Long-term multicenter experience with a second-generation implantable pacemaker-defibrillator in patients with malignant ventricular tachyarrhythmias. The Guardian Multicenter Investigators Group.

A second-generation implantable pacemaker-cardioverter-defibrillator was evaluated in 200 patients with sustained ventricular tachycardia, ventricular fibrillation or prior cardiac arrest. The device permits demand ventricular pacing for bradyarrhythmias and for long QT interval or tachycardia suppression, uses programmable (3 to 30 J) energy shocks for conversion of ventricular tachycardia and ventricular fibrillation and is used with conventional pacing and defibrillation leads. Ventricular tachycardia/fibrillation recognition is based on the ventricular electrogram rate and requires reconfirmation before shock delivery. Two hundred patients (mean age 62 years, mean left ventricular ejection fraction 36%) were enrolled and followed up for 0 to 23 months (mean 12). Epicardial lead system implantation was performed with use of an anterolateral thoracotomy (38%), median sternotomy (26%) and subxiphoid (20%) or subcostal (16%) approach. Perioperative mortality rate was 5.5% (all nonarrhythmic deaths). Implant defibrillation threshold ranged from 3 to 30 J (mean 15), with initial programmed shock energy ranging from 3 to 30 J (mean 22). Ventricular tachycardia/fibrillation sensing threshold ranged from 0.7 to 1.8 mV (median 1) and the tachycardia detection interval from 288 to 416 ms (median 320). Reprogramming of implant variables was necessary for reliable electrographic sensing (54 patients), programmed shock therapy (61 patients) and tachycardia detection rate (63 patients). Device activation for potential shock delivery occurred in 111 patients (55.5%) with actual shock delivery after ventricular tachycardia/fibrillation reconfirmation in 66 patients (33%). During follow-up study, there was a 1% arrhythmia mortality rate, 6.5% cardiac mortality rate and 10.5% total mortality rate. This study demonstrates that the programmable implantable pacemaker-cardioverter-defibrillator is effective in preventing arrhythmic death, yet reduces patient exposure to repeated shock therapy. Reprogramming is usually necessary during follow-up for optimal function.

Antiarrhythmic efficacy of N-acetylprocainamide in patients with premature ventricular contractions.

Oral administration of a 1.5-gm dose of N-acetylprocainamide (NAPA) to 9 patients with premature ventricular contractions (PVCs) confirmed previous indirect evidence that this metabolite of procainamide has antiarrhythmic efficacy and potency comparable to those of procainamide. Although the mechanism by which NAPA acts as an antiarrhythmic drug is not known, it was found that the 6 patients with coupled PVCs responded to NAPA therapy and that the 3 patients without coupled PVCs failed to respond. Coupling interval prolongation also occurred during NAPA therapy in 4 of the 6 responding patients. These observations suggest that NAPA may terminate coupled PVCs by slowing and then interrupting conduction of re-entrant impulses, as has been proposed for procainamide. NAPA plasma concentrations of 7.4-17.2 mug/ml were well tolerated by the patients and produced an average fall of 3 mm Hg in mean arterial pressure and a 7.6% mean increase in corrected QT interval.

Reproducibility of programmed electrical stimulation responses in patients with ventricular tachycardia or fibrillation associated with coronary artery disease.

Invasive electrophysiologic studies were performed in 102 patients with sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) using an aggressive programmed electrical stimulation (PES) protocol. The study was repeated after 2.0 +/- 2.9 days in all patients with no intercurrent changes in antiarrhythmic therapy. Patients with coronary artery disease (n = 72) were identified and PES results of these patients were analyzed and compared with results of patients without coronary artery disease. Multiple clinical and electrophysiologic factors were analyzed to determine any association with concordance of PES responses. No significant difference in concordance of PES responses was found in the 2 groups of patients. PES responses were groups into 3 categories: (1) noninducible, (2) nonsustained VT, and (3) sustained VT. Kappa values of PES responses of noninducible and sustained VT in both groups were higher and therefore the PES responses were more reproducible than nonsustained VT. The induction of sustained monomorphic VT was more reproducible than a PES response of nonsustained or sustained polymorphic VT. Inducible sustained VT with a rate of greater than or equal to 250 beats/min was less reproducible than induction of sustained VT with a rate less than 250 beats/min. Induction of VT by 3 extrastimuli was less reproducible than with any other mode. This short-term variability may account for false negatives associated with PES-directed antiarrhythmic therapy. Because of these findings, it is recommended that nonsustained VT and sustained polymorphic or rapid polymorphic VT should not be used as PES end points to guide antiarrhythmic therapy.

Long-term arrhythmic outcome in survivors of ventricular fibrillation with absence of inducible ventricular tachycardia.

While programmed electrical stimulation of the heart is useful in directing therapy in cardiac arrest survivors who exhibit inducible ventricular tachycardia (VT), controversy exists as to the risk of recurrent ventricular fibrillation (VF) and need for antiarrhythmic therapy in patients without inducible VT during drug-free control programmed stimulation studies. In this study, the clinical features and arrhythmic outcome of 43 survivors of VF without inducible VT at control programmed stimulation were examined. In 38 patients, factors that may have played a potentiating role in the genesis of VF included ischemia in 15, proarrhythmia in 18, rapid rate response to atrial fibrillation in 3 and acute alcoholism in 2. Three patients required antiarrhythmic drugs for supraventricular tachyarrhythmia and 40 patients were discharged without antiarrhythmic therapy. At 32 +/- 21 months (range 1 to 82), 37 (92%) have remained free of arrhythmic recurrence while 3 have had sustained subsequent major arrhythmic events (syncope 1 patient, VF 1, sudden cardiac death 1). Thus, survivors of VF without inducible VT at drug-free control programmed stimulation are characterized by (1) potentiating factors--often identifiable and correctable--that may be important to the genesis of VF; (2) generally low risk of arrhythmic recurrence; and (3) effective long-term management often achieved without the use of additional antiarrhythmic drugs or antitachycardia/defibrillation devices.

Safety and efficacy of oral sotalol for sustained ventricular tachyarrhythmias refractory to other antiarrhythmic agents.

The safety and efficacy of oral sotalol were evaluated in 481 patients with drug-refractory sustained ventricular tachyarrhythmias (VT) in an open-label multicenter study. After drug-free baseline evaluations, therapy was initiated at 80 mg every 12 hours, with upward dose titrations of 160 mg/day being allowed at intervals of 72 hours to a maximum dose of 480 mg every 12 hours. Efficacy determinations were made by either programmed electrical stimulation (PES) or Holter monitoring responses. Of the 481 patients enrolled, 473 underwent acute-phase titration. Of the 269 patients assessable by PES, 94 (34.9%) exhibited complete response (suppression of inducible VT), with an additional 67 patients (24.9%) exhibiting partial response. Of the 109 patients assessable by Holter monitoring, 43 (39.4%) exhibited a complete response. There were no significant differences between responders and nonresponders with regard to left ventricular ejection fraction. Although response rates tended to improve as the sotalol dose was increased to 640 mg/day, efficacy was most commonly achieved at a sotalol dose of 320 mg/day. Sotalol was discontinued because of adverse effects in 42 (8.9%) of the acute-phase patients. The most common adverse effect was proarrhythmia, which was observed in 23 patients (4.9%). Proarrhythmia took the form of torsades de pointes in 12 patients and an increase in VT episodes in 11. In 3 acute-phase patients (0.6%), sotalol was discontinued because of the emergence of congestive heart failure. A total of 286 patients entered the long-term phase. Life-table estimates of the proportion of patients who remained free of recurrence of arrhythmia at 12, 18, and 27 months were 0.76, 0.72, and 0.66, respectively. There were no significant differences in time to recurrence of arrhythmia as related to PES response, Holter monitor response, baseline left ventricular ejection fraction, or history of congestive heart failure. Among the 70 patients (24.5%) in whom there was recurrence of arrhythmia, sudden death occurred in 17 and sustained VT in 41. Sotalol was discontinued owing to presumed adverse effects in 21 (7.3%) of the long-term patients, including 8 with proarrhythmia; proarrhythmia consisted of torsades de pointes in 3 patients and increased episodes of VT in 5. These findings suggest that sotalol is an effective drug for the long-term treatment of patients with drug-refractory sustained VT. Proarrhythmia was observed in only 6.4% of the study population and tended to occur during the acute titration phase. The need to discontinue therapy because of congestive heart failure was uncommon.(ABSTRACT TRUNCATED AT 400 WORDS)

Safety and efficacy of sotalol in patients with drug-refractory sustained ventricular tachyarrhythmias.

The safety and efficacy of oral sotalol, an investigational beta-adrenergic blocker with class III antiarrhythmic drug properties, were examined in a multicenter study in 236 patients with sustained ventricular tachyarrhythmias. In 104 patients, the index arrhythmia was a cardiac arrest, and all patients had undergone at least 3 previous unsuccessful antiarrhythmic trials (mean = 5 per patient). In the 106 patients assessed by programmed electrical stimulation, sotalol completely suppressed induction of ventricular tachycardia (VT) in 33 (31%) and rendered VT slower (greater than 100 ms prolongation of cycle length) or more difficult to induce in 29 (27%). Using continuous 24-hour ambulatory monitoring methods, sotalol complete- and partial-response rates were 51 and 12%, respectively. Of the 236 acute-phase patients, 151 were discharged receiving long-term sotalol therapy. The median sotalol dose was 480 mg/day. At a mean follow-up of 346 +/- 92 days, 27 patients (18%) had recurrence of sustained arrhythmia; 9, sudden death; 11, sustained VT; 5, automatic defibrillator discharge; and 2, syncope. Adverse effects forced discontinuation of therapy in 10 patients (7%): 6 secondary to symptomatic bradyarrhythmia, 2 due to refractory heart failure, 1 due to torsades de pointes, and 1 from bronchospasm. Life-table analysis of sotalol's overall long-term efficacy at 6, 12 and 18 months were 80, 76 and 72%, respectively. Although mean follow-up was short (less than 1 year), neither acute-phase programmed stimulation nor 24-hour ambulatory monitoring responses were significantly predictive of subsequent arrhythmic outcome. Proarrhythmia was documented in 18 patients (7%), 17 during the acute phase and 1 during long-term follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Extended endocardial resection for the treatment of ventricular tachycardia and ventricular fibrillation.

A total of 40 patients with drug-refractory, life-threatening cardiac rhythm disturbances--ventricular tachycardia in 23 patients and ventricular fibrillation in 17 patients--underwent extended endocardial resection (EER) of scar tissue. Scarring was due to myocardial infarction in 38 patients, to previous congenital heart operation in 1 patient, and to sarcoidosis of the heart in 1. The EER procedure was directed by epicardial and endocardial mapping data whenever possible, and was usually combined with revascularization, aneurysmectomy, or, in 5 patients, mitral valve replacement. Operative mortality was 10%, incident to poor preoperative ventricular function and hemorrhage secondary to previous cardiac surgical procedures. Thirty-three of the 36 survivors (92%) are free of arrhythmia at follow-up periods ranging from 3 to 36 months (mean, 12.5 months); the arrhythmia in the remaining 3 patients is now drug controlled. Thirty-three patients had postoperative electrophysiological studies, and in 30 (91%), the arrhythmia was no longer inducible. The results of surgical treatment for ventricular tachycardia and ventricular fibrillation were similar. The results also proved satisfactory whether the EER procedure was directed by visual observation or mapping.

Operative therapy for ventricular arrhythmia.

The history of surgical attempts to control ventricular arrhythmia is reviewed and current methodology is presented in detail. The results of the various surgical approaches and future trends in the management of this troublesome condition are discussed.

Patients with heart rhythm disturbances: variables associated with increased psychologic distress.

The spectrum of psychologic distress in patients with serious heart rhythm disturbances (HRD) has not been well defined. A survey of personal and clinical background data and general psychologic status was made of 136 patients with serious HRD defined as sustained or symptomatic ventricular tachycardia or fibrillation. Two questionnaires were used: the SCL-90-R, a standard self-report symptom inventory of present psychologic status, and a functional capacity and occupational status questionnaire developed by us. Of the 105 respondents, 89 completed both questionnaires, the results of which form the basis of this report. The patients with HRD were found to have significantly elevated SCL-90-R scores reflective of an increase in overall psychologic distress (Global Severity Index, Positive Symptom Distress Index, and Positive Symptom Total) as well as significantly higher scores on the specific constructs. Within the HRD population, univariate analysis revealed three variables significantly correlated with increased psychologic distress: (1) requiring long-term antiarrhythmic medication, (2) being forced to modify work status, and (3) having more advanced cardiac impairment. Patients who had two or more of these variables, termed risk factors, reported significantly more symptoms and greater psychologic distress than those with zero or one risk factor. We conclude that patients with serious HRD have greater psychologic distress than do normal subjects. Within the HRD group, patients requiring long-term medical treatment for their arrhythmia, those forced to modify work status, and those with more advanced cardiac impairment are at greater risk for emotional sequelae, and patients with two or more of the identified risk factors are more likely to have elevated psychologic distress.(ABSTRACT TRUNCATED AT 250 WORDS)

Lithium treatment: prescribing and monitoring habits in hospital and general practice.

OBJECTIVES: To define current clinical practice of lithium prescribing and monitoring and to compare hospital based practice with general practice. DESIGN: Prospective study of doctors' practice. SETTING: Psychiatric hospital day and outpatient facilities and general practices in Edinburgh and Midlothian district (population 600,000). SUBJECTS: 458 patients taking lithium who had been stabilised and who remained as outpatients during the year of study. 219 were treated by their general practitioner and 190 by the hospital; 49 had shared care or care transferred during the study. MAIN OUTCOME MEASURES: Daily dose, duration of treatment, psychiatric diagnosis, mean annual serum lithium concentration, frequency of occurrence of and response to raised serum concentrations. RESULTS: Compared with hospital doctors general practitioners were more likely to prescribe lithium three or more times daily (43/219 (general practice) v 10/190 (hospital); chi 2 = 18.6, p = 0.001) and to estimate serum concentrations less frequently (4.5 v 5.3 measurements/year; t = 3.04, p = 0.003), and their patients were more likely to experience raised lithium concentrations (39/219 v 17/190; chi 2 = 6.8, p = 0.01). One third of doctors made no response to raised lithium concentrations in the next six weeks. CONCLUSIONS: General practitioners and hospital doctors care for similar types of patients and the stringency of lithium surveillance varies greatly among doctors. Certain aspects of practice give cause for concern and could be improved by following more uniform guidelines.

A cross-sectional study of glomerular function in 740 unselected lithium patients.

Creatinine clearance was estimated using a formulaic method from serum creatinine, age and sex in 740 unselected lithium-treated patients in southeastern Scotland. Psychiatric history and details of prescribing and monitoring of lithium treatment were obtained from existing case registers. Lithium treatment duration and glomerular filtration, controlling for the effects of age, were weakly related, but only in males. Cases who had been exposed to higher serum lithium concentrations had lower creatinine clearance than those maintained within therapeutic range. Of cases within the lowest quartile of renal function, proportionally more were supervised in general practice rather than at hospital clinics. Suggestions are made for the clinical practice of monitoring serum lithium concentrations and serum creatinine.

Exercise induced fatal sinusoidal ventricular tachycardia secondary to moricizine.

Moricizine has been touted as having a low incidence of proarrhythmic effects. We present a case of proarrhythmia from moricizine, which presented as exercise induced ventricular tachycardia, and review the literature suggesting that this antiarrhythmic drug shares the proarrhythmic profile of other agents with predominant type Ic action. We conclude that moricizine has certain clinical and electrophysiological features that resemble type Ic antiarrhythmic agents. Precautions similar to those used when prescribing other drugs of this type should be followed when prescribing moricizine, including predischarge exercise testing.

Cardiac conduction defects in polymyositis: electrophysiologic studies in four patients.

The clinical electrophysiologic findings in four patients with biopsy-proven polymyositis and bifascicular block are described. Atrioventricular (AV) block developed in two of these four patients, and intracardiac electrophysiologic studies documented the site of spontaneous block to be distal to the His bundle in one, whereas in the second marked His-ventricular prolongation was found, and distal block developed at low paced atrial rates. Sinus node and AV nodal function were normal in all four. These electrophysiologic data provide the first documentation of the site of AV block in patients with polymyositis and correlate well with findings of previous pathologic studies that have shown extensive fibrosis of the distal His bundle and bundle branches.

Operative therapy of malignant ventricular rhythm disturbances.

Pre- and postoperative electrophysiologic study (EPS), intraoperative cardiac mapping, and extended endocardial resection of scar (EER) has enabled us to identify subgroups among 94 patients who have had operation to control or prevent malignant ventricular arrhythmia. Operative mortality was 8.5% and cure or prevention of ventricular arrhythmia was accomplished in 92% of survivors. Group 1: 13 patients were resuscitated from "sudden death" due to ventricular fibrillation (VF). All had exercise-induced VF and/or ventricular tachycardia (VT). Preoperative EPS revealed no inducible VT/VF. All had coronary artery disease, without evidence of myocardial infarction (MI) or ventricular wall motion abnormality; all were cured with conventional myocardial revascularization. Group 2: 65 patients had MI with residual left ventricular wall motion abnormality, usually aneurysm. The malignant arrhythmia, either sustained VT (38 patients) or VF (27 patients), was inducible by EPS but not usually by exercise, and all were refractory to medical therapy. Treatment was operative mapping, aneurysmectomy, EER, and coronary revascularization. Operative mortality was 11.9%; 90% of survivors are arrhythmia free, off drugs; 10% are now drug responsive. Group 3: 3 patients without coronary disease had VT or VF caused by endocardial sarcoidosis or operative scar from a previous congenital heart operation. Treatment was EPS, operative mapping, and excision of abnormal endocardial scar with no operative mortality. Group 4: 13 patients underwent aneurysmectomy for indication other than arrhythmia, but had preoperative ventricular irritability which was not life-threatening. Operation was aneurysmectomy, prophylactic EER, and revascularization with no mortality and no postoperative arrhythmic events. After many years of unpredictable and unsatisfactory results from various empirical surgical approaches, the operative treatment of malignant ventricular arrhythmia is now based on sound electrophysiologic principles.

Amiodarone in patients with previous drug-mediated torsade de pointes. Long-term safety and efficacy.

The safety and efficacy of long-term amiodarone therapy were examined in 12 patients who had previously developed torsade de pointes as a complication of previous antiarrhythmic therapy. The QTc intervals were determined at the time of torsade de pointes (570 +/- 40 ms), after 7 days of amiodarone loading (490 +/- 70 ms), and after 3 months of chronic amiodarone administration (580 +/- 80 ms). Compared to a drug-free control period, QTc was significantly prolonged (P less than 0.05) at the time of torsade de pointes, after amiodarone loading, and after 3 months of amiodarone therapy. The QTc intervals at the time of torsade de pointes and after chronic amiodarone treatment were not significantly different. At 16 +/- 7 months of follow-up, all patients remained free of subsequent torsade de pointes, syncope, or sudden death. In addition, 5 of 6 patients with a history of sustained ventricular tachycardia remained free from arrhythmic recurrence despite persistence of inducible ventricular tachycardia during programmed stimulation studies done before discharge. We conclude that amiodarone can often be used safely and effectively in patients who have previously had an episode of drug-mediated torsade de pointes. Amiodarone-induced QTc prolongation, even when marked, does not predict recurrent torsade de pointes. These observations also suggest that the propensity for a drug to produce this arrhythmia is dependent on other electrophysiologic effects in addition to its ability to simply lengthen repolarization.

Programmed electrical stimulation to determine the need for antiarrhythmic therapy in patients with complex ventricular ectopic activity.

Patients with complex ventricular ectopy (greater than or equal to Lown grade III) and organic heart disease (OHD) are at increased risk for sudden cardiac death. Despite this fact, many such patients will remain free of symptomatic ventricular arrhythmia and thus are unnecessarily exposed to antiarrhythmic drug toxicity and arrhythmic potentiation. Programmed stimulation (PS) was used to direct therapy in 88 patients with asymptomatic ventricular ectopy complicating OHD. Thirty-three had inducible ventricular tachycardia (VT) and underwent treatment. The 55 patients without inducible VT (less than or equal to 6 repetitive ventricular responses) are the focus of this study. Three patients required treatment for persistent cardiac awareness. The remaining 52 have been followed for 22 months off antiarrhythmic drugs and all have remained free of subsequent major arrhythmic events. Therefore, in patients with complex ventricular ectopy, OHD, and absence of prior symptomatic ventricular arrhythmia, PS identifies patients at low risk for future disabling or life-threatening arrhythmic episodes and patients with absence of inducible VT can usually be managed without antiarrhythmic drugs.

Uptake of 99mTc-exametazime shown by single photon emission computed tomography before and after lithium withdrawal in bipolar patients: associations with mania.

BACKGROUND: Early manic relapse following lithium discontinuation offers an important opportunity to investigate the relationship between symptoms, effects of treatment and regional brain activation in bipolar affective disorder. METHOD: Fourteen stable bipolar patients on lithium were examined with neuropsychological measures, clinical ratings and single photon emission computed tomography (SPECT) before and after acute double-blind withdrawal of lithium. Brain perfusion maps were spatially transformed into standard stereotactic space and compared pixel-by-pixel. A parametric analysis was used to examine the change in brain perfusion on lithium withdrawal, and the relationship between symptom severity and brain perfusion separately both between and within subjects. RESULTS: Lithium withdrawal was associated with an important redistribution of brain perfusion, with increases in inferior posterior regions and decreases in limbic areas, particularly anterior cingulate cortex. Seven of the 14 patients developed manic symptoms during the placebo phase, correlating with relative increases in perfusion of superior anterior cingulate and possibly left orbito-frontal cortex. CONCLUSIONS: The important effect of lithium withdrawal on brain perfusion implies that after withdrawal of lithium, the brain develops an abnormal state of activity in limbic cortex. The structures involved did not co-localise with those apparently modulated by manic symptoms.