Intracoronary streptokinase in evolving acute myocardial infarction

Intracoronary application of thrombolytic agents, particularly streptokinase, can recanalize arteries that had been totally occluded in patients with evolving acute myocardial infarction (AMI). Numerous uncontrolled trials have testified to the effectiveness of thrombolytic therapy in most patients in reestablishing flow to the infarct-related coronary artery. Follow-up of patients in whom reperfusion has been established has often demonstrated small but significant increases in the left ventricular ejection fraction. In contrast, in other patients in whom thrombolytic therapy failed to reopen the occluded vessel, the left ventricular ejection fraction usually does not change during follow-up. In most reported uncontrolled trials, few complications are described and the mortality rate in patients treated by this therapy may be lower than expected. These data have been used as the basis for widespread application of this technique in many catheterization laboratories around the world. Our initial experience at the University of Florida in 23 patients has not been as successful as other uncontrolled trials previously reported. Reperfusion was accomplished in only 12 patients. Of 17 who survived their AMI, only five demonstrated an improved left ventricular ejection fraction of at least 10%. Serious complications, including bleeding from catheterization sites or allergic reactions to streptokinase, occurred. Controlled trials to critically evaluate this new therapy are needed and are in progress.     

Effects of prostacyclin on systemic and coronary hemodynamics in the dog

The hemodynamic effects of intravenous and intracoronary prostacyclin (PGl₂) were evaluated in anesthetized, open-chest instrumented dogs. Coronary artery and aortic blood flows, aortic and left ventricular (LV) diastolic pressure, and heart rate were measured continuously. With intravenous PGl₂ both left anterior descending (LAD) and circumflex (LCX) coronary artery blood flows remained unchanged; both arterial and LV diastolic pressures declined; coronary resistance declined progressively with increasing PGl₂; peak reactive hyperemic flow following 10-second coronary artery occlusion declined progressively with increasing PGl₂; heart rate responses were variable at low doses but increased at high dose; and aortic blood flow increased consistently. With intracoronary PGl₂ both LAD and LCX coronary blood flows increased promptly in dose-related manner. In dogs with critical coronary artery narrowing (loss of reactive hyperemia) created by an external plastic occluder, intravenous prostacyclin (0.5 μg/kg/min) did not after flow in the narrowed coronary artery, but increased flow in the non-narrowed coronary artery (p < 0.02) as both systemic arterial and LV diastolic pressures declined. These results show that PGl₂ has potent direct coronary and systemic vasodilator actions.     

Thromboxane release in coronary artery disease: spontaneous versus pacing-induced angina

To determine thromboxane A2 release in coronary artery disease, we measured its stable metabolite thromboxane B2 by radioimmunoassay in 20 patients. In 15 patients with stable disease (last angina episode greater than 96 hours before study), coronary venous thromboxane B2 concentrations were lower than in aortic blood (mean 109 +/- 36 vs 194 +/- 40 pg/ml, p less than 0.001). In contrast, in five other patients with spontaneous angina, coronary venous thromboxane B2 concentrations were higher than aortic thromboxane B2 concentrations during the angina episode (mean 1716 +/- 316 vs 875 +/- 388 pg/ml, p less than 0.02). Plasma thromboxane B2 levels were in the normal range (mean 175 +/- 35 pg/ml) in patients with stable angina but significantly (p less than 0.02) higher in patients with spontaneous angina. With atrial pacing to the point of chest pain and/or ECG changes in patients with stable coronary artery disease, aortic thromboxane B2 concentrations increased in 10 of 13 patients (mean 283 +/- 70 pg/ml, p less than 0.02). Coronary venous thromboxane B2 concentrations increased in seven patients at peak pacing rates (mean 223 +/- 76 pg/ml) and in three other patients after termination of pacing. These data indicate that release of thromboxane A2 is much greater during spontaneous angina than with pacing stress in patients with coronary artery disease. Thromboxane A2 released during spontaneous or pacing-induced angina may modulate coronary and systemic vascular tone. Enhanced thromboxane A2 activity may either precede or follow myocardial ischemia and could be a factor in the initiation and propagation of the ischemic episode.     

Role of platelet antagonists in coronary artery disease: implications in coronary artery bypass surgery and balloon-catheter dilatation

Platelets play an important role in regulation of hemostasis and maintenance of vascular tone. Endothelial disruption occurring during coronary artery bypass surgery and balloon-catheter dilatation may promote platelet adhesion, aggregation, and thrombus formation. Recent studies suggest that platelet-endothelial interaction is mediated in part through products of arachidonic acid metabolism. Understanding of the platelet interaction with blood vessels is important in pharmacologic interventions directed at prevention of thrombus formation in bypass grafts. Although it remains to be proved, use of platelet-suppressive drugs may also improve patency of coronary arteries after balloon-catheter dilatation.     

Comparison of platelet function during exercise in normal subjects and coronary artery disease patients: Potential role of platelet activation in myocardial ischemia

Platelet function parameters as influenced by exercise stress were evaluated in 22 patients with coronary artery disease (CAD) and in 13 normal subjects. Upon exercise stress, 14 CAD patients exhibited positive tests and eight exhibited negative tests. Platelet counts during exercise increased similarly in normal and CAD patients. Platelet aggregation response to ADP was unaffected by exercise both in normal and CAD patients. Platelets from 7 of the 14 CAD patients with positive stress tests had increased sensitivity to endoperoxide analog (U-46619) defined as less than 200 ng/ml U-46619 required for 50% platelet aggregation. Resting plasma beta-thromboglobulin (B-TG) levels, an index of in vivo platelet activation, were significantly higher in CAD patients compared to normal subjects (74 +/- 7 and 41 +/- 5 ng/ml, respectively; p less than 0.02). During exercise plasma B-TG levels increased in normal subjects to 60 +/- 5 ng/ml. In contrast, B-TG levels increased to 102 +/- 14 ng/ml in CAD patients (p less than 0.01 compared to normal subjects). These increases were transient and B-TG declined to preexercise values soon after exercise. Eleven of the 12 CAD patients with positive exercise stress tests had increases in plasma B-TG levels, whereas only three of the eight CAD patients with negative stress tests had any increase. These observations of increased platelet activation in certain CAD patients during exercise may be related to exercise-induced myocardial ischemia.     

The significance of platelet-vessel wall prostaglandin equilibrium during exercise-induced stress

Alterations in platelet-generated thromboxane A₂ (TXA₂) and vessel wall-generated prostacyclin (PGI₂) have been assoclated with myocardial ischemia. To examine TXA₂ - PGI₂ equilibrium at rest and during exercise stress, we studied 13 normal subjects and 15 coronary artery disease patients. Plasma TXB₂ and 6-keto-PGF_1α were measured as stable metabolites of TXA₂ and PGI₂, respectively, by radioimmunoassay. In normal subjects, plasma TXB₂ levels increased 24% during exercise from 135 ± 30 to 168 ± 42 pg/ml (p = NS). Plasma 6-keto-PGF_1α levels increased 224% from 54 ± 17 to 175 ± 57 pg/ml (p < 0.05). In coronary artery disease patients, although resting plasma TXB₂ levels (mean 136 ± 43 pg/ml) were comparable to levels in normal subjects, a greater increase (82%) occurred during exercise (mean 248 ± 70 pg/ml; p < 0.02 compared to resting levels). Resting plasma 6-keto-PGF_1α levels (mean 94 ± 28 pg/ml) were also similar to normal subjects but increased only by 43% during exercise (mean 134 ± 53 pg/ml; p = NS compared to resting levels). These data suggest that: in normal subjects TXA₂ and PGI₂ increase during exercise, PGI₂ increasing more than TXA₂, and although coronary disease patients have resting TXA₂ and PGI₂ levels in the normal range, TXA₂ levels increase more than PGI₂ levels during exercise. These observations may have a bearing on the mechanism of exercise-induced angina pectoris in certain coronary artery disease patients.     

Clinical outcome after treatment of rest angina with calcium blockers: comparative experience during the initial year of therapy with diltiazem, nifedipine, and verapamil

The clinical outcome after the initial year of therapy with either diltiazem (D), nifedipine (N), or verapamil (V) was examined in 45 patients with rest angina. Age, frequency of angina, duration of symptoms, and ejection fraction were similar in all three treatment groups. Coronary artery disease was present in 60% of patients (5 of 13 given D, 8 of 16 given N, and 14 of 16 given V). Coronary spasm was suspected (ST elevation with angina) or documented (angiographically) in 35 (78%) patients. Twenty-nine (64%) patients had greater than 50% decrease in angina without a coronary event (9 taking D, 11 taking N, and 9 taking V). Coronary events (sudden death, infarction, and hospitalization for unacceptable angina control or bypass surgery) occurred in 13 (29%) patients (two taking D, four taking N, and seven taking V). To achieve these responses, 20 (44%) patients required additional antianginal drugs (long-acting nitrates, beta blockers, or other calcium blockers). Four of these 20 patients were taking D, nine were taking N, and seven were taking V. Seventeen (38%) patients experienced a side effect (none taking D, 6 taking N, and 11 taking V). Although rest angina can be controlled in the majority of patients during the initial year of treatment with calcium blockers, additional therapy is often required. Furthermore, the clinical course of patients presenting with rest angina remains unpredictable, even during calcium blocker treatment. Morbid events continue to occur, related in part to the extent of coronary artery disease.     

Platelet function studies in coronary artery disease. V. Evidence for enhanced platelet microthrombus formation activity in acute myocardial infarction.

Circulating platelet microthrombi were evaluated during the acute and convalescent phases of illness in 44 patients admitted to the hospital for chest pain. Similar studies were performed in 10 healthy volunteers and 6 patients with infection. Circulating platelet microthrombi were significantly increased during the acute phase in 22 patients with transmural myocardial infarction compared with values in the other 22 patients without myocardial infarction, the healthy volunteers and the patients with infection alone. This increase in circulating platelet microthrombi declined to normal levels by the 7th hospital day in all but two patients who had evidence of extension of myocardial infarction and died. In contrast, circulating platelet microthrombi were similar in acute and convalescent phases of patients with chest pain but without myocardial infarction and were comparable with values in healthy volunteers. This study suggests that increased circulating platelet microthrombi may be related to tissue necrosis associated with transmural myocardial infarction.     

Effect of diltiazem in patients with variant angina: A randomized double-blind trial

Effects of diltiazem on frequency of angina and nitroglycerin (NTG) consumption were studied in 12 patients with variant angina (rest pain with ST elevation). Either diltiazem in two dosage schedules (120 mg/day and 240 mg/day), or placebo was administered in a randomized double-blind program over 10 weeks. Significant decreases in angina frequency and TNG consumption were observed when diltiazem treatment periods were compared to placebo periods. Furthermore, when placebo periods following diltiazem were compared to placebo periods following placebo, significant “carry-over” effect with respect to reduced angina frequency was observed. No patient had an increase in angina frequency or TNG consumption on diltiazem compared to placebo. No “rebound effects” or changes in blood pressure or heart rate were observed. One patient complained of dry mouth on diltiazem. These findings, although in a limited number of patients, suggest that diltiazem is effective in decreasing angina frequency and TNG consumption in patients with variant angina. These encouraging results warrant evaluation of diltiazem in a larger patient population over a longer time period.     

Hemodynamic significance of the length of a coronary arterial narrowing

The hemodynamic significance of the length of a coronary arterial narrowing is unclear. Accordingly, the influence of the length of a given coronary narrowing on coronary hemodynamic responses was studied in 14 dogs. Recordings were made as short fixed diameter reductions were progressivley lengthened to 5, 10 and 15 mm by the addition of plastic occluders. Resting coronary blood flow decreased and pressure gradients developed across short (snare) narrowings greater than 80 percent (critical stenosis). Short 40 to 60 percent narrowings had no significant resting hemodynamic influence, but increasing their length to 10 and 15 mm consistently resulted in significant pressure gradients and flow reductions. Reactive hyperemic coronary blood flow expressed as repayment of flow debt (after 10 seconds of coronary occlusion) decreased progressively as these narrowings were lengthed. The effect of 15 mm long narrowings on resting and reactive hyperemic flows was similar to that of short 90 percent narrowings. These data indicate that there is uncertainty about the significance of coronary diameter reductions previously considered hemodynamically unimportant. In our studies, significant changes in resting and reactive hyperemic coronary flows and resting pressure gradients occurred as the length of a given degree of narrowing was increased.     

Electrocardiographic changes with coronary artery spasm

The presence or absence of important ECG changes (e.g., ST elevation or depression ≥ 1 mm) was evaluated in 79 consecutive patients with coronary artery spasm. In eight of these patients ECG changes usually did not accompany episodes of rest angina. Evaluation before, during, and after cardiac catheterization included multiple ECGs and ambulatory monitoring during angina. Our observations suggest that the ECG may not always be a sensitive indicator of coronary spasm. Thus the diagnosis of transient myocardial ischemia secondary to coronary spasm should not necessarily be excluded because of a lack of ECG changes during rest angina.     

Electrocardiographic and vectorcardiographic abnormalities in Fabry's disease.

Fabry's disease has been reported to be associated with ECG abnormalities. Thirty-two patients with this disease followed in the University of Minnesota had ECG's and 15 had VCG's. An abonrmal rhythm was observed in two patients on initial examination and four more developed abnormal rhythm on follow-up examinations. A short PR interval (120 msec. or less) was seen in five patients. Thirteen others had a PR interval that was less than 140 msec. Conduction abnormalities involving the A-V node or His bundle or its branches were present in 22 per cent of the patients, most frequently the intraventricular conduction defects progressing to the right bundle branch block. Atrial or ventricular enlargement was seen in 60 per cent of the patients, left ventricular hypertrophy being the most common. ST-T changes with or without chamber enlargement were seen in 10 patients. One patient had an anterior myocardial infarction pattern on his ECG. Hemizygosity was found to be associated with significantly more abnormalities than heterozygosity. The severity of conduction defects also increased with the duration of the disease process. Vectorcardiography in this study did not provide significant additional information other than that observed on the ECG alone. Since the pathology usually reveals myocardial fibers, conduction system, and blood vessels infiltrated with glycosphingolipid, it is believed that lipid infiltration is responsible for conduction defects, chanber enlargement, and other abnormalities. Although Fabry's disease is rate, it may be amenable to therapy; therefore, recognition of cardiac involvement is important.     

Analysis of coronary responses to nifedipine alone and in combination with intracoronary nitroglycerin in patients with coronary artery disease

Left coronary artery (CA) dilation responses to nifedipine and nitroglycerin (NTG) were studied in patients with CA disease. Quantitative angiography was used to measure the diameter of CAs before and after nifedipine (10 mg buccal) and the addition of NTG (200 μg) given into the left CA. Ninety-three CA segments were measured. The CA diameter was unchanged in 60 segments after nifedipine and was increased in only 27. Diameters of six other segments decreased. The average percentage of dilation of the various CA segments after nifedipine ranged from ?2% to 14%. After NTG, CA dilation compared with control diameters occurred in 84 of the 93 segments. Only eight CA segments were unchanged and one other decreased. The average percentage of dilation of the various CA segments after NTG ranged from 8% to 35% compared with control diameters. Compared with diameters observed after nifedipine, NTG caused dilation in 82 of 93 CA segments; 10 appeared unchanged and one decreased. The diameter of eight coronary stenoses was also measured and was increased in three after nifedipine. After NTG the diameter of six of the eight stenoses increased compared with control diameter, and in four of the six that showed dilation, the diameter was larger than after nifedipine alone. These data suggest that nifedipine does not cause appreciable dilation of epicardial CA in patients with coronary disease. The capacity of NTG to induce dilation appears preserved after nifedipine. Although dilation of epicardial CAs and coronary stenoses was not apparent after nifedipine in our patients at rest, it is possible that nifedipine's clinically beneficial effects are mediated in some patients through prevention of increases in coronary tone.     

Influence of myocardial revascularization on survival. Controversies in cardiology: Part II.

Coronary bypass surgery can be performed with a low rate of morbidity and mortality and can successfully reduce or eliminate symptomatic angina pectoris. However, it is not yet clear whether the procedure prolongs life. A definitive answer to this question requires long-term prospective data on patients undergoing surgical or medical therapy who are comparable in degree of ventricular impairment, severity of symptoms and type and extent of coronary artery disease.