Biomedical subjects

H J Duff

Publications and source records attributed to H J Duff.

At least 55 records · Page 3Linked to original sources

PubMed1994

Amiloride-quinidine interaction: adverse outcomes.

OBJECTIVES: Previous studies have reported beneficial antiarrhythmic effects when selected drugs were combined. The purpose of this study was to assess whether a favorable interaction would occur with amiloride and quinidine. DESIGN: The antiarrhythmic and electrophysiologic effects of quinidine alone and in combination with amiloride were assessed in 10 patients with inducible sustained ventricular tachycardia. Parallel electrophysiologic studies assessed this drug combination in guinea pig papillary muscle. RESULTS: None of the patients had adverse effects during quinidine monotherapy. However, seven of 10 patients had adverse responses to the combination treatment: three patients had suppression of inducible ventricular tachycardia during quinidine monotherapy but had sustained ventricular tachycardia induced during combination treatment; three other patients had somatic side effects that resulted in discontinuation of the combination therapy but were absent during quinidine monotherapy; and one patient had 12 episodes of sustained ventricular tachycardia during this combination therapy. The patient had no such response during monotherapy. Surface QRS duration was significantly more prolonged during combination therapy than during monotherapy. Parallel electrophysiologic effects assessed this drug combination in guinea pig papillary muscle. The combination of amiloride (1 mumol/L) and quinidine (10 mumol/L) synergistically decreased the maximum rate of rise of phase 0 of the action potential (Vmax) (43 +/- 12 V/sec) compared with quinidine alone (24 +/- 9 V/sec) because of a greater degree of tonic block of Vmax (14% +/- 6%) as compared to quinidine alone (3% +/- 3%) with no significant change in action potential duration. CONCLUSIONS: Amiloride exaggerates the effects of quinidine on QRS duration in patients and on Vmax during in vitro study, which implies that the proarrhythmic effect of the combination of amiloride and quinidine may be associated with synergistic increase in sodium channel blockade.

Action Potentials↗

PubMed1994

Class I antiarrhythmic drugs: allosteric inhibitors of [3H] batrachotoxinin binding to rat cardiac sodium channels.

This study assessed whether class I antiarrhythmic drugs allosterically inhibit [3H]batrachotoxinin A 20-alpha-benzoate ([3H]BTXB) binding to sodium channels on freshly isolated rat cardiac myocytes. All class I drugs tested inhibited equilibrium [3H]BTXB binding in a concentration-dependent manner. Scatchard analysis showed that disopyramide, flecainide, transcainide, lidocaine and amiodarone reduced [3H]BTXB maximum binding (Bmax) whereas procainamide, mexiletine, quinidine, quinine, tocainide, propafenone, encainide and O-demethylencainide increased [3H]BTXB KD but had little effect on Bmax. Kinetic [3H]BTXB binding assays were used to assess the mechanism by which class I drugs inhibit [3H]BTXB binding. Drugs that increase the unidirectional dissociation rate constant (k-1) of [3H]BTXB probably bind to sodium channels to which [3H]BTXB is already bound. Although all class I drugs increased the k-1 of [3H]BTXB, they did so weakly and at concentrations above the IC50 values of the drugs. Thus, drug binding to [3H]BTXB-bound channels does not appear to be the predominant mechanism underlying their ability to inhibit [3H]BTXB binding. Conversely, drugs which allosterically decrease the unidirectional association rate constant (K+1) of [3H]BTXB probably bind to channels to which [3H]BTXB is not already bound. All class I drugs decreased the k+1 of [3H]BTXB, indicating drug binding to [3H]BTXB-free channels. The estimated affinities of drugs for [3H]BTXB-free channels correlated closely with the IC50 values of these drugs (r = 0.94, P < .001), suggesting that this effect is a common and major determinant in their ability to inhibit [3H]BTXB binding. The results are discussed in light of electrophysiologic theories of class I antiarrhythmic drug action.

Allosteric Regulation↗

PubMed1993

Characteristics of patients with nonfatal cardiac arrest 3 to 180 days after acute myocardial infarction.

Patients who survive a tachyarrhythmic cardiac arrest in the first 6 months after acute myocardial infarction (AMI) are at risk for recurrent arrests, but the magnitude, timing and characteristics of this phenomenon are unknown. This study characterizes the nature of recurrent tachyarrhythmic cardiac arrests in the absence of reversible factors or new myocardial necrosis in patients between 3 and 180 days after AMI. We retrospectively assessed 28 patients (mean age 61 +/- 12 years) who survived an initial cardiac arrest a median of 10 days after AMI. Mean left ventricular ejection fraction was 36 +/- 9%. Fourteen patients (50%) had at least 1 recurrence of cardiac arrest, and 10 had > 2 arrests. Almost all (92%) recurrent cardiac arrests occurred within 5 days of the preceding arrest, and the high-risk periods were similar after the first, second or third cardiac arrest. Very fast ventricular tachycardia (mean cycle length 212 +/- 30 ms) was the documented responsible arrhythmia in 44 of 51 cardiac arrests. The morphology was either polymorphic, monomorphic or sinusoidal. No clinical or laboratory values could be found that predicted whether a patient would have a recurrent arrest. Nineteen patients (68%) survived to leave the hospital and have been followed for up to 96 months. For these, actuarial 5-year overall survival was 76% and actuarial 5-year arrhythmia-free probability was 80%. Thus, patients who survive a cardiac arrest in the first 6 months after AMI are at high risk of recurrent cardiac arrest for a further 5 days, and the arrests are due to characteristically fast ventricular tachycardias.(ABSTRACT TRUNCATED AT 250 WORDS)

Actuarial Analysis↗

PubMed1993

Risks of developing supraventricular and ventricular tachyarrhythmias after implantation of a cardioverter-defibrillator, and timing the activation of arrhythmia termination therapies.

The clinical courses of 39 consecutive recipients (mean age 61 +/- 12 years, and mean left ventricular ejection fraction 0.32 +/- 0.15) of an automatic implantable cardioverter-defibrillator (ICD) were examined to determine the risks of developing ventricular tachycardia (VT) and supraventricular tachyarrhythmias (SVT) after surgery, with ventricular response rates fulfilling ICD detection criteria. ICD system leads were implanted by thoracotomy in 25 patients and by using nonthoracotomy lead systems in 14. Six patients (18%) developed SVT after surgery, whereas 14 (36%) developed sustained VT. The median times to the development of both SVT and VT were 2 days. By actuarial analysis, the probability of developing VT after surgery was significantly greater than that of SVT during hospitalization (p = 0.04). This significant excess of postoperative VT over SVT was most marked in patients aged < or = 61 years, those who received nonthoracotomy rather than epicardial lead systems, those who presented with VT rather than ventricular fibrillation, and those who received > 20 intraoperative defibrillation shocks. These observations recommend the activation of ICD therapies immediately after implantation.

Age Factors↗

PubMed1993

Comparison of biphasic and monophasic shocks for defibrillation using a nonthoracotomy system.

A comparison of defibrillation thresholds was made using biphasic and monophasic shocks delivered by a nonthoracotomy lead system in 2 clinically distinct groups of patients. The first group were patients receiving an implantable cardioverter-defibrillator who were studied before surgery with their chests closed. The second group were patients undergoing coronary artery bypass grafting (CABG) who were studied before surgery with their chests open but reapproximated. Biphasic defibrillation thresholds (stored energy) were significantly (p < 0.001) less than monophasic ones in subjects with the implantable cardioverter-defibrillator (12.3 +/- 5.3 vs 21.1 +/- 9.3 J) or CABG (14.6 +/- 7.1 vs 24.2 +/- 12.6 J). These values are less than were previously reported with a similar nonthoracotomy lead configuration. There were no significant differences between the 2 groups in all measurements derived from corresponding shock waveforms, although impedance tended to be greater in patients with CABG. However, subjects with CABG had greater left ventricular ejection fractions and did not have history of potentially lethal ventricular arrhythmias. Despite these differences, the conclusion that biphasic shocks are more effective would have been made in a study of either group alone. It is concluded that patients with CABG who have not had preceding potentially lethal ventricular arrhythmias may be a potential source of surrogate subjects for defibrillation research such as epicardial mapping, which requires that the chest be open.

Coronary Artery Bypass↗

PubMed1993

Infarct artery patency predicts outcome of serial electropharmacological studies in patients with malignant ventricular tachyarrhythmias.

BACKGROUND: Surviving myocardial cells near the infarct border zone form the arrhythmogenic substrate for sustained ventricular tachycardia (VT) in humans. Infarct-related artery (IRA) patency may modulate the electrophysiological function of this arrhythmogenic substrate and its response to antiarrhythmic drug therapy. We postulated that effective antiarrhythmic drug therapy selected during serial electrophysiological studies in patients with VT after a myocardial infarction would be identified more frequently when the IRA is patent than when chronically occluded. METHODS AND RESULTS: Consecutive patients (n = 64) with documented coronary artery disease and remote myocardial infarction presenting with spontaneous sustained VT or ventricular fibrillation (VF) were studied. These patients underwent 4 +/- 2 electropharmacological studies identifying effective antiarrhythmic drug therapy in 16 (25%) patients. Drug responders did not differ significantly from nonresponders in demographic, electrocardiographic, angiographic, or hemodynamic measurements. A patent IRA was associated with antiarrhythmic drug response significantly more frequently than was an occluded IRA (45% versus 9%, p = 0.001). Patency of the IRA was the only independent predictor of response to antiarrhythmic drug therapy in this study population. The sensitivity and specificity of using a patent IRA to predict successful drug testing were 81% and 67%, respectively. CONCLUSIONS: The outcome of electropharmacological studies was predicted by the patency of the IRA. A patent IRA was associated with a greater probability of finding effective drug therapy.

Aged↗

PubMed1993

Electrocardiographic correlates of spontaneous termination of ventricular tachycardia in patients with coronary artery disease.

BACKGROUND: In vitro studies have reported that beat-to-beat variance in tachycardia cycle length and in conduction and repolarization properties can result in spontaneous termination of reentrant arrhythmias. The purpose of this study was to define the ECG patterns associated with spontaneous termination of ventricular tachycardia in humans late after myocardial infarction. METHODS AND RESULTS: The QRS durations, QT intervals, and cycle lengths were measured on a beat-to-beat basis during episodes of sustained and spontaneously terminating ventricular tachycardias (VT) induced at antiarrhythmic drug-free and drug-assessment electrophysiological studies. Twenty-six patients were studied. Four categories of inducible ventricular tachycardia were studied: inducible sustained ventricular tachycardia in an antiarrhythmic drug-free state, spontaneously terminating ventricular tachycardia in an antiarrhythmic drug-free state, sustained ventricular tachycardia on antiarrhythmic therapy, and spontaneously terminating ventricular tachycardia on antiarrhythmic therapy. The ECG patterns that were statistically related to spontaneous termination of ventricular tachycardia included impingement of the QTP interval on the tachycardia cycle length (P < .001) both in the presence and absence of drugs, transient shortening of QRS just before termination, and paradoxical prolongation of QTP after abrupt shortening of ventricular tachycardia cycle length. In addition, greater beat-to-beat variances in tachycardia cycle lengths, QT intervals, and QRS durations were statistically associated with spontaneously terminating ventricular tachycardia. These ECG patterns did not occur during sustained episodes of ventricular tachycardia during the antiarrhythmic drug-free state or during ineffective antiarrhythmic drug therapy. CONCLUSIONS: A dynamic interplay between QRS duration, QT interval, and cycle length of tachycardia and their variances are associated with spontaneous termination of ventricular tachycardia in humans late after infarction. This study of ECG changes associated with spontaneous termination of ventricular tachycardia provides insight into potential mechanisms of antiarrhythmic drug efficacy.

Anti-Arrhythmia Agents↗

PubMed1993

Myocardial uptake and pharmacodynamics of procainamide in patients with coronary heart disease and sustained ventricular tachyarrhythmias.

Little information is available currently regarding the time course of myocardial accumulation and the onset of the electrophysiologic effects of antiarrhythmic drugs in humans. The myocardial uptake and pharmacodynamics of the antiarrhythmic drug, procainamide, were studied during i.v. infusion in nine patients with ventricular tachycardia undergoing electrophysiologic study. Myocardial procainamide uptake was determined by serial measurements of arterial-coronary sinus drug concentration differences and measurement of coronary sinus blood flow during a 50-min procainamide infusion. The myocardial uptake of procainamide was 10 +/- 4% (mean +/- S.D.) of the total dose at 50 min. Coronary sinus procainamide concentrations equilibrated with arterial concentrations within 30 min of the start of the infusion. However, peripheral venous procainamide concentrations did not reach equilibrium with the arterial compartment during the 50-min drug infusion. Changes in the QRS duration, ventricular conduction time, QTc and ventricular refractory periods correlated in a linear fashion with changes in the plasma procainamide concentrations. The slopes of the arterial and coronary sinus concentration-effect relationships were similar and significantly greater than the slopes of the peripheral venous concentration-effect relationships (P < .05). Thus, procainamide equilibrates rapidly, but not instantaneously, in the myocardium. Short-term electrophysiologic effects correlate best with the arterial and coronary sinus drug concentrations. During this period, venous procainamide concentrations do not accurately reflect the myocardial concentration, effects or the eventual steady-state relationships.

Aged↗

PubMed1993

Interaction between selected sodium and potassium channel blockers in guinea pig papillary muscle.

Previous studies have reported that enhanced antiarrhythmic effects occur when agents that prolong repolarization are combined with agents that block the sodium channels. The mechanism(s) of this interaction have not been elucidated. In this study, the interactions between the prolongation of action potential duration (APD) by a potassium channel blocker and the reduction in the maximal upstroke velocity of phase 0 of action potential (Vmax) by sodium channel blockers were investigated in guinea pig papillary muscle using conventional microelectrode techniques. Agents that produce selective electrophysiologic effects were chosen, including low concentrations of barium chloride (BaCl2), which selectively blocks the inwardly rectifying potassium current without effects on other repolarizing or depolarizing currents, O-demethyl-encainide (ODME), which blocks the activated sodium channel with slow onset/offset kinetics, and mexiletine, which preferentially blocks the inactivated sodium channel with rapid onset/offset kinetics. Mexiletine (4 x 10(-6) M) decreased Vmax from 195 +/- 29 V/sec at baseline to 180 +/- 26 V/sec (P < .05). Whereas BaCl2 (10(-5) M) prolonged action potential duration, it had no effect on Vmax. However, the addition of BaCl2 to mexiletine synergistically decreased Vmax from 180 +/- 26 V/sec with mexiletine to 166 +/- 18 V/sec (P < .05). ODME (3 x 10(-7) M) decreased Vmax from 179 +/- 17 V/sec at baseline to 133 +/- 15 V/sec (P < .01). However, the addition of BaCl2 to ODME did not produce a further decrease in Vmax as compared with ODME alone. In summary, a synergistic effect on Vmax was observed when BaCl2 and mexiletine were combined.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1992

Use-dependent electrophysiologic effects of amiodarone in coronary artery disease and inducible ventricular tachycardia.

Amiodarone produces use-dependent block of cardiac sodium channels in vitro. This study assessed whether similar use-dependent block occurred in 19 patients with coronary artery disease and inducible, sustained, monomorphic ventricular tachycardia treated with amiodarone. Beat-to-beat measurements of ventricular paced QRS durations during 12-beat trains at cycle lengths of 700, 600, 400 and 300 ms were analyzed at a baseline antiarrhythmic drug-free study and after 2 and 10 weeks of amiodarone therapy. At the drug-free study, there were no significant changes in paced QRS durations within the 12-beat trains at any pacing cycle lengths. After 2 and 10 weeks of amiodarone therapy, progressive prolongation of paced QRS durations occurred over the 12-beat trains at pacing cycle lengths of 600, 400 and 300 ms (p less than 0.05). Significant changes in QRS duration were not observed at a pacing cycle length of 700 ms. This progressive prolongation in QRS duration can be fitted as a function of beat number to a monoexponential equation and occurred with an onset time constant of 1.02 +/- 0.41 beats (306 +/- 122 ms) at a pacing cycle length of 300 ms. The magnitude of QRS prolongation increased as the pacing cycle length was shortened. The magnitudes of QRS prolongation were similar after 2 and 10 weeks of amiodarone therapy. In conclusion, use-dependent prolongation in QRS duration occurs at rapid pacing cycle lengths in humans receiving amiodarone.

Amiodarone↗

PubMed1992

Comparison of atrial overdrive pacing with and without extrastimuli for termination of atrial flutter.

Atrial overdrive pacing has been successfully used to terminate atrial flutter. This study compared the efficacy of atrial extrastimuli following a rapid pacing train to overdrive pacing without atrial extrastimuli for the termination of atrial flutter. Patients were randomized to treatments of short or long burst atrial overdrive pacing or atrial overdrive pacing followed by atrial extrastimuli in a crossover study design. A total of 22 patients (73%) had successful conversion of atrial flutter to sinus rhythm. The success rates in patients exposed to each therapy, including crossover therapies, were 62% with the atrial extrastimuli method, 8% with the short burst pacing method, and 8% with the long burst pacing method (p less than 0.001). Transient atrial fibrillation developed in 15 patients and in 9 of these this arrhythmia preceded conversion to sinus rhythm. Sustained atrial fibrillation was induced in 3 additional patients but never with the atrial extrastimuli method. In conclusion, the method of delivering atrial extrastimuli after a rapid pacing train is highly efficacious for the termination of atrial flutter. Furthermore, this method is more effective than atrial overdrive pacing methods delivered at the same pacing cycle length. These observations have important implications for the programming of antitachycardia pacemakers.

Aged↗

PubMed1992

Effects of left ventricular dysfunction on the circadian variation of ventricular premature complexes in healed myocardial infarction.

Circadian variation in the onset of cardiovascular events including sudden cardiac death, myocardial infarction and ventricular arrhythmias has been described. The effect of left ventricular (LV) dysfunction on the circadian variation of ventricular premature complex (VPC) frequency was evaluated in 132 patients with frequent VPCs and reduced LV function after myocardial infarction. Patients were prospectively divided in 2 groups based on LV ejection fraction (EF) (those with LVEF less than or equal to 0.30, and those with LVEF between 0.30 and 0.45). Median hourly VPC frequencies and heart rates were compared between the 2 groups. Subgroup analyses based on treatment with beta-adrenoceptor blocking agents and on New York Heart Association functional class were also performed. In patients with LVEF greater than 0.30, a distinct circadian variation of VPCs, and the expected morning increase in VPC frequency were present. In contrast, a distinct circadian variation of VPCs was absent in patients with LVEF less than or equal to 0.30. A circadian variation of VPC frequency was also absent in patients with severe symptomatic congestive heart failure (New York Heart Association class III-IV). Treatment with beta-adrenoceptor blocking agents was associated with a loss of the circadian variation of VPC frequency. The circadian variation of heart rate was also blunted in the group treated with beta-adrenoceptor blocking agents. The proportion of subjects manifesting a positive correlation between heart rate and VPC frequency was lower in subjects with LVEF less than or equal to 0.30 (26%) than in those with LVEF greater than 0.30 (46%) (p less than 0.05). Thus, circadian variation of VPC frequency is absent in patients with severe LV dysfunction.

Adrenergic beta-Antagonists↗

PubMed1992

Electrocardiographic body surface mapping in patients with ventricular tachycardia. Assessment of utility in the identification of effective pharmacological therapy.

BACKGROUND: Body surface maps of net QRST deflection areas (isointegrals) reflect regional ventricular repolarization properties. Vulnerability to ventricular tachyarrhythmias is associated with maps that feature multiple islands (extrema) of positive and negative values; such maps reflect regional disparity of ventricular recovery properties. The value of body surface mapping in prediction of the efficacy of antiarrhythmic therapy for ventricular tachyarrhythmias has not been determined. METHODS AND RESULTS: Isointegral ECG body surface mapping was performed in 51 patients with inducible ventricular tachycardia having programmed stimulation studies at baseline and after oral quinidine therapy. The degree of nondipolarity of QRST isointegral distribution was expressed by the number of extrema and by the percentage contribution of nondipolar eigenvectors after Karhunen-Loeve transformation. QRST isointegral nondipolarity was greater in ventricular tachycardia patients than in 51 age- and sex-matched normal subjects expressed as mean number of extrema (4.1 +/- 2.8 versus 2.0 +/- 0.2, respectively), mean eigenvector-determined nondipolar content percentages (12.4 +/- 10.1% versus 4.5 +/- 4.9%), prevalence of abnormal numbers of extrema (63% versus 4%), or prevalence of abnormal nondipolar content percentages (33% versus 4%) (each p less than 0.01). Quinidine prevented ventricular tachycardia induction in 14 patients. Patients for whom quinidine was or was not effective had similar nondipolarity indexes at baseline. However, maps on quinidine differed as a function of antiarrhythmic efficacy. Although effective therapy produced no significant mean changes in nondipolarity, ineffective therapy increased the number of extrema compared with baseline (5.4 +/- 3.4 versus 3.8 +/- 2.5, respectively) (p = 0.002). Individually, 43% of patients on effective therapy had drug-induced decreases in numbers of extrema compared with 14% of those on ineffective therapy (p = 0.02). Furthermore, 29% of patients on effective therapy showed drug-induced increases in numbers of extrema compared with 62% of those on ineffective therapy (p = 0.03). CONCLUSIONS: QRST isointegral body surface mapping shows promise as a noninvasive measure of drug efficacy in patients with ventricular tachycardia.

Anti-Arrhythmia Agents↗

PubMed1992

Precordial QT interval dispersion as a marker of torsade de pointes. Disparate effects of class Ia antiarrhythmic drugs and amiodarone.

BACKGROUND: Patients with a history of class Ia drug-induced torsade de pointes have been treated with chronic amiodarone without recurrence of torsade de pointes despite comparable prolongation of the QT interval. We hypothesized that in such patients, class Ia drugs cause nonhomogeneous prolongation of cardiac repolarization times, whereas amiodarone causes homogeneous prolongation of cardiac repolarization times. METHODS AND RESULTS: Thirty-eight consecutive patients who received both class Ia drug therapy and chronic amiodarone therapy were evaluated. Standard 12-lead ECGs at baseline and during each therapy were used to calculate precordial QT interval dispersion (maximum QT in leads V1 through V6 minus minimum QT leads V1 through V6) as a measure of regional variabilities in ventricular repolarization times. Nine of these patients had torsade de pointes during class Ia drug therapy. In these nine patients, class Ia drug therapy and amiodarone significantly prolonged the maximum QT interval to comparable extents. However, class Ia drug therapy but not amiodarone therapy significantly increased precordial QT interval dispersion (101 +/- 37 versus 49 +/- 26 msec; baseline, 44 +/- 12 msec; p = 0.002). In the 29 patients without class Ia drug-induced torsade de pointes, neither class Ia drug therapy nor amiodarone therapy significantly increased QT interval dispersion (50 +/- 6 versus 69 +/- 7 msec; baseline, 54 +/- 5 msec). None of the patients with class Ia drug-induced torsade de pointes had recurrent torsade de pointes during chronic amiodarone therapy. CONCLUSIONS: An increase in regional QT interval dispersion during class Ia antiarrhythmic drug therapy is associated with torsade de pointes. Chronic amiodarone therapy in patients with a history of class Ia drug-induced torsade de pointes produces comparable maximum QT interval prolongation but does not increase QT interval dispersion. This characteristic may explain its apparent safe use in patients with a history of class Ia drug-induced torsade de pointes.

Aged↗

PubMed1992

Class I and IV antiarrhythmic drugs and cytosolic calcium regulate mRNA encoding the sodium channel alpha subunit in rat cardiac muscle.

Previous studies have shown that chronic in vivo treatment with the antiarrhythmic drug mexiletine produces an increase in sodium channel number. We examined whether chronic mexiletine treatment would similarly regulate the level of mRNA encoding the cardiac sodium channel. RNA isolated from cardiac tissue was probed with a 2.5-kilobase cRNA transcribed with T7 RNA polymerase from the clone Na 8.4, which encodes nucleotides 3361-5868 of the alpha subunit of the RIIA sodium channel subtype. Chronic mexiletine treatment produced a 3-fold increase in the level of mRNA encoding sodium channel alpha subunits. Previous studies of cultured skeletal muscle cells had suggested that chronic sodium channel blockade may mediate an increase in sodium channel mRNA by changes in cytosolic Ca2+ concentration. To address this issue, we assessed whether verapamil would also produce up-regulation of the level of mRNA encoding the sodium channel and whether the calcium ionophore A23187 would produce the opposite effect on mRNA level. Verapamil treatment increased sodium channel mRNA level up to 3-fold, whereas in vitro A23187 treatment decreased the mRNA level 5-fold. The combination of verapamil and mexiletine produced no further increase in the mRNA level, compared with that seen with the single agents, suggesting a convergent second messenger pathway for the actions of these two drugs. These data show that the level of mRNA encoding sodium channels is substantially increased during antiarrhythmic drug treatment and suggest that change in cytosolic Ca2+ concentration is the second messenger involved in the regulation of levels of mRNA encoding the alpha subunit of the cardiac sodium channel.

Animals↗

PubMed1992

Drug therapy of ventricular tachycardia: a cost comparison of randomized noninvasive and invasive approaches.

OBJECTIVE: Economic evaluation of noninvasive (suppression of ventricular arrhythmias detected by ambulatory monitoring) and invasive (suppression of arrhythmias induced by programmed stimulation) approaches to antiarrhythmic drug selection for ventricular tachyarrhythmias. DESIGN/SETTING: Randomized clinical trial/tertiary-care hospital. PATIENTS: Of 124 consecutive patients referred for treatment of symptomatic ventricular tachyarrhythmias, 57 consenting patients were eligible to have drug therapy selected by either noninvasive or invasive approaches. MEASUREMENTS: Costs of initial and follow-up (26 +/- 15 months) admissions for the two groups were compared. This economic evaluation also considered relative efficacies of the approaches using the primary outcome variable of symptomatic, sustained ventricular tachyarrhythmia recurrence (including sudden death). RESULTS: Initial hospitalization for therapy selection was less costly by the noninvasive approach ($6,869 +/- 4,019) than by the invasive approach ($13,164 +/- 6,740) (P less than 0.001). However, the noninvasive approach generated higher follow-up hospital costs ($9,204 +/- 9,217) than the invasive approach ($3,784 +/- 4,944) (P = 0.01). Thus, total hospital costs of the noninvasive ($16,073 +/- 9,423) and invasive approaches ($16,949 +/- 7,174) were equivalent. The two-year actuarial probability of a recurrent, sustained, symptomatic ventricular tachyarrhythmia was greater in noninvasive (0.50 +/- 0.10) than in invasive (0.20 +/- 0.08) approach patients (P = 0.02). CONCLUSIONS: The lower initial hospital costs of the noninvasive approach are offset by greater follow-up costs. Within two years the costs of the two approaches are equivalent. Thus, greater antiarrhythmic efficacy can be achieved by the invasive approach to drug selection without increasing total hospital costs.

Anti-Arrhythmia Agents↗

PubMed1991

Transcainide: biochemical evidence for state-dependent interaction with the class I antiarrhythmic drug receptor.

The mechanism of action of the lidocaine derivative transcainide was examined using [3H]batrachotoxinin 20 alpha-benzoate, which binds specifically to and stabilizes activated states of the sodium channel. Transcainide (IC50 0.3 microM) inhibited equilibrium [3H]batrachotoxinin binding to sodium channels present on freshly isolated rat cardiac myocytes. Scatchard analysis of [3H]batrachotoxinin binding showed that transcainide both reduced maximal binding and altered the KD for [3H]batrachotoxinin binding, indicating noncompetitive, allosteric inhibition. Inhibition by transcainide of [3H]batrachotoxinin binding was reversible within 60 min. We used state-dependent [3H]batrachotoxinin binding assays to examine whether transcainide preferentially binds to activated or nonactivated sodium channels. Transcainide had little effect on the k-1 of [3H]batrachotoxinin even at concentrations 1000-fold greater than its IC50, indicating low affinity of transcainide for activated channels. However, transcainide decreased the k + 1 of [3H]batrachotoxinin at a concentration very close to its IC50 concentration for inhibiting equilibrium [3H]batrachotoxinin binding. The results are discussed in terms of a model in which transcainide inhibits [3H]batrachotoxinin binding by binding specifically to and stabilizing a nonactivated state of the cardiac sodium channel.

Animals↗

PubMed1991

Cyclic AMP-dependent regulation of the number of [3H]batrachotoxinin benzoate binding sites on rat cardiac myocytes.

We sought to assess the effect of an increase in cAMP on sodium channels on adult rat cardiac ventricular myocytes. Sodium channels were studied with the use of the radiolabeled sodium channel-specific toxin [3H] batrachotoxinin benzoate ([3H]BTXB). Forskolin, isoproterenol, prostaglandin E1, cholera toxin, and pertussis toxin each increased cAMP levels and decreased the number of [3H]BTXB binding sites without changing the affinity of [3H]BTXB for the sodium channel. The cAMP analog 8-bromo-cyclic AMP (8-Br-cAMP) reduced the number of [3H]BTXB binding sites from 19 fmol/10(5) cells to 11 fmol/10(5) cells. [3H]BTXB binding site down-regulation was reversible, cAMP dose-dependent, and time-dependent. To test the hypothesis that the cAMP effect was mediated by cAMP-dependent phosphorylation, we determined the effect of 8-Br-cAMP on [3H]BTXB binding after preincubation of myocytes with N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide dihydrochloride (H8), a protein kinase A inhibitor. H8 inhibited 70% of the decrease in the number of [3H]BTXB binding sites induced by 8-Br-cAMP. Thus increases in intracellular cAMP in cardiac myocytes reversibly induced a decrease in the number of [3H]BTXB binding sites via cAMP-dependent protein phosphorylation, possibly of the sodium channel.

8-Bromo Cyclic Adenosine Monophosphate↗