Cardiologists
39 years of experience
Video profile
Accepting new patients
Oak Knoll-Edgewood Park
Cardiovascular Medicine and Cardiac Arrhythmias
2900 Whipple Ave
Ste 205
Redwood City, CA 94062
650-363-5262
Locations and availability (3)

Education ?

Medical School Score Rankings
University of Cincinnati (1971)
  • Currently 3 of 4 apples
Top 50%

Awards & Distinctions ?

Awards  
Castle Connolly's Top Doctors™ (2012 - 2013)
Patients' Choice Award (2010 - 2012)
Compassionate Doctor Recognition (2010 - 2012)
On-Time Doctor Award (2009)
Associations
Heart Rhythm Society
American Board of Internal Medicine

Affiliations ?

Dr. Winkle is affiliated with 11 hospitals.

Hospital Affilations

Score

Rankings

  • El Camino Hospital
    Cardiology
    2500 Grant Rd, Mountain View, CA 94040
    • Currently 3 of 4 crosses
    Top 50%
  • Stanford Hospital and Clinics
    Cardiology
    300 Pasteur Dr, Stanford, CA 94305
    • Currently 3 of 4 crosses
    Top 50%
  • Seton Medical Center
    Cardiology
    1900 Sullivan Ave, Daly City, CA 94015
    • Currently 2 of 4 crosses
  • Community Hospital of Los Gatos
    Cardiology
    815 Pollard Rd, Los Gatos, CA 95032
    • Currently 1 of 4 crosses
  • California Pacific Medical Center- Davies Campus
    Cardiology
    45 Castro St, San Francisco, CA 94114
    • Currently 1 of 4 crosses
  • Sequoia Hospital *
    Cardiology
    170 Alameda De Las Pulgas, Redwood City, CA 94062
    • Currently 1 of 4 crosses
  • Stanford Med Center
  • Sequoia Health Services
  • Stanford University Hospital *
  • Sequoia Hospital - Redwood City
  • Sequoia Hospital District
  • * This information was reported to Vitals by the doctor or doctor's office.

    Publications & Research

    Dr. Winkle has contributed to 90 publications.
    Title Patterns of Cognitive Recovery in Sudden Cardiac Arrest Survivors: the Pilot Study.
    Date July 1996
    Journal Heart & Lung : the Journal of Critical Care
    Excerpt

    OBJECTIVE: To determine the prevalence, type, severity, and natural evolution of cognitive impairments in survivors of sudden cardiac arrest over time and to assess the relation of selected clinical and psychologic variables to those outcomes. DESIGN: Longitudinal with repeated measures. Twenty-five consecutive patients underwent extensive neuropsychologic testing during hospitalization within 3 weeks of their initial cardiac arrest. Of these, 17 completed additional testing at 6 to 9 weeks, 12 to 15 weeks, and 22 to 25 weeks after the event. SETTING: Cardiac electrophysiologic services at a university teaching hospital, a community hospital, and home. OUTCOME VARIABLES: Orientation, attention, concentration, immediate recall, early retention, delayed recall, reasoning, motor speed, and motor regularity were measured. RESULTS: During hospitalization, 72% of the patients had mild to severe impairments in one or more cognitive areas. Memory, particularly delayed recall, was the most common deficit. At 6 months after the arrest event, 29% (5 of 17) of the patients continued to be impaired, and all had deficits in delayed recall. Depression was significantly related to deficits in attention and delayed recall at 6 months only. Time to postarrest awakening was the most reliable predictor of long-term cognitive functioning in this patient sample. CONCLUSION: A significant minority of sudden death survivors incur long-term cognitive impairments, particularly in delayed recall or short-term memory. The occurrence of long-term cognitive deficits in these patients can be estimated from the duration of unconsciousness after resuscitation (time-to-awakening).

    Title Intravenous Amiodarone for Recurrent Sustained Hypotensive Ventricular Tachyarrhythmias. Intravenous Amiodarone Multicenter Trial Group.
    Date January 1996
    Journal Journal of the American College of Cardiology
    Excerpt

    OBJECTIVES. We sought to determine the response rate and safety of intravenous amiodarone in patients with ventricular tachyarrhythmias refractory to standard therapies. BACKGROUND. Numerous small retrospective reports suggest a response of refractory ventricular tachyarrhythmias to intravenous amiodarone, yet no controlled prospective trials exist. METHODS. Two hundred seventy-three patients with recurrent hypotensive ventricular tachyarrhythmias refractory to lidocaine, procainamide and bretylium were randomized to receive one of three doses of intravenous amiodarone: 525, 1,050 or 2,100 mg/24 h (mean [+/- SE] dose 743.7 +/- 418.7, 1,175.2 +/- 483.7, 1,921.2 +/- 688.8 mg, respectively) by continuous infusion over 24 h. RESULTS. Of the 273 patients, 110 (40.3% response rate) survived 24 h without another hypotensive ventricular tachyarrhythmic event while being treated with intravenous amiodarone as a single agent (primary end point). A significant difference in the time to first recurrence of ventricular tachyarrhythmia (post hoc analysis) over the first 12 h was observed when the combined 1,050- and 2,100-mg dose groups were compared with the 525-mg dose group (p = 0.046). The number of supplemental (150 mg) infusions of intravenous amiodarone (given for breakthrough destabilizing tachyarrhythmias) during hours 0 to 6 (prespecified secondary end point) was significantly greater in the 525-mg dose group than in the 2,100-mg dose group (1.09 +/- 1.57 vs. 0.51 +/- 0.97, p = 0.0043). However, there was no clear dose-response relation observed in this trial with respect to success rates (primary end point), time to first recurrence of tachyarrhythmia (post hoc analysis) or mortality (secondary end point) over 24 h. CONCLUSIONS. Intravenous amiodarone is a relatively safe therapy for ventricular tachyarrhythmias refractory to other medications.

    Title Automatic Implantable Cardioverter Defibrillator: Surgical Approaches for Implantation.
    Date October 1992
    Journal Journal of Cardiac Surgery
    Excerpt

    Surgical approaches for implantation of the automatic cardioverter defibrillator are sternotomy, left thoracotomy, subxiphoid, and subcostal. Although any one of these may be combined with insertion of one or more of the electrodes transvenously, surgical entry into the chest is required for every noninvestigational defibrillator implantation operation. The approaches differ in exposure provided for selecting electrode sites and for handling untoward events, in amount and location of tissue that must be divided or dissected, and in average time required. The operation is an electrical one. Its purpose is to obtain reliable rhythm sensing so that defibrillation or cardioversion shocks will occur only when necessary, and to obtain low enough defibrillation thresholds for shocks of 30 joules or less to have a 10-joule defibrillation safety margin. Many of the patients have had previous cardiac operations. They usually have low or very low ejection fractions. Intraoperative electrophysiological testing with often multiple defibrillation episodes is required. The choice of approach varies with the state of the patient, the institutional experience, and the surgeon. This article describes technique, and the advantages and disadvantages of the four approaches as used by four surgeons in four different institutions.

    Title Clinical Pharmacology of Intravenous Enoximone: Pharmacodynamics and Pharmacokinetics in Patients with Heart Failure.
    Date September 1991
    Journal American Heart Journal
    Excerpt

    Twenty-one patients with heart failure (New York Heart Association [NYHA] class II to IV) received a 24-hour infusion of enoximone followed by a 12-hour washout period. Patients were randomly assigned to one of four treatment groups. Groups I to III received an 0.5 mg/kg bolus, followed by a maintenance infusion of 2.5, 5.0, or 10.0 micrograms/kg/min. Group IV patients received a maintenance infusion of 5.0 micrograms/kg/min without a loading dose. Serial assessment of hemodynamics, plasma levels of enoximone and enoximone sulfoxide, and ventricular ectopy were performed. Enoximone produced a clinically significant increase in cardiac index, and a decrease in mean pulmonary artery wedge pressure and systemic vascular resistance in all groups. Enoximone mildly increased heart rate, and had a minimal effect on mean arterial pressure. There was no statistically significant change in ventricular ectopy during the infusion. Significant hemodynamic improvement was noted at even the lowest infusion rate, and did not increase in linear fashion at higher infusion rates. In patients who did not receive an initial loading bolus of 0.5 mg/kg, the increase in cardiac index was delayed by approximately 1 hour. Plasma concentrations of both enoximone and its major metabolite continued to rise throughout the 24-hour infusion in group III (10.0 micrograms/kg/min), rather than reaching steady state as predicted by the terminal exponential half-lives of these compounds. This is suggestive of nonlinear pharmacokinetics and indicates a potential for excessive accumulation of enoximone and its metabolite during prolonged infusion. These findings may have important implications in guiding the intravenous administration of enoximone.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Comparison of Pre- and Postoperative Conduction Patterns in Patients Surgically Cured of Atrioventricular Node Reentrant Tachycardia.
    Date March 1991
    Journal Journal of the American College of Cardiology
    Excerpt

    Patients with atrioventricular (AV) node reentrant tachycardia characteristically have short and constant retrograde His-atrium conduction times (H2A2 intervals) during the introduction of ventricular extrastimuli. It has therefore been suggested that the tachycardia circuit involves retrograde conduction up an accessory pathway located in perinodal tissue. If the mechanism of surgical cure of AV node reentrant tachycardia is interruption of this accessory pathway, postoperative changes in retrograde conduction would be expected. Thirteen patients with drug-refractory AV node reentrant tachycardia underwent surgery. Preoperatively, H2A2 intervals were short and constant. During AV node reentrant tachycardia, earliest atrial activation was seen near the His bundle and was 0 to 25 ms before ventricular activation in all patients except one. Surgery consisted of dissection of right atrial septal and anterior inputs to the AV node and central fibrous body. Postoperatively, the H2A2 interval remained short and constant compared with preoperative values although it was slightly prolonged (74 +/- 18 versus 61 +/- 21 ms, p less than 0.005). Twelve of the 13 patients are free of tachycardia after 28 +/- 13 months and no patient has had evidence of AV node block. Thus, surgical cure of AV node reentrant tachycardia is highly successful; however, there is no reason to postulate an accessory pathway or use of perinodal tissue as part of the tachycardia circuit and the mechanism of surgical success remains obscure.

    Title Pharmacodynamics of Enoximone During Intravenous Infusion.
    Date November 1990
    Journal International Journal of Cardiology
    Excerpt

    Twenty-one patients with heart failure (NYHA class II-IV) received a 24-hour infusion of enoximone, followed by a 12-hour washout period. Patients were randomly assigned to one of four treatment groups. Groups I-III received a 0.5 mg/kg bolus, followed by a maintenance infusion of 2.5, 5.0 or 10.0 micrograms/kg/minute. Group IV patients received a maintenance infusion of 5.0 micrograms/kg/minute without the bolus. Serial assessments of haemodynamics, plasma levels of enoximone and enoximone sulphoxide, and ventricular ectopy were performed. Enoximone produced a significant increase in cardiac index (28.1-46.7%) and a decrease in mean pulmonary artery wedge pressure (6.4-35.7%) and systemic vascular resistance (34.7-78.9%). Enoximone had minimal effect on heart rate and blood pressure. In patients who did not receive an initial bolus of 0.5 mg/kg, haemodynamic changes were delayed by approximately 1 hour. Significant haemodynamic improvement was noted at even the lowest infusion rate and did not increase in linear fashion at higher infusion rates. During infusion of enoximone at 10.0 micrograms/kg/minute, both enoximone and its sulphoxide accumulated non-linearly and did not achieve a steady state. No significant adverse effects were noted in these patients. Enoximone infusion at rates greater than 5.0 micrograms/kg/minute may confer minimal additional haemodynamic benefit, while resulting in significant accumulation of enoximone and enoximone sulphoxide. Ventricular ectopy did not increase significantly in most patients.

    Title Defibrillator "twiddler's" Syndrome.
    Date October 1990
    Journal Pacing and Clinical Electrophysiology : Pace
    Title Effect of Duration of Ventricular Fibrillation on Defibrillation Efficacy in Humans.
    Date May 1990
    Journal Circulation
    Excerpt

    The currently available automatic implantable cardioverter-defibrillator has proven highly successful for termination of ventricular tachycardia and fibrillation. Newer devices, however, permit lower energy shocks to be delivered initially and longer episodes of arrhythmia to occur before shocks are delivered. These changes may result in longer durations of arrhythmia before successful termination. Little is known about the effects of the duration of ventricular fibrillation on the efficacy of defibrillating shocks. In this study, we examined the efficacy of defibrillating shocks in 22 patients undergoing automatic implantable cardioverter-defibrillator implantation or generator change. Defibrillating shocks ranging from 300 to 600 V (5.9-24.2 J) were delivered in matched pairs after 5 and 15 seconds of ventricular fibrillation. For the 300-V shocks (5.9 J), defibrillation was accomplished in 82% of patients when the shocks were given after 5 seconds of ventricular fibrillation and in only 45% of patients when the shocks were delivered after 15 seconds (p less than 0.01). At higher energies, there was no difference in the efficacy of defibrillation shocks delivered after 5 compared with 15 seconds of ventricular fibrillation. The postshock aortic, systolic, and diastolic blood pressures were significantly lower when the shocks were given after 15 seconds of ventricular fibrillation than after only 5 seconds. We conclude that the duration of ventricular fibrillation affects defibrillation efficacy especially at energies that are relatively low compared with maximal device outputs and that longer episodes of ventricular fibrillation cause more postshock hemodynamic depression. These observations have implications for defibrillation threshold testing at the time of device implantation and for the design and programming of future automatic implantable antitachycardia devices.

    Title Long-term Outcome with the Automatic Implantable Cardioverter-defibrillator.
    Date May 1989
    Journal Journal of the American College of Cardiology
    Excerpt

    The automatic implantable cardioverter-defibrillator was implanted in 270 patients because of life-threatening arrhythmias over a 7 year period. There was a history of sustained ventricular tachycardia or fibrillation, or both, in 96% of these patients, 80% had one or more prior cardiac arrests and 78% had coronary artery disease as their underlying diagnosis. The average ejection fraction was 34%, and 96% of these patients had had an average of 3.4 antiarrhythmic drug failures per patient before defibrillator implantation. There were four perioperative deaths and eight patients had generator infection or generator erosion, or both, during the perioperative period or during long-term follow-up. Concomitant antiarrhythmic drug therapy was given to 69% of patients. Shocks from the device were given to 58% of patients. and 20% received "problematic" shocks. The device was removed from 16 patients during long-term follow-up for a variety of reasons. There were 7 sudden cardiac deaths and 30 nonsudden cardiac deaths, 18 of which were secondary to congestive heart failure. The actuarial incidence of sudden death, total cardiac death and total mortality from all causes was 1%, 7% and 8%, respectively, at 1 year, and 4%, 24% and 26% at 5 years. The automatic implantable cardioverter-defibrillator nearly eliminates sudden death over a long-term follow-up period in a high risk group of patients. It has an acceptable rate of complications or problems, or both, and most late deaths in these patients are nonsudden and of cardiovascular origin.

    Title Clinical Experience with Sotalol in Patients with Drug-refractory Ventricular Arrhythmias.
    Date February 1989
    Journal Journal of the American College of Cardiology
    Excerpt

    Sixty-five patients with symptomatic, drug-refractory, sustained ventricular tachycardia or fibrillation were treated with oral sotalol (80 to 480 mg twice daily). Sotalol was withdrawn in 11 patients because of continued inducibility of ventricular tachycardia at the time of follow-up electrophysiologic study. Therefore, the clinical effectiveness of sotalol could be evaluated in 54 patients followed up for 11.5 +/- 6 months (range 0.2 to 25). The actuarial incidence of successful sotalol therapy was 54 +/- 13% at 6 months and 47 +/- 13% at 12 months. In 39 patients who underwent electrophysiologic testing while receiving oral sotalol, the drug prevented the reinduction of ventricular tachycardia/fibrillation in 8 (20%). During follow-up study, arrhythmia recurred in 1 (17%) of 6 patients whose ventricular tachycardia was noninducible with oral sotalol and in 8 (44%) of 18 with inducible tachycardia but who were continued on oral sotalol therapy. Adverse effects were noted in 28 patients (42%), requiring drug withdrawal in 13 (22%) and dose reduction after hospital discharge in 10 (15%). Exacerbation of ventricular arrhythmia occurred in six patients (9%), one of whom had associated hypokalemia. Sotalol is frequently useful in the control of intractable, life-threatening ventricular arrhythmias, and its efficacy appears to be predicted by programmed stimulation. However, there is a high rate of limiting side effects, which precludes its use in a large number of patients, and a substantial risk of arrhythmia exacerbation.

    Title Worsening of Ventricular Tachycardia by Amiodarone.
    Date August 1988
    Journal Journal of Clinical Pharmacology
    Excerpt

    The details of worsening of ventricular tachycardia in 8 (4.1%) of 194 patients receiving treatment with amiodarone are reported. Two forms of amiodarone-induced tachycardia were recognized: first, the development of new tachycardias (three patients) and second, a change in the pattern of recurrence of clinical tachycardia (five patients). In retrospect, the time from the initiation of amiodarone to the initial documentation of worsening ranged from 1 to 23 days (mean +/- SD, 9.4 +/- 8.2 days) and the time from the initiation of therapy to the recognition of worsening ranged from 6 to 26 days (14.6 +/- 10.1 days). Seven patients survived the worsening of tachycardia and one died. The total dose of amiodarone received and the duration of administration did not correlate with time to manifestation or time to resolution of worsening. This report emphasizes that worsening of ventricular tachycardia as a result of amiodarone is often difficult to differentiate from inadequate drug loading or early recurrence of 2 patient's clinical tachycardia. Further, because of the pharmacokinetics of the drug, the manifestations of worsening may be prolonged. In the cases reported, it ranged from 2 to 26 days (7.9 +/- 8.3 days), which is longer than previously reported. Because of the potential for amiodarone to cause life-threatening worsening of ventricular tachycardia and in accordance with current results, a period of in-hospital monitoring of at least 10 days at the start of therapy with amiodarone is recommended.

    Title Transvenous Catheter Ablation of Extranodal Accessory Pathways.
    Date June 1988
    Journal Journal of the American College of Cardiology
    Excerpt

    Twelve patients with an accessory pathway and recurrent symptomatic reciprocating tachycardia or atrial fibrillation, or both, underwent attempted transvenous catheter ablation of the accessory pathway. In one patient with a small right coronary artery, the pathway was along the right free wall. In 11 patients, the pathway was located at or within 15 mm of the coronary sinus os. For these patients, a quadripolar electrode catheter was placed in the coronary sinus and positioned, if possible, so that the proximal pair of electrodes straddled the pathway. For those patients with a pathway greater than 5 mm within the coronary sinus, the most proximal electrode was placed at the os. This proximal pair of electrodes was connected to the cathodal output of a defibrillator with an anterior chest wall patch serving as the current sink. Two shocks were then delivered for a cumulative energy of 500 to 600 J (stored energy). Among the eight patients with a pathway at or within 5 mm of the coronary sinus os, conduction over the pathway was abolished in five and modified in one. Among the four patients with a pathway farther from the os (10 to 15 mm) and along the right free wall, pathway conduction was modified only in two. Rupture of the coronary sinus did not occur in any patient. There were no serious complications. Minor damage surrounding the area of ablation was seen at the time of surgical division of the accessory pathway in two of five patients with unsuccessful ablation who subsequently underwent surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Comparison of Defibrillation Efficacy in Humans Using a New Catheter and Superior Vena Cava Spring-left Ventricular Patch Electrodes.
    Date March 1988
    Journal Journal of the American College of Cardiology
    Excerpt

    The automatic implantable cardioverter-defibrillator currently utilizes an electrode system that requires a major operation for implantation. Effective defibrillation using an implantable cardioverter-defibrillator catheter positioned transvenously would eliminate the morbidity associated with such surgery. Fifteen patients undergoing defibrillator implantation were studied to compare the efficacy of the catheter with that of the superior vena cava spring (6.7 cm2, anode)-left ventricular patch (13.5 cm2, cathode) electrode system using truncated exponential waveforms with 60% tilt. The catheter is 11F in diameter and tripolar. A distal platinum-iridium tip used for pacing was separated by 4 mm from a middle 4.3 cm2 platinum electrode; these were positioned at the right ventricular apex. The proximal 8.5 cm2 platinum electrode was situated at the superior vena cava-right atrial junction. Defibrillation was performed using the middle (cathode) and proximal (anode) electrodes. Ventricular fibrillation was induced by alternating current six times, and defibrillation shocks of 1, 5, 10, 15, 20 or 25 J were given in random order, first using the catheter and then the spring-patch system. Rescue shocks of higher energy were given if there was failure. Although very low energy levels appeared to be slightly more efficacious when using the spring-patch system, there was no statistically significant difference between the electrode systems for any of the energies tested. Permanent implantation of the catheter would have been suitable in 45% of the patients, as compared with 54% of patients with the spring-patch system (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Electrophysiology of Ethmozine (moricizine Hcl) for Ventricular Tachycardia.
    Date November 1987
    Journal The American Journal of Cardiology
    Excerpt

    Moricizine HCl, an antiarrhythmic phenothiazine drug, was investigated for its efficacy against ventricular tachycardia (VT) in a group of 60 patients from 8 institutions using electrophysiologic testing before and after oral administration. Moricizine HCl significantly prolonged PR, QRS, AH and HV intervals and cycle length for atrioventricular nodal block, but had minimal or no effect on repolarization or cardiac refractory periods. Induction of sustained VT (in 33 patients) and nonsustained VT (in 14 patients) occurred at baseline. During moricizine HCl therapy, sustained VT was induced in 31 patients and nonsustained VT in 7 patients. In individual patients, suppression of VT induction was obtained in 18% of patients with sustained VT and in 27% of patients with nonsustained VT. Cycle length of induced VT was significantly prolonged by moricizine HCl therapy. During prospective follow-up of 37 patients, electrophysiologic study predicted recurrence of nonrecurrence of VT with a sensitivity value of 82% and specificity of 65%.

    Title Role of Extrastimulus Prematurity and Intraventricular Conduction Time in Inducing Ventricular Tachycardia or Ventricular Fibrillation Secondary to Coronary Artery Disease.
    Date October 1987
    Journal The American Journal of Cardiology
    Excerpt

    The influence of extrastimulus prematurity and changes in intraventricular conduction time on ventricular tachycardia (VT) inducibility were evaluated in 78 patients with coronary artery disease undergoing electrophysiologic study. In a retrospective portion, the effect of adding ventricular extrastimuli vs shortening the ventricular drive cycle length on extrastimulus prematurity and VT inducibility was evaluated in 59 consecutive patients with inducible ventricular arrhythmias (group I). In a prospective component, changes in intraventricular conduction of the last ventricular extrastimulus and the relation to initiation of VT were evaluated in 19 consecutive patients undergoing programmed electrical stimulation (group II). Single (V2), double (V3) and triple (V4) ventricular extrastimuli were introduced during ventricular drive pacing (V1) at multiple cycle lengths. Although reduction of drive cycle length facilitated arrhythmia induction in 25% of patients, addition of an extrastimulus was a more potent method in group I patients. However, the mechanism of arrhythmia induction is not dependent on attainment of shorter coupling intervals with either method. In group II patients QRS duration and intraventricular conduction time of the extrastimuli increased as the coupling interval was reduced. Significant changes in QRS duration and intraventricular conduction time of the extrastimuli that initiated VT were not observed.

    Title Implantation of the Automatic Implantable Cardioverter Defibrillator (aicd): Practical Aspects.
    Date February 1987
    Journal Pacing and Clinical Electrophysiology : Pace
    Excerpt

    Most patients who are resuscitated from an episode of sudden cardiac death or one of sustained ventricular tachycardia (VT) can now be treated using serial electrophysiologic testing as a guide to drug therapy. Recurrence rates are low if an antiarrhythmic regimen can be found which prevents induction of VT. Patients failing serial drug testing have a high recurrence rate (approximately 50%/year). Most clinicians now refer such patients for either experimental antiarrhythmic therapy or electrical intervention. The most promising of the electrical interventions (including tachycardia converting pacemakers and intraoperative mapping) has been the automatic implantable cardioverter defibrillator (AICD). Only recently has the AICD been released from investigative status by the Food and Drug Administration. It can be implanted safely and with favorable clinical outcome if the techniques of implantation are well understood and used often. The text incorporates the authors' experience in implanting nearly 200 devices and is intended as a practical guide to the use of the AICD.

    Title Ethmozine: Electrophysiology, Hemodynamics, and Antiarrhythmic Efficacy in Patients with Life-threatening Ventricular Arrhythmias.
    Date September 1986
    Journal American Heart Journal
    Excerpt

    Thirteen patients with drug-resistant, life-threatening ventricular arrhythmias and inducible sustained ventricular tachycardia (VT) at electrophysiologic study received moricizine HC1 (ethmozine), 10 mg/kg/day orally. Eight patients underwent electrophysiologic study before and after drug administration; the arrhythmia became noninducible in one. In five other patients, spontaneous sustained VT occurred after 1 to 5 days of drug therapy, and one patient had a worsening of arrhythmias on ethmozine. Ethmozine prolonged infranodal conduction time (HV interval) (51.4 +/- 13.8 msec to 69.3 +/- 17.7 msec [mean +/- SD]), PR interval (201 +/- 28.1 msec to 244 +/- 62.2 msec), and QRS interval (123 +/- 27 msec to 147 +/- 32 msec). Ventricular refractory periods were not consistently affected, and only the one patient who became noninducible had an increase in effective ventricular refractory period (280 to 310 msec). The drug had no significant effect on sinus cycle length or sinus node recovery time, atrial conduction or refractoriness, or atrioventricular nodal refractoriness. Ethmozine had no effect on radionuclide ejection fraction (25.5 +/- 12.7% to 28.2 +/- 13.8%) or cardiac index (2.4 +/- 0.7 to 3.0 +/- 0.6 ml/min/m2) and caused no significant changes in mean aortic, right atrial, pulmonary arterial, or pulmonary capillary wedge pressures. Although the drug is well tolerated and produces no untoward hemodynamic effects, ethmozine is relatively ineffective in patients with sustained VT refractory to conventional antiarrhythmic agents.

    Title Results of Operations for Ventricular Tachycardia in 105 Patients.
    Date July 1986
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    Operations to treat ventricular tachycardia refractory to antiarrhythmic drugs were performed in 105 patients. Intraoperative epicardial activation sequence maps were completed in 83% and endocardial maps in 57%. Mapping could be used to guide 79% of operations. When no useful mapping data were obtained, patients had visually guided antiarrhythmic operations (17%) or conventional cardiac operations (4%). The most frequently performed antiarrhythmic procedures, alone or in combination, were endomyocardial resection (45%), cryothermal destruction (44%), and encircling procedures (20%). Operative mortality was 16%, including 6% from heart failure and 4% from ventricular tachycardia. Emergency operation (p = 0.002) and New York Heart Association heart failure class (p = 0.01) were independent preoperative risk factors for cardiac operative mortality in the 98 patients with coronary artery disease. At postoperative electrophysiologic study performed in 79 patients, ventricular tachycardia could not be induced in 75% of patients who had map-guided operations and 36% who had visually guided ones (p = 0.001). During follow-up of 23 +/- 21 months, results of postoperative electrophysiologic study predicted ventricular tachycardia recurrence. At 2 years the actuarial incidence of freedom from arrhythmia recurrence was 50% +/- 10% in patients with and 78% +/- 6% in patients without inducible ventricular tachycardia (p = 0.001); it was 71% +/- 5% in patients who had map-guided operations and 37% +/- 12% in patients who had visually guided ones (p = 0.004). Ventricular tachycardia recurrence was infrequent in survivors of map-guided operations; benefits of surgical treatment for ventricular tachycardia were limited by high operative mortality and frequent arrhythmia recurrence when no useful mapping data were obtained.

    Title Esophageal Electrocardiography: a New Technology Revives an Old Technique.
    Date April 1986
    Journal The American Journal of Cardiology
    Excerpt

    This study evaluates the clinical use of an easily swallowed bipolar electrode for recording an esophageal electrocardiogram (ECG). Fourteen patients were selected for bedside diagnosis (ECG group) because of arrhythmias difficult to evaluate using a standard 12-lead ECG. A second group of 27 non-selected patients scheduled for routine 24-hour ambulatory electrocardiographic recordings (ambulatory ECG group) had an esophageal ECG recorded as the "third channel." All 14 patients (100%) in the ECG group had excellent-quality tracings, and the esophageal ECG was diagnostic in 12 cases (86%). Of 27 patients in the ambulatory ECG group, 19 (70%) had fairly good to excellent-quality 24-hour esophageal pill tracings, with the esophageal ECG contributing to correct arrhythmia diagnosis in 11 patients (41%). It is concluded that this easily swallowed esophageal electrode provides an excellent-quality short-term ECG and often permits proper arrhythmia diagnosis in selected patients with arrhythmias. Good-quality 24-hour esophageal ambulatory electrocardiographic recordings can also be obtained that contribute to arrhythmia diagnosis in a limited number of unselected patients, and should be even more clinically useful in carefully selected patients.

    Title The Mechanisms of Ventricular Tachycardia in Humans Determined by Intraoperative Recording of the Electrical Activation Sequence.
    Date August 1985
    Journal International Journal of Cardiology
    Excerpt

    We recorded ventricular activation sequence during ventricular tachycardia in 76 patients who underwent surgical therapy of refractory ventricular tachycardia. Ventricular tachycardia arose from a discrete site (focal origination) in 28 patients (37%) or resulted from reentry around scar (macroreentry) in 22 patients (29%). The mechanism responsible for ventricular tachycardia was not discernable in the remaining 26 patients (34%), usually because of inadequacy of activation data. We conclude: (1) although focal originating of ventricular tachycardia is common, more frequently the mechanism is either macroreentry or uncertain, as assessed by conventional recording techniques; thus, a search for the "site of earliest activation" during ventricular tachycardia frequently may fail to direct rationally the operative procedure; (2) conventional techniques for intraoperative study of electrical activation during ventricular tachycardia are inadequate.

    Title Pharmacokinetics of Oral Cibenzoline in Arrhythmia Patients.
    Date July 1985
    Journal Clinical Pharmacokinetics
    Excerpt

    The pharmacokinetics of oral cibenzoline were studied in 30 arrhythmia patients as part of an ascending multiple-dose efficacy study. The elimination half-life of the drug following repetitive dosing ranged from 7.6 to 22.3 hours, with a harmonic mean of 12.3 hours (n = 24), and increased with age and decreasing renal function. The drug exhibited apparent dose proportional and linear pharmacokinetics over the range of doses studied. Multivariate analysis revealed that the patients' age and serum creatinine concentration accounted for 71% of the variability in the range of beta values (terminal elimination rate constant), and that 69.5% of the intersubject variability in the steady-state trough plasma concentrations could be accounted for by the patients' age, weight and serum creatinine concentration. These data suggest that, although there is some intersubject variability in the elimination and accumulation of cibenzoline, much of the variability can be explained by the patients' age, weight and renal function.

    Title Clinical Experience, Complications, and Survival in 70 Patients with the Automatic Implantable Cardioverter/defibrillator.
    Date February 1985
    Journal Circulation
    Excerpt

    Seventy patients received the automatic implantable defibrillator, five original devices and 72 modified second-generation devices using only bipolar rate sensing and delivering an R wave synchronous cardioverting/defibrillating shock, for either ventricular tachycardia or fibrillation. The primary clinical arrhythmia was sustained ventricular tachycardia in 32 patients, ventricular fibrillation in 20 patients, and both ventricular tachycardia and fibrillation in 18 patients. Before implantation of the device the patients had survived 3.1 +/- 2.3 arrhythmic episodes, including 1.9 +/- 1.7 cardiac arrest, and had received 4.0 +/- 2.1 antiarrhythmic drugs without improvement. Sixty-eight patients ultimately received devices. After a follow-up period of 8.9 +/- 7.7 months (range 1 to 33), 37 patients received a total of 463 discharges. Inability to determine the precise reason for most discharges and the unpleasant nature of the discharges were the major clinical problems encountered. Complications included postoperative death (one patient), lead problems (six patients), inadequate energy requiring explanation (two patients), and pocket infection (one patient. Life-table analysis revealed 6 and 12 month cardiovascular survival of 95.0% and 89.9% and sudden death survival of 98.2%. In our experience, survival with the automatic implantable cardioverter/defibrillator exceeds that with other forms of therapy.

    Title Treatment with Oral Lorcainide in Patients with Sustained Ventricular Tachycardia and Fibrillation.
    Date February 1985
    Journal American Heart Journal
    Excerpt

    Fifty patients with drug-refractory (failed 7 +/- 2 other drug trials) sustained ventricular tachycardia or fibrillation were treated with oral lorcainide. Twenty-three patients underwent programmed stimulation both before and after oral lorcainide, and all 23 remained inducible, although ventricular tachycardia cycle length was prolonged and mean arterial pressure was higher. Lorcainide was discontinued in 23 patients prior to hospital discharge because of death in four patients, side effects in five patients, spontaneous clinical arrhythmia recurrence in six patients, and ventricular tachyarrhythmias induced at electrophysiologic study in eight patients. Twenty-seven patients were discharged on an average dose of 169 +/- 56 mg twice a day, including 15 in whom ventricular tachycardia remained inducible. During long-term follow-up the drug was discontinued in 15 patients; three because of side effects, three because of clinical nonfatal arrhythmia recurrence, two who selected other alternative therapy, and seven patients who died suddenly due to ventricular tachyarrhythmias. Twelve patients remain on long-term lorcainide. The actuarial 1-year chance of being arrhythmia free was 38.9%, and 1-year cardiovascular and arrhythmia survival rates were 56.8% and 60.4%, respectively. Based on our data we conclude that: In this extremely drug-resistant patient population the clinical efficacy of lorcainide is low; lorcainide should not be used empirically in such highly drug-resistant patients; persistent ventricular tachyarrhythmia inducibility at electrophysiologic study implies a poor prognosis in patients treated with oral lorcainide; the incidence of becoming noninducible during oral lorcainide therapy in highly drug-resistant patients appears low; and for patients in whom the drug seems partially beneficial it could be used in conjunction with a backup automatic implantable cardioverter/defibrillator.

    Title Chronic Lorcainide Therapy for Symptomatic Premature Ventricular Complexes: Efficacy, Pharmacokinetics and Evidence for Norlorcainide Antiarrhythmic Effect.
    Date January 1985
    Journal The American Journal of Cardiology
    Excerpt

    Chronic premature ventricular complexes (PVCs) have been effectively suppressed by oral lorcainide as reported in previous short-term studies. The plasma level-effect relation of lorcainide may be affected by the possible cardioactivity of norlorcainide, a metabolite that accumulates after repeated oral doses. This study evaluated the long-term efficacy of lorcainide in suppressing chronic symptomatic PVCs, and examined the relation of arrhythmia suppression to plasma concentrations of lorcainide and norlorcainide. Fourteen patients were treated with lorcainide, 200 to 400 mg/day, 12 of whom achieved nearly complete suppression of arrhythmias after treatment for 1 year. Chronic lorcainide treatment was well tolerated; no patient discontinued treatment because of adverse effects. Lorcainide and norlorcainide plasma concentrations remained stable after the first week of therapy. Antiarrhythmic activity persisted throughout the year. Upon drug withdrawal, the mean lorcainide washout half-life was 14.3 +/- 3.7 hours and the mean norlorcainide washout half-life was 31.9 +/- 8.9 hours. The return of arrhythmias occurred well after the lorcainide plasma concentration had decreased to subtherapeutic levels, suggesting an antiarrhythmic effect of norlorcainide. Thus, long-term lorcainide therapy is effective in treating chronic symptomatic PVCs and is well tolerated by most patients. The metabolite norlorcainide appears to have antiarrhythmic activity independent of lorcainide.

    Title Comparative Electrophysiology of Lorcainide and Norlorcainide in the Dog.
    Date December 1984
    Journal Journal of Cardiovascular Pharmacology
    Excerpt

    Electrophysiologic effects of intravenous lorcainide and its major metabolite, norlorcainide, were examined in 18 anesthetized dogs, using intracardiac electrophysiologic measurements and programmed stimulation. Lorcainide and norlorcainide were studied separately, using six dogs for each experiment. Each compound was administered by a series of 5 one-h graded infusions each involving a loading dose over 15 min followed by a 45-min maintenance infusion. Plasma concentrations ranged from 94 +/- 34 to 1345 +/- 471 ng/ml for lorcainide and 81 +/- 22 to 1344 +/- 458 ng/ml for norlorcainide. Six additional dogs were studied, using a combination of a constant lorcainide infusion and four progressively increasing doses of norlorcainide. Both lorcainide and norlorcainide caused concentration-dependent prolongation of PR interval, QRS duration, AH and HV intervals, atrial and ventricular effective refractory periods, and the atrioventricular nodal functional refractory period. For each electrophysiologic parameter, plots of percent change as a function of log plasma concentration were nearly superimposable for lorcainide and norlorcainide. Plots for the combined treatment group using the total plasma concentration of lorcainide and norlorcainide were similar to those for each compound alone. We conclude that in dogs norlorcainide has considerable electrophysiologic activity, and is approximately equieffective and equipotent when compared with lorcainide, and that the electrophysiologic effects of the two compounds appear additive.

    Title Practical Aspects of Automatic Cardioverter/defibrillator Implantation.
    Date December 1984
    Journal American Heart Journal
    Title Facilitation of Ventricular Tachyarrhythmia Induction by Isoproterenol.
    Date November 1984
    Journal The American Journal of Cardiology
    Excerpt

    Ventricular tachyarrhythmia induction was facilitated during infusion of isoproterenol in 21 of 60 patients with ventricular tachycardia (VT) or ventricular fibrillation (VF) in whom programmed electrical stimulation alone failed to reproducibly induce sustained ventricular tachyarrhythmias. Of 44 patients with no ventricular tachyarrhythmias induced before isoproterenol infusion, 11 had a sustained ventricular tachyarrhythmia and 1 patient had unsustained VT induced by isoproterenol alone or by programmed stimulation during the infusion. In 9 of 16 patients in whom nonreproducible or unsustained ventricular tachyarrhythmias were induced before isoproterenol infusion, more reproducible or more sustained ventricular tachyarrhythmias were induced during the infusion. Tachyarrhythmia induction was facilitated by isoproterenol in 20 of 40 patients with sustained VT clinically, but in only 1 of 20 patients with unsustained VT or VF clinically. Among patients with sustained VT clinically, those with exercise-provoked VT and those who had not been tested with stimulation at a second right ventricular site or in the left ventricle were more likely to have induction facilitated by isoproterenol. Drugs effective against induction of isoproterenol-facilitated ventricular tachyarrhythmias were identified in 13 of 25 trials. These drugs were effective during a mean follow-up of 17 months in 7 of 9 long-term trials.

    Title Propafenone Disposition Kinetics in Cardiac Arrhythmia.
    Date September 1984
    Journal Clinical Pharmacology and Therapeutics
    Excerpt

    Propafenone disposition kinetics were studied after intravenous and oral doses in patients with ventricular arrhythmias. Plasma concentration-time data were fit to a two-compartment model for all but one patient, whose data required fitting to a three-compartment model. The model-independent calculated values of clearance, steady-state volume of distribution, and terminal t1/2 were 11.2 +/- 4.8 ml/min/kg, 3.6 +/- 2.1 l/kg, and 5.0 +/- 3.6 hr. After 5 days on oral propafenone, elimination t1/2 was 6.2 +/- 3.3 hr. The longer t1/2s and the estimates of steady-state bioavailability above 100% suggests that clearance decreases during chronic oral dosing. Considerable intersubject variability was noted in all disposition parameters.

    Title Measurement of Cardioversion/defibrillation Thresholds in Man by a Truncated Exponential Waveform and an Apical Patch-superior Vena Caval Spring Electrode Configuration.
    Date April 1984
    Journal Circulation
    Excerpt

    Defibrillation/cardioversion thresholds were measured in 33 patients undergoing defibrillator implants. Each patient had a 12 cm2 patch placed near the left ventricular apex via a thoracotomy and a 10 cm2 spring lead placed pervenously at the right atrial-superior vena caval junction. Ventricular tachycardia of stable morphology, polymorphic ventricular tachycardia, or ventricular fibrillation was induced four times in each patient and 1, 5, 10, and 25 J truncated exponential shocks with 60% tilt were given in a random sequence. The conversion rate was constant (77%, 86%, 87%, 85%) with increasing energy for ventricular tachycardia but progressively increased for polymorphic ventricular tachycardia and ventricular fibrillation (8%, 33%, 58%, 92%). The ventricular tachycardia acceleration rates for 1, 5, 10, and 25 J were 23%, 14%, 10%, and 15%. Patients not reliably converted with 25 J may require repositioning of leads or two patches. We conclude that for the spring-patch electrodes, increasing energy from 1 to 25 J improves the conversion rate for polymorphic ventricular tachycardia and ventricular fibrillation; the ventricular tachycardia conversion rate is constant. Acceleration of ventricular tachycardia occurs at all energies. Defibrillator implantation requires extensive intraoperative electrophysiologic testing to ensure safe and reliable termination of ventricular tachycardia and fibrillation.

    Title Pharmacodynamics of the Initiation of Antiarrhythmic Therapy with Lorcainide.
    Date March 1984
    Journal The American Journal of Cardiology
    Excerpt

    Lorcainide is an antiarrhythmic drug with unusual pharmacokinetics and an active metabolite, norlorcainide, which complicate oral drug loading. In order to characterize the accumulation of lorcainide and norlorcainide and to define the onset of antiarrhythmic action during lorcainide loading, 9 patients with frequent ventricular ectopic beats were studied. During lorcainide loading with 100 mg orally twice daily, frequent ambulatory electrocardiographic recordings were monitored and blood samples for drug concentrations were determined. There was a 10-fold range of intersubject variation in plasma concentrations. Despite a half-life of only 8.9 +/- 2.3 hours, lorcainide did not reach steady state until after 4.5 days of therapy. Norlorcainide had a half-life of 26.5 +/- 7.2 hours and was estimated to come to steady state after 7 to 10 days. There was considerable intersubject variation in time of onset of antiarrhythmic response (2 to more than 4.5 days) and a 4- to 5-fold range of intersubject variation in threshold therapeutic plasma concentration (lorcainide 40 to 200 ng/ml, norlorcainide 80 to 300 ng/ml). These observations suggest that lorcainide should be started at low doses and the dose should not be increased more frequently than once a week.

    Title Clinical Efficacy and Electrophysiology of Imipramine for Ventricular Tachycardia.
    Date March 1984
    Journal The American Journal of Cardiology
    Excerpt

    Invasive electrophysiologic studies were performed before and during treatment with imipramine in 18 patients with inducible ventricular tachycardia (VT). All received imipramine, 50 mg twice daily for 3 days, and then 100 mg twice daily for 3 days. Imipramine increased the infranodal conduction times (HV) (from 58 +/- 7.8 to 65 +/- 10 ms) and QRS duration (from 133 +/- 21 to 153 +/- 39 ms) and significantly decreased sinus cycle length (from 875 +/- 145 to 711 +/- 116 ms) and maximal corrected sinus nodal recovery time (from 457 +/- 656 to 380 +/- 603 ms). The Wenckebach cycle length tended to decrease and the QT interval to increase, but these changes were not statistically significant. Atrial and ventricular refractory periods, atrioventricular nodal conduction times and induced VT cycle length did not change significantly. Imipramine prevented induction of VT in 2 patients, and VT was more difficult to induce in 1 patient. These 3 patients received chronic imipramine therapy. The 2 patients in whom no VT could be induced while taking imipramine have had no recurrence of arrhythmia at 6 and 12 months of follow-up. The third patient died suddenly 4 months after discharge from the hospital. One patient had worsening of arrhythmias while taking imipramine and 61% had minor adverse effects. The mean combined plasma imipramine and desmethylimipramine concentration at the time of the repeat electrophysiologic study was 227 +/- 114 ng/ml. Imipramine is effective against VT in some patients; however, like other type I antiarrhythmic drugs, the rate of efficacy is low.

    Title Recordings of Basal Ventricular Preexcitation from Electrode Catheters in Patients with Accessory Atrioventricular Connections.
    Date February 1984
    Journal Circulation
    Excerpt

    To determine the effects of ventricular preexcitation via accessory atrioventricular connections (ACs) on the sequence of basal ventricular activation, electrophysiologic study records of 22 patients with AC were reviewed. In each, AC site was confirmed by mapping done at operation. Local ventricular preexcitation (VP), defined as earlier timing of a local ventricular electrogram relative to the surface electrocardiographic QRS onset in preexcited compared with in normal QRS complexes, was assessed at the coronary sinus and at the ventricular septal summit recorded from the His bundle site. Five patients with concealed AC did not have VP. VP patterns with manifest AC were similar during average fusion QRS complexes and maximum ventricular preexcitation. Left free wall and left crux AC produced VP apparent on the ventricular electrogram recorded at the coronary sinus alone. With anteroseptal AC, VP was noted only at the ventricular septal summit. Posteroseptal AC produced VP that was apparent on the ventricular electrogram recorded at the coronary sinus and on the electrogram of the ventricular septal summit. Right free wall AC preexcited neither of these basal ventricular regions. The observation of VP patterns may help in localizing AC and may be particularly useful in patients without retrograde AC function at electrophysiologic study.

    Title Clinical Efficacy and Electrophysiology of Oral Propafenone for Ventricular Tachycardia.
    Date January 1984
    Journal The American Journal of Cardiology
    Excerpt

    Sixteen patients with ventricular tachycardia (VT) or nonfatal cardiac arrest were treated with propafenone (P), 900 mg/day. Electrophysiologic studies were performed before and during therapy with P. All patients had inducible sustained VT at the baseline study. During P therapy, VT was not inducible in 1 patient, was unsustained in 1 and was harder to induce in 2 patients. P increased the cycle length of VT from 307 +/- 67 to 382 +/- 107 ms. Five patients began outpatient therapy with P, including 2 in whom VT was slowed to less than 125 beats/min. Two are arrhythmia-free during follow-up of 2 and 8 months. P significantly increased intraatrial conduction time (from 44 +/- 12 to 72 +/- 22 ms), AH interval (from 115 +/- 36 to 152 +/- 45 ms), HV interval (from 55 +/- 18 to 92 +/- 42 ms), QRS duration (from 140 +/- 36 to 180 +/- 48 ms) and QT interval (from 402 +/- 30 to 459 +/- 60 ms). P increased atrial (from 247 +/- 36 to 288 +/- 38 ms) and ventricular (from 249 +/- 20 to 277 +/- 32 ms) effective refractory periods, Sinus cycle length did not change, but the corrected sinus node recovery time increased (from 162 +/- 85 to 821 +/- 1,607 ms). P aggravated arrhythmias in 4 patients. The plasma P concentration, measured either at the time of electrophysiologic studies of when therapy was discontinued, was 753 +/- 428 ng/ml. P suppressed ventricular ectopic beats in 33% and increased them in 1 patient. P has antiarrhythmic activity against VT similar to that of other antiarrhythmic drugs and has potential for serious adverse effects in some patients.

    Title Clinical Pharmacology of Propafenone.
    Date September 1983
    Journal Circulation
    Excerpt

    We determined the efficacy, pharmacokinetics, and plasma concentration-response relationships of propafenone, a promising new antiarrhythmic drug. Thirteen patients with frequent and complex ventricular premature beats were studied after receiving four increasing doses, during drug washout and during a randomized double-blind placebo-controlled trial, to evaluate the optimal dose in each patient. A nonlinear relationship was found between propafenone dose and steady-state mean concentration with a 10-fold increase in drug concentration as dose increased threefold from 300 to 900 mg/day. There was great intersubject variability in elimination half-life (mean 6 hr, range 2.4 to 11.8), steady-state mean concentration on 900 mg/day of propafenone (mean 1008 ng/ml, range 482 to 1812), and "therapeutic" plasma concentration (mean 588 ng/ml, range 64 to 1044). The interaction of these three parameters in individual patients determined the duration of the antiarrhythmic action of propafenone during washout (mean 11.5 hr, range 4 to 22). There was a greater than 90% reduction of ventricular premature beats in 10 subjects during dose ranging and in seven during double-blind crossover. Side effects requiring discontinuation of the drug occurred in three patients and included apparent worsening of arrhythmias in two. We conclude that propafenone effectively suppresses ventricular arrhythmias and that nonlinear drug accumulation and intersubject variability in elimination of half-life, steady-state mean plasma concentration, and therapeutic concentration indicate a need for individual therapy.

    Title Comparison of the Electrophysiologic Effects of Intravenous and Oral Lorcainide in Patients with Recurrent Ventricular Tachycardia.
    Date August 1983
    Journal Circulation
    Excerpt

    The electrophysiologic effects of intravenous lorcainide (2.2 mg/kg) in 10 patients were compared with the electrophysiologic effects of oral lorcainide (mean dose 400 mg/day for 8 days) in 11 patients, all with recurrent ventricular tachycardia that could be induced with programmed stimulation. Intravenous and oral lorcainide resulted in similar prolongation of the QRS, QT, and HV intervals, but only oral lorcainide resulted in prolongation of the AH interval and atrial and ventricular effective refractory periods. After both oral and intravenous lorcainide, ventricular tachycardia could still be induced, but the arrhythmia was slower and better tolerated hemodynamically. The mean plasma lorcainide level during a maintenance intravenous infusion was 1254 +/- 662 ng/ml compared with a lorcainide level of 562 +/- 41 ng/ml and a norlorcainide level of 1212 +/- 653 ng/ml after oral dosing. No norlorcainide was detected in plasma after intravenous lorcainide. These data suggest that the short-term electrophysiologic effects of intravenous lorcainide may be different from those of short-term therapy with the oral drug. These differences should be considered during short-term studies of lorcainide.

    Title Prognostic Significance of the Number of Induced Ventricular Complexes During Assessment of Therapy for Ventricular Tachyarrhythmias.
    Date August 1983
    Journal Circulation
    Excerpt

    We analyzed 255 long-term trials of antiarrhythmic therapy, each of which had been evaluated at electrophysiologic study, to identify the maximum number of induced ventricular complexes consistent with the long-term efficacy of antiarrhythmic therapy. All patients had spontaneous and inducible sustained ventricular tachycardia or ventricular fibrillation. The incidence of therapeutic efficacy at 1 month and throughout follow-up was similar for trials in which zero, one, two, three, four, five, six to 10, and 11 to 15 complexes were induced, but significantly lower (p less than .001) for trials in which 16 or more complexes were induced. The cumulative incidence of efficacy at 1 year was 75 +/- 5% for 0 to 5 induced complexes, 72 +/- 11% for six to 10 complexes, 83 +/- 15% for 11 to 15 complexes, 42 +/- 10% for 16 complexes to 15 sec, and 48 +/- 6% for sustained ventricular tachycardia. At 1 year, the incidence of "sudden death-free" survival was higher for patients in trials that prevented initiation of sustained ventricular tachycardia than for those in trials that permitted initiation of sustained ventricular tachycardia (91 +/- 3% vs 75 +/- 6%; p = .01). The duration of the arrhythmia induced at therapy assessment was in the range of 11 to 20 complexes for only 4% of trials. Antiarrhythmic therapy is likely to be effective if as many as 15 complexes are induced at therapy assessment. The best cutoff, between 11 and 20 complexes, is difficult to identify because of the small fraction of trials in this range. Patients in whom initiation of sustained ventricular tachycardia is not prevented are at high risk for arrhythmia recurrence and sudden death.

    Title The Automatic Implantable Defibrillator: Local Ventricular Bipolar Sensing to Detect Ventricular Tachycardia and Fibrillation.
    Date August 1983
    Journal The American Journal of Cardiology
    Excerpt

    The first-generation automatic implantable defibrillator implanted in man sensed arrhythmias by monitoring a transcardiac electrocardiographic signal. This sensing system reliably detected ventricular fibrillation and sinusoidal ventricular tachycardia but failed to sense all nonsinusoidal ventricular tachycardias. To solve this problem, a new ventricular tachycardia detection scheme was developed using a local ventricular bipolar electrogram and electronic circuits using rate averaging and automatic gain control to permit sensing of electrograms down to 0.1 mV. This detection scheme was tested during electrophysiologic studies in 11 patients with ventricular tachycardia and fibrillation. All 22 episodes of induced ventricular tachycardia with a rate above the selected cutoff were detected after an average of 5.1 +/- 1.8 seconds. No episodes below the rate cutoff were detected. The bipolar circuits also reliably detected ventricular fibrillation. Arrhythmia detection and signal quality in 9 patients receiving automatic defibrillators using the new bipolar rate detection circuit were compared with the findings in 5 patients previously receiving units that sensed arrhythmias using the transcardiac electrocardiographic signal. Compared with the transcardiac monitoring units the newer bipolar units had shorter and more uniform sense times (5.5 +/- 1.4 versus 12.2 +/- 7.1 seconds). It is concluded that malignant ventricular tachyarrhythmias can be sensed accurately using bipolar rate detection and that this system has numerous advantages over the previously used transcardiac electrocardiographic signal.

    Title Amiodarone: Clinical Efficacy and Toxicity in 96 Patients with Recurrent, Drug-refractory Arrhythmias.
    Date July 1983
    Journal Circulation
    Excerpt

    Ninety-six patients with recurrent, drug-refractory tachyarrhythmias were treated with amiodarone for 8.0 +/- 7.5 months (range 1 day to 27 months): 77 for recurrent ventricular tachycardia or ventricular fibrillation (VT/VF), two for complex ventricular ectopy, and 17 for supraventricular tachyarrhythmias. The actuarial incidence of successful amiodarone therapy was 52 +/- 7% at 12 months and 28 +/- 9% at 24 months for patients with VT/VF. Neither patient with complex ventricular ectopy was successfully treated. Among the patients with supraventricular tachyarrhythmias, 64.7% were successfully treated for 7.7 +/- 7.6 months (range 1 to 22 months). Amiodarone toxicity occurred in 66 of 91 patients (72.5%) treated for more than 1 week. Fourteen patients had therapy-limiting toxicity. Of these 14, six had pulmonary toxicity, four had arrhythmia exacerbation, one had hepatitis, one had renal toxicity, one had rash, and one had erythema nodosum. The actuarial incidence of therapy-limiting side effects was 27 +/- 7% at 15 months. We conclude that amiodarone is useful in the treatment of refractory tachyarrhythmias but that the rate of efficacy in VT/VF is lower and the incidence of significant toxicity is higher than has been generally appreciated.

    Title Safety and Efficacy of Intravenous Quinidine.
    Date July 1983
    Journal The American Journal of Medicine
    Excerpt

    The safety and efficacy of intravenous quinidine were evaluated in a patient population with a high prevalence of left ventricular dysfunction and intraventricular conduction delays. Quinidine gluconate (mean dose 9.1 +/- 1.6 mg/kg) was administered during electrophysiologic study to 100 patients with ventricular or supraventricular tachyarrhythmias. Clinical heart failure was present in 68 percent of the patients. Left ventricular end-diastolic pressure, cardiac index, and left ventricular ejection fraction were abnormal in 62, 48, and 70 percent, respectively. Major intraventricular conduction delays (QRS of 120 msec or more) were present in 27 percent, and the H-V interval was prolonged (over 55 msec) in 28 percent. Despite the prevalence of these abnormalities, quinidine was discontinued because of hypotension in only 10 patients. Saline solution was infused to maintain preload in 37 percent, and hypotension responded promptly to saline solution infusion or discontinuation of quinidine infusion in all subjects. Hypotension was not more common in patients with more severe left ventricular dysfunction. QRS duration, H-V interval, QTc, and right ventricular effective refractory period increased significantly (p less than 0.001) after quinidine administration. Heart block or QRS widening of 50 percent or more did not occur. Quinidine prevented arrhythmia induction in 26 percent of patients who received full doses. Ventricular tachycardia cycle length increased in all 41 patients in whom identical forms were induced before and after quinidine (287 +/- 71 msec versus 361 +/- 93 msec, p less than 0.001). Intravenous quinidine may be administered safely to patients with intraventricular conduction delays and moderate heart failure. When antiarrhythmic efficacy is assessed by electrophysiologic study, quinidine compares favorably with other antiarrhythmic agents.

    Title Determinants of Survival in Patients with Ventricular Tachyarrhythmias.
    Date July 1983
    Journal The New England Journal of Medicine
    Excerpt

    We analyzed data from 239 patients with sustained ventricular tachycardia or ventricular fibrillation to determine prognosis, predictors of survival, and the prognostic value of inducing arrhythmia and assessing therapy at the time of electrophysiologic study. Therapy predicted to be effective on the basis of electrophysiologic study was administered over a sustained period. There were 71 cardiac deaths, including 44 sudden deaths, during a mean (+/- S.D.) follow-up period of 14.8 +/- 13.9 months (range, one day to 67 months). At one, two, and three years, the actuarial incidence of sudden death was 17 +/- 3, 25 +/- 4, and 34 +/- 6 per cent, and that of cardiac death was 28 +/- 3, 37 +/- 4, and 50 +/- 6 per cent. Multivariate regression analyses demonstrated that the two strongest predictors of both sudden death and cardiac death were a higher New York Heart Association functional class (P less than 0.0001 for sudden death and P less than 0.0001 for cardiac death) and the failure of any therapy to be identified as potentially effective on the basis of electrophysiologic study (P = 0.0019 and P = 0.0003). The majority of deaths in patients with ventricular tachyarrhythmias were sudden, but the severity of heart failure was the strongest independent predictor of mortality. Response to therapy during electrophysiologic study was also an independent predictor of survival.

    Title Mortality in Patients with Implanted Automatic Defibrillators.
    Date June 1983
    Journal Annals of Internal Medicine
    Excerpt

    Fifty-two patients who survived several arrhythmic cardiac arrests had implantation of an automatic defibrillator along with additional cardiovascular surgery as indicated. The mean follow-up was 14.4 months and the longest was 3 years. In the hospital, the implanted devices identified and reverted 82 episodes of spontaneous and 81 of 99 episodes of induced malignant tachyarrhythmias. There were 62 automatic resuscitations in 17 patients outside the hospital. Twelve patients died; four of the deaths were not witnessed. These deaths represent a 22.9% total and 8.5% sudden-death 1-year mortality rate. Because the expected 1-year mortality in patients without the automatic defibrillator was calculated to be 48%, there was an estimated 52% decrease in anticipated total deaths. The automatic implantable defibrillator can identify and correct potentially lethal ventricular tachyarrhythmias, leading to a substantial increase in 1-year survival in properly selected high-risk patients.

    Title Possible Contribution of Encainide Metabolites to the Long-term Antiarrhythmic Efficacy of Encainide.
    Date May 1983
    Journal The American Journal of Cardiology
    Excerpt

    To establish long-term efficacy and the relation between drug plasma concentration and antiarrhythmic response, 12 patients with encainide-responsive frequent complex ventricular ectopic activity underwent 1 year of therapy with encainide. Twenty-four hour ambulatory electrocardiograms were obtained at baseline and every 2 months. Drug withdrawal with concomitant plasma sampling and electrocardiographic monitoring was performed at 6 and 12 months. Average group premature ventricular contraction (PVC) suppression during the year was 97 to 99%, with nearly total suppression of pairs and salvos. The most common adverse effects were transient visual disturbances and dizziness or lightheadedness. During a dose interval (6 to 12 hours) the concentration of encainide metabolites exceeded that of encainide by several-fold. The median time of arrhythmia return after drug withdrawal was 12 to 14 hours. At the time of arrhythmia return encainide was generally no longer detectable but the average concentration of O-demethylencainide and 3 methoxy-O-demethylencainide was 72 +/- 49 and 172 +/- 74 ng/ml, respectively. It is concluded that encainide therapy is extremely effective for continuous long-term suppression of complex ventricular arrhythmias and its metabolites contribute significantly to its antiarrhythmic action during chronic oral therapy.

    Title Clinical Factors Predicting Successful Electrophysiologic-pharmacologic Study in Patients with Ventricular Tachycardia.
    Date April 1983
    Journal Journal of the American College of Cardiology
    Excerpt

    Data from 142 patients who had sustained ventricular tachycardia or ventricular fibrillation were analyzed to determine if clinical variables predict response to antiarrhythmic drugs at electrophysiologic study. Effective antiarrhythmic drugs were identified for 43 patients (30%). Ten of 25 variables analyzed were univariate predictors of drug response at the probability (p) level of less than 0.05. Stepwise logistic regression identified three variables independently predictive of drug response: fewer coronary arteries with 70% or greater stenosis (p less than 0.001), female sex (p less than 0.002) and fewer episodes of arrhythmia (p less than 0.03). A function incorporating these three variables was constructed to predict the probability of drug response, and ranges of the predictor function corresponding to high, intermediate and low probabilities of drug response were identified. Response rates in the high (greater than 50%), intermediate and low (less than 10%) probability ranges were 28 (58%) of 48, 10 (27%) of 37 and 5 (9%) of 57, respectively. Thus 40% of the patients who had a less than 10% likelihood of benefit from electrophysiologic-pharmacologic study were classified into the low probability range. When the predictor function was applied prospectively to 25 additional patients, response rates in the three probability ranges were 3 (50%) of 6, 1 (12%) of 8 and 0 (0%) of 11. These data show that analysis of clinical variables can be used to estimate the probability of benefit from electrophysiologic-pharmacologic study.

    Title Lorcainide Disposition Kinetics in Arrhythmia Patients.
    Date February 1983
    Journal Clinical Pharmacology and Therapeutics
    Excerpt

    Lorcainide disposition kinetics were studied after intravenous and oral administration to patients with ventricular arrhythmias. After intravenous doses ranging from 100 to 200 mg, blood samples were drawn and plasma was analyzed for lorcainide concentration by high-pressure liquid chromatography. A three-compartment model was used to fit the data. The model-independent calculated values for clearance, steady-state volume of distribution, and terminal half-life were 14.4 +/- 3.28 ml/min/kg, 6.33 +/- 2.23 l/kg, and 7.8 +/- 2.2 hr. After nine doses of oral lorcainide (100 mg every 12 hr) blood samples were drawn and analyzed for lorcainide and its active metabolite, norlorcainide. The lorcainide and norlorcainide half-lifes were 9.6 +/- 2.8 and 26.8 +/- 8.2 hr. Mean steady-state level of norlorcainide was 2.2 +/- 0.9 times the level of lorcainide. The data suggest that the clearance of lorcainide decreases with time during long-term dosing.

    Title Antiarrhythmic Drug Combinations in the Treatment of Ventricular Tachycardia.
    Date January 1983
    Journal Circulation
    Excerpt

    Combinations of antiarrhythmic drugs are frequently used to treat refractory ventricular tachycardia (VT), but few scientific data support this practice. We examined the efficacy and electrophysiology of 110 antiarrhythmic drug combination trials at electrophysiologic study in 74 patients with recurrent ventricular tachycardia. Lidocaine was combined with quinidine in 33 trials, procainamide in 22 and encainide in 20. Propranolol was combined with quinidine in 17 trials, procainamide in 12 and encainide in six. All individual drugs tested (except propranolol, which was usually not tested individually) had failed at electrophysiologic study or clinically in the presence of usually accepted plasma concentrations. Lidocaine in combination with quinidine was effective in 3% of the trials, with procanamide in 5% and with encainide in none of the trials. Propranolol in combination with quinidine was effective in 18% of the trials, with procainamide in 17% and with encainide in none of the trials. The electrophysiologic effects of the tested drug combinations were dominated by the individual effects of the type 1 antiarrhythmic agents. We conclude that the tested antiarrhythmic drug combinations are infrequently effective in preventing VT induction at electrophysiologic study when each agent has failed individually. The addition of lidocaine or propranolol to quinidine, procainamide or encainide does not produce significant synergistic or new effects on the electrophysiologic variables analyzed.

    Title Decreased Incidence of Antiarrhythmic Drug Efficacy at Electrophysiologic Study Associated with the Use of a Third Extrastimulus.
    Date December 1982
    Journal American Heart Journal
    Excerpt

    Drug trials during electrophysiologic study were performed in 166 patients with sustained ventricular tachycardia (VT) or ventricular fibrillation. In the first 21 patients (group I), a maximum of two extrastimuli was used. In 145 subsequent patients (group II), drug efficacy was assessed using three extrastimuli if one or two failed to induce VT. The incidence of acute drug efficacy was 15 of 21 (71%) in group I, but only 44 of 145 (30%) in group II (p less than 0.01). To assess the influence of the third extrastimulus on the differing incidence of acute drug efficacy, we examined the 69 group II patients whose VT was initially induced by one or two extrastimuli. Acutely effective agents were identified for 19 of these 69 patients using up to three extrastimuli to define efficacy. In 24 of te 50 patients for whom no effective drug could be found, VT was induced with one or two extrastimuli during all drug trials. In the remaining 26 patients VT could be induced after drug administration only with use of three extrastimuli. If efficacy had been defined using a maximum of two extrastimuli, these 26 patients would have been considered responsive to drug testing. Overall, 45 to 69 (65%) rather than 19 of 69 (28%) would have had a favorable response (p less than 0.001). Fourteen group I patients and 17 group II patients in whom VT was initially induced by one or two extrastimuli received chronic therapy with agents predicted effective during acute drug trials. At 18 months, the cumulative percent of patients free of arrhythmia recurrence by actuarial analysis was 79 +/- 14% in group I and 80 +/- 14% in group II (NS). Use of three extrastimuli during drug trials is associated with a lower incidence of acute drug efficacy. Limited data suggest that prophylaxis against VT induction by three, rather than two, extrastimuli may not be a stronger predictor of chronic efficacy in patients whose VT is initially induced by one or two extrastimuli. Further study is needed to identify optimal pacing methods for antiarrhythmic drug assessment.

    Title Acute Hemodynamic Effects of Intravenous Encainide in Patients with Heart Disease.
    Date September 1982
    Journal American Heart Journal
    Excerpt

    Encainide, a new antiarrhythmic drug, was given intravenously (0.9 mg/kg) to 18 patients over 15 minutes to evaluate the hemodynamic effects. Hemodynamics and drug plasma concentrations were measured during and 30 minutes postdrug infusions. Encainide infusion was associated with a decrease in cardiac index from 2.6 +/- 0.7 to 2.4 +/- 0.7 L/min/m2 (p less than .05), a significant decrease in stroke work index and left ventricular end-diastolic pressure, and with a rise in systemic vascular resistance. There was no change in systemic or pulmonary arterial pressure, left ventricular dp/dt, or pulmonary vascular resistance. The patients were studied 30 to 60 minutes after cardiac angiography. Comparison of hemodynamic values obtained preangiography with those obtained postangiography (before, during, and after drug infusion) strongly suggests that many of the observed effects were due to radiographic contrast media (initial osmotic volume loading and subsequent diuresis). We conclude that if encainide has any significant hemodynamic effects after intravenous use, it is a modest decrease in cardiac output, possibly as a result of decreased left ventricular filling pressure.

    Title Surgery for Ventricular Tachycardia: Efficacy of Left Ventricular Aneurysm Resection Compared with Operation Guided by Electrical Activation Mapping.
    Date July 1982
    Journal Circulation
    Excerpt

    Sixty-five patients underwent surgery for recurrent ventricular tachyarrhythmias. The 32 patients in group 1 underwent simple left ventricular aneurysm resection. The 33 patients in group 2 underwent myocardial resection or incision guided by intraoperative mapping of the electrical activation sequence. The clinical, hemodynamic and angiographic characteristics of the two groups were similar. Although actuarial survival in the two groups was similar through 24 months, late attrition in group 1 patients has left only 21 +/- 13% (+/- SEM) alive by life-table analysis at 94 months. Arrhythmia recurrence has been greater in group 1 than in group 2. In group 1, 50 +/- 9% of patients at risk at 3 months had recurrences by actuarial analysis. In group 2, only 13 +/- 6% at 1 month, 17 +/- 7% at 3 months and 29 +/- 9% at 24 months relapsed. Death was caused by ventricular tachyarrhythmias in 12 of the 17 patients (71%) who died in group 1, but only three of 12 (25%) who died in group 2. We conclude that surgery of the left ventricle, guided and modified by intraoperative mapping of the electrical activation sequence, frequently eliminates ventricular tachyarrhythmias and may be more effective than blind resection of left ventricular aneurysm.

    Title Metabolite Cumulation During Long-term Oral Encainide Administration.
    Date May 1982
    Journal Clinical Pharmacology and Therapeutics
    Excerpt

    Cumulation of encainide and its major metabolites, O-demethylencainide (ODE), 3-methoxy-ODE (MODE), and N-demethylencainide (NDE) was examined in patients with frequent complex ventricular ectopy. After 6 mo on encainide patients were admitted to Stanford University Hospital and the drug was discontinued for 24 hr. During this time blood samples were drawn to characterize the cumulation and disposition of the drug and metabolites. The mean steady-state concentrations of encainide, ODE, and MODE were 56.3, 214.6, and 184.6 ng/ml after doses ranging from 100 to 250 mg/day. The concentration ratios of ODE/encainide and MODE/encainide were 5.02 +/- 2.61 and 5.15 +/- 4.13. NDE was detected in the plasma of only one patient. Elimination half lifes of encainide and ODE were 1.16 +/- 0.5 and 11.41 +/- 9.58 hr. MODE disappeared slowly and at 24 hr the plasma concentration was still 59.8 +/- 39.9% of its mean steady-state concentration. Our data indicate that the metabolites of encainide cumulate in the plasma of patients on long-term oral therapy and must be considered when evaluating its clinical efficacy.

    Title Randomized Double-blind Placebo Controlled Crossover Trial Documenting Oral Lorcainide Efficacy in Suppression of Symptomatic Ventricular Tachyarrhythmias.
    Date May 1982
    Journal American Heart Journal
    Excerpt

    Lorcainide, a new antiarrhythmic drug, was given to 10 patients with frequent (greater than 1/min) premature ventricular contractions (PVCs) on a baseline 24-hour Holter monitor. Each patient received lorcainide, 100 mg twice daily, and an identical placebo, in a randomized double-blind crossover trial, with 1 week in each treatment period. Before the trial and at the end of each period, routine laboratory, clinical evaluation, 12-lead ECG's, and 24-hour ambulatory ECG recordings were performed. Trough drug plasma concentration measurements were done at the end of each treatment period. All patients had reduction in PVCs, comparing drug to placebo, averaging 82.3 +/- 19.7% (mean +/- SD, p less than 0.01 by Wilcoxin ranked sum), and there was also significant decrease in the number of ventricular pairs and runs. Levels of the major metabolite, norlorcainide, ranged from 34 to 254 ng/ml (mean 160 ng/ml) and exceeded those for lorcainide, range 6 to 169 ng/ml (mean 79 ng/ml). Prolongation of PR, QRS, and QTc intervals was evident during drug therapy, as was decrease in heart rate, but these changes were minimal. The major adverse effect noted was sleep disturbance, which was often initially severe, but improved during the week of therapy.

    Title Programmed Ventricular Stimulation in Predicting Vulnerability to Ventricular Arrhythmias and Their Response to Antiarrhythmic Therapy.
    Date May 1982
    Journal American Heart Journal
    Excerpt

    In predicting vulnerability to ventricular arrhythmias and their response to antiarrhythmic therapy, several factors and questions need to be considered, including the following. (1) Ventricular tachycardia (VT) can be induced in most patients who have recurrent sustained VT. (2) Because induced VT can often be pace terminated, termination by pacing should be attempted before cardioversion is applied. (3) Acutely effective antiarrhythmic agents are no longer being found for the majority of patients undergoing electrophysiologic-pharmacologic study in our series. (4) Specific VT-induction programs affect both the inducibility of VT and acute efficacy of drugs at electrophysiologic study; this point requires examination. (5) Arrhythmia-induction studies may not product high yield in patients with clinical ventricular fibrillation or unsustained VT. (6) It is as yet unclear whether some drugs, such as amiodarone, can be accurately evaluated by using arrhythmia-induction techniques. (7) Induction of the repetitive ventricular response by V2 stimulation is not a useful method for antiarrhythmic drug selection in patients with recurrent ventricular tachyarrhythmias. (8) Adequate data do not yet exist to identify either the ECG-monitoring technique or the arrhythmia-induction technique as the preferred method for selecting antiarrhythmic drugs for chronic therapy of patients with recurrent ventricular tachyarrhythmias. A study to compare the accuracies of the two techniques is both feasible and needed.

    Title Relative Efficacy of Blind Left Ventricular Aneurysm Resection for the Treatment of Recurrent Ventricular Tachycardia.
    Date February 1982
    Journal The American Journal of Cardiology
    Excerpt

    Coronary arterial bypass grafting and left ventricular aneurysm resection and the two combined have been reported effective in control of refractory ventricular tachyarrhythmias; 82 percent of a pool of 127 patients (from 22 reports) survived after surgery. However, the follow-up period in this group is short and the extent of medical therapy is not well defined. Actuarial analysis of results of conventional left ventricular aneurysm resection in 32 Stanford patients with well documented ventricular tachyarrhythmias shows an arrhythmia recurrence rate of 50 +/- 9 percent (mean +/- standard error of the mean) during the postoperative hospitalization. In contrast, after 10 months only 11 +/- 9 percent of 18 patients who underwent myocardial resection guided by intraoperative electrical activation sequence mapping experienced arrhythmia recurrence. These data demonstrate that simple left ventricular aneurysm resection is less effective in preventing ventricular tachyarrhythmias than originally believed. Preliminary data suggest that surgery of the left ventricle guided by intraoperative mapping may provide more effective control of ventricular tachyarrhythmias. However, intraoperative mapping has many technical and interpretive problems. Investigations are needed to determine the roles of conventional and new operative approaches to treatment of medically refractory ventricular tachyarrhythmias.

    Title Mechanisms of Ventricular Tachycardia: Wide, Complex Ignorance.
    Date February 1982
    Journal American Heart Journal
    Title Malignant Ventricular Tachyarrhythmias Associated with the Use of Encainide.
    Date January 1982
    Journal American Heart Journal
    Excerpt

    In patients treated with the antiarrhythmic drug, encainide, the agent appeared to cause or exacerbate malignant ventricular tachyarrhythmias in 11 cases. The most common type of arrhythmia associated with encainide toxicity was polymorphic ventricular tachycardia (VT) resulting in cardiac arrest. In contrast to drug-induced arrhythmias commonly encountered with quinidine and other type I antiarrhythmic drugs, encainide-induced rhythm was not associated with marked QT prolongation, was not necessarily initiated by R-on-T premature ventricular beats, and usually did not self-terminate. Two patients could not be resuscitated from the rhythm, and several others required prolonged or multiple resuscitations. The risk of encainide-induced ventricular tachyarrhythmias was 11% in 90 patients receiving the drug for recurrent sustained VT and/or fibrillation (VF), 2.2% in 47 patients receiving the drug for chronic complex ventricular ectopic activity. Encainide-induced arrhythmias occurred 29.8 +/- 11.3 hours (range 17 to 48 hours) after starting chronic oral maintenance doses or after dose increases, or 1 to 2 hours after single large doses. Patients experiencing this adverse effect could not be distinguished from those who did not on the basis of encainide dose, degree of QRS widening, or clinical status. We recommend that patients with history of sustained VT or VF have encainide therapy started only in a hospital setting with continuous ECG monitoring and capabilities for cardiopulmonary resuscitation. Dose changes should not be made more frequently than every 48 hours, and patients should not be discharged from the hospital until they have been on stable dose of encainide for a minimum of 48 hours.

    Title Clinical Pharmacology and Antiarrhythmic Efficacy of Encainide in Patients with Chronic Ventricular Arrhythmias.
    Date September 1981
    Journal Circulation
    Excerpt

    We determined the pharmacokinetics, efficacy and therapeutic plasma concentration of encainide, a new antiarrhythmic drug that affects His-Purkinje conduction but not ventricular refractoriness. Nine patients with frequent and complex premature ventricular complexes were studied in a 3-day double-blind protocol. Each day, each patient received 75 mg of i.v. or oral encainide or placebo. Frequent blood samples for encainide plasma concentration determination and continuous ambulatory ECGs were obtained. There was a marked intersubject variation in bioavailability (mean 42 +/- 24%, range 7.4-82%), clearance (13.2 +/- 5.6 ml/min/kg, range 3.75-22.1 ml/min/kg) and half-life (3.4 +/- 1.7 hours i.v., 2.5 +/- 0.8 hours oral). Eight of nine patients had more than 90% suppression of premature ventricular complexes for 3-36 hours. Minimal antiarrhythmic plasma concentration was higher (39 +/- 54 ng/ml, range 3.5-170 ng/ml) after i.v. dosing than after oral dosing (14 +/- 16 ng/ml, range 1.5-48 ng/ml), suggesting an active metabolite after oral dosing in many patients. Minimal side effects were seen despite high peak plasma concentrations (range 794-1556 ng/ml i.v., 36-495 ng/ml oral). The minimal ratio of toxic to therapeutic plasma concentration ranged from 4.3-326 (median 23) after oral dosing. Antiarrhythmic action was associated with an 11-44% widening of the QRS complex that was not associated with other adverse effects. We conclude that encainide effectively suppresses ventricular arrhythmias. Despite a variable bioavailability, high clearance and short half-life, its wide ratio of toxic to therapeutic concentration and probable active metabolite permit a long duration of action, which should allow a reasonable dose schedule in most patients during chronic oral dosing.

    Title Electrophysiologic Effects of N-acetylprocainamide in Human Beings.
    Date June 1981
    Journal The American Journal of Cardiology
    Excerpt

    The electrophysiologic properties of N-acetylprocainamide (NAPA) were studied in 10 patients undergoing cardiac catheterization. Each patient received two successive intravenous infusions: one loading infusion over 15 minutes and one maintenance infusion at a slower rate for 30 minutes. Eight patients received 10.5 mg/kg body weight and two received larger doses (16 and 21 mg/kg, respectively). NAPA plasma concentration was measured at 5 minute intervals from 0 to 25 minutes, and then at 15 and 30 minutes of the second infusion. Mean blood pressure and electrophysiologic data obtained by programmed stimulation were recorded before drug administration and at 15 and 30 minutes of the infusion when the concentration of NAPA was nearly constant in each patient (range 12 to 35 microgram/ml). NAPA decreased blood pressure (p less than 0.005), increased corrected Q-T interval (p less than 0.01) and increased the atrial and ventricular effective refractory periods from 267 +/- 40 to 307 +/- 41 ms (p less than 0.01) and from 278 +/- 37 to 301 +/- 32.8 ms (p less than 0.05), respectively. NAPA did not significantly change sinus cycle length or sinus nodal recovery time, conduction intervals (A-H, H-V, P-R, QRS), atrioventricular nodal functional refractory period or nodal Wenckebach cycle length. The patient receiving the largest dose experienced mild nausea when the plasma concentration was above 35 microgram/ml. These data show that the electrophysiology of NAPA in human beings is different from that reported for procainamide. At the plasma concentrations studied NAPA increases atrial and ventricular refractory periods without increasing cardiac conduction times

    Title Tocainide for Drug-resistant Ventricular Arrhythmias: Efficacy, Side Effects, and Lidocaine Responsiveness for Predicting Tocainide Success.
    Date February 1981
    Journal American Heart Journal
    Excerpt

    Tocainide therapy has been evaluated in 38 patients with ventricular arrhythmias. Thirty-one had recurrent sustained ventricular tachycardia and/or fibrillation and 29 required prior cardioversions. These arrhythmias could not be managed with quinidine, procainamide, disopyramide, or propranolol. Tocainide doses averaged 1,500 mg/day (range 600 to 2,400) and the majority of patients had plasma concentrations from 6 to 12 micrograms/ml. Twenty-two patients (61%) had their arrhythmias controlled with tocainide and 16 (39%) did not. Tocainide dose and plasma concentrations were similar for responders and nonresponders. Lidocaine was effective in 26 patients and 16 (63%) of these had their arrhythmias controlled with tocainide. Of 12 patients in whom lidocaine was known to be ineffective or who had not been previously treated, only two (17%) had arrhythmias controlled with tocainide (P < 0.02). Side effects occurred in approximately two thirds of patients but required discontinuation of long-term tocainide in only three patients.

    Title Time Dependency of Ventricular Fibrillation Thresholds Determined Using Trains of Stimuli.
    Date December 1980
    Journal The American Journal of Physiology
    Excerpt

    When determining ventricular fibrillation threshold (VFT), considerable time elapses from beginning a VFT measurement until the actual occurrence of ventricular fibrillaion (VF). We have defined this elapsed time as the "time to VF" and examined the effect of varying time to VF on the measured value of VFT. We induced VF in anesthetized dogs with a 100-Hz train of 16 4-ms stimuli applied to the right ventricular epicardium. The time to VF was varied by changing either the increment of fibrillation current increase (0.5, 1.0, or 2.0 mA) from one train to the next and/or the number of atrial paced beats between trains (6-192 beats). For 0.5-mA current increments, as time to VF increased from 66 to 454 s, VFT fell progressively from 15.3 +/- 4.8 to 6.7 +/- 1.1 mA. When time to VF exceeded 454 s, VFT increased again. Current increments of 1.0 and 2.0 mA had a similar time dependency of VFT. For any time to VF the VFT was lower when small current increments (i.e., more trains) were used to induce VF. Pretreatment with reserpine in six dogs abolished the time dependency. We conclude that time elapsed from the beginning of a VFT determination until VF actually occurs and the total number of trains used are important determinants of the VFT, probably because of local catecholamine release by the stimuli.

    Title Accuracy of the Ventricular Tachycardia-induction Study for Predicting Long-term Efficacy and Inefficacy of Antiarrhythmic Drugs.
    Date December 1980
    Journal The New England Journal of Medicine
    Excerpt

    We evaluated the prophylactic effect of antiarrhythmic agents against induction of ventricular tachycardia by extrastimulation in 51 patients with recurrent ventricular tachycardia. These patients subsequently underwent 58 long-term trials with tested agents. In 39 trials an agent predicted to be effective by electrophysiologic study was administered, and in 19 a drug predicted to be ineffective was used. There were no clinical differences between the two treatment groups. During a mean follow-up period of 8.2 months, arrhythmias recurred significantly less frequently in the group treated with drugs predicted to be effective than in the other group (P < 0.001); at six months 80 per cent of the patients in the former group were successfully treated, as compared with 33 per cent in the latter group. At 18 months the corresponding figures were 68 per cent and 11 per cent. We conclude that the arrhythmia-induction technique accurately predicts the clinical effectiveness of drugs used in the long-term treatment of recurrent ventricular tachycardia.

    Title Effects of Encainide (mj9067) on the Ventricular Fibrillation Threshold in Anesthetized Dogs.
    Date November 1980
    Journal Journal of Cardiovascular Pharmacology
    Excerpt

    The right ventricular epicardial ventricular fibrillation threshold (VFT) was determined during paced supraventricular rhythm using 100 Hz trains of stimuli at 15 min intervals in dogs before and during the intravenous administration of encainide, a new antiarrhythmic drug. With each VFT determination, simultaneous blood samples were obtained for determination of drug concentration. In 6 control dogs, VFT determined every 15 min during a 210 administered as a 90 min intravenous infusion at three successive rates (0.01, 0.02 and 0.04 mg/kg/min) for 30 min each. VFT measured at 5 and 20 min of each infusion increased from a mean control of 11.5 +/- 1.5 (+/-SE) to 20.2 +/- 2.2 mA (p less than 0.01) after 20 min of the third infusion. The maximal effect occurred during the second infusion with plasma concentration of 594 +/- 46 ng/ml and then reached a plateau. In group II (n = 6), encainide was administered in four successive sequences, each one including a bolus loading intravenous dose followed by a 45 min intravenous infusion. VFT measured at 30 and 45 min of each infusion when the encainide plasma concentration was close to a steady state increased significantly (p less than 0.01) after the second infusion from 11.8 +/- 2 to 27.3 +/- 4 mA. Two dogs in group II developed transient complete atrioventricular block at an encainide plasma concentration of greater than 800 ng/ml. These results show that the new antiarrhythmic drug encainide increases the VFT in anesthetized dogs.

    Title Intravenous N-acetylprocainamide Disposition Kinetics in Coronary Artery Disease.
    Date September 1980
    Journal Clinical Pharmacology and Therapeutics
    Excerpt

    N-Acetylprocainamide (NAPA) disposition kinetics was studied in eight patients with coronary artery disease. NAPA was given over a 45-min period by intravenous infusion, and blood samples were drawn at specified times for 24 hr. NAPA plasma levels were determined by a specific high-pressure liquid chromatography (HPLC) procedure and the concentration-time data were fit to a three-compartment model. Mean (+/- SD) values for the elimination half-life, the total body clearance, and the steady-state volume of distribution were 9.53 +/- 3.22 hr, 1.98 +/- 0.40 ml/min/kg, and 1.30 +/- 0.18 1/kg. There was moderate intersubject variability in disposition. The data reported here differ from those reported for normal subjects.

    Title The Relationship Between the Repetitive Extrasystole Threshold and the Ventricular Fibrillation Threshold in the Dog. Non-parallel Changes Following Pharmacological Intervention.
    Date June 1980
    Journal Circulation Research
    Title Role of Concentration-dependent Plasma Protein Binding in Disopyramide Disposition.
    Date September 1979
    Journal Journal of Pharmacokinetics and Biopharmaceutics
    Title Electrode-catheter Arrhythmia Induction in the Selection and Assessment of Antiarrhythmic Drug Therapy for Recurrent Ventricular Tachycardia.
    Date January 1979
    Journal Circulation
    Excerpt

    We performed intracardiac electrophysiologic studies in 33 patients with recurrent ventricular tachycardia. Nineteen patients underwent one, 10 patients two, and four patients three serial electrophysiologic studies. Ventricular tachycardia was successfully induced in 83% of the patients, and pacing methods were successful in terminating tachycardia in 71% of the studies, although pacing-induced acceleration of ventricular tachycardia occurred at least once in 36% of the studies. Seventeen of the 33 patients (52%) required a total of 24 external direct current cardioversions during study. In 21 patients a variety of antiarrhythmic drugs were given I.V. and attempts at ventricular tachycardia induction were repeated to assess prophylactic effects of the drugs. An acutely effective drug or combination of drugs was found in 15 of the patients (71%). Fourteen of the 15 were placed on chronic oral therapy with the effective agent and were followed for an average period of 8.1 months (range one to 33 months). In all 14 patients we could document complete (13 patients) or partial (one patient) long-term prophylaxis against ventricular tachycardia. We conclude that drug efficacy trials in patients with recurrent ventricular tachycardia using intracardiac pacing techniques is a rapid and accurate method of selecting effective long-term antiarrhythmic therapy.

    Title Dose-dependent Acebutolol Disposition After Oral Administration.
    Date December 1978
    Journal Clinical Pharmacology and Therapeutics
    Excerpt

    The relationship between dose and area under the blood concentration-time curve has been studied in 6 healthy subjects following both oral and intravenous doses of acebutolol. There is a more than proportional increase in area with increasing oral doses, and the area over a dosing interval following multiple oral doses is greater than the total area after a single dose of the same size. The role of an acetyl metabolite in producing these effects is discussed, as is the relevance of these observations to the clinical use of acebutolol.

    Title Cardiac Biopsy Evidence for a Cardiomyopathy Associated with Symptomatic Mitral Valve Prolapse.
    Date November 1978
    Journal The American Journal of Cardiology
    Excerpt

    Right ventricular endomyocardial biopsy was performed in 14 patients with mitral valve prolapse to determine the existence of an associated cardiomyopathic process. All 14 patients had echocardiographic, angiographic or auscultatory evidence of mitral valve prolapse, and all were symptomatic. The group had a high incidence rate of conduction system abnormalities (50 percent) and arrhythmias (64 percent), but only one patient had a significant hemodynamic abnormality. Light microscopy revealed an increase in endocardial and interstitial fibrosis in eight patients (57 percent). Electron microscopy, performed in 11 patients, showed mitochondrial degenerative changes in all 11. Nuclear chromatin clumping, intracell edema and myocyte degeneration were frequently present. It is concluded that endomyocardial and myocardial abnormalities exist in some symptomatic patients with idiopathic mitral valve prolapse.

    Title Antiarrhythmic Drug Effect Assessed from Ventricular Arrhythmia Reduction in the Ambulatory Electrocardiogram and Treadmill Test: Comparison of Propranolol, Procainamide and Quinidine.
    Date October 1978
    Journal The American Journal of Cardiology
    Excerpt

    A 5 week study was performed in 17 patients with frequent ventricular ectopic complexes. The study design comprised an initial control period, 1 week each of treatment with propranolol (240 mg daily), procainamide (3.0 g daily) and quinidine (1.8 g daily) and a final control period. Twenty-four hour ambulatory electrocardiograms and maximal exercise tests were performed each week. For the group, the total number and qualitative types of ventricular ectopic complexes were similar during the two control periods; however, there were large variations among individual patients. Each drug reduced the total number of ventricular ectopic impulses and the percent of patients with each qualitative type. There was agreement between the ambulatory electrocardiogram and treadmill test in three quarters of the drug evaluations. Although it is possible to determine antiarrhythmic drug effects for a group, spontaneous variability in the occurrence of ventricular arrhythmias makes it difficult to evaluate the effects in individual patients.

    Title Effects of Tocainide on Ventricular Fibrillation Threshold. Comparison with Lidocaine.
    Date September 1978
    Journal The American Journal of Cardiology
    Title Contribution of Ambulatory Electrocardiographic Monitoring to Antiarrhythmic Management.
    Date August 1978
    Journal The American Journal of Cardiology
    Title Antiarrhythmic Drugs: Clinical Pharmacology and Therapeutic Uses.
    Date July 1978
    Journal Drugs
    Title Long-term Tocainide Therapy for Ventricular Arrhythmias.
    Date June 1978
    Journal Circulation
    Excerpt

    Long-term tocainide therapy has been evaluated in 17 patients with ventricular arrhythmias. Ventricular tachycardia and/or fibrillation was recurrent and sustained in nine patients, and symptomatic but unsustained in three others. Five patients had frequent but only mildly symptomatic ventricular irritability. In all patients, arrhythmias could not be managed with quinidine, procainamide or propranolol. Tocainide doses ranged from 300 to 700 mg every 8 hours (mean steady-state plasma concentrations ranged from 5.75 to 12.18 microgram/ml). Tocainide therapy was unsuccessful in eight patients; three died during therapy and five had no antiarrhythmic response. The data suggest that evaluation of long-term drug efficacy, using the criterion of reduction of asymptomatic arrhythmias, is best documented by multiple sequential ambulatory electrocardiographic recordings, both on and off the drug. Tocainide controlled arrhythmias in nine patients (53%), with criteria of success being continued reduction of ectopic beats and/or control of symptomatic recurrences. Seven patients remain on therapy. Side effects generally have been minor and well-tolerated.

    Title Clinical Electrophysiologic Effects of Tocainide.
    Date May 1978
    Journal Circulation
    Excerpt

    The electrophysiologic properties of tocainide were evaluated by electrophysiologic studies in 11 patients before, during and after a constant intravenous infusion of the drug for 15 minutes. Peak plasma tocainide concentrations averaged 11.0 +/- 1.7 microgram/ml (SEM), range 3.7 to 22.7. AH, HV, QRS, QTc and RR intervals were measured every 5 minutes during sinus and atrial-paced rhythms and showed small changes which were not statistically significant for HV and QRS. Mild shortening of RR was significant (P less than 0.05) at 15 minutes only. AH tended to increase slightly for spontaneous (but not paced) rhythm, becoming significant at 15 minutes only (P less than 0.05). QTc decreased slightly, a change which was significant (P less than 0.05) for paced but not spontaneous rhythm. A progressive rise in mean arterial pressure occurred during infusion and persisted through 30 minutes (P less than 0.001). Comparison of electrophysiologic studies at 0 and 30 minutes showed decreased in mean effective refractory periods of atrium, A-V node, and right ventricle by 17, 22, and 23 msec, respectively (P less than 0.05, 0.01, 0.01). Functional refractory period of the A-V node showed an average decrease which was not significant. Sinus node recovery time and Wenckebach cycle length were unchanged. The drug was well tolerated in all 11 patients. Hypotension in a twelfth patient may or may not have been drug related. These results obtained at therapeutic plasma concentrations suggest qualitative similarities between the conduction system effects of tocainide and those published for lidocaine.

    Title The Hemodynamic Effects of Intravenous Tocainide in Patients with Heart Disease.
    Date May 1978
    Journal Circulation
    Excerpt

    In order to evaluate its hemodynamic actions, tocainide, a new orally effective antiarrhythmic drug, was given intravenously over a 15 minute period to 12 patients with compensated left ventricular dysfunction. Doses were 0.5 (4 patients) or 0.75 (8 patients) mg/kg/min. Hemodynamics and drug plasma concentrations were measured at the end and 15 minutes after the end of the infusion. Tocainide infusion produced small but statistically significant increases in the pulmonary and systemic vascular resistance, aortic and pulmonary arterial pressure, and left and right ventricular end-diastolic pressure. There was no significant change in left ventricular dp/dt, heart rate, or cardiac index. In patients with compensated left ventricular dysfunction, tocainide produces a small rise in vascular resistance and arterial pressure. Overall cardiac function is maintained with a small increase in left ventricular end-diastolic pressure.

    Title Electrophysiological Effects of Acebutolol.
    Date April 1978
    Journal British Heart Journal
    Title Clinical Pharmacokinetics of Antiarrhythmic Drugs.
    Date December 1977
    Journal Progress in Cardiovascular Diseases
    Title Acebutolol Metabolite Plasma Concentration During Chronic Oral Therapy.
    Date December 1977
    Journal British Journal of Clinical Pharmacology
    Excerpt

    1 We have measured the plasma concentration of acebutolol and a major metabolite in patients on chronic oral therapy with this drug, using a new assay, specific for each species. Our study suggests: 2 The acetyl metabolite was present in concentrations greater than those of acebutolol at all times during the dosing interval in all seven subjects. 3 The ratio of the mean steady-state plasma concentrations of the acetyl metabolite to unchanged acebutolol was 2.7 +/- 1.0. 4 Previous studies using non-specific methods that measure plasma concentrations of the acetyl metabolite and acebutolol as a single species cannot be used to determine pharmacokinetic parameters or to provide reliable correlations of plasma drug concentration with effect. 5 Future studies determining plasma concentration of acebutolol should take this metabolite into account. 6 Further work will be necessary to determine the metabolite's contribution to acebutolol's effects in man.

    Title Acebutolol Disposition After Intravenous Administration.
    Date December 1977
    Journal Clinical Pharmacology and Therapeutics
    Excerpt

    The disposition of acebutolol has been studied following intravenous doses of 0.25 to 1.0 mg/kg in 9 healthy subjects using a specific chromatographic assay to determine concentrations of drug in blood. The mean blood clearance was 6.55 ml/min/kg and the mean renal clearance, 2.68 ml/min/kg. Blood clearance was found to have a coefficient of variation of 14% for the group, to be independent of dose, and to remain essentially constant over approximately 3 wk. The fraction of the dose excreted in the urine unchanged was 0.405. Data were fitted to an equation for a two-compartment model. The mean fast and slow half-lives were 6.08 and 156.8 min, respectively. The volume of the central compartment was 0.223 L/kg, and the volume of distribution at steady-state was 1.165 L/kg. The fraction of acebutolol unbound to plasma proteins was 0.743 and was independent of drug concentration in the range examined. Data obtained from 15-min infusions were used to predict plateau blood concentrations with good accuracy during an 8-hr dosage regimen.

    Title Monitoring Electrocardiographic Data in Ambulatory Patients.
    Date December 1977
    Journal Medical Instrumentation
    Excerpt

    Sustained periods of extremely rapid or slow heart rate or initiation of the heartbeat from an ectopic focus can lead to serious clinical impairment or even death. Because disturbances of cardiac rhythm are ofter intermittent and evanescent, the development of systems for recording electrocardiograms in ambulatory patients for later analysis has been of clinical utility in diverse forms of heart disease. The basic components of such systems include a compact portable tape recorder for recording electrocardiographic data and a playback system with facilities for data analysis. Recently, semi-automated, computer-assisted analysis of this electrocardiographic data and quantitative analysis of the frequency of abnormal rhythms have become possible. In addition to widespread application for diagnostic purposes, ambulatory electrocardiographic techniques are now being used to evaluate new drugs for the treatment of cardiac rhythm disturbances and to define subsets of cardiac patients in whom treatment of rhythm disturbances may be desirable.

    Title Response Optimization of Drug Dosage: Antiarrhythmic Studies with Tocainide.
    Date August 1977
    Journal Clinical Pharmacology and Therapeutics
    Excerpt

    The benefits of using antiarrhythmic response to optimize dosage regimens of antiarrhythmic drugs in individual patients have been examined. Graded antiarrhythmic response and simultaneously measured plasma drug concentrations have been obtained in 15 patients receiving multiple oral doses of a new antiarrhythmic, tocainide. Plasma drug concentration-antiarrhythmic response data from each of 11 subjects responding to the drug have been fitted by a generalized concentration effect function which is valid over the entire range of response. With the use of experimentally determined pharmacokinetic parameters to define the dose-plasma concentration relationship and plasma drug concentration-response parameters estimated for individual patients, simulations were carried out to show the effect of various dosage regimens on antiarrhythmic response in individual patients. Such simulations provide a means of assessing antiarrhythmic effect in the range of clinical interest (80% to 100% of maximum effect), where the antiarrhythmic effect is a nonlinear function of dose, plasma drug concentration, or their logarithms. The simulations also demonstrate that for identical daily doses and dosing intervals patients show marked variability in antiarrhythmic response.

    Title Hemodynamic Effects of Intravenously Administered Quinidine on the Transplanted Human Heart.
    Date August 1977
    Journal The American Journal of Cardiology
    Excerpt

    The acute hemodynamic effects of intravenously administered quinidine were studied in five heart transplant recipients with an anatomically denervated heart. Quinidine, 10 mg/kg body weight, was infused over a 20 minute period, and mild wall left ventricular dynamics were measured with a new technique using metallic markers surgically implanted in the myocardial wall. Heart rate was maintained constant with atrial pacing, and aortic blood pressure was measured through an indwelling catheter. In each patient the hemodynamic responses to quinidine were similar. End-diastolic, end-systolic and stroke volumes decreased by an average of 19, 26 and 18 percent, respectively. Cardiac output decreased by a mean 0.92 liters/min (-18%), and the mean aortic blood pressure decreased by 10 mm Hg (-11%). All of these changes were statistically significant. Three indexes of the contractile state of the left ventricle--mean circumferential velocity, mean systolic diameter shortening and ejection fraction--were not significantly changed. We conclude that quinidine exerts no acute inotropic myocardial effects in the human transplanted heart and that, when given intravenously, its hemodynamic action is most consistent with venodilatation.

    Title Surgical Management of Life-threatening Ventricular Arrhythmias in Patients with Coronary Artery Disease.
    Date July 1977
    Journal Circulation
    Excerpt

    Twenty-one patients with coronary artery disease and severe, symptomatic ventricular arrhythmias underwent cardiac surgery after failure of medical managememt. All had coronary artery disease and either localized areas of severe hypokinesis (three patients), or ventricular aneurysms (18 patients) documented angiographically prior to surgery. Operation within one month after acute infarction resulted in an 80% in-hospital mortality, whereas operation more than one month postinfarction showed a 20% mortality. Operative treatment that included myocardial resection had a significantly lower mortality (P less than 0.05) than that which did not. With an average of 36.5 months of follow-up, 13 of the 21 patients were long-term survivors, despite the persistence of ventricular arrhythmias. Surgical treatment which includes myocardial resection and occurs more than one month after infarction should be considered in patients with symptomatic ventricular arrhythmias and severe, well-localized left ventricular wall motion abnormalities.

    Title Suppression of Premature Ventricular Contractions by Acebutolol.
    Date May 1977
    Journal Circulation
    Excerpt

    The antiarrhythmic action of the beta-blocking drug, acebutolol, was evaluated in patients with frequent premature ventricular contractions (PVCs). In the 12 hours following administration of a single 300 mg oral dose, 8 of 10 patients showed a greater than 50% reduction in PVC frequency, and statistical analysis indicated that PVC reduction persisted for 10 hours after the single dose. Analysis of plasma concentrations of acebutolol and an acetyl metabolite indicated that after single oral doses of plasma concentrations of the metabolite exceed those of unchanged acebutolol. When patients were studied during periods of 300 mg doses every 8 hours, eight of 11 showed a 70% reduction in PVC frequency, and analysis showed that the therapeutic effect was present throughout the 24-hour monitoring period. Acebutolol slowed the heart rate and prolonged the PR interval without affecting the QT interval. Significant clinical or laboratory toxicity was not encountered. In the small group studied, acebutolol was found to be safe and effective for short-term administration to patients with frequent PVCs and possessed a relatively long duration of antiarrhythmic action.

    Title Characteristics of Ventricular Tachycardia in Ambulatory Patients.
    Date May 1977
    Journal The American Journal of Cardiology
    Excerpt

    This study analyzes 94 episodes of the ventricular tachycardia recorded in the ambulatory electrocardiograms of 23 patients with stable cardiac disease. The episodes were asymptomatic in 19 patients, and only one episode resulted in ventricular fibrillation. Eighty-five percent of the episodes occurred when the underlying heart rate was less than 100 beats/min, and 17 percent occurred during sleep. The rate of the ventricular tachycardia was between 120 and 180 beats/min in 78 percent of the episodes and showed a modest correlation with the underlying heart rate (r = 0.59, P less than 0.001). Only 14 of the 94 episodes were initiated by R on T premature ventricular contractions, and the mean prematurity index (+/- standard deviation) (R-R'/Q-T) for all episodes was 1.31 +/- 0.28. Episodes of ventricular tachycardia recorded during ambulatory electrocardiographic monitoring are usually self-limited and asymptomatic. They occur during ordinary nonexertional activity and are frequently initiated by late couples premature ventricular contractions.

    Title Propranolol for Patients with Mitral Valve Prolapse.
    Date April 1977
    Journal American Heart Journal
    Excerpt

    This study evaluates propranolol's effect on symptoms, arrhythmias, and exercise tolerance in 16 patients with mitral valve prolapse. Three patients (19 per cent) experienced symptomatic deterioration with propranolol therapy, seven (44 per cent) were unchanged, and six (37 per cent) noted an over-all symptomatic improvement, primarily due to a reduction in palpitation. Symptomatic improvement continues in these six patients an average of 12.5 months after beginning propranolol therapy. Treatment with propranolol alleviated chest pain in only two of eight patients and it did not improve the ability to perform treadmill exercise. Fatigue did not improve, and in three patients appeared for the first time during propranolol therapy. Premature ventricular contractions were reduced by at least 75 per cent in five of nin patients (56 per cent), and paroxysmal ventricular tachycardia was eliminated in three of four patients. We conclude that propranolol is not uniformly effective in patients with mitral vale prolapse. A trial of propranolol may be instituted fro patients with mitral valve prolapse who have severe symptoms and/or arrhythmias, but the drug should only be continued in those who demonstrate clinical and/or antiarrhythmic response.

    Title The Electrophysiologic Effects of Quinidine in the Transplanted Human Heart.
    Date April 1977
    Journal The Journal of Clinical Investigation
    Excerpt

    Using His bundle recording techniques, we examined direct and autonomically mediated conduction system effects of quinidine in five cardiac transplant recipients who have anatomically denervated hearts. We made control conduction interval and refractory period measurements, and then infused 10 mg/kg quinidine gluconate over a 20-min period. At 30 min, we determined the electrophysiologic changes induced by quinidine. Quinidine significantly increased the atrial-His (AH) interval (from 97+/-9 [SEM] to 108+/-7 ms, P less than 0.001), the His-ventricular (HV) inteval (from 43.9 +/- 1 to 52.8 +/- 3 ms, P less than 0.01), the donor heart sinus cycle length (from 599 +/- 38 to 630 +/- 56 ms, P less than 0.08), and the atrial effective refractory period (from 214 +/- 14 to 241 +/- 11 ms, P less than 0.01). Quinidine significantly decreased the innervated, remnant atrial sinus cycle length (from 847 +/- 104 to 660 +/- 96 ms, P less than 0.01) and the blood pressure. The mean plasma concentration of quinidine at the time that electrophysiologic measurements were repeated was 4.37 +/- 0.449 micrograms/ml. We conclude that quinidine's predominant sinus nodal and atrioventricular nodal effects in man are autonomically mediated and opposite to its direct actions upon these structures. On the other hand, quinidine's prevailing effect on atrial refractoriness and His-Purkinje conduction in man is direct.

    Title Beta Blockers in the Treatment of Acute Arrhythmias [proceedings].
    Date March 1977
    Journal Heart & Lung : the Journal of Critical Care
    Title Clinical Efficacy and Pharmacokinetics of a New Orally Effective Antiarrhythmic, Tocainide.
    Date January 1977
    Journal Circulation
    Excerpt

    Tocainide, a new oral antiarrhythmic agent, was studied in man in a short-term protocol designed to evaluate the efficacy, kinetics, and toxicity of this compound. Premature ventricular contractions (PVCs) were suppressed by less than 70% in 11 of 15 patients compared with pre-drug placebo controls. For these 11 responders, there was an average PVC reduction of 91% +/- 10 (range 70 to 100%) at tocainide doses not associated with side effects. Mild transient central nervous system toxicity was observed in some patients near the time of peak concentrations during the highest dose administered. The drug was found to have linear kinetics over the dose range studied and a plasma half-life of 13.5 +/- 2 hours. Plasma concentration-response curves indicate antiarrhythmic activity over all plasma concentrations, with 70% PVC reduction above 6.0 mug/ml. This study suggests that tocainide is a safe and effective antiarrhythmic agent during short-term administration and is worthy of further clinical trials.

    Title Treatment of Recurrent Symptomatic Ventricular Tachycardia.
    Date August 1976
    Journal Annals of Internal Medicine
    Excerpt

    Eleven consecutive patients with recurrent ventricular arrhythmias were treated by an aggressive protocol and followed up prospectively. Arrhythmias, symptoms, and cardiac lesions were defined. Antiarrhythmic drugs were given on schedule, with blood levels determining dose; success or failure was defined by elimination or recurrence of symptomatic arrhythmias. When drug therapy failed, left ventricular aneurysmectomy was done when appropriate. Recurrent ventricular tachycardia was most frequently responsible for symptoms; coronary artery disease was the most frequent underlying disease. Symptomatic arrhythmias were eliminated in 8 of 11 patients (5 with drugs and 3 with aneurysmectomies), with a 16.5-month symptom-free average follow-up. An average of 2.9 therapeutic trials per patient was needed to control symptomatic arrhythmias. The average time from entry into the study until the start of ultimately effective therapy was 18 days. Therapy that eliminated symptoms did not eliminate all premature ventricular contractions, and occasionally even brief asymptomatic episodes of ventricular tachycardia persisted. Recurrent symptomatic ventricular arrhythmias can be controlled in many patients by rigorous application of current therapies.

    Title The Status of Cardiac Transplantation, 1975.
    Date November 1975
    Journal Circulation
    Excerpt

    Since December 1967, 263 human cardiac transplant operations have been performed throughout the world. Eighty-two of these were performed at Stanford University Medical Center, In 1974, 27 such operations were performed, 15 at Stanford Survival rates for the entire Standford series are 48% at one year and 25% at three years; survival rates at one and three years for patients surviving the first three critical months after transplantation are 77% and 42%, respectively. Recipients under the age of 55 years, with New York Heart Association Class IV cardiac disability, are selected for transplant procedures according to criteria dictated by experience over the past seven years. A routine immunsuppressive regimen for organ transplantation, incorporating prednisone, azathioprine, and antithymocyte globulin is employed early postoperatively, and prednisone and azathioprine are used for indefinite maintenance therapy. Acute cardiac graft rejection in nearly all recipients is diagnosed by clinical signs, electrocardiographic changes, and percutaneous transvenous endomyocardial biopsy. Ninety-five percent of acute rejection episodes are reversible with appropriate immunosuppressive treatment, but infectious complications are common and have accounted for 56% of all postoperative deaths. The Stanford experience in cardiac transplantation has demonstrated the potential therapeutic value of this procedure. Maximum survival now extends beyond five years. Satisfactory graft function has been documented in long-term surviving patients, the majority of whom have enjoyed a high degree of social and physical rehabilitation.

    Title Arrhythmias in Patients with Mitral Valve Prolapse.
    Date August 1975
    Journal Circulation
    Excerpt

    Resting ECGs, exercise treadmill tests and 24-hour ambulatory ECGs were recorded and analyzed in 24 unselected patients with mitral valve prolapse. Arrhythmias were frequent. There were three distinct groups of patients, defined on the basis of total number of premature ventricular contractions (PVCs) during the 24 hours; there were no PVCs in 25%, and frequent PVCs in 50%. Complex ventricular arrhythmias, including ventricular tachycardia in five patients, were found almost exclusively in the group with frequent PVCs. Fifteen of the 24 patients demonstrated atrial premature contractions (APCs) during the 24 hours. Complex atrial arrhythmias were found among patients with infrequent, as well as those with frequent, APCs. Supraventricular tachycardia was detected in seven of these patients. The incidence of ACPs decreased during sleep in 67% of the patients and showed no change during sleep in 33%. A poor correlation was found between symptoms recorded in patient diaries and changes noted on 24-hour ECG recordings. The peak PVCs/15 min and peak ACPs/15 min during a 24-hour period of monitoring was found to be an excellent guide to the total number of PVCs and APCs occurring during that period. This permits an accurate prediction of the total number of PVCs in 24 hours after performing an exact PVC count on only 15 minutes of ECG data. Finally, the 24-hour ambulatory ECG was sensitive than the treadmill test and both were superior to the 12-lead ECG for detecting arrhythmias in these patients.


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