QTc prolongation and risk of coronary heart disease.
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Aged↗
Biomedical subjects
J S Sarma
Publications and source records attributed to J S Sarma.
Relation between QT and RR intervals.
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Adult↗
Circadian and power spectral changes of RR and QT intervals during treatment of patients with angina pectoris with nadolol providing evidence for differential autonomic modulation of heart rate and ventricular repolarization.
This study evaluates the effects of autonomic manipulation by chronic beta blockade with nadolol on the circadian and power spectral changes of heart rate and QT interval. It was hypothesized that differential innervation of the atria and ventricles by sympathetic and parasympathetic fibers may produce differential effects on heart rate and QT interval variabilities. Holter recordings of 12 male patients (age 63 +/- 7 years) with stable angina were analyzed before and after 3 weeks of nadolol therapy. The QT intervals were individually normalized by an exponential formula to study the circadian variation of QTc. Power spectra of RR and uncorrected QT intervals were obtained by fast-Fourier analysis from 256 consecutive sinus beats during the day at maximal heart rate and during the night at minimal heart rate. Frequency-specific variability was determined from areas under the spectral plots. Both heart rate and QTc exhibited significant circadian patterns (p < 0.01) in opposite phase with each other. Mean heart rate was significantly reduced with nadolol (81 +/- 12 vs 67 +/- 12 beats/min, p < 0.001), with greater reduction during daytime. The mean QTc was unexpectedly reduced after nadolol treatment, with borderline significance (p = 0.06). The RR variability in the frequency range of 0.05 to 0.25 Hz was significantly increased with nadolol at 3:00 A.M. (p < 0.01) but not at 1:00 P.M. The QT variability in the same frequency range of was not significantly increased with nadolol. The power spectra of RR and QT intervals were dissimilar except at the lower frequencies around 0.05 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)
Angina Pectoris↗
Amiodarone decreases Na,K-ATPase alpha 2 and beta 2 expression specifically in cardiac ventricle.
Studies have suggested that chronic amiodarone treatment (a class III antiarrhythmic) may have effects on the myocardium that resemble those of hypothyroidism. Since hypothyroidism is associated with decreased expression of Na,K-ATPase alpha 1, alpha 2 and beta 1 subunits in heart and alpha 2 subunit in skeletal muscle, we aimed to test the hypothesis that chronic in vivo administration of amiodarone would result in changes in the expression of Na,K-ATPase isoforms that resembled those seen in hypothyroid rat. Rats were treated with 40 micrograms/g body weight amiodarone for 3 and 6 weeks. Na,K-ATPase alpha 1, alpha 2, beta 1 mRNA and protein levels and beta 2 mRNA were measured in cardiac ventricle and skeletal muscle. After 3 weeks of amiodarone cardiac alpha 1, alpha 2 and beta 1 protein levels were decreased to 0.65, 0.42, and 0.54 of control, respectively. After 6 weeks of treatment, cardiac alpha 1 and beta 1 levels returned to control and alpha 2 remained depressed. At the mRNA level alpha 2 and beta 2 decreased to 0.6-fold of control after 6 weeks treatment. There was no effect of amiodarone on skeletal muscle Na,K-ATPase expression at either time point. We conclude that the effects of amiodarone on myocardial Na,K-ATPase expression are similar to those of hypothyroidism after 3 weeks of amiodarone treatment, but by 6 weeks the similarities are limited to the decrease in alpha 2 and beta 2 expression.(ABSTRACT TRUNCATED AT 250 WORDS)
Amiodarone↗
Effects of amiodarone on the circadian rhythm and power spectral changes of heart rate and QT interval: significance for the control of sudden cardiac death.
Effects of chronic amiodarone therapy on the circadian rhythmicity and power spectral changes of heart rate and QT intervals from Holter recordings were evaluated in three groups of patients: group 1 baseline (n = 10); group 2, treated for 3 to 6 months (n = 11); and group 3, treated for > 1 year (n = 13). Amiodarone reduced heart rate, which reached steady state at 3 to 6 months; bradycardia was evident during the entire 24 hours. The corrected QT (QTc) interval increased as a function of treatment duration. It was 457 +/- 39, 530 +/- 28 (p < 0.001), and 581 +/- 36 (p < 0.0002) msec for groups 1, 2, and 3, after 6 months, respectively. The circadian rhythmicity of QTc was abolished in group 3. Power spectral analysis showed a tendency for amiodarone to reduce both R-R and QT interval variabilities, suggesting inhibition of autonomic control on the heart by the drug. The effectiveness of amiodarone against ventricular arrhythmias may result in part from the sustained bradycardia in concert with continuous uniform prolongation of myocardial repolarization.
Aged↗
Controlling cardiac arrhythmias by lengthening repolarization: rationale from experimental findings and clinical considerations.
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Action Potentials↗
Electrophysiologic effects of ambasilide (LU 47110), a novel class III antiarrhythmic agent, on the properties of isolated rabbit and canine cardiac muscle.
Electrophysiologic effects of ambasilide in canine isolated cardiac muscle driven at 1 Hz and in rabbit sinoatrial (SA) node preparations were determined by standard microelectrode technique. Ambasilide (10(-7)-10(-5) M) produced concentration-dependent increases in action potential duration measured at -80 mV (APD-80) repolarization time in canine ventricular muscle and in Purkinje fibers. APD measured at -20 mV (APD-20) was also increased in ventricular muscle, but it shortened with 10(-5) M in Purkinje fibers; at this concentration, there was a negligible change in the amplitude and the maximum upstroke velocity (Vmax) of action potentials and in the resting membrane potential. With the stimulation frequency between 30/min and 120/min, ambasilide (10(-5) M) produced a parallel increase in APD-80 as well as in APD-20 of ventricular muscle. In Purkinje fibers, the prolonging effect of ambasilide on APD-80 was more pronounced at lower stimulation frequency, whereas APD-20 shortened at all stimulation frequencies. Ambasilide at 10(-5) M also produced a prolongation of the effective refractory period (ERP) in Purkinje fibers. The drug produced no significant change in the frequency-dependent relationship between ERP and APD-80. A small but significant frequency-dependent inhibition of Vmax was noted in both ventricular muscle and Purkinje fibers. When the stimulus cycle length was reduced from 1,000 to 300 ms, Vmax in ventricular muscle decreased by 8.4 +/- 3.4% in control solution but by 22.6 +/- 5.6% after 10(-5) M ambasilide (n = 8, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Aminobenzoates↗
Effect of ambasilide, a new class III agent, on plateau currents in isolated guinea pig ventricular myocytes: block of delayed outward potassium current.
The actions of ambasilide (LU-47110) on the action potential and membrane currents of isolated guinea pig ventricular myocytes were studied using voltage clamp techniques. Ambasilide (1 microM) prolonged the action potential (APD) at 20, 50 and 90% repolarization by 11.2 +/- 4.3, 13.8 +/- 3.9 and 13.6 +/- 3.7%, respectively, compared to control (n = 10). APD prolongation was attributed to the block of delayed rectifier outward current (Ik) in a concentration-dependent fashion (0.01-10 microM). The effects on the APD and Ik were both partially reversed after perfusion with drug-free Tyrode's solution. The block of Ik by ambasilide was compared to that by E-4031 (5 microM), a putative selective blocker of that fast, inwardly rectifying component of Ik identified in guinea pig ventricle. E-4031 produced about 65% block of Ik for pulse durations between 80 and 420 msec, but the block decreased as the pulse duration increased further, the block accounting for 34 +/- 5% of Ik at 6.3 sec. In contrast, the percentage of reduction of Ik by 10 microM ambasilide did not produce a consistent magnitude of block over a similar range of short depolarizations, but rather progressively decreased Ik as the pusle duration lengthened. Block at the end of a 2-sec pulse was about 48 +/- 8%, more block than could be attributed to an E-4031-sensitive current block alone. Whereas E-4031 (5 microM) shifted the activation curve of Ik 10 mV toward positive potentials and decreased the slope factor, k, by about 4 mV, ambasilide (5 microM) had no effect on these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)
Action Potentials↗
Amiodarone toxicity. II. Desethylamiodarone-induced phospholipidosis and ultrastructural changes during repeated administration in rats.
The contribution of desethylamiodarone (DEA), principal metabolite of the antiarrhythmic drug amiodarone, to the major side effects of amiodarone is unclear. The effects of repeated DEA administration to rats on tissue drug accumulation, ultrastructural changes, and phospholipid concentrations were studied. Two groups (n = 8/group) of male Sprague-Dawley rats (250 g body wt) were administered a 5% aqueous solution of DEA (Dose I, 40 mg/kg/day; Dose II, 60 mg/kg/day) intraperitoneally for 21-23 days, while a third group (control, n = 8) received saline. DEA levels were significantly higher with Dose II compared to Dose I in the lung, liver, kidney, spleen, heart, and serum while the tissue to serum ratios were similar with both doses for all tissues except the heart. DEA administration caused a significant elevation in the lipid phosphorus levels of liver, lung, and alveolar macrophages compared to control levels. A strong positive correlation (p less than 0.01) was found between tissue DEA levels and lipid phosphorus for the above tissues. Electron microscopy revealed the presence of lipid inclusion bodies in liver, lung, and alveolar macrophages of DEA-treated rats. A dose-dependent increase in the percentage of vacuolar surface area was found in the lung and alveolar macrophages. The tissue ultrastructural changes after repeated DEA dosing were qualitatively similar to our previous findings with amiodarone. Increased lung and liver phospholipid levels with repeated DEA doses may result from a potent inhibitory action of DEA on tissue phospholipase A as has been observed by others in in vitro studies.
Amiodarone↗
Circadian rhythmicity of rate-normalized QT interval in hypothyroidism and its significance for development of class III antiarrhythmic agents.
Lengthening of repolarization and refractoriness occurs in hypothyroidism; it is associated with a reduced probability of arrhythmias, with the converse occurring in hyperthyroidism. Because the QT interval and its circadian rhythmicity relative to heart rate is poorly defined in man, we used our new computer-assisted technique to measure QT interval in our analysis of 24-hour Holter tapes before and after (8 to 12 weeks) thyroxine (T4) replacement in 10 patients with hypothyroidism; the findings were compared to those in 6 normal control subjects. QTc interval was prolonged (p less than 0.02) and heart rate decreased (p less than 0.005) during the hypothyroid state. Data were analyzed for circadian rhythmicity by repeated-measures analysis. Circadian variation in QTc and heart rate was statistically significant during hypothyroid and euthyroid states (p less than 0.001) as well as in control subjects, but the circadian rhythmicity of QTc interval and heart rate were out of phase; the maximum prolongation of QTc occurred between midnight and 6 A.M., at a time when heart was at its lowest. QTc interval remained significantly prolonged after 8 to 12 weeks of T4 replacement, when biochemical indexes of hypothyroidism had returned to normal values. The computer-assisted QTc interval determination technique that we used, and our data on the circadian rhythmicity of QTc and heart rate, have significant implications for the development of new class III antiarrhythmic agents.
Adult↗
Tissue drug accumulation and ultrastructural changes during amiodarone administration in rats.
Pulmonary and hepatotoxicity are the two major side effects of chronic amiodarone therapy. We studied the accumulation of amiodarone and its principal metabolite, desethylamiodarone, in lung and liver of rats treated ip for 21 to 23 days with either 40 or 80 mg/kg/day amiodarone. The ultrastructural changes in liver, lung, and alveolar macrophages in saline controls and in rats on the two amiodarone dosage regimens were investigated. There was a dose-dependent increase in amiodarone and desethylamiodarone levels in serum and in tissues. The desethylamiodarone/amiodarone ratios in liver and lung, but not in serum, increased significantly with increasing dose. Serum also contained another metabolite, monodeiodinated desethylamiodarone. Increase in vacuolization and presence of whorled lamellar inclusion bodies in alveolar macrophages occurred with an increase in dose and higher lung amiodarone and desethylamiodarone levels. Electron microscopy of the liver of amiodarone-treated rats revealed the presence of large inclusion bodies partially filled with amorphous material in the cytoplasm. The quantitative relationship of the above changes to organ toxicity and to phospholipidosis that accompanies amiodarone administration remains to be established.
Amiodarone↗
Effect of propranolol on the QT intervals of normal individuals during exercise: a new method for studying interventions.
A new method was used to study the effect of a single dose of propranolol on the QT intervals during exercise in 11 normal volunteers. They exercised maximally on a bicycle ergometer and repeated the test after taking propranolol (40 mg) by mouth two hours before. Electrocardiograms were continuously recorded on magnetic tape and the cardiac cycle length (RR interval) and the QT interval were measured every five seconds by a computer aided method. The RR-QT data from each test during the exercise phase were analysed by an exponential formula, QT = A - B x exp (-k x RR) and by Bazett's formula, QT = K x square root of (RR). Three reference QT intervals, QTc1, QTc2, and QTc3, estimated at RR = 400, 700, and 1000 ms respectively from the regression curves of both formulas were compared. The exponential formula, which consistently gave a better fit with the data, showed that propranolol had a biphasic action on the QT intervals during exercise. It significantly prolonged the mean (SD) interval at longer cycle lengths (from 287 (27) to 305 (18) ms at RR = 1000 ms and shortened it at shorter cycle lengths (from 198 (14) to 179 (16) ms at RR = 400 ms). In contrast, Bazett's formula did not show any significant effect when the same raw data were used. The exponential formula can be adapted to study other interventions or conditions that affect QT intervals.
Adult↗
Effect of ethanol on regional myocardial blood flow and hemodynamics, before and after coronary artery ligation in dogs.
The effects on regional myocardial blood flows (RMBF) and hemodynamics due to ethanol administered before and after acute coronary artery ligation (CAL) in 18 anesthetized dogs were studied. Ethanol was administered to seven dogs (group I) prior to CAL and to six dogs (group II) after CAL; five dogs (group III, control) received only saline before and after CAL. Uniform blood ethanol levels (180 +/- 30 mg/dl) were maintained in groups I and II after initial ethanol administration. In these groups the heart rate and rate-pressure product (which reflects myocardial oxygen consumption) remained stable, but pulmonary arterial pressures were elevated. Other hemodynamic parameters remained stable in all groups. Ethanol caused a significant transmural increase of RMBF (p less than 0.001) in both groups I and II. In group II the increase was significant in both nonischemic and ischemic tissues, with no apparent redistribution of flow among the myocardial layers. The percentage increase of RMBF due to ethanol was highest in group II nonischemic tissue (95-107%) compared to the corresponding ischemic tissue (57-60%) and the group I myocardial tissue (36-47%) prior to CAL (p less than 0.001). The observed differences between ethanol pre- and posttreatments suggest different interactions between ethanol and catecholamines. The results also confirm that vasodilatory reserve is present in the acutely ischemic myocardium and that the local availability of ethanol is important for coronary vasodilatation.
Animals↗
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.
Adolescent↗
QT interval revisited.
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Electrocardiography↗
An exponential formula for heart rate dependence of QT interval during exercise and cardiac pacing in humans: reevaluation of Bazett's formula.
A new exponential formula to characterize the human RR-QT relation was evaluated in comparison with Bazett's formula in 16 subjects: 10 healthy, normal men (ages 18 to 30 years) who exercised on a stationary bicycle, and 6 patients (ages 50 to 80 years; 2 women and 4 men) with rate-programmable VVI pacemakers whose rates were changed by an external programmer. The RR and QT intervals for heart rate in the range of 50 to 180 beats/min were measured from electrocardiographic tracings recorded at a paper speed of 100 mm/s. The data from each subject were fitted separately by 4 formulas by an appropriate regression analysis using a statistical package program: (F1) QT = A1 - B1*Exp(-k1*RR); (F2) QT = A2[1-Exp-(-k2*RR)]; (F3) QT = A3* square root (RR) + B3; and (F4) QT = A4* square root (RR), where all A, B, and k are regression parameters. The relative goodness of fit of data by the 4 formulas was assessed by the mean-squared residual and the Akaike Information Criterion using Wilcoxon signed-ranks tests. This analysis confirmed that F1 is the best model among the formulas tested and F4 (Bazett's formula) is the least acceptable for both exercised and paced groups. The deviations from Bazett's formula were more striking for the paced group than for the exercised group, as reflected by the mean-squared residual values for F4 (715 +/- 86 for the paced group vs 384 +/- 41 for the exercised group, p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Ventricular refractory periods in relation to rate and test-site VT intervals in anesthetized and conscious dogs: a canine model for conscious state measurements.
The functional relationship of ventricular effective refractory period (ERP) with basic cycle length (BCL) of stimulated ventricular depolarization and VT intervals of test-site unipolar ventricular electrograms were studied in five conscious and eight anesthetized (sodium pentobarbital, 30 mg/kg) open-chested dogs. The range of BCLs studied was 300 to 1000 ms, achieved through ventricular stimulation following chemically-induced complete AV block. In the conscious animal model developed for this study, two-to-four ventricular electrode leads were exteriorized and the ventricular rate was maintained by an implanted programmable VVI pacemaker. In all animals studied, the BCL-ERP relation was closely represented by the empirical equation ERP = A-B.Exp(-k.BCL), and the VT-ERP relation over the same range of BCLs was linear: ERP = C + D.VT. The correlation coefficients were in the range of 0.991 to 0.999. The mean values of the parameters in the above equations determined by the appropriate non-linear or linear regression analysis showed significant differences between the two groups of animals studied. In three conscious animals a strong linear correlation between the test-site VT intervals and simultaneously measured QT intervals measured from the lead II surface electrogram was demonstrated (r = 0.993 to 0.998). For a fixed site of stimulation, the morphology of ventricular depolarization complexes as well as the corresponding T-waves remained essentially unaltered with BCL for both myocardial and surface electrograms. The possible applications of developed canine model and the results of the present study include: (1) the study of the rate-dependent effects of cardioactive drugs on ventricular electrophysiology and, (2) the improved design of electronic refractory periods of rate programmable pacemakers.
Anesthetics↗
A digital module for cardiac pacemaker assessment.
The accuracy of a digital pacemaker testing module incorporated into a digital recording electrocardiograph has been tested against two other methods of waveform recording. Measurements of rate (pulse interval), pulse width, pulse amplitude and ratio of trailing edge to the leading edge amplitude were found to be highly accurate. The pulse shapes were faithfully recorded. The practical clinical use of the method is discussed.
Electrocardiography↗