Studies on the localization of the cardiac glycoside receptor.

The purpose of this study was to see whether the receptor for cardiac glycosides might be localized upon or within the plasma membrane of digitalis-sensitive cells. Ouabain and digoxin were joined covalently to several large protein molecules. These macromolecular conjugates are too large to enter intact cells; consequently, any pharmacologic or biochemical effects which they display should arise from interaction with a cell surface receptor. Conjugates were tested in several cardiac glycoside-sensitive systems: (a), contractility response of isolated cardiac muscle; (b), active (86)Rb(+) uptake by red cells; (c), enzymatic activity of isolated myocardial microsomal (Na(+) + K(+))-activated adenosine triphosphatase (ATPase); and (d), enzymatic activity of solubilized red cell (Na(+) + K(+))-activated ATPase. Results demonstrated that in all of these systems, the macromolecular-glycoside conjugates were 100- to 1000-fold less active than the free glycosides. Careful chromatographic examination of the various conjugates revealed that they contained a small but persistent free cardiac glycoside contaminant. The amount of this species ranged from 0.1 to 1.0% of the total macromolecule-bound glycoside, and its presence fully explains the levels of biologic activity observed with the conjugates. To try to minimize steric factors which could interfere with glycoside-receptor interaction, digoxin and ouabain were also coupled to macromolecule via long, flexible polyamide side-chains. These extended chain conjugates, in which the cardiac glycoside potentially lay some 30 A removed from the surface of the macromolecule, also exhibited negligible digitalis-like effects when tested upon isolated cardiac muscle, red cell (86)Rb(+) uptake, and enzymatic activity of cardiac microsomal (Na(+) + K(+))-ATPase. However, the extended chain conjugates were fully active when examined with the solubilized red cell (Na(+) + K(+))-ATPase system. To further ensure that the chemical reactions used to couple macromolecule to glycoside did not inactivate the drug, all conjugates were subjected to extensive proteolytic digests exhibited full pharmacologic activity. Digoxin was also coupled to the tripeptide alanylglycylglycine, and the resulting conjugate was fully active. Taken together, these results suggest that if the receptor(s) for cardiac glycosides is associated with the plasma membrane, then it may lie deep within it.

Early reversal of right ventricular dysfunction in patients with acute pulmonary embolism after treatment with intravenous tissue plasminogen activator.

To assess abnormalities of right heart function and their reversal with thrombolysis in pulmonary embolism, serial imaging and Doppler echocardiographic studies were performed before and after a 6 hour intravenous infusion of 80 to 90 mg of recombinant tissue-type plasminogen activator (rt-PA) in seven patients with segmental or lobar acute pulmonary embolism. None of the five men and two women had known prior pulmonary hypertension. Substantial clot lysis and improvement in pulmonary blood flow, as determined by serial pulmonary angiography and perfusion lung scanning, were achieved in all. Coincident with clot lysis, pulmonary artery systolic pressure decreased (from 42 +/- 11 to 26 +/- 7 mm Hg, p less than 0.005), right ventricular diameter decreased (from 3.9 +/- 1.0 to 2.0 +/- 0.5 cm, p less than 0.005) and left ventricular diameter increased (from 3.7 +/- 0.9 to 4.4 +/- 0.6 cm, p less than 0.01). Right ventricular wall movement, initially mildly, moderately or severely hypokinetic in one, two and four patients, respectively, normalized in five and improved to mild hypokinesia in two. Tricuspid regurgitation was present before lytic therapy in six patients. In five, flow velocity in the tricuspid regurgitant jets indicated a peak systolic right ventricular minus right atrial pressure gradient of 25 to 52 mm Hg. Tricuspid regurgitation was detected early after lytic therapy in only two patients. Systolic septal flattening was noted before but not after lysis. These findings confirm that pulmonary emboli may result in appreciable right ventricular dysfunction and dilation, resultant tricuspid regurgitation, abnormal septal position and decreased left ventricular size.(ABSTRACT TRUNCATED AT 250 WORDS)

Time course of left ventricular dilation after myocardial infarction: influence of infarct-related artery and success of coronary thrombolysis.

Dilation of the left ventricle after myocardial infarction is common, occurs rapidly (within 2 weeks of infarction) and may be self-limited. To evaluate the time course of postinfarction left ventricular dilation and to assess the impact of successful coronary thrombolysis, serial radionuclide left ventricular volume analyses were performed in 36 patients undergoing attempted thrombolysis for acute transmural myocardial infarction. All patients underwent cardiac catheterization, coronary angiography and attempted thrombolysis within 7 h of the onset of symptoms. The site of coronary occlusion was the left anterior descending coronary artery in 17 patients, the right coronary artery in 18 and, in 1 patient, occluded bypass grafts to the right and left circumflex coronary arteries. Attempted reperfusion using a thrombolytic agent was successful in 22 individuals, occurring 5 +/- 1 h after the onset of symptoms. Gated radionuclide ventriculography was performed early (mean time 1 day after admission, n = 36), subacutely (mean time 11 days postinfarction, n = 36) and late after infarction (mean time 10.5 months, n = 25), and a geometric technique was used to measure serial left ventricular end-diastolic volume. Left ventricular end-diastolic volume for the entire group increased significantly (p less than 0.01) from 153 +/- 30 ml at baseline to 172 +/- 45 ml (at 11 days) to 220 +/- 63 ml (at 10.5 months). Twenty of 36 patients showed greater than 20% increase in left ventricular end-diastolic volume (dilation) with time. This appeared early in seven patients, occurred remote from infarction in seven others and showed a progressive pattern in six.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracoronary thallium-201 scintigraphy after thrombolytic therapy for acute myocardial infarction compared with 10 and 100 day intravenous thallium-201 scintigraphy.

Thallium-201 imaging has been utilized to estimate myocardial salvage after thrombolytic therapy for acute myocardial infarction. However, results from recent animal studies have suggested that as a result of reactive hyperemia and delayed necrosis, thallium-201 imaging may overestimate myocardial salvage. To determine whether early overestimation of salvage occurs in humans, intracoronary thallium-201 scans 1 hour after thrombolytic therapy were compared with intravenous thallium-201 scans obtained approximately 10 and 100 days after myocardial infarction in 29 patients. In 10 patients with angiographic evidence of coronary reperfusion, immediate improvement in thallium defects and no interim clinical events, there was no change in imaging in the follow-up studies. Of nine patients with coronary reperfusion but no initial improvement of perfusion defects, none showed worsening of defects in the follow-up images. Six of these patients demonstrated subsequent improvement at either 10 or 100 days after infarction. Seven of 10 patients with neither early evidence of reperfusion nor improvement in perfusion defects had improvement of infarct-related perfusion defects, and none showed worsening. In conclusion, serial scanning at 10 and 100 days after infarction in patients with no subsequent clinical events showed no worsening of the perfusion image compared with images obtained in acute studies. Therefore, there is no evidence that thallium-201 imaging performed early in patients with acute myocardial infarction overestimates improvement.

Thrombolytic therapy of acute pulmonary embolism: current status and future potential.

Recombinant human tissue-type plasminogen activator (rt-PA), a relatively clot-specific fibrinolytic agent, represents a novel and promising approach to thrombolytic therapy of pulmonary embolism. Therefore, the efficacy and safety of peripheral intravenous rt-PA therapy were assessed in 47 patients with angiographically documented pulmonary embolism. The drug regimen was 50 mg over 2 hours followed by repeat angiography and, if necessary, an additional 40 mg over 4 hours. By 6 hours, 44 of the 47 patients had angiographic evidence of clot lysis that was slight (n = 5), moderate (n = 12) or marked (n = 27). Among the 34 patients with pulmonary hypertension before treatment (mean pulmonary artery pressure exceeding 17 mm Hg), the pressure decreased from 43/17 (mean 27) to 31/13 (mean 19) mm Hg (p less than 0.0001). Fibrinogen decreased 33% from baseline at 2 hours and 42% from baseline at 6 hours. There were two major complications that required surgical control of bleeding: hemorrhage from a pelvic tumor and mediastinal tamponade in a patient 8 days after coronary artery bypass surgery. The initial results demonstrate that, among selected patients, peripheral intravenous rt-PA can rapidly and, for the most part, safely lyse pulmonary embolism within 6 hours.

Time course of serum cardiac enzymes after intracoronary thrombolytic therapy. Creatine kinase, creatine kinase MB isozyme, lactate dehydrogenase, and serum glutamic-oxaloacetic transaminase.

We analyzed the time course of serum creatine kinase (CK), the CK MB isozyme, lactate dehydrogenase (LDH), and serum glutamic-oxaloacetic transaminase (SGOT) activity and calculated rates of increase and decline for CK in 24 consecutive patients with acute myocardial infarction (AMI) who received intracoronary thrombolytic therapy. In 19 patients with successfully reperfused infarcts, peak CK activity occurred at 14.1 +/- 1.1 hours after onset of symptoms, the maximal rate of CK rise was 595 +/- 102 IU/L/hr, and the fractional disappearance rate (Kd) was (86 +/- 6) X 10(-5)/min. The peak CK MB activity occurred at 12.9 +/- 0.8 hours and the MB Kd was (223 +/- 39) X 10(-5)/min. In five patients in the nonreperfused group the peak CK (24.9 +/- 4.5 hours) and CK MB (22.7 +/- 3.3 hours) activity occurred later, the maximal rate of CK rise (281 +/- 37 IU/L/hr) was less, and the CK Kd [(68 +/- 5) X 10(-5)/min] and MB Kd [(116 +/- 28) X 10(-5)/min] were lower. The peak CK, CK MB, cumulative CK release, and area under the curve were not different. Except for a shortened time to peak SGOT in the reperfused (17.1 +/- 1.3 hours) compared with the nonreperfused (29.1 +/- 5.6 hours) groups, the time course of LDH and SGOT were not different. Thus, the initial serum CK kinetics and time to peak SGOT may be useful in assessing the reperfusion status in patients with AMI receiving thrombolytic therapy without coronary angiography or in those who may have spontaneous recanalization.

Limitations of echocardiographic techniques in evaluation of left atrial masses.

Four patients with large left atrial masses documented angiographically or pathologically, or both, were studied with M mode echocardiography (four patients) and two dimensional echocardiography (three patients) within 2 to 5 days of angiographic or pathologic diagnosis. The left atrium appeared clear of echos in two patients subsequently documented to have a left atrial thrombus weighing 35 and 100 g, respectively, and located within the body of the left atrium. Definitely abnormal echoes were visualized in a third patient only in the inferior aspect of the left atrium immediately beneath the posterior root of the aorta. Subsequently, a 70 g left atrial myxoma filling almost the entire left atrium was found. In the fourth patient, who had a 125 g left atrial myxoma, the two dimensional four chamber apical view demonstrated tumor filling almost the entire left atrium. Long axis cross-sectional and M mode echocardiograms less clearly demonstrated the extent of the mass. Even large left atrial tumors located within the body of the left atrium may not be apparent or may be underestimated in size by currently available ultrasonic techniques. The relatively homogenous nature of certain masses may be, in part, responsible for the inability to visualize some of them adequately with echocardiography.

Sustained effect of orally administered isosorbide dinitrate on exercise performance of patients with angina pectoris.

The efficacy of oral isosorbide dinitrate was evaluated in nine hospitalized patients with chronic angina pectoris and positive maximal bicycle exercise tests. Patients were randomized double-blind to receive either 20 mg of isosorbide dinitrate or placebo on successive days after a control maximal upright bicycle exercise test. On each day hourly exercise tests were performed for 4 hours after drug administration to an end point of fatigue or angina pectoris. Mean systolic blood pressure 4 hours after the administration of isosorbide dinitrate was 25 mm Hg less than the control value (P less than 0.001). The values for resting heart rate and exercise-attained heart rate-blood pressure product were not significantly different from the values after placebo. The duration of exercise was prolonged (P less than 0.025) for at least 3 hours, and less ST depression (P less than 0.01) was observed up to 3 hours after the administration of isosorbide dinitrate compared with control values. The demonstration of sustained imporved exercise performance and previously described hemodynamic effects with the use of higher doses suggests that adequate blood levels of isosorbide dinitrate or mononitrate metabolites may be important for the efficacy of oral organic nitrates.

Clinical significance of coronary arterial ectasia.

In a study group of 2,457 consecutive patients undergoing cardiac catheterization, 30 patients had coronary arterial ectasia, an irregular dilatation of major vessels up to seven times the diameter of branch vessels. The frequency of hypertension, abnormal electrocardiogram and history of myocardial infarction was greater than that in a control group with obstructive coronary artery disease. Patients with ectasia did not differ from patients with obstructive disease in sex, age, prevalence of angina or presence of metabolic abnormalities. Six deaths occurred in the group with ectasia during a mean follow-up period of 24 months (annual rate of 15 percent). Extensive destruction of the musculoelastic elements was evident, resulting in marked attenuation of the vessel wall. The short-term prognosis in this group is the same as in medically treated patients with three vessel obstructive coronary artery disease.

Value of a noninvasively induced ventricular extrasystole during echocardiographic and phonocardiographic assessment of patients with idiopathic hypertrophic subaortic stenosis.

Fifteen patients with idiopathic hypertrophic subaortic stenosis had a ventricular extrasystole induced with a new external mechanical cardiac stimulator during noninvasive evaluation of left ventricular outflow tract obstruction. Ten patients were monitored with simultaneous echocardiogram, phonocardiogram and indirect carotid pulse tracing; five were monitored with the phonocardiogram and indirect carotid pulse tracing alone. Nine of the 15 patients showed obstruction in the beat after the ventricular extrasystole, as defined by appearance of the characteristic bifid carotid pulse contour and, where recorded, an increase in systolic anterior motion of the mitral valve on echocardiography. Six patients did not show obstruction. All nine patients with obstruction had greater than 20 msec prolongation of uncorrected systolic ejection time in the post-extrasystolic beat of the carotid pulse tracing. Change in the uncorrected ejection time was + 0.038 +/- 0.15 second (mean +/- standard deviation) in these nine patients compared with -0.003 +/- 0.005 second in the six not showing obstruction (P less than 0.01). Six patients underwent cardiac catheterization: Three patients without obstruction after a noninvasively induced ventricular extrasystole had no obstruction at catheterization and three patients with obstruction after noninvasively induced ventricular premature beats demonstrated obstruction at rest or after provocative maneuvers during catheterization. These results indicate that the noninvasive induction of a ventricular extrasystole is a useful and easily performed procedure for both diagnosing and evaluating the dynamic left ventricular outflow tract obstruction of idiopathic hypertrophic subaortic stenosis.

Medically refractory unstable angina pectoris. I. Long-term follow-up of patients undergoing intraaortic balloon counterpulsation and operation.

Of 82 patients with medically refractory unstable angina pectoris seen between October 1972 and January 1978, 60 patients underwent a combination of intraaortic balloon pump counterpulsation, cardiac catheterization and coronary revascularization. Most patients had atherosclerotic involvement of the vessels of the anterior left ventricular wall, 48 patients (80 percent) had abnormalities of left ventricular wall contraction and 22 patients (36 percent) had evidence of acute myocardial injury. One operative and one late death occurred. The perioperative infarction rate was 5 percent. Survivors, followed up for 3 to 63 months (mean 31 months), have done remarkably well; 77 percent are considered employable,and more than 90 percent are in functional class I or II.

Effect of sublingually administered nitroglycerin on regional myocardial blood flow in patients with coronary artery disease.

The effect of sublingually administered nitroglycerin on regional myocardial specific blood flow (in ml/min per 100 g tissue) was evaluated with a xenon-133 washout technique in 31 patients in a resting nonstressed state. Eight patients had normal coronary arteriograms (Group 1), 12 had coronary artery disease without collateral vessels (Group 2) and 11 had coronary artery disease with collateral vessels (Group 3). Although nitroglycerin caused a similar decrease in mean arterial blood pressure and blood pressure-heart rate product in all three groups, the decrease in regional myocardial blood flow was significantly less in Group 3 (-8+/-6% [mean+/-standard error of the mean]) than in Group 1 (-31+/-5%), P less than 0.05); an intermediary decrease occurred in Group 2 (-23+/-5%). Within Group 3, there was a mean increase in regional myocardial blood flow after nitroglycerin in the five patients whose collateral vessels were of a higher angiographic grade and arose from non-stenosed coronary arteries, whereas a reduction was observed in the six patients with none or only one of these findings (+10+/-7% versus -23+/-3%, P less than 0.001). This study suggests that even in the resting state, in some patients with coronary artery disease enhancement of regional myocardial blood flow can occur after sublingual administration of nitroglycerin and is probably mediated through well functioning collateral vessels. It is possible that the drug's effects on both the coronary and systemic circulation may relieve angina in some patients with coronary artery disease.

Intracoronary thallium-201 assessment of thrombolysis in acute myocardial infarction. Validation of the method of imaging before and after therapy.

In order to study acute changes in perfusion with intracoronary thrombolytic therapy, we have used ten times the pretherapy intracoronary thallium-201 dose for the posttherapy study. Because of the larger posttherapy dose, the posttherapy images had ten times as many counts as the pretherapy images. Since the change in image quality between the pretherapy and posttherapy studies might affect interpretation, we studied the effect of image statistics on interpretation of perfusion scintigraphy. The pretherapy and posttherapy images were scored on a four-point scale in five segments on each of three views. In 31 patients, Poisson-distributed pseudorandom noise was added to the posttherapy study in order to match the statistical accuracy of the pretherapy study. A blinded interpretation of the pretherapy and posttherapy noise-added images was performed in the same way as the initial unblinded interpretation. The mean difference between the unblinded pretherapy and posttherapy scores (the improvement in thallium distribution with therapy) was 2.5+/-0.8 (standard error) compared with the difference between the blinded pretherapy and posttherapy noise-added scores which was 2.6+/-1.0. The correlation between readings of similar pairs of data was higher than the correlation between pretherapy and posttherapy studies. Thus, the difference in statistic quality of the pretherapy and posttherapy studies did not affect the interpretation of these studies. Therefore, our evaluation of pretherapy and posttherapy studies using a ten-fold increase in thallium-201 dosage is valid.

Dynamic left ventricular outflow tract obstruction when the anterior leaflet is retained at prosthetic mitral valve replacement.

Dynamic left ventricular outflow tract obstruction developed in a patient in whom the anterior leaflet was retained at mitral valve replacement. It was caused by systolic anterior movement of the native anterior leaflet. Reduced outflow tract diameter, resulting from both posterior displacement of the septum and anterior displacement of the native anterior leaflet by porcine stents, was likely instrumental in promoting dynamic obstruction.

Streptokinase and tissue plasminogen activator in acute myocardial infarction.

The use of thrombolytic agents for the treatment of myocardial infarction is increasing. Many community hospitals are infusing SK intravenously and those with cardiac catheterization laboratories often use intracoronary SK and angioplasty. Tissue plasminogen activator is undergoing extensive clinical trials, and reports of this research should add to our knowledge of this new therapy. Recently, benefits from thrombolytic therapy such as increased ejection fraction, improved regional wall motion, and short-term decreases in mortality have been documented. Both the GISSI trial that recruited 11,712 patients in Italy and the Netherlands trial documented significant short-term decreases in mortality after therapy with SK compared with control groups. As this information reaches the medical community, we may see an increase in the use of thrombolytic therapy during acute myocardial infarction. Additionally, community education service organizations should reemphasize the importance of seeking help early after the signs and symptoms of acute myocardial infarction appear to promote early treatment and potential salvage of greater amounts of myocardium. The long-term prognosis of patients who have been successfully reperfused and the best management after thrombolytic therapy is not yet known. Future problems and benefits from this therapy are still to be determined.

Assessment of regional wall motion and perfusion by multigated myocardial scintigraphy after intracoronary Tl-201.

Fourteen patients undergoing intracoronary thrombolysis for acute myocardial infarction had intracoronary injection of thallium-201 to assess myocardial salvage after reperfusion. Scintigrams of the perfused myocardium were gated and compared with both ungated scans and radionuclide ventriculograms (multigated blood pool scintigrams) to determine the value of gated perfusion images for studies of both perfusion and regional wall motion. Multigated and ungated thallium images provided comparable information about regional myocardial perfusion. Correlation between multigated thallium images of regional wall motion and radionuclide ventriculograms was poor (tau = 0.44). Assessment of wall motion was most accurate in well-perfused segments and least accurate in partially perfused segments.

Extrinsic compression of the heart by tumor masquerading as cardiac tamponade.

A patient with known intrathoracic tumor presented with findings suggestive of cardiac tamponade. At cardiac catheterization, the entire heart was displaced superiorly and anteriorly by the tumor mass, and this accounted for the observed cardiac hemodynamics, in the absence of discernible pericardial effusion.

An additional angiographic sign for determining coronary artery dominance in obstructive coronary artery disease.

An additional angiographic sign for determining coronary artery dominance is proposed. This sign is based on the anatomic pattern of the infraventricular branches in the left anterior oblique view. It is especially helpful in patients in whom the right coronary and/or left circumflex coronary arteries are completely occluded and distal vessels are filled via collaterals.