James E. Rosenthal

Diurnal pattern of QTc interval: how long is prolonged? Possible relation to circadian triggers of cardiovascular events.

OBJECTIVES This study sought to evaluate the range and variability of the QT and corrected QT (QTc) intervals over 24 h and to assess their pattern and relation to heart rate variability. BACKGROUND Recent Holter monitoring data have revealed a high degree of daily variability in the QTc interval. The pattern of this variability and its relation to heart rate variability remain poorly characterized. METHODS We developed and validated a new method for continuous measurement of QT intervals from three-channel, 24-h Holter recordings. Average RR, QT, QTc and heart rate variability were measured from 5-min segments of data from 21 healthy subjects. RESULTS Measurement of 6,048 segments showed mean (+/- SD) RR, QT and QTc intervals of 830 +/- 100, 407 +/- 23 and 445 +/- 16 ms, respectively (mean QTc interval for men 434 +/- 12 ms, 457 +/- 10 ms for women, p < 0.0001). The average maximal QTc interval was 495 +/- 21 ms and the average QTc range 95 +/- 20 ms. The maximal QTc interval was > or = 500 ms in 6 subjects and > or = 490 ms in 13. The 95% upper confidence limit for the mean 24-h QTc interval was 452 ms (men 439 ms, women 461 ms). The RR, QT and QTc intervals and the high frequency component of heart rate variability were greater during sleep. Both the QTc interval and the variability between hourly minimal and maximal QTc intervals reached their circadian peak shortly after awakening, before declining to daytime levels. CONCLUSIONS The maximal QTc interval over 24 h in normal subjects is longer than heretofore thought. Both QT and QTc intervals are longer during sleep. The QTc interval and QTc variability reach a peak shortly after awakening, which may reflect increased autonomic instability during early waking hours, and the time of the peak value corresponds in time to the period of reported increased vulnerability to ventricular tachycardia and sudden cardiac death. These findings have implications regarding the definition of QT prolongation and its use in predicting arrhythmias and sudden death.

Evaluation of Five QT Correction Formulas Using a Software-Assisted Method of Continuous QT Measurement from 24-Hour Holter Recordings

To evaluate and compare QT correction formulas in healthy subjects, we used 24-hour Holter monitoring because it allows the assessment of QT intervals over a large range of rates. Computer-assisted QT-interval measurements were obtained from 21 subjects. QT-RR relations for individuals and the group were fitted by regression analysis to 5 QT prediction formulas: simple Bazetts, modified Bazetts, linear (Framingham), modified Fridericias and exponential (Sarmas). There were no significant differences in mean squared residuals between formulas. When using individually calculated regression parameters, each formula gave good or acceptable QT correction over the entire range of RR intervals. Simple Bazetts formula (which uses no regression parameters) was unreliable at high rates. Akaike information criteria rank was: Sarmas, Framingham, modified Bazetts, Fridericias, and simple Bazetts. When group-based regression parameters were applied to individuals, no formula had a clear advantage over simple Bazetts. We conclude that any formula that invokes regression parameters unique to each individual provides satisfactory QT correction. Determination of these parameters requires long-term recording to obtain an adequate range of rates. Group-based regression parameters give poor correction. When individual parameters cannot be determined, as in a 12-lead electrocardiogram, no formula provides an advantage over the familiar simple Bazetts.

QT Interval Dispersion in Healthy Subjects and Survivors of Sudden Cardiac Death: Circadian Variation in a Twenty- Four-Hour Assessment

Twenty-four-hour acquisition of QT dispersion (QTd) from the Holter and the circadian variation of QTd were evaluated in 20 survivors of sudden cardiac death (SCD), in 20 healthy subjects, and in 14 control patients without a history of cardiac arrest who were age, sex, diagnosis and therapy matched to 14 SCD patients. Computer-assisted QT measurements were performed on 24-hour Holter recordings; each recording was divided into 288 5-minute segments and templates representing the average QRST were generated. QTd was calculated as the difference between QT intervals in leads V1 and V5 for each template on Holter. The 24-hour mean QTd was significantly greater in SCD patients (40 +/- 28 ms) than in healthy subjects (20 +/- 10 ms) and control patients (15 +/- 5 ms) (p <0.05). There was a circadian variation in QTd with greater values at night (0 to 6 A.M.) than at daytime (10 A.M. to 4 P.M.) in healthy subjects (25 +/- 13 vs 15 +/- 8 ms, p <0.001) and control patients (18 +/- 10 vs 12 +/- 4 ms p <0.05), whereas in SCD patients there was no significant difference between night and day values (45 +/- 31 vs 37 +/- 28 ms, p = NS). It is concluded that QTd measured by Holter was greater in SCD patients than in healthy subjects and matched control patients during the entire day. QTd has a clear circadian variation in normal subjects, whereas this variation is blunted in SCD patients. QTd measured on Holter differentiates survivors of cardiac arrest and may be a useful tool for risk stratification.

Contribution of variable entrance and exit block in protected foci to arrhythmogenesis in isolated ventricular tissues.

Automatic foci with membrane potentials in the range characterized by depolarizationinduced automaticity exhibit entrance block. The present study demonstrates a role of variable entrance and exit block in arrhythmogenesis. We studied canine interventricular septa with the right bundle branch exposed, isolated false tendons and isolated feline papillary muscle using standard microelectrode techniques. Foci of automaticity were produced either by focal application of electric current or by exposure of the preparations to Tyrodes solution containing 1.5–2.0 mM KCI. Foci induced by mild depolarization exhibited entrance block with exit conduction and were subject to electrotonic modulation. With greater depolarization, varying degrees of exit block developed. Various rhythms, including Wenckebach periodicity, resulted. Delayed emergence of electrotonically accelerated activity led to closely coupled extrasystoles resembling reentrant activity. Exit conduction in some preparations was facilitated by enhanced normal pacemaker activity (membrane potentials −70 mVor greater) in tissue peripheral to the focus. Also, when there were two sites of automaticity separated by an area of depressed conduction, intermodulation between the two automatic regions generated complex arryhthmias. Shifts in maximum diastolic potential also changed conduction and led to changes in arrhythmic patterns. In some experiments, focal automaticity was terminated by single stimuli. We conclude that complex and variable behavior of automatic foci may result in activity with characteristics previously attributed to other arrhythmic mechanisms.

Automaticity and entrance block induced by focal depolarization of mammalian ventricular tissues.

Isolated canine interventricular septa were studied with standard microelectrode tech-niques. Focal automaticity was induced by applying depolarizing current through an extracellular pipet in contact with the right bundle branch (RBB) of the ventricular specialized conducting system. Automaticity appeared with depolarization to transmembrane potentials of −50 mV or less. The spontaneous activity was neither depressed nor accelerated when overdrive suppression was at-tempted. Activity originating within the focus propagated into fully polarized surrounding tissue. However, entrance block, phasically related to the spontaneous cycle length, was an intrinsic property of these foci. Early premature beats initiated outside the focus failed to enter the focus, but the resulting electrotonus delayed the next automatic beat. Late premature beats captured and thereby accelerated the focus. Thus, the automatic foci could be entrained by extrafocal activity. Consequently, continuous pacing at various rates precipitated complex rhythms with fixed coupling. Similar foci with exit conduction, entrance block, and electrotonic modulation also were demonstrated in focally depolarized papillary muscles in feline septal preparations. The unique properties of focally depolarized areas in which spontaneous activity is generated at low membrane potentials provide a mechanism capable of generating a wide array of arrhythmias. Circ Res 47: 238-248, 1980

Relation between QT and RR intervals during exercise testing in atrial fibrillation

The ability to predict the RR-QT relation over a range of heart rates was evaluated in 10 patients with atrial fibrillation (AF) and in 10 control subjects in sinus rhythm. The data from each subject were fitted by regression into 3 QT prediction formulas (the square root formula of Bazett, the cube root formula of Fridericia and the exponential formula of Sarma) applied in standard form and modified with a weighted average of the preceding 5 RR intervals. The goodness-of-fit of each formula was evaluated using mean square residual and Akaike information criterion. For AF, the mean square residuals did not differ among the 3 standard QT prediction formulas (Bazett 624 +/- 274, Fridericia 625 +/- 274 and Sarma 611 +/- 267) and among the 3 modified QT prediction formulas (Bazett 507 +/- 325, Fridericia 496 +/- 255 and Sarma 495 +/- 328). The weighted average modification produced a significant decrease in mean square residuals for all 3 equations (p less than 0.05) in all patients. These findings were confirmed by Akaike information criterion. Goodness-of-fit in sinus rhythm was similar to previously published reports, and significantly better than the fit for AF (p less than 0.0001). For 9 of the 10 patients with AF, sinus rhythm electrocardiograms were obtained and the above regression equations were used to predict QT intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

The missing second: What is the correct unit for the Bazett corrected Qt interval?

Abstract When Taran and Szilagyi 6 reexpressed the Bazett formula in its commonly used form, they eliminated the seemingly useless step of dividing by 1 second by requiring that RR be expressed in seconds. However, this produced the confusion with regard to the correct unit. Incorporation of the 1-second expression allows the QTc to be expressed in the unit that is both logical and arithmetically correct (namely that of the original QT), and eliminates any requirement regarding the units in which the original QT and RR are measured.

Does heart rate identify sudden death survivors? Assessment of heart rate, QT interval, and heart rate variability

The objective was to test whether the circadian variability of several electrocardiographic variables distinguishes sudden cardiac death survivors from heart disease patients without a history of cardiac arrest and from normal subjects. Heart rate, heart rate variability, and QT interval have been reported to identify survivors of sudden cardiac death. Computer-assisted continuous QT measurement and heart rate variability analysis were performed on 24-hour Holter records for three groups: (1) 14 sudden death survivors; (2) 14 control patients with diagnosis and therapy matched to survivors; and (3) 14 healthy subjects. There were no significant differences in 24-hour mean RR and QT intervals between groups. However, heart rate was significantly different between the three groups at night but not during the day because the expected nighttime decline was markedly blunted in survivors and somewhat blunted in control patients. The QT interval and frequency domain heart rate variability measures followed a similar circadian pattern. The mean QTc was significantly longer in control patients. The QTc had a wide range in all groups, but less in sudden death survivors. Of ten common time and frequency domain heart rate variability indices, only SDANN and SDNN were significantly lower in sudden death survivors. Reduced circadian variation of heart rate, with marked blunting of the nighttime heart rate decline, identifies sudden cardiac death survivors as well as does SDANN and SDNN, and, in contrast to heart rate variability measures, can easily be obtained from a Holter report without complex calculations.

Electrophysiological effects of anti-free radical interventions in canine Purkinje fibers ☆

To assess whether free radicals affect the characteristic sequence of events in an in vitro model of ischemia and reperfusion, isolated canine cardiac Purkinje fibers were exposed to anti-free radical agents, superoxide dismutase 50 U/ml; catalase 600 U/ml; mannitol 2 mM and 20 mM and combined superoxide dismutase, catalase, and mannitol 20 mM. Fibers were superfused for 60 min with altered Tyrodes solution which mimicked some conditions of ischemia (glucose-free, containing lactate, equilibrated with 90% N2-10% CO2), and then re-exposed to normal, oxygenated Tyrodes solution. Anti-free radical agents alone had no electrophysiological effects. Ischemic conditions resulted in moderate depolarization in most preparations (10 control; 43 treated) but in severe depolarization, to less than -60 mV, in some (3 control, 11 treated). Re-exposure to normal, oxygenated solution resulted in prompt initial hyperpolarization followed by marked depolarization, and finally by recovery to baseline maximum diastolic potential. Anti-free radical agents had not effect on maximum diastolic potential during exposure to ischemic conditions or on initial hyperpolarization following re-exposure to oxygenated solution. Preparations that became severely depolarized during exposure to ischemic conditions were not protected by anti-free radical interventions from developing marked depolarization following re-exposure to oxygenated solution. However, in fibers only moderately depolarized by the ischemic conditions, all anti-free radical interventions except mannitol, 2 mM significantly attenuated depolarization following re-exposure to oxygenated solution. Anti-free radical interventions significantly reduced the number of preparations that became markedly depolarized (to less than -65 mV) during re-exposure to oxygenated solution (except for mannitol, 2 mM). Agents had no effect on the occurrence of abnormal automaticity; the occurrence of inexcitability was reduced, but not significantly, except when all agents were used in combination. The results suggest that free radical production may contribute to electrophysiological abnormalities when Purkinje fibers are re-exposed to oxygenated Tyrodes solution after they have been exposed to ischemic conditions.

ECG Telemetry and Long Term Electrocardiography

Long term electrocardiographic (LTECG) recording is a method of recording the ECG over a designated period of time. This technology allows detection of intermittent arrhythmias, ST segment changes, and repolarization abnormalities. It provides a method for determining whether periodic symptoms are associated with cardiac arrhythmias. Technological advances in the past few years have provided a diversity of recording, transmitting, and analysis systems. Four general types of devices are currently available: continuous recorders, intermittent or event recorders, instruments for real-time recording and transmission of ECGs, and implantable recorders. Types of electrocardiographic recorders are shown in Table 18.1.