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.     

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.     

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.     

Platelet function studies in coronary artery disease. VII. Effect of aspirin and tachycardia stress on aortic and coronary venous blood

The effects of orally administered aspirin (650 mg) on platelet aggregation patterns and counts in aortic and coronary venous blood were evaluated in patients with coronary artery disease. Studies were conducted at rest and during the stress of tachycardia. Before administration of aspirin, platelet aggregation and counts were lower (p < 0.01) in coronary venous blood than in aortic blood. The stress of tachycardia resulted in increased (p < 0.01) platelet aggregation only in coronary venous blood. After administration of aspirin, differences in platelet aggregation and counts between coronary venous and aortic blood at rest were eliminated, and the tachycardia-associated increase in coronary venous blood platelet aggregation was significantly reduced. These observations suggest that aspirin influences and abolishes the changes that occur in blood platelet function as platelets traverse the atherosclerotic myocardial vascular bed. The absence of an increase in platelet aggregation during the stress of tachycardia after administration of aspirin may have important pathophysiologic and therapeutic implications.     

Platelet function studies in coronary heart disease. IX. Increased platelet prostaglandin generation and abnormal platelet sensitivity to prostacyclin and endoperoxide analog in angina pectoris

Platelet prostaglandin generation (malondialdehyde production) and platelet sensitivity to prostacyclin (a vasodilator and platelet aggregation inhibitor) and to epoxymethanodienoic acid (EMA) (a vasoconstrictor and platelet aggregation stimulant endoperoxide analog) were studied in patients with angina pectoris and in control subjects. Platelet malondialdehyde production was higher in patients than in control subjects (mean ± standard error of the mean 2.50 ± 0.30 versus 1.70 ± 0.13 nmol/10⁹ platelets, p < 0.02). Platelets from patients were significantly less sensitive to prostacyclin's antiaggregatory effects than were those from control subjects (amount of prostacyclin required for 50 percent platelet aggregation inhibition 1.90 ± 0.35 versus 0.68 ± 0.05 ng, p < 0.02). Furthermore, less EMA was required to induce 50 percent platelet aggregation in patients with angina pectoris than in the normal subjects (133 ± 8 versus 194 ± 16 ng, p < 0.001). These observations suggest that increased platelet prostaglandin generation and abnormal platelet sensitivity to prostacyclin and endoperoxide analog in certain patients with coronary artery disease are important potential mechanisms in the pathogenesis of myocardlal ischemia.     

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.     

Percutaneous transluminal coronary angioplasty in acute myocardial infarction

Percutaneous transluminal coronary angioplasty (PTCA) has, in general, been restricted to therapy for patients with angina pectoris. Thrombolytic therapy and guide wire recanalization have been used to recanalize coronary arteries in patients with evolving myocardial infarction. Recently we and others have examined the use of PTCA to recanalize the acutely occluded artery associated with the early evolving phase of myocardial infarction. PTCA was performed as definitive therapy in eight patients with acute myocardial infarction. Seven of these had totally occluded arteries to the region of infarct. The infarct-related artery was open within 20 minutes in each of these cases. PTCA recanalization resulted in evidence for reperfusion in each case. Residual stenoses either were not present or were minimal. The procedure was well tolerated. These preliminary results suggest that PTCA may be a reasonable alternative to intracoronary thrombolytic therapy in certain patients with acute evolving myocardial infarction.     

Role of blood platelets and prostaglandins in coronary artery disease

In the last decade, several studies evaluating blood platelet function in patients with coronary heart disease have been reported. Although several platelet function abnormalities such as enhanced platelet aggregation, decreased platelet survival and increase in platelet release reaction in the stable condition and during stress in patients with myocardial ischemia have been recognized, the mechanism of these abnormalities is just beginning to be understood. Discovery of certain platelet and endothelium-generated prostaglandins has provided some information as to the possible mechanism of platelet dysfunction. Abnormalities of prostaglandin production and platelet sensitivity to various prostaglandins may have an important bearing on the enhanced platelet aggregation In vivo, genesis of atherosclerosis and probably precipitation of acute ischemic events. Since the discovery of these prostaglandins, the precise mode of action of several commonly used platelet-active drugs has been clarified. Development of new drugs acting at selective steps in the prostaglandin pathways may provide some exciting novel therapeutic procedures in patients with coronary heart disease.     

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.     

Platelet function studies in coronary artery disease. X. Effect of dipyridamole

To evaluate the effects of dipyridamole on blood platelet function in patients with coronary artery disease, platelet counts and aggregation were examined in aortic and coronary venous blood. Before administration of dipyridamole, platelet counts and aggregation in response to adenosine diphosphate were less (p <0.02) in coronary venous than in aortic blood. Dipyridamole administration (100 mg) resulted in an increase in platelet counts and platelet aggregation in coronary venous blood so that the differences in aortic and coronary venous blood values were eliminated. These phenomena were probably related to inhibitory actions of dipyridamole. on platelet adhesion to atherosclerotic vessels. To further study the mechanism of action, the direct effects of dipyridamole on in vitro platelet aggregation were evaluated. Although dipyridamole, in the concentrations used, had no effect on in vitro platelet aggregation, it greatly potentiated the aggregation inhibitory actions of exogenous prostacyclin. In vivo potentiation of endogenous prostacyclin and inhibitory actions on platelet adhesion are the most likely mechanisms of the potentially beneficial actions of dipyridamole.     

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.     

Platelet function in hypertension and effect of therapy

Platelet function was evaluated in 10 hypertensive and 11 normal subjects. In the placebo phase, the plasma beta thromboglobulin level (an index of platelet activation in vivo) was significantly (p less than 0.01) higher in the hypertensive than in the normal subjects; other tests of platelet function gave similar results in the two groups. After control of blood pressure with lofexidine (a centrally acting imidazoline derivative), plasma beta thromboglobulin levels decreased in 9 of the 10 hypertensive patients, but increased in one who showed no change in blood pressure. These studies suggest that enhanced platelet activation in primary hypertension may be associated with increased vascular resistance.     

Mexiletine, a new antiarrhythmic agent, for treatment of premature ventricular complexes

This double-blind crossover study was designed to compare the safety and efficacy or mexiletine, a new class I antiarrhythmic agent, with those of a placebo in reducing premature ventricular complexes. Twelve patients who had a median of 294 such complexes/hour were admitted to the study. Eleven completed 4 weeks of trial with mexiletine and placebo with ambulatory electrocardiographic (Holter) recordings taken at the end of each treatment period. The doses given were designed to reduce the frequency of premature ventricular complexes by 50 percent or more from the baseline value. Mexiletine significantly reduced the rate of premature ventricular complexes by comparison with placebo (-66 percent versus 3 percent, p = 0.032). In addition, mexiletine reduced the median number/hour of ventricular couplets observed. After 4 weeks of therapy, 2, 2, 1 and 6 patients, respectively, were taking 100, 200, 300 and 400 mg of mexiletine every 8 hours. Mexiletine produced no significant change in baseline values including electrocardiographic intervals, blood pressure or heart rate. The most frequently observed adverse effects were digestive difficulties (eight patients taking mexiletine, four taking placebo) and central nervous system effects (seven taking mexiletine, five taking placebo). These data show the efficacy and safety of mexiletine in the treatment of premature ventricular complexes in a majority of patients.     

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.     

Comparative hemodynamic effects of intravenous nitroprusside and oral prazosin in refractory heart failure

Beneficial effects of vasodilator therapy in heart failure have been amply described. Afterload reduction with intravenous nitroprusside improves hemodynamic values in patients with left ventricular dysfunction. The oral vasodilator prazosin was given to 10 patients with refractory heart failure, and its hemodynamic effects were compared with those of intravenous nitroprusside in the same patients. With prazosin, heart rate remained unchanged, mean arterial pressure decreased 13 percent (P < 0.01), left ventricular filling and mean pulmonary arterial pressures decreased 31 and 24 percent, respectively (both P < 0.01) and cardiac index and left ventricular stroke work increased by 31 and 30 percent, respectively (both P < 0.01). Resistance levels in the systemic and pulmonary vascular beds declined by 29 and 27 percent, respectively (both P < 0.01). The hemodynamic changes appeared 1 hour after administration of a single dose of oral prazosin and persisted for 6 hours.Intravenous infusion of nitroprusside resulted in similar changes in heart rate and arterial pressure but greater reduction in left ventricular filling and mean pulmonary arterial pressures (P < 0.05). Left ventricular stroke work index increased more with nitroprusside (P < 0.01); however, changes in cardiac index and systemic and pulmonary vascular resistance levels were identical. Further, systolic pressure-heart rate product (index of myocardial oxygen demand) decreased significantly with oral prazosin as well as nitroprusside. These results suggest that prazosin has salutary effects on cardiovascular hemodynamics in heart failure, probably because of its vasodilator properties. These effects are qualitatively similar to those observed with intravenous infusion of nitroprusside. However, quantitatively, intravenous nitroprusside is slightly more potent.