Chronobiology of acute myocardial infarction: cardiac arrhythmia suppression trial (CAST) experience.

The onset of acute myocardial infarction (AMI) has been shown to occur in a reproducible pattern with a peak in mid-morning and a secondary peak in late afternoon and early evening. More detailed information on the timing of this catastrophic event may provide important pathophysiologic information. Using the database from the Holter Registry of the Cardiac Arrhythmia Suppression Trial (CAST) (n = 22,516), the day of the week, the month, and season of the onset of AMI was obtained and correlated with demographic characteristics. The pattern of the day of onset for the entire population was significantly nonuniform (p <0.0001) with a Monday peak and a weekend nadir. This pattern was observed in most of the examined subgroups. Analysis of seasonal data revealed nonuniform distribution (p <0.001) with a peak in winter and autumn. We conclude that AMI is not a random event but occurs in definite patterns related to the day of the week and the season of the year. These patterns were observed in a wide variety of patient subgroups and appear related to climate, occupation, and other factors.

Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction. The RAPID II Investigators.

BACKGROUND: The therapeutic benefit of thrombolytic therapy has been shown to correlate directly with completeness (TIMI grade 3 flow) and speed of reperfusion of the infarct-related coronary artery. The purpose of the RAPID II study was to determine whether a double-bolus regimen of reteplase, a recently developed deletion mutant of wild-type tissue plasminogen activator, could improve 90-minute coronary artery patency rates achieved with the most successful standard regimen, an "accelerated" front-loaded infusion of alteplase. METHODS AND RESULTS: Three hundred twenty-four patients with acute myocardial infarction were randomized to receive (along with intravenous heparin and aspirin) either a 10 plus 10 megaunits double bolus of reteplase or front-loaded alteplase. The primary end point of "patency at 90 minutes, graded according to the TIMI classification" was centrally assessed in a blinded fashion. Infarctrelated coronary artery patency (TIMI grade 2 or 3) and complete patency (TIMI grade 3) at 90 minutes after the start of thrombolytic therapy were significantly higher in the reteplase-treated patients (TIMI grade 2 or 3: 83.4% versus 73.3% for front-loaded alteplase-treated patients, P = .03; TIMI grade 3: 59.9% versus 45.2%, P = .01). At 60 minutes, the incidence of both, patency and complete patency, was also significantly higher in reteplase-treated patients (reteplase versus alteplase, TIMI grade 2 or 3: 81.8% versus 66.1%, P = .01; TIMI grade 3: 51.2% versus 37.4%, P < .03). Reteplase-treated patients required fewer acute additional coronary interventions (13.6% versus 26.5%, P < .01), and 35-day mortality was 4.1% for reteplase and 8.4% for alteplase (P = NS). There were no significant differences between reteplase and alteplase in bleedings requiring a transfusion (12.4% versus 9.7%) or hemorrhagic stroke (1.2% versus 1.9%). CONCLUSIONS: Reteplase, when given as a double bolus of 10 plus 10 megaunits to patients with acute myocardial infarction, achieves significantly higher rates of early reperfusion of the infarct-related coronary artery and requires significantly fewer acute coronary interventions than front-loaded alteplase without an apparent increased risk of complications.

Mortality following ventricular arrhythmia suppression by encainide, flecainide, and moricizine after myocardial infarction. The original design concept of the Cardiac Arrhythmia Suppression Trial (CAST).

OBJECTIVE: To test the hypothesis that in survivors of myocardial infarction, the suppression of ventricular premature depolarizations improves survival free of cardiac arrest and arrhythmic death. DESIGN: International, prospective, multicenter, randomized, placebo-controlled trial. SETTING: University and community hospitals. PATIENTS: A total of 3549 patients with myocardial infarction and left ventricular dysfunction. INTERVENTION: Administration of encainide, flecainide, moricizine, or placebo to suppress ventricular premature depolarizations. MAIN OUTCOME MEASURES: Overall survival and survival free of cardiac arrest or arrhythmic death were compared in patients randomized to long-term, active antiarrhythmic drug therapy vs corresponding placebo, using the stratified log rank statistic. RESULTS: At 1 year from the time of randomization to blinded therapy, 95% of placebo-treated patients vs 90% of active drug-treated patients remained alive (P = .0006). Similarly, at 1 year, 96% of placebo-treated patients vs 93% of active drug-treated patients remained free of cardiac arrest or arrhythmic death (P = .003). CONCLUSIONS: The suppression of asymptomatic or mildly symptomatic ventricular arrhythmias after myocardial infarction does not improve survival and can increase mortality. Treatment strategies designed solely to suppress these arrhythmias should no longer be followed.

Antiarrhythmic and hemodynamic evaluation of indecainide and procainamide in nonsustained ventricular tachycardia.

The present trial was a placebo-controlled, randomized, parallel study comparing indecainide to procainamide. A 24-hour intravenous phase measured and compared invasive hemodynamics, followed by oral administration for assessment of arrhythmia suppression. Thirty-two patients (mean age 61 years) with asymptomatic or mildly symptomatic nonsustained ventricular tachycardia (VT) were evaluated, 15 while receiving indecainide and 17 while receiving procainamide. A total of 8 patients had serious toxicity during the intravenous phase; 6 receiving indecainide experienced increased left ventricular dysfunction or worsening arrhythmia (sustained VT, arrhythmic death) while 2 receiving procainamide developed serious hypotension. Proarrhythmia developed in 3 of 15 (20%) of the indecainide patients, but in no procainamide patient. In those tolerating indecainide, long-term suppression of ventricular premature complexes (VPCs) and of runs of VT was more consistent than with procainamide. While indecainide was a potent suppressor of spontaneous VPCs and VT, patients with significant left ventricular dysfunction could not tolerate it. The indecainide patients developing serious toxicity had a common hemodynamic profile: ejection fraction less than 25%, elevated left ventricular filling pressures, low cardiac and stroke volume index and minimal cardiac reserve. Indecainide has a poor risk-benefit ratio in patients similar to the current population, who have potentially lethal ventricular arrhythmias and severe left ventricular dysfunction.

Surgical treatment of right atrial focal tachycardia in adults.

Although successful operative treatment of atrial focal tachycardia has been reported in children, there are only isolated reports of surgical treatment of this arrhythmia in adults. In this case series of eight patients (aged 10 to 53 years) with drug-resistant right atrial focal tachycardia, results of electrophysiologic studies, surgical techniques and long-term follow-up are described. Atrial focal tachycardia was reproduced during electrophysiologic study, and endocardial mapping localized the earliest onset of atrial activation in the right atrium in all patients. Epicardial mapping confirmed the location of atrial tachycardia foci in seven of eight patients whose tachycardia was inducible intraoperatively. Of four patients treated with epicardial cryoablation alone, two had recurrent tachycardia and required a second procedure. None have had arrhythmia recurrence. In all four patients after right atrial excision (two of whom had intraoperative recurrence of atrial focal tachycardia after epicardial cryoablation alone), there has been no recurrence during a clinical follow-up period of 11 to 67 months (mean 30). It is concluded that in adult patients 1) electrophysiologic study with endocardial and epicardial mapping permits successful surgical treatment of atrial focal tachycardia; 2) epicardial cryoablation alone may be associated with recurrence of atrial focal tachycardia either intraoperatively or postoperatively; and 3) subtotal right atrial resection appears to be a well tolerated procedure with no long-term recurrence of atrial focal tachycardia.

Relation of left ventricular dilation during acute myocardial infarction to systolic performance, diastolic dysfunction, infarct size and location.

The quantification of left ventricular (LV) volumes and assessment of their relation to systolic and diastolic dysfunction, infarct size and anatomic location were performed in 54 patients with a first acute myocardial infarction (AMI). Blood pool radionuclide angiography was used to assess LV end-diastolic, end-systolic, and stroke volume indexes, ejection fraction and peak diastolic filling rate. Infarct size was estimated from plasma MB creatine kinase activity. Substantial LV dilation occurred within the initial 24 hours of AMI. The peak diastolic filling rate was low, even in those patients with a normal ejection fraction. In comparison with inferior AMI (n = 25), patients with anterior AMI (n = 29) had a larger end-diastolic volume index (105 +/- 8 vs 81 +/- 4 ml/m2, p less than 0.01) and end-systolic volume index (64 +/- 7 vs 37 +/- 4 ml/m2, p less than 0.001), but similar stroke volume index (41 +/- 3 vs 43 +/- 2 ml/m2, difference not significant). No significant relation was noted between infarct size estimated by MB creatine kinase and any volumetric index. On repeat study (day 10 after AMI), end-diastolic and end-systolic volume indexes increased further (p less than 0.05 vs day 1) but ejection fraction and peak diastolic filling rate were unchanged. It was concluded that: (1) LV dilation occurs within hours of AMI in both inferior and anterior AMI, but is more marked in the latter; (2) significant LV diastolic dysfunction is the rule, even in patients with preserved LV systolic function; and (3) LV dilation is an early compensatory mechanism that maintains normal stroke volume, even in patients with severely reduced LV function.

Effects of Ethmozine (moricizine HCl) on ventricular function using echocardiographic, hemodynamic and radionuclide assessments.

Ventricular arrhythmias combined with left ventricular (LV) dysfunction in patients portend a poor prognosis. Most antiarrhythmic agents have not been sufficiently investigated to adequately describe detrimental effects on LV function; we report the effects of moricizine HCl on ventricular function in 4 trials highlighting patients with LV dysfunction. Quantitative 2-dimensional echocardiography was used to evaluate 81 patients pre- and posttreatment. There was no change in mean global LV ejection fraction (EF) during placebo compared with moricizine HCl therapy (47 +/- 15% vs 46 +/- 14%, p greater than 0.05). In a separate trial, radionuclide LVEF at rest and exercise tolerance testing were performed in 24 patients with life-threatening ventricular arrhythmias who had a mean control LVEF of 40 +/- 19%. No significant change during moricizine HCl therapy (38 +/- 19%, p greater than 0.05) was detected and exercise parameters were unchanged. Rest and exercise LV function was measured during right-sided heart catheterization in a placebo-controlled study of 20 patients with ventricular tachycardia. Moricizine HCl was well tolerated without hemodynamic deterioration in all but 3 patients, who could be identified by their inability to increase stroke volume index during exercise. Finally, the relation between initial LV function and resultant antiarrhythmic efficacy indicates that moricizine HCl controls arrhythmias best in patients with LVEF greater than 30%.

Antiarrhythmic efficacy and hemodynamic effects of cibenzoline in patients with nonsustained ventricular tachycardia and left ventricular dysfunction.

This was a prospective single-blind, placebo-controlled study of cibenzoline in 21 patients with five or more runs of nonsustained ventricular tachycardia (VT) and left ventricular dysfunction (mean left ventricular ejection fraction 36 +/- 24%). Ambulatory electrocardiographic monitoring revealed a baseline of 616 +/- 431 runs of VT/day on placebo. Of the 18 patients tolerating the drug, 14 (77%) patients initially had a 75% or greater reduction in VT (177 +/- 164 runs of VT/day, p less than .05). A repeat ambulatory electrocardiogram documented long-term suppression of VT in 13 of 14 patients at 1 month (2.1 +/- 1.3 runs VT/day, p less than .01), in 10 of 14 patients at 3 months (2.5 +/- 1.9 runs VT/day, p less than .01), and in nine of 14 patients at 6 months (1.5 +/- 0.8 runs VT/day, p less than .01). Aggravation of arrhythmia or drug failure was seen in four of 18 (22%) patients (new onset of sudden cardiac death, two patients; sustained VT, two patients). Hemodynamic measurements were obtained with the use of right heart catheterization in patients at rest and exercising during the placebo phase and after 60 hr of oral cibenzoline. Group hemodynamic variables, both measured and derived, showed no detrimental effect of cibenzoline. However, in three of 21 patients (mean ejection fraction 21%), cibenzoline was discontinued due to severe depression of left ventricular function. Caution is recommended in the use of cibenzoline in patients with left ventricular ejection fractions of less than 25%.

Spontaneous variability of ventricular arrhythmias in patients at increased risk for sudden death after acute myocardial infarction: consecutive ambulatory electrocardiographic recordings of 88 patients.

The Cardiac Arrhythmia Pilot Study, sponsored by the National Heart, Lung, and Blood Institute, is a multicenter, prospective, randomized, double-blind trial designed to identify patients having 10 or more ventricular premature complexes (VPCs) per hour within 6 to 60 days of acute myocardial infarction. The present investigation selected patients after acute myocardial infarction who had ambulatory electrocardiographic qualifying arrhythmia for CAPS. An additional baseline electrocardiogram was recorded before enrollment in the study to assess baseline spontaneous variability of VPCs. A total of 88 patients (15 women, 73 men, aged 57 +/- 10 years) were studied. The 43 patients (49%) receiving beta-blocking drugs were included because the dose was not altered between the 2 consecutive electrocardiographic recordings. This investigation shows that a 95% reduction in VPCs is required to document a significant drug effect rather than variability alone if 1 day of control and 1 day of treatment electrocardiographic recording are compared. Similarly, based on 1 day of electrocardiographic recording before and after antiarrhythmic therapy, 1,780% increase in VPC frequency is required to establish "arrhythmia aggravation" from an antiarrhythmic drug rather than from variability alone based on a 95% confidence interval. Variability of ventricular arrhythmias is independent of left ventricular function, whereas patients taking beta-blocking therapy tend to have greater VPC variability (p = 0.052), even though VPC frequencies were lower (59 +/- 19 vs 138 +/- 31 VPCs/hour, p less than 0.006) than those not taking beta-blocking drugs.

Comparison of left ventricular diastolic function as determined by nuclear cardiac probe, radionuclide angiography, and contrast cineangiography.

In this investigation, determinations of peak diastolic filling rate (PDFR) and ejection fraction (EF) by two distinct nuclear techniques--gated radionuclide angiography (RNA) and nuclear cardiac probe (NCP)--were compared with contrast ventriculography in 44 patients with coronary artery disease (CAD). In addition, PDFR was tested as a potential index of the severity of disease. Good agreement in PDFR was found between NCP and contrast ventriculography (r = 0.83, p less than 0.001), but there was poor correlation between RNA and contrast ventriculography. Ejection fraction measured by either RNA or NCP correlated well with contrast ventriculography (r = 0.96 and r = 0.73, respectively). A positive correlation was found between PDFR and the EF measured by the NCP (r = 0.79) and by contrast ventriculography (r = 0.64), but poor correlation was found between these parameters by RNA. Patients with multivessel CAD had lower PDFR than patients with single vessel disease when studied by the NCP (1.6 +/- 0.4 versus 2.5 versus 0.6 EDV/sec [mean +/- s.d.], p less than 0.0001), but not by RNA. Thus, compared with contrast ventriculography, determination of PDFR is more accurate by NCP than by RNA. Furthermore, the PDFR measured by NCP, but not by RNA, may be a potentially useful index of the extent of CAD.

Hemodynamic effects of moricizine at rest and during supine bicycle exercise: results in patients with ventricular tachycardia and left ventricular dysfunction.

To evaluate the hemodynamic effects of moricizine, 20 patients with frequent nonsustained ventricular tachycardia (VT) with a mean left ventricular ejection fraction (EF) of 39 +/- 14% were enrolled in a prospective single-blind, placebo-controlled study. Hemodynamic measurements were performed at rest and during supine bicycle exercise on placebo and moricizine therapy (10 mg/kg/day). Although 16 of 19 patients experienced no rest or exercise deterioration in hemodynamic parameters during drug dosing, three patients had acute deterioration of pulmonary capillary wedge pressure and cardiac index (CI) on moricizine. During follow-up of 6 +/- 3 months, two subgroups were identified: 10 of 19 patients had effective long-term reduction in VT, whereas 9 of 19 patients had poor control of ventricular arrhythmia or congestive heart failure and were discontinued from the trial. Baseline EF and hemodynamic parameters at rest were similar in both patient subgroups. However, protocol dropouts had a hemodynamic response to exercise on moricizine that was significantly depressed as compared to patients with a favorable antiarrhythmic outcome (p less than 0.02). The following hemodynamic profile characterizes patients unlikely to have an antiarrhythmic response to moricizine: an increase in CI of less than 1.0 L/min/m2 and no increase in left ventricular stroke work index during supine exercise.

Complex ventricular arrhythmias associated with the mitral valve prolapse syndrome. Effectiveness of moricizine (Ethmozine) in patients resistant to conventional antiarrhythmics.

On the basis of epidemiologic studies, more than 10 million Americans have echocardiographic evidence of mitral valve prolapse. Although ventricular arrhythmias occur frequently (over 50 percent of patients with mitral valve prolapse), they rarely result in sustained ventricular tachycardia or sudden cardiac death. However, a common problem in clinical practice is a patient with mitral valve prolapse and symptomatic complex ventricular arrhythmias refractory or intolerant to both beta blockers and conventional type I antiarrhythmics. These drugs are known to have frequent side effects, toxicity, and proarrhythmic effects. In 17 patients with mitral valve prolapse who presented with symptomatic complex ventricular arrhythmias and who were unresponsive to an average of the three conventional agents, moricizine (Ethmozine) was effective in suppressing 90 percent of ventricular premature depolarizations, 99 percent of nonsustained runs of ventricular tachycardia, as well as all sustained runs of ventricular tachycardia, resulting in abolition of palpitations, dizziness, and syncopal episodes. Its efficacy as well as its low frequency of minor side effects makes it ideal for future consideration in the population with mitral valve prolapse, who are frequently young and may therefore require therapy for many years.

Efficacy and safety of moricizine in patients with ventricular tachycardia: results of a placebo-controlled prospective long-term clinical trial.

This was a prospective, placebo-controlled, single-blind trial of moricizine (ethmozine) in a dose averaging 10 mg/kg/day in 50 patients, the single entrance criterion being the presence of 10 or more runs of nonsustained ventricular tachycardia (VT) on a screening 24 hr ambulatory electrocardiographic (ECG) recording. Electrophysiologic study was not included as part of this trial design. The placebo frequency of VT (average 3 days of recording) was 1036 +/- 479 runs of VT per day. Most patients (31/50) had coronary artery disease. The study population had a mean left ventricular ejection fraction (LVEF) of 36 +/- 16%; 20 patients also had a history of sustained VT. Protocol failure was defined as failure to achieve a 75% or greater reduction in runs of VT (as judged by ambulatory ECG recording) and/or recurrence of sustained VT while on moricizine. Among the 48 patients treated with moricizine, the drug was initially efficacious in 35 (73%), with two-thirds having total abolition of nonsustained VT. Although it was effective in reducing runs of nonsustained VT, moricizine was ineffective in preventing the recurrence of sustained VT (63% failure rate). Side effects were uncommon and the drug was well tolerated in most patients with LVEFs of 30% or less.

The changing base line of complex ventricular arrhythmias. A new consideration in assessing long-term antiarrhythmic drug therapy.

Initial base-line electrocardiograms are used to assess the efficacy of treatment for ventricular arrhythmias. This approach assumes that in the absence of treatment the frequency of arrhythmia would remain constant. To test the validity of this assumption, we studied 26 clinically stable patients with symptomatic but not life-threatening ventricular arrhythmias, during two periods of placebo treatment separated by a mean of 17 months. As compared with the initial placebo period, there were significant reductions in ventricular premature depolarizations (50 per cent), pairs (65 per cent), and ventricular tachycardia (83 per cent) during the second period of placebo administration (P less than or equal to 0.05 for all comparisons). Over one third of the patients gave the appearance of receiving successful therapy during the second placebo period, even when the reported spontaneous variability of ventricular arrhythmia was taken into consideration. If unrecognized, these long-term spontaneous changes in the frequency of arrhythmia could result in continuation of unnecessary and potentially toxic therapy and lead to incorrect conclusions regarding the efficacy of antiarrhythmic drugs in clinical trials. We therefore recommend that the frequency of arrhythmia be reassessed annually in the absence of treatment in patients similar to those in our study. These recommendations should not be applied to patients with life-threatening ventricular arrhythmias.

Analysis of the spontaneous variability of ventricular arrhythmias: consecutive ambulatory electrocardiographic recordings of ventricular tachycardia.

Results are reported of analysis of the variability of complex ventricular arrhythmias in a cohort of 110 patients selected for the presence of ventricular tachycardia (VT). All patients were enrolled in investigational antiarrhythmic drug trials and had an average of 4 consecutive days of placebo ambulatory electrocardiographic recording to serve as the database for this study. Using a statistical approach incorporating analysis of variance, the minimum percent reductions of ventricular premature complexes, couplets and VT were calculated to establish "drug effect" rather than variability at a significance level of 0.05. The relative variability of ventricular arrhythmias in prognostically important groups was also analyzed: (1) coronary artery disease (CAD) (n = 57) vs no CAD (n = 53); (2) patients with a left ventricular ejection fraction of 40% or less (n = 52) vs those with an ejection fraction greater than 40% (n = 58); and (3) patients with frequent runs of VT (10 or more runs/day, n = 63) vs infrequent VT (n = 47). Multiple regression analysis revealed that patients with CAD have significantly greater premature ventricular complex variability than patients without CAD (p less than 0.01). Also, patients with frequent VT runs have greater VT variability than that previously reported in smaller studies, thus requiring greater VT reductions to establish drug effect. Whether the variability of ventricular arrhythmia is itself an independent risk factor for sudden cardiac death is unknown.

The clinical significance of ventricular arrhythmias after myocardial infarction.

Based on a sound foundation of data in thousands of patients who underwent ambulatory ECG recording after myocardial infarction, it is clear tht ventricular arrhythmias are harbingers of sudden cardiac death. Ambulatory electrocardiography, usually performed for 24 hours, continues to be the standard by which clinicians can identify patients at risk for sudden cardiac death after acute myocardial infarction. Ideally, this test should be performed in the late hospitalization phase of acute myocardial infarction, usually 1 to 2 days prior to discharge from the hospital, and the results made known to the clinician prior to the patient's departure from the hospital. Although performed less frequently, low-level exercise testing prior to discharge from the hospital has been shown in some studies to be of prognostic value in defining a group at high risk for sudden cardiac death. This test offers the additional benefit of allowing the clinician to more knowledgeably prescribe an exercise regimen after hospitalization. The specific role of electrophysiologic testing is presently under clinical investigation. At present, only patients with documented spontaneous sustained ventricular tachycardia or sudden cardiac death after myocardial infarction should be candidates for this study. Although it may be possible in the future that electrophysiologic testing will also be used in patients with high-risk arrhythmia detected on ambulatory electrocardiography, at present this is the subject of clinical investigation in academic medical centers and is not recommended as part of standard therapy.

Transcription of ribosomal protein genes carried on F' plasmids of Escherichia coli.

The transcriptional activity of the DNA sequences coding for certain ribosomal proteins has been measured in Escherichia coli. Two partial diploid strains were isolated from mating of a recA, argD, aroE recipient and an Hfr with an origin at 69.5 min. One contained an F' element carrying the genes from 69.5 to 72.7 min including the rpsL locus (72.4) and the second was diploid for the genes from 69.5 to 71.5 min but did not include any mapped ribosomal protein loci. The molecular weights of the plasmids were estimated to be 140 and 110 x 10(6) daltons, respectively. The extent of in vivo transcription of the chromosomal genes on the plasmid and the ribosomal protein mRNA fraction of the total cellular RNA weer calculated from DNA-RNA liquid hybridization experiments using both DNA and RNA excess procedures. The results indicated a high degree of transcriptional activity concentrated in the ribosomal protein sequences with 83% of the F' chromosomal sequences transcribed into mRNA products representing about 0.12% of the total cellular RNA.