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.     

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)     

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.     

Effect of a single oral dose of moxifloxacin (400 mg and 800 mg) on ventricular repolarization in healthy subjects

BACKGROUND: Moxifloxacin is a new fluoroquinolone. In vitro studies have suggested that it could prolong ventricular repolarization. The main objective of this study was to measure the actual effect of single oral doses of moxifloxacin on QT interval duration in healthy volunteers. METHODS: Nine men and 9 women participated in a double-blind, randomized, placebo-controlled, crossover study. Each participant received single oral doses (400 mg and 800 mg) of moxifloxacin or placebo. At the time of expected moxifloxacin maximum concentration, several electrocardiographic recordings were obtained at rest and during the course of a submaximal exercise test. QT interval and the corresponding RR interval value were measured within a wide range of RR intervals in each subject. RESULTS: ANOVA showed that both moxifloxacin doses increased mean QT intervals compared with placebo. The mean QT interval duration at RR = 1000 ms was 379 +/- 24 ms during placebo, 394 +/- 33 ms during moxifloxacin 400 mg (P < .05), and 396 +/- 28 ms during moxifloxacin 800 mg (P < .05). Moxifloxacin-induced QT interval prolongation remained significant at all tested heart rates. The increase in QT interval duration relative to placebo remained between 2.3% +/- 2.8% and 4.5% + 3.8% across the range of RR intervals tested. CONCLUSION: Moxifloxacin prolongs QT interval duration. The amplitude of this effect is small, and the risk of moxifloxacin-induced torsades de pointes is expected to be minimal when the drug is administered at the recommended dose of 400 mg/d. However, moxifloxacin should not be used in patients with predisposing factors of torsades de pointes such as electrolyte disturbances and bradycardia or during coadministration of proarrhythmic drugs.     

Paced QT dispersion and QT morphology after radiofrequency atrioventricular junction ablation: impact of left ventricular function

Catheter ablation of the atrioventricular junction (AVJ) is a widely accepted treatment for drug refractory atrial fibrillation. Unfortunately, there have been some reports of pause dependent ventricular arrhythmias associated with QT interval prolongation, mainly in patients with reduced LV function. The present investigation evaluates the association of LV function with QT dispersion in response to a sudden rate drop. ECGs were' recorded on 20 patients (13 with normal LV function) on the day following AVJ ablation while paced at a range of ventricular rates (40-120 beats/min), and during a sudden drop from 80 to 40 beats/min. The maximum QT interval (QTmax), minimum QT interval (QTmin), and QT interval dispersion (QTdisp) were compared. In both groups, the QTmax and QTmin increased at slower paced heart rates while the QTdisp did not change. In response to a sudden rate drop from 80 to 40 beats/min, the QTmax increased in both groups of LV function (trend), while the QTmin increased in those with normal LV function (24 +/- 22 ms), but not in those with reduced LV function (0 +/- 14 ms; P = 0.01). Consequently, the QTdisp increased significantly in those with reduced LV function (31 +/- 23 ms) but not in normal LV function (-5 +/- 29 ms; P = 0.01). Morphological QTU changes developed following the sudden rate drop in 67% of the reduced LV versus 8% of the normal LV (P = 0.02) function groups. Following AVJ ablation, QTdisp increased during a sudden rate drop in patients with reduced LV function, but not in patients with normal LV function.     

The imprecision in heart rate correction may lead to artificial observations of drug induced QT interval changes

Because of the known limitations of the Bazett and other heart rate correction formulas, it has been proposed that studies of drug induced QT interval changes should use several different heart rate correction formulas and that the consistency of findings by a majority of such formulas should be considered as valid. The aim of this article was to show that such an approach is inappropriate. Using the database of the EMIAT trial, data of QT and RR intervals were taken from electrocardiograms of the first postrandomization visit of 1,402 patients. Of these, 309 were on amiodarone and beta-blockers, 395 on amiodarone and off beta-blockers, 318 on beta-blockers and off amiodarone, and 380 off amiodarone and off beta-blockers. An investigation of drug induced QT interval changes was modeled by evaluating the corrected QT (QTc) interval differences between patients on and off amiodarone, and on and off beta-blockers. A set of 31 previously published heart rate correction formulas was used. In addition to calculating the QTc difference between on and off drug for each formula, the success of heart rate correction was judged by computing correlation coefficients between QTc and RR intervals (ideally corrected QTc values should be independent of heart rate). The difference between on and off drug QT intervals was also evaluated by logarithmic regression models between uncorrected QT and RR intervals in data taken from patients on and off treatment. The QTc interval prolongation on amiodarone was confirmed by all heart rate correction formulas but the extent of the prolongation differed from formula to formula and ranged from 13.6 to 30.9 ms. Of the 31 formulas, 3 reported QTc interval shortening on beta-blockers (up to -11.8 ms) and 28 reported QTc interval prolongation (up to +16.8 ms). The distribution of the results provided by the different formulas suggested that beta-blocker treatment led to a QTc interval prolongation by approximately 7 ms (e.g., +7.4 ms by the Fridericia formula, P = 0.002). The on treatment QTc changes obtained by different formulas were closely correlated to their correction success. Formulas that provided QTc intervals almost independent of the RR intervals estimated approximately 20 ms QTc prolongation on amiodarone and no QTc change on beta-blockers. QT/RR regression analysis confirmed that while amiodarone led to substantial QT prolongation, there was no change of QT interval on beta-blockers beyond the change in heart rate. The study showed that the concept of "majority voting" by different heart rate correction formulas is inappropriate and may lead to erroneous conclusions.     

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.     

Relationship Between Atrioventricular Delay and Oxygen Consumption in Patients with Sick Sinus Syndrome: Relevance to Rate Responsive Pacing

To develop a dromotropic-controlled rate adaptive algorithm for patients with sick sinus syndrome (SSS) and intact AV conduction, 14 pace-maker patients with SSS underwent cardiopulmonary exercise testing (CPX). During exercise, the pace-maker was programmed in an AAT mode without rate adaptation, whereby 3 patients developed supraventricular arrhythmia and 11 patients kept sinus rhythm. Chronotropic incompetence (CI) at heart rate (HR) < 95 beats/min at the anaerobic threshold (AT) was found in five patients. In patients with chronotropic competence (CC), the HR increase was significantly greater than in CI patients (rest: 73.2 +/- 12.6 vs. 64.2 +/- 4.0 beats/min;AT:101.2 +/- 6.2 vs. 82.0 +/- 5.1 beats/min;peak: 135.2 +/- 10.7 vs. 103.2 +/- 10.9 beats/min). There was no significant difference in the AVD between CC and CI patients (rest: 167.7 +/- 38.6 vs. 170.8 +/- 22.5 ms, AT: 156.2 +/- 30.7 vs. 163.6 +/- 21.6 ms, peak: 144.7 +/- 29.0 vs. 152.4 +/- 15.0 ms). The correlation coefficient between HR increase and VO2 was +1.0 and between AVD decrease and VO2 - 1.0 in both groups. An increase in pacing rate from 75 beats/min to 120 beats/min without exercise (overpacing) led to a prolongation of the AV interval of about 30.6 +/- 14.2 ms. Based on this closed loop control with negative feedback, a dromotropic rate adaptive algorithm for patients with SSS and intact AV conduction could be developed.     

Comparison of Formulae for Heart Rate Correction of QT Interval in Exercise Electrocardiograms

The study investigated the differences in five different formulae for heart rate correction of the QT interval in serial electrocardiograms recorded in healthy subjects subjected to graded exercise. Twenty-one healthy subjects (aged 37+/-10 years, 15 male) were subjected to graded physical exercise on a braked bicycle ergometer until the heart rate reached 120 beats/min. Digital electrocardiograms (ECG) were recorded on baseline and every 30 seconds during the exercise. In each ECG, heart rate and QT interval were measured automatically (QT Guard package, Marquette Medical Systems, Milwaukee, WI, USA). Bazett, Fridericia, Hodges, Framingham, and nomogram formulae were used to obtain QTc interval values for each ECG. For each formula, the slope of the regression line between RR and QTc values was obtained in each subject. The mean values of the slopes were tested by a one-sample t-test and the comparison of the baseline and peak exercise QTc values was performed using paired t-test. Bazett, Hodges, and nomogram formulae led to significant prolongation of QTc intervals with exercise, while the Framingham formula led to significant shortening of QTc intervals with exercise. The differences obtained with the Fridericia formula were not statistically significant. The study shows that the practical meaning of QT, interval measurements depends on the correction formula used. In studies investigating repolarization changes (e.g., due to a new drug), the use of an ad-hoc selected heart rate correction formula is highly inappropriate because it may bias the results in either direction.     

Pacemaker implantation as a risk factor for heart failure in young adults with congenital heart disease

AIM: Complete postoperative heart block following open-heart surgery and sinus node dysfunction are indications for permanent cardiac pacing in children with congenital heart defects. The purpose of our study was to evaluate if cardiac pacing is a risk factor of heart failure during longtime follow-up of grown ups with congenital heart disease (GUCH). METHODS: For an objective assessment of heart failure, NT-Pro brain natriuretic peptide (BNP) and maximal oxygen uptake index (VO2max) during the cardiopulmonary exercise testing were measured in 346 consecutive GUCH patients during a longtime follow-up examination. RESULTS: Thirty-nine of these patients who had pacemaker implantation had significantly increased BNP levels (448.2 +/- 76.8 vs 123.8 +/- 9.7 pg/mL, P < 0.0001) and significantly decreased VO(2max) (22.5 +/- 0.9 vs 27.4 +/- 0.4, P < 0.0001). Heart failure in pacemaker patients was associated with significantly prolonged QRS complex durations (171.1 +/- 8.3 ms vs 108.7 +/- 1.8 ms, P < 0.0001), increased right ventricular end diastolic diameters (38.7 +/- 2.1 mm vs 27.8 +/- 0.5mm, P < 0.0001), lower heart rates at rest (69.5 +/- 1.9/min vs 82 +/- 1/min, P < 0.0001), and at exercise (140.3 +/- 5.8/min vs 163.5 +/- 1.2/min, P < 0.0001). Mean fractional shortening of the left ventricle was normal in both patient groups. CONCLUSION: Pacemaker implantation may be associated with heart failure during longtime follow-up of GUCH indicated by significantly elevated BNP levels and decreased VO2max. Possible explanations are prolongation of QRS complex duration, decreased maximal heart rates during exercise, and dilatation of the right ventricle.     

Shorter AV Delays Provide Improved Echocardiographic Hemodynamics during Exercise in Patients Receiving Cardiac Resynchronization Therapy

Background: Although atrial ventricular (AV) intervals are often optimized at rest in patients receiving cardiac resynchronization therapy (CRT), there are limited data on the impact of exercise on optimal AV interval.
Methods: In 15 patients with CRT, AV intervals were serially programmed while patients were supine and at rest, and during exercise with heart rates that averaged 20 and 40 beats per minute above their resting rates. Echocardiographic Doppler images were acquired at each programmed AV interval and each rate. Three independent echocardiographic criteria were retrospectively used to determine each patient's optimal AV interval as a function of exercise-induced increased heart rates: the duration of left ventricular filling, stroke volume, and a clinical assessment of left ventricular function.
Results: A negative correlation between the optimal AV interval and heart rate was observed across all patients using all three independent criterion: the maximum left ventricular filling time (slope =–0.77, intercept = 151.9, r = 0.55, P < 0.001), maximum stroke volume (slope =–0.93, intercept = 183.3, r = 0.50, P = 0.002), or the subjective clinical assessment (slope =–1.06, intercept = 182.0, r = 0.72, P < 0.001). Consistent trends were observed between all three parameters for 12 out of the 15 patients.
Conclusions: These results suggest that in patients indicated for CRT, rate-adaptive functions may be useful to shorten AV intervals with increased rate, in order to maximize left ventricular filling, stroke volume, and clinical left ventricular function. Further studies are necessary to determine the clinical impact of these rate-adaptive algorithms.     

Hysteresis of electrocardiographic depolarization-repolarization intervals during dynamic physical exercise and subsequent recovery

The post-exercise electrocardiographic QT interval is shortened relative to that at similar heart rates during exercise or pre-exercise rest. This lag in QT adaptation to the recovering heart rate is described as "hysteresis". No previous studies have quantified the influence of ECG electrode placement on hysteresis following physical exercise. Six males and six females of similar age, mass and aerobic fitness undertook progressive sub-maximal bicycle exercise. A three-channel ECG was recorded continuously during pre-exercise, exercise and recovery. Beat-to-beat NN (cardiac interval) and QT(a) interval (Q wave onset to T wave apex) data were measured for each sinus heart beat. QT(a)-NN hysteresis was calculated as the difference in QT(a) magnitude at identical heart rates during the rest/exercise and post-exercise recovery periods. There were some significant (p < 0.05) between-channel and between-gender differences in calculated hysteresis values. Hysteresis was generally greatest during the second or third minute post-exercise; ranges of means for all channels were 10.9 +/- 11.7 ms to 25.5 +/- 16.8 ms (males) and 19.1 +/- 10.3 ms to 28.4 +/- 3.0 ms (females). For males only, hysteresis values calculated using channel 1 between 1 and 3 min post-exercise were generally significantly (p < 0.05) different to those between 4 and 10 min. Similar trends were observed in females. QT(a)-NN hysteresis is significantly affected by the locations of the ECG electrodes used to record the surface ECG. These results emphasize the need for standardization of ECG electrode placement in future investigations.     

Analysis of the QT interval and its variability in healthy adults during rest and exercise

The aim of the present study was to quantify the variability of electrocardiographic QT and RR intervals during rest and dynamic physical exercise, and to interpret these variabilities in terms of relative autonomic modulation of the atrial and ventricular myocardium. We also sought to characterize the relationships between QT, heart rate-corrected QT (QT(c)) and RR intervals, and to consider their associations with differential autonomic regulation. Nine males and eight females of similar age (22.8 +/- 4.7 years), mass (75.5 +/- 13.0 kg) and aerobic fitness (43.6 +/- 7.7 ml kg(-1) min(-1)) (mean +/- SD) undertook progressive bicycle exercise. A three-lead Holter ECG was recorded continuously during pre-exercise, exercise and recovery, and mean values of RR, QT, QT(c), QT variability index (QTVI) and mean-normalized QT variance (QTVN) were determined. At the onset of exercise QTVI increased rapidly compared with rest and remained significantly elevated throughout exercise and recovery. There were significant differences between QT(a)VI and QT(e)VI (QT measured from Q wave onset to T wave apex (QT(a)) and T wave end (QT(e)), respectively) throughout the experimental protocol. QTVI was significantly reduced in males compared with females prior to exercise but was similar thereafter. We suggest that physical exercise perturbs the resting QT-RR relationship owing to the onset of differential parasympathetic modulation of the atrial and ventricular myocardium. QTVI can be used to quantify the relative autonomic influence on the atrial and ventricular myocardium during rest and exercise, and might be related to HR-dependent and HR-independent influences on the QT interval.     

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.     

Effect of ischemic stroke on the dynamic beat-to-beat QT-RR relationship

The ECGs of 26 patients following ischemic stroke and 18 control patients with various orthopedic problems, all without primary heart disease, were examined to characterize the dynamic behavior of uncorrected QT interval in relation to changing RR interval during physiotherapy effort. ECG waveforms were analyzed to extract beat-to-beat QT and RR intervals. Based on performing multiple cross-correlations, the relationship between the RR and QT intervals was calculated using the following general formula QTi = c RRib-1. Linear regression was performed on the logarithms of QT and RR measurements to estimate the constant (a = log c) and the slope (b) values, reflecting the dynamic change of QT during physiotherapy effort. Having these two values, the dynamic QT extrapolated to a heart period of 1 second (QTcd) was calculated. It was found that the mean slope (b) of the linear regression line in the ischemic stroke group was significantly lower than in the control group (0.26 +/- 0.08 vs 0.33 +/- 0.08, P < 0.02), and the constant (a) was significantly higher (1.83 +/- 0.21 for the ischemic stroke vs 1.61 +/- 0.23 for the controls, P < 0.002). No significant difference was found in QTcd values between the two groups (386 +/- 27 ms for the ischemic stroke vs 392 +/- 25 ms for the controls, P > 0.05). In conclusion, hemispheric brain infarction seems to result in alteration in the autonomic activity during exercise manifesting itself as distorted dynamic behavior of the QT interval.     

Systolic time intervals and the QT-QS2 interval in young female diabetics

To detect subclinical cardiomyopathy in diabetic patients without evidence of coronary artery disease, systolic time intervals were measured in 51 insulin-treated young female diabetics (mean age 27 years and mean duration of diabetes 12 years) and in 15 healthy women of the same age. The ratio of the pre-ejection period to the left ventricular ejection time (PEP/LVET) was used as an index of left ventricular performance. The PEP/LVET ratio was normal in all diabetics and did not differ statistically from that in the control group. The electrical (QT) and electromechanical (QS2) systole were measured from the same high velocity recordings. The QT-QS2 interval (mean +/- SD) was shorter in the diabetic group (-16 +/- 22 ms vs. -33 +/- 9 ms, p less than 0.01). Ten diabetics but none of the healthy women, had the QT interval longer than the QS2. This was a result of both shortening of the QS2 and prolongation of the QT. In conclusion, our results suggest normal myocardial contractility in these young female diabetics. The significance and mechanism of the shortened QT-QS2 interval in the diabetics need further investigation.     

Alterations in the Baroreceptor Reflex in Conscious Dogs with Heart Failure

The effectiveness of the baroreceptor reflex in conscious dogs with experimental cardiac hypertrophy and heart failure was compared with that in a group of normal conscious dogs. Cardiac hypertrophy and heart failure were produced by tricuspid avulsion and progressive pulmonary stenosis. The sensitivity of the baroreceptor reflex to transient hypertension was assessed by determining the slope of the regression line relating the prolongation of the R-R interval to the rise in systolic arterial pressure during the transient elevation of arterial pressure induced by an intravenous injection of 1-phenylephrine. The mean slope averaged 22.4+/-2.3 msec/nm Hg in 16 normal animals. 23.1 +/-1.5 in five sham-operated animals, and was significantly reduced to 8.3 +/-0.8 in 10 dogs with hypertrophy alone (P < 0.001), and to 3.3+/-0.5 in nine dogs with heart failure (P < 0.001). The response to baroreceptor hypotension was compared during bilateral carotid artery occlusion (BCO) in six normal and six heart failure dogs previously instrumented with Doppler flow transducers on the superior mesenteric and renal arteries. During BCO, in normal dogs arterial pressure increased 52+/-4 mm Hg, heart rate 33+/-2 beats/min, mesenteric resistance 0.17+/-0.03 mm Hg/ml per min, and renal resistance 0.37+/-0.10 mm Hg/ml per min. In the heart failure group all of these variables increased significantly less (P < 0.01); arterial pressure rose 25 +/-3 mm Hg, heart rate 13 +/-4 beats/min, mesenteric resistance 0.04+/-0.007 mm Hg/ml per min, and renal resistance 0.18+/-0.09 mm Hg/ml per min.Thus, in heart failure, all measured systemic and regional circulatory adjustments consequent to baroreceptor hypo- and hypertension are markedly attenuated. This study demonstrates a profound derangement of a major cardiovascular control mechanism in experimental heart failure.     

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.     

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.     

Greater quinidine-induced QTc interval prolongation in women

BACKGROUND: Prolongation of the electrocardiographic QT interval by drugs is associated with the occurrence of a potentially lethal form of polymorphic ventricular tachycardia termed torsades de pointes. Women are at greater risk than men for development of this adverse event when taking drugs that prolong the QT interval. To determine whether this may be the result of gender-specific differences in the effect of quinidine on cardiac repolarization, we compared the degree of quinidine-induced QT interval lengthening in healthy young men and women. METHODS: Twelve women and 12 men received a single intravenous dose of quinidine (4 mg/kg) or placebo in a single-blind, randomized crossover trial. Total plasma and protein-free concentrations of quinidine and 3-hydroxyquinidine were measured in serum. QT intervals were determined and corrected for differences in heart rate with use of the method of Bazett (QTc = QT/RR1/2). RESULTS: As expected, the mean QTc interval at baseline was longer for women than for men (mean +/- SD; 407 +/- 7 versus 395 +/- 9 ms, P < .05). The slope of the relationship between change in the QTc interval (delta QTc) from baseline to the serum concentration of quinidine was 44% greater for women than for men (mean +/- SE; 42.2 +/- 3.4 versus 29.3 +/- 2.6 ms/microg per mL, P < .001). These results were not influenced by analysis of 3-hydroxyquinidine, free concentrations of quinidine and 3-hydroxyquinidine, or the JT interval. CONCLUSIONS: Quinidine causes greater QT prolongation in women than in men at equivalent serum concentrations. This difference may contribute to the greater incidence of drug-induced torsades de pointes observed in women taking quinidine and has implications for other cardiac and noncardiac drugs that prolong the QTc interval. Adjustment of dosages based on body size alone are unlikely to substantially reduce the increased risk of torsades de pointes in women.