Proarrhythmic effects of class Ic drugs.

Three cases managed with class Ic antiarrhythmic drugs but with subsequent aggravation of arrhythmias are reported herein. A 58-year-old man given 300 mg of flecainide for atrial flutter developed sinus arrest and transient ventricular fibrillation. A 42-year-old man with a postoperative condition of tetralogy of Fallot who received 300-mg doses of flecainide for sustained ventricular tachycardia had spontaneous sustained ventricular tachycardia. A 74-year-old man given 150 mg of propafenone for atrial tachycardia developed sustained ventricular tachycardia. The present cases illustrate that class Ic drugs may exacerbate ventricular arrhythmias, and their use may reveal concealed sinus node dysfunction. This may be due to marked slowing of conduction and prolonged ventricular refractoriness, which are characteristic of the class Ic drugs; also, it is probable that the patients' underlying cardiac conditions served as contributing factors.

Effects of atrioventricular block on ventricular fibrillation threshold in dog.

The effects of complete atrioventricular block (CAVB) on ventricular vulnerability were studied 1 week after a transcatheter electrical ablation of the AV junction in 18 closed-chest dogs. All dogs exhibited CAVB and a stable ventricular escape rhythm with a mean cycle length of 1795 +/- 600 ms. Although QT interval during CAVB was significantly prolonged compared with that during the sinus rhythm, QTc interval was significantly shortened. The ventricular fibrillation threshold was significantly elevated after creation of the block (from 9.35 +/- 2.28 to 12.3 +/- 3.69 mA, p less than 0.01). Thus, CAVB which is not associated with QTc prolongation would be even less likely to play an important role in producing ventricular fibrillation presumably including torsades de pointes or polymorphous ventricular tachycardia.

"Torsades de pointes" and atrioventricular block.

In order to elucidate the trigger factor of the production of torsades de pointes (TdP), electrophysiological study was conducted in 15 patients with atrioventricular (AV) block; 6 with TdP (TdP group) and 9 without TdP (control group). In the TdP group, all had an episode of syncope and frequent ventricular premature beats (VPBs) on routine ECG, while four (44%) had syncope and three (33%) had VPBs in the control group. Aging, QRS width, ventricular cycle length, QT interval, and block site from His bundle electrogram were similar in both groups, however the QTc interval was significantly (p less than 0.01) longer in the TdP group than in the control group (580 +/- 112 vs. 459 +/- 37, respectively). Furthermore, four patients (67%) in the TdP group showed advanced AV block in which a slow ventricular rate and an irregular rhythm were characteristic, whereas only one control (11%) showed advanced AV block and all other control patients (89%) had complete AV block. These data indicate that patients with advanced atrioventricular block associated with prolonged QTc interval and frequent ventricular premature beats might induce torsades de pointes.

Effects of dibutyryl cyclic AMP on ventricular vulnerability during atrioventricular block in dog.

The effects of dibutyryl cyclic AMP (DBcAMP) on ventricular vulnerability during complete atrioventricular block (CAVB) were studied one week after transarterial electrical ablation of the AV junction in 18 closed-chest dogs. All dogs exhibited CAVB and a stable ventricular escape rhythm with a mean cycle length of 1812 +/- 638 ms. After the administration of DBcAMP at a rate of 0.1 mg/kg/min for 30 min, the ventricular cycle length was significantly shortened, and the QTc interval was slightly prolonged, although the QT interval did not change. The ventricular fibrillation threshold after the administration of DBcAMP was significantly increased (from 12.2 +/- 3 84 to 18.4 +/- 5.08 mA, p less than 0.01). Thus, it was demonstrated that DBcAMP exhibited suppressive effects on the ventricular vulnerability in the experimentally induced CAVB.

Electrophysiologic characteristics at initiation of ventricular tachycardia and ventricular fibrillation in a canine infarct model.

Local ventricular activation time and the conduction time during sinus rhythm at the induction of ventricular tachycardia (VT) and ventricular fibrillation (VF) were investigated using a canine model of chronic myocardial infarction. Of 26 dogs studied, 15 had inducible VT, 10 had inducible VF, and 1 had no inducible arrhythmias. Bipolar local ventricular electrograms were recorded during sinus rhythm from 136 sites in 10 dogs with VT and 164 sites in 11 dogs with VF. Mean activation time in dogs with inducible VT was significantly longer than in dogs with inducible VF. Furthermore, simultaneous local ventricular electrograms were recorded during the induction of VT (74 episodes) or VF (38 episodes) from the infarct border zone at the endocardium (B-EN), the epicardium (B-EP), and normal sites (N-EN, N-EP). During VT induction, the activation time at N-EN and N-EP was significantly longer than during VF induction (N-EN: 94 +/- 21, 70 +/- 19 ms; N-EP: 83 +/- 21, 64 +/- 10 ms; p < 0.05). Conduction time was measured at the initiation of VT or VF induced by orthodromic or antidromic pacing. The conduction times of the last paced beat between N-EN and B-EP (35 +/- 11, 62 +/- 24 ms), N-EN and N-EP (35 +/- 12, 14 +/- 13 ms), B-EN and B-EP (16 +/- 10, 38 +/- 25 ms), and B-EP and N-EP (77 +/- 27, 44 +/- 12 ms) were significantly different in dogs with inducible VT (p < 0.05), but not in dogs with VF.(ABSTRACT TRUNCATED AT 250 WORDS)

[Signal-averaged electrocardiograms in young athletes--sudden death during exercise].

Our objective was to evaluate the incidence of abnormal SAECG in young athletes, and to evaluate the relationship between abnormal SAECG and electrocardiographic and echocardiographic parameters. The presence of an abnormal SAECG was evaluated in 796 athletes (mean age 19 years), and its relation to findings on 12-lead electro-cardiograms, echocardiograms, and arrhythmias was studied, as recorded by the Holter monitor. An abnormal SAECG was defined as two of the three following criteria: filtered QRS duration > or = 114 msec, root mean squared voltage in the terminal 40 msec < or = 20 microV, or duration < 40 microV > or = 38 msec. Abnormal SAECGs were present in 68 (8.5%) of the athletes and were associated with a smaller left ventricular mass. Athletes who performed anaerobic exercise tended to exhibit a high incidence of abnormal SAECG, which was associated with smaller left ventricular mass. No serious ventricular arrhythmias were observed on Holter monitoring for 24h and during a follow-up period of 20 +/- 10 months in 796 subjects. Continuous anaerobic exercise may induce abnormal SAECG due to the development of delayed myocardial conduction or to electrical inhomogeneity in the cardiac tissue. The presence of an abnormal SAECG was unrelated to the development of arrhythmias in young athletes.

Effect of telmisartan on cholesterol levels in patients with hypertension - Saga Telmisartan Aggressive Research (STAR).

Saga Telmisartan Aggressive Research (STAR) is a single-arm, prospective multi-center trial to evaluate the effectiveness of treatment with telmisartan in patients with hypertension. A total of 197 patients with a systolic blood pressure of > or =140 or a diastolic blood pressure of > or =90 mmHg were enrolled in this study, and were prescribed 20 to 80 mg/day of telmisartan for 6 months. In all patients, both systolic and diastolic blood pressures decreased (159+/-20 to 135+/-12 mmHg, p<0.0001, 87+/-12 to 75+/-8 mmHg, p<0.0001, respectively). In addition, total cholesterol (TC) levels decreased from 200+/-40 to 188+/-33 mg/dl (p<0.05). In patients with TC > or =220 mg/dl, the change was more striking (249+/-33 to 204+/-31 mg/dl, p<0.0001). Even in patients receiving statins, TC levels still were decreased (216+/-51 to 190+/-31 mg/dl, p<0.02). In addition, TC levels were also decreased even in patients receiving telmisartan in exchange for other ARBs with TC > or =220 mg/d. Triglyceride (TG) levels were decreased (270+/-199 to 175+/-74 mg/dl, p<0.005) in patients with TG levels > or =150 mg/dl. Fasting blood glucose (FBG) was decreased (158+/-68 to 138+/-60 mg/dl, p<0.05) in patients with FBG > or =110 mg/dl. These results suggest that telmisartan may have favorable effects on lipid and glucose metabolism, in addition to lowering blood pressure. The profound effect of telmisartan to lower cholesterol suggests a potential use in hypertensive patients with dyslipidemia.

Use of monophasic action potentials to evaluate postpacing T wave changes.

We examined the relationship between postpacing T wave changes and monophasic action potentials recorded from the ventricle in dogs. MAPs were recorded from the right and left ventricle before and after cessation of pacing. The duration of the MAP was calculated as the time in milliseconds from the upstroke to 90% repolarization (MAPD90). T waves in limb leads were flat or had a biphasic pattern, eventually becoming negative after pacing. The Q-T interval of the escape beat after pacing was prolonged compared with the control. After right ventricular pacing, the average duration of MAPD90 in the right ventricle, but not in the left ventricle, was prolonged. (right MAPD: control 275 +/- 10 ms; after pacing: 311 +/- 17 ms, p < 0.05; left MAPD: control: 266 +/- 23 ms, after pacing: 284 +/- 26 ms, NS). After left ventricular pacing, the average duration of MAPD90 in the left ventricle, but not in the right ventricle, was prolonged (right MAPD: control: 247 +/- 75 ms, after pacing: 287 +/- 39 ms, NS; left MAPD: control: 257 +/- 23 ms, after pacing: 303 +/- 25 ms, p < 0.05). Furthermore, the average duration of MAPD90 at the pacing site became progressively prolonged over time. These results suggest that myocardial cells retain the memory of abnormal repolarization associated with pacing.

Arrhythmogenic effects of graded coronary blood flow reductions superimposed on prior myocardial infarction in dogs.

BACKGROUND: We studied arrhythmogenesis and its underlying pathophysiology during graded reductions of coronary blood flow, superimposed on prior myocardial infarction to test the hypothesis that spontaneous ventricular fibrillation and induced ventricular tachycardia are dependent on different patterns of coronary flow reduction in hearts with prior myocardial infarction. METHODS AND RESULTS: In 10 sham-operated dogs (control group) and 24 dogs with 3-week-old experimental apical myocardial infarction, the left circumflex coronary artery was constricted to produce four grades of flow reduction: 25%, 50%, 75%, and 100%. Among the sham-operated control animals, only one of 10 (10%) developed spontaneous ventricular fibrillation and only two of nine (22%) were inducible into sustained ventricular tachycardia during 100% circumflex coronary artery flow reduction. No spontaneous ventricular fibrillation or inducible ventricular tachycardia occurred with lesser grades (25%, 50%, or 75%) of flow reduction among the control animals. In the myocardial infarction group, five of 24 dogs (21%) were inducible before flow reduction. However, 50% flow reduction in the myocardial infarction group resulted in inducibility of ventricular tachycardia in 12 of 24 dogs (50%); nine of 16 (56%) during 75% flow reduction; and six of 11 (55%) with 100% flow reduction. In addition, none of the dogs in the myocardial infarction group developed spontaneous ventricular fibrillation during 25% or 50% flow reduction, whereas six of 22 (27%) developed ventricular fibrillation during 75% flow reduction and 10 of 21 (48%) during 100% flow reduction. In dogs with spontaneous ventricular fibrillation during flow reduction, the total myocardial mass of the ischemic "risk" zone and infarcted zone was significantly greater than in those without spontaneous ventricular fibrillation (68 +/- 5% versus 56 +/- 6% [p less than 0.01]). There was no difference in the total myocardial mass of the ischemic risk zone and infarcted zone between dogs with and without inducible ventricular tachycardia during flow reduction. CONCLUSIONS: In canine model of subacute myocardial infarction, superimposed ischemia increased the likelihood of inducible sustained ventricular tachycardia with lesser grades of coronary flow reduction compared with that necessary to allow spontaneous ventricular fibrillation. The underlying pathophysiology appears to differ between spontaneous ventricular fibrillation and electrically induced sustained ventricular tachycardia.

Long-term administration of probucol and QTc interval prolongation.

Electrocardiographic QTc intervals were measured in twenty-one hypercholesterolemic patients before and after long-term probucol (500-1,000 mg/day for 30 months) treatment. Probucol reduced serum total cholesterol (TC), triglyceride (TG), and high density lipoprotein-cholesterol (HDL-C). Mean QTc interval prolongation after probucol was 17 msec. A positive correlation was found between the change in QTc interval after probucol (delta QTc) and the total amount of probucol administered. delta QTc was negatively correlated to the pre-treatment QTc interval. No correlation was observed between serum probucol concentrations and delta QTc. Neither clinical evidence of cardiotoxicity nor critical arrhythmias were noted during the treatment period.

Electrophysiological properties in paroxysmal atrial fibrillation complicated with the Wolff-Parkinson-White syndrome: comparison with paroxysmal atrial fibrillation alone.

Electrophysiological studies were performed in 26 patients with atrial fibrillation (AF). Thirteen patients had the Wolff-Parkinson-White (WPW) syndrome (group A), and another 13 patients did not have the WPW syndrome (group B). The right atrium effective refractory period was significantly shorter in group A than in group B. The wavelength index which was defined as the ratio of the refractory period to the conduction delay was significantly lower in group A than in group B. Accordingly, patients in group A had a greater tendency to produce atrial reentry than those in group B.

Hyperinsulinemia in patients with spastic angina pectoris.

We evaluated the association between coronary spasm and hyperinsulinemia (high immunoreactive insulin, IRI) in patients with angina pectoris. The study cohort comprised 30 patients with spastic angina pectoris, 30 patients with angina pectoris showing fixed-obstructive coronary sclerosis and 30 control subjects who were matched for body mass index, age and sex. A 75-gram oral glucose test was performed, and blood sugar and IRI were serially measured concomitant with serum total cholesterol, triglyceride and HDL cholesterol. The IRI level at 60 min, the peak IRI during the test, sigma IRI and sigma IRI/sigma blood sugar were significantly higher in the patients than in the controls. Total cholesterol and LDL cholesterol levels were significantly increased in patients showing fixed-obstructive coronary sclerosis compared to controls.

Efficacy of procainamide on ventricular tachycardia: relation to prolongation of refractoriness and slowing of conduction.

The effect of procainamide on intraventricular conduction and refractoriness, and the prevention of induction of ventricular tachycardia (VT) were studied in 29 patients who had remote myocardial infarction and inducible sustained monomorphic VT. AFter intravenous administration of 15 mg/kg procainamide, induction of VT was suppressed in seven (24%) patients (responders), while in 22 (76%) VT was still inducible (nonresponders). The percent change in paced QRS duration at a cycle length (CL) of 400 msec produced by procainamide was significantly less in responders than in nonresponders: 29.8 +/- 3.9% versus 38.9 +/- 10.8% (p = 0.0020). The percent change in the right ventricular effective refractory period (ERP) at CLs of 600 and 400 msec was significantly greater in responders than in nonresponders: 14.6 +/- 6.9% versus 7.9 +/- 7.3% (p = 0.0414) for ERP at a CL of 600 msec and 15.1 +/- 7.0% versus 8.0 +/- 7.4% (p = 0.0386) for ERP at a CL of 400 msec. Stepwise discriminant analysis showed that greater percent increase in ERP at a CL of 400 msec and lesser percent increase in paced QRS duration at a CL of 400 msec were significantly independent markers for the responders. These findings suggest that lesser slowing of conduction and greater prolongation of refractoriness by procainamide tend to abolish reentry within the reentrant circuit. Greater slowing of conduction and lesser prolongation of refractoriness tend to stabilize a reentrant circuit, and promote the continued induction of VT.

Predictors of sustained ventricular tachycardia inducibility in patients with nonsustained ventricular tachycardia and chronic coronary artery disease.

To assess the likelihood of inducing sustained ventricular tachycardia, we analyzed a cohort of 58 retrospective and 18 prospective patients with chronic coronary artery disease who underwent electrophysiologic study because of spontaneous nonsustained ventricular tachycardia (three or more beats, lasting less than 30 seconds, at a rate greater than 100/min). In 24 of the 58 retrospective patients (41%) sustained ventricular tachycardia was inducible. Stepwise logistic regression identified two "major" variables--left ventricular aneurysm/dyskinesis/akinesis (p = 0.0001; relative risk = 11.88) and ejection fraction less than 40% (p = 0.0002; relative risk = 9.69)--and one "minor" variable--nonsustained ventricular tachycardia longer than 10 beats (p = 0.0151; relative risk = 4.21)--as significant predictors of inducibility. Nineteen patients with both major variables had a high probability of inducibility (greater than 90%). Nineteen patients with neither major variable had a low probability of inducibility (less than 5%). The remaining 20 patients with only one of the major variables had an intermediate probability of inducibility (14% to 75%). The significance of the third minor factor, nonsustained ventricular tachycardia longer than 10 beats, was confined to this intermediate group, in which it could be used to segregate relatively high (65% to 75%) and relatively low (14% to 20%) probability of inducibility. Prospective application of the predictor function stratified 18 additional patients into three groups with high (six patients), intermediate (seven patients), and low (five patients) probability of inducibility. The observed rate of inducibility in each group was 5 of 6 (83%), 2 of 7 (29%), and 0 of 5 (0%), respectively. These data suggest that patients with nonsustained ventricular tachycardia and chronic coronary artery disease can be stratified into subgroups with high, intermediate, and low probability of inducibility of sustained ventricular tachycardia on the basis of ejection fraction and regional ventricular wall motion defects alone.

Observations on the initiation of sustained ventricular tachycardia by programmed stimulation.

We analyzed the initiation of sustained monomorphic ventricular tachycardia (VT) by programmed ventricular stimulation (PVS) in 50 consecutive patients who had clinical VT or aborted sudden cardiac death with remote myocardial infarction. In 25 of 50 patients, the first induced QRS complex of VT was morphologically identical to the succeeding QRS complexes of VT (type I). In 25 other patients, the first VT beat had a different morphology (type II). Type I had a significantly longer VT cycle length than type II (333 +/- 65 msec and 293 +/- 66 msec, P = 0.036). Type II VT initiation required more aggressive stimulation protocol than type I (type I: type II; number of extrastimulus required for induction 2.5 +/- 0.9 : 3.0 +/- 0.6, P = 0.026; shortest extrastimuli coupling interval 244 +/- 28 msec : 220 +/- 23 msec, P = 0.002). The interval between the last extrastimulus and the onset of the first VT beat was 408 +/- 88 msec in type I and 336 +/- 75 msec in type II (P = 0.004). Furthermore, there was good correlation between the VT cycle length and the interval from last extrastimulus to the onset of nonpaced beat in type I but not in type II.(ABSTRACT TRUNCATED AT 250 WORDS)

A transarterial approach of electrical ablation of atrioventricular junction in a dog model: comparison of the effects between high and low energy shocks.

To analyze the effectiveness of a transarterial catheter technique for electrical ablation of the atrioventricular junction, 30 mongrel dogs were studied by means of synchronized electrical shock between the catheter adjacent to the noncoronary cusp and a metal plate behind the dog's back using a standard cardioversion unit. These dogs were classified into two groups according to the energy delivered. The high energy group received more than 100 joules (group A) and the low energy group received from 20 to 60 joules (group B). Complete atrioventricular block was induced by a single shock in all dogs. In group A, ventricular premature beats appeared in all dogs; ventricular fibrillation and ventricular tachycardia appeared immediately in half (6/12) after electrical ablation. No ventricular dysrhythmias occurred in group B. Temporary right ventricular pacing was also performed in 10 out of 12 dogs in group A after electrical ablation. In contrast only one dog required pacing in group B. The cycle length of the subsidiary pacemaker rhythm was essentially identical in both groups. The QRS duration of the subsidiary pacemaker rhythm in group A was significantly longer in group B (P less than 0.01). The extent of myocardial damage induced by electrical ablation in group B was more localized than those in group A. However, the histological lesion representing the granulation tissue with necrosis and slight chronic inflammatory cell infiltration, was identical between both groups A and B. It was concluded that this technique of low energy electrical ablation of the atrioventricular junction adjacent to the noncoronary cusp via a transarterial approach was useful in producing an experimental model of chronic complete AV block.

Effects of verapamil on electrophysiological properties in paroxysmal atrial fibrillation.

Verapamil is used to control ventricular response during atrial fibrillation (AF). Limited data is available on the effects of verapamil on atrial vulnerability in human AF. The effects of intravenous verapamil (0.15 mg/kg) on electrophysiological properties of the atrium were investigated in 12 patients with documented paroxysmal AF by electrophysiological studies. Sinus cycle length, sinus node recovery time, and the effective refractory period of the right atrium were not significantly affected by verapamil. The intraatrial conduction delay zone was significantly increased (33 +/- 20 msec before verapamil versus 50 +/- 22 msec after verapamil, P < 0.01), and the maximal intraatrial conduction delay was also significantly prolonged by verapamil, both to the His bundle region (30 +/- 12 msec before verapamil versus 42 +/- 15 msec after verapamil, P < 0.01) and to the coronary sinus (40 +/- 15 msec before verapamil versus 53 +/- 17 msec after verapamil, P < 0.01). The fragmented atrial activity zone was significantly increased (15 +/- 14 msec before verapamil versus 25 +/- 22 msec after verapamil, P < 0.02), and the percentile fragmented atrial activity was also significantly increased by verapamil (149 +/- 18 msec before verapamil versus 174 +/- 44 msec after verapamil, P < 0.05). The repetitive atrial firing zone remained unchanged. Sustained AF spontaneously occurred in only one patient after the administration of verapamil. Thus, verapamil may modulate the abnormal atrial electrophysiology in paroxysmal AF, and would favor production of atrial reentry.

Wavelength index: a predictor of the response to disopyramide in paroxysmal lone atrial fibrillation.

We investigated whether the new parameter wavelength index could predict the response to chronic disopyramide therapy in patients with paroxysmal atrial fibrillation (AF). Twenty-seven patients with AF underwent electrophysiologic studies and the wavelength index was determined before and after intravenous administration of disopyramide. Then all patients were treated with oral disopyramide for 6 months. In 17 patients, AF was eliminated (group A), while it persisted in another 10 patients (group B). The ratio of the wavelength index before and after intravenous disopyramide was higher in group A than in group B. Thus, the wavelength index proved useful for predicting the response of AF to disopyramide.