Robert E. Goldstein

Thrombogenic Factors and Recurrent Coronary Events

BACKGROUND Thrombosis is a pivotal event in the pathogenesis of coronary disease. We hypothesized that the presence of blood factors that reflect enhanced thrombogenic activity would be associated with an increased risk of recurrent coronary events during long-term follow-up of patients who have recovered from myocardial infarction. METHODS AND RESULTS We prospectively enrolled 1045 patients 2 months after an index myocardial infarction. Baseline thrombogenic blood tests included 6 hemostatic variables (D-dimer, fibrinogen, factor VII, factor VIIa, von Willebrand factor, and plasminogen activator inhibitor-1), 7 lipid factors [cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, lipoprotein(a), apolipoprotein (apo)A-I, and apoB], and insulin. Patients were followed up for an average of 26 months, with the primary end point being coronary death or nonfatal myocardial infarction, whichever occurred first. The hemostatic, lipid, and insulin parameters were dichotomized into their top and the lower 3 risk quartiles and evaluated for entry into a Cox survivorship model. High levels of D-dimer (hazard ratio, 2.43; 95% CI, 1.49, 3.97) and apoB (hazard ratio, 1.82; 95% CI, 1.10, 3.00) and low levels of apoA-I (hazard ratio, 1.84; 95% CI, 1.10, 3.08) were independently associated with recurrent coronary events in the Cox model after adjustment for 6 relevant clinical covariates. CONCLUSIONS Our findings indicate that a procoagulant state, as reflected in elevated levels of D-dimer, and disordered lipid transport, as indicated by low apoA-1 and high apoB levels, contribute independently to recurrent coronary events in postinfarction patients.

Blood Fibrinolytic Activity in Man Diurnal Variation and the Response to Varying Intensities of Exercise

This investigation was undertaken in normal subjects to define the relationship between the intensity of exercise and magnitude of fibrinolytic response and to examine the effect of diurnal variations on the exercise response. Fibrinolytic activity was measured on fibrin plates and expressed as mm2. Diurnal variations occurred with lowest activity at 8:00 AM (mean, 66 mm2), and peak activity between 5:00 and 8:00 PM (mean, 266 mm2, P<0.001). Five minutes of maximal treadmill exercise caused a marked increase in mean activity from 90 to 658 mm2 (P<0.001). Five minutes of 70% maximal exercise produced no significant increase, but 30 minutes increased activity to 626 mm2 (P<0.005). In contrast, 30 minutes of 40% maximal exercise produced a small elevation from 80 to 173 mm2 (P<0.005). Maximal and 40% maximal exercise evoked greater responses at 4:00 PM than 8:00 AM. Exercise produces increases in fibrinolytic activity which are related to the relative intensity of exercise, its duration, and the time of day it is performed. Short bursts of intense exercise cause marked increases, but more prolonged bouts of moderate exercise are required to produce similar increases. The increases with prolonged mild exercise are small and comparable to those observed during resting diurnal variations.

Impairment of autonomically mediated heart rate control in patients with cardiac dysfunction.

Patients with cardiac disorders have defective parasympathetic control of heart rate. To evaluate the possibility of similar changes in sympathetic control of heart rate, we compared reflex chronotropic responses to 80° upright tilt and nitroglycerin-induced hypotension in 31 cardiac patients and 7 normal individuals before and after partial parasympathetic blockade with atropine. Tilting revealed an attenuation of the normal heart rate increase in patients; the magnitude of this defect was greatest in patients with more severe symptoms (class HI) and evidence of left ventricular dysfunction (the heart rate increase averaged 25 ± 3 beats/min in normal subjects, 12 ± 2 beats/min in class I-II patients, and 7 ± 1 beats/min in class HI patients). Class m symptoms due to mechanical causes (mitral stenosis), however, were not associated with this defect. A marked reduction in heart rate rise with hypotension was seen only in those class HI patients without mitral stenosis (0.4 ± 0.1 beats min−1 mm Hg−1 vs. 3.0 ± 0.5 beats min−lmm Hg−1 in normal subjects). This abnormality also persisted after atropine administration, thus confirming a defect in the sympathetic as well as the parasympathetic component of baroreceptor-mediated reflex heart rate control in patients with cardiac dysrunction. Infusions of isoproterenol produced equivalent rises in heart rate in patients and normal individuals, excluding a reduction in beta-receptor responsiveness as a cause of impaired sympathetic influence. Norepinephrine depletion, however, is a well-recognized concomitant of cardiac failure. It is possible that the reduction in sympathetically mediated heart rate responses results in part from depletion of the sympathetic neurotransmitter.

Beneficial Effects of Vagal Stimulation and Bradycardia During Experimental Acute Myocardial Ischemia

It is commonly believed that vagally-mediated bradycardia predisposes to ventricular fibrillation (VF) during acute myocardial ischemia. Recent experimental studies, however, have shown that bradycardia and vagal stimulation independently raise the threshold for electrically induced VF in the ischemic canine heart. To determine the influence of vagal stimulation on the spontaneous development of VF occurring during acute myocardial ischemia, open-chest dogs with acute coronary occlusion were observed with and without electrical vagal stimulation. When heart rate was allowed to fall, mean time to VF was 14.7 ± 2.1 min (SE) in the control dogs (heart rate about 180/min), 23.4 ± 1.9 (P < 0.01) in the dogs with low intensity vagal stimulation (heart rate about 100/min), and 28.6 ± 0.9 (P < 0.001) in dogs with high intensity vagal stimulation (heart rate about 60/min). Only 10% of the control animals survived after 30 min of occlusion compared with 40% (NS) of the dogs with low intensity vagal stimulation and 71% (P < 0.05) of the dogs with high intensity vagal stimulation. Thus, vagal stimulation and bradycardia were associated with a postponement or prevention of VF. In a second series of animals with heart rate maintained constant by right ventricular pacing, vagal stimulation continued to exert a protective effect against the development of VF. Time to VF was increased from 11.0 ± 2.0 min in control animals to 22.6 ± 2.5 in dogs with vagal stimulation (P < 0.005), and percent survival was enhanced (12% in control animals versus 57% in the vagally stimulated group, P < 0.02). Similar results were observed in a third series of dogs in which electrical stimulation was applied to the peripheral ends of the cut cervical vagi. We conclude that vagal stimulation, with or without accompanying bradycardia, reduces the incidence of spontaneous VF in experimental coronary occlusion. Thus, enhanced vagal tone might act to reduce, rather than increase, the risk of arrhythmic death occurring during acute myocardial ischemia in man.

Acute takeoffs of the coronary arteries along the aortic wall and congenital coronary ostial valve-like ridges: association with sudden death.

Congenital coronary artery anomalies have been associated with sudden death. Twenty-two patients who were victims of sudden death (mean age 46) and who had no significant anatomic cause of death were examined at autopsy and compared with 19 patients who died of known causes (control group). The hearts of these 41 patients were examined for abnormalities of acute angle takeoff of the coronary artery and presence of ostial valve-like ridges. Of the 22 patients who died suddenly, 13 (59%) had acute angle takeoff of the coronary artery and 9 (41%) had ostial valve-like ridges. Of the 19 control subjects, 4 (21%) had acute angle takeoff and only 2 (11%) had an ostial valve-like ridge. The difference was statistically significant (p = 0.015 and 0.031, respectively). It is suggested that aortic root dilation may compress coronary arteries with acute angle takeoff and that ostial valve-like ridges may act as occlusion valves. Thus, either may cause acute obstruction of the proximal coronary artery and lead to sudden death. A very lethal combination for sudden death would be the presence of severe coronary artery disease, an acute angle takeoff and an ostial valve-like ridge.

Clinical and Circulatory Effects of Isosorbide Dinitrate Comparison with Nitroglycerin

In order to resolve current controversies on isosorbide dinitrate (ISDN), we employed a particularly sensitive testing protocol to evaluate effects of sublingual ISDN and nitroglycerin on the exercise capacity of patients with angina. Ten minutes after ISDN 21 of 23 patients exercised longer (average 2.7 minutes, P < 0.001) than after placebo. Benefit was evident in only a minority of patients tested one hour and in none tested two hours after either ISDN or nitroglycerin. A given amount of exercise resulted in lower mean blood pressure (average 13 mm Hg, P < 0.001), higher heart rate (average 10 beats/min, P < 0.001), and shorter ejection time (average 0.04 second, P < 0.001) after ISDN. Similar changes were seen after nitroglycerin. The product of blood pressure, heart rate, and ejection time, an index of myocardial O2 consumption, was unchanged at angina after ISDN or nitroglycerin despite the increased exercise capacity, suggesting that clinical improvement after these drugs may be due to circulatory changes causing decreased myocardial O2 demand. We conclude that sublingual ISDN closely resembles nitroglycerin in its alteration of circulatory responses to exercise and in the duration of the resultant improvement in exercise capacity.

Sustained Effects of Nitroglycerin Ointment in Patients with Angina Pectoris

Cutaneous absorption of nitroglycerin is a well-documented phenomenon which may have unique advantages for the sustained prophylaxis of angina pectoris. Therefore, we have examined the effects of nitroglycerin ointment and placebo on exercise capacity in 14 patients with angina pectoris. Nitroglycerin ointment produced a significant increase in exercise capacity which persisted for at least three hours. Concomitant sustained changes in systolic blood pressure and resting heart rate were observed. Electrocardiographic evidence of myocardial ischemia was significantly reduced. Chronic administration in six patients did not reduce the effects of either nitroglycerin ointment or sublingual nitroglycerin. Nitroglycerin ointment appears to be a truly long-acting nitrate. While evidence of nitrate toxicity or tolerance was not observed in the present study, additional information is required before the widespread use of this agent can be recommended.

Impairment of cardiac function in patients with pectus excavatum, with improvement after operative correction.

Abstract Although pectus excavatum is thought to impair cardiac performance, no consistent hemodynamic abnormalities have been identified. We hypothesized that cardiac function might be impaired during upright exercise when the heart descends into the pectus deformity. Catheterization of the right side of the heart in six patients with pectus excavatum gave normal results, and the hemodynamic response to supine exercise was normal. In contrast, cardiac output (CO) during intense upright exercise was low in two patients, at the lower limits of normal in one, and low normal in two. The CO and stroke-volume responses to mild upright exercise also differed from normal. After operative repair in three patients, CO during intense upright exercise increased an average of 38 per cent, and hemodynamic responses to mild upright exercise also changed toward normal. No alterations occurred in the response to supine exercise. Thus, pectus excavatum can reduce the pumping capacity of the heart during upright exercise, ...

Coronary constriction by leukotriene C4, D4, and E4 in the intact pig heart.

Leukotrienes are naturally occurring vasoactive metabolites of arachidonic acid that increase during inflammatory reactions and anaphylaxis. Coronary constriction and reduced myocardial contractility after leukotriene C4 and D4 administration were demonstrated in the isolated guinea pig heart. To explore the effects of leukotrienes in the in situ, blood-perfused heart, we administered leukotrienes C4, D4, and E4 into the coronary artery of the domestic pig. Increasing doses (0.1, 0.3, 1.0, and 3.0 micrograms) of leukotrienes C4, D4, and E4 were injected into the left anterior descending coronary artery of 8 open-chest domestic pigs. Significant dose-related reduction in coronary blood flow was observed after each leukotriene administration. Three micrograms of each leukotriene produced the following maximal decreases (mean +/- standard error); C4 = 80 +/- 9%, p less than 0.001; D4 = 81 +/- 3%, p less than 0.001; E4 = 64 +/- 12%, p less than 0.005. In several instances, surface electrograms recorded from the myocardial region exposed to leukotrienes showed signs of focal myocardial ischemia, sometimes accompanied by ventricular arrhythmia. Significant elevation of left ventricular end-diastolic pressure was observed after large doses (1 or 3 micrograms) of leukotrienes C4 and D4. Minimal (5 to 10%) decreases in mean arterial pressure and no change in heart rate were observed after leukotriene injection. We conclude that leukotrienes C4, D4, and E4 are extremely potent coronary constrictors in the in situ heart. The intensity of response and associated electrocardiographic signs of ischemia suggest that constriction is mainly due to a primary effect on vascular smooth muscle. However, coronary flow reduction may also reflect consequences of a primary negative inotropic action. Leukotrienes may play a significant role in the pathogenesis of a variety of cardiac disorders, particularly those associated with extensive inflammatory changes.

Angina Pectoris: Pathophysiology, Evaluation, and Treatment

Abstract Accurate assessment of the effects and mechanisms of action of any intervention altering exercise performance of patients with angina pectoris caused by coronary artery disease requires us...