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Biomedical subjects

P Dorian

Publications and source records attributed to P Dorian.

At least 37 records · Page 2Linked to original sources
PubMed2000

Is electrical storm in ICD patients the sign of a dying heart? Outcome of patients with clusters of ventricular tachyarrhythmias.

BACKGROUND: Electrical storm in patients with implanted cardioverter defibrillators (ICDs) is purported to carry an ominous prognosis. METHODS AND RESULTS: We retrospectively compared 40 patients with electrical storm (defined as three or more episodes of ventricular arrhythmia requiring ICD therapy in a 24 h period) with those only having isolated appropriate ICD therapy (n=57) and with patients having no or only inappropriate ICD therapy (n=125). All patients received ICDs for documented sustained VT or VF. There was no significant difference in age, sex, ejection fraction, total follow-up time, or underlying heart disease between any of the three groups. Patients who had electrical storm received their first appropriate ICD therapy 275 +/- 369 days post-implant (35% had storm as their first event) with storm occurring an average of 599 +/- 710 days post-implant. Patients had 1.5 +/- 1.0 storms in total (median= 1), with 55 +/- 91 episodes per storm. There were no significant differences in actuarial survival at 5-year follow-up between the three groups. Eighty percent of storm patients were alive 5 years post-implant. CONCLUSION: Storm is a common occurrence in ICD patients, can occur at any time during the follow-up period, and does not independently confer increased mortality.

Defibrillators, Implantable↗
PubMed2000

Rate dependence of the effect of antiarrhythmic drugs delaying cardiac repolarization: an overview.

Prolongation of the cardiac action potential and refractoriness (class III effect) is a potentially beneficial electrophysiological mechanism of action. However, this effect may be diminished or eliminated at rapid heart rates, so-called 'reverse rate dependence' of prolongation of repolarization. Action potential duration normally shortens as heart rate increases, due to increases in outward repolarizing currents, and/or decreases in inward depolarizing currents. The assessment of the effect of drugs on action potential duration is complicated by inter-species differences in ionic currents mediating repolarization, heterogeneity within the heart in repolarizing currents, and differential effect of drugs in different species, during differing experimental conditions, and at different rates of stimulation. In general, most drugs which predominantly block the IKr repolarizing current exhibit reverse rate-dependent effects on cardiac repolarization. Drugs or combinations of drugs which produce multiple ionic channel blocks and possibly those which block the IKs current, may be less prone to this potentially undesirable effect.

Action Potentials↗
PubMed2000

The defibrillator in acute myocardial infarction trial (DINAMIT): study protocol.

BACKGROUND: The implantable cardioverter/defibrillator (ICD) has been shown to be superior to antiarrhythmic drug therapy for the secondary prevention of sudden cardiac death. Its role in the primary prevention of sudden death after myocardial infarction is unknown. Methods and Results The Defibrillator in Acute Myocardial Infarction Trial (DINAMIT) is a randomized, open-label, parallel-group comparison of ICD therapy versus no ICD therapy in selected survivors of acute myocardial infarction. It will test the hypothesis that reduction of sudden arrhythmogenic death by means of the ICD will result in reduction of overall mortality rates in patients at high risk after acute myocardial infarction. Accordingly, this international multicenter study aims to enroll patients shortly after their infarction (day 6 to day 40) who have reduced left ventricular function (left ventricular ejection fraction </=0. 35) and impairment of cardiac autonomic function shown by depressed heart rate variability (standard deviation of normal-to-normal R-R intervals </=70 ms) or elevated average 24-hour heart rate (mean 24-hour R-R interval </=750 ms, assessed by Holter monitoring). Patients will be followed for approximately 3 years on average with subsequent data analysis based on the intent-to-treat principle. Primary outcome is all-cause death. The trial is expected to be completed in 2003. CONCLUSIONS: DINAMIT is the first prospective study to evaluate the benefit of ICD therapy for the primary prevention of sudden cardiac death in patients at high risk after acute myocardial infarction.

Defibrillators, Implantable↗
PubMed2000

Permanent explantation of implantable cardioverter defibrillators.

Although ICD therapy is seen as an irrevocable mode of therapy in most patients, a small number of patients do have their devices permanently explanted. The long-term outcome in these patients has not been described. The purpose of this single center study was to evaluate the long-term outcome of patients whose ICD was explanted and not replaced and to propose clinical variables that can be considered when making the decision to discontinue therapy. Ten of 323 (3.1%) patients in our ICD registry had their devices permanently explanted or turned off between 1986 and December 1998. The devices had been in place for 39 +/- 31 months preexplant. No patient had received appropriate therapy prior to surgery, which was indicated for infection or lead fracture. All patients are alive and well 75 +/- 30 months postexplant with 1 (10%) patient requiring late reimplantation. We reviewed the English language literature describing ICD explanation without replacement. A total of 151 patients were reported in eight studies and were followed for up to 30 months postexplant. Excluding patients with terminal illness or heart transplantation 57.6% survived without reimplantation. In selected patients, after not using an ICD for a long period and when clinical circumstances justify, device therapy may be discontinued with some degree of safety.

Adult↗
PubMed2000

Can antiarrhythmic agents be selected based on mechanism of action?

When selecting an antiarrhythmic agent the clinician needs to be able to accurately predict the probability that a particular drug will serve its intended purpose in a given patient. This is difficult because of the complexity of variables which govern the relationship between drug administration and clinical outcome. The efficacy of a drug may potentially be predicted from its mechanism of action. At least two classifications of antiarrhythmic agents based on mechanism of action have been proposed. The Vaughan Williams classification is based on the predominant electrophysiological effects of a drug on the action potential. In the Sicilian Gambit approach, a number of potential targets ('vulnerable parameters') for drug action are identified and antiarrhythmic drugs or substances that affect cardiac electrophysiology are characterised by their actions on each of these. The usefulness of these classification systems in predicting antiarrhythmic drug efficacy are limited. Furthermore, in the Vaughan Williams classification not all drugs in the same class have identical effects, whereas some drugs in different classes have overlapping actions. The Sicilian Gambit requires in-depth knowledge regarding cellular and molecular targets of antiarrhythmic agents which may make it intimidating or simply impractical for regular clinical use. Surrogate measures such as 24-hour Holter monitoring and programmed electrical stimulation have been used to predict anti-arrhythmic drug efficacy. However, studies such the Cardiac Arrhythmia Suppression Trial (CAST) have shown that suppression of ventricular ectopy on Holter monitoring does not necessarily correlate with improved survival and may in fact be dangerous. Conversely, studies using programmed electrical stimulation to assess drug effect on variables such as tachycardia inducibility, refractory period and ventricular tachycardia cycle length show that suppression of tachycardia inducibility, prolongation of refractory period and prolongation of ventricular tachycardia cycle length, are all associated with reduced recurrence of tachycardia and possibly improved survival. The most practical use of the current classification systems applied to antiarrhythmic agents may be in their ability to predict with reasonable accuracy, the risk and type of proarrhythmia based on the mechanism of action of an agent.

Anti-Arrhythmia Agents↗
PubMed2000

Mechanisms of action of class III agents and their clinical relevance.

Antiarrhythmic agents are broadly classified according to their mode of action in order to provide a basis for rational drug choice when managing particular rhythm disturbances. However, a great deal of variability exists within each drug class and treatment decisions require a greater understanding of the pharmacological characteristics of individual drugs in order to tailor treatment to a specific clinical presentation. Class III drugs in particular form a heterogeneous group of agents, some of which selectively block ion channels while others have multi-channel blocking properties. An improved understanding of the relevance of the specific mechanism of action is now proving essential in predicting the value of individual drugs in clinical practice. Selective I(Kr) blocking agents increase action potential duration and refractoriness to the greatest extent at slow rates. Therefore, efficacy may be reduced at higher heart rates, the situation in which serious arrhythmias are most likely to occur. This so-called 'reverse use dependence' can be overcome with certain drug combinations, such as sotalol plus either quinidine or procainamide, drugs with multi-channel blocking properties, such as amiodarone, and possibly with drugs which block the I(Ks) as well as the I(Kr) potassium current, such as azimilide and ambasilide.

Anti-Arrhythmia Agents↗
PubMed1999

Nocturnal and daytime panic attacks--comparison of sleep architecture, heart rate variability, and response to sodium lactate challenge.

BACKGROUND: The purpose of this study was to determine if nocturnal panic patients have greater autonomic dysregulation than patients with daytime panic. METHODS: Three groups were studied: patients who suffer from panic attacks during sleep (n = 12), those who suffer from daytime panic attacks only (n = 12), and control subjects (n = 12). Each subject underwent 24-hour holter monitoring for heart rate variability (HRV), an overnight sleep recording, and sodium lactate challenge during wakefulness. RESULTS: There was a marked subjective response to the sodium lactate challenge in the panic disorder (PD) patients but not in control subjects. Each group showed changes in HRV in response to sodium lactate challenge. The decrease in HRV measures was more marked in PD patients as a whole than in control subjects. During non-rapid eye movement (REM) sleep the value for total power (TP) was significantly higher in the nocturnal panic patients. The PD patients as a whole had higher values for TP and low-frequency (LF) power during REM sleep than control subjects. There were no significant differences between the two PD groups in sleep architecture. The PD patients as a whole had lower sleep efficiency and less stage 4 sleep than control subjects. CONCLUSIONS: These findings indicate that there are substantial differences between PD and control subjects in autonomic regulation and that there are small differences between patients with daytime panic attacks and those with sleep-related panic attacks.

Adult↗
PubMed1999

Amiodarone interaction with beta-blockers: analysis of the merged EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) databases. The EMIAT and CAMIAT Investigators.

BACKGROUND: Investigations with in vitro and animal models suggest an interaction between amiodarone and beta-blockers. The objective of this work was to explore if an interaction with beta-blocker treatment plays a role in the decrease of cardiac arrhythmic deaths with amiodarone in patients recovered from an acute myocardial infarction. METHODS AND RESULTS: A pooled database from 2 similar randomized clinical trials, the European Amiodarone Myocardial Infarction Trial (EMIAT) and the Canadian Amiodarone Myocardial Infarction Trial (CAMIAT), was used. Four groups of post-myocardial infarction patients were defined: beta-blockers and amiodarone used, beta-blockers used alone, amiodarone used alone, and neither used. All analyses were done on an intention-to-treat basis. Unadjusted and adjusted relative risks for all-cause mortality, cardiac death, arrhythmic cardiac death, nonarrhythmic cardiac death, arrhythmic death, or resuscitated cardiac arrest were lower for patients receiving beta-blockers and amiodarone than for those without beta-blockers, with or without amiodarone. The interaction was statistically significant for cardiac death and arrhythmic death or resuscitated cardiac arrest (P=0.05 and 0.03, respectively). Findings were consistent across subgroups. CONCLUSIONS: These findings are based on a post hoc analysis. However, they confirm prior results from in vitro and animal experiments suggesting an interaction between beta-blockers and amiodarone. In practice, not only is the adjunct of amiodarone to beta-blockers not hazardous, but beta-blocker therapy should be continued if possible in patients in whom amiodarone is indicated.

Adrenergic beta-Antagonists↗
PubMed1999

An open-label preliminary trial of sertraline for treatment of major depression after acute myocardial infarction (the SADHAT Trial). Sertraline Anti-Depressant Heart Attack Trial.

BACKGROUND: Depression occurs frequently in patients with acute myocardial infarction and is associated with increased mortality rates. It is not known whether serotonin reuptake inhibitors would be safe and effective for patients with depression after myocardial infarction and whether such treatment would reduce mortality rates. METHODS AND RESULTS: We conducted a multicenter, open-label, pilot study of sertraline treatment in patients with major depressive disorder identified 5 to 30 days after admission for acute myocardial infarction. Outcome measures included cardiovascular and hemostatic function, adverse events, and mood ratings. Twenty-six patients were enrolled in the study. During treatment there were no significant changes in heart rate, blood pressure, cardiac conduction, or left ventricular ejection fraction, and there was a trend toward reduced ventricular ectopic activity. There were no changes in coagulation measures. Bleeding time increased in 12 patients, decreased in 4 patients, and was unchanged in 2 patients. Three (12%) patients withdrew from treatment prematurely because of adverse events. Significant improvements in mood ratings occurred over the course of treatment. CONCLUSIONS: Sertraline treatment was associated with clinical improvement and was well tolerated in >85% of the patients in this open-label treatment trial for patients with major depression after myocardial infarction. These results encourage further controlled trials to establish the effects of treatment for this high-risk population.

Adult↗
PubMed1999

Azimilide decreases defibrillation voltage requirements and increases spatial organization during ventricular fibrillation.

INTRODUCTION: Drugs with class III antiarrhythmic properties generally decrease defibrillation threshold (DFT). However, the concentration effect relation for this effect and drug effects on ventricular fibrillation (VF) itself are not well understood. The objectives of this study were to determine the effect of azimilide (NE-10064), a new class III agent, on DFT, and on spatial organization during VF. METHODS: Defibrillation patch electrodes were sutured to the right and left ventricular epicardium in 12 open-chest anesthetized dogs. The delayed up-down algorithm was used to measure DFT and to estimate the shock strength (voltage) with a 50% probability of successful defibrillation (V50). The magnitude squared coherence (MSC), which measures the spatial relation in the frequency domain, was measured during VF between two unipolar epicardial electrodes 3 mm apart. The V50, MSC, electrophysiologic parameters, and plasma concentrations were determined before and after four cumulative i.v. doses of azimilide (2, 7, 17, and 30 mg/kg). RESULTS: Azimilide elicited a dose dependent reduction of V50 and increase in MSC. Compared with baseline, azimilide lowered mean V50 by 2 +/- 9%, 10 +/- 18%, 11 +/- 14% and 19 +/- 5%, and increased MSC by 17 +/- 20%, 32 +/- 31%, 20 +/- 44% and 27 +/- 20% (p < 0.05 for dose effect) at 2, 7, 17 and 30 mg/kg, respectively. Mean increases in monophasic action potential duration at 90% repolarization (3-11%), ventricular effective refractory period (6-13%) at 400 msec paced cycle length, and VF cycle length (5-37%) (p < 0.01 for dose effect) were observed with the 4 increasing doses of azimilide, respectively. CONCLUSION: Azimilide significantly decreases DFT and increases coherence in VF in a dose dependent manner.

Algorithms↗
PubMed1999

The class III effect of azimilide is not associated with reverse use-dependence in open-chest dogs.

Certain class III antiarrhythmic agents manifest loss of effect at short cycle lengths (CLs). This effect may limit their efficacy in the presence of tachycardia. We studied the frequency-dependent effect of azimilide (NE-10064), a new class III agent, on the right ventricular monophasic action potential (APD90) in 12 open-chest dogs. The monophasic action-potential duration at different pacing CLs (140-400 ms), during sinus rhythm, and ventricular fibrillation CL (VFCL) from left epicardial electrograms were recorded before and after increasing doses of intravenous azimilide. At pacing CL of 400 ms, APD90 was significantly prolonged after 7, 17, and 30 mg/kg of azimilide by 5.4, 7.7, and 10.7%, respectively. The extent of APD90 prolongation was independent of rate. Azimilide increased the APD90 by similar amounts at CL of 400 ms and at the fastest possible stimulation rate maintaining 1:1 capture (mean, 171 +/- 23 ms): by 2.6 +/- 8.6% and 5.6 +/- 5.9% at 2 mg/kg, 5.4 +/- 4.8% and 4.8 +/- 4.7% at 7 mg/kg, 7.7 +/- 5.6% and 9.9 +/-4.5% at 17 mg/kg, and 10.7 +/- 2.6% and 19.3 +/- 11.9% at 30 mg/kg, respectively. Azimilide caused no changes in arterial blood pressure or heart rate. Azimilide prolongs APD90 even at very short CLs. The absence of reverse use-dependence of effect on APD90 may have clinical importance.

Action Potentials↗
PubMed1999

Validation of a noninvasive measure of local myocardial repolarization in a conscious human model: adaptation of repolarization to changes in rate.

INTRODUCTION: A commercial pacemaker sensor measure of the unipolar endocardial stimulus to T wave interval may accurately reflect changes in the monophasic action potential duration at 90% repolarization (APD90). This sensor system was used to study the kinetics of adaptation of repolarization duration to changes in heart rate in humans. METHODS AND RESULTS: Patients were studied using an external pacemaker capable of displaying all stimulus to T wave intervals for each paced beat. Right ventricular stimulation was delivered via the pacemaker and compared simultaneously to APD90. Steady-state pacing was simulated by 60 seconds of pacing at cycle lengths (CLs) 350 to 700 msec. Adaptation to a new ventricular rate was analyzed with a sudden 200-msec decrease in CL. The relation between repolarization measure and steady-state CL (n = 16) was linear with a slope of 0.16 and 0.19 for APD90 and stimulus to T wave interval, respectively (P = NS). The adaptation of both repolarization measures to a sudden change in rate were best modeled by a biexponential function. Stimulus to T wave interval exhibited a parallel course to APD90, and an analysis of normalized differences between APD90 and stimulus to T wave interval followed an approximately normal distribution, with 93.5% of the paired differences within 2 SD of the mean. CONCLUSION: A pacemaker sensor measure of stimulus to T wave interval accurately parallels APD90 during both steady-state and sudden changes in rate. Repolarization in human endocardium follows a linear relation to steady-state CL and adapts to a new rate with a biexponential function. This model represents a novel method for studying human cardiac repolarization.

Action Potentials↗
PubMed1999

Antiarrhythmic drugs and ventricular defibrillation energy requirements.

PURPOSE: To understand the potential interaction between antiarrhythmic therapy and the implantable cardioverter-defibrillator (ICD) in patients who receive pharmacologic therapy as an adjunct to ICD therapy. DATA SOURCES: MEDLINE searching was employed and the information was indexed from approximately 3600 journals published world-wide from 1966 to 1998. STUDY SELECTION AND DATA EXTRACTION: Data were collected from 66 of approximately 455 originally identified articles and abstracts using explicit methodological criteria. RESULTS: The ICD therapy has been widely used for therapy of life-threatening ventricular arrhythmias (VT/VF) and prevention of recurrence of sudden cardiac death. Studies reported that 40%-70% or 10%-40% of ICD patients required concomitant antiarrhythmic medication to reduce the frequency of sustained arrhythmic episodes and to minimize the frequency of device discharges. Most studies on antiarrhythmic drug-ICD interactions have been performed in experimental animals. Antiarrhythmic drugs can influence the effectiveness of ICD to terminate arrhythmias through their effects on defibrillation threshold (DFT). Studies have demonstrated a rise in DFTs with class Ib agent lidocaine and class Ic agents encainide and flecainide. Class Ia agents, as well as amiodarone, bretylium and propafenone may have more variable effects on DFT probably because of the difference between acute and chronic drug dosing, dose-related changes, active metabolites, and reproducibility in determining DFT. Class III agents, with the exception of amiodarone, consistently decrease DFT. These drugs can be used as front-line agents in ICD patients. CONCLUSIONS: Antiarrhythmic drugs can increase, decrease, or have no effect on DFT. Class III agents except amiodarone can be safely administered in conjunction with ICD patients as long as the interaction between these therapeutic modalities is appreciated.

Animals↗
PubMed1998

The Canadian Registry of Atrial Fibrillation: a noninterventional follow-up of patients after the first diagnosis of atrial fibrillation.

The Canadian Registry of Atrial Fibrillation (CARAF) is a nondirected, follow-up study of 1,086 patients who are enrolled at 6 centers across Canada at the time of initial electrocardiographically documented diagnosis of atrial fibrillation (AF). Enrollment commenced in 1991 with an intended 10-year follow-up. Comprehensive baseline data, including clinical history, laboratory, and echocardiographic variables were collected. The patients were treated by their own referring physicians and CARAF did not direct their care. Detailed follow-up was performed at 3 months, 1 year, then yearly, with echocardiograms repeated every 2 years. Several studies, which evaluated patient populations, predictors of events, and cardiac structure and functioning, have been performed and are ongoing. Thyroid function was evaluated at baseline, and, of 707 patients evaluated, only 6 patients were found to be hyperthyroid. Symptoms during AF were evaluated and a profile of the types of symptoms and the predictors of symptoms was compiled. Antiarrhythmic drug use is being followed. Sotalol and propafenone were the most commonly used medications, with the use of antiarrhythmic drugs increasing with recurrence of AF. The use of anticoagulants was assessed. The overall use of warfarin was relatively low, but its use increased dramatically with the presence of various risk factors including congestive heart failure, hypertension, and previous stroke. The one risk factor that did not result in increased use of warfarin was hypertension. Therefore, CARAF was able to identify that hypertension appears to be under-recognized and undertreated in its risk for thromboembolic events. CARAF is just now reaching maturity, with the majority of patients having > or=4 years of follow-up. Therefore, extensive investigations are currently under way that will evaluate the baseline characteristics and utilize these as predictors of recurrence of AF, progression to chronicity, and the occurrence of major events such as stroke and death. A very large cohort of patients with serial echocardiograms over 4 years will permit an understanding of the progression of structural and valvular disease. Therefore, CARAF offers a unique opportunity for comprehensive, nondirected follow-up of patients from their initial diagnosis of AF.

Atrial Fibrillation↗
PubMed1998

A double-blind placebo-controlled evaluation of the human electrophysiologic effects of zatebradine, a sinus node inhibitor.

The purpose of this study was to evaluate the electrophysiologic effects of zatebradine, a sinus node inhibitor, in human subjects. Patients without structural heart disease were randomized to receive intravenous zatebradine (23 patients) or placebo (12 patients). Electrophysiologic measures were obtained at baseline and repeated at 40 and 70 min after drug administration. In the placebo group, there were no significant changes in any parameter over time. After zatebradine, sinus node function changed significantly at 40 min, with no further change at 70 min; sinus cycle length was prolonged by 16 and 17% (p < 0.001), and corrected sinus node recovery time was prolonged by 30 and 22% (p = 0.008). Similarly, atrioventricular node function changed significantly at 40 min, with no further change at 70 min; atrio-His interval was prolonged by 15 and 15% (p = 0.02), atrioventricular node effective refractory period was prolonged by 12 and 11% (p = 0.01), and Wenckebach cycle length was prolonged by 15 and 11% (p = 0.002). Atrial refractoriness, His-Purkinje conduction, ventricular refractoriness, and action-potential duration were not affected by zatebradine. Zatebradine, a sinus node inhibitor, alters the conduction and refractory properties of the human atrioventricular node, in addition to the expected effect on sinus node function.

Action Potentials↗
PubMed1998

When pacemakers fail: an analysis of clinical presentation and risk in 120 patients with failed devices.

Although pacemaker recalls are common, the optimal mechanism for risk assessment and triage of patients at risk for sudden loss of device system function is unknown. A retrospective chart review of 120 patients with factory proven failed devices was performed. Logistic regression analysis was used to determine clinical correlates of emergency room versus outpatient clinic presentation at time of device failure. Twenty-two patients (18%) presented to emergency and 98 (82%) to clinic. Sixty-three devices had no device output at the time of presentation. Multivariate logistic regression analysis revealed that antiarrhythmic drug use (odds ratio: 7.4, 95% CI: 2.0-28.0), atrioventricular nodal disease as an indication for pacing (odds ratio: 2.8, 95% CI: 1.2-3.0), and female gender (odds ratio: 2.2, 95% CI: 1.0-4.5) were the only significant correlates of emergency room presentations. Pacemaker dependency (escape heart rate < 40 beats/min) did not correlate with location of presentation even though no device output at the time of presentation was associated with emergency room presentation (odds ratio: 2.5, 95% CI: 1.1-5.8). Neither the presence of structural heart disease nor symptoms at the time of device implantation (syncope or presyncope) were correlated with location of presentation upon unexpected device failure. Although there were no deaths in the 120 failed devices studied, there were 26 deaths in the total group of 227 patients with recalled devices that could not be studied. Antiarrhythmic drug use, electrocardiographic pacing indication, and female gender may be more sensitive predictors of emergency room presentation and significant symptoms in the event of unanticipated pacemaker failure. The inability of any retrospective analysis to accurately assess mortality in the setting of pacemaker system failure underscores the need for prospective databases in recall situations.

Age Factors↗