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.     

The Ventricular Paced QT Interval—The Effects of Rate and Exercise

Changes in the QT and QTc intervals in 19 patients were studied at a ventricular paced rate difference of 50 beats/min. In all patients the measured QT interval shortened as the pacing rate was increased, from a mean value of 441 ms to 380 ms (p < 0.001), but when correct ed for heart rate the QTc- lengthened from a mean value of 518 ms to 575 ms. In 11 patients the QT in terval was measured at rest and immediately following exercise sufficient to increase the atrial rate by approximately 50 beats/min at identical ventricular paced rates. In all patients exercise-induced QT interval shortening from a mean value of 433 ms to 399 ms (p < 0.001). These results show first that Bazett's formula is unsuitable for correction of QT interval changes induced by ventricular pacing, and second that heart rate and changes in sympathetic tone independently influence the duration of the QT interval. It is suggested that these resuits are relevant to the design of physiological pacemakers in which the duration of the QT interval influences the discharge frequency of the pacemaker and to the consideration of ventricular pacing for the treatment of abnormal repolarization syndromes. (PACE, Vol. 5, May-June, 1982)     

QT dispersion and signal-averaged electrocardiogram in hemodialysis and CAPD patients.

OBJECTIVE: The aim of this study was to compare QT dispersion (QTd) and signal-averaged electrocardiogram (SA-ECG) parameters that may predict risk of malignant arrhythmias in patients on hemodialysis (HD), on continuous ambulatory peritoneal dialysis (CAPD), and in controls. SETTING: Controlled cross-sectional study in a tertiary-care setting. PATIENTS: 28 HD (M/F 18/10; mean age 32 +/- 9 years), 29 CAPD (M/F 17/12; mean age 34 +/- 10 years), and 29 healthy controls (M/F 17/12; mean age 32 +/- 8 years) were included. INTERVENTIONS: On ECG, minimum (QTmin) and maximum (QTmax) QT duration and their difference (QTd) were measured. In SA-ECG, duration of filtered QRS, HFLA signals less than 40 microV, and RMS voltage (40 ms) were also measured. RESULTS: Higher serum Ca2+ and lower K+ levels were found in CAPD compared to HD. All QT parameters were increased in HD and CAPD compared to controls. QT dispersion was significantly prolonged in HD compared to CAPD. In HD, QTd was correlated with left ventricular (LV) mass index (r = 0.53, p = 0.004), but not in CAPD (r = -0.09, p = 0.63). QT dispersion was significantly prolonged in patients with LV hypertrophy compared to patients without hypertrophy on HD (68 +/- 18 ms vs 49 +/- 18 ms, p = 0.008). In the analysis of SA-ECG, 3 of the 28 (11%) HD and 2 of the 29 (7%) CAPD patients had abnormal late potentials. Patients on HD and CAPD had significantly higher filtered-QRS duration compared to controls (105 +/- 15 ms and 104 +/- 12 ms vs 95 +/- 5 ms, respectively, p = 0.04). Patients with LV hypertrophy had higher filtered-QRS duration compared to patients without hypertrophy (109 +/- 12 ms vs 95 +/- 8 ms, p < 0.001). CONCLUSION: Dialysis patients had prolonged QTd and increased filtered-QRS duration in SA-ECG compared to controls. Patients on HD had longer QTd than patients on CAPD. QTd has been correlated to LV mass index in HD, but not in CAPD. This difference might be due to the effect of different dialysis modalities on electrolytes, especially the higher serum Ca2+ levels.     

Effects of aging and gender on QT dispersion in an overtly healthy population

The objective of this study was to measure the normal variation of QT dispersion (QTd) with respect to age and gender. The QT interval is a measure of the duration of ventricular depolarization and repolarization, while the QTd is a measure of the variability of the ventricular recovery time. The QTd has been suggested as a means of identifying those patients at risk for sustained ventricular tachyarrythmias and sudden cardiac death (SCD). A total of 250 patients (120 women, 130 men; age range 20-86 years) were recruited for this study. The QT intervals were measured in each of the 12 standard leads of the electrocardiogram. Data are presented as mean (mu) +/- SD. The QTd did not vary significantly within the same gender. A significant difference (P < 0.001) was noted in QTd between men (age [mu] = 53.3 +/- 15.6 years, QTd = 0.044 +/- 0.019 s) and women (age [mu] = 52.1 +/- 15.1 years, QTd = 0.034 +/- 0.015 s). Overall, men had a greater QTd, while women had a longer QT. In conclusion, we found that men had a longer QTd, which may explain the increased risk of SCD. However, women have a longer QT interval with a smaller QTd. A longer QTmin, as opposed to a longer QTmax, is responsible for the shorter QTd in women. This longer QTmin in women may predispose to an increased risk of drug induced torsades de pointes.     

Time Dependent Changes in Duration of Ventricular Repolarization After AV Node Ablation: Insights into the Possible Mechanism of Postprocedural Sudden Death

DIZON, J., et al. : Time Dependent Changes in Duration of Ventricular Repolarization After AV Node Ablation: Insights into the Possible Mechanism of Postprocedural Sudden Death. Although effective, there is a disturbing incidence of sudden death after AV node ablation. The mechanism may be related to proarrhythmia associated with prolongation in ventricular repolarization from the sudden decrease in heart rate. To examine this issue, we studied 15 patients undergoing complete radiofrequency ablation of the AV node for rapid atrial arrhythmias. Twelve‐lead ECGs of paced rhythms at rates of 60, 80, 100, and 120 beats/min were recorded at time points of 30 minutes, 24 hours, 1 week, and 1 month after ablation. The QT interval was measured in the limb and precordial leads with the best T wave offset. The change in the QT interval (ΔQT) relative to the measurement at 30‐minute postablation was calculated. For comparison, a similar procedure was performed on patients receiving pacemakers for primary bradycardia (n = 5 ). The mean QT interval at 60 beats/min, 30‐minutes postablation was significantly longer than at time points thereafter (482 ± 39 vs 446 ± 28 ms at 1 month, limb leads, for example, P < 0.05 ). Analysis of ΔQT revealed a significant shortening of the QT interval at nearly every paced rate at every time point relative to the value at 30‐minute postablation. The QT intervals shortened and stabilized after 24 hours. Neither the QT interval nor ΔQT changed significantly in patients paced for primary bradycardia. We conclude that there is a relative increase in the duration of ventricular repolarization after AV node ablation, which then decreases and stabilizes after 24 hours. Such changes are not seen in patients being paced for primary bradycardia. This data is consistent with the hypothesis that sudden death after AV node ablation may be related to proarrhythmia from prolonged ventricular repolarization.     

Acute sleep deprivation is associated with increased QT dispersion in healthy young adults

Background: Sleep deprivation (SD) is known to be associated with worse cardiovascular outcome including mortality. We investigated the association between acute SD and electrocardiographic maximum QT interval (QTmax), QT, and corrected QT dispersion (QTd/cQTd), which are known to be among predictors of ventricular arrhythmias and sudden death.
Methods: We obtained electrocardiograms of 37 healthy young volunteers (age: 28.45 ± 7.97 years; 11 women) after a night with regular sleep and repeated after a night with sleep debt. We measured minimum QT interval (QTmin), QTmax, QTd, and cQTd in milliseconds.
Results: Average sleep time of the subjects were 7.7 ± 0.8 hours during regular sleep and 1.7 ± 1.6 hours during a night with sleep debt (P < 0.001). Subjects had similar values of QTmin in milliseconds after a night of sleep debt when compared to after regular sleep (347.56 ± 29.75 vs 344.59 ± 20.89; P = 0.51), whereas they had significantly higher values of QTmax, QTd, and cQTd (396.48 ± 30.11 vs 378.10 ± 23.90; P = 0.001, 49.45 ± 9.11 vs 33.51 ± 10.05; P < 0.001 and 54.92 ± 10.42 vs 37.23 ± 10.81; P < 0.001, respectively). In Pearson's correlation analysis, QTmax, QTd, and cQTd were inversely correlated with sleep time (P = 0.012, r =–0.291; P < 0.001, r =–0.625 and P < 0.001, r =–0.616, respectively)
Conclusions: In conclusion, we clearly demonstrated that even one night of SD is associated with significant increase in QTmax, QTd, and cQTd in healthy young adults despite remaining within normal limits. These electrocardiographic changes in acute SD might contribute to development and/or recurrence of arrhythmias. This implication deserves further studies for clarifying the possible linkage between SD and arrhythmias.     

Assessment of QT interval duration and dispersion in athlete's heart

An athlete's heart is characterized by morphological and functional changes occurring as a consequence of regular physical exercise. We sought to determine if these physiological changes lead to ventricular repolarization abnormalities in trained athletes. Forty-four trained athletes and 35 sex- and age-matched healthy sedentary controls were included in the study. A 12-lead surface electrocardiogram (ECG) was obtained from all participants. Maximum QT (QTmax) and minimum QT (QTmin) interval durations, QT dispersion (QTd) and corrected QT dispersion (QTcd) were calculated for each ECG record. Heart rate, systolic and diastolic blood pressure values were found to be identical in both groups. QTmax and QTmin interval durations were not statistically different between the athletic and control groups. Similarly, QTd and QTcd did not differ significantly between the two groups. No association was observed between an athlete's heart and ventricular heterogeneity compared with healthy sedentary controls, despite physiological and structural changes.     

QT interval is prolonged but QT dispersion is maintained in patients with primary aldosteronism

The relationship between QT duration and its dispersion in patients with primary hyperaldosteronism is not clearly known. We studied 26 patients (nine males and 17 females) with primary hyperaldosteronism. The serum potassium levels were low (2.32 +/- 0.52 mmol/l), did not correlate with serum renin or aldosterone levels, or aldosterone/renin ratio (ARR). The maximum QT intervals (QTmax) were prolonged (502 +/- 62 ms), correlated well with ARRs (p = 0.005) and aldosterone levels (p = 0.019), but not to renin (p = 0.517) or potassium levels (p = 0.196). The QT dispersions (QTd) were small (60 +/- 28.8 ms) and did not correlate with potassium, renin or aldosterone levels. QTmax but not QTd correlate with aldosterone levels in patients with primary aldosteronism. The maintenance of repolarisation homogeneity with relatively unchanged QT dispersion may contribute to our understanding of the clinical observation that ventricular tachydysrhythmia is rare among patients with primary aldosteronism.     

Full Ventricular Capture Indicated by the QT Interval Function

The atrioventricular (AV) interval is critical in dual chamber (DDD) pacing in patients with hypertrophic obstructive cardiomyopathy (HOCM) to obtain full ventricular capture (FVC) with maximal reduction of the left ventricular (LV) outflow gradient and optimal LV diastolic filling. We studied the relationship of FVC, fusion, spontaneous AV conduction, and the QT interval. Methods: 11 patients with various cardiac diseases and stable AV conduction received a QT sensing Diamond (tm) Vitatron, DDD pacemaker. Software was downloaded into the pacemaker. In the DDD pacing mode, with the QT interval measured from the ventricular pacing stimulus to the end of the T wave, the AV interval was shortened from 400 ms, in 20-ms steps, to 90 ms. At 90 ms the stimulation rate was increased by 30 beats/mm and the AV interval was increased stepwise. FVC and fusion was examined on the surface ECG, Results: At 400 ms interval, spontaneous AV conduction inhibited the pacemaker. Shortening the AV interval resulted in pacing with a short QT interval. Further reduction of the AV interval resulted in a longer QT interval up to a point where the QT interval became stable. This point, the bending point in the plot of measured QT interval versus shortened AV intervals, coincided with the point of FVC. The relation of the QT-AV interval plot and the point of fusion was comparable when lengthening the AV interval at a 30 beats/mm faster stimulation rate. Conclusion: The bending point in the QT interval versus AV interval plots showed a good correlation with the FVC and fusion points observed on ECG. The results suggest that automatic discrimination between fusion and full capture using QT interval measurements may be feasible.     

皮肤黏膜淋巴结综合征患儿QT间期离散度和P波离散度变化

目的　探讨用预测可能发生心律失常的心电学指标QT间期离散度 (QTd)和P波离散度 (Pd)来研究皮肤黏膜淋巴结综合征 (MCLS)患儿发生心律失常的可能性。方法　MCLS患儿 6 2例 (13例伴有冠脉扩张 ) ,随机匹配 79例健康儿童为对照。采用广东中山SR - 10 0 0A心电综合自动分析仪描记 12导联同步体表心电图 (12ECG) ,选择波形清晰的 3个心动周期 ,在人工干预下自动测量窦性节律时心率 (HR)、QTmax、QTmin、Pmax、Pmin ,计算QTd及Pd ,连测 3次后取其平均值。结果　与对照组比较 ,MCLS组急性期心率增快 (P <0 0 1) ,QTmax、QTmin缩短 ,QTd增大 ,Pmax增加 ,Pmin缩短 ,Pd增大 ;恢复期QTd、Pmax、Pd延长 ,其差异均有显著性 (P <0 0 1或P <0 0 5 )。伴有冠脉扩张与不伴有冠脉扩张的MCLS患儿之间QTmax、QTmin、QTd、Pmax、Pmin、Pd差异无显著性 (P >0 0 5 )。结论　MCLS能引起QTd及Pd增加 ,有可能发生严重心律失常 ,临床上不容忽视     

QT interval dispersion in ventricular beats: a noninvasive marker of susceptibility to sustained ventricular arrhythmias

Increased QT dispersion (QTd) calculated from sinus beats has been shown to identify patients prone to sustained VT. However, predictive accuracy of this parameter is limited. Electrophysiological properties of the myocardium may be altered by a premature ventricular beats, which is a well-established trigger for sustained VT. Therefore, the author hypothesised that QTd in spontaneous or paced ventricular beats may improve identification of patients with inducible sustained VT. In 28 consecutive patients (men, mean age 61 +/- 13 years) who underwent programmed ventricular stimulation, the values of QTd calculated in sinus and ventricular beats were compared between inducible and noninducible patients. The mean QTd values obtained using three different methods differed significantly, QTd in paced ventricular beats being the highest, QTd in spontaneous ventricular beats was intermediate, and QTd in sinus beats was the lowest (83.9 +/- 30 vs 63.0 +/- 29 ms vs 53.9 +/- 27 ms, P < 0.0001 and P < 0.004, respectively). In 13 (46%) patients sustained VT was induced. QTd values were significantly higher in inducible than noninducible patients (QTd sinus beats: 67.5 +/- 31 vs 42.1 +/- 11 ms, P = 0.02; QTd spontaneous ventricular beats: 79.3 +/- 35 vs 46.7 +/- 13 ms, P = 0.008, and QTd-paced ventricular beats: 104.8 +/- 32 vs 65.9 +/- 9 ms, P = 0.0009). The receiver operator characteristic curves showed that at a sensitivity level of 100%, the highest specificity for identification of inducible patients had QTd measured in paced ventricular beats (87%) followed by QTd in spontaneous ventricular beats (45%), and QTd in sinus beats (40%). In conclusion, (1) QTd in ventricular beats is greater than in sinus beats, and (2) QTd calculated from paced ventricular beats identifies patients with inducible sustained VT better than QTd measured during sinus rhythm.     

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.     

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.     

QT interval dispersion and autonomic modulation in subjects with anxiety

This study was designed to assess Q-T interval dispersion as a marker of electrical instability in subjects with anxiety. Recent observations have shown that the presence of anxiety symptoms increases the risk of sudden death. The Kawachi anxiety questionnaire identified 29 subjects (male/female ratio 13:16) who scored 0, 22 subjects (male/female ratio 14:8) who scored 1, and 37 subjects (male/female ratio 13:24) who scored 2 or more. In all subjects we measured electrocardiographic interlead QT dispersion and autonomic function through spectral analysis of R-R interval and blood pressure variabilities and left ventricular mass. Compared with subjects who scored 0, those reporting 2 or more symptoms showed increased heart rate-corrected QT dispersion (54.9+/-1.7 ms vs. 34.9+/-3.2 ms, P<.001), sympathetic modulation (normal logarithm low-frequency power/high-frequency power 0.59+/-0.1 vs. 0.12+/-0.04, P<.05), and left ventricular mass (120.7+/-3.5 g/m2 vs. 97.9+/-2.8 g/m2, P<.001). Probably because it augments sympathetic activity, anxiety causes left ventricular mass to increase and, like hypertension, increases heart rate-corrected Q-T interval dispersion. The consequent electrical instability could be the substrate responsible for inducing fatal ventricular arrhythmias.     

Optimal sensed atrio-ventricular interval determined by paced QRS morphology

BACKGROUND: In cardiac resynchronization therapy (CRT), the atrio-ventricular (AV) and interventricular (VV) intervals have to be optimized. For maximal optimization, the paced and sensed AV intervals have to be determined. We hypothesized that the morphology of the paced QRS complex at the optimal paced AV interval (PAV) can be used to determine the optimal sensed AV (SAV) interval in patients with normal AV conduction. PATIENTS AND METHODS: In 16 patients with implanted CRT devices, the optimal PAV and V-V interval were determined by invasive measurement of left ventricle (LV) dP/dt(max). A 12-lead electrocardiogram (ECG) was recorded at the optimum setting. Subsequently, during atrial sensing ventricular pacing, the SAV interval was changed until the QRS morphology was identical to the morphology at the optimal PAV interval. The optimal SAV interval was verified by repeated measurement of LV dP/dt(max). RESULTS: By optimization of the PAV and VV interval, the LV dP/dt(max) increased from 639 +/- 204 to 789 +/- 223 mmHg/s (+23%; P = 0.0000002). The optimized PAV was 149 +/- 19 ms; the optimized SAV was 100 +/- 20 ms and the corresponding LV dP/dt(max) at this interval was 774 +/- 204 ms (+21%; P = 0.000004). LV dP/dt(max) at optimized SAV - 20 ms and optimized SAV + 20 ms was 747 +/- 213 mmHg/s (P = 0.00004) and 751 +/- 203 mmHg/s (P = 0.0000003), respectively. The mean difference in optimized PAV and optimized SAV was 49 +/- 17 ms, ranging from 20 to 80 ms. CONCLUSIONS: The QRS morphology at optimized PAV can be used as a template to determine the optimal SAV, provided that the patient has normal AV conduction.     

Clinical assessment of drug-induced QT prolongation in association with heart rate changes

BACKGROUND: The formulas for heart rate (HR) correction of QT interval have been shown to overcorrect or undercorrect this interval with changes in HR. A Holter-monitoring method avoiding the need for any correction formulas is proposed as a means to assess drug-induced QT interval changes. METHODS: A thorough QT study included 2 single doses of the alpha1-adrenergic receptor blocker alfuzosin, placebo, and a QT-positive control arm (moxifloxacin) in 48 healthy subjects. Bazett, Fridericia, population-specific (QTcN), and subject-specific (QTcNi) correction formulas were applied to 12-lead electrocardio-graphic recording data. QT1000 (QT at RR = 1000 ms), QT largest bin (at the largest sample size bin), and QT average (average QT of all RR bins) were obtained from Holter recordings by use of custom software to perform rate-independent QT analysis. RESULTS: The 3 Holter end points provided similar results, as follows: Moxifloxacin-induced QT prolongation was 7.0 ms (95% confidence interval [CI], 4.4-9.6 ms) for QT1000, 6.9 ms (95% CI, 4.8-9.1 ms) for QT largest bin, and 6.6 ms (95% CI, 4.6-8.6 ms) for QT average. At the therapeutic dose (10 mg), alfuzosin did not induce significant change in the QT. The 40-mg dose of alfuzosin increased HR by 3.7 beats/min and induced a small QT1000 increase of 2.9 ms (95% CI, 0.3-5.5 ms) (QTcN, +4.6 ms [95% CI, 2.1-7.0 ms]; QTcNi, +4.7 ms [95% CI, 2.2-7.1 ms]). Data corrected by "universal" correction formulas still showed rate dependency and yielded larger QTc change estimations. The Holter method was able to show the drug-induced changes in QT rate dependence. CONCLUSIONS: The direct Holter-based QT interval measurement method provides an alternative approach to measure rate-independent estimates of QT interval changes during treatment.     

Clinical characteristics and treatment of short QT syndrome

Short QT syndrome is a new inherited disorder associated with familial atrial fibrillation and/or sudden death or syncope. To date, three different mutations in genes encoding cardiac ion channels (KCNH2, KCNQ1 and KCNJ2) have been identified as causing short QT syndrome. All mutations lead to a gain in function of the affected current (IK(r), IK(s )and IK(1)). The syndrome is characterized in the few patients identified so far by a shortened QT interval of less than 300-325 ms after correction for heart rate at rates below 80 beats per minute. However, no boundary or limit for the QT interval can yet be determined, as more knowledge about this disease is still restricted to a small patient population. Furthermore, the QT interval lacks adaptation to heart rate. The majority of patients exhibit shortened atrial and ventricular effective refractory periods and inducibility of ventricular fibrillation. Death already occurs in newborns, so the short QT syndrome may also account for deaths classified as sudden infant death syndrome. The therapy of choice in families with a history of sudden death or syncope seems to be the implantable cardioverter-defibrillator. Whether patients without a family history of sudden death or symptoms need a defibrillator cannot yet be answered, and requires further investigation. Pharmacologic treatment has only been investigated in patients with a mutation in KCNH2 (HERG), and it could be demonstrated that the mutant currents may be insufficiently suppressed by drugs that are targeted to block the specific current (e.g., sotalol or ibutilide) in patients with a mutation in the IK(r-)coding gene KCNH2 (HERG). Interestingly, in this specific patient population, quinidine proved to be efficient in prolonging the QT interval and normalizing the effective refractory periods. Implantable cardioverter-defibrillator therapy is associated with an increased risk of inappropriate therapies for T-wave oversensing, although this risk can be resolved by reprogramming implantable cardioverter-defibrillator detection algorithms.     

QT interval prolongation after oxytocin bolus during surgical induced abortion

BACKGROUND: Although oxytocin, a uterotonic agent, may cause short-term vasodilation that results in severe hypotension, it is still routinely given as an intravenous bolus injection during surgical suction curettage. Two reported cases of ventricular tachycardia after oxytocin bolus in patients with long QT interval syndrome led us to assess the effect of oxytocin on QT interval. METHOD: Thirty-eight healthy women scheduled for a surgical suction curettage with general anesthesia were enrolled. General anesthesia was induced by propofol and maintained by either propofol (n = 18) or sevoflurane (n = 20). Electrocardiographic recordings were obtained before and at 1, 2, 3, and 5 minutes after a 10-U intravenous bolus of oxytocin. RESULTS: Intravenous oxytocin induced a pronounced QTc interval prolongation of 41 +/- 21 ms ( P < .0001), which was maximal 1 minute after administration. The QTc interval returned to control values 3 minutes after oxytocin bolus. Oxytocin bolus also induced an increase in heart rate of 19 +/- 10 beats/min and a significant decrease in systolic arterial pressure of 11 +/- 9 mm Hg (both P < .0001). The drug used to maintain anesthesia was not an independent factor of QT interval prolongation in ANOVA analysis. CONCLUSIONS: Oxytocin intravenous bolus induced a large and transient QTc interval prolongation, suggesting that it may lead to proarrhythmia in circumstances favoring QTc interval increase.     

Dynamic beat-to-beat modeling of the QT-RR interval relationship: analysis of QT prolongation during alterations of autonomic state versus human ether a-go-go-related gene inhibition

Methods to correct the QT interval for heart rate are often in disagreement and may be further confounded by changes in autonomic state. This can be problematic when trying to distinguish the changes in QT interval by either drug-induced delayed repolarization or from autonomic-mediated physiological responses. Assessment of the canine dynamic QT-RR interval relationship was visualized by novel programming of the dynamic beat-to-beat confluence of data or "clouds". To represent the nonuniformity of the clouds, a bootstrap sampling method that computes the mathematical center of the uncorrected beat-to-beat QT value (QTbtb) with upper 95% confidence bounds was adopted and compared with corrected QT (QTc) using standard correction factors. Nitroprusside-induced reflex tachycardia reduced QTbtb by 43 ms, whereas an increase of 55 and 16 ms was obtained using the Bazett (QTcB) and Fridericia (QTcF) formulae, respectively. Phenylephrine-induced reflex bradycardia increased QTbtb by 3 ms but decreased QTcB by 20 ms and QTcF by 12 ms. Delayed repolarization with E-4031 (1-[2-(6-methyl-2-pyridyl)ethyl]-4-methylsulfonylaminobenzoyl)-piperidine), an inhibitor of rectifier potassium current, increased QTbtb by 26 ms but QT prolongation calculations using QTcF and QTcB were between 12 and 52% less, respectively, when small decreases in heart rate (5-8 beats per minute) were apparent. Dynamic assessment of beat-to-beat data, using the bootstrap method, allows quantification of QT interval changes under varying conditions of heart rate, autonomic tone, and direct repolarization that may not be distinguishable with use of standard correction factors.     

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.