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Background: High-power, short-duration (HPSD) radiofrequency ablation (RFA) reduces procedure time; however, safety and efficacy thresholds vary with catheter design., Objective: The study sought to determine optimal HPSD ablation conditions with a novel flexible-tipped, contact force-sensing RFA catheter., Methods: RFA lesions were created in thigh muscle (16 swine) over a range of conditions (51-82 W, 2-40 g, 8-40 mL/min irrigation). An intracardiac study was performed (12 swine) to characterize steam pop thresholds. Lesions were created in a second intracardiac study (14 swine, n = 290 pulmonary vein isolation [PVI] lesions) with combinations of radiofrequency power, duration, and contact force. PVI was tested, animals were sacrificed, and lesions were measured., Results: The likelihood of coagulation formation in the thigh model was <20% when power was ≤79 W, when contact force was ≤40 g, when duration was ≤11 seconds, and when irrigation rates were 8 to 40 mL/min. The impact of contact force on lesion safety and efficacy was more pronounced using HPSD (60 W/8 seconds) compared with conventional ablation (30 W/45 seconds) ( P = .038). During PVI, focal atrial lesions ranged in width from 4.2 to 12.5 mm and were transmural 80.8% of the time. PVI was achieved in 13 of 14 veins. Logistic regression identified that the optimal parameters for radiofrequency application were 60 to 70 W with a duration <8 seconds and <15 g contact force., Conclusions: Optimal HPSD lesions with this this flexible-tipped, force-sensing RFA catheter were created at 60 to 70 W for <8 seconds with <15 g contact force. Chronic studies are ongoing to assess radiofrequency parameter refinements and long-term lesion durability using these conditions., (© 2023 Heart Rhythm Society. Published by Elsevier Inc.)

Background: High-power, short-duration (HPSD) radiofrequency ablation (RFA) may reduce ablation time. Concerns that catheter-mounted thermocouples (TCs) can underestimate tissue temperature, resulting in elevated risk of steam pop formation, potentially limit widespread adoption of HPSD ablation., Objective: The purpose of this study was to compare the safety and efficacy of HPSD and low-power, long-duration (LPLD) RFA in the context of pulmonary vein isolation (PVI)., Methods: An open-irrigated ablation catheter with a contact force sensor and a flexible-tip electrode containing a TC at its distal end (TactiFlex TM Ablation Catheter, Sensor Enabled TM , Abbott) was used to isolate the left pulmonary veins (PVs) in 12 canines with HPSD RFA (50 W for 10 seconds) and LPLD RFA (30 W for a maximum of 60 seconds). PVI was assessed at 30 minutes and 28 ± 3 days postablation. Computed tomographic scans were performed to assess PV stenosis after RFA. Lesions were evaluated with histopathology., Results: A total of 545 ablations were delivered: 252 with LPLD (0 steam pops) and 293 with HPSD RFA (2 steam pops) ( P = .501). Ablation time required to achieve PVI was >3-fold shorter for HPSD than for LPLD RFA ( P = .001). All 24 PVs were isolated 30 minutes after ablation, with 12/12 LPLD-ablated and 11/12 HPSD-ablated PVs still isolated at follow-up. Histopathology revealed transmural ablations for HPSD and LPLD RFA. No major adverse events occurred., Conclusion: An investigational ablation catheter effectively delivered RFA lesions. Ablation time required to achieve PVI with HPSD with this catheter was >3-fold shorter than with LPLD RFA., (© 2022 Heart Rhythm Society. Published by Elsevier Inc.)

Objective: Sham-controlled trials provided proof-of-principle for the blood pressure-lowering effect of catheter-based renal denervation (RDN). However, indicators for the immediate assessment of treatment success are lacking. This study sought to investigate the impact of RDN on renal renin arteriovenous difference (renal renin AV-Δ) following a hypotensive challenge (HC)., Methods: Twelve hypertensive Ossabaw swine underwent either combined surgical and chemical (n = 3) or catheter-based RDN (n = 9). A telemetry monitor was implanted to acquire hemodynamic data continuously. Before and after RDN, a sodium nitroprusside-induced HC was performed. Renal renin AV-Δ was calculated as the difference of plasma renin concentrations drawn from the renal artery and vein., Results: In total, complete renal renin AV data were obtained in eight animals at baseline and six animals at baseline and 3 months of follow-up. Baseline renal renin AV-Δ correlated inversely with change in 24-h minimum systolic (- 0.764, p = 0.02), diastolic (r = - 0.679, p = 0.04), and mean (r = - 0.663, p = 0.05) blood pressure. In the animals with complete renin secretion data at baseline and follow-up, the HC increased renal renin AV-Δ at baseline, while this effect was attenuated following RDN (0.55 ± 0.34 pg/ml versus - 0.10 ± 0.16 pg/ml, p = 0.003). Renin urinary excretion remained unchanged throughout the study (baseline 0.286 ± 0.187 pg/ml versus termination 0.305 ± 0.072 pg/ml, p = 0.789)., Conclusion: Renin secretion induced by HC was attenuated following RDN and may serve as an indicator for patient selection and guide successful RDN procedures., (© 2020. The Author(s).)

Background: Although lesion transmurality is required for durable pulmonary vein isolation, excess ablation is associated with increased risk of complications., Objective: We sought to understand the impact of interrupted radiofrequency (RF) delivery conditions on lesion characteristics in the atrial free wall., Methods: Thirty-three (11 left atrial, 22 right atrial) RF ablation lesions were created in the atria of 6 swine using power control mode (25 W, target contact force 15 g) with 1 of 3 conditions: 15 seconds ablation (n = 8), 30 seconds ablation (n = 14), or 2 15-second ablations at the same site separated by a 2-minute interruption (15 seconds × 2) (n = 11)., Results: Thirty of 33 lesions were transmural. Rates of transmurality ( P = .45) and endocardial lesion width (5.6 ± 1.2 mm, P = .70) were similar between conditions. Mean tissue thickness was 1.7 ± 0.8 mm for transmural lesions. Wide variability in bipolar electrogram attenuation was observed across and within conditions and there were no significant between-group differences. Although impedance reductions were numerically greater in the 30-second and 15-second × 2 conditions (-14.6 ± 6.6 ohms and -14.0 ± 4.4 ohms, respectively) compared to the 15-second condition (-10.3 ± 6.4 ohms), variability was large, and differences were not statistically significant ( P = .243). Impedance changes after ablation were largely transient., Conclusion: A single 15-second ablation at 25 W (target contact force of 15 g) with good stability produced similarly sized lesions compared to 30-second ablations and 2 15-second ablations at the same site in atrial free wall tissue. These data suggest over-ablation in the atria is common, larger-diameter lesions may require greater power, and many clinically available parameters of lesion size may be unreliable on the posterior wall.

Background: Irreversible electroporation (IRE) is a nonthermal ablation modality. A 200-J application can create deep myocardial lesions, but gas bubbles are created at the ablation electrode. Cerebral effects of these bubbles are unknown., Objective: The purpose of this study was to investigate gas microemboli-induced brain lesions after IRE and radiofrequency (RF) ablation to the left side of the canine heart, using magnetic resonance imaging (MRI) and histopathology., Methods: In 11 canines, baseline cerebral MRI scans were performed. In 9 animals, after retrograde femoral artery access, 12 ± 4 200-J IRE applications were administered in the ascending aorta. In 2 animals, 30 minutes of irrigated 30-W RF ablation using 10-30g of contact force was applied in the left ventricle. At days 1 and 5 after ablation, MRI was repeated. The brain tissue then was histopathologically examined., Results: All ablations and follow-up were uneventful. Intracardiac echography confirmed gas bubble formation after each IRE application. Neurologic examination was normal. MRI scans were normal in all animals at day 1 and were normal in 10 of 11 animals at day 5. In 1 animal, a single <2-mm-diameter lesion in the right temporal region could not be excluded as a small infarct or early hemorrhagic site. Histopathologic analysis of the same region showed no pathologic changes. In all other animals, gross and microscopic pathology were normal., Conclusion: MRI images alone or in combination with histologic follow-up did not reveal treatment-related embolic events. Gross and microscopic pathology did not reveal evidence of treatment-related embolic events. IRE seems to be a safe ablation modality for the brain., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

[Figure: see text].

Background: During catheter ablation, delivery of radiofrequency (RF) energy to a target site is sometimes interrupted by catheter instability and clinical factors. The impact of interruption of RF delivery on lesion characteristics has not been characterized., Objective: The purpose of this study was to determine the impact of interruption of RF application on lesion size., Methods: Forty-two RF ablation lesions (21 left ventricle, 21 right ventricle) were created in the ventricles of 6 swine using power control mode (30 W; target contact force 15g) with 1 of 3 conditions: 15-second ablation (15s), 30-second ablation (30s), or two 15-second ablations (15s×2) at the same site separated by a 2-minute pause., Results: Lesion volume was significantly larger for 30s lesions (501 ± 146 mm 3 ) compared to both 15s×2 (314 ± 98 mm 3 ) and 15s (242 ± 104 mm 3 ) lesions (P <.001 for both pairwise comparisons). Compared to 15s lesions, lesion volume was numerically greater for 15s×2 lesions, but this did not reach statistical significance (P = .087). Differences in lesion volume between 30s and 15s×2 lesions were driven mainly by differences in lesion width (10.7 ± 1.1 mm vs 9.1 ± 1.7 mm; P = .04) rather than depth (9 ± 1.2 mm vs 8.4 ± 1.2 mm; P = .29). There were no differences in mean contact force by group. There was no difference in total force-time integral for the 30s and 15s×2 lesion groups [median 444 (interquartile range 312) g∙s vs 380 (164) g∙s; P = 1]., Conclusion: Compared to lesions resulting from continuous RF ablation, lesions resulting from interrupted ablation have a smaller overall lesion volume, predominantly due to smaller lesion width. These data suggest that if disruption in energy delivery occurs, lesions may need closer spacing to avoid gaps., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: Anatomic placement of lesions may impact efficacy of radio-frequency (RF) catheter renal denervation (RDN). However, it is unclear if it is necessary to perform treatments post bifurcation with systems that may provide deeper penetration to achieve successful RDN., Methods: Sixteen domestic swine (n=16) were randomly assigned to 4 groups: 1) 8 lesions created in the branch arteries using the Spyral catheter (SP8); 2) 8 lesions created in the branch arteries plus 4 lesions created in the main artery using the SP catheter (SP12); 3) 8 lesions created in the main artery using the EnligHTN catheter with the distal position as close as possible to the bifurcation (EN8); and 4) 12 lesions created in the main artery using the EN catheter with the distal position as close as possible to the bifurcation (EN12)., Results: Each arm showed statistically significant changes in kidney norepinephrine (NE, ng/g) between treated kidneys vs. untreated contralateral control. There were no statistically significant differences in tissue NE% reductions across each arm based on catheter, anatomic location, & number of lesions (p=0.563): EN8 -74±34%, EN12 -95±3%, SP8 -76±16%, SP12 -82±17% (p=0.496). A total of 46 lesions were measured for lesion depth: EN main (3.3±2.8mm) vs. SP branch (2.0±1.0mm, p=0.039), SP main (2.9±1.6mm) vs. SP branch (p=0.052), and EN main vs. SP main (p=0.337)., Conclusions: Distally-focused main renal artery treatment using the EN system appears to be equally efficacious in reducing tissue NE levels compared with SP treatment in the branches plus main renal arteries, advocating for device-specific procedure execution., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Transmural lesions are essential for efficacious ablation. There are, however, no accurate means to estimate lesion depth., Objective: Explore use of the electrical coupling index (ECI) from the EnSite Contact™ System as a potential variable for lesion depth estimation., Methods: Radiofrequency (RF) ablation lesions were created in atria and the thighs of swine using an irrigated RF catheter. Power was 30 W for 20 or 30 seconds intracardiac and 30-50 W for 10-60 seconds for the thigh. Intracardiac, the percentage change in ECI during ablation was compared with transmurality and collateral damage occurrence. For the thigh model, an algorithm estimating lesion depth was derived. Factors included: power, duration, and change in the ECI subcomponents (ΔECI+) during ablation. The ΔECI+ algorithm was compared to one using power and duration (PD) alone., Results: Intracardiac, lesions with ≥12% reduction in ECI were more likely to be transmural (92.3% vs. 59.4%, P < 0.001). Twenty-second lesions were less likely to cause collateral damage compared to 30 seconds (33% vs. 70%, P = 0.003), while transmurality was similar. With the thigh model, ΔECI+ had a better correlation than the PD algorithm (P < 0.01). Accuracy of the ΔECI+ algorithm was unimproved with inclusion of tip orientation, while PD improved (R(2) = 0.64)., Discussion: Change in ECI provides evidence of transmural versus nontransmural swine intracardiac atrial lesions. A lesion depth estimation algorithm using ECI subcomponents is unaffected by tip orientation and is more accurate than using PD alone., Conclusion: Use of ECI as a factor in a lesion depth algorithm may provide clinically valuable information regarding the efficacy of intracardiac RF ablation lesions., (© 2010 Wiley Periodicals, Inc.)

This Point/Counterpoint presents a scholarly debate of the mechanisms underlying the electrocardiographic and arrhythmic manifestations of Brugada syndrome (BrS), exploring in detail the available evidence in support of the repolarization vs. depolarization hypothesis., (Copyright 2010 Elsevier Ltd. All rights reserved.)

We consider the isotropic-to-nematic transition in liquid crystals confined to aerogel hosts, and assume that the aerogel acts as a random field. We generally find that self-averaging is violated. For a bulk transition that is weakly first order, the violation of self-averaging is so severe that even the correlation length becomes non-self-averaging: no phase transition remains in this case. For a bulk transition that is more strongly first order, the violation of self-averaging is milder, and a phase transition is observed.

Computer simulations are presented of the isotropic-to-nematic transition in a liquid crystal confined between two parallel plates a distance H apart. The plates are neutral and do not impose any anchoring on the particles. Depending on the shape of the pair potential acting between the particles, we find that the transition either changes from first order to continuous at a critical film thickness H=H(x) , or that the transition remains first order irrespective of H . This demonstrates that the isotropic-to-nematic transition in confined geometry is not characterized by any universality class, but rather that its fate is determined by microscopic details. The resulting capillary phase diagrams can thus assume two topologies: one where the isotropic and nematic branches of the binodal meet at H=H(x), and one where they remain separated. For values of H where the transition is strongly first order the shift Deltaepsilon of the transition temperature is in excellent agreement with the Kelvin equation. Not only is the relation Deltaepsilon proportional, variant 1/H recovered but also the prefactor of the shift is in quantitative agreement with the independently measured bulk latent heat and interfacial tension.

Introduction: T-wave alternans (TWA) is characterized by beat to beat alteration in the amplitude, polarity and/or morphology of the electrocardiographic T wave. TWA has been reported in patients with the Brugada syndrome (BS) and is thought to be associated with an increased risk for development of VT/VF. The cellular mechanisms involved are not well-defined and are the subject of this investigation., Methods: In an experimental model of BS composed of an arterially perfused canine right ventricular wedge preparation pretreated with verapamil (1-7 microM), an agent with sodium and calcium channel blocking activity, we simultaneously recorded transmembrane action potentials from two epicardial and one endocardial site, together with a pseudo-ECG. At select frequencies, verapamil induced alternans of both the T-wave amplitude and QT interval. The alternans resulted from either loss of the epicardial action potential dome on alternate beats or concealed phase 2 reentry within the epicardium on alternate beats. Loss of the epicardial action potential dome significantly increased transmural dispersion of repolarization (TDR) when compared with control (18.0 +/- 7.8 ms vs. 82.1 +/- 16.8 ms, P < 0.001, n = 8). During alternans, TDR was greater in beats displaying a more negative T wave (55.1 +/- 45.2 ms vs. 89.8 +/- 39.3 ms, P < 0.001, n = 22 data points from 8 preparations)., Conclusions: Our data indicate that TWA in an experimental model of the Brugada syndrome is due to alternating loss of the epicardial AP dome and/or concealed phase 2 reentry, both serving to increase TDR and create the substrate for the development VT/VF.

The Brugada syndrome is a congenital syndrome of sudden cardiac death first described as a new clinical entity in 1992. Electrocardiographically characterized by a distinct coved-type ST segment elevation in the right precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young and otherwise healthy adults, and less frequently in infants and children. The ECG manifestations of the Brugada syndrome are often dynamic or concealed and may be revealed or modulated by sodium channel blockers. The syndrome may also be unmasked or precipitated by a febrile state, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, and hypokalemia, as well as by alcohol and cocaine toxicity. An implantable cardioverter-defibrillator (ICD) is the most widely accepted approach to therapy. Pharmacological therapy aimed at rebalancing the currents active during phase 1 of the right ventricular action potential is used to abort electrical storms, as an adjunct to device therapy, and as an alternative to device therapy when use of an ICD is not possible. Isoproterenol and cilostazol boost calcium channel current, and drugs like quinidine inhibit the transient outward current, acting to diminish the action potential notch and thus suppress the substrate and trigger for ventricular tachycardia/fibrillation (VT/VF).

Resynchronization therapy involving right ventricular endocardial and left ventricular epicardial pacing improves cardiac output, quality of life, and New York Heart Association functional class in patients with congestive heart failure. Although a great deal of attention has been directed at showing the mechanical benefits and in fine-tuning the biventricular pacing configuration and protocol, little attention has been focused on the consequences of reversing the direction of activation of the left ventricular wall. Recent basic science and clinical studies have shown a proarrhythmic effect of reversing the direction of activation of the left ventricular wall. Reversal of the normal activation sequence prolongs the QT interval and increases the existing transmural dispersion of repolarization, creating the substrate and trigger for re-entrant arrhythmias under long QT conditions. A number of case reports of R-on-T extrasystoles and ventricular tachyarrhythmia induction as a result of biventricular pacing support this observation, and raise concern that biventricular pacing may be proarrhythmic in select cases, particularly when associated with a prolonged QT interval. Our focus in this review is on current understanding of transmural heterogeneity of repolarization that exists across the left ventricular wall, how this dispersion of repolarization is amplified as a consequence of reversal of the normal activation sequence, and how these basic experimental findings may apply to patients receiving cardiac resynchronization therapy.

Introduction: ST-Segment elevation is a common electrocardiogram (ECG) manifestation of acute transmural myocardial ischemia in leads facing the injury. Acute myocardial ischemia involving the right-ventricular (RV) outflow tract is known to induce a Brugada-like ECG. In this paper, we examined the electrophysiological bases for the similarities between the ECG characteristics of the Brugada syndrome model induced by terfenadine (5 mumol/L) and the ECG manifestations of the acute transmural no-flow ischemia model., Methods: For both experimental simulations, we used isolated arterially perfused canine RV wedge preparations to record transmembrane action potentials (AP) from endocardium and epicardium together with a transmural pseudo-ECG (ECG); basic cycle length=400 to 2000 ms., Results: In the presence of a prominent Ito-mediated AP notch, no-flow ischemia causes true ST-segment elevation because of selective depression and loss of the AP dome at some epicardial sites. In the absence of a prominent AP notch, ischemia ultimately produces an apparent ST-segment elevation, which is secondary to a prolongation of the R wave caused by marked transmural conduction delays. Similarly, in the Brugada syndrome model generated in preparations displaying a large epicardial Ito, ST-segment elevation was due to loss of the epicardial AP dome at some sites but not at others. Transmural conduction delay giving the appearance of ST-segment elevation is also observed in the Brugada model in preparations exhibiting smaller AP notch. In both models, propagation of the dome from the site at which it is maintained to a site at which it is lost may result in closely coupled phase 2 reentrant extrasystoles., Conclusion: Our results suggest that Ito can modulate the electrocardiographic manifestation of acute ischemia as well as that of the Brugada syndrome, and that both clinical entities are the result of a similar electrophysiological substrate.

Ranolazine is a novel antianginal agent capable of producing anti-ischemic effects at plasma concentrations of 2 to 6 microM without a significant reduction of heart rate or blood pressure. This review summarizes the electrophysiologic properties of ranolazine. Ranolazine significantly blocks I(Kr) (IC(50) = 12 microM), late I(Na), late I(Ca), peak I(Ca), I(Na-Ca) (IC(50) = 5.9, 50, 296, and 91 microM, respectively) and I(Ks) (17% at 30 microM), but causes little or no inhibition of I(to) or I(K1). In left ventricular tissue and wedge preparations, ranolazine produces a concentration-dependent prolongation of action potential duration (APD) in epicardium, but abbreviation of APD of M cells, leading to either no change or a reduction in transmural dispersion of repolarization (TDR). The result is a modest prolongation of the QT interval. Prolongation of APD and QT by ranolazine is fundamentally different from that of other drugs that block I(Kr) and induce torsade de pointes in that APD prolongation is rate-independent (ie, does not display reverse rate-dependent prolongation of APD) and is not associated with early after depolarizations, triggered activity, increased spatial dispersion of repolarization, or polymorphic ventricular tachycardia. Torsade de pointes arrhythmias were not observed spontaneously nor could they be induced with programmed electrical stimulation in the presence of ranolazine at concentrations as high as 100 microM. Indeed, ranolazine was found to possess significant antiarrhythmic activity, acting to suppress the arrhythmogenic effects of other QT-prolonging drugs. Ranolazine produces ion channel effects similar to those observed after chronic exposure to amiodarone (reduced late I(Na), I(Kr), I(Ks), and I(Ca)). Ranolazine's actions to reduce TDR and suppress early after depolarization suggest that in addition to its anti-anginal actions, the drug possesses antiarrhythmic activity.

Background: Ranolazine is a novel antianginal agent capable of producing antiischemic effects at plasma concentrations of 2 to 6 micromol/L without reducing heart rate or blood pressure. The present study examines its electrophysiological effects in isolated canine ventricular myocytes, tissues, and arterially perfused left ventricular wedge preparations., Methods and Results: Transmembrane action potentials (APs) from epicardial and midmyocardial (M) regions and a pseudo-ECG were recorded simultaneously from wedge preparations. APs were also recorded from epicardial and M tissues. Whole-cell currents were recorded from epicardial and M myocytes. Ranolazine inhibited I(Kr) (IC50=11.5 micromol/L), late I(Na), late I(Ca), peak I(Ca), and I(Na-Ca) (IC50=5.9, 50, 296, and 91 micromol/L, respectively) and I(Ks) (17% at 30 micromol/L), but caused little or no inhibition of I(to) or I(K1). In tissues and wedge preparations, ranolazine produced a concentration-dependent prolongation of AP duration of epicardial but abbreviation of that of M cells, leading to reduction or no change in transmural dispersion of repolarization (TDR). At [K+]o=4 mmol/L, 10 micromol/L ranolazine prolonged QT interval by 20 ms but did not increase TDR. Extrasystolic activity and spontaneous torsade de pointes (TdP) were never observed, and stimulation-induced TdP could not be induced at any concentration of ranolazine, either in normal or low [K+]o. Ranolazine (5 to 20 micromol/L) suppressed early afterdepolarizations (EADs) and reduced the increase in TDR induced by the selective I(Kr) blocker d-sotalol., Conclusions: Ranolazine produces ion channel effects similar to those observed after chronic amiodarone (reduced I(Kr), I(Ks), late I(Na), and I(Ca)). The actions of ranolazine to suppress EADs and reduce TDR suggest that, in addition to its antianginal actions, the drug may possess antiarrhythmic activity.

Objective: We hypothesized that a combination of I(Na) and I(Ca) blockade may be more effective in causing loss of the epicardial action potential (AP) dome and precipitating the Brugada syndrome (BS). The present study was designed to test this hypothesis in an in vitro model of BS., Background: The Brugada syndrome is characterized by an ST segment elevation in the right precordial ECG leads and a high risk of sudden death. The ECG sign of BS is often concealed, but can be unmasked with potent sodium channel blockers. Using canine right ventricular (RV) wedge preparations, we previously developed an experimental model of BS using flecainide to depress the AP dome in RV epicardium., Methods: Intracellular APs and a transmural ECG were simultaneously recorded from canine RV wedge preparations., Results: Terfenadine (5-10 microM)-induced block of I(Ca) and I(Na) caused heterogeneous loss of the epicardial AP dome, resulting in ST segment elevation, phase 2 reentry (12/16), and spontaneous polymorphic VT/VF (6/16). Flecainide (

Background: Epicardial pacing of the left ventricle (LV) has been shown to prolong the QT interval and predispose to the development of torsade de pointes arrhythmias. The present study examines the cellular basis for QT prolongation and arrhythmogenesis after reversal of the direction of activation of the LV wall., Methods and Results: A transmural ECG and transmembrane action potentials were simultaneously recorded from epicardial, M, and endocardial cells of arterially perfused canine LV wedge preparations. QT interval increased from 297.6+/-3.9 to 314.0+/-5.7 ms (n=12; P<0.001) and transmural dispersion of repolarization (TDR) increased from 35.5+/-5.2 to 70.3+/-6.2 ms (n=12; P<0.001) as pacing was shifted from endocardium to epicardium. Conduction time between M and epicardial cells increased from 12.1+/-1.2 to 24.2+/-1.5 ms (n=12; P<0.001). Amplification of TDR was further accentuated in the presence of rapidly activating delayed rectifier potassium current blockers (E-4031 and cisapride), increasing from 50.5+/-7.6 to 86.1+/-6.2 ms (n=8; P<0.01). Torsade de pointes arrhythmias could be induced during epicardial, but not endocardial, pacing of LV in the presence of rapidly activating delayed rectifier potassium current blockade., Conclusions: Reversal of the direction of activation of the LV wall, as occurs during biventricular pacing, leads to a prominent increase in QT and TDR as a result of earlier repolarization of epicardium and delayed activation and repolarization of the midmyocardial M cells. The increase in TDR creates the substrate for the development of torsade de pointes under long-QT conditions.

Unlabelled: The Brugada syndrome (BS) has been linked to mutations in SCN5A. Despite equal hereditary transmission of the mutation between the sexes, the syndrome is 8 to 10 times more likely to occur in males. As recently reported, SCN5A mutations such as G1406R lead to development of BS phenotype principally in males and conduction disease phenotype in females. We hypothesized that these differences may be related to a larger transient outward current (Ito)-mediated right ventricular (RV) epicardial (Epi) action potential (AP) notch in males versus females, resulting in a higher incidence of all-or-none repolarization at the end of phase 1 and phase 2 re-entry (P2R) when challenged with sodium and calcium channel block. Using canine RV wedge preparations, we developed an experimental model of the BS using terfenadine to depress the AP dome in RV Epi., Results: RV Epi AP phase 1 amplitude corrected to phase 2 amplitude was 12% smaller in males (n=18) compared to females (n=8, P<.05) at a cycle length of 2,000 ms. When exposed to 5 microM terfenadine for up to 2 hours, 6 of 7 male but only 2 of 7 female preparations exhibited spontaneous P2R, generating a closely coupled extrasystole. Two of 6 male and 1 of 2 female preparations displaying P2R developed polymorphic VT/VF. Female and male preparations that failed to develop P2R displayed progressive conduction impairment with continued exposure to terfenadine and developed polymorphic and monomorphic VT/VF when paced at rapid rates. Male preparations pretreated with 4-aminopyridine to inhibit Ito displayed progressive conduction impairment but not Brugada syndrome., Conclusion: Our data suggest that the presence of a more prominent Ito-mediated notch in the Epi of males predisposes males to the development of the Brugada phenotype and that a smaller Epi notch in females relegates them to development of progressive conduction problems under conditions in which inward currents are compromised.

Background: The Brugada syndrome displays an autosomal dominant mode of transmission with low penetrance. Despite equal genetic transmission of the disease, the clinical phenotype is 8 to 10 times more prevalent in males than in females. The basis for this intriguing sex-related distinction is unknown. The present study tests the hypothesis that the disparity in expression of the Brugada phenotype is a result of a more prominent I(to)-mediated action potential notch in the right ventricular (RV) epicardium of males versus females., Methods and Results: We studied epicardial tissue slices, arterially perfused wedge preparations, and dissociated epicardial myocytes isolated from male and female canine hearts. RV epicardium action potential phase 1 amplitude was 64.8+/-2.0% of that of phase 2 in males compared with 73.8+/-4.4% in females (P<0.05) at a cycle length of 2000 ms. I(to) density was 26% smaller and time constant for inactivation 17% smaller at +40 mV in female versus male RV epicardial cells (P<0.05). The other functional characteristics of I(to), including the voltage dependence of inactivation and time course of reactivation, were no different between the sexes. Pinacidil caused loss of action potential dome in male, but not female, RV epicardial tissue slices. Terfenadine (5 micromol/L) induced phase 2 reentry in 6 of 7 male but only 2 of 7 female arterially perfused wedge preparations. Two of 6 male and 1 of 2 female preparations developed polymorphic ventricular tachycardia/ventricular fibrillation., Conclusions: Our results suggest that the predominance of the Brugada phenotype in males is a result of the presence of a more prominent I(to) in males versus females.

History of the tripodal mandibular subperiosteal implant and the evolution of its design are discussed. Basic principles of bone physiology are reviewed especially as they relate to bone response to loading. Modeling and remodeling are controlled by a strain-related environment. Modeling can alter the shape and volume of bone. This aspect of bone growth has been reported with transosteal implants. A case report is presented in which apparent bone growth occurred following placement of a hydroxylapatite-coated subperiosteal implant. The implant was successfully revised following an acute infection around one of the permucosal sites.

To define whether capillary permeability traits at the site of a burn differ according to injury severity, a canine hind leg lymphatic was cannulated to measure macromolecular permeability in response to three different scalding solutions. Leg venous pressure was raised to approximately 40 mm Hg and maintained until a minimal lymph-to-plasma total protein ratio (CL/CP)min and steady-state lymph flow (QL; microliter/min/100 g) was attained. The protein reflection coefficient (1-CL/CP), fluid filtration coefficient (Kf; microliter/min/mm Hg/100 g), and QL were determined before and for 6 hr after a 5-sec hind paw immersion in either 100 degrees C (n = 7), 80 degrees C (n = 7), or 70 degrees C (n = 7) water. A group of five animals served as controls. In the absence of any systemic hemodynamic alterations, the 100 and 80 degrees C scald groups experienced significant (P < 0.05, ANOVA) increases in QL, CL/CP, and Kf as compared to respective preburn values and time-matched unburned control values. Most monitored parameters were significantly higher following 100 degrees C injury vs 80 degrees C injury. Parameters in the 70 degrees C group did change after scald, but were not significantly different from preburn values or from the control group. Alterations in capillary permeability to protein and fluid flux measured at the burn site are graded, not all or none phenomena, being dependent upon the severity of injury.

Background: Pentafraction is a pentastarch derivative hypothesized to limit burn edema by "sealing" damaged capillaries, restoring a barrier to fluid translocation and macromolecular (protein) flux., Methods: Canine hind paw lymph flow (QL) and lymph (CL) and plasma (CP) protein concentrations were measured before and for 6 hours after (1) 5-second 100 degrees C (n = 6) or 80 degrees C (n = 6) foot paw scald, (2) 100 degrees C (n = 5) or 80 degrees C (n = 5) foot paw scald followed 30 minutes later by a 4 cc/kg bolus of 6% pentafraction, or (3) pentafraction infusion without scald (n = 5). Before scald or pentafraction infusion, hind paw venous pressure was elevated and maintained by outflow restriction until a steady state, minimal CL/CP was reached. The reflection coefficient, sigma d, was determined as 1-CL/CP, and the (fluid) filtration coefficient (Kf) was calculated., Results: Scalding uniformly produced statistical (p < 0.05, ANOVA) increases in QL, CL/CP, sigma d, Kf, and paw weight gain. Postburn pentafraction infusion produced no enduring alterations in any measured parameter as compared with those of animals who received a matched severity scald without pentafraction., Conclusions: Pentafraction does not appreciably ameliorate the adverse microcirculatory consequences observed at the site of burn injury.

Dexamethasone exerted tissue-specific effects on rat vitamin D receptor levels: upregulation of receptors in intestine, downregulation in kidney, and no effect on receptors in testis, heart, and lung. Scatchard analysis showed selective downregulation of the low affinity receptor site (Kd = 0.9 nM) in kidney, thus unmasking a high affinity binding site (Kd = 0.05 nM). The single low affinity site in intestine (Kd = 0.3-0.7 nM) was upregulated, while the single high affinity site in testis (Kd = 0.07-0.09 nM) was not changed. These results demonstrate the existence of two types of nuclear binding sites in rat kidney and establish that there are similarities between the high affinity binding site in the rat kidney and the single high affinity receptor site in the testis.

Ozone is an oxidizing agent possessing potent in vitro microbicidal capacity. This study was designed to address the extent to which irrigation of the contaminated abdominal cavity using a saline solution primed with ozone is effective in reducing morbidity and mortality. Gelatin capsules containing different quantities of a premixed slurry of filtered human fecal material were implanted in the peritoneal cavities of a preliminary series of rats. Three inocula concentrations were selected for later experiments, based upon their ability to produce morbid consequences: (1) high (100% 1-day mortality), (2) medium (70% 3-day mortality, 100% abscess rate in survivors), and (3) low (100% 10-day survival, 100% abscess rate). Fecal and abscess bacteriology were similar in all rats. The peritoneal cavities of 240 rats then underwent fecal-capsule implantation (three groups of 80 rats/inoculum concentration). At celiotomy 4 hours later, equal numbers of rats from each group were randomly assigned to one of four protocols: (1) no irrigation, (2) normal saline irrigation, (3) saline-cephalothin irrigation, and (4) ozonated saline irrigation. Each treatment lasted 5 minutes, using 100 ml of irrigation fluid. Mortality was significantly reduced when, in lieu of no irrigation, any of the irrigation solutions were used. Additionally, ozonated saline statistically proved the most effective irrigating solution for reducing abscess formation in survivors.

This study correlated the Canter's Background Interference Procedure (BIP) scores of 141 adult epileptics with the five variables of age at onset of symptoms, etiology, type of symptoms, severity of generalized background dysrhythmia, and locus of lesion. These variables did not correlate significantly with the BIP scores, contrary to expectations. The BIP's nearly 50% false negative rate was much higher than that of the Trail Making Test, using either Reitan's or Russell's cutting scores for Trails A (33% and 21%, respectively) or Trails B (35% and 28.5%, respectively). The BIP often does not agree with abnormal neurological diagnoses, but often does agree with psychiatric diagnoses of Organic Brain Syndrome (OBS). The authors argue that this is due to the BIP's normative history and to its sensitivity to organic concreteness. The authors suggest that future BIP validity studies include a behavioral measure of OBS as criterion.