Lawrence S. Cohen

Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge.

Intravenous administration of 80 mg of recombinant tissue plasminogen activator (rt-PA, 40, 20, and 20 mg in successive hours) and streptokinase (SK, 1.5 million units over 1 hr) was compared in a double-blind, randomized trial in 290 patients with evolving acute myocardial infarction. These patients entered the trial within 7 hr of the onset of symptoms and underwent baseline coronary arteriography before thrombolytic therapy was instituted. Ninety minutes after the start of thrombolytic therapy, occluded infarct-related arteries had opened in 62% of 113 patients in the rt-PA and 31% of 119 patients in the SK group (p less than .001). Twice as many occluded infarct-related arteries opened after rt-PA compared with SK at the time of each of seven angiograms obtained during the first 90 min after commencing thrombolytic therapy. Regardless of the time from onset of symptoms to treatment, more arteries were opened after rt-PA than SK. The reduction in circulating fibrinogen and plasminogen and the increase in circulating fibrin split products at 3 and 24 hr were significantly less in patients treated with rt-PA than in those treated with SK (p less than .001). The occurrence of bleeding events, administration of blood transfusions, and reocclusion of the infarct-related artery was comparable in the two groups. Thus, in patients with acute myocardial infarction, rt-PA elicited reperfusion in twice as many occluded infarct-related arteries as compared with SK at each of seven serial observations during the first 90 min after onset of treatment.

Intravenous recombinant tissue-type plasminogen activator in patients with acute myocardial infarction: a report from the NHLBI thrombolysis in myocardial infarction trial.

The efficacy and safety of a 3 hr, 80 mg intravenous infusion of recombinant tissue-type plasminogen activator (rt-PA) were investigated in 47 patients with acute myocardial infarction. Coronary angiography, performed before the administration of rt-PA and for 90 min thereafter, demonstrated that 37 patients had total coronary occlusion before therapy. After 90 min of rt-PA (50 mg), reperfusion of the infarct-related artery was observed in 25 patients (68%). Continuous infusions of heparin for anticoagulation were administered for 8 to 10 days. Of 36 patients who underwent follow-up coronary cineangiography, 21 had initially presented with total occlusion and had experienced reperfusion at 90 min. Sustained perfusion of the infarct-related artery was observed in 14 (67%) of these 21 initially reperfused patients. Late angiography was performed in nine patients who initially demonstrated subtotal occlusion of the infarct-related artery; sustained perfusion was observed in eight (89%). Significant bleeding was observed in 15 patients (32%). A hematoma at the site of the acute catheterization accounted for most instances of significant bleeding (11/15, 73%). Administration of rt-PA resulted in a significant decline in fibrinogen and plasminogen while amounts of fibrin(ogen) degradation products rose. In no patient, however, did fibrinogen levels decline to less than 140 mg/dl. Thus, rt-PA, administered as a brief 80 mg intravenous infusion, is capable of restoring blood flow in a high proportion of patients with acute myocardial infarction due to total coronary obstruction. Declines in plasma fibrinogen and plasminogen are observed. If combined with heparin anticoagulation and invasive vascular procedures, significant bleeding is a common complication.(ABSTRACT TRUNCATED AT 250 WORDS)

Left Ventricular Papillary Muscles Description of the Normal and a Survey of Conditions Causing them to be Abnormal

The left ventricular papillary muscles appear to be the last portions of the heart to be perfused by coronary arterial blood. As a consequence they are sensitive anatomic markers of myocardial ischemia. Foci of necrosis or fibrosis therefore are commonly seen in these structures, particularly the posteromedial papillary muscle, which has a poorer blood supply than does the anterolateral muscle. Coronary arterial luminal narrowing is the most common cause of necrosis or fibrosis of the left ventricular papillary muscles. Other conditions, all associated with inadequate cardiac output, which may produce these lesions include left ventricular outflow tract obstruction, especially that resulting from congenitally malformed aortic valves, acute valvular regurgitation (infective endocarditis), various cardiomyopathies, and primary endocardial fibroelastosis with or without anomalous origin of one or both coronary arteries from the pulmonary trunk. Various infiltrative diseases, including inflammation (Aschoff bodies, sarcoid, abscesses), amyloid, iron, and neoplasms, also may involve the papillary muscles. Their most common congenital malformation is the parachute or single papillary muscle. Fibrosis or necrosis of adjacent left ventricle free wall without involvement of the papillary muscles themselves may simulate clinically “papillary muscle dysfunction.’ The anterior papillary muscle of the right ventricle is frequently affected by conditions which also affect the left ventricular papillary muscles. Whether or not necrosis or fibrosis of the right ventricular papillary muscle causes tricuspid regurgitation, however, is unknown at present.

Amelioration of angina pectoris in idiopathic hypertrophic subaortic stenosis with beta-adrenergic blockade.

Beta-adrenergic receptor blockade has been demonstrated to reduce obstruction of the left ventricular outflow tract in patients with idiopathic hypertrophic subaortic stenosis (IHSS) and has also proved helpful in reducing angina pectoris due to ischemic heart disease. Accordingly, the effects of oral propranolol on the level and duration of exercise required to produce angina in seven patients with IHSS were compared with a placebo. Improvement in exercise performance was observed in six patients taking propranolol orally in doses ranging from 80 mg to 480 mg daily. Clinical improvement was sustained in the four patients given propranolol since discharge from the hospital for periods up to 15 months, and in three it has been possible to obviate corrective operations. The mechanism by which propranolol is efficacious in this disease is probably related to the diminution of myocardial O2 requirements resulting from the reduction of wall tension, velocity of contraction, and heart rate induced by beta-adrenergic receptor blockade.

Depression of cardiac function by streptomycin and other antimicrobial agents

Abstract Signs of toxicity of the eighth cranial nerve in a patient receiving streptomycin who also had persistent hypotension after cardiac surgery led to investigation of the effects of streptomycin and other antibiotic agents on cardiac function. In 18 open chest dogs, there was a dose-dependent depression of cardiovascular function as a result of the intravenous administration of streptomycin in doses of 2.5, 10 and 40 mg/kg. Similar depressions were demonstrated after administration of tetracycline, kanamycin, vancomycin, erythromycin and colymycin. In 4 intact dogs given streptomycin, 2 g intramuscularly, cardiac output decreased 26 percent and mean arterial pressure decreased 22 percent 1 hour after administration. The average level of streptomycin in the blood at 1 hour was 35 μg/ml, within the usual therapeutic range for patients. In the isolated perfused cat heart, streptomycin, tetracycline, kanamycin, vancomycin and chloramphenicol caused a profound decrease in contractile force. These data should not be extrapolated directly to clinical situations since most of the experiments did not parallel precisely the usual form of antibiotic administration. In the presence of infection, antibiotic drugs are among the most effective agents available. However, the physician must be aware of the potential for cardiac depression, especially in patients with an already compromised cardiac status or with impaired renal function.

High dose intravenous streptokinase for acute myocardial infarction: Preliminary results of a multicenter trial

To assess the efficacy of intravenous streptokinase in patients with acute myocardial infarction, 40 patients (30 men and 10 women, mean age 54 years) with acute myocardial infarction were given 1.5 million U of streptokinase intravenously in 1 hour, and coronary arteriography was performed repeatedly to assess reperfusion. Streptokinase treatment was begun 270 +/- 86 (mean +/- SD) minutes after the onset of chest pain. Of the 40 patients, 34 had total or near total coronary occlusion before streptokinase administration. In 14 (41%) of these 34 patients, some reperfusion occurred during the 90 minutes after the administration of streptokinase, but in only 11 of the 14 was reperfusion present at 90 minutes. After streptokinase administration, all patients received heparin for 8 to 10 days; they were subsequently administered aspirin and dipyridamole. Clinical evidence of reocclusion during the first 24 hours of heparin therapy occurred in one patient. Thus, when given to patients with acute myocardial infarction and total coronary occlusion an average of 4 1/2 hours after the onset of chest pain, high dose intravenous streptokinase achieves reperfusion in only about 40% and results in sustained reperfusion in only about 30%.

Significance of an Atrial Gallop Sound in Mitral Regurgitation A Clue to the Diagnosis of Ruptured Chordae Tendineae

The incidence of atrial gallop sounds was studied in 51 patients with pure mitral regurgitation of sufficient severity to require operative treatment. Seventeen patients were in sinus rhythm. Nine of them had atrial gallop sounds and mitral regurgitation secondary to ruptured chordae tendineae, while six without atrial gallop sounds had primary valvular disease. The degrees of disability or the hemodynamic findings did not differ among the patients with ruptured chordae tendineae and those with primary valvular disease and sinus rhythm. However, the duration of symptoms and the history of a heart murmur were much shorter and the left atrium tended to be smaller in patients with ruptured chordae tendineae than in those with primary valvular disease. Sinus rhythm in a symptomatic patient with severe mitral regurgitation, therefore, should suggest the diagnosis of ruptured chordae tendineae. If, in addition, an atrial gallop sound is found the diagnosis of ruptured chordae tendineae is even more likely.

Severe Mitral Regurgitation Following Acute Myocardial Infarction and Ruptured Papillary Muscle Hemodynamic Findings and Results of Operative Treatment in Four Patients

The results of operative treatment are described in four patients who sustained myocardial infarctions and in whom ruptured left ventricular papillary muscles caused severe mitral regurgitation. All were men between 51 and 69 years of age, and the intervals between myocardial infarction and operation were 3 to 15 months. Each patient manifested severe congestive heart failure. All were in sinus rhythm and had an apical holosystolic murmur and an atrial gallop sound. Three of the four had severe pulmonary hypertension (60 to 80 mm Hg systolic), grossly elevated mean left atrial pressure, and v waves 37 to 45 mm Hg. In all the cardiac index was abnormally low (average 1.8 L/min/m2). In all four patients the mitral valve was replaced with a 2M Starr-Edwards prosthesis. In two of the excised valves, one head of the posterior papillary muscle was infarcted and had ruptured, and in the other two the anterior papillary muscle was similarly involved. All patients survived, and all have derived distinct symptomatic improvement at intervals of 7 to 16 months. Hemodynamic studies were repeated 11 months postoperatively in one patient; although he is asymptomatic and the cardiac index is increased, intracardiac pressures remain elevated, and residual impairment of left ventricular function is evident. In a second patient the left ventricle apparently retained satisfactory functional capacity for symptomatic benefit has been paralleled by striking reductions in pulmonary arterial and left atrial pressures measured six months postoperatively.

Heart motion video-tracking (radarkymography) in diagnosis of congenital and acquired heart disease

Abstract Heart motion video-tracking (radarkymography) is a technic for recording the movements of cardiovascular structures. Over 100 patients with a variety of congenital and rheumatic heart lesions were studied. Characteristic graphic linear tracings were obtained in patients with mitral valve disease, obstruction to the aortic outflow tract, ventricular aneurysms and coarctation of the aorta. Radarkymography offers certain advantages over electrokymography, which to date has been the major technic for recording motion of the cardiac silhouette.

Direct Measurement of Instantaneous Coronary Blood Flow after Total Correction of Anomalous Left Coronary Artery

An anomalous left coronary artery was excised from the pulmonary artery and connected by a reversed segment of autogenous saphenous vein to the ascending aorta in a 20-year-old man. Before it was anastomosed to the aorta, retrograde flow of oxygenated blood from coronary artery to pulmonary artery occurred predominantly during diastole; the pressure in the left main coronary artery was 30/15 mm Hg and rose to systemic levels following occlusion of the coronary artery at its junction with the pulmonary artery. After transplantation to the aorta, the vessel was encircled with an electromagnetic flow probe and instantaneous left coronary artery blood flow was measured simultaneously with the pressures in the left ventricle and ascending aorta. The pattern of instantaneous coronary blood flow and its relation to ventricular and aortic pressure were similar to the pattern that has been observed in normal animals. Mean flow through the left coronary artery was 104 ml/min. Following operation, the left ventricular enddiastolic pressure decreased to normal levels and the anastomosis was proved to be patent. Transplantation of the anomalous coronary artery to the systemic circulation restores normal coronary dynamics and may be preferable to simple ligation.