Echocardiography during infusion of dobutamine for identification of reversibly dysfunction in patients with chronic coronary artery disease.

OBJECTIVES: The aim of this study was to test whether the contractile response of akinetic myocardium to low dose dobutamine is useful for detecting myocardial viability in patients with coronary artery disease and persistent left ventricular dysfunction. BACKGROUND: In some patients with chronic coronary artery disease, persistent abnormalities of left ventricular wall motion can be reversed by successful coronary artery bypass surgery. Thus, identification of potentially reversible dysfunction has important therapeutic and prognostic implications. Echocardiography during infusion of low dose dobutamine can detect viable myocardium in patients after thrombolytic therapy. However, there is no detailed information on the use of this method in patients with chronic left ventricular dysfunction without reperfusion. METHODS: We studied 33 selected patients with angiographically proved coronary artery disease and persistent left ventricular dysfunction. The effect of dobutamine infusion (5 micrograms/kg body weight per min, followed by 10 micrograms/kg per min) on left ventricular wall motion was evaluated by transthoracic echocardiography before coronary artery bypass grafting and compared with that obtained immediately after the operation (evaluated by intraoperative epicardial echocardiography) and both 2 weeks and 3 months later. Left ventricular wall motion was analyzed qualitatively by dividing the left ventricle into 16 segments, and a score was assigned to each region. RESULTS: Before coronary artery bypass surgery, 314 segments were akinetic. Of these, 183 became normokinetic immediately after revascularization, and 15 became hypokinetic. Dobutamine infusion was able to predict improvement in 178 of the 205 segments that recovered function after revascularization (sensitivity 86.8%) and to identify 89 of the 109 segments that did not recover postoperatively (specificity 81.6%). Mean (+/- SD) segment scores were 2.24 +/- 0.35 at baseline, 1.49 +/- 0.34 (p < 0.001) after dobutamine infusion, 1.51 +/- 0.38 (p < 0.001) immediately after and 1.51 +/- 0.38 (p < 0.001) 2 weeks after coronary artery bypass and 1.55 +/- 0.37 (p < 0.001) at 3-month follow-up. CONCLUSIONS: Echocardiography during infusion of low dose dobutamine is a safe and accurate method for identifying reversible dysfunctioning myocardium and predicts early reversibility of wall motion after surgical revascularization in selected patients with coronary artery disease with chronic left ventricular dysfunction.

PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2.

BACKGROUND: The effect of alteplase versus heparin in pulmonary embolism has not been studied extensively with serial pulmonary angiograms. OBJECTIVES: The aim of this randomized, open trial was to evaluate the efficacy and safety of alteplase followed by heparin, versus heparin alone, in 36 patients with angiographically documented pulmonary embolism. METHODS: Twenty patients were allocated randomly to a 2-h infusion of alteplase (10 mg bolus, then 90 mg over 2 h) followed by heparin; the other 16 patients were given intravenous heparin at a continuous infusion rate of 1,750 IU/h. RESULTS: The vascular obstruction, assessed by the Miller index at pulmonary angiography, decreased significantly in alteplase-treated patients (p less than 0.01) from a baseline of 28.3 +/- 2.9 to a value of 24.8 +/- 5.2 2 h after the start of infusion; in the heparin group there was no change (from 25.3 +/- 5.3 to 25.2 +/- 5.4). Mean pulmonary artery pressure decreased significantly from a baseline of 30.2 +/- 7.8 mm Hg to 21.4 +/- 6.7 in the alteplase group and increased in the heparin group (from 22.3 +/- 10.5 to 24.8 +/- 11.2 mm Hg). For a subset of patients, lung scans were performed at baseline and on days 7 and 30. There were no differences between the two groups in the follow-up lung scans, but there were significant decreases from the baseline values. Bleeding occurred in 14 of 20 alteplase-treated patients and in 6 of 16 in the heparin group (p = NS). There were three major bleeding episodes in the alteplase group and two in the heparin group. Two patients died after fibrinolysis (one of acute renal failure after cardiac tamponade and one of cardiac arrest after cerebral hemorrhage) and one patient in the heparin group died of recurrent pulmonary embolism. CONCLUSIONS: Alteplase resulted in a greater and faster improvement of the angiographic and hemodynamic variables compared with heparin. However, the high frequency of bleeding observed with alteplase in this trial suggests that patients should be carefully selected before thrombolytic therapy is given.

Oxygen free radicals and myocardial damage: protective role of thiol-containing agents.

It has been suggested that the sudden presence of oxygen during reperfusion after a period of ischemia may be toxic for the myocardial cell. The oxygen molecule is capable of producing reactions in the cell, forming highly reactive free radicals, and inducing lipid peroxidation of membranes, altering their integrity and increasing their fluidity and permeability. The ischemic and reperfused cardiac cell is the prime candidate for this reaction sequence and may explain the molecular mechanism underlying the pathologic events related to membrane dysfunction and calcium homeostasis. However, the myocardium has a series of defense mechanisms including the enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase plus other endogenous antioxidants such as vitamin E, ascorbic acid, and cysteine to protect the cell against the cytotoxic oxygen metabolites. The prerequisite for oxygen free radical involvement in ischemia and reperfusion damage is that ischemia alters the defense mechanisms against oxygen toxicity. It is known that ischemia may impair mitochondrial SOD and, with reperfusion, oxidative stress may occur as shown by tissue accumulation and release of oxidized glutathione. This tripeptide molecule in the cofactor of glutathione peroxidase, the enzyme that removes hydrogen and lipid peroxides. Its formation and subsequent release is a reliable index of oxidative damage. In our study, we investigated the effects of N-acetylcysteine on oxidative damage in the isolated rabbit heart. N-acetylcysteine increases, in a dose-dependent manner (from 10(-7) to 10(-5) M), the myocardial glutathione content and provides an important degree of protection against ischemia and reperfusion. Oxidative stress does not occur, mitochondrial function is maintained, enzyme release is reduced, and contractile recovery is increased. Similarly, we administered N-acetylcysteine in the pulmonary artery of coronary artery disease patients undergoing coronary bypass grafting (150 mg/kg in 1 hour followed by 150 mg/kg in 4 hours). The degree of oxidative stress on reperfusion was reduced and recovery of cardiac function improved. In this article, we review the cardioprotective role of thiol-containing agents.

Effects of acute and chronic ibopamine administration on resting and exercise hemodynamics, plasma catecholamines and functional capacity of patients with chronic congestive heart failure.

The effects of acute and chronic ibopamine treatment on resting and exercise hemodynamics, exercise capacity and plasma catecholamines were evaluated in 25 patients with chronic heart failure, using a double-blind, parallel, placebo-controlled design. During 2 months of therapy with either placebo or ibopamine (100 mg, 3 times daily), 1 patient was withdrawn from each group for worsening heart failure, New York Heart Association functional class improved in 4 patients on ibopamine and in 1 on placebo, and furosemide dose could be decreased in 4 on ibopamine and in no patient on placebo. Acute ibopamine administration induced, in comparison with placebo, a significant increase of cardiac and stroke volume indexes both at rest and peak exercise, with a reduction of systemic vascular resistance. These hemodynamic changes were maintained also after chronic therapy, with no evidence of tolerance development. Exercise capacity (evaluated as peak exercise duration and oxygen consumption, and ventilatory threshold) did not significantly change. Resting and peak exercise norepinephrine plasma levels were significantly reduced after both acute and chronic ibopamine administration. Thus, the hemodynamic and neurohumoral effects of ibopamine make this drug potentially useful for the chronic treatment of congestive heart failure.

Echo-phonocardiographic evaluation of the Björk-Shiley mitral prosthesis.

Ninety patients were studied with combined echophonocardiography after Björk-Shiley disc prosthetic mitral valve replacement. They were evaluated every 6 months (mean follow-up 6 years). Nine cases of left ventricular (LV) failure and 6 cases of prosthetic malfunction (5 paravalvular leaks and 1 thrombosis) were detected; 1 case was confirmed at necropsy and the other 5 cases were surgically verified and repaired. The following measures of prosthetic malfunction were evaluated: opening and closing velocity, maximal amplitude of the prosthesis, septal motion 6 months after operation, LV diastolic diameter, protodiastolic hump, variations during same record of the interval between aortic valve closure sound to the phono and mitral valve opening to the echo, and interval between aortic valve closure sound and maximal excursion of the LV posterior wall. All measures studied were useful for detecting prosthetic malfunction, but 2 are more useful in individual cases: variations of the interval between second heart sound and mitral valve opening and the interval between the aortic valve closure sound and LV posterior wall motion. These 2 intervals also allow discrimination between normal function, prosthetic malfunction and LV failure.

Exercise hyperventilation chronic congestive heart failure, and its relation to functional capacity and hemodynamics.

The ventilatory response to exercise was evaluated in 26 normal sedentary men and 68 patients with chronic heart failure using the slope of the relation between minute ventilation (VE) and carbon dioxide production (VCO2). All subjects underwent maximal upright bicycle cardiopulmonary exercise testing; 33 patients also underwent right-sided cardiac catheterization. The slope of VE/VCO2 was calculated by linear regression analysis using data from all the exercise tests and the first 60% of exercise duration; a high correlation was seen between these results (r = 0.83; p less than 0.001). The slope of VE/VCO2 was significantly, though weakly, related to peak exercise work load, oxygen consumption and ventilatory threshold (r = -0.49, -0.56 and -0.49, respectively), several peak exercise hemodynamic parameters and peak exercise dead space/tidal volume ratio (r = 0.70). With use of multivariate analysis, the only independent determinants of the slope were peak exercise dead space/tidal volume ratio and cardiac index. Thus, in patients with heart failure, exercise hyperventilation can contribute to the impairment of functional capacity and can be considered a compensatory response to abnormal hemodynamics and lung blood distribution in order to keep blood gas concentrations normal.

Assessment of peak oxygen consumption, lactate and ventilatory thresholds and correlation with resting and exercise hemodynamic data in chronic congestive heart failure.

To determine the clinical value of respiratory gas analysis during exercise, oxygen consumption (VO2) at peak exercise and at lactate and ventilatory threshold was assessed in 34 patients with chronic heart failure who underwent maximal exercise testing with expiratory gas monitoring and serial determinations of mixed venous lactate and hemodynamics by Swan-Ganz catheterization. A lactate threshold, defined as the point of abrupt increment of blood lactate, could be identified in every patient; the ventilatory threshold, detected on the basis of the respiratory changes, was found in 26 patients (77%). Lactate and ventilatory thresholds were significantly related to each other (r = 0.94; p less than 0.001) and to peak VO2 (r = 0.89; p less than 0.001 in both). Among the resting hemodynamic measurements, peak VO2 was significantly related only to total pulmonary resistances (r = -0.35). Among the parameters at maximal exercise, it was positively related to cardiac index, stroke work, stroke volume index and mean arterial pressure (r = 0.89, 0.74, 0.74 and 0.56, respectively) and inversely related to systemic vascular and total pulmonary resistances (r = -0.74 and -0.63). Using multivariate stepwise regression analysis only maximal cardiac index and, to a lesser degree, total pulmonary resistance were related to peak VO2. Similar correlations were found between the hemodynamics and the lactate and ventilatory threshold. Thus, peak VO2, lactate and ventilatory thresholds can be detected in most patients with chronic heart failure. These parameters are highly correlated to each other and bear similar relations to the hemodynamic response to exercise. The cardiac index is the main central hemodynamic determinant of exercise capacity.

Effects of acute K-strophantidin administration on left ventricular relaxation and filling phase in coronary artery disease.

In 10 patients with coronary artery disease, preserved left ventricular (LV) performance and absence of previous myocardial infarction, the effects of an acute intravenous administration of k-strophantidin (0.005 mg/kg over 10 minutes) on selected parameters of both LV systolic and diastolic function, including relaxation, were evaluated. An increase in positive first derivative of LV pressure (dP/dt) and in the ratio between dP/dt and the pressure developed (dP/dt/P) (1,530 +/- 287) 1,600 +/- 329 mm Hg/s [p less than 0.05], and 30 +/- 6 to 34 +/- 8 s-1 [p less than 0.05], respectively) demonstrated the inotropic effect of k-strophantidin, whereas volumetric parameters of systolic function (end-systolic and stroke volume indexes, and ejection fraction) did not show any significant change. However, LV relaxation was impaired by k-strophantidin injection; in fact, mean values of T constant were significantly increased from 50 +/- 12 to 55 +/- 13 ms (p less than 0.01). Lowest LV and end-diastolic pressures increased from 8 +/- 4 to 11 +/- 4 mm Hg (p less than 0.05) and from 17 +/- 6 to 20 +/- 8 mm Hg (p less than 0.05), respectively. The end-diastolic volume and maximal rate of volumetric increase during the early and late filling phases were not modified by k-strophantidin. Mean aortic pressure increased from 110 +/- 10 to 120 +/- 12 mm Hg (p less than 0.001). Therefore, in patients with coronary artery disease and LV preserved performance, an acute intravenous administration of k-strophantidin appears to stimulate contractility and to worsen relaxation, and minimal LV and end-diastolic pressures.

Metabolic derangement in ischemic heart disease and its therapeutic control.

The term myocardial ischemia describes a condition that exists when fractional uptake of oxygen in the heart is not sufficient to maintain the rate of cellular oxidation. This leads to extremely complex situations that have been extensively studied in recent years. Experimental research has been directed toward establishing the precise sequence of biochemical events leading to myocyte necrosis, as such knowledge could lead to rational treatments designed to delay myocardial cell death. At the present time, there is no simple answer to the question of what determines cell death and the failure to recover cell function after reperfusion. Problems arise because: (1) ischemic damage is not homogeneous and many factors may combine to cause cell death; (2) severity of biochemical changes and development of necrosis are usually linked (both the processes being dependent on the duration of ischemia) and it is impossible to establish a causal relation; and (3) the inevitability of necrosis can only be assessed by reperfusion of the ischemic myocardium. Restoration of flow, however, might result in numerous other negative consequences, thus directly influencing the degree of recovery. From the clinical point of view, we have recently learned that there are several potential manifestations and outcomes associated with myocardial ischemia and reperfusion. Without a doubt, ventricular dysfunction (either systolic or diastolic) of the ischemic zone is the most reliable clinical sign of ischemia, since electrocardiographic changes and symptoms are often absent. The ischemia-induced ventricular dysfunction, at least initially, is reversible, as early reperfusion of the myocardium results in restoration of normal metabolism and contraction. In the ischemic zone, recovery of contraction may occur instantaneously or, more frequently, with a considerable delay, thus yielding the condition recently recognized as the "stunned" myocardium. On the other hand, when ischemia is severe and prolonged, cell death may occur. Reperfusion at this stage is associated with the release of intracellular enzymes, damage of cell membranes, influx of calcium, persistent reduction of contractility, and eventual necrosis of at least a portion of the tissue. This entity has been called "reperfusion damage" by those who believe that much of the injury is the consequence of events occurring at the moment of reperfusion rather than a result of changes occurring during the period of ischemia. The existence of reperfusion damage, however, has been questioned, and it has been argued that, with the exception of induction of arrhythmias, it is difficult to be certain that reperfusion causes further injury. The existence of such an entity has clinical relevance, as it would imply the possibility of improving recovery with specific interventions applied at the time of reperfusion. In 1985, Rahimtoola described another possible outcome of myocardial ischemia. He demonstrated that late reperfusion (after months or even years) of an ischemic area showing ventricular wall-motion abnormalities might restore normal metabolism and function. He was the first to introduce the term "hibernating myocardium," referring to ischemic myocardium wherein the myocytes remain viable but in which contraction is chronically depressed. In this article we review our data on metabolic changes occurring during ischemia followed by reperfusion, obtained either in the isolated and perfused rabbit hearts or in ischemic heart disease patients undergoing intracoronary thrombolysis or aortocoronary bypass grafting.

Diagnosis of acute myocardial infarction by indium-111 antimyosin antibodies and correlation with the traditional techniques for the evaluation of extent and localization.

This clinical study evaluated the accuracy of planar myocardial scintigraphy with antimyosin monoclonal antibodies radiolabeled with indium-111 (AMA-Fab) in the detection and localization of acute myocardial infarction (AMI). Fifty-seven patients admitted for suspected AMI were studied; 17 patients underwent thrombolytic therapy with intravenous streptokinase and 11 had clinical signs of reperfusion; 9 had had a previous myocardial infarction. Fifty of 57 patients were discharged from the coronary care unit with a confirmed diagnosis of AMI. The AMA-Fab study results were positive for AMI in 49 patients (98%) and negative in 1 (2%). Among the 7 patients without AMI, 5 had unstable angina, 1 had Prinzmetal's variant angina and 1 had acute pancreatitis. AMA-Fab results were negative in 6 of 7 patients (85%) and positive in 1 (15%). Therefore, the sensitivity and specificity of AMA-Fab scintigraphy were 0.98 and 0.85, respectively. To assess accuracy in defining the extent and location of AMI, AMA-Fab results were compared with those of the electrocardiogram, echocardiogram, technetium-99m pyrophosphate myocardial scintigraphy and coronary angiography and left ventriculography. AMA-Fab scintigraphy showed a good concordance with the traditional techniques in the topographic definition of the infarcted regions. No uptake of AMA-Fab was seen in the regions of previous old infarcts. Ten healthy volunteers also underwent AMA-Fab scintigraphy. No evidence of myocardial tracer uptake was noted in them. No adverse reactions or side effects were noted after injection of AMA-Fab in any patient. It is concluded that planar myocardial scintigraphy with AMA-Fab is a reliable method for AMI detection and location.

Protective effects of calcium antagonists against ischaemia and reperfusion damage.

The most positive results in this area have been those of the second Danish Study Group on Verapamil in Myocardial Infarction (1990) which assessed the benefit of treatment with verapamil from the second week after myocardial infarction. Verapamil produced a significant reduction in both mortality and reinfarction rates. Consequently, it may be concluded that treatment with calcium antagonists, such as verapamil and diltiazem, should not be used in the acute phase of myocardial infarction, but rather as prophylaxis to prevent reinfarction by protecting against myocardial ischaemia. The lack of reported cardioprotective efficacy with calcium antagonists, which contrasts with experimental predictions, can be explained by the inappropriate timing of administration and the use of dihydropyridine, which can be detrimental in myocardial infarction. These is little or no evidence to show that calcium antagonists are cardioprotective in patients with myocardial infarction or unstable angina. Thus, the randomised trials studying acute myocardial infarction reveal no overall effect of treatment on mortality in the short or long term. The prototype calcium antagonists differ in their effects on the reinfarction rate in these patients. With verapamil there is a small tendency for a reduction in reinfarction, with nifedipine a clear worsening, and with diltiazem a reduction almost reaching statistical significance. The general lack of protective efficacy is presumably a result of the drugs being administered too late after the onset of ischaemia.

Cardiovascular effects induced by the injection of a new nonionic contrast medium (Iopamidol): experimental study in dogs.

The hemodynamic effects induced by the injection in the pulmonary artery of the new nonionic water soluble contrast medium Iopamidol were compared with those obtained by the injection of two other currently used contrast media (meglumine diatrizoate and sodium iothalamate). The experiments were carried out in nine mongrel dogs. Hemodynamic variables were continuously measured prior to, during, and for 8 minutes after injection of the contrast media. Injections of iopamidol produced significantly smaller decreases in aortic pressure (p less than 0.01), contractile indices (p less than 0.01), and peripheral resistances (p less than 0.01), and changes in heart rate and in cardiac output were less pronounced. At 3-4 minutes after injection, an increase in Vmaxd was observed with all three contrast media, but it was significantly lower after injecting Iopamidol. The role of hyperosmolality in causing cardiovascular changes is discussed. The less significant changes induced by Iopamidol appear to be the result of its lower osmolality, which is about a third that of meglumine diatrizoate or sodium iothalamate.

Serum enzymes in acute myocardial infarction after intracoronary thrombolysis.

Serum kinetics of total creatine kinase (CK), CK-MB isoenzyme, aspartate aminotransferase (AST), lactate dehydrogenase (LD) and alpha-hydroxybutyrate dehydrogenase (HBD) activities were studied in twenty patients with acute myocardial infarction randomly assigned to receive either intracoronary urokinase (group A) or conventional (control) therapy (group B). The temporal characteristics of enzyme changes described were the time lag from onset of chest pain until maximum catalytic concentration value, the rate at which enzymes are released into blood, the peak value of the serum enzyme curves and (d) the fractional disappearance rate (Kd) for each enzyme considered. Thrombolytic treatment induced earlier peak times in group A: for CK, 10.8 vs 27.0 h, for CK-MB, 10.4 vs 23.1, for AST, 13.9 vs 31.3, for LD, 24.4 vs 49.1, and for HBD, 20.5 vs 48.5 (for all enzymes, p less than 0.001). The maximal rate of release for the enzymes was at least twofold greater in group A. Enzyme peak activities and Kd were not significantly different between the groups. The most significant discrimination between the two groups was obtained with AST peak time (Hartz overlap index (Oi) = 0.11) and CK-MB peak time (Oi = 0.12).

The metabolical effects of L-carnitine in angina pectoris.

We determined the effects of L-carnitine on myocardial metabolism in 18 patients with angiographically-proven coronary artery disease, subjected to two rapid coronary sinus pacing evaluations. L-Carnitine converted lactate production to extraction and increased the percentage of free fatty acid extraction. These results suggest that L-carnitine may be of use to improve the metabolism of coronary artery disease patients.

Myocardial metabolism during intracoronary thrombolysis. Two illustrative cases.

Arterial and coronary sinus difference for potassium, lactate, glucose, free fatty acids and creatine kinase was measured every 5 minutes in two patients undergoing successful intracoronary thrombolysis of left anterior descending occlusion. In the first patient, reperfusion, 160 minutes after the onset of pain, was followed by a transient and limited release of creatine kinase in the coronary sinus, improvement in the electrocardiogram and restitution of left ventricular contraction. In the second patient, reperfusion 365 minutes after the onset of pain, was also accompanied by a limited release of creatine kinase. Reocclusion of the left anterior descending coronary artery, however, necessitated further thrombolysis which led to a massive release of creatine kinase and permanent loss of wall-motion. It is suggested that, in this case, reperfusion damage had occurred. The arteriovenous differences showed a wash-out of potassium and lactate during reperfusion in each case. The interpretation of the entire sequence of arteriovenous changes, however, could be shown to depend critically on the state of regional perfusion.

Hemodynamic pattern following K-strophanthin in normal and coronary artery disease patients.

Hemodynamic effects of K-strophanthin (0.005 mg/kg i.v.) were evaluated in 7 normal and in 13 non-failing coronary artery disease patients (CAD). Volumetric parameters were obtained by single plane left ventricular angiography. The indexes of "pump" function, the end-systolic pressure-volume relationship and the ratio of peak pressure to systolic volume were also evaluated. Heart rate was maintained constant by atrial pacing. In normal subjects K-strophanthin exerted small effects without peripheral vasoconstriction. CAD patients showed different response to K-strophanthin in vascular tone: an increase (Group 1) or a decrease (Group 2) in total systemic resistance (TSR). No significant differences were found in basal values between the two CAD groups. In Group 2 the indexes of "pump" function increased after K-strophanthin and the end-systolic pressure-volume points shifted upward and to the left, while in Group 1 no improvement in cardiac function was observed and the end-systolic pressure-volume points shifted upward and to the right. Furthermore, we found a direct significant correlation between the percent changes of TSR and end-systolic volume index, and a negative significant correlation between the percent changes of TSR and stroke volume index. Our results show that K-strophanthin in CAD non-failing patients can have either a positive effect or a lack of improvement in ventricular performance. These effects correlate with changes in total systemic resistance.

Different outcomes of the reperfused myocardium: insights into the comments of stunning and hibernation.

There are several potential outcomes of myocardial ischaemia. When ischaemia is severe and prolonged, irreversible damage occurs and there is no recovery of contractile function. Interventions aimed at reducing mechanical activity and oxygen demand either before ischaemia or during reperfusion have been shown to delay the onset of ischaemic damage and to improve recovery during reperfusion. When myocardial ischaemia is less severe but still prolonged, myocytes may remain viable but exhibit depressed contractile function. Under these conditions, reperfusion restores complete contractile performance. This type of ischaemia leading to a reversible, chronic left ventricular dysfunction has been termed 'hibernating myocardium'. It is important clinically recognize hibernation as reperfusion of hibernating myocardium by angioplasty or heart surgery restores contraction and this correlates with long term survival. A third possible outcome after a short period of myocardial ischaemia is a transient post-ischaemic ventricular dysfunction, a situation termed 'stunned myocardium'.

Bioavailability and related heart function index of digoxin capsules and tablets in cardiac patients.

A loading dose of digoxin (750 microgram) in two commercial formulations was administered to 14 patients with heart disease according to a crossover design. One formulation consisted of soft gelatin capsules containing a solution of digoxin; the other formulation was compressed tablets. All parameters investigated, i.e., serum peak height, time of the peak, area under the serum level--time curve (AUC), and area above the Q--S2I (electromechanical systole) decrease (obtained from polycardiographic evaluation), showed better bioavailability of digoxin capsules than tablets, averaging 36.3%. The better bioavailability of digoxin capsules than tablets seems to be more evident in heart disease patients than that encountered previously in healthy subjects. The AUC and the area above the Q-S2I decrease were linearly correlated only with digoxin capsules.

Effects of changes in intravascular volume on atrial size and plasma levels of immunoreactive atrial natriuretic peptide in uremic man.

To study the trigger for the release of atrial natriuretic peptide (ANP) in man, we measured the atrial areas (AA) by 2-D echocardiography, the total blood volume (TBV) by 131I-serum albumin and plasma immunoreactive ANP (i-ANP) concentrations by radioimmunoassay, after prior plasma extraction, for 10 dialyzed uremic patients. Measurements were made when the patients were volume-loaded or volume-depleted by isoosmotic ultrafiltration and again 48 h later, when they were again volume-loaded. Analysis of plasma extracts by high-performance gel permeation chromatography revealed that the greatest amount of the i-ANP fraction was a peptide eluting like human synthetic alpha-ANP. Ultrafiltration consistently decreased the TBV, while spontaneous regain of body-fluids caused TBV to rise to pre-ultrafiltration levels. Changes in TBV were closely related in time to changes in both right (RAA) and left (LAA) atrial area and in plasma i-ANP concentrations. Significant direct relationships were found between TBV and RAA, TBV and i-ANP and between both LAA and RAA and i-ANP. Furthermore, the decreases and the increases in TBV, RAA and LAA were closely correlated with changes in i-ANP. Multiple regression analysis, however, revealed that the changes in plasma i-ANP were mainly related to the changes in RAA, with little or no relationship to the changes in TBV or LAA. These findings are evidence for a positive feed-back between the level of intravascular filing volume, extent of atrial distention and amount of i-ANP released into the blood stream.

Hemodynamic advantage of combined administration of oral ibopamine and nitroprusside in patients with ischemic and idiopathic congestive cardiomyopathy.

The hemodynamic effects of combined administration of ibopamine (Ib) (150 mg orally) with nitroprusside (NP) (50-150 micrograms/min intravenously) were compared with those of NP alone in 17 patients with severe congestive heart failure due to coronary artery disease (7 patients) or idiopathic cardiomyopathy (10 patients). Hemodynamic measurements were obtained using a Swan-Ganz thermodilution catheter and a bedside thermodilution cardiac output computer. Nitroprusside alone produced a significant decrease (-12.4%) in mean arterial pressure, mean pulmonary arterial pressure (-28.3%), and systemic vascular resistance (-22.6%), and a significant increase in stroke volume index (23.1%). The administration of combined NP and Ib produced a further significant increase of stroke volume index (20.1%) with a concomitant and significant reduction of systemic vascular resistance (-19.4%); heart rate, mean systemic and pulmonary arterial pressures did not change significantly from the values observed with NP alone. Moreover, stroke work index, although not significantly modified with the vasodilator alone, was significantly increased over control values with NP + Ib association. Although NP alone induced similar effects in both the ischemic and idiopathic cardiomyopathies, the association of Ib gave a more favorable, though not significant, hemodynamic response in the subjects with primitive cardiomyopathy than in the ischemic ones. Thus, the association of Ib to NP therapy, in patients with congestive heart failure, further increases stroke volume index and stroke work index with a concomitant reduction of systemic vascular resistance, without any significant change in mean systemic and pulmonary arterial pressures, or heart rate. These results point out the possibility of associating Ib with other orally active vasodilators in the chronic treatment of congestive heart failure.