular tachyarrhythmias in stored electrograms of patients with ICDs. The study analyzed 228 spontaneous ventricular tachyarrhythmia episodes in 52 patients (mean age 64 +/- 10 years, 49 men, 3 women) and compared them with 146 electrograms of baseline rhythm recorded during regular ICD follow-up. Mean ventricular cycle length (CL), QT interval, and QTc were measured before the onset of ventricular tachyarrhythmia and during baseline rhythm. Prior to ventricular tachyarrhythmias onset, CL was significantly shorter than during baseline rhythm (714 +/- 139 vs 828 +/- 149 ms, P < 0.0001). By contrast, the QT interval (430 +/- 67 ms) and QTc interval (518 +/- 67 ms) were significantly prolonged before the onset of ventricular tachyarrhythmias as compared to baseline rhythm (QT 406 +/- 67 ms, QTc 450 +/- 61 ms; P < 0.0001). CL, QT, and QTc changes were independent of concomitant treatment with antiarrhythmic drugs. Ventricular tachyarrhythmias are preceded by a significant prolongation of the QT and QTc intervals. This phenomenon may represent a greater than normal disparity of repolarization recovery times possibly facilitating the development of ventricular tachyarrhythmias.     

QT dispersion in children with ventricular arrhythmia and a structurally normal heart

In adults, increased QT dispersion has been shown to predict arrhythmic risk as well as risk of sudden death in several clinical settings. It is not known whether or not QT dispersion is increased in children with idiopathic ventricular arrhythmia. We studied three groups of children: (1) 20 patients with idiopathic VT (aged 3-18 years; mean 11.2 years); (2) 30 patients with benign PVCs (aged 1-20 years; mean 10.5 years); and (3) 30 control subjects (aged 4-17 years; mean 12 years). Standard ECGs were reviewed and the dispersion of both QT and JT intervals was compared. No patient had structural heart disease or long QT syndrome. The QT and QTc dispersion (QT delta, QTc delta) among the three groups did not differ: QTc delta of the VT group was 70 ms +/- 30 ms, QTc delta of PVC patients was 60 ms +/- 30 ms, and the QTc delta of the control group was 65 ms +/- 30 ms. The JTc delta among the three groups did not differ as well: JTc delta of the VT group was 70 ms +/- 30 ms, the JTc delta of the PVC group was 60 msec +/- 25 msec, and the JTc delta of the control group was 70 ms +/- 30 ms. We conclude that QT and JT dispersion are not significantly altered in children with idiopathic VT or benign PVCs when compared to control subjects. QT dispersion is not a reliable marker for arrhythmic risk in children with idiopathic ventricular arrhythmias and structurally normal hearts.     

Holter monitoring in the evaluation of congenital long QT syndrome

Background: 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. Objective: We sought to determine the prevalence of positive Holter monitor tests and its diagnostic significance in evaluating LQTS. Methods: 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. Results: 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. Conclusion: 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. (PACE 2011; 34:1100–1104)     

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.     

Effect of nebivolol on QT dispersion in hypertensive patients with left ventricular hypertrophy.

Hypertensive patients with left ventricular hypertrophy (LVH) have increased QT dispersion, which is considered an early indicator of end-organ damage and a non-invasive marker of risk for clinically important ventricular arrhythmias and cardiac mortality. The purpose of this study was to examine the effect of nebivolol antihypertensive therapy on QT dispersion in hypertensive subjects. Twenty-five subjects (15 men and 10 women, mean age 53.6 +/- 4.5 years) with essential arterial hypertension and mild-to-moderate LVH (blood pressure: 147.2 +/- 6.2/90.6 +/- 3.8 mmHg; left ventricular mass indexed: 149.1 +/- 10.7 g/m(2)) were compared with 25 age-matched healthy control subjects. All the participants underwent a complete clinical examination, including electrocardiogram for QT interval measurements. The QT dispersion was defined as the difference between the longest and the shortest QT interval occurring in the 12-lead electrocardiogram. The QT dispersion was corrected (QTc) with Bazett's formula. Hypertensive subjects were treated with 5 mg daily of nebivolol. The ECG and echocardiogram were repeated after four weeks of treatment. At baseline, hypertensive patients showed QT dispersion (56.9 +/- 6.4 vs. 31.7 +/- 8.4 ms, P < 0.001) and QTc dispersion (58.3 +/- 6.2 vs. 33.2 +/- 7.8 ms, P < 0.001) significantly higher than control subjects. Four-week nebivolol treatment reduced blood pressure from 147.2 +/- 6.2/90.6 +/- 3.6 mmHg to 136.3 +/- 3.1/83.3 +/- 2.5 mmHg (P < 0.0001), and resting heart rate from 75.3 +/- 4.7 to 64.2 +/- 3.0 bpm (P < 0.001), without significant change in left ventricular mass (LVMi: 149.1 +/- 10.7 vs. 151.4 +/- 9.8 g/m(2), ns). Nebivolol-based treatment improved QT dispersion (56.9 +/- 6.4 vs. 40.5 +/- 5.8 ms, P < 0.001) and QTc dispersion (58.3 +/- 6.2 vs. 42.2 +/- 5.6 ms, P < 0.001), which remained higher than in control subjects (P < 0.001 in both cases). The reduction of QT dispersion did not correlate with arterial BP reduction. In conclusion, nebivolol reduced increased QT dispersion in hypertensive subjects after four weeks. This effect, occurred without any change in LVM, did not seem to be related to the blood pressure lowering and could contribute to reduce arrhythmias as well as sudden cardiac death in at-risk hypertensive patients.     

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.     

Prolongation of the QT interval in heart failure occurs at low but not at high heart rates

Abnormal left ventricular structure and function as in, for example, left ventricular hypertrophy or chronic heart failure, is associated with sudden cardiac death and, when the ejection fraction is depressed, with prolongation of the QT interval. The dependence on heart rate of QT interval prolongation in these conditions, and the relationship of any abnormalities either to deranged autonomic nervous system function or to an adverse prognosis, has not been well studied. We therefore investigated (1) the dependence on heart rate of the QT interval, and (2) the relationship between both QT interval and the QT/heart rate slope and markers of adverse prognosis in these two conditions. The QT interval was measured at rest and during exercise in 34 subjects with heart failure, 16 subjects with left ventricular hypertrophy and 16 age-matched controls with normal left ventricular structure and function. QTc (corrected QT) intervals at rest were significantly longer in heart failure patients (471+/-10 ms) than in controls (421+/-6 ms) or in subjects with hypertrophy (420+/-6 ms) (P<0.05). At peak exercise, despite the attainment of similar heart rates, the QT intervals no longer differed from each other, being 281+/-7 ms for controls, 296+/-11 ms in hypertrophy and 303+/-10 ms in heart failure (no significant difference). The QT/heart rate slope was significantly increased in heart failure [2.3+/-0.1 ms.(beats/min)(-1)] compared with controls [1.55+/-0.06 ms.(beats/min)(-1)] and hypertrophy [1. 66+/-0.1 ms.(beats/min)(-1)] (P<0.001). In left ventricular hypertrophy, despite animal data suggesting that QT interval prolongation should occur, no abnormalities were found in QT intervals at rest or during exercise. The QT/heart rate slope did not relate to any markers for an adverse prognosis, except that of prolongation of QT interval. Long QT intervals were associated principally with impairment of left ventricular systolic function. Our data emphasize the dynamic nature of the QT interval abnormalities found in heart failure.     

Isoproterenol exacerbates a long QT phenotype in Kcnq1-deficient neonatal mice: possible roles for human-like Kcnq1 isoform 1 and slow delayed rectifier K+ current

To determine whether the neonatal mouse can serve as a useful model for studying the molecular pharmacological basis of Long QT Syndrome Type 1 (LQT1), which has been linked to mutations in the human KCNQ1 gene, we measured QT intervals from electrocardiogram (ECG) recordings of wild-type (WT) and Kcnq1 knockout (KO) neonates before and after injection with the beta-adrenergic receptor agonist, isoproterenol (0.17 mg/kg, i.p.). Modest but significant increases in JT, QT, and rate-corrected QT (QTc) intervals were found in KO neonates relative to WT siblings during baseline ECG assessments (QTc = 57 +/- 3 ms, n = 22 versus 49 +/- 2 ms, n = 28, respectively, p < 0.05). Moreover, JT, QT, and QTc intervals significantly increased following isoproterenol challenge in the KO (p < 0.01) but not the WT group (p = 0.57). Furthermore, whole-cell patch-clamp recordings show that the slow delayed rectifier K+ current (IKs) was absent in KO but present in WT myocytes, where it was strongly enhanced by isoproterenol. This finding was confirmed by showing that the selective IKs inhibitor, L-735,821, blocked IKs and prolonged action potential duration in WT but not KO hearts. These data demonstrate that disruption of the Kcnq1 gene leads to loss of IKs, resulting in a long QT phenotype that is exacerbated by beta-adrenergic stimulation. This phenotype closely reflects that observed in human LQT1 patients, suggesting that the neonatal mouse serves as a valid model for this condition. This idea is further supported by new RNA data showing that there is a high degree of homology (>88% amino acid identity) between the predominant human and mouse cardiac Kcnq1 isoforms.     

Electrocardiographic features in a patient with the coexistence of long QT syndrome and coronary vasospasm

A 20-year-old woman suffered from cardiopulmonary arrest due to ventricular fibrillation. The electrocardiogram after resuscitation showed prolonged QTc interval with bifid T wave. On the third hospital day, the QTc interval and the T-wave changes improved. However, the QTc interval was distinctively prolonged after administration of epinephrine, oral glucose load, and intracoronary acetylcholine (Ach) into the left coronary artery. Moreover, an injection of Ach into the right coronary artery provoked severe coronary spasm. This is a case of the coexistence of long QT syndrome (LQTS) and coronary vasospasm, which may give an important clinical implication for the treatment of LQTS.     

Genotype-specific clinical manifestation in long QT syndrome

The congenital form of long QT syndrome (LQTS) is characterized by QT prolongation in the electrocardiogram (ECG) and a polymorphic ventricular tachycardia, Torsade de Pointes (TdP) mainly as a result of an increased sympathetic tone during exercise or mental stress. Recent genetic studies have so far identified seven forms of congenital LQTS caused by mutations in genes of the potassium and sodium channels or membrane adapter located on chromosomes 3, 4, 7, 11, 17 and 21. It is of particular importance to examine the genotype-phenotype correlation, especially in the LQT1, LQT2 and LQT3 forms of LQTS, which make up more than 90% of genotyped patients with LQTS, because it would enable us to manage and treat genotyped patients more effectively.     

Hyperbaric oxygen therapy decreases QT dispersion in diabetic patients

Diabetes mellitus is frequently associated with the malignant ventricular arrhythmias and sudden death. The QT dispersion is the difference between the longest and shortest QT interval calculated from the standard 12-lead electrocardiogram. The QT dispersion is suggested as an index of myocardial electrical activity. An increase in QT dispersion is associated with the malignant ventricular arrhythmias and sudden cardiac death. Diabetic patients receive hyperbaric oxygen (HBO) therapy for non-healing lower extremity ulcers. The aim of this study was to determine the effect of HBO therapy on QT dispersion in diabetic patients. Thirty diabetic patients (18 male and 12 female, 59.9 +/- 10 years), who were planning to undergo ten sessions of HBO therapy in two weeks for non-healing lower extremity ulcers, were consecutively enrolled into the study. The 12-lead resting electrocardiography recordings were taken before the first HBO therapy and after the 10th HBO-therapy session. QT intervals were measured on electrocardiogram. QT intervals were corrected for heart rate by using Bazett's formula (corrected QT [QTc] = QT/ radical R - R [seconds]). QTc dispersion was significantly decreased from 59.8 +/- 17.4 msec to 52.2 +/- 15.5 msec after ten sessions of HBO therapy (p < 0.05). However, maximum QTc, minimum QTc and mean QTc did not change significantly after HBO therapy. We have concluded that HBO therapy may reduce the risk of malignant ventricular arrhythmia and sudden cardiac death in diabetic patients when applied repetitively.