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AIMS/HYPOTHESIS: Opening of ATP-sensitive potassium (K(ATP)) channels during myocardial ischaemia shortens action potential duration and is believed to be an adaptive, energy-sparing response. Thiazolidinedione drugs block K(ATP) channels in non-cardiac cells in vitro. This study determined whether thiazolidinedione drugs block cardiac K(ATP) channels in vivo. METHODS: Experiments in 68 anaesthetised pigs determined: (1) effects of inert vehicle, troglitazone (10 mg/kg i.v.) or rosiglitazone (0.1 or 1.0 mg/kg i.v.) on epicardial monophasic action potential (MAP) during 90 min low-flow ischaemia; (2) effects of troglitazone, rosiglitazone or pioglitazone (1 mg/kg i.v.) on response of MAP to intracoronary infusion of a K(ATP) channel opener, levcromakalim; and (3) effects of inert vehicle, rosiglitazone (1 mg/kg i.v.) or the sarcolemmal K(ATP) blocker HMR-1098 on time to onset of ventricular fibrillation following complete coronary occlusion. RESULTS: With vehicle, epicardial MAP shortened by 44+/-9 ms during ischaemia. This effect was attenuated to 12+/-8 ms with troglitazone and 6+/-6 ms with rosiglitazone (p<0.01 for both vs vehicle), suggesting K(ATP) blockade. Intracoronary levcromakalim shortened MAP by 38+/-10 ms, an effect attenuated to 12+/-8, 13+/-4 and 9+/-5 ms during co-treatment with troglitazone, rosiglitazone or pioglitazone (p<0.05 for each), confirming K(ATP) blockade. During coronary occlusion, median time to ventricular fibrillation was 29 min in pigs treated with vehicle and 6 min in pigs treated with rosiglitazone or HMR-1098 (p<0.05 for both vs vehicle), indicating that K(ATP) blockade promotes ischaemic ventricular fibrillation in this model. CONCLUSIONS/INTERPRETATION: Thiazolidinedione drugs block cardiac K(ATP) channels at clinically relevant doses and promote onset of ventricular fibrillation during severe ischaemia.

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The Medtronic Jewel PCD model 7219, introduced in 1994, was the first downsized, pectoral implantable cardioverter defibrillator (ICD), and many of these units are approaching or have reached the elective replacement indicator (ERI). Unlike later Medtronic ICDs and most other ICDs, in which ERI is defined by battery voltage, the ERI in the model 7219 series is defined when either the capacitor charge time to full output is repeatedly> or =14.5 s or when battery voltage is< or =4.91 V. In this study we examined which of the two ERI criteria was met first in patients with this device model. We also assessed the effects of manual dumping and recharging and of increasing the automatic capacitor reformation frequency on prolonged charge times. In 16 patients with follow-up <2 years, 15 reached the charge time ERI before battery voltage ERI. Manual dumping and recharging led to spuriously low charge times due to residual charge at the start of recharging, and increasing the automatic capacitor reformation frequency to once a month did not decrease prolonged charge times. Because of persistently prolonged charge times, 15 patients had generator changes. None of these patients had reached battery voltage ERI (battery voltage at time of explantation 5.06+/-0.06 V). Thus in this early pectoral device, prolonged charge times occur commonly before battery voltage ERI is reached. Whether prolonged charge times will have an impact on device longevity in later model ICDs is unknown.

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R-848 and imiquimod belong to a class of immune response modifiers that are potent inducers of cytokines, including IFN-alpha, TNF-alpha, IL-12, and IFN-gamma. Many of these cytokines can affect the acquired immune response. This study examines the effects of R-848 on aspects of acquired immunity, including immunoglobulin secretion, in vivo cytokine production, and Ag-specific T cell cytokine production. Results are compared with those of Th1 CpG ODN. R-848 and CpG ODN are effective at skewing immunity in the presence of Alum toward a Th1 Ab response (IgG2a) and away from a Th2 Ab response (IgE). R-848 and CpG ODN are also capable of initiating an immune response in the absence of additional adjuvant by specifically enhancing IgG2a levels. Both R-848 and imiquimod showed activity when given subcutaneously or orally, indicating that the compound mechanism was not through generation of a depot effect. Although CpG ODN behaves similarly to R-848, CpG ODN has a distinct cytokine profile, is more effective than R-848 when given with Alum in the priming dose, and is active only when given by the same route as the Ag. The mechanism of R-848's adjuvant activity is linked to cytokine production, where increases in IgG2a levels are associated with IFN-alpha, TNF-alpha, IL-12, and IFN-gamma induction, and decreases in IgE levels are associated with IFN-alpha and TNF-alpha. Imiquimod also enhances IgG2a production when given with Ag. The above results suggest that the imidazoquinolines R-848 and imiquimod may be attractive compounds for use as vaccine adjuvants and in inhibiting pathological responses mediated by Th2 cytokines.

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Imiquimod (also known as R-837 and S-26308) is an imidazoquinoline immune response modifier and is available in the US and several other countries for the treatment of external genital warts. Imiquimod has no direct antiviral activity but demonstrates efficacy in several animal models of virus infection. The drug is recognized by antigen presenting cells including monocytes, macrophages, B-cells and dendritic cells and induces these cells to produce cytokines including interferon-alpha (IFN-alpha) and others. Imiquimod's ability to inhibit primary lesion development in the guinea pig model of Herpes simplex virus (HSV) intravaginal infection was studied. Imiquimod given intravaginally reduced primary lesions, reduced virus shedding and reduced virus content of spinal cords from HSV infected guinea pigs. A single drug application of 0.5 mg/kg reduced lesion frequency when given between 24 h before inoculation to 16 h after inoculation. A single drug application of 5 mg/kg reduced lesion frequency and severity when administered between 72 h before inoculation to 24 h after inoculation. The antiviral effect resulting from interferon induction in the animal lasts much longer than the drug itself, thus imiquimod is different than drugs having direct antiviral activity. Twice daily drug application for 4 days was effective when initiated up to 72 h after inoculation, however, once lesions began to appear, imiquimod treatment was not able to stop lesion development. Imiquimod treatment inhibited lesion development and/or virus shedding in guinea pigs inoculated with HSV-1, HSV-2 or virus isolates resistant to acyclovir. Imiquimod is currently in clinical trials for treating human HSV infections.

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Implantable cardioverter defibrillator undersensing leading to delayed or aborted therapy delivery has been reported with induced arrhythmias and following failed defibrillator shocks. We describe a case in which spurious redetection of sinus rhythm during a spontaneous episode of ventricular fibrillation resulted in aborted device therapy.

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OBJECTIVES: To evaluate whether use of beta-adrenergic blocking agents, alone or in combination with specific antiarrhythmic therapy, is associated with improved survival in persons with ventricular fibrillation (VF) or symptomatic ventricular tachycardia (VT). BACKGROUND: The ability of beta-blockers to alter the mortality of patients with VF or VT receiving contemporary medical management is not well defined. METHODS: Survival of 1,016 randomized and 2,101 eligible, nonrandomized patients with VF or symptomatic VT followed in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial through December 31, 1996 was assessed using Cox proportional hazards analysis. RESULTS: The 817 (28%) patients discharged from hospital receiving beta-blockers had less ventricular dysfunction, fewer symptoms of heart failure and a different pattern of medication use compared with patients not receiving beta-blockers. Before adjustment for important prognostic variables, beta-blockade was not significantly associated with survival in randomized or in eligible, nonrandomized patients treated with specific antiarrhythmic therapy. After adjustment, beta-blockade remained unrelated to survival in randomized or in eligible, nonrandomized patients treated with amiodarone alone (n = 1142; adjusted relative risk [RR] = 0.96; 95% confidence interval [CI] 0.64-1.45; p = 0.85) or a defibrillator alone (n = 1347; adjusted RR = 0.88; 95% CI 0.55 to 1.40; p = 0.58). In contrast, beta-blockade was independently associated with improved survival in eligible, nonrandomized patients who were not treated with specific antiarrhythmic therapy (n = 412; adjusted RR = 0.47; 95% CI 0.25 to 0.88; p = 0.018). CONCLUSIONS: Beta-blocker use was independently associated with improved survival in patients with VF or symptomatic VT who were not treated with specific antiarrhythmic therapy, but a protective effect was not prominent in patients already receiving amiodarone or a defibrillator.

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Capacitor charging accounts for most of the delay between arrhythmia detection and therapy delivery in ICDs. Long capacitor charge times may increase the risk of syncope in patients with poorly tolerated arrhythmias. To determine if there are clinically important differences in charge time among currently available devices, we analyzed charge times at various delivered energy levels in three manufacturers' devices: Medtronic, CPI, and Ventritex. Charge times were measured for shocks delivered for spontaneous or induced arrhythmias occurring from time of implant to 4 months after implant. A total of 343 shocks were assessed in 63 patients with ICDs: 16 Medtronic (MicroJewel II, model 7223Cx), 14 CPI (Mini II, model 1762), and 33 Ventritex (Cadet and Contour, models V-115 and V-145). The curves of the relationship between charge time and delivered energy for the three types of devices were significantly different, with Medtronic charge times shorter than CPI or Ventritex (P < 0.0001), and CPI charge times shorter than Ventritex (P = 0.002). The difference in mean charge times between the Ventritex and Medtronic devices ranged from 1.7 seconds at a delivered energy of 10 +/- 2.5 J to 8.0 seconds at a delivered energy of 30 +/- 2.5 J. Thus, clinically important differences in charge time exist among the three types of defibrillators studied. These results should be considered in selecting an ICD for patients with poorly tolerated arrhythmias.

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The purpose of this work was to develop a topical formulation of imiquimod, a novel immune response modifier, to induce local cytokine production for the treatment of external genital and perianal warts. A pH-solubility profile and titration data were used to calculate a pKa of 7.3, indicative of a weak base. Solubility experiments were conducted to identify a solvent that dissolves imiquimod to achieve a 5% formulation concentration. Studies to select surfactants, preservatives, and viscosity-enhancing excipients to formulate an oil-in-water cream indicated that fatty acids were the preferred solvent for topical imiquimod formulations, and isostearic acid (ISA) was selected. A relationship existed between the fatty acid composition of four commercially available ISA sources and the solubility of imiquimod. A combination of polysorbate 60, sorbitan monostearate, and xanthan gum was used to produce a physically stable cream. The preservative system included parabens and benzyl alcohol to meet the USP criteria for preservative activity. An in vitro method was developed to demonstrate that imiquimod was released from the formulation. Topical application of the formulation induced local cytokine activity in mice.

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Cytokines produced by antigen-presenting cells are known to affect the development and cytokine profile of T cells. The immune response modifiers imiquimod and R-848 were previously shown to stimulate human and mouse cultures to secrete interferon-alpha. Results from the present study demonstrate that R-848 and imiquimod are capable of inducing interleukin-12 and interferon-gamma in mouse and human cell cultures. Both CD4(+) and CD8(+) T lymphocytes were responsible for producing IFN-gamma following stimulation with R-848. Macrophages were required for induction of interferon-gamma by R-848 and the cytokines IFN-alpha and IL-12 mediated this response. R-848 and imiquimod were also found to inhibit IL-4 and IL-5 production in mouse and human culture systems. The inhibition of IL-5 in response to R-848 is seen in cultures containing CD4(+) lymphocytes and macrophages and is mediated in part by IFN-alpha. These data suggest that imiquimod and R-848 may have clinical utility in diseases where cell-mediated immune responses are important and in diseases associated with overexpression of IL-4 or IL-5 such as atopic disease.

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BACKGROUND: During bradycardia pacing in Ventritex Cadence (Models V-100 and V-110) implantable cardioverter-defibrillators, amplifier gain is maximal and oversensing and false tachyarrhythmia detection have been reported. Newer Ventritex devices (Cadet, Model V-115 and Contour, Model V-145) have a modified automatic gain control that may minimize oversensing. METHODS AND RESULTS: We prospectively studied 50 patients (22 with Cadence, 28 with Cadet or Contour). Electrograms were evaluated for oversensing during bradycardia pacing. The bradycardia pacing refractory period required to prevent oversensing of T waves of paced beats and the time and number of beats required to achieve minimum gain after cessation of pacing were assessed. The bradycardia pacing refractory period could be left at its default setting of 350 ms in only 15 (30%) of 50 patients. The mean bradycardia pacing refractory period required to avoid oversensing of paced T waves was 386+/-32 ms. During pacing, oversensing of nonpaced T waves was seen in 12 (24%) devices, with similar incidence in Cadence devices (18%) and Cadet and Contour devices (29%, p = not significant). The time and number of beats to achieve minimum gain after pacing were longer in Cadence devices (19.0+/-4.5 vs 4.6+/-1.2 sec; 21.3+/-3.3 vs 5.0+/-0.4 beats, both p < 0.001). CONCLUSIONS: The incidence of oversensing at maximum gain is similar in both types of devices, but more rapid changes in autogain levels in the newer devices may reduce the likelihood of false tachyarrhythmia detection.

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We report a patient who received a CPI Ventak AV II DR ICD for ventricular tachycardia and complete heart block without an escape rhythm. During induced nonsustained ventricular tachycardia, the device, although programmed to deliver noncommitted shocks, acted like a committed device. This phenomenon is due to undocumented behavior that is likely to occur in any patient who is pacemaker dependent and has nonsustained ventricular tachycardia.

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Beta blockers have traditionally been considered relatively poor antiarrhythmic agents for patients with ventricular arrhythmias. This view is based on the observations that beta blockers are less effective in suppressing spontaneous ventricular ectopy or inducible ventricular arrhythmias than are the class I and class III agents. However, there are convincing data that beta blockers can have a clinically important antiarrhythmic effect and prevent arrhythmic and sudden death. Beta blockers have multiple potential effects that can contribute to a therapeutic antiarrhythmic action, including an antiadrenergic/vagomimetic effect, a decrease in ventricular fibrillation threshold, and prevention of a catecholamine reversal of concomitant class I/III antiarrhythmic drug effects. Postinfarction trials, recent congestive heart failure studies, and observations in patients who are at risk for sustained ventricular arrhythmias all suggest a potent antiarrhythmic effect of beta blockade.

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Ischemic heart disease is the most frequent cardiac abnormality in patients with sustained or nonsustained ventricular tachyarrhythmias. The goals of therapy in such patients are to decrease the severity and incidence of symptoms and prolong life. In this article, we review the current views on antiarrhythmic drug therapy and an implantable cardioverter-defibrillator (ICD) in patients with ischemic heart disease. The importance of beta blockade as part of the therapy is emphasized. In addition, the superiority of sotalol and amiodarone over class I drugs, the benefits of combined treatment with amiodarone and a beta blocker, and the impact and limitations of current trials comparing the effectiveness of drug therapy with that of an ICD are all considered. Also discussed is the combined use of an antiarrhythmic drug and an ICD. In this approach sotalol is generally the agent of choice, with amiodarone the second choice.

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Radiofrequency catheter ablation has been used to treat idiopathic left ventricular tachycardia with high success rates. The majority of reported cases have exhibited the typical findings of right bundle branch block morphology with left axis deviation and originate from within or near the left posterior fascicle. We report a case of idiopathic left ventricular tachycardia originating from within or near the left anterior fascicle, which was successfully ablated using a local Purkinje potential as a guide.

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ALDARA (imiquimod cream 5%) recently became available for the treatment of genital and perianal warts; however, the topical mechanism of action of imiquimod is not fully understood. Imiquimod, and its analogs R-842, S-27609, and S-28463, are potent anti-viral and anti-tumor agents in animal models. Much of the biologic activity of these compounds can be attributed to the induction of cytokines, including interferon-alpha, tumor necrosis factor-alpha, interleukins-1, -6, -8, and others. This study was performed to characterize the response of mice and rats to topical application of imiquimod and S-28463 and also to evaluate these agents in cultures of murine and human skin cells. Topical administration of imiquimod or S-28463 to the flanks of hairless mice and rats leads to increases in local concentrations of interferon and tumor necrosis factor in the skin. The concentrations of interferon and tumor necrosis factor were higher at the site of drug application than in skin from the contralateral flank or skin from untreated animals. Interferon-alpha mRNA levels were also elevated in the skin of mice after topical application of either imiquimod or S-28463. In vitro, both imiquimod and S-28463 induced increases in interferon and tumor necrosis factor in cultures of cells isolated from hairless mouse skin. Imiquimod also increased interleukin-8 concentrations in human keratinocyte and fibroblast cultures, whereas S-28463 induced increases in tumor necrosis factor in fibroblast cultures. These results demonstrate that imiquimod and S-28463 stimulate production of cytokines in the skin after topical application, which may play a major role in its activity in genital wart patients.

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Spontaneous variability over time in the ease of induction of ventricular arrhythmias may mimic a drug effect and affect the predictive value of drug therapy guided by programmed stimulation. We assessed the effect of baseline reproducibility of arrhythmia induction on the incidence and accuracy of drug efficacy predictions in the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial. Patients with sustained ventricular tachyarrhythmias induced twice during baseline electrophysiologic testing with the same stimulation technique, i.e., induced at the same pacing site with the same drive cycle length and number of extrastimuli, were identified from the ESVEM database. These patients with highly reproducible arrhythmia induction were compared to those with less reproducible arrhythmias. Of 473 randomized patients with reproducibility data, 313 (66%) had highly reproducible arrhythmias. In patients randomized to electrophysiologic testing, baseline arrhythmia reproducibility did not affect the incidence of drug efficacy predictions (70 of 157 [45%], drug efficacy predictions in patients with highly reproducible arrhythmias vs 34 of 79 [43%] with less reproducible arrhythmias, p = 0.890). Drug efficacy predictions obtained by electrophysiologic testing in patients with highly reproducible arrhythmias were not associated with decreases in arrhythmia recurrence (p = 0.202), all-cause mortality (p = 0.301), cardiac death (p = 0.358), or arrhythmic death (p = 0.307) compared to those with less reproducible arrhythmias. Analysis of patients with highly reproducible sustained monomorphic ventricular tachycardia led to similar results. In the ESVEM trial, most patients had highly reproducible arrhythmia induction during baseline electrophysiologic testing. Reproducibility of arrhythmia induction in the baseline state had no effect on the incidence or accuracy of drug efficacy predictions.

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BACKGROUND: Acute ventricular dilatation has important electrophysiological effects: Dilatation shortens action potential duration and refractoriness without an apparent effect on conduction velocity. These effects have been implicated as a potential mechanism of arrhythmias in patients with congestive failure. Because the influence of cycle length on these phenomena has not been studied, we examined the effects of dilatation during ventricular pacing at cycle lengths from 1000 to 150 ms. METHODS AND RESULTS: Thin epicardial layers were created in isolated, perfused rabbit left ventricles (n=7). A fluid filled latex balloon was secured in the left ventricle to dilate the left ventricle. Mapping was performed with 248 epicardial electrodes. Longitudinal conduction velocity (76+/-1 cm/s; mean+/-SEM) and transverse conduction velocity (26+/-1 cm/s) were not influenced by dilatation at any cycle length. In contrast, the effects of dilatation in decreasing left ventricular effective refractory period (ERP) were significantly greater at shorter drive cycle lengths: The decrease in ERP was 2+/-2 ms (a 1% change) at a drive cycle length of 1000 ms and 18+/-4 ms (a 20% change) at a drive cycle length of 150 ms. In 10 additional intact, isolated perfused rabbit hearts, dilatation decreased ERP to a greater degree during 250 ms drive cycle length pacing than during pacing at 400 ms (25+/-4 versus 16+/-3 ms; P=.01). CONCLUSIONS: Acute dilatation exaggerates the normal rate-dependent shortening of refractoriness but does not influence transverse or longitudinal conduction velocity. This observation suggests that the electrophysiological effects of acute dilatation may be greater during tachycardia than at slower cycle lengths. This may have implications for arrhythmias in patients with congestive heart failure.

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Sudden cardiac death due to ventricular arrhythmias is a significant cause of mortality in patients with structural heart disease. Over the past several decades, the introduction of new pharmacologic and nonpharmacologic therapy has expanded the treatment options available. This article will focus on the use of antiarrhythmic medication for the treatment of ventricular arrhythmias and will review the following: (1) treatment goals for various clinical populations, (2) the mechanisms of antiarrhythmic and proarrhythmic actions of antiarrhythmic medications, and (3) empiric versus guided pharmacologic therapy.

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INTRODUCTION: Ventricular dilatation has important electrophysiologic effects, but its effect on ventricular defibrillation threshold (DFT) is unknown. METHODS AND RESULTS: A fluid-filled, latex balloon was placed in the left ventricular cavity of 19 isolated rabbit hearts. In each experiment, an undilated volume (equivalent to a left ventricular end-diastolic pressure of approximately 0 mmHg) was compared to a dilated volume achieved by adding 1.0 mL of saline (n = 10) or 5% dextrose (n = 9) to the intracavitary balloon. Left ventricular effective refractory period (ERP) and DFT were determined at each volume. Defibrillation was attempted with a monophasic shock delivered between a patch electrode positioned over the posterior left ventricle (cathode) and a metallic aortic cannula (anode). DFT was determined using a modified "down/up" protocol with 10 V steps. Ventricular dilatation increased the left ventricular end-diastolic pressure from 0 +/- 0.5 mmHg to 35 +/- 3 mmHg (P < 0.001), decreased the average left ventricular ERP 15% (from 116 +/- 3 msec to 99 +/- 3 msec; P < 0.001), and increased the average DFT 30% (from 96 +/- 4 V to 125 +/- 7 V; P < 0.001). In one third of experiments, the dilated DFT was > or = 150% of the DFT at zero volume. The mechanism of the observed increase in DFT is unknown but may be related to the decrease in refractoriness observed with ventricular dilatation. CONCLUSION: Acute ventricular dilatation in this model increased DFT an average of 30%, an effect not previously described. This observation may have implications for patients with implantable cardioverter defibrillators.

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