QT Interval Adaptation Research Articles

Identifying coronary artery flow reduction and ischemia using quasistationary QT/RR-interval hysteresis measurements

Because myocardial ischemia induces QT/RR hysteresis, a correlation was hypothesized to exist between the extent of myocardial flow reduction and the magnitude of QT/RR hysteresis. Graded reductions in regional myocardial perfusion in the distribution of the left anterior descending coronary artery in open-chest pigs were used to model 1-vessel coronary artery disease. At each reduced level of left anterior descending coronary artery flow, the heart was electrically paced at progressively higher and lower rates between an initial control and maximum heart rate values. Digitized surface and intramyocardial electrograms and aortic pressure were used to measure QT/RR hysteresis, QT-interval adaptation, ST- and TQ-segment depression, and cardiac contractility. Intraexperimental blood samples were analyzed to assess inflammatory response (interleukin 6), oxidative stress (protein carbonyls), and myocyte injury (creatine kinase). Higher values of QT/RR hysteresis correlated with the severity of ischemia as assessed by TQ-segment depression in intramyocardial electrograms ( P = .002). Lower flow rates were strongly associated with higher values of QT/RR hysteresis and slower QT-interval adaptation ( P ≤ .004), and were less correlated with the magnitude of ST- and TQ-segment depression ( P ≥ .02). Significant increases in systemic measures of inflammation, oxidative stress, and cardiac myocyte injury and major decrease in cardiac contractility preceded the most severe stages of flow reduction (30% and 20% of normal flow). We determined QT/RR hysteresis index thresholds corresponding to these mechanical and immunochemical responses. QT/RR hysteresis is a strong indicator of reduced myocardial perfusion and may provide information for noninvasive assessment of mechanical and immunochemical changes associated with early stages of coronary artery disease.

Impaired T‐Amplitude Adaptation to Heart Rate Characterizes IKr Inhibition in the Congenital and Acquired Forms of the Long QT Syndrome

The QTc interval prolongation is not a perfect surrogate marker of the presence of an increased risk for arrhythmic events. In the search for alternative markers, we investigated the T-amplitude and QT interval adaptation to heart rate (HR) in patients with the congenital long QT syndrome (LQTS) and individuals with sotalol-induced QT prolongation. Our investigation is based on the analysis of continuous 12-lead digital Holter recordings in: 49 LQT1 carriers, 25 LQT2 carriers, 37 healthy individuals off drugs and on 160 mg of sotalol, and 21 of them also on 320 mg of sotalol. The Holter recordings were used to investigate repolarization parameters and their HR dependency. A loss of HR dependency of the T-amplitude was found as a common feature in individuals with impaired I(kr) kinetics: LQT2 carriers and subjects on sotalol. The T-amplitude/RR slope was significantly (P < 0.05) flatter in LQT2 (0.31 +/- 0.27 microV/ms) than in both LQT1 (0.62 +/- 0.40 microV/ms) and healthy individuals (0.55 +/- 0.29 microV/ms). A dose-dependent reduction of the T-amplitude/RR slope was also observed in subjects on sotalol (160 mg dose: 0.26 +/- 0.19 microV/ms; 320 mg dose: 0.21 +/- 0.14 microV/ms). The QT/RR slope was less effective than T-amplitude/RR slope in differentiating between congenital and drug-induced repolarization delay. Impaired adaptation of T-amplitude to changing HR is a common electrocardiographic feature associated with KCNH2 mutation and I(kr) blockade by sotalol. This ECG marker may play an important role in the future of the assessment of the penetrance of KCNH2 mutation and the identification of a drug effect on the I(kr) kinetics.

Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short QT Intervals, and Sudden Cardiac Death

Cardiac ion channelopathies are responsible for an ever-increasing number and diversity of familial cardiac arrhythmia syndromes. We describe a new clinical entity that consists of an ST-segment elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death. Eighty-two consecutive probands with Brugada syndrome were screened for ion channel gene mutations with direct sequencing. Site-directed mutagenesis was performed, and CHO-K1 cells were cotransfected with cDNAs encoding wild-type or mutant CACNB2b (Ca(v beta2b)), CACNA2D1 (Ca(v alpha2delta1)), and CACNA1C tagged with enhanced yellow fluorescent protein (Ca(v)1.2). Whole-cell patch-clamp studies were performed after 48 to 72 hours. Three probands displaying ST-segment elevation and corrected QT intervals < or = 360 ms had mutations in genes encoding the cardiac L-type calcium channel. Corrected QT ranged from 330 to 370 ms among probands and clinically affected family members. Rate adaptation of QT interval was reduced. Quinidine normalized the QT interval and prevented stimulation-induced ventricular tachycardia. Genetic and heterologous expression studies revealed loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the alpha1- and beta2b-subunits of the L-type calcium channel. Confocal microscopy revealed a defect in trafficking of A39V Ca(v)1.2 channels but normal trafficking of channels containing G490R Ca(v)1.2 or S481L Ca(v beta2b)-subunits. This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada syndrome phenotype is combined with shorter-than-normal QT intervals.

IKr and IKs remodeling differentially affects QT interval prolongation and dynamic adaptation to heart rate acceleration in bradycardic rabbits

Bradycardic ventricular electrical remodeling predisposes to lethal tachyarrhythmias. We investigated the early temporal sequence and reversibility of electrical remodeling in a rabbit complete heart block model subjected to bradycardic ventricular pacing for either 2 or 8 days, with a third group of animals undergoing 8 days of bradycardic pacing followed by 8 days of physiological-rate pacing. At specified time points after complete heart block induction and pacing initiation, steady-state QT interval measurements and variability as well as dynamic QT interval adaptation to abrupt heart rate acceleration were assessed in the absence and presence of isoproterenol. Rapidly (I(Kr)) and slowly (I(Ks)) activating delayed rectifier repolarizing K(+) tail current densities were evaluated using whole cell patch clamp in isolated right ventricular myocytes. Steady-state QT interval prolongation at both 2 and 8 days was associated with moderate I(Kr) reduction. I(Ks) downregulation was apparent by day 2 but more profound at day 8. Dynamic QT interval adaptation was impaired under baseline conditions at day 8 but only during isoproterenol administration at day 2. Both in vivo and cellular manifestations of remodeling reverted toward control values after 8 days of physiological-rate pacing. In conclusion, in this bradycardic model, I(Ks) downregulation 1) proceeds more gradually but more extensively than that of I(Kr) and 2) is most prominently associated with impaired dynamic QT interval adaptation to heart rate acceleration. Isoproterenol blunts the dynamic QT interval response in animals with partially downregulated I(Ks), consistent with stress-related phenomena in known I(Ks)-impaired states. Relative early sparing of I(Ks) could explain the delay in the onset of lethal tachyarrhythmia predisposition in bradycardic electrical remodeling. Reversibility of remodeling supports the potential utility of preventive pacing intervention soon after bradycardia onset.

A51. Adrenergic stimulation unmasks impaired dynamic QT interval adaptation to abrupt heart rate change in early bradycardic remodeling

A51. Adrenergic stimulation unmasks impaired dynamic QT interval adaptation to abrupt heart rate change in early bradycardic remodeling

Continuous Positive Airway Pressure Treatment Improves the QT Rate Dependence Adaptation of Obstructive Sleep Apnea Patients

QT rate dependence is one of the major properties of ventricular repolarization, with its circadian and autonomic modulations. The alteration of cardiac autonomic tone occurring in obstructive sleep apnea syndrome (OSAS) patients could explain the altered rate-dependent adaptation of the myocardial repolarization. Thus, we postulated that dynamic alterations in QT interval adaptation could be ameliorated in OSAS patients under continuous positive airway pressure (CPAP) treatment. To assess ventricular repolarization features in patients with OSAS, we compared QT parameters and their dynamicities along RR intervals from 24-hour ECG. The study groups consisted of 38 consecutive OSAS patients and 38 healthy age-matched subjects. The syndrome was confirmed for OSAS patients according to standard polysomnographic criteria (apnea plus hypopnea index: 56.9 +/- 28.4/h). A second polysomnography synchronized with 24-hour ECG Holter and realized under efficient CPAP therapy confirmed the control of sleep-related breathing disorder. QT length related to heart rate was found significantly altered in patients with OSAS compared with controls (QTend/RR slope: -0.126 +/- 0.031 vs -0.173 +/- 0.038; P < 0.01). This flattened relationship was significantly improved with the treatment of the OSAS (-0.151 +/- 0.051; P < 0.01 vs pretreatment status). There was no significant impact of CPAP therapy on ventricular ectopic activity as well as on static repolarization parameters (QT, RT, QTc, RTc) measured separately over daytime and nighttime. The prognostic implications of such findings and the protective role of CPAP treatment to prevent sudden cardiac death in OSAS need to be evaluated.

Refeeding normalizes the QT rate dependence of female anorexic patients

We postulated that dynamic alterations in QT interval adaptation could characterize patients with anorexia nervosa (AN) and could be restored after weight gain. To assess ventricular repolarization features, we evaluated the QT dynamicity along RR intervals from 24-hour electrocardiographic data of patients with AN before and after refeeding. Ten young women with AN (19 +/- 3 years) were included in the study. The QT/RR slope was found significantly enhanced compared with normals (-1.82 +/- 0.62 vs -1.40 +/- 0.30; p < 0.05). This slope returned to normal range values after refeeding. The QT/RR slope was significantly correlated with the body mass index (r = 0.59; p < 0.007) in the patient group.

Errors and misconceptions in ECG measurement used for the detection of drug induced QT interval prolongation

Drug-induced changes in cardiac repolarisation receive substantial attention by regulatory agencies. Since there are presently no established accurate possibilities of testing the propensity to torsade induction during clinical drug development, the regulators require drug-related QT interval changes to be thoroughly investigated with almost all new pharmacological agents. Small QT interval changes are easy to miss and the regulators therefore expect the relevant studies to be very precise. Such a precision is not easy to achieve and different strategies have been proposed. The purpose of this article is to review the most frequent misconceptions and errors in the electrocardiogram handling and measurements related to the detection to drug-induced QT interval changes. Specifically, the article discusses (a) the possibilities of automatic measurement by standard electrocardiographic equipment, (b) the danger of casual measurement by central laboratories handling the electrocardiograms, (c) the selection of recording leads for QT interval measurement, and (d) the problem of the so-called heart rate hysteresis of the QT interval adaptation. Suggestions are made for drug developers of what study design and quality control aspects are needed to avoid the most frequent imprecisions.

Alteration of the QT rate dependence in anorexia nervosa.

Myocardial repolarization has been evaluated in patients with anorexia nervosa (AN) with conflicting results. The authors postulated that dynamic alterations in QT interval adaptation could characterize these patients. This study compared QT dynamicity along RR intervals from 24-hour ECG data of patients with and without AN. Twenty-five patients (23 women) fulfilling the Diagnostic and Statistical Manual (DSM IV) criteria for AN were included in the study. All underwent 24-hour ECG Holter recordings, allowing QT and RR measurements, and heart rate variability (HRV) analysis in free-living conditions. A group of 25 sex- and age-matched healthy subjects served as controls. Compared with controls, AN patients presented with relative bradycardia, more particularly during night periods but neither mean QT nor corrected mean QT length (calculated using Bazett formula) over the 24 hours of monitoring differed. However, QT/RR slope was found significantly enhanced compared with normals (-2.00 +/- 0.53 vs - 1.42 +/- 0.40) (P = 0.006): QT length related to heart rate was found longer for a heart rate <55 beats/min in AN. Mean 24-hours QT length appears unaltered in AN in the absence of electrolytic disorders. However, the QT/RR relationship was enhanced reflecting the specific autonomic imbalance encountered in this population. The clinical implications of such findings need to be discussed since an equivalent enhancement of QT/RR slope has been described after myocardial infarction in patients presenting life-threatening ventricular arrhythmias.

Estimation of the QT/RR hysteresis lag

The process of QT interval adaptation to heart rate (HR) changes was evaluated by considering weighted averages of RR intervals to characterize the influence of previous cardiac cycles. An optimum adaptation pattern was individually derived for each patient and several descriptors of the QT/RR hysteresis were subsequently calculated. The values of these parameters showed that the QT adaptation to HR changes is highly individual and, consequently, any generalized approach may lead to inappropriate conclusions.

Alteration of QT rate dependence reflects cardiac autonomic imbalance in patients with obstructive sleep apnea syndrome.

QT rate dependence is one of the major properties of ventricular repolarization with its circadian and autonomic modulations. The authors postulated that dynamic alterations in QT interval adaptation could help characterize patients with cardiac autonomic alterations, like those with obstructive sleep apnea syndrome (OSAS). To assess ventricular repolarization features in patients with OSAS, QT parameters and their dynamicity along RR intervals were compared from 24-hour ECG data of patients with and without this syndrome, assessing cardiac autonomic nervous system equilibrium by means of time-domain and frequency-domain analyses of heart rate variability (HRV). The study group consisted of 74 consecutive patients referred to the Sleep Laboratory for clinically suspected OSAS. The syndrome was confirmed in 30 (40.5%) patients according to standard polysomnographic criteria. QT length related to heart rate (HR) was found significantly shorter for HR < 70 beats/min in patients with OSAS(-1.32 +/- 0.35)compared with patients without OSAS(-1.99 +/- 0.40; P < 0.01). This flattened relationship was correlated with the severity of the sleep related disorder. Using multiple linear regression analysis, the apnea/hypopnea index and nocturnal normalized high frequencies (HFnu) were the most significant predictors of the QT/RR slope(R = 0.61; P < 0.0001). OSAS is significantly associated with a flattened relationship between QT duration and RR interval at low HRs. The alteration of cardiac parasympathetic tone occurring in severe OSAS patients may explain this altered rate dependent adaptation of myocardial repolarization.

Beat-to-beat QT interval variability in coronary patients

Changes in ventricular repolarization have been described in patients after myocardial infarction, whereas data for coronary patients without prior myocardial infarction are lacking. This study was designed to evaluate ventricular repolarization in coronary patients with effort angina pectoris. Beat-to-beat QT interval variability (QTV) using 5-minute resting high-resolution ECG recordings was measured in 26 men (mean age 62.1 years) with effort angina pectoris and without prior myocardial infarction, and in 30 age-matched men without clinically evident coronary heart disease (controls). To evaluate the degree of coronary artery disease in coronary patients, coronary angiography was performed. Coronary patients displayed significantly higher values of QTV compared with the control patients (P<.001). Rate adaptation of QT interval correlated significantly with the degree of coronary artery disease in the study group patients (P<.05). The significant association between QTV and coronary heart disease suggests altered ventricular repolarization in coronary patients without prior myocardial infarction.

QT dispersion, daily variations, QT interval adaptation and late potentials as risk markers for ventricular tachycardia.

The aim of the study was to determine the value and correlation between QT dispersion, daily variations in the QT interval and late potentials as risk markers for ventricular tachycardia. QT dispersion was defined as the difference between the longest and the shortest QT interval in 12 electrocardiographic leads, QTc variability as the difference between the maximal and minimal QTc interval during 24-h Holter monitoring and QT interval adaptation as the regression line between heart rate and the uncorrected QT interval. One hundred and forty-five patients, 3 months after myocardial infarction were included in the study. QT dispersion significantly increased with the severity of arrhythmia (modified Lown's classification; P< 0.001). The level of 80 ms was associated with ventricular tachycardia with a sensitivity of 72.7% and a specificity of 86.4%. The greater daily variability of the QTc interval in patients with ventricular tachycardia was insignificant (P > 0.05). QT interval adaptation did not discriminate between patients with ventricular tachycardia from those in other groups. Late potentials were associated with ventricular tachycardia with a sensitivity of 50% and a specificity of 90.3%. Large QT dispersion and late potentials were risk markers for ventricular tachycardia, but there was no correlation between QT dispersion, daily variations in the QT interval and late potentials in patients 3 months after myocardial infarction.

Left Ventricular Hypertrophy in Hypertensive Patients Is Associated With Abnormal Rate Adaptation of QT Interval

Objectives. This study sought to examine whether the responses of the QT interval to changes in the heart rate were altered in left ventricular hypertrophy (LVH).Background. The QT interval has been shown to have a delayed adaptation to sudden changes in heart rate in normal subjects. Abnormalities in the adaptation of the QT interval to changes in the RR interval may facilitate the development of ventricular arrhythmias.Methods. Consecutive newly diagnosed hypertensive subjects, not taking any medications, were age and gender matched for LVH (n = 21) versus no LVH (n = 16). QT interval dynamics were analyzed under visual control using a validated algorithm with automatic QT measurements at the end of the T wave. A computerized Holter system was developed to study the QT interval response to changes in the RR interval. The adaptive response of the QT interval was measured as the ratio of the slope from 10% to 90% of the QT change relative to the RR interval change (dQT/dRR10–90). Steady state adaptation was also studied as the percent shortening and lengthening of the QT interval during acceleration and deceleration of heart rate.Results. The adaptive response of the QT interval measured as dQT/dRR10–90was increased in the LVH group compared with that in the control subjects during both acceleration (0.33 ± 0.06 vs. 0.18 ± 0.02, p = 0.02) and deceleration phases (0.23 ± 0.04 vs. 0.16 ± 0.02, p = 0.03). In the LVH group, the percent lengthening of the QT interval was greater (7.6 ± 0.7 vs. 5.1 ± 0.2, p = 0.03), whereas the percent shortening was not significantly different (5.71 ± 0.5 vs. 4.6 ± 0.3, p = 0.43), than that in control subjects.Conclusions. The QT interval response to changes in the RR interval is rapid and exaggerated in LVH. These abnormalities of the QT interval response demonstrate that there are altered repolarization dynamics in patients with LVH that may make them vulnerable to serious ventricular arrhythmias.(J Am Coll Cardiol 1997;29:778–84)

Rate-corrected QT interval: Techniques and limitations

The duration of the QT interval on the surface electrocardiogram represents the time required for all ventricular depolarization and repolarization processes to occur. Among the many physiologic and pathologic factors that contribute to the QT interval, heart rate plays a major role. Several approaches have been used to correct the QT interval, all of which take into account the heart rate at which the interval is measured. The simplest and most common approach to correcting the QT interval is to divide its value by the square root of the preceding RR interval expressed in seconds, i.e., by using Bazett's formula. This calculation provides a corrected QT (QT c) interval that represents the QT interval normalized for a heart rate of 60 beats/min. However, several studies have shown that Bazett's correction formula is not optimal. Fridericia's cube-root formula has been shown to perform better in correcting the QT interval for heart rate. Other formulas require the measurement of several QT-RR pairs at various heart rates to obtain a reliable QT c interval and are therefore not easily usable. Any correction formula is likely to introduce an error in assessing the QT c interval. Although the importance of this error should not be minimized, the corrected QT interval remains useful in assessing the effects of drugs on the duration of repolarization. For this purpose, Fridericia's cube-root formula is preferable to Bazett's square-root formula. However, correcting the QT interval for heart rate may conceal important information, such as the kinetics of QT-interval adaptation to a change in heart rate. The most reliable method for assessing the QT interval during drug administration is to avoid QT correction and to measure QT intervals at fixed heart rates.

Hysteresis in the Human RR‐QT Relationship During Exercise and Recovery

The present study was undertaken to test the hypothesis that the human RR-QT relationship during dynamic exercise differs markedly from that during the recovery phase. Fourteen subjects from the age of 16 to 71 years exercised on a treadmill according to the Bruce protocol. Electrocardiograms were recorded continuously on a magnetic tape, from 1 minute before exercise to 10 minutes into recovery. An exponential formula, proposed by us earlier, closely represented the exercise RR-QT data. However, it was not appropriate for the often S-shaped recovery curves which invariably deviated from the exercise curves, exhibiting hysteresis. Initially, all recovery QT intervals were shorter than the exercise values, but later in the recovery, some crossed the exercise curves from below, resulting in longer QT intervals. The recovery data were fitted by a third degree polynomial, and the hysteresis was calculated as the area between the exercise and recovery curves within a 150 ms range of the RR interval starting from its minimum value. The mechanisms for the occurrence of hysteresis are likely to involve the sympatho-adrenal activity in the early post-exercise period and the time course of QT interval adaptation to rapid changes in the RR interval.