Long-Term Outcome Following Programmed Electrical Stimulation in Patients with High-Grade Ventricular Ectopy

To determine if programmed electrical stimulation (PES) could be utilized to identify patients with high-grade ventricular ectopy at low- or high-risk for sudden cardiac death, we performed PES in 40 patients with high-grade ventricular ectopy refractory to conventional antiarrhythmic agents. Twenty-one patients had a previous myocardial infarction, five had cardiomyopathy, six had hypertension, three had valvular heart disease and five had no known structural heart disease. The mean age was 50 years (range, 18 to 76). During programmed ventricular stimulation, eight patients had inducible sustained (more than 30 seconds) monomorphic ventricular tachycardia (Group I) but in 32 patients sustained ventricular tachycardia was not inducible (Group II). None of the five patients without structural heart disease were inducible while seven out of 21 (33%) patients with previous myocardial infarction had inducible ventricular tachycardia (VT). Antiarrhythmic therapy was instituted in patients with inducible VT; patients without inducible VT did not receive antiarrhythmic agents. In Group I, seven of the eight patients are alive (mean follow-up, 16 months) and in Group II, 28 of the 32 patients are alive (mean follow-up, 17 months). None of the five deaths were sudden. We conclude that in the absence of antiarrhythmic therapy, the incidence of sudden cardiac death is very low in patients with high-grade ventricular ectopy who do not have inducible monomorphic ventricular tachycardia during programmed ventricular stimulation.     

Ranolazine reduces ventricular tachycardia burden and ICD shocks in patients with drug-refractory ICD shocks

Background: There are limited options for patients who present with antiarrhythmic‐drug (AAD)‐refractory ventricular tachycardia (VT) with recurrent implantable cardioverter defibrillator (ICD) shocks. Ranolazine is a drug that exerts antianginal and antiischemic effects and also acts as an antiarrhythmic in isolation and in combination with other class III medications. Ranolazine may be an option for recurrent AAD‐refractory ICD shocks secondary to VT, but its efficacy, outcomes, and tolerance are unknown. Methods and Results: Twelve patients (age 65 ± 9.7 years) were treated with ranolazine. Eleven (92%) were male, and 10 (83%) had ischemic heart disease with an average ejection fraction of 0.34 ± 0.13. All patients were on a class III AAD (11 amiodarone, one sotalol), with six (50%) receiving mexilitene or lidocaine. Five patients had a prior ablation and two were referred for a VT ablation at the index presentation. The QRS increased nonsignificantly from 128 ± 31 ms to 133 ± 31 ms, and the QTc increased nonsignificantly from 486 ± 32 ms to 495 ± 31 ms after ranolazine initiation. Over a follow‐up of 6 ± 6 months, 11 (92%) patients had a significant reduction in VT and no ICD shocks were observed. VT ablation was not required in those referred. In two patients, gastrointestinal side effects limited long‐term use. Of these two patients, one died due to progressive heart failure. In one patient, severe hypoglycemia limited dosing to 500 mg daily, but this was sufficient for VT control. Conclusion: Ranolazine proved effective in reducing VT burden and ICD shocks in patients with AAD‐refractory VT. Ranolazine should be further tested for this indication and considered for clinical application when other options have proven ineffective. (PACE 2011; 34:1600–1606)     

Fulguration of Ventricular Tachycardia Using High Cumulative Energy: Results in Thirty-one Patients with a Mean Follow-Up of Twenty-seven Months

Catheter electrical ablation of ventricular tachycardia (VT) was attempted in 31 patients (57 ± 15 years) who had refractory recurrent VT. Fifteen patients had coronary artery disease, seven had arrhythmogenic right ventricular dysplasia, four had cardiomyopathy and five had no structural heart disease. Ten patients were NYHA class III-IV. Ten patients experienced cardiac arrest or syncope during VT. Twenty-two patients had only one documented morphologic type of spontaneous VT. Whereas nine patients had more than one: the VT was incessant or daily in 17 patients. One to 16 shocks (mean 5.6) of 160 to 240 joules each (1162 ± 1060 joules) were delivered to the endocardial exit site of VT—as identified by endocardial activation mapping (29 patients) and pacemapping (31 patients)—during one (22 patients) or more than one session (nine patients). Cumulative delivered energy was 840 ± 558 joules for right ventricular VT (11 patients) and 1362 ± 1240 joules for left ventricular VT (20 patients). Reversible side effects occurring immediately after shocks included: nonclinical VT (two patients), ventricular fibrillation (two patients), AV block (three patients). Mean CK—MB fraction 6 hours after shocks was 93 ± 46 IU/1. An electrophysiology study performed 7 to 10 days later demonstrated that the original clinical VT was inducible in seven patients, nonclinical monomorphic VT was inducible in eight patients and no VT was inducible in 13 patients. The procedure was successful in 25/29 patients (86%) who had no recurrence of the original VT (or sudden death) either on no antiarrhythmic therapy (16 patients) or on the same regimen that was ineffective before ablation (nine patients) over a follow-up period of 27 ± 11 months. A nonclinical VT occurred in two patients. The ablation result was not interpretable in two patients and unsuccessful in four patients: the endocardial activation time at site of shocks was –5 ± 5 ms in the failures versus ?43 ± 29 ms in the successes (P < 0.05).     

Amiodarone in the Management of Patients with Ventricular Tachycardia and Ventricular Fibrillation

Fifty-eight patients with symptomatic ventricular tachycardia (VT) or ventricular fibrillation (VF) were treated with amiodarone. All had clinical episodes of VT/VF or inducible VT during electropharmacologic testing despite treatment with maximumtolerated doses of conventional antiarrhythmic agents. Chronic treatment with amiodarone was begun at a dose of 800–1000 mg per day. Thirty-two patients were also treated with a previously ineffective conventional agent. Thirty patients underwent programmed ventricular stimulation after 2.6 ± 1.7 months (mean ± S. D.) of treatment with amiodarone at a mean daily dose of 588 ± 155 mg. VT was induced in 25 patients (sustained in 20, nonsustained in five). Seventeen patients had a recurrence of VT or VF after 0.5–9 months of treatment with amiodarone (fatal in seven, non-fatal in 10). Forty-one patients (71%) had no recurrence of symptomatic VT or VF while being treated with amiodarone (mean follow-up period, 17.1 ± 12.4 months). Among the 25 patients who had inducible VT with programmed ventricular stimulation while being treated with amiodarone, 19 patients (76%) have had no recurrence of symptomatic VT or VF overa follow-up period of 21.5 ± 7.3 months. Ambulatory electrocardiographic recordings obtained after one week of treatment with amiodarone were not helpful in predicting clinical response. Twenty-two patients (38%) developed ataxia and/or an intention tremor which improved with a decrease in the amiodarone dose. Amiodarone, either by itself or in combination with conventional antiarrhythmic drugs, has a significant therapeutic effect in high risk patients with refractory VT. The finding of inducible VT during electropharmacologic testing in patients taking amiodarone does not preclude a favorable clinical response. Neurologic toxicity is common in patients treated with 600–800 mg per day of amiodarone.     

The Signal Averaged Electrocardiogram and Programmed Stimulation in Patients with Complex Ventricular Arrhythmias

TURITO, G., ET AL.: The Signal Averaged Electrocardiogram and Programmed Stimulation in Patients with Complex Ventricular Arrhythmias. The signal averaged electrocardiogram (SA-ECG), programmed electrical stimulation (PES), and left ventricular ejection fraction (EF) studies were utilized for risk stratification and management of patients with complex ventricular arrhythmias and nonsustained ventricular tachycardia (VT). The study population included 90 patients (63 with coronary artery disease and 27 with dilated cardiomyopathy). Sustained monomorphic VT was induced in 22 cases (24%), ventricular fibrillation (VF) in 10 (11%), and no sustained VT/VF in 58 (64%). An abnormal SA-ECG was recorded in 23 patients (26%) and was more common in patients with than in those without induced sustained VT (68% vs 12%, p < 0.0001). None of 33 patients with normal SA-ECG and EF ≥ 40% had induced VT. Patients were followed-up for 2.5 ± 0.8 years off antiarrhythmic therapy, unless they had induced sustained VT. The 3-year sudden death rate was 19% in the group with induced sustained VT, 0 in that with induced VF, and 9% in that without induced VT/VF (P = NS). The 3-year total cardiac mortality was higher in patients with than in those without EF < 40% (27% vs 7%, p < 0.05). It is concluded that patients with organic heart disease and spontaneous nonsustained VT may not need PES or antiarrhythmic therapy if SA-ECG is normal and EF is ≥ 40%, since their risk of induced VT and sudden death is low. On the other hand, patients with abnormal SA-ECG and/or EF < 40% may require PES, since their risk for induced VT is high. Antiarrhythmic therapy may also be considered in these patients. (PACE, Vol. 13, December, Part II 1990)     

Results of Electrophysiological Testing and Long-Term Follow-Up in Patients Sustaining Cardiac Arrest Only While Receiving Type IA Antiarrhythmic Agents

Therapeutic management of patients sustaining a cardiac arrest while receiving antiarrhythmic agents can be difficult since the role of the drug in possibly facilitating the arrhythmia is often difficult to define. To determine if the response to programmed stimulation could give insight into which patients may have experienced a drug-induced cardiac arrest, we studied 29 patients (61 +/- 9 years) with no prior history of sustained ventricular tachyarrhythmias (VT) who suffered a cardiac arrest only while receiving type Ia antiarrhythmic agents. Patients with documented myocardial infarction, acute ischemia, electrolyte abnormalities, or torsade de pointes were excluded from the study. Twenty-four patients had coronary artery disease with prior myocardial infarction (ejection fraction 28% +/- 9%) and five patients had idiopathic dilated cardiomyopathy (ejection fraction 31% +/- 6%). During baseline electrophysiological testing, 19 patients (66%) had inducible sustained ventricular arrhythmias: uniform VT, n = 14 (group I), polymorphic VT or ventricular fibrillation, n = 5 (group II). Ten patients (group III) had no inducible sustained ventricular arrhythmias. To determine if rechallenge with a type Ia agent could facilitate induction of a sustained ventricular arrhythmia in group III, eight patients underwent ten electrophysiological studies during therapy with either procainamide or quinidine. Only two patients developed sustained VT in response to programmed stimulation. Patients in groups I and II received therapy guided by electrophysiological testing, including antiarrhythmic agents alone (n = 8), subendocardial resection (n = 4), or an implantable cardioverter defibrillator (n = 7). Patients in group III received antiarrhythmic agents empirically (n = 3), or for treatment of atrial tachyarrhythmias (n = 2) or nonsustained VT (n = 1). In addition, four patients in group III received an implantable cardioverter defibrillator. During a mean follow-up of 28 +/- 27 months (range: 1 day-84 months) 13 patients died suddenly or received a defibrillator shock preceded by syncope or presyncope: group I: n = 5; group II: n = 2; group III: n = 6. In conclusion: (1) most patients sustaining a cardiac arrest only in the presence of type Ia antiarrhythmic agents have inducible sustained VT in the absence of antiarrhythmic agents, and (2) the risk of recurrent VT persists in patients without inducible sustained arrhythmias in the drug-free state, regardless of whether they manifest inducible arrhythmias after rechallenge with a type Ia agent.     

Reduction of Antiarrhythmic Drug Use in Patients Receiving Implantable Cardioverter Defibrillators

Widespread use of implantable cardiovertfir defibrillators (ICDs) for the treatment of ventricular tachycardia (VT) and ventricular fibrillation (VF) occurred in the late 1980s and early 1990s. Additionally, there has been increasing appreciation during this time for both the lack of efficacy and praarrhythmic activity of antiarrhythmic drugs to treat these cardiac arrhythmias. We evaluated the use of antiarrhythmic drugs from 1987 to 1991 (5-year period) at the time of ICD implantation in 25,450 patients. The use of all classes of antiarrhythmic agents decreased from 61% to 24% during this time period (P < 0.05), In addition, there was a significant reduction in antiarrhythmic agent use for each drug class (P < 0.05) with the exception of Class II agents (beta blockers). These changes in drug use occurred independent of any changes in age, sex, ejection fraction, prevalence of coronary artery disease, or type of ventricular arrhythmia (VT vs VF).     

Clinical Observations and Outcome of Ventricular Tachycardia Ablation in Patients with Left Ventricular Assist Devices

Background: Ablation of ventricular tachycardia (VT) in patients with left ventricular assist devices (LVAD) is challenging and not well documented. This report describes our experience with endocardial VT ablation in six patients with an LVAD. Methods: We retrospectively reviewed the clinical records of LVAD patients who underwent an ablation procedure for refractory VT. Results: A total of eight ablation procedures were performed in six patients who, during the last 2 weeks before the ablation procedure, received a total of 101 appropriate shocks for VT. A closed aortic valve (n = 2) or aortic atheroma (n = 1) required a transseptal catheterization in three of six patients. The apical LVAD cannula served as a VT substrate in two of six patients. VT was eliminated in four patients and markedly reduced in two others. The latter two patients experienced a total of only four implantable cardioverter defibrillator (ICD) shocks during a follow‐up of 130 and 493 days. Intravenous antiarrhythmic medications used in five of six patients before ablation were discontinued in all. The ablation procedures permitted hospital discharge in four of six patients. Five patients died during follow‐up (228 ± 207 days after the procedure). The cause of death was unrelated to cardiac arrhythmias. One patient is still alive 1,205 days after the procedure. Conclusion: Ablation of VT in LVAD patients is feasible and can result in a markedly decreased VT burden with a reduction of ICD shocks. The subsequent discontinuation of intravenous antiarrhythmic medications may facilitate hospital discharge. (PACE 2012; 35:1377–1383)     

Effects of Coronary Artery Bypass Grafting on Ventricular Arrhythmias: Results with Electrophysiological Testing and Long-Term Follow-Up

Myocardial revascularization was performed in 56 patients with coronary artery disease who presented with ventricular tachycardia (VT) (n = 39) or ventricular fibrillation (n = 17). There were 46 men and 10 women, aged 65 ± 10 years. Three vessel (n = 42) or left main disease (n = 4) was present in 82%. Left ventricular ejection fraction averaged 36%± 11%. Electrophysioiogical studies were performed preoperatively in all patients; 50 (89%) had inducible ventricular arrhythmias. Sustained monomorphic VT was induced in 40 patients (cycle length 284 ± 61 msec). Reproducible symptomatic nonsustained VT was induced in four patients and ventricular fibrillation in six patients, while six patients had no inducible arrhythmia. Preoperatively the patients with inducible VT failed 3.3 ± 1.2 drug trials during electrophysiological studies. In addition to coronary bypass, 22 patients also received an automatic implantable cardioverter defibrillator (ICD), 26 patients received prophylactic ICD patches, and 1 patient had resection of a false aneurysm. There were no perioperative deaths. Postoperative electrophysiological studies were performed in all 56 surgical survivors. Ventricular tachyarrhythmia could not be induced in the six patients who had no inducible VT preoperatively and in 13 of 40 (33%) with preoperatively inducible sustained VT or in 19 of 50 (38%) patients with any previously inducible ventricular arrhythmia, thus a totaJ of 25 patients (45%) had no inducible VT postoperatively. Of the remaining, 11 patients were treated with antiarrhythmic drugs alone, 11 had already received an ICD (combined with drugs in 7), and another 9 received the ICD postoperatively (combined with drugs in 4). At a mean foJJow-up of 28 ± 21 months there were 11 deaths (20%): 2 sudden, 5 nonsudden cardiac, and 4 noncardiac deaths. There were 16 nonfatal VT recurrences (29%): 14 among patients with persistently inducible arrhythmias, and onJy 2 among those with no inducible arrhythmia postoperatively (P = 0.004); 13 occurred in patients with an ICD (P = 0.01). Thus among these patients with malignant ventricular arrhythmias who underwent revascuJarization, 45% had no inducible arrhythmia postoperatively with 33% of those with preoperatively inducible sustained VT apparently rendered noninducible by revascularization, while the majority (70%) remained free of major arrhythmic events during long-term follow-up. We conclude that myocardial revascularization alone can result in no ventricular arrhythmia induction in selected patients with VT inducible prior to surgery. Long-term follow-up of such patients indicates a low sudden death and arrhythmia recurrence rate. Furthermore, in patients with persistently inducible ventricular tachyarrhythmias after coronary revascuJarization, the sudden death rate is low despite a high frequency of nonfatal arrhythmia recurrence when antiarrhythmic medications are guided by programmed stimulation or an ICD is used.     

Endocardial Catheter Ablation for Refractory Ventricular Tachycardia Associated with Coronary Artery Disease

Percutaneous endocardial electrode catheter ablation using stored direct current (DC) electrical energy was performed in five patients with recurrent ventricular tachycardia (VT) refractory to many antiarrhythmic drugs, including amiodarone. All had prior myocardial infarction and poor left ventricular function with ejection fractions ranging from 20% to 40%. Endocardial catheter and pace mappings were used to localize the earliest site of activation during VT. Under general anesthesia, two to six shocks with 200 to 300 joules DC energy per shock were delivered to the localized sites. Immediate complications included ventricular fibrillation in one patient, transient QRS complex widening in two patients, transient complete AV block with persistent first-degree AV block in one patient, and transient asystole in two patients. None had inducible VT immediately following ablation, or 4 to 6 days later; none had evidence of intracardiac clot by two-dimensional (2D) echocardiography on the third to fifth day. Peak creatine kinase ranged from 189 to 1610 IU/L with 9% to 18% MB fraction. During a follow-up of 6 to 30 months, three patients had no recurrence of VT. Two patients had recurrent VT with a slower rate, which was controlled with antiarrhythmic drugs. None had worsening of congestive heart failure. Two patients died of nonarrhythmic causes. We conclude that nonsurgical endocardial ablation of VT with an electrode catheter is effective for the treatment of refractory VT in selected patients with coronary artery disease.     

Risk Factors for Tachycardia Events Caused by Antiarrhythmic Drugs: Experience From the ESVEM Trial

BACKGROUND: In the Electrophysiology Study versus Electrocardiographic Monitoring (ESVEM) trial, up to seven antiarrhythmic drugs were randomly assigned to 486 patients with a history of sustained ventricular arrhythmia. At baseline, all the patients had inducible sustained ventricular tachycardia (VT) and had >/=10 premature ventricular beats (PVBs) per hour on 48-hour Holter monitoring. A total of 1,229 drug trials were performed. Antiarrhythmic drugs were discontinued during hospitalization because of ventricular tachyarrhythmias thought to be a proarrhythmic effect of the antiarrhythmic drugs in 96 of 479 patients (20%) who received drugs. Proarrhythmic effects were defined as sustained VT, ventricular fibrillation or arrhythmic death, torsade de pointes, or distinct intolerable worsening of the baseline arrhythmia after at least three doses of the drug. METHODS AND RESULTS: Eighteen baseline characteristics were analyzed for factors that would predict a higher incidence of proarrhythmia. These included type of heart disease, previous myocardial infarction, symptom activity scale, gender, type of arrhythmia, VT/ventricular fibrillation, age, left ventricular ejection fraction (LVEF), PVB frequency, heart rate, QRS duration, and QT interval. Multiple logistic regression analysis identified increased mean PVB frequency (P =.003) and increased heart rate (P =.026) as significant predictors of proarrhythmia. Decreased LVEF (<25%) exhibited only a trend toward significance (P =.073). When proarrhythmia was redefined as sustained VT, cardiac arrest of arrhythmic death, or torsade de pointes (n = 59), PVB frequency (P =.003) and heart rate (P =.034) were still the only significant baseline predictors. CONCLUSIONS: In the ESVEM study, higher PVB frequency and higher heart rate were significant predictors of drug-induced proarrhythmia.     

Value of Serial Electropharmacological Testing in Managing Patients Resuscitated from Cardiac Arrest

Electrophysiologic studies were performed in 11 patients (9 men, 2 women; mean age: 59.9 yrs) who had survived an episode of cardiac arrest due to ventricular tachycardia (VT) or ventricular fibrillation. The purpose of the studies was to evaluate the usefulness of serial acute drug testing in selecting an effective chronic antiarrhythmic regimen. Ten of the patients were suffering from chronic ischemic heart disease with one or more previous myocardial infarctions while one had no evidence of structural heart disease. A ventricular aneurysm was present in four of them. During control electrophysiologic study, a sustained VT was induced by ventricular stimulation (single and double extrastimuli at various paced ventricular cycle lengths plus bursts of rapid ventricular pacing) in nine of the ten patients (90%) who were studied while not receiving antiarrhythmic drugs; a non-sustained VT was induced in one of them (10%). In three patients (30%) VT could be initiated only by right ventricular stimulation at a side different from the apex (outflow tract). No arrhythmia was observed in the only patient who was studied while taking amiodarone orally (400 mg/day for more than three months). During serial acute drug testing a totally effective drug regimen (successful in preventing the induction of any ventricular arrhythmia) was found in seven of the ten patients (70%) who underwent this procedure and a partially effective drug regimen (a sustained VT was no longer inducible; it was easier to interrupt and it was considerably slower) was found in two patients (20%). None of the nine patients who received chronic antiarrhythmic therapy based on the results of serial acute drug testing died suddenly during a mean follow-up of 14 months (range: 3-28) and only one had a recurrence of cardiac arrest. The latter, however, was taking antiarrhythmic drugs at a dosage less than that proved to be effective during electropharmacological testing. The only patient who refused serial acute drug testing and received an empiric antiarrhythmic therapy died suddenly at the 21st month of follow-up. These results indicate that serial electropharmacological testing is useful in selecting an effective long-term drug regimen in survivors of cardiac arrest.     

Sotalol Is More Powerful Than Propranolol in Suppressing Complex Ventricular Arrhythmias

BACKGROUND: Sotalol has combined type II and type III antiarrhythmic properties. Although the beta-blocking action of sotalol is thought to contribute to its antiarrhythmic actions, few data are available from direct comparative clinical trials with pure beta-blocking drugs. METHODS AND RESULTS: In this double-blind, randomized, multicenter, placebo-controlled, parallel study, we have compared the antiarrhythmic efficacy and safety of treatment with sotalol vs propranolol in 181 patients with organic heart disease and frequent (>30 ventricular premature complexes [VPCs]/h) repetitive ventricular premature complexes. Eighty-seven were randomized to receive sotalol and 94 received propranolol. The demographic and clinical characteristics of the two groups were identical, and the majority of patients had coronary artery disease or hypertensive heart disease. Most patients had a long-standing history (>5 years) of ventricular arrhythmias and, in a significant proportion, antiarrhythmic therapy with other drugs had failed in the past. After withdrawal of all antiarrhythmic drugs and 1 week of placebo, qualified patients were randomized to sotalol (320 mg/day) or propranolol (120 mg/day). patients not achieving adequate response were given higher doses of sotalol (640 mg/day) or propranolol (240 mg/day)At baseline, both groups had comparable frequency of total VPCs/hour (274/h and 255/h for sotalol and propranolol groups, respectively) which was reduced to 71 VPCs/h and 109/VPCs/h, respectively, at the end of phase 1. At final evaluation there was a significantly greater response to sotalol as demonstrated by 80% reduction in VPCs/hour with sotalol compared with only 50% reduction noted in the propranolol group. Adequate therapeutic response was also achieved in a significantly greater percentage of patients on sotalol compared with propranolol (56% vs 29%, P =.02). Sotalol was also superior to propranolol in suppressing the VT events/day during phase 1 (89% vs 78% reduction in VT events/day, P <.05). Sotalol was more effective than propranolol in all subgroups and in patients with heart rate <75 beats per minute. CONCLUSIONS: Sotalol is more powerful than propranolol in suppressing ventricular arrhythmias documented on Holter recordings. The superiority of sotalol appears to be related to its combined class II and class III antiarrhythmic actions.     

Celiprolol does not protect against ventricular tachycardia or sudden death in the conscious canine: a comparison with pindolol in assessing the role of intrinsic sympathomimetic activity

The antiarrhythmic and antifibrillatory effects of the beta-1 adrenoceptor antagonist celiprolol were evaluated in a chronic canine model of myocardial infarction and sudden death. Programmed electrical stimulation (PES) was performed in conscious animals 3 to 5 days after a 2-hr occlusion/reperfusion of the left anterior descending coronary artery. Dogs in which PES resulted in a reproducible nonsustaining or sustained ventricular tachycardia (VT) were randomized to receive i.v. celiprolol (3 mg/kg, n = 10) or vehicle (n = 10). PES and measurement of electrophysiologic (parameters were repeated after 30 min and the animals were entered into the sudden death protocol by introducing a 150-microA anodal current to the lumen of the left circumflex coronary artery via a surgically implanted silver wire electrode. Celiprolol failed to prevent the induction of VT, and the outcome of the sudden death protocol did not differ from vehicle with respect to either sudden (within 1 hr of ischemia) or delayed (greater than 1 hr) mortality. VT cycle length and ventricular refractoriness were prolonged (P less than .05) by celiprolol, but other electrophysiologic parameters were unaffected. Heart rate was not altered after drug, but celiprolol antagonized the ischemia-induced increase in rate seen in the vehicle group. Similar electrophysiologic results and mortality data were apparent in a third group of dogs which received pindolol (0.09 mg/kg, n = 8). The failure of both drugs to protect against ischemic ventricular fibrillation in a model in which beta adrenoceptor antagonism has previously proved beneficial may be due in part to related cardiostimulant properties shared by celiprolol and pindolol.     

Heart failure

Survival of patients with heart failure has improved over the past decade due to advances in medical therapy. However, sudden cardiac death continues to cause 35 to 65% of death. Ventricular arrhythmias are important causes of sudden cardiac death in patients with heart failure. The risks of antiarrhythmic drugs are increased in patients with heart failure. Therefore, in the absence of a clear indication, antiarrhythmic drug therapy should be avoided. A number of recent randomized trials have provided evidence that beta-adrenergic blockers, angiotensin-converting enzyme(ACE) inhibitors and angiotensin II receptor blockers(ARB) significantly reduces the risk of sudden death in patients with chronic congestive heart failure. For patients who have a history of sustained ventricular tachycardia(VT) or ventricular fibrillation(VF) amiodarone or an implantable cardioverter defibrillator(ICD) should be considered, and these therapy may benefit some high risk patients who have nonsustained VT.     

In vivo antiarrhythmic and cardiac electrophysiologic effects of a novel diphenylphosphine oxide IKur blocker (2-isopropyl-5-methylcyclohexyl) diphenylphosphine oxide

The antiarrhythmic efficacy of the novel ultrarapid delayed rectifier potassium current (IKur) blocker (2-isopropyl-5-methylcyclohexyl) diphenylphosphine oxide (DPO-1) was compared with efficacies of the standard class III rapidly activating component of delayed rectifier potassium current (IKr) blockers [+-N-[1'-(6-cyano-1,2,3,4-tetrahydro-2-napthalenyl)-3,4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,4'-piperidin]-6-yl] methanesulfonamide hydrochloride (MK499) and ibutilide and the class IC agent propafenone in a canine model of Y-shaped intracaval and right atrial free wall surgical lesions producing the substrate for reentrant atrial flutter. Electrocardiographic and cardiac electrophysiologic effects also were assessed at the effective antiarrhythmic doses of test agents. DPO-1 terminated atrial arrhythmia (six/six preparations; 5.5 +/- 2.0 mg/kg i.v.) while significantly increasing atrial relative and effective refractory periods (+15.7 and +15.2%, respectively) but having no significant effects on ventricular refractory periods or electrocardiogram (ECG) intervals. Effective antiarrhythmic doses of MK499 (five/five preparations; 0.004 +/- 0.002 mg/kg i.v.) and ibutilide (five/five preparations; 0.003 +/- 0.001 mg/kg i.v.) similarly increased atrial relative (+23.2 and +25.1%, respectively) and effective (+21.6 and +31.9%, respectively) refractory periods. However, antiarrhythmic doses of MK499 and ibutilide also consistently and significantly increased ventricular relative (+9.9 and +7.6%, respectively) and effective (+10.4 and +9.9%, respectively) refractory periods, rate-corrected ECG QTc (+6.7 and +7.8%, respectively), and paced QT (+7.3 and +8.5%, respectively) intervals. Doses of propafenone that terminated atrial arrhythmia (five/five preparations; 0.94 +/- 0.54 mg/kg i.v.) significantly increased ECG QRS interval (+11.1%). These findings support the approach of atrial selective modulation of refractoriness through block of IKur for the development of potentially safer and more effective atrial antiarrhythmic agents.     

Electrophysiological, Rate Dependent, and Autonomic Effects of the Class III Antiarrhythmic Almokalant After Myocardial Infarction in the Pig

Ventricular arrhythmias remain a major problem, in particular in patients with left ventricular dysfunction or heart failure. In this group of patients, Class I drugs were shown to be ineffective, and they even increased mortality during chronic treatment. New antiarrhythmic agents should preferably not only have pure antiarrhythmic effects, but should also be free from adverse autonomic properties. In the present study, the electrophysiological, rate dependent and autonomic effects of intravenously administered almokalant, a new Class III antiarrhythmic drug, were investigated in nine pigs surviving a myocardial infarction. The ventricular effective refractory period (VERP) increased after almokalant (loading dose: 0.05 μmoLkg ^?1 .min^?1, continuous infusion: 0.0025 uμmol/kg^?1.min^?1) from 292 ± 25 to 308 ± 13 ms (pacing cycle length [PCL] 500 ms + 1 extrasystole [ES]), from 249 ± 19 to 261 ± 16 ms (PCL 400 ms +1ES), and from 209 ± 18 to 219 ± 18ms (PCL 300 ms +1ES). The VERPs increased most after three ES at PCL 400 ms: from 167 ± 27 to 186 ± 29 ms (P < 0.05) and at PCL 300 ms: from 159 ± 29 to 174 ± 27 ms (P < 0.05). The ventricular monophasic action potential durations (MAPD) were similarly prolonged and the ratio VERP/MAPD did not change. Prolongation of MAPD after almokalant remained present at short pacing cycle lengths. Before almokalant infusion, sustained monomorphic ventricular tachycardia (VT) was inducible in two pigs, and nonsustained VT in a third animal. After almokalant, only one pig remained inducible. Two weeks after myocardial infarction, heart rate variability and baroreflex sensitivity were reduced. Furthermore, subsequent electrophysiological testing transiently reduced these parameters of autonomic activity. During almokalant however, no changes in autonomic functions were observed after programmed stimulation. Heart rate variability decreased after myocardial infarction from 6.3 ± 2.5 ms to 5.4 ± 4,2 ms (P = NS}. After programmed stimulation, it further decreased to 2.8 ± 2.0 ms (P = 0.028). Almokalant infusion prevented autonomic deterioration: 3.3 ± 2.2 ms before stimulation and 3.3 ± 1.3 after stimulation (P = NS). In postinfarct pigs, almokalant prolongs VERP and MAPD at shorter pacing cycle lengths. The results indicate absence of reverse rate dependence and of adverse autonomic changes.     

Evaluation of Patients with Bundle Branch Block and "Unexplained" Syncope: A Study Based on Comprehensive Electrophysiologic Testing and Ajmaline Stress

Thirty-five patients with bundle branch block (BBB) and unexplained syncope underwent electrophysiologic study (EPS) including programmed ventricular stimulation and ajmaline administration (1 mg/kg, IV) to induce infra-His block. A prolonged HV interval (greater than 55 ms) was present in 16 of the 35 patients. Ajmaline-induced HV block occurred in 12 patients (complete HV block in 10, and 2:1 HV block in two). Monomorphic ventricular tachycardia (VT) was inducible in nine (25.7%) and polymorphic VT in two patients (5.7%). Left ventricular ejection fraction (LVEF) was less than 40% in five patients (45.5%) with inducible VT. Two patients had an unexpected co-existence of inducible HV block and VT. The remaining 14 patients (40%) had no detectable abnormality. The incidence of inducible VT was higher (45% vs 13.3%), and the presence of negative studies was lower (30% vs 53.3%) in patients with structural heart disease (n = 20), when compared to those with no significant heart disease (n = 15) (differences not significant [NS]). During a mean follow-up period of 16.5 +/- 9.2 months, all the patients with inducible HV block have been asymptomatic after having received permanent pacemakers. Patients with inducible monomorphic VT (except one with poor left ventricular function who died suddenly) have also been asymptomatic on antiarrhythmic drugs. Of the remaining patients, seven with normal EPS, two with prolonged HV intervals but no inducible HV block (despite being given permanent pacemakers) and one patient with polymorphic VT on antiarrhythmic drugs continue to have recurrent syncope. Approximately 60% of patients with BBB and unexplained syncope have clinically significant electrophysiologic abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)     

Spironolactone therapy is associated with reduced ventricular tachycardia rate in patients with cardiomyopathy

Introduction: Multiple pharmacological therapies currently in prevalent clinical use for cardiac diseases have antifibrotic properties. Spironolactone, a potent antifibrotic agent, is currently used for advanced heart failure. Therapies such as HMG‐CoA reductase inhibitors (statins) and angiotensin‐converting enzyme inhibitors (ACEi) also have antifibrotic properties. However, the effect of these medications on the ventricular arrhythmia phenotype is currently unknown. Therefore, we set out to define the ventricular arrhythmia rates in patients actively treated with such therapies. Methods and Results: We retrospectively evaluated the ventricular tachycardia (VT) rates in patients with structural heart disease actively treated with therapies with antifibrotic properties. VT rates were significantly diminished in patients treated with spironolactone (158 ± 26 beats per minute [bpm], n = 21) compared to patients on no medications (205 ± 22 bpm, n = 13) or those who were on similar heart‐failure therapies but not on spironolactone (186 ± 32 bpm, n = 82). In addition, we observed that VT rates showed a significant trend toward lower rates in patients receiving either statins or ACEi, compared to patients on no medical therapy. In multivariate analysis, spironolactone therapy was identified as the single most significant variable for reduced VT rate. Conclusion: Use of spironolactone in patients with heart failure is associated with reduced VT rate. Similar but less‐significant reductions in VT rates were observed with use of other pharmacological agents with antifibrotic properties, such as statins and ACEi. Our findings, at least in part, could account for reduction in sudden cardiac death rates documented with use of these therapies. (PACE 2011; 34:309–314))     

Absence of a morning peak in ventricular tachycardia and fibrillation events in nonischemic heart disease: analysis of therapies by implantable cardioverter defibrillators

A growing number of Japanese patients are being treated with ICDs. Efforts are warranted to minimize the rates of ICD shocks that cause discomfort and anxiety. The circadian distribution of ICD discharges was investigated in 80 patients (57+/-10 years of age, 69 men) from ten Japanese medical centers. The underlying heart disease was ischemic in 27 versus nonischemic in 53 patients. All patients had refractory VT or VF, and received appropriate shocks confirmed by stored data retrieved from the memory of the ICD. In the analysis of 354 appropriate shocks delivered in the overall population, a morning peak in VT or VF episodes was observed. However, subgroup analyses of the circadian distribution of ICD shocks revealed that the morning peak in VT or VF episodes was confined to patients with ischemic heart disease and was blunted by treatment patients with beta-adrenergic blockers. The absence of a morning peak in appropriate ICD shocks among patients with nonischemic heart disease remains unexplained and was unrelated to the use of beta-adrenergic blockers. In conclusion, the circadian pattern of appropriate ICD discharges was related to the underlying heart disease. In patients with ischemic heart disease, recurrences of VT or VF peaked in the morning. In contrast, in patients without ischemic heart disease, the episodes of VT or VF were evenly distributed during waking hours. Beta-adrenergic blockers appeared to blunt the morning peak in VT or VF among patients with ischemic heart disease.