Thoracotomy Elevates the Defibrillation Threshold and Modifies the Defibrillation Dose-Response Curve

Thoracotomy Elevates the Defibrillation Threshold. Introduction : Despite innovations in nonthoracotomy defibrillation systems, thoracotomies are still required in some clinical settings and are utilized in many animal-based research protocols. The effect of a thoracotomy on defibrillation energy, however, has not been well characterized.
Methods and Results : Ten dogs in the immediate testing; group underwent defibrillation testing immediately following a thoracotomy: another ten dogs in the delayed testing group were given 48 to 72 hours of recovery before defibrillation testing. A right ventricular endocardial coil to cutaneous thoracic patch biphasic system was used. At the time of defibrillation testing, the immediate testing group had a faster mean heart rate (144.7 ± 30.2 vs 105.8 ± 17.5 beats/min, P < 0.01), higher mean pulmonary artery pressures (systolic: 18.14 ± 9.48 vs 11.28 ± 6.46 mmHg. P = 0.1; diastolic: 6.59 ± 2.88 vs 3.89 ± 1.75 mmHg, P <0.051, and higher mean defibrillation shock impedance (89.0 ± 11.6 vs 70.9 ± 7.3 ω, P < 0.002) than the delayed group. The mean ED₅₀ (energy with a 50% success rate) was significantly higher in the immediate group than in the delayed group (26.9 ± 14.9 vs 14.2 ± 6.9 J, P < 0.05), and the slopes of the dose-response curves were significantly different (P = 0.03).
Conclusion : In a right ventricular endocardial to cutaneous patch system, thoracotomy significantly and transiently increased the defibrillation threshold and modified the defibrillation dose-response curve.     

I(Ks) block by HMR 1556 lowers ventricular defibrillation threshold and reverses the repolarization shortening by isoproterenol without rate-dependence in rabbits

Introduction: The slow delayed rectifier K⁺ current (I_Ks) contributes little to ventricular repolarization at rest. It is unclear whether I_Ks plays a role during ventricular fibrillation (VF) or ventricular repolarization at rapid rates during β-adrenergic stimulation.
Methods and Results: In an in vivo rabbit model, we evaluated the effects of HMR 1556 (1 mg Kg⁻¹+ 1 mg kg ⁻¹ hr ⁻¹ i.v.), a selective I_Ks blocker, on monophasic action potential duration at 90% repolarization (MAPD₉₀), ventricular effective refractory period (VERP), and defibrillation threshold (DFT). In perfused rabbit hearts, the effects of HMR 1556 (10 and 100 nM) in the presence of isoproterenol (5 nM) on MAPD₉₀ and VERP were studied at cycle lengths (CLs) 200–500 msec. In vivo , HMR 1556 prolonged MAPD₉₀ by 6 ± 1 msec at CL 200 msec (P < 0.01, n = 6), lowered DFT from 558 ± 46 V to 417 ± 31 V (P < 0.01), and decreased the coefficient of variation in the VF inter-beat deflection intervals from 8.9 ± 0.6% to 6.5 ± 0.4% (P < 0.05) compared with control. In perfused rabbit hearts, isoproterenol shortened MAPD₉₀ by 5 ± 1 msec at CL 200 msec and 11 ± 4 msec at CL 500 msec (P < 0.05, n = 7). This shortening was reversed by HMR 1556 (P < 0.05), and both effects were rate-independent.
Conclusion: I_Ks block increases VF temporal organization and lowers DFT, and I_Ks that is activated following β-adrenergic stimulation contributes to ventricular repolarization without rate dependence.     

Regional hyperkalemia increases ventricular defibrillation energy requirements: role of electrical heterogeneity in defibrillation

INTRODUCTION: Increased spatial electrical heterogeneity has been associated with impaired defibrillation efficacy. The current study investigated the relationship between electrical heterogeneity and defibrillation efficacy by manipulating spatial electrical heterogeneity. METHODS AND RESULTS: We increased spatial electrical heterogeneity by infusing potassium chloride (2 to 4 mEq/hour) or placebo in the left anterior descending artery in 13 pentobarbital anesthetized swine. Electrophysiologic measurements at five myocardial sites and defibrillation energy requirement (DER) values were determined at baseline and during regional hyperkalemia (n = 7) or placebo (n = 6). Regional potassium infusion was titrated to a 20% reduction in action potential duration in the perfused region. Regional hyperkalemia increased biphasic DER values by 87% (P = 0.02), whereas infusion of placebo did not alter defibrillation efficacy. Regional hyperkalemia decreased myocardial repolarization and refractoriness in the perfused region by 21% (P < 0.001) and 18% (P = 0.01), respectively. However, regional hyperkalemia increased ventricular fibrillation cycle length (VFCL) by 39% (P = 0.008). Consequently, dispersions of repolarization, refractoriness, and VFCL were significantly increased by 169%, 92%, and 200%, respectively. Regional hyperkalemia also increased ventricular conduction time to the perfused region by 54% (P = 0.006), indicating conduction velocity dispersion, while not affecting local pacing threshold or local voltage gradient. CONCLUSION: Regional hyperkalemia increased DER values. Regional hyperkalemia likely impairs defibrillation by increasing myocardial electrical heterogeneity, which supports the theory that electrical heterogeneity promotes nonuniform propagation of early postshock activations, thereby inhibiting defibrillation.     

Ethanol Has Direct Inhibitory Effects on Steroidogenesis in Human Granulosa Cells: Specific Inhibition of LH Action

We have evaluated the direct effects of ethanol (EtOH) on the production of progesterone (P) and estradiol-17β (E₂) by cultured human granulosa cells obtained during in vitro fertilization procedures. On day 3 of culture, cells were divided into control and ethanol (20 m m ) groups and stimulated by hFSH (50 ng/ml), h lh (0–50 ng/ml), FSH+LH, 8 Br-cAMP (0.25 m m ) and androstenedione (10⁻⁷ M). Experiments were terminated on days 7 and 9 and DNA, P, and E₂ were measured. Ethanol inhibited P and E₂ secretion stimulated by LH; however, there was no significant effect of ethanol on P and E₂ production in the control group or when the cells were stimulated by FSH or cAMP. EtOH also had no effect on androstenedione stimulated E₂ production. There was no significant difference in the DNA contents of the human granulosa cells in the ethanol group as compared with the control group. These results are the first demonstration of a direct effect of ethanol on cultured granulosa-lutein cells and suggest that ethanol may inhibit action of LH on the corpus luteum. A direct selective toxic effect of EtOH on the ovary may be responsible for some of the reproductive abnormalities observed in alcoholic women.     

Normal human follicle development: an evaluation of correlations with oestradiol, androstenedione and progesterone levels in individual follicles

OBJECTIVE  The mechanism of dominant follicle selection remains obscure.We have investigated the association between follicle diameter and follicular steroid levels in individual human ovarian follicles throughout the menstrual cycle.
DESIGN  Fluid from ovarian follicles ( n  = 326) was obtained in vivo during surgery from 55 regularly cycling women with proven fertility. Follicles were divided into dominant (diameter > 9 mm, n  = 45) and non-dominant (diameter ≤ 9 mm, n  = 281) based on ultrasound measurements.
MEASUREMENTS  Fluid was assayed for oestradiol (E₂), androstenedione (AD), and progesterone (P).
RESULTS  Median P and E₂ levels were significantly lower ( P  < 0.0001) and AD levels significantly higher ( P  = 0.03) in non-dominant as compared to dominant follicles. In non-dominant follicles AD ( r  = 0.14, P  = 0.02), but not P and E₂, levels were correlated to follicular diameter, and significant changes in steroid concentrations across the menstrual cycle were absent. In dominant follicles, diameter was positively correlated with P and E₂ ( P  < 0.001) levels, and inversely correlated with AD concentrations ( P  = 0.01).
CONCLUSIONS  Results indicate that (1) intrafollicular oestradiol concentrations rise only in follicles exceeding 9 mm in diameter and correlate with the diameter of these dominant follicles, suggesting that significant increase in aromatase enzyme activity occurs only in the dominant follicle (2) a cycle-independent accumulation of andro-stenedione with size occurs in non-dominant follicles, and (3) progesterone production occurs in the largest dominant follicles only, suggesting a limited, if any, role for progesterone during follicle development.     

A Prospective Randomized Comparison in Humans of 90-μF and 120-μF Biphasic Pulse Defibrillation Using a Unipolar Defibrillation System

90-μF and 120-μF Biphasic Pulse Transvenous Defibrillation. Introduction: Capacitance is known to influence defibrillation. Optimal biphasic waveform capacitance for transvenous unipolar defibrillation systems in man is currently being defined. In an effort to improve defibrillation efficacy, we examined the relative defibrillation efficacy of a 65% tilt biphasic pulse from a 90-μF capacitor compared to a 65% tilt biphasic pulse from a 120-μF capacitor in a prospective, randomized fashion in 16 consecutive cardiac arrest survivors undergoing defibrillator surgery.
Methods and Results: The transvenous unipolar pectoral defibrillation system uses a single endocardial RV anodal defibrillation coil and the shell of an 80-cc volume (88 cm² surface area) pulse generator (Medtronic Model 7219C PCD "active CAN") as the cathode for the first phase of the biphasic shock: RV⁺→ CAN⁻. Defibrillation thresholds for each capacitance were determined prospectively in a randomized fashion. The defibrillation threshold results for the 90-μF capacitance were: leading edge voltage 383 ± 132 V; stored energy 7.4 ± 5.0 J; and resistance 57 ± 10 ω. The results for the 120-μF capacitance were: leading edge voltage 315 ± 93 V (P = 0.002); stored energy 6.5 ± 3.7 J (P = 0.21); and resistance 57.0 ± 11 ω (P = 0.87).
Conclusions: We conclude that 90-μF, 65% tilt biphasic pulses used with unipolar pectoral defibrillation systems have equivalent stored energy defibrillation efficacy compared to 120-μF, 65% tilt pulses. Use of lower capacitance is possible in present implantable defibrillators without compromising defibrillation.     

Selective Inhibition of Luteinizing Hormone Action by Ethanol in Cultured Human Granulosa Cells

To extend further our previous observations on the inhibition of luteinizing hormone (LH)-induced increases in steroid secretion by ethanol (EtOH) ( Alcohol. Clin. Exp. Res. 14:522–527, 1990), cultured human granulosa cells were pretreated with several EtOH concentrations (0– 100 m m ), and cells were stimulated with human LH (25 ng/ml) or human follicle stimulating hormone (FSH) (100 ng/ml) and the secretion of 17-β-estradiol (E₂) and progesterone (P) was measured. EtOH significantly increased basal E₂ secretion in a dose-related manner (0–20 m m ); however, in the same concentration range EtOH did not produce consistent changes in FSH-stimulated E₂ secretion. In contrast, EtOH decreased LH-stimulated E₂ secretion between 0–20 m m such that at 20 m m EtOH, the positive effect of LH was abolished. EtOH increased P secretion by 40% at 20 m m and at 100 m m , there was a 100% increase. The FSH-stimulated P secretion was not consistently changed by EtOH, whereas LH-stimulated P secretion was decreased in a dose-dependent manner. LH/human chorionic gonadotropin (hCG) receptors in cells exposed to EtOH showed a 15% ( p < 0.01) and a 47% decrease at 20 m m and 50 m m EtOH, respectively. At 50 m m EtOH, there was a decrease in LH/hCG receptor number from 2900/cell to 1670/cell, without a change in receptor affinity for hCG and 50 m m EtOH decreased LH/hCG receptors in intact granulosa cells in a time-dependent manner. These results indicate that the selective effects of EtOH on LH action in human granulosa cells may be mediated in part by an action on LH/hCG receptors.     

Paroxysmal Atrial Fibrillation Maintained by Nonpulmonary Vein Sources Can Be Predicted by Dominant Frequency Analysis of Atriopulmonary Electrograms

Introduction: Increasing evidence suggests that high-frequency excitation in the pulmonary vein (PV) plays a dominant role in the maintenance of paroxysmal atrial fibrillation (AF). However, in a certain population of patients, AF remains inducible after PV isolation (PVI). We sought to clarify whether dominant frequency (DF) analysis of atriopulmonary electrograms can predict paroxysmal AF maintained by non-PV sources.
Methods and Results: Sixty-one patients with paroxysmal AF (aged 59 ± 12 years) were studied. Before PVI, bipolar electrograms during AF were recorded simultaneously from three PV ostia, the coronary sinus (CS), and the septum and free wall of the right atrium (RA). DF was obtained by fast Fourier transform (FFT) analysis. AF was rendered noninducible after PVI in 39 of the 61 patients (noninducible group), but was still inducible in the remaining 22 (inducible group). Among the six recording sites, the highest DF was documented in the PV in all of the patients in the noninducible group; the maximum DF among the three PVs (PV-DF_max) was higher than that among the CS and two RA sites (atrial DF_max; 7.2 ± 1.0 Hz vs 5.8 ± 0.7 Hz, P < 0.0001). In contrast, the highest DF was documented in the CS or RA in 45.5% of the patients in the inducible group; PV-DF_max was comparable with atrial DF_max (6.6 ± 0.8 Hz vs 6.6 ± 0.6 Hz). AF inducibility after PVI was predicted by a PV-to-atrial DF_max gradient of <0.5 Hz, with a sensitivity of 90.9% and a specificity of 89.7%.
Conclusion: Paroxysmal AF maintained by non-PV sources can be predicted by the PV-to-atrial DF gradient.     

Early recurrence of ventricular fibrillation after successful defibrillation during prolonged global ischemia in isolated rabbit hearts

Introduction: The mechanisms that lower the efficacy of electrical defibrillation during prolonged global ischemia remain unclear.
Methods and Results : Epicardial activation patterns during attempted electrical defibrillation were studied in 18 Langendorff-perfused rabbit hearts at baseline, after 5-minute no-flow global ischemia and after 10-minute reperfusion. DFT₅₀ (voltage required to achieve 50% probability of successful defibrillation) was determined at each stage. Defibrillation was considered successful if postshock sinus/idioventricular rhythm was present. Prolonged global ischemia converted type 1 VF (multiple wandering wavelets) into type 2 VF (repetitive epicardial breakthroughs, REBs). The mean DFT₅₀ after 5-minute ischemia (96 ± 39 V) was significantly lower when compared with that at baseline (154 ± 47 V, P < 0.0001) and after 10-minute reperfusion (145 ± 47 V, P < 0.001). However, the incidence of early (within 10 seconds) VF recurrence after successful shock during prolonged global ischemia (23 of 78, 29.5%) was much higher than that at baseline (2 of 60, 3.3%) and after 10-minute reperfusion (5 of 63, 7.9%; P < 0.0001). Mapping data showed that the VF wavefronts during prolonged global ischemia were initially halted by the shock, followed by one to five ventricular escape beats. These beats then triggered REBs and early VF recurrence. In eight out of 11 episodes, the REBs before and after successful shock arose from the same location near the interventricular septum.
Conclusions : There is a significant reduction of DFT₅₀ during prolonged global ischemia. However, defibrillation appears to fail when the preexisting REBs near the interventricular septum induce early VF recurrence. Shock per se cannot eliminate the substrates of these REBs.     

Effect of Atrial Natriuretic Peptide on Electrical Defibrillation Efficacy

ANP and Defibrillation. Introduction : In vitro studies have suggested that human atrial natriuretic peptide (ANP) modulates the electrophysiologic properties of myocardial cells. This study assessed whether ANP could influence defibrillation efficacy.
Methods and Results : In 35 anesthetized dogs, the transcardiac defibrillation threshold (DFT) as well as hemodynamic and electrophysiologic variables were determined before and during treatment with ANP (n = 11), hydralazine (n = 11), or saline (n = 13). ANP (1.5 μg/kg + 0.2 μg/kg per min) increased the plasma concentration of cyclic GMP (a second messenger for ANP) and significantly decreased aortic blood pressure (mean 100 ± 11 mmHg to 83 ± 15 mmHg). ANP also prolonged ventricular repolarization (effective refractory period 157 ± 7 msec to 165 ± 11 msec) and markedly reduced DFT (5.4 ± 1.2 J to 3.8 ± 0.7 J [P < 0.01]) without changing pulmonary artery pressure or sinus cycle length. Neither saline nor hydralazine (1.5 mg/kg) had a significant effect on DFT (saline 4.7 ± 2.1 J to 4.6 ± 2.4 J; hydralazine 4.3 ± 2.0 J to 4.2 ± 1.9 J), although hydralazine caused pronounced hypotension (mean aortic pressure 103 ± 9 mmHg to 74 ± 13 mmHg).
Conclusion : These results suggest that ANP increases defibrillation efficacy, and that this effect is not necessarily shared by other vasodilating agents.     

OESTROGEN DYNAMICS IN ADRENAL VENOUS EFFLUENTS IN CONGENITAL VIRILIZING ADRENAL HYPERPLASIA

Four patients with untreated congenital virilizing adrenal hyper-plasia (partial 21-hydroxylase deficiency) were studied by bilateral adrenal vein catheterization. Simultaneous right and left adrenal and peripheral blood samples were collected for determination of oestrone (E₁) and oestradiol (E₂. The concentrations of both were higher in the adrenal effluents than in the peripheral blood samples, indicating their secretion by the adrenals. All patients were also studied during a sequential test of suppression (0.5 h after i.v. administration of 4 mg dexamethasone) and stimulation (5 min after i.v. administration of 250 μg ACTH 1–24; Synacthen). Mean peripheral E₂ concentrations did not change significantly whereas E₁ increased above control levels after stimulation. In contrast, suppression of adrenal venous blood concentrations with dexamethasone, and stimulation with ACTH, was demonstrated for every patient. The results indicate that in congenital adrenal hyperplasia the adrenal glands secrete significant amounts of E₁ and E₂.     

Effects of a Class III Antiarrhythmic Drug and Biphasic Shocks on the Postdefibrillation Refractory Period of Relatively Refractory Myocardium

Refractory Period and Defibrillation. Introduction : This study was designed to test whether the refractory state of nondepolarized myocardium is a major determinant of electrical defibrillation.
Methods and Results : Postshock recovery interval (PSRI) was estimated by measuring the residual refractory period after an appropriately timed field stimulus (1 to 16 V). The PSRI and transcardiac defibrillation threshold (DFT) were compared before and during the administration of E-4031, a new Class III antiarrhythmic drug (group I, n = 10), or between monophasic and biphasic shocks (group 2, n = 14) in anesthetized open chest dogs. Group 1: E-4031 reduced the DFT from 2.6 ± 0.6 J to 1.8 ± 0.6 J (P < 0.01). The PSRI increased with the increase of the applied voltage and was almost always greater during K-4031 Infusion than at baseline. There was an inverse correlation between the changes of DFT and PSRI measured with a 14-V stimulus (r =−0.80, P < 0.01) and a 16-V stimulus (r =−0.80, P < 0.01). Group 2: Mean DFTs were not statistically different between the two waveforms (3.3 ± 1.0 J vs 2.9 ± 1.4 J). However, there also was an inverse correlation between the differences in individual PSRIs and DFTs of the two waveforms (10-V stimulus: r =−0.62, P < 0.05; 16-V stimulus: r =−0.75, P < 0.01).
Conclusions : Modulation of defibrillation efficiency by E-4031 infusion or by changes of the shock waveform was related to the effect of these interventions on PSRI. These results suggest an independent role for the refractoriness of nondepolarized myocardium in the mechanism of defibrillation.     

Estrogen-Dependent Enhancement of NO Production in the Nucleus Tractus Solitarius Contributes to Ethanol-Induced Hypotension in Conscious Female Rats

Background:  Our previous pharmacological and cellular studies showed that peripheral (cardiac and vascular) nitric oxide synthase (NOS)-derived NO is implicated in the estrogen (E₂)-dependent hypotensive action of ethanol in female rats. The objective of this study was to test the hypothesis that enhanced NO production in the nucleus tractus solitarius (NTS) is implicated in the E₂-dependent hypotensive action of ethanol.
Methods:  To achieve this goal, we utilized in vivo electrochemistry to measure real time changes in neuronal NO to investigate the acute effects of intragastric ethanol (0, 0.5, or 1 g/kg) on NO in NTS neurons, blood pressure (BP), and heart rate (HR) in conscious female rats in the absence (ovariectomized, OVX, rats) or presence of E₂.
Results:  In sham operated (SO) rats, ethanol elicited dose-related increase in NTS NO and reduction in BP. These neurochemical and BP effects of ethanol were absent in OVX rats. Whether the neurochemical effect of ethanol and the associated hypotension are dependent on rapid E₂ signaling was investigated. In OVX rats pretreated, 30 minutes earlier, with E₂ (1 μg/kg), intragastric ethanol (1 g/kg) increased NTS NO and reduced BP and these responses were comparable to those obtained in SO rats.
Conclusions:  The present findings suggest that increased production of NO in NTS neurons contributes to ethanol-evoked hypotension in female rats. Further, ethanol enhancement of neuronal NO production in the brainstem is dependent on rapid E₂ signaling.     

Postprandial augmentation of bradycardia-dependent ST elevation in patients with Brugada syndrome

Introduction : In patients with Brugada syndrome, the circadian variation of ST elevation could be modulated by the autonomic nervous activity and RR interval. Recently, glucose-induced insulin secretion was also reported to contribute to fluctuation of ST elevation. Therefore, we assessed the effects of taking meals on the ST-RR relationship in the daily life of patients with Brugada syndrome.
Methods and Results: Twenty-eight patients with Brugada syndrome, who had the type I ST elevation, were categorized into 12 symptomatic and 16 asymptomatic patients. Unipolar lead (V₂) Holter ECG was recorded and ST-RR relationships for a 2-hour period were compared before and after each meal. From ST-RR linear regression lines, ST-RR slope (mm/sec) and ST(mm) at RR intervals of both 0.6 seconds and 1.2 seconds (ST_(0.6) and ST_(1.2)) were determined. The ST-RR slope increased significantly after lunch (2.6 ± 0.4 vs 4.4 ± 1.2, P < 0.05) and dinner (2.1 ± 1.0 vs 5.2 ± 1.9, P < 0.01) in symptomatic patients, but not in asymptomatic patients. In both groups, ST_(0.6) was not different before or after each meal. However, ST_(1.2) increased after each meal in symptomatic patients. After dinner, ST_(1.2) was significantly higher in symptomatic patients than in asymptomatic patients (5.0 ± 2.7 vs 3.6 ± 0.8, P < 0.05). Postprandial increase in both ST-RR slope and ST_(1.2) was greatest at dinner in symptomatic patients; however, this tendency was not seen in asymptomatic patients.
Conclusions: In symptomatic patients with Brugada syndrome, bradycardia-dependent augmentation of ST elevation was enhanced for the postprandial period, especially after dinner. This could be related to occurrence of ventricular fibrillation in the late evening.     

Alpha1-Adrenergic Receptor Modulation of Repolarization in Canine Purkinje Fibers

Alpha-Agonists and Repolarization. Introduction: Alpha-adrenergic receptor stimulation increases contractility and prolongs repolarization. These effects are modulated by α₁-adrenergic receptor-mediated inhibition of transsarcolemmal potassium currents.
Methods and Results: We used standard microelectrode techniques to study the actions of 4-aminopyridine (4-AP), which blocks the transient outward current, I_to, and WAY-123,398, which blocks the delayed rectifier, I_k, on canine Purkinje fiber action potential prolongation induced by phenylephrine. At a basic cycle length of 1 second, phenylephrine (0.1 to 10 μ) dose-dependently prolonged action potential duration at 90% repolarization (APD₉₀) from 331 ± 10 msec to 400 ± 12 msec (P < 0.05) at phenylephrine, 10 μ. Phenylephrine did not change phase 1 or plateau height. 4-AP (0.1 mM) decreased phase 1 magnitude, shifted plateau height to more positive potentials (from 0.1 ± 1.8 mV to 14.3 ± 1.1 mV [P < 0.05]), and shortened APD₉₀ from 318 ± 9 msec to 294 ± 8 msec (P < 0.05). 4-AP did not block phenylephrine effects on APD₉₀, which increased, at 10 μ phenylephrine, from 294 ± 8 msec to 342 ± 6 msec (P < 0.05). In contrast, WAY-123,398 (0.1 μ) prolonged APD₉₀ from 360 ± 6 msec to 452 ± 6 msec (P < 0.05), and had no effect on plateau height. In the presence of WAY-123,398, phenylephrine no longer increased APD_9o.
Conclusion: (1) Agents that block I_to shorten APD in Purkinje fibers; and (2) the α-agonist mediated increase of APD in canine Purkinje fibers can be explained by inhibition of I_k.     

Lidocaine's Effect on Defibrillation Threshold are Dependent on the Defibrillation Electrode System: Epicardial Versus Endocardial

Lidocaine's Effect on Defibrillation Depends on Lead System. Introduction: Epicardial and endocardial defibrillation electrode systems affect myocardial electrophysiology and sympathetic function differently. Thus, we postulate that antiarrhythmic drugs will interact with these electrode systems differently. Methods and Results: Defibrillation energy requirements (DER) at 20% (ED₂₀), 50% (ED₅₀), and 80% (ED₈₀), success were measured at baseline and during lidocaine (10 mg/kg per hour) or D5W treatment for epicardial and endocardial electrodes. Pigs were randomized to treatment (lidocaine or D5W) and electrode system, which resulted in four experimental groups: (1) epicardial electrode + D5W; (2) epicardial electrode + lidocaine; (3) endocardial electrode + D5W; and (4) endocardial electrode + lidocaine. ED₅₀ DER (mean ± SEM) values at baseline for groups 1–4 were 10.6 ± 1, 8.5 ± 1, 12.6 ± 1, and 12.3 ± 1 J, respectively. DER values for groups 1 and 3 during D5W were similar to baseline. Conversely, lidocaine increased ED₅₀ DER values from 8.5 ± 1 to 13.5 ± 2 J (P < 0.05) in group 2 animals (epicardial electrodes). When lidocaine was administered to group 4 animals (endocardial electrodes), however, ED₅₀ DER values remained similar to baseline values (12.3 ± 1 to 14.3 ± 2 J, P = NS). Lidocaine increased ED₅₀ DER values by 59% with the epicardial electrode system, which was significantly greater than the 16% increase with the endocardial electrode system (P < 0.05). Electrophysiologic response and electrode impedance were similar between electrode systems. Conclusion: Lidocaine increases DER values to a greater extent when using epicardial versus endocardial electrode system. Thus, drug-device interactions are dependent on the electrode system. These data suggest that the electrophysiologic milieu created by endocardial defibrillation mitigates the effects that lidocaine has on DER values.     

Potent Antiarrhythmic Effects of Chronic Amiodarone in Canine Pulmonary Vein Sleeve Preparations

Objectives: To examine the effects of chronic amiodarone on the electrophysiology of canine pulmonary vein (PV) sleeve preparations and left ventricular wedge preparation.
Background: Amiodarone is commonly used for the treatment of ventricular and supraventricular arrhythmias. Ectopic activity arising from the PV plays a prominent role in the development of atrial fibrillation (AF).
Methods: Standard microelectrode techniques were used to evaluate the electrophysiological characteristics of superfused PV sleeve (left superior or inferior) and arterially perfused left ventricular (LV) wedge preparations isolated from untreated and chronic amiodarone-treated dogs (amiodarone, 40 mg/kg daily for 6 weeks).
Results: In PV sleeves, chronic amiodarone (n = 6) induced a significant increase in action potential duration at 90% repolarization (APD₉₀) and a significant use-dependent reduction in V_max leading to 1:1 activation failure at long cycle lengths (basic cycle length of 124 ± 15 ms in control vs 420 ± 320 ms after chronic amiodarone [P < 0.01]). Diastolic threshold of excitation increased from 0.3 ± 0.2 to 1.8 ± 0.7 mA (P < 0.01). Delayed and late phase 3 early afterdepolarizations and triggered activity could be induced in PV sleeve preparations using acetylcholine (ACh, 1 μM), high calcium ([Ca²⁺]_o= 5.4 mM), isoproterenol (Iso, 1 μM), or their combination in 6 of 6 untreated PV sleeves, but in only 1 of 5 chronic amiodarone-treated PV sleeve preparations. V_max, conduction velocity, and 1:1 activation failure were much more affected in PV sleeves versus LV wedge preparations isolated from amiodarone-treated animals.
Conclusions: The results point to potent effects of chronic amiodarone to preferentially suppress arrhythmogenic substrates and triggers arising from the PV sleeves of the dog.     

Relationship between dominant prolongation of the filtered QRS duration in the right precordial leads and clinical characteristics in Brugada syndrome

Background: Electrical abnormalities in the RVOT may be involved in Brugada syndrome.
Objectives: We investigated the relationship between the signal-averaged ECG (SAECG) and electrophysiologic study (EPS), especially focusing on conduction delay in the outflow tract of the right ventricle (RVOT) and its contribution to clinical characteristics.
Methods: Twenty-four patients with Brugada syndrome (23 men and 1 woman; 61 ± 16 years old) were studied. We assessed the presence of late potential (LP) in SAECG and the filtered QRS duration in the right precordial leads (V₁ or V₂; RfQRS) and in the left precordial leads (V₅ or V₆; LfQRS) and the difference between them. In 18 patients, SAECG was evaluated for an LP on three separate occasions.
Results: SAECG was positive for LP in 15 patients at least once; and in 7 patients, SAECG was positive for an LP on multiple occasions, and 6 of 7 patients (86%) had a history of cardiac arrest. The difference between RfQRS and LfQRS was significantly greater in patients with cardiac arrest than in patients with syncope or in asymptomatic patients; 29 ± 10, 14 ± 11 (P < 0.01), and 7 ± 5 msec (P < 0.001), respectively. All patients were alive and one patient with cardiac arrest had an appropriate VF therapy delivered by the ICD.
Conclusions: The dominant prolongation of the filtered QRS duration in the right precordial leads may be related to the risk of arrhythmic event in Brugada syndrome.     

Polymorphisms of the SHBG gene contribute to the interindividual variation of sex steroid hormone blood levels in young, middle-aged and elderly men

Objective  In men there is a large interindividual variation of SHBG levels and consequently of testosterone (T) and E₂ levels. Family and twin studies suggested a strong genetic contribution, besides metabolic and hormonal influences. The aim of this study was to examine the influence of a missense mutation in exon 8 (Asp327Asn) and a (TAAAA)_n-repeat in the promoter region of the SHBG gene, on SHBG and sex steroid serum concentrations in a population of healthy men.
Design  SHBG and hormone levels were measured in 1485 men, contributed by three independent cohort studies and representing three different age groups (young, middle-aged and elderly men). The number of TAAAA-repeats was determined by fragment-analysis; carriers of the Asn³²⁷-allele were identified using restriction fragment length polymorphism analysis.
Results  In the different age groups, carriers of six TAAAA-repeats presented with higher SHBG (young 19%, middle-aged 20% and elderly 26%; P < 0·001) and T (young 9%, middle-aged 22% and elderly 21%; P < 0·05) levels compared to non-carriers. For free T, a modest increase was found for carriers in the middle-aged group, but not for the young and elderly group. E₂ and free E₂ did not differ between carriers and non-carriers in the different age-groups. The Asn³²⁷-allele was associated with higher mean SHBG (14·20%, P  < 0·001) and T levels (7·33%; P  = 0·01) in the middle-aged group only.
Conclusions  Our findings show that and the (TAAAA)_n-repeat and the Asp327Asn polymorphism contribute to the genetically determined interindividual variation in total serum T levels in healthy men through variation in SHBG concentrations.     

Effect of interferon gamma on intrahepatic haemodynamics of the cirrhotic rat liver

Sublethal injury of the liver with carbon tetrachloride (CCI₄) induces the modulation of hepatic stellate cells to their myofibroblast (MFB) phenotype. Pretreatment or concomitant treatment with interferon gamma (IFNγ) has been shown to inhibit this phenomenon. The aim of this study was to investigate the influence of IFNγ treatment (50 000 IU s.c. each day for 5 days) in rats with an established cirrhosis. Cirrhosis was induced with nine doses of CCI⁴. Comparison of biopsies before and after treatment with IFNγ showed that the number of MFB present, identified by their α-smooth muscle actin immunoreactivity, was markedly reduced. Pressure-flow curves were constructed in isolated perfused liver preparations from IFNγ-treated and saline-treated cirrhotic rats and analysed to obtain the extrapolated zero-flow intercept (P⁰, an index of hepatic vascular distensibility) and the vasodilator-induced change in resistance at a flow rate of 1 mL/min per g (ΔR₁ an indication of the level of intrinsic vascular tone). In IFNγ-treated rats, portal venous pressure measured in vivo was significantly reduced compared with controls (11.9±1.2 vs 16.0 ± 0.5 mmHg, P < 0.05), P₀ was lower (2.03 ± 0.18 vs 2.87 ± 0.32 mmHg, P < 0.05) and ΔR₁ was decreased (0.39 ± 0.15 vs 1.02 ± 0.19 mmHg/mL per min per g, P < 0.05). The findings indicate that treatment with IFNγ is effective in reducing MFB density in established CCI₄-cirrhosis in the rat and results in a marked improvement in intrahepatic haemodynamics.