Ventricular vulnerability in diabetes and myocardial norepinephrine release

Previously the authors have observed a reduction of the ventricular fibrillation threshold (VFT) in a mild diabetic model. This investigation examines the role of more severe hyperglycemia in altering the ventricular fibrillation threshold and how the sympathetic nervous system modulates the response. Alloxan diabetes was induced in eight male mongrel dogs 3-5 years of age (Group 2), for comparison with matched controls (Group 1). Hemoglobin A1c rose from 2.9 +/- .4-7.8 +/- .3% and body weight was maintained with daily insulin. After 1 year, anesthesia was induced with chloralose and an electrode catheter placed at the right ventricular apex. VFT was 41.7 +/- 1.8 ma in Group 1 and 27.8 +/- 2.1 ma in the diabetics of Group 2 (p less than .001). There was significantly greater decline of VFT in response to epinephrine infusion in Group 2. The threshold in diabetics rose to normal levels after infusion of the beta-blocking agent, esmolol. Subsequently, the response of the cardiac sympathetic system was assessed during ventricular pacing at 200 beats/minute. Serial paired blood samples were taken from catheters in the aorta and coronary sinus for catecholamine assay by HPLC. Both groups had similar coronary blood flow responses by the thermal method, as well as changes in arterial pressure. While no change occurred in Group 1, a progressive rise of norepinephrine (NE) concentration was observed in coronary venous effluent of Group 2 (p less than .01). The basal arterial-coronary sinus difference was-123 +/- 52 pg/ml, which rose during pacing in Group 2 to a peak of -376 +/- 9.3 pg/ml.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dispersion of ventricular repolarization and arrhythmia: study of two consecutive ventricular premature complexes

The effect of two consecutive ventricular premature stimuli (S1S2) during atrial pacing on dispersion of repolarization and inducibility of ventricular arrhythmias was studied in 16 dogs under control conditions and in four dogs in the presence of an increased dispersion of repolarization during atrial pacing induced by general hypothermia and regional warm blood perfusion via selective cannulation of the distal branch of left anterior decending coronary artery. Dispersion of repolarization was measured as the maximal difference between the ends of six simultaneously recorded monophasic action potentials (MAPs) from anterior ventricular surface, and consisted of MAP duration difference and activation time difference. Dispersion of repolarization during atrial pacing at control was 29 +/- 7 msec (activation time difference 4 +/- 6 msec, MAP duration difference 25 +/- 8 msec), that after S1 at paraseptal the site was 81 +/- 8 msec (activation time difference 73 +/- 12 msec, MAP duration difference 8 +/- 5 msec), and that after S1S2 was 148 +/- 27 msec (activation time difference 103 +/- 21, MAP duration difference 44 +/- 26 msec). Neither S1 nor S1S2 induced ventricular arrhythmia. Hypothermia and regional warm blood reperfusion increased dispersion of repolarization during atrial pacing to 70 +/- 22 msec (activation time difference 9 +/- 3 msec, MAP duration difference 61 +/- 19 msec). During hypothermia and regional warm blood reperfusion, S1 produced a dispersion of repolarization of 149 +/- 29 msec (activation time difference 85 +/- 8 msec, MAP duration difference 64 +/- 23 msec) and did not induce ventricular arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of procainamide on the induction of ventricular fibrillation by sequential ventricular stimulation

The effect of procainamide on ventricular vulnerability to fibrillation was studied in 13 anesthetized open-chest dogs. Epicardial electrograms were recorded through forty bipolar electrodes placed on the surface of exposed ventricles. Ventricular fibrillation (VF) was induced by sequential extrastimulation. The number of extrastimuli required to induce repetitive extrasystole (RE) or VF were defined as repetitive extrasystole threshold (RET) or ventricular fibrillation threshold (VFT). The epicardial electrograms at the onset of ventricular arrhythmia were divided every 100 msec after the last extrastimulation, and the ratio of recordings with activation time of more than 50 msec during each divided period was defined as "chaotic score". Intravenous injection of procainamide at the dose of 20 mg/kg failed to increase RET but successfully increased VFT from 4.4 +/- 0.9 to 7.0 +/- 1.8 in hearts with necrosis. Procainamide significantly reduced chaotic score from 36 +/- 12% to 14 +/- 7% at 5 sec after the induction of ventricular arrhythmias. We concluded that the antifibrillatory action of procainamide is based on a reduction of the number of chaotic multiple reentries, but not on the prevention of reentry per se.     

Cellular mechanisms of vagally mediated atrial tachyarrhythmia in isolated arterially perfused canine right atria

INTRODUCTION: Increased vagal tone significantly enhances susceptibility to atrial fibrillation (AF); however, the cellular mechanisms responsible for vagally mediated AF are not completely understood. METHODS AND RESULTS: In 12 isolated arterially perfused canine right atria, high-resolution optical mapping techniques were used to measure action potentials during control conditions, during intracardiac parasympathetic nerve stimulation (IPS; 30 to 50 Hz) as a surrogate for vagal stimulation, and during acetylcholine (ACh) infusion (10 to 30 microM). During steady-state pacing, action potential duration was shorter during ACh infusion (43 +/- 9 msec) than during IPS (78 +/- 7 msec, P < 0.001) or control (129 +/- 5 msec, P < 0.001). In contrast, repolarization gradients were larger during IPS (13 +/- 3 msec/mm) than during ACh infusion (3 +/- 1 msec/mm, P < 0.01) or control (5 +/- 1 msec/mm, P < 0.01). Transmural repolarization gradients were relatively small for each intervention tested. During ACh infusion, atrial tachyarrhythmia (AT) was easily initiated with a single premature stimulus and was associated with a focal pattern of activation (84%). AT also was easily initiated by a single premature stimulus during IPS; however, when repolarization gradients were large, patterns of conduction block and incomplete macroreentry were often observed (64%). Importantly, AT initiation during IPS was associated with focal activity (36%) when repolarization gradients were small. CONCLUSION: In contrast to ACh infusion, IPS generally increased dispersion of repolarization and was often associated with patterns of conduction block and incomplete macroreentry, similar to that associated with in vivo cervical vagal stimulation. However, IPS also was associated with a focal pattern of initiation that was independent of local repolarization gradients. These results suggest that during vagal stimulation, AT initiation does not always depend on repolarization gradients.     

Repolarization inhomogeneities in ventricular myocardium change dynamically with abrupt cycle length shortening

BACKGROUND. In single heart cells, abrupt changes in stimulation rate elicit complex alterations in repolarization. The effects of rate change on dispersion of repolarization, however, have not been well characterized. METHODS AND RESULTS. To determine the effects of abrupt cycle length (CL) shortening on spatial inhomogeneity of repolarization in a syncytium of ventricular cells, 124 action potentials were simultaneously recorded from Langendorff-perfused guinea pig hearts using high-resolution optical mapping with voltage-sensitive dye. The distribution of ventricular action potential durations (APDs) mapped during each cardiac cycle was used to calculate mean APD and repolarization dispersion index (DI), defined as the variance of the distribution. After abruptly shortening CL from 500 to 300 msec, mean APD declined exponentially in normoxic controls (by 23 +/- 3 msec, p less than 0.0001). This response was characterized by beat-to-beat oscillations of APD that were synchronized at all ventricular sites. After 30 minutes of hypoxia, mean APD decreased from 175.0 +/- 13.3 to 76 +/- 25.7 msec. However, during hypoxia, abrupt CL shortening lowered mean APD by only an additional 6 +/- 6 msec, and APD oscillations were no longer synchronized throughout the ventricle. In controls, beat-to-beat DI decreased significantly (-51.0 +/- 6.8%, p less than 0.01) by the sixth post-CL shortening beat and then recovered (by 15-20 beats). In contrast, DI failed to decrease during hypoxia (+7.1 +/- 23%). Two mechanisms for the transient decline of DI in controls were identified: synchronous APD oscillations and transient diminution of the apical-to-basal ventricular APD gradient. CONCLUSIONS. These data demonstrate that inhomogeneity of ventricular repolarization, as measured by DI, changes dynamically with CL shortening. Furthermore, the hypoxic ventricle does not attenuate DI after abrupt CL shortening and thereby lacks a physiological response expected to diminish vulnerability to arrhythmias.     

Changes in myocardial repolarization in patients undergoing balloon valvuloplasty for congenital pulmonary stenosis: evidence for contraction-excitation feedback in humans

Alterations in ventricular loading conditions lead to changes in action potential duration and arrhythmias via contraction-excitation feedback; a decrease in load leads to prolongation of repolarization. To determine whether changes in right ventricular load alter ventricular repolarization in man, the corrected QT interval, a measure of overall ventricular repolarization, was measured in 32 patients before and after valvuloplasty for pulmonary stenosis. Right ventricular systolic pressure decreased (82.5 +/- 30.7 to 40.5 +/- 9.5 mm Hg, p less than .001) and the QTc increased concurrently (409.1 +/- 24.3 to 440.7 +/- 28.0 msec, p less than .001) after successful valvuloplasty. The increase in QTc was most marked for those patients with a greater than 30 mm Hg decrease in right ventricular pressure (40.0 +/- 23.3 vs 16.3 +/- 21.3 msec, p = .006). In a subset of seven patients in whom monophasic action potentials were recorded, monophasic action potential duration, a measure of local repolarization, was prolonged (230.0 +/- 24.3 vs 216.9 +/- 21.9, p less than .001) after successful valvuloplasty, confirming that the QTc prolongation reflected changes in local ventricular repolarization. In addition, during nine acute right ventricular outflow tract occlusions in a subset of six patients, monophasic action potential duration shortened (206.6 +/- 17.6 vs 221.7 +/- 20.9 msec, p less than .01) and early afterdepolarizations developed consistent with contraction-excitation feedback. These data suggest that, in humans, changes in mechanical load are associated with changes in ventricular repolarization consistent with contraction-excitation feedback.     

Heterogeneous regional endocardial repolarization is associated with increased risk for ischemia-dependent ventricular fibrillation after myocardial infarction

Repolarization Heterogeneity and Sudden Death Risk. INTRODUCTION: The aim of this study was to investigate whether the characteristics of endocardial ventricular repolarization are associated with differential risk for sudden death. Prolonged surface QT interval is associated with increased arrhythmic risk after myocardial infarction (MI), but the underlying mechanism of QT prolongation and its relation to lethal arrhythmias are unclear. METHODS AND RESULTS: Ventricular fibrillation (VF) risk was assessed in 12 dogs 1 month after anterior MI during an exercise test coupled with brief circumflex coronary occlusion. Susceptible dogs (n = 5) developed VF during the brief ischemic episode, whereas resistant dogs did not (n = 7). Surface QT interval was measured at rest. Endocardial electroanatomic catheter maps of left ventricular repolarization were obtained in four unique regions identified by echocardiography and compared between groups. Compared to resistant dogs, susceptible dogs were characterized by prolonged surface QT intervals (240 +/- 10 msec vs 222 +/- 7 msec, P = 0.04). In addition, they had lower baroreflex sensitivity (9.7 +/- 1.5 msec/mmHg vs 28 +/- 9.8 msec/mmHg, P < 0.01) and a tachycardic response to acute ischemia suggesting higher propensity for stronger sympathetic reflexes. Surface QT interval prolongation in susceptible dogs was due to a marked heterogeneity of endocardial left ventricular repolarization (239 +/- 42 msec, basal anterior wall vs 197 +/- 35, lateral wall; P < 0.001). Resistant animals had no regional differences in endocardial repolarization. CONCLUSION: Sympathetic activation following MI not only produces adverse structural remodeling but also contributes to adverse electrophysiologic remodeling resulting in heterogeneous ventricular repolarization and in a myocardial substrate conducive to lethal reentrant arrhythmias.     

Ventricular filling slows epicardial conduction and increases action potential duration in an optical mapping study of the isolated rabbit heart

INTRODUCTION: Mechanical stimulation can induce electrophysiologic changes in cardiac myocytes, but how mechanoelectric feedback in the intact heart affects action potential propagation remains unclear. METHODS AND RESULTS: Changes in action potential propagation and repolarization with increased left ventricular end-diastolic pressure from 0 to 30 mmHg were investigated using optical mapping in isolated perfused rabbit hearts. With respect to 0 mmHg, epicardial strain at 30 mmHg in the anterior left ventricle averaged 0.040 +/- 0.004 in the muscle fiber direction and 0.032 +/- 0.006 in the cross-fiber direction. An increase in ventricular loading increased average epicardial activation time by 25%+/- 3% (P < 0.0001) and correspondingly decreased average apparent surface conduction velocity by 16%+/- 7% (P = 0.007). Ventricular loading did not significantly alter action potential duration at 20% repolarization (APD20) but did at 80% repolarization (APD80), from 179 +/- 7 msec to 207 +/- 5 msec (P < 0.0001). The dispersion of APD20 was decreased with loading from 19 +/- 2 msec to 13 +/- 2 msec (P = 0.024), whereas the dispersion of APD80 was not significantly changed. These electrophysiologic changes with ventricular loading were not affected by the nonspecific stretch-activated channel blocker streptomycin (200 microM) and were not attributable to changes in myocardial perfusion or the presence of an electromechanical decoupling agent (butanedione monoxime) during optical mapping. CONCLUSION: Acute loading of the left ventricle of the isolated rabbit heart decreased apparent epicardial conduction velocity and increased action potential duration by a load-dependent mechanism that may not involve stretch-activated channels.     

Antidysrhythmic actions of meobentine sulfate

The antiarrhythmic efficacy of meobentine sulfate, a bethanidine derivative lacking inhibitory effects on adrenergic neuronal function, was assessed in three canine models. Intravenous meobentine sulfate, administered in dosages of 5.0, 10,0, and 20.0 mg/kg, produced a dose-related increase in the ventricular fibrillation threshold (VFT) under nonischemic conditions (7.6 +/- 1.8 mA vs 37.8 +/- 8.6 mA) (20 mg/kg; p less than 0.05) and during regional myocardial ischemia (5.6 +/- 1.5 mA vs 41.8 +/- 9.1 mA) (20 mg/kg; p less than 0.05). The VFT was also increased in the presence of chronic ischemic injury (6.4 +/- 1 mA to 31 +/- 10 mA) (20 mg/kg; p 0.05). In the conscious dog, 4 days after an anterior myocardial infarction, programmed electrical stimulation (PES) produced nonsustained ventricular tachycardia (VT) in five dogs. After meobentine sulfate administration, eight of nine animals had sustained VT and one animal developed ventricular fibrillation (VF). At a dose of 20 mg/kg, there was prolongation of the cycle length of the VT (169 +/- 11 msec to 237 +/- 20 msec), prolongation of the QRS duration (58 +/- 2.6 msec to 71 +/- 3.7 msec), and prolongation of the delay in epicardial activation. There was an enhanced potential after meobentine administration for programmed stimulation to produce ventricular arrhythmias with the introduction of fewer premature impulses. In the third canine model, conscious dogs with a previous anterior myocardial infarction developed VF in response to electrically induced left circumflex coronary artery injury. Meobentine (20 mg/kg) failed to prevent VF in eight of eight dogs. These results suggest that while meobentine sulfate significantly increases the electrical VFT, it does not protect the conscious canine from the induction of ventricular tachyarrhythmias in response to PES, and it does not prevent VF in a conscious canine model of sudden coronary death.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of effect of conduction direction on action potential durations in anisotropic ventricular strips of pig heart

INTRODUCTION: The influence of activation sequence on the rate of rise of the depolarization phase of action potentials in atrial or ventricular muscles has been well established. However, whether myocardial fiber orientation is important in modulating the repolarization process is unclear. METHODS AND RESULTS: We examined the influence of activation sequence on the repolarization phase of action potentials in epicardial tissues from the right and left ventricles of domestic pigs. Whereas cells from the right ventricle exhibited direction-dependent differences in action potential duration at 30%, 50%, and 90% of full repolarization (190.6 +/- 31.1 msec vs 181.8 +/- 32.8 msec, 240.3 +/- 23.5 msec vs 236.7 +/- 25.4 msec, and 291.3 +/- 23.7 msec vs 287.4 +/- 25.1 msec for longitudinal and transverse propagation, respectively; P < 0.001), a similar duration of repolarization during both directions of propagation was observed in cells from the left ventricle at 50% and 90% of full repolarization (241.4 +/- 39.4 msec and 285.5 +/- 39.5 msec vs 240.4 +/- 38.9 msec and 284.9 +/- 39.6 msec for longitudinal and transverse propagation respectively; P = NS). A slight but significant difference was found at 30% of full repolarization in cells from the left ventricle (190.4 +/- 39.0 msec vs 187.0 +/- 38.0 msec for longitudinal and transverse propagation, respectively; P < 0.05). In the left ventricle, the duration of repolarization did not change as the distance between the recording site and stimulation site increased. CONCLUSION: The direction of wavefront propagation with respect to fiber orientation may not play an important role in modulating the duration of repolarization in epicardial cells from the left ventricle.     

Electrophysiological effects of left ventricular hypertrophy. Effect of calcium and potassium channel blockade.

BACKGROUND. To define the arrhythmogenic effects of left ventricular hypertrophy (LVH) in the intact heart, we carried out a detailed electrophysiological assessment in our previously validated feline aortic-banding model and then tested the effects of agents that blocked either the slow inward calcium or voltage-dependent potassium channel. METHODS AND RESULTS. We measured intraventricular and interventricular conduction times, excitability thresholds, ventricular effective refractory periods, and monophasic action potential duration at several sites in cats with LVH as well as in concurrent control (sham-operated) cats. In addition, we assessed vulnerability to ventricular arrhythmia using direct measurement of ventricular fibrillation (VF) thresholds and by standard techniques of programmed stimulation. Despite finding no difference between LVH and sham-operated cats in mean values for several electrophysiological parameters, the former group was significantly more vulnerable to VF, with more spontaneous VF and lower VF thresholds. Compared with the sham controls, LVH cats also had a greater dispersion of effective refractory period (35 +/- 11 versus 12 +/- 4 msec, p less than 0.01) and monophasic action potential duration at 90% repolarization (69 +/- 25 versus 39 +/- 7 msec, p less than 0.02). Verapamil had no significant effect on these electrophysiological parameters, nor did it affect VF threshold. However, risotilide, an inhibitor of the voltage-dependent potassium channel, narrowed dispersion of the effective refractory period and monophasic action potential duration concomitant with a marked reduction in ventricular vulnerability. CONCLUSIONS. LVH has a pronounced effect on dispersion of refractoriness and repolarization and renders the ventricle more vulnerable to fibrillation. Blockade of the voltage-dependent potassium channel, but not the slow inward calcium channel, narrows the dispersion of recovery of excitability and protects against VF.     

Monophasic Action Potential Recordings from Intact Mouse Heart: Validation, Regional Heterogeneity, and Relation to Refractoriness

INTRODUCTION: The monophasic action potential (MAP) technique has been validated in humans and larger animals, but, in mice, MAP recordings available to date show little resemblance to the murine ventricular transmembrane action potential (TAP) measured by conventional microelectrodes. We developed a miniaturized MAP contact electrode technique to establish in isolated mouse hearts: (1) optimal electrode size; (2) validation against TAP; (3) relationship between repolarization and refractoriness; and (4) regional repolarization differences. METHODS AND RESULTS: In 30 Langendorff-perfused mouse hearts, MAP electrodes of tip diameter 1.5, 1.0, and 0.25 mm were tested by comparing MAPs and TAPs from epicardial and endocardial surfaces of both ventricles. Only the MAP contact electrode of 0.25-mm tip diameter consistently produced MAP recordings that had wave shapes nearly identical to TAP recordings. MAP durations measured at 30%, 50%, 70%, and 90% repolarization (APD30, APD50, APD70, APD90) highly correlated with TAP measurements (r = 0.97, P < 0.00001). APD50 was significantly longer in endocardial than in epicardial recordings (right ventricle: 9.3+/-1.1 msec vs 3.9+/-1.1 msec; left ventricle: 9.9+/-2.1 msec vs 6.2+/-1.9 msec; both P < 0.001), demonstrating transmural repolarization differences. Effective refractory period (ERP) determined at basic cycle lengths from 70 to 200 msec correlated with 80%+/-6% of total repolarization, with an ERP/APD90 ratio of 0.85+/-0.14. CONCLUSION: Murine myocardial repolarization, regional repolarization heterogeneity, and relation to refractoriness can be assessed reliably by this miniaturized MAP contact electrode technique, which renders action potential wave shapes similar to that of intracellular microelectrodes. This technique may be useful for exploring repolarization abnormalities in genetically altered mice.     

Pertussis toxin treatment blocks hyperpolarization by muscarinic agonists in chick atrium

Atrial and ventricular adenylate cyclase activity and atrial membrane potentials were measured in hearts from hatched chicks at 2-3 days after intravenous administration of pertussis toxin (0.5-1.0 micrograms, total) or saline. Both in atrium and ventricle, treatment with pertussis toxin antagonized inhibition by carbachol of basal and isoproterenol-stimulated adenylate cyclase activity without changing either basal or isoproterenol-stimulated adenylate cyclase. In atria from pertussis toxin-treated animals (5.4 mM potassium), carbachol hyperpolarized the resting membrane by 0.3 +/- 0.3 mV (n = 9) and did not increase resting potassium conductance. In contrast, carbachol hyperpolarized the resting membrane by 4.5 +/- 0.8 mV (n = 11) and increased resting potassium conductance more than 4-fold in saline-treated animals. Carbachol did not significantly affect the atrial action potential peak or duration at 50% repolarization of pertussis toxin-treated animals. This muscarinic agonist reduced action potential peak by 7.8 +/- 1.2 mV and the duration at 50% repolarization by 22.1 +/- 3.0 msec in atria from saline-treated animals. Pertussis toxin treatment also prevented the negative inotropic effect and the inhibition of calcium-dependent action potentials caused by carbachol in atrial muscle. Neither the affinity nor the maximal specific binding of [3H]quinuclidinyl benzilate in ventricular homogenates was changed by pertussis toxin treatment. The apparent affinity of carbachol for muscarinic receptor was slightly (approximately 2-fold) diminished in pertussis toxin-treated animals. The inhibition of carbachol-induced hyperpolarization by pertussis toxin treatment implicates a guanosine 5'-triphosphate-dependent protein (Ni or a similar protein) as an essential link that permits muscarinic receptor to regulate atrial potassium channels.     

Magnesium suppression of early afterdepolarizations and ventricular tachyarrhythmias induced by cesium in dogs

The mechanism by which magnesium therapy suppresses some ventricular tachyarrhythmias characterized by a prolonged QT interval (e.g., torsades de pointes) is unknown. Since early afterdepolarizations have been proposed as a cause of the long QT syndrome and the related ventricular tachyarrhythmias, we hypothesized that magnesium therapy would suppress both the early afterdepolarizations and the ventricular arrhythmias. The present study was performed to test that hypothesis. Using monophasic action potentials (MAP) recorded with a contact electrode from the right ventricular endocardium to demonstrate early afterdepolarizations, cesium chloride (168 mg/kg iv) was administered before, during, and 1 to 2 hr after discontinuation of a magnesium infusion (1 to 2 mg/kg/min for 20 to 30 min). Before magnesium infusion, cesium induced early afterdepolarizations that were 49.7 +/- 1.6% (mean +/- SE) of the amplitude of the corresponding monophasic action potential. The amplitude of the early afterdepolarization decreased to 31.2 +/- 3.8% of the MAP amplitude during magnesium infusion (p less than .003) and increased to 48.0 +/- 4.0% 1 to 2 hr after termination of the magnesium infusion (p less than .003). Cesium induced sustained monomorphic ventricular tachycardia, torsades de pointes, or ventricular fibrillation in 12 of 13 dogs before magnesium infusion, and in eight of 11 dogs 1 to 2 hr after stopping infusion, but in only three of 13 dogs during magnesium infusion. Cesium prolonged the corrected QT interval from 338 +/- 16 msec (control) to 387 +/- 14 msec before (p less than .003), 356 +/- 12 msec during (p less than .003), and 406 +/- 16 msec after stopping the magnesium infusion (p less than .003).(ABSTRACT TRUNCATED AT 250 WORDS)     

Repolarization dynamics in patients with long QT syndrome

INTRODUCTION: Dynamics of ventricular repolarization may contribute to cardiac arrhythmias in subjects with the long QT syndrome (LQTS). The aim of the present study was to assess the dynamics of repolarization duration and the dynamics of repolarization complexity in LQTS patients and their unaffected family members. METHODS AND RESULTS: Twelve-lead 24-hour ambulatory ECG recordings were obtained from LQTS patients (n = 38) and unaffected family members (n = 20). The 24-hour dynamics of the QT interval, T wave complexity (TWC) index measured by principal component analysis, and the RR interval were analyzed using standard deviation (SD) and square root of the mean squared differences of successive values of the parameters (RMSSD). QT variability, mean TWC, and TWC variability were increased in the LQTS patients compared with unaffected family members (QT-SD: 38 +/- 20 msec vs 19 +/- 7 msec, P = 0.0001; QT-RMSSD: 36 +/- 20 msec vs 14 +/- 8 msec, P = 0.0001; TWC: 27.7% +/- 11.1% vs 20.4% +/- 6.7%, P = 0.003; TWC-SD: 6.7% +/- 2.8% vs 4.6% +/- 1.8%, P = 0.003; TWC-RMSSD: 5.3% +/- 2.8% vs 3.7% +/- 1.2%, P = 0.004, respectively). At the same time, the measures of heart rate variability were similar between the affected and unaffected LQTS subjects (SD of normal-to-normal RR intervals [SDNN]: 94 +/- 25 msec vs 89 +/- 37 ms, P = 0.56; RMSSD: 49 +/- 26 msec vs 49 +/- 34 ms, P = 0.97, respectively). CONCLUSION: Despite similar heart rate variability, QT variability and the variability of TWC are significantly increased in LQTS patients compared with unaffected family members, suggesting that disturbances in temporal dynamics of repolarization and repolarization complexity in LQTS patients possibly increase vulnerability to arrhythmias.     

Sodium channel block produces opposite electrophysiological effects in canine ventricular epicardium and endocardium.

Using microelectrode techniques we compared the effects of tetrodotoxin (TTX, 2-3 microM), DL-propranolol (1-3 micrograms/ml), and flecainide acetate (10-15 microM) on isolated canine ventricular epicardial (epicardium) and endocardial (endocardium) tissues. Propranolol, TTX, and flecainide decreased Vmax and phase 0 amplitude in a use-dependent manner in both tissues. The effects of propranolol were slow to develop and wash out. TTX and propranolol always abbreviated action potential duration in endocardium. Action potential duration was abbreviated by 23.8 +/- 5.6 msec after propranolol (1 microgram/ml, basic cycle length [BCL] = 1,000 msec) and 10.8 +/- 12.9 msec after TTX (2 microM, BCL = 1,000 msec). In epicardium, the reduction of phase 0 and 1 amplitudes led to a slowing of the second action potential upstroke and an increase in the amplitude of phase 2. This accentuation of the notch resulted in a paradoxical prolongation of the epicardial action potential. Action potential duration was prolonged 34.4 +/- 11.3 msec after 4 hours of exposure to propranolol (1 microgram/ml, BCL = 1,000 msec), 11.1 +/- 6.3 msec after 15 minutes of exposure to TTX (2 microM, BCL = 1,000 msec), and 19.9 +/- 8.2 msec after 25-45 minutes of exposure to flecainide (15 microM, BCL = 500 msec). With stronger sodium block, phase 1 terminated at more negative potentials, the second upstroke often failed to appear, and an all-or-none repolarization ensued causing a marked abbreviation of the epicardial action potential. In some epicardial preparations, we observed marked abbreviation at some sites but prolongation at other sites after sodium blockade with flecainide. The dispersion of repolarization was often attended by reentrant activity. The differential response of epicardium and endocardium to sodium blockade was not observed when the preparations were pretreated with 4-aminopyridine or ryanodine, agents known to diminish the transient outward current and epicardial notch. Acceleration-induced prolongation of refractoriness was observed after sodium blockade in epicardium but not in endocardium. Postrepolarization refractoriness also occurred in epicardium but not in endocardium after TTX, propranolol, or flecainide exposure. The data indicate that propranolol, TTX, and flecainide, via their action to block sodium current, may exert opposite effects on action potential duration and refractoriness in cells spanning the ventricular wall. The presence of the transient outward current in epicardium but not in endocardium appears to contribute importantly to these differences.(ABSTRACT TRUNCATED AT 400 WORDS)     

Changes in velocity of left ventricular filling measured by color M-mode during dobutamine stress echocardiography

Myocardial ischaemia affects left ventricular relaxation. The velocity of propagation of rapid left ventricular filling flow (VPF, cm/s) measured by colour M-mode is strongly correlated with the haemodynamic constant of left ventricular relaxation (Tau). The authors compared the changes in VPF during stress echocardiography with Dobutamine in a control group of non-coronary patients (Group 1, N = 12) and a group of coronary patients (Group 2, N = 29). Coronary angiography was performed in all patients. The basal VPF were similar in both groups (Group 1: 68.3 +/- 22.7 cm/s vs Group 2: 66.2 +/- 23.1 cm/s, NS). The VPF at the peak of dobutamine infusion were significantly different from the values observed under basal conditions in Group 1 (105.1 +/- 25.0 cm/s, p < 0.001) whereas this difference was not significant in Group 2 (67.4 +/- 19.3 cm/s, NS). There were significant differences between the two groups for peak values (p < 0.001) and for percentage variation of VPF (peak-basal value/basal value) with respect to the basal values (Group 1: 63 +/- 43% vs Group 2: 9 +/- 39%, p < 0.01). A percentage variation of VPF < 25% (Group 1: 3/12 patients and Group 2: 23/29 patients) allows detection of coronary artery disease with a sensitivity of 79% and a specificity of 75%. During Dobutamine infusion, the velocity of propagation of left ventricular filling flow increases less in coronary patients than in non-coronary patients. The study of this quantitative parameter of left ventricular relaxation seems to be a valuable tool for detecting the presence of coronary artery disease during stress echocardiography.     

In vivo induction of "focal" triggered ventricular arrhythmias and responses to overdrive pacing in the canine heart

Delayed afterdepolarizations and triggered activity were evoked in focal areas of myocardium in vivo by local exposure of endocardium to ouabain by means of a catheter electrode system capable of recording monophasic action potentials (MAPs) and delivering ouabain to the recording site. MAPs were recorded from the septum and the posterior wall of the left ventricle with silver-silver chloride electrode catheters. Ouabain (10(-5) M) was infused through the MAP recording catheter onto the endocardial surface of the septum. After infusion of 10 micrograms/kg ouabain, the amplitude of MAPs recorded from the septum (the site of ouabain infusion) decreased from 37.4 +/- 11.8 to 32.0 +/- 10.1 mV (p less than 0.01), MAP duration at 50% repolarization shortened from 160 +/- 29 to 148 +/- 34 msec (p less than 0.01), and MAP duration at 90% repolarization shortened from 198 +/- 38 to 189 +/- 46 msec (p less than 0.01). MAPs recorded from the posterior wall (the reference site) were unchanged. Delayed afterdepolarizations were recorded at the site of ouabain infusion, but not at the reference site, when the heart was paced at cycle lengths of 200-600 msec. Additional infusion of ouabain induced sustained monomorphic ventricular tachycardia (VT) (mean cycle length, 369 +/- 12 msec) in all 15 dogs studied. The mean concentration of ouabain required to induce VT was 20.9 +/- 10.0 micrograms/kg. Paced QRS complexes when stimulated at the site of ouabain infusion had the same morphology as those of spontaneous VT. Local perfusion of verapamil, 0.015-0.034 mg/kg, through the MAP recording catheter onto the site of ouabain infusion completely eliminated VT and premature ventricular contractions. After perfusion of verapamil, delayed afterdepolarizations could no longer be induced by pacing. These observations indicate that induced VT originated from the site of ouabain infusion, and the presence of delayed afterdepolarizations before development of VT strongly suggests that the induced VT was due to triggered activity. Using this model, we examined the responses to rapid ventricular pacing of "focal" triggered VT. The first beat of the reinitiated tachycardia displayed the same morphology as the spontaneous VT. Local perfusion of verapamil, 0.015-0.034 mg/kg, through the MAP recording catheter onto the site of ouabain infusion completely eliminated VT and premature ventricular contractions. After perfusion of verapamil, delayed afterdepolarizations could no longer be induced by pacing. These observations indicate that induced VT originated from the site of ouabain infusion, and the presence of delayed afterdepolarizations before development of VT strongly suggests that the induced VT was due to triggered activity.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of cocaine intoxication on the threshold for stun gun induction of ventricular fibrillation.

OBJECTIVES: This study sought to assess cocaine's effects on Taser-induced ventricular fibrillation (VF) threshold in a pig model. BACKGROUND: Stun guns are increasingly used by law enforcement officials to restrain violent subjects, who are frequently intoxicated with cocaine and other drugs of abuse. The interaction of cocaine and the stun gun on VF induction is unknown. METHODS: We tested five adult pigs using a custom device built to deliver multiples of standard neuromuscular incapacitating (NMI) discharge that matched the waveform of a commercially available electrical stun gun (Taser X-26, Taser International, Scottsdale, Arizona). The NMI discharges were applied in a step-up and step-down fashion at 5 body locations. End points included determination of maximum safe multiple, minimum VF-inducing multiple, and ventricular fibrillation threshold (VFT) before and after cocaine infusion. RESULTS: Standard NMI discharges (x1) did not cause VF at any of the 5 locations before or after cocaine infusion. The maximum safe multiple, minimum VF-inducing multiple, and VFT of NMI application increased with increasing electrode distance from the heart. There was a 1.5- to 2-fold increase in these values at each position after cocaine infusion, suggesting decreased cardiac vulnerability for VF. Cocaine increased the required strength of NMI discharge that caused 2:1 or 3:1 ventricular capture ratios at all of the positions. No significant changes in creatine kinase-MB and troponin-I were seen. CONCLUSIONS: Cocaine increased the VFT of NMI discharges at all dart locations tested and reduced cardiac vulnerability to VF. The application of cocaine increased the safety margin by 50% to 100% above the baseline safety margin.     

Nonuniform recovery of excitability in the left ventricle

The purpose of this study was to determine left ventricular activation, dispersion of refractoriness, and total recovery time in patients with coronary artery disease and ventricular tachycardia and in patients with the long QT syndrome and to compare these patients with a group of normal patients. Left ventricular endocardial catheter mapping and left ventricular refractory period determination were performed in 18 patients. Group 1 consisted of seven patients with no heart disease and no arrhythmia; group 2 consisted of six patients with previous infarction and sustained ventricular tachycardia; and group 3 consisted of five patients with prolonged QT interval and previous cardiac arrest. Total left ventricular endocardial activation was significantly longer in group 2 (75 +/- 23 msec, mean +/- SD) compared with group 1 (34 +/- 9 msec, p less than 0.01) and group 3 (42 +/- 5 msec, p less than 0.05). Dispersion of refractoriness was significantly greater in group 3 (87 +/- 27 msec) than in group 1 (40 +/- 14 msec, p less than 0.01) and group 2 (53 +/- 14 msec, p less than 0.05). Dispersion of total recovery time was significantly greater in group 2 (90 +/- 30 msec) than in group 1 (52 +/- 14 msec, p less than 0.05) as well as group 3 (114 +/- 43 msec) compared with group 1 (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)