Inhibition of murine tumor growth by an interferon-inducing imidazoquinolinamine.

The low-molecular-weight imidazoquinolinamine derivative, 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (imiquimod, previously described as R-837), induced alpha-interferon (IFN-alpha) in mice. IFN induction was identified at oral doses as low as 3 mg/kg. The 10% lethal dose for daily treatment with imiquimod was 200 mg/kg. Oral treatment with 30 mg/kg imiquimod once every three days significantly inhibited MC-26 colon carcinoma. Delay of treatment from day 1 to day 5, when tumors were easily palpable, did not reduce benefits. Ten daily treatments were slightly more effective than five. However, delivery of the same total dose of imiquimod either once every day for 20 days, once every 4 days, once every 7 days, or once every 10 days inhibited tumor growth to the same level. The antitumor effects of imiquimod were significantly abrogated by an antiserum to murine IFN-alpha, suggesting that the antitumor effect was to a substantial extent mediated by IFN induction. Imiquimod also significantly reduced the number of lung colonies in mice inoculated i.v. with MC-26 tumor cells. Combination of treatment with imiquimod and cyclophosphamide was significantly (P less than 0.01) better than treatment with either drug alone. Combination treatment with cyclophosphamide led to cures in some of the mice inoculated either s.c. or i.v. with MC-26 cells. Treatment with imiquimod also inhibited the growth of RIF-1 sarcoma and Lewis lung carcinoma but was ineffective for P388 leukemia. Imiquimod is an oral IFN-alpha inducer with antitumor effectiveness for transplantable murine tumors.

Oversensing during ventricular pacing in patients with a third-generation implantable cardioverter-defibrillator.

OBJECTIVES: The purpose of this study was to identify the causes of oversensing during ventricular pacing in patients with a third-generation implantable cardioverter-defibrillator. BACKGROUND: Third-generation implantable cardioverter-defibrillators have the capability for bradycardia pacing as well as antitachycardia pacing and defibrillation. With the Ventritex Cadence Tiered Therapy Defibrillator System, the pulse generator sensitivity is increased during bradycardia pacing to prevent undersensing of an arrhythmia with small amplitude signals. METHODS: Records from 85 consecutive patients who underwent implantation of a Cadence device for treatment of ventricular tachyarrhythmias were reviewed. RESULTS: Four patients required continuous pacing for bradyarrhythmias. In three of these patients, ventricular pacing was accomplished using the bradycardia pacing feature of the Cadence device. All three experienced spurious device discharges or had aborted shocks for oversensing. Analysis of real-time and stored electrograms revealed intermittent high frequency, large amplitude noise in two patients and oversensing of maximally gained R and T waves in the remaining patient. No evidence of lead fracture was found in any patient. The problem was solved by implantation of a separate permanent pacemaker in two patients and was partially solved by reprogramming of the device in the remaining patient. CONCLUSIONS: Although the Cadence implantable cardioverter-defibrillator has the capability for ventricular pacing in patients with bradyarrhythmias, certain features of its automatic gain control circuit limit its utility in this instance. Oversensing occurs commonly, leading to device discharges or aborted shocks. Implantation of a separate permanent pacemaker may be required in patients who have a Cadence device for tachyarrhythmia control and who also need pacing for bradycardia.

Effects of flecainide on defibrillation thresholds in the anesthetized dog.

The effects of flecainide on defibrillation thresholds in 21 open chest, anesthetized dogs were studied. Defibrillation was accomplished using nontruncated exponential pulses delivered through two epicardial patches. Multiple shocks of varying energy were administered after 10 s of ventricular fibrillation in random order. The percent success was plotted against the energy delivered for each dog. A sigmoidal curve was fit to the data and the energy associated with 50% success (E50) calculated. Flecainide (n = 16) or saline solution (n = 5) was then infused and E50 again determined. Flecainide infusion produced mean (+/- standard error of the mean) plasma levels of 610 +/- 111 ng/ml. Defibrillation thresholds were obtainable in 10 of 16 dogs that received flecainide infusion. Flecainide infusion increased E50 by 75% (from 6.5 +/- 1.9 to 11.4 +/- 2.6 J) (P less than 0.05). Infusion of saline solution did not significantly affect defibrillation energy. Of 16 dogs that received flecainide infusion, 12 had one or more complications: 6 had ventricular fibrillation resistant to defibrillation, 6 developed severe hypotension after successful defibrillation and 5 had spontaneous ventricular fibrillation after successful defibrillation. These effects were not seen in any control dogs. Flecainide infusion significantly increases defibrillation threshold and has important adverse arrhythmic and hemodynamic effects in this experimental preparation.

Effects of ventricular fibrillation and defibrillation on pacing threshold in the anesthetized dog.

The effects of transthoracic and internal defibrillation on the bipolar ventricular pacing threshold in 20 anesthetized dogs were examined. Ventricular pacing was accomplished with a computer-controlled, constant voltage pacemaker that permitted rapid determination of pacing threshold. Defibrillation at various energy levels was administered during ventricular pacing and after ventricular fibrillation of 5, 15, 30, 45, 60 or 120 s duration in the 20 dogs. Defibrillation during pacing or within 15 s after initiation of ventricular fibrillation did not significantly increase threshold, regardless of defibrillation energy or mode of delivery. Defibrillation after ventricular fibrillation lasting greater than or equal to 30 s increased (p less than 0.05) threshold determined 6 s after defibrillation. The increase in threshold (in volts) determined 6 s after defibrillation was an exponential function of fibrillation duration (30 s = 0.30 +/- 0.09 V; 45 s = 0.53 +/- 0.13 V; 60 s = 2.24 +/- 1.05 V), but was independent of defibrillation energy or mode of delivery. Threshold returned to control values 15 to 30 s after defibrillation. Cardiopulmonary bypass to maintain coronary perfusion prevented the increase in pacing threshold even after ventricular fibrillation of up to 2 min duration. Pacing threshold is not increased by transthoracic or internal defibrillation, but is increased by ventricular fibrillation of sufficient duration to create substantial myocardial hypoxemia.

Beta-blocker use and survival in patients with ventricular fibrillation or symptomatic ventricular tachycardia: the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial.

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.

Cytokine induction in mice by the immunomodulator imiquimod.

Imiquimod has been identified as a potent antiviral and antitumor agent in animal models. The biological activity associated with imiquimod has been attributed to its induction of interferon (IFN)-alpha. The present studies evaluated imiquimod administered orally for its ability to stimulate production of IFN and other cytokines in mice. The cytokine profile induced by imiquimod was compared with other known immunomodulators. Imiquimod was found to stimulate increased serum IFN in mice. Daily dosing of imiquimod for five consecutive days led to diminished production of IFN in mice as measured after the final dose. Elevated levels of serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 but not IL-1 alpha were found in serum from mice treated with imiquimod. Imiquimod produced significantly higher levels of IFN but lower levels of TNF and IL-6 and IL-1 alpha than lipopolysaccharide. Polyinosinic acid:polycytidylic acid induced significantly higher amounts of IFN but lower levels of TNF and IL-6 than imiquimod. Imiquimod stimulated significantly higher levels of IFN when compared with 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) and similar levels of IFN when compared with tilorone. Neither ABPP nor tilorone induced TNF or IL-6. Finally, imiquimod stimulated TNF, IFN, and IL-6 production in cultures of mouse spleen and bone marrow cells. These studies demonstrate that imiquimod induces not only IFN but other cytokines as well, all of which may contribute to its biological activity.

Cytokine induction by the immunomodulators imiquimod and S-27609.

Imiquimod (R-837, S-26308) and the analogue S-27609 were evaluated for cytokine induction in human blood cells. Both compounds induced interferon-alpha (IFN), tumor necrosis factor-alpha (TNF), interleukin (IL)-1 beta, and IL-6 with S-27609 being 5 to 10 times more potent. Imiquimod and S-27609 also induced IL-1 alpha, IL-1 receptor antagonist, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF), and macrophage inflammatory protein-1 alpha. The profile of cytokines induced by imiquimod and S-27609 was different from those seen with lipopolysaccharide and polyinosinic-polycytidylic acid. Kinetic studies with both imiquimod and S-27609 revealed induction of cytokines as early as 1-4 h after stimulation. Although most of the cytokines produced by S-27609 were secreted, significant concentrations of IL-1 alpha and IL-1 beta remained intracellular. Monocytes were largely responsible for the cytokines produced. Finally, S-27609-induced mRNA expression for TNF, IFN, and IL-8, and this induction did not require protein synthesis. Taken together, these studies extend previous findings by showing induction of additional cytokines and providing insight into the mechanism of cytokine induction by these molecules.

Effects of mechano-electrical feedback: potential arrhythmogenic influence in patients with congestive heart failure.

Experimental studies have demonstrated that changes in mechanical loading conditions have important, and potentially arrhythmogenic, electrophysiologic effects. These studies have, for the most part, involved the effects of acute dilatation in the structurally normal heart. The ionic basis of these changes remains incompletely understood. Although there is abundant evidence that mechano-electrical feedback occurs in man, additional studies are required to clarify whether the mechanical and hemodynamic abnormalities present in patients with congestive heart failure are a significant contributor to the clinical arrhythmias in these patients. Ongoing studies should clarify this important issue.

Mechanical correlates of contraction-excitation feedback during acute ventricular dilatation.

OBJECTIVE: The purpose was to examine the mechanical correlates of the electrophysiological changes that occur during acute left ventricular dilatation. METHODS: Ten isolated, retrogradely perfused, ejecting rabbit hearts were studied. Left ventricular volume was adjusted by varying left atrial perfusion pressure. Left ventricular pressure was measured directly. Changes in left ventricular chamber dimensions at the level of an epicardial electrode were evaluated with two dimensional echocardiography and wall stress was calculated from these measures. Regional left ventricular electrophysiological properties were measured at two left atrial perfusing pressures. RESULTS: Increases in left atrial perfusion pressure resulted in significant increases in left ventricular end diastolic and end systolic pressures, epicardial and endocardial circumference, and wall stress. Only changes in diastolic wall stress correlated with changes in ventricular refractoriness (r = 0.69, p = 0.027). CONCLUSIONS: Left ventricular dilatation results in shortening of ventricular refractoriness in the isolated, ejecting rabbit heart. Regional changes in refractoriness are best correlated with changes in wall stress.

Cytokine induction in hairless mouse and rat skin after topical application of the immune response modifiers imiquimod and S-28463.

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.

Comparison of intravenous and oral verapamil dosing.

To compare the effects of intravenous and oral verapamil we examined the prolongation of the PR interval in 11 patients after (1) a single 10 mg IV bolus given over 2 min, (2) a single oral dose of 120 mg, and (3) a sustained concentration-maintaining infusion. Maximal PR interval prolongation was delayed relative to peak plasma verapamil concentration in all patients after the bolus and in seven of 11 patients after oral dosing. In all 11 patients oral verapamil was less potent than a single intravenous bolus of verapamil; the plasma verapamil concentration corresponding to a 10% prolongation of the PR was 39.5 +/- 21.7 ng/ml after the bolus and 146.3 +/- 75.1 ng/ml after the oral dose (P = 0.001). However, there was no such difference between oral verapamil and an infusion in six patients. The plasma verapamil concentration corresponding to a 10% PR prolongation was 35.7 +/- 24 ng/ml after the bolus, 132.5 +/- 80.8 ng/ml after the oral dose, and 85.2 +/- 29.9 ng/ml after the infusion. Maximum PR prolongation (drug efficacy) was comparable for the three methods of administration. There was no evidence of tachyphalaxis during prolonged infusions. We conclude that both oral doses and infusions of verapamil are less potent then bolus doses, but that drug efficacy at the concentrations reached is equivalent for the three. Plasma verapamil concentrations determined after bolus doses appear to underestimate effective plasma concentration when the drug is given by the oral or infusion methods.

Verapamil plasma binding: relationship to alpha 1-acid glycoprotein and drug efficacy.

The relationship between alpha 1-acid glycoprotein (AAG) plasma concentration and plasma verapamil binding was examined in samples obtained 15 minutes after 10 mg IV verapamil to 15 subjects. There was a good correlation (r = 0.83) between the binding ratio and AAG concentration, suggesting that AAG could bind verapamil. This was confirmed in vitro by the addition of AAG to an albumin solution, which resulted in a strong correlation between binding ratio (r = 0.99) and AAG concentration. The relationship between both free and total plasma concentrations and the effects of verapamil on the PR interval was also examined several times after 10 mg IV verapamil in seven of the subjects. While there was a correlation between log of both concentrations and the percent prolongation in PR interval (P less than 0.001), the correlation was stronger with free drug concentration (r2 = 0.58) than with total plasma concentration (r2 = 0.36). The range of free concentrations associated with a given effect (220%) was also narrower than that for total concentration (300%). While these data indicate that AAG is responsible for most of the variability in plasma verapamil binding, which in turn contributes somewhat to variation in effectiveness of a given total plasma concentration, neither of these causes of individual variations is likely to have a major clinical impact in patients who, apart from arrhythmia, are otherwise healthy.

Pirmenol kinetics and effective oral dose.

The oral form of pirmenol has not been administered to man. Pirmenol was given by mouth to eight patients with chronic, stable premature ventricular beats (PVBs) to determine effective dose and kinetics. The patients were evaluated with a dose-ranging protocol following by a double-blind, crossover, placebo-controlled study of doses that were effective during dose ranging. Oral doses of 150 to 250 mg induced at least 90% suppression of PVBs 18 of the 19 times they were administered during both protocols. During the double blind experiment, a single oral dose of pirmenol suppressed 95 +/- 8% PVBs/hr (mean +/- SD) for 3 consecutive hr, while placebo suppressed 4 +/- 42% PVBs/hr (P less than 0.01). a 90% or greater reduction in PVBs persisted for a median of 6 hr (range 1 to 8 hr). The range of plasma pirmenol concentrations associated with an at last 90% reduction in PVBs was 0.7 to 2.0 micrograms/ml. Median half-life (t1/2) was 9.3 hr (range 6.0 to 12.4) with 86.6 +/- 2.4% protein binding and 82.6 +/- 23.6% bioavailability. At peak drug level there was lengthening of the QTc interval (0.036 sec, P less than 0.05), but no change in heart rate, blood pressure, PR interval or QRS duration, or symptoms. In this single-dose study, pirmenol effectively reduced PVBs, has a relatively long t1/2, and was minimally toxic.

Hydrogen peroxide decreases effective refractory period in the isolated heart.

Although previous investigations have concluded that reactive oxygen metabolites contribute to reperfusion arrhythmias, the experimental models employed also had a significant amount of tissue injury, which may have contributed to the observed electrophysiologic effects. We studied whether exposure of the intact heart to a reactive oxygen metabolite at doses that are not associated with histologic evidence of cell necrosis would alter myocardial refractoriness, suggesting that subtle and reversible oxidative stress could alter myocardial electrophysiologic properties and perhaps contribute to ventricular arrhythmias. Isolated rabbit hearts were perfused for 30 min with low doses of hydrogen peroxide (H2O2), either 10(-5), 5 x 10(-6), or 10(-6)-M H2O2 versus vehicle alone; followed by a 30-min washout period without H2O2. Infusion of H2O2 for 30 min decreased ventricular epicardial effective refractory period (ERP) in a dose-dependent manner compared to saline controls (delta ERP). The delta ERP versus time curves during the last 10 min of H2O2 infusion were different (p less than 0.01) for each of the three H2O2 doses. Creatine phosphokinase and reversible oxidized glutathione release occurred during 10(-5)-M H2O2 infusion, but not with lower H2O2 doses. Exposure of the intact heart to low concentrations of H2O2, in a range that caused subtle oxidative injury, decreased ventricular ERP in a dose-dependent manner. Thus, H2O2 generation could contribute to ventricular arrhythmias, even in settings of sublethal and potentially reversible oxidative injury.

Cellular requirements for cytokine production in response to the immunomodulators imiquimod and S-27609.

Imiquimod (R-837) and its analog, S-27609, belong to a class of imidazoquinolinamines that have potent antitumor and antiviral effects in animals. Much of their biologic activity is a result of the induction of cytokines, including interferon-alpha (IFN-alpha), tumor necrosis factor alpha (TNF), and others. In this study, the cells responsible for S-27609- and imiquimod-induced cytokine production were characterized. E rosette+ T cells were not the major cell population responsible for IFN-alpha and TNF in response to S-27609 or imiquimod. In contrast, E rosette- cells and unseparated PBMC produced similar concentrations of IFN-alpha and TNF in response to S-27609 and imiquimod. Elimination of monocytes by treatment with the lysosomotropic agent L-leucine methyl ester (LME) or depletion using antibody to CD14 and immunomagnetic beads abrogated IFN-alpha and TNF production induced by S-27609, imiquimod, or LPS but not poly(I)/(C). LME treatment also abolished interleukin (IL)-1 alpha, IL-beta, IL-6, and IL-8 production stimulated by S-27609 and imiquimod. Removal of HLA-DR+ or CD36+ monocytes also caused a significant reduction in S-27609- and imiquimod-induced IFN-alpha and TNF. Elimination of B cells, NK cells, and dendritic cells did not significantly reduce cytokine induction in response to S-27609. Thus, the cell population responsible for the majority of cytokine release in human PBMC in response to S-27609 and imiquimod is a E rosette-, CD14+, CD36+, HLA-DR+ monocyte.

General principles of antiarrhythmic therapy for ventricular tachyarrhythmias.

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.

Effects of upright posture on atrioventricular nodal reentry and dual atrioventricular nodal pathways.

The electrophysiologic effects of upright posture (45 degrees upright tilt) were studied in 17 patients with dual atrioventricular (AV) nodal pathways, AV nodal reentry or both. Discontinuous AV nodal conduction curves were observed in 16 patients while supine, but in only 11 patients while upright. Fast pathway refractoriness was shortened: the anterograde fast pathway effective refractory period decreased from 360 +/- 22 to 275 +/- 14 ms (mean +/- standard error of the mean), the anterograde fast pathway block cycle length shortened from 448 +/- 28 to 348 +/- 20 ms and the retrograde fast pathway block cycle length shortened from 425 +/- 29 to 338 +/- 24 ms (all p less than 0.01). The anterograde slow pathway block cycle length shortened from 378 +/- 29 to 316 +/- 17 ms (p less than 0.05). AV nodal reentrant tachycardia was induced in 5 patients while supine (2 sustained, 3 nonsustained) and in 6 patients while upright (4 sustained, 2 nonsustained). Tachycardia cycle length shortened during upright posture, from 413 +/- 30 to 345 +/- 22 ms (p less than 0.01), primarily due to shortened anterograde slow pathway conduction time, from 322 +/- 23 to 268 +/- 20 ms (p less than 0.05). Upright posture thus enhances conduction in patients with dual AV nodal pathways, facilitating AV nodal reentry. Electrophysiologic testing in the upright position may yield additional clinical important information in patients with dual AV nodal pathways.

Hemodynamic effects of acute atrioventricular sequential pacing in patients with left ventricular dysfunction.

Acute atrioventricular (A-V) sequential pacing was compared with ventricular pacing in seven men with symptomatic left ventricular failure (New York Heart Association functional class III and IV) and depressed left ventricular ejection fraction (mean 29 percent, range 18 to 40). Cardiac index was higher during A-V sequential pacing than during ventricular pacing for every patient at paced rates of 75 to 100 beats/min. The mean increment was 17 percent (range 10 to 37) at a paced rate of 75 beats/min, 23 percent (range 8 to 45) at a paced rate of 85 beats/min and 29 percent (range 19 to 55) at a paced rate of 100 beats/min. The increase in cardiac index in an individual patient did not correlate with baseline characteristics including functional class, cardiothoracic ratio, resting ejection fraction, cardiac index or balloon-occluded pulmonary wedge pressure. Arterial pressure varied from beat to beat during ventricular pacing because of the changing relation of atrial to ventricular systole. When an atrial contraction preceded a ventricular paced beat by a physiologic interval intraarterial pulse pressure uniformly increased. That increase correlated strongly (r = 0.993) with the increase in cardiac index that occurred during A-V sequential pacing. Measurement of the pulse pressure during A-V dissociation is a simple technique that may be useful for predicting the degree of improvement in cardiac output expected with methods of pacing that restore A-V synchrony.

Importance of beta blockade in the therapy of serious ventricular arrhythmias.

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.

Effects of upright posture on atrioventricular accessory pathway conduction.

The electrophysiologic effects of 45 degrees head-up tilt were studied in 19 patients with atrioventricular accessory pathways. Upright posture enhanced both anterograde and retrograde accessory pathway conduction when compared to the supine position: the anterograde block cycle length decreased from 374 +/- 52 ms (mean +/- standard error) (supine) to 303 +/- 33 ms (tilt) (p less than 0.05); anterograde effective refractory period decreased from 286 +/- 17 to 249 +/- 10 ms (p less than 0.05); retrograde block cycle length shortened from 331 +/- 36 to 291 +/- 35 ms (p less than 0.05); retrograde effective refractory period decreased from 312 +/- 26 ms to 274 +/- 15 ms (p less than 0.05). During induced atrial fibrillation the mean RR interval and the shortest RR interval between preexcited beats decreased approximately 10% with head-up tilt. During orthodromic reciprocating tachycardia, tachycardia cycle length shortened 15%. Tachycardia rate during electrophysiologic study in the head-up position more closely approximated the rate of clinical tachycardia than did the rate in the supine position. Head-up tilt significantly enhances anterograde and retrograde accessory pathway conduction, increases the rate of arrhythmias using an accessory pathway and may be clinically useful in the assessment of patients with an accessory pathway.