Metoprolol CR/XL in patients with heart failure: A pilot study examining the tolerability, safety, and effect on left ventricular ejection fraction.

BACKGROUND: This study was designed to investigate the tolerability, safety, and effect on left ventricular function of a new long-acting preparation of metoprolol, metoprolol succinate (CR/XL). METHODS AND RESULTS: Sixty patients were randomly assigned with a 2:1 ratio, drug versus placebo, administered with a gradually increasing dose of 12.5 to 150 mg of blinded medication during an 8-week period and continued for 6 months. The average peak dose achieved was 99 mg and 132 mg in the metoprolol succinate and placebo groups, respectively. The drug was well tolerated and there was no significant difference in drug withdrawals, New York Heart Association class, or quality of life assessment. The increase in left ventricular ejection fraction measure at baseline and 6 months measured by radioisotopic ventriculography was greater in the metoprolol succinate group (27. 5% to 36.3%) than in the placebo group (26% to 27.9%) (P <.015). Examination of serial Holter electrocardiographic recordings indicate that metoprolol succinate therapy was associated with a significant (P <.05) decrease in total ventricular ectopy at 8 weeks of therapy and a decrease in ventricular couplets and nonsustained ventricular tachycardia at 8 through 26 weeks of therapy. No changes were observed in plasma norepinephrine during therapy except a transitory significant (P <.05) increase in N terminal proatrial natriuretic factor at 8 weeks in the metoprolol succinate group. CONCLUSIONS: This study indicates that treatment with metoprolol succinate for a 6-month period is safe and well tolerated and is associated with an increase in left ventricular ejection fraction and a decrease in ventricular ectopic beats.

Comparative efficacy of short-term intravenous infusions of milrinone and dobutamine in acute congestive heart failure following acute myocardial infarction. Milrinone-Dobutamine Study Group.

The purpose of this study was to compare the hemodynamic and clinical effects of milrinone, a vasodilating and positive inotropic agent, with those of dobutamine in patients with congestive heart failure (CHF) following acute myocardial infarction (AMI). Thirty-three patients in Killip classification II or III within 12 h to 5 days after AMI were randomized in a multicenter, open-label clinical trial to receive a 24-h infusion of milrinone or dobutamine. Drugs were titrated to achieve at least a 30% increase in cardiac index (CI) from mean baseline or at least a 25% decrease in mean pulmonary capillary wedge pressure (MPCWP) from baseline. Both drugs improved CI, MPCWP, and other hemodynamic parameters. Criteria for decrease in MPCWP were met by 94% (15/16) of the milrinone-treated patients and 57% (8/14) of dobutamine-treated patients (p = 0.03). Both groups met the minimum efficacy criterion for CI. Maximal reduction in MPCWP over 0-3 h was greater in the milrinone group (-53.2%) than in the dobutamine group (-31.0%; p < or = 0.01); reductions were sustained over 24 h. Both drugs improved echocardiographic global ejection fraction and were generally well tolerated. The short-term infusion of milrinone may have a role in the management of CHF following AMI, especially when the aim is the rapid reduction of pulmonary congestion.

Dose-related efficacy and bleeding complications of double-chain tissue plasminogen activator in acute myocardial infarction. The Wellcome Tissue Plasminogen Activator Study Group.

Although the efficacy of recombinant tissue-type plasminogen activator (rt-PA) in acute myocardial infarction has been demonstrated, little formal dose-ranging information is available. This study examined the use of duteplase, the double-chain rt-PA subsequently used in the Third International Study of Infarct Survival, in a multicenter trial of 267 patients with evolving acute myocardial infarction assigned to receive 1 of 6 weight-adjusted doses. The primary end point was infarct vessel patency after 90 minutes of drug infusion. Patency was defined as Thrombolysis in Myocardial Infarction trial grade 2 or 3 perfusion, and was determined by an independent core laboratory masked to treatment assignment. Patency was present in 48% of patients receiving the lowest dose range and 78% of those receiving the highest, with an association between thrombolytic dose and patency (p = 0.009). The frequency of serious bleeding complications also correlated with the total dose of rt-PA infused (p = 0.003). Bleeding complications were primarily related to instrumentation; blood loss requiring transfusion or otherwise deemed clinically significant occurred in 12% of patients (central nervous system hemorrhage occurred in 1.1%). Thus, higher doses of rt-PA are associated both with increased efficacy and increased risk of serious bleeding complications. Weight-adjusted dosing may provide an optimal risk-benefit ratio for thrombolysis during acute myocardial infarction.

Myocardial infarct imaging in patients with technetium-99m 2,3-dimercaptosuccinic acid. Superiority of technetium-99m pyrophosphate.

Technetium-99m 2,3-dimercaptosuccinic acid (Tc-99m DMSA) has been used successfully for imaging acute myocardial infarction in a canine model. The application in humans, however, has not been previously reported. In order to determine the feasibility of using this agent in clinical studies and to compare the agent to technetium-99m pyrophosphate (Tc-99m PPi), ten patients with proven myocardial infarction were studied. While imaging of transmural infarctions in humans was achieved using Tc-99m DMSA, scores for the Tc-99m DMSA images (1.8 +/- 0.96) were not as high as for Tc-99m PPi (2.5 +/- 0.45) (P less than 0.05). Discordance among four independent interpreters was greater for images obtained with Tc-99m DMSA. The superiority of Tc-99m PPi was evident whether images were obtained early (within 24 hours) or late (within five days). Although DMSA images were not obscured by rib uptake, they were less sensitive (63%) than Tc-99m PPi (97%). A potential advantage of Tc-99m DMSA in imaging acute myocardial infarction is that radiotracer concentration in the infarct occurs primarily in the early postinfarction period. The longer postinfarction that Tc-99m DMSA imaging was attempted, the lower the concentration of radiotracer. Thus, Tc-99m DMSA would not be expected to have the same persistence pattern as Tc-99m PPi into the remote postinfarction period. The persistent positivity of Tc-99m PPi has made it difficult to diagnose reinfarction.

Direct determination of distribution volume and disappearance rate of native creatine kinase in humans.

Distribution volume (DV) and disappearance rate (Kd) of native creatine kinase (CK), parameters needed for enzymatic estimation of infarct size, have not been characterized in humans. Values for these parameters have been determined in experimental models and extrapolated for use in humans. During hemodynamic monitoring, 100 to 150 ml of enzyme-rich plasma was collected from 10 patients with acute myocardial infarction, stored at -30 degrees C for a maximum of 6 days, and then rapidly reinfused back to the same patient after return of CK serum activity to baseline levels. After reinfusion, blood samples were obtained at 5- to 15-minute intervals for 2 hours and at 30- to 60-minute intervals for an additional 10 hours. In each specimen, total CK activity and MM-CK and MB-CK concentrations were determined by spectrophotometry and radioimmunoassay. Data were analyzed by either nonlinear least-squares approximation or the noncompartmental approach after baseline subtraction. Concentration of immunologically active molecules appeared to decline in parallel to enzymatic activity. In three patients a double exponential decay was demonstrated. All others exhibited single exponential decay, with a Kd of 0.0023 +/- 0.00057 (SD) min-1. DV averaged 3284 +/- 693 (SD) ml, 5% of body weight. There was no correlation between Kd estimated from terminal portions of CK time-activity curves following infarction and Kd calculated after reinfused plasma. It was concluded that a one-compartment model using values for Kd and a DV compatible with plasma volume is suitable for clinical application, and that true Kd cannot be determined from the terminal portion of CK time-activity curves after acute infarction.

Silicon avalanche radiation detectors: the basis for a new in vivo radiation detection probe.

Recent advances in semiconductor technology have made it possible to develop practical silicon avalanche radiation detectors. These detectors are analogous in operation to a gas proportional counter, but are capable of extreme miniaturization. Most importantly these devices have overcome the in vivo limitations of past semiconductor detectors with respect to noise, microphonics, and adaptability to relatively harsh environments. The operation and some useful characteristics of an avalanche detector are outlined. The performance of a probe mounted detector in an in vivo setting is described which illustrates one application of the silicon avalanche detector in this milieu.

Calcium channel blockers: indications and limitations 1. Clinical pharmacology and use as antiarrhythmic agents.

In the atmosphere of euphoria that often surrounds introduction in the new drugs, indications may be exaggerated and limitations downplayed. This two-part article carefully assesses the advantages and disadvantages of the new calcium channel blocking drugs. In the various indications for which their use has been approved and looks into possible future applications.

Calcium channel blockers: indications and limitations 2. Use in angina and other cardiac disorders.

As discussed in part 1 of this article (page 97), intravenous verapamil (Calan, Isoptin) has established antiarrhythmic value. Attention now centers, however, on the antianginal value of the calcium channel blocking drugs because of the recent introduction of oral preparations for control of variant, stable and unstable angina.

Serial plasma catecholamine response early in the course of clinical acute myocardial infarction: relationship to infarct extent and mortality.

Clinical and experimental evidence suggest that sympathoadrenal activation contributes to mortality in patients with ischemic heart disease. To determine the level of sympathoadrenal activation in the very early phase of acute myocardial infarction (AMI) and to determine if location of infarction (anterior versus inferior) was related to sympathoadrenal activation, we studied norepinephrine (NE) and epinephrine (E) within 4 hours after the onset of symptoms and prior to any rise in plasma creatine kinase (CK). Mean (+/- SE) initial (NE = 591 +/- 111 pg/ml and E = 73 +/- 19 pg/ml), peak (NE = 1356 +/- 178 and E +/- 1098 +/- 608) and average (NE = 815 +/- 142 and E = 252 +/- 68) plasma catecholamine concentrations were considerably above normal (NE = 228 +/- 10 and E = 34 +/- 2 pg/ml, n 60) and values were similar for inferior and anterior infarctions. During an 18-month follow-up, three patients died in whom the AMI mean NE and E and peak CK were higher than in the eight late survivors. Thus the three AMI patients with peak EP values greater than 1000 died, whereas the eight AMI patients with peak EP values less than 1000 survived (p less than 0.01). The magnitude of sympathoadrenal activation early in the course of clinical AMI appeared related to the extent of myocardial damage and late mortality.

Deleterious influence of hypothyroidism on evolving myocardial infarction in conscious dogs.

To study the influence of hypometabolism on evolving myocardial infarction in a model with intact autoregulation, we investigated 53 awake dogs after coronary artery occlusion. Severe hypothyroidism was induced by the intravenous administration of 131I. Animals were instrumented to obtain hemodynamic measurements, and regional myocardial blood flow was measured with radioactive microspheres. Infarct size was determined by the creatine kinase depletion method, and dysrhythmia analysis was performed from 24-h Holter monitor tapes in animals matched for infarct size. The microarchitecture of hypothyroid myocardium was determined by the electron microscope. Before coronary occlusion, mean systemic pressure in hypothyroid dogs was reduced by 14% and cardiac output reduced by 32%, with no change in left ventricular end-diastolic pressure, first derivative of left ventricular pressure rise, (dP/dt), or heart rate. After coronary occlusion, there was deterioration in hemodynamic measurements in both groups, with lower absolute levels of mean systemic blood pressure and cardiac output obtained in hypothyroid dogs. Hypothyroidism was detrimental to evolving infarction with a 36% increase in infarct size present in hypothyroid dogs (30 +/- 2%) compared to euthyroid controls (22 +/- 3%), P less than 0.05. Dysrhythmias were more severe in hypothyroid dogs. There were no changes in the relationship between regional myocardial blood flow and the extent of infarction after coronary occlusion. Abnormalities in microarchitecture were present in hypothyroid dog myocardium. Severe hypometabolism in this model was associated with alterations in hemodynamics, more severe dysrhythmias and changes in microarchitecture. The combined effect of these alterations resulted in an overall detrimental influence of hypothyroidism on evolving myocardial necrosis in this model.

Imaging of experimental myocardial infarction with technetium-99m 2,3-dimercaptosuccinic acid.

We have studied the use of Tc-99m-labeled 2,3-dimercaptosuccinic acid (Tc-99m DMSA) to scintigraph acute myocardial infarction after coronary occlusion in dogs. Optimal images were obtained 5 hr after injection of radiotracer, with consistent delineation 48 hr after occlusion. Delivery of tracer was dependent on blood flow. Uptake of tracer correlated to extent of infarction as determined by the myocardial depletion of creatine kinase. Myocardial Tc-99m DMSA was protein-bound.

Noninvasive visualization of right coronary artery aneurysms.

2 cases of right coronary artery aneurysm visualized with M-mode and cross-sectional echocardiography are described. Echocardiographic visualization of right coronary artery aneurysms is possible when substantial dilation is located proximally.

Verapamil in atrial fibrillation and atrial flutter.

A double-blind randomized study was performed to compare the efficacy of intravenous verapamil with saline in 28 patients with a rapid ventricular rate and atrial fibrillation or atrial flutter. Conversion of atrial fibrillation to sinus rhythm occurred in none of 14 patients after saline and in 3 of 20 patients (15%) 7 to 160 min after verapamil. The ventricular rate in atrial fibrillation was slowed greater than or equal to 15% in 2 of 14 patients (14%) by saline, in 17 of 20 patients (85%) by 1 dose of verapamil (p less than 0.001), and in 19 of 20 patients (95%) by 1 or 2 doses of verapamil (p less than 0.001). Conversion of atrial flutter to sinus rhythm occurred in none of 4 patients after saline and in 1 of 7 patients (14%) 105 min after verapamil. The ventricular rate in atrial flutter was slowed greater than or equal to 15% in none of 4 patients by saline, in 4 of 7 patients (57%) by 1 dose of verapamil, and in 7 of 7 patients (100%) by 1 or 2 doses of verapamil (p less than 0.001).

Reduction of early ventricular arrhythmia by acebutolol in patients with acute myocardial infarction.

To assess the effects of intravenously administered acebutolol (1-20 mg every 4 hours for 24 hours) on cardiac rhythm and performance, we studied 72 patients with evolving myocardial infarction. Twenty-five patients were treated with acebutolol beginning 6 hours after the first increase in the level of plasma creatine kinase. Enzymatically estimated infarct size was compared with that of 25 controls matched for predicted infarct size. Observed infarct sizes were not significantly different in the 2 groups (37 +/- 5 and 30 +/- 5 CK-gram equivalents, respectively). Mean heart rate, diastolic blood pressure, and cardiac output declined from control values during treatment with acebutolol, but remained within the normal range. Mean pulmonary artery pressure and pulmonary artery occlusive pressure were unchanged. In a group of 22 treated patients matched with 22 control subjects for frequency of ventricular extrasystoles, acebutolol effected a prompt reduction in frequencies of ventricular extrasystoles and repetitive arrhythmias, whereas values were not significantly changed in controls during the corresponding intervals. Accordingly, acebutolol may be a useful antiarrhythmic agent in selected patients with acute myocardial infarction with adversely altering haemodynamic stability or enzymatically estimated infarct size.