Thrombin Generation and Activity During Coronary Angioplasty: Influence of Angiographic Lesion Morphology.

OBJECTIVE: To investigate the relationships between coronary atherosclerotic plaque injury, lesion morphology, and activation of the coagulation cascade. BACKGROUND: Balloon angioplasty of coronary lesions may result in intracoronary thrombin generation and activity. It is unknown whether the angiographic morphology of the lesion prior to intervention, an indicator of the presence of thrombus in the lesion, is a determinant of the degree of coagulation cascade activation. METHODS AND RESULTS: Biochemical markers of thrombin generation (prothrombin fragment F1+2) and thrombin activity (fibrinopeptide A; FPA) were measured in coronary blood before, 1 and 10 minutes after percutaneous transluminal coronary angioplasty (PTCA) in 24 patients with an angiographically complex lesion morphology and 24 patients with an angiographically simple lesion morphology. Using previously defined criteria, 18 of the 48 patients (38%) demonstrated a significant rise in coronary plasma F1+2; 8 of these 18 (44%) had simple and 10 of 18 (55%) had complex angiographic lesion morphologies (p=NS). With respect to thrombin activity, 15 of the 48 patients (31%) demonstrated a significant rise in coronary plasma FPA; 7 of these 15 patients (47%) had a simple lesion morphology and 8 (53%) had a complex morphology (p=NS). When analyzed as a group, patients with complex lesion morphologies demonstrated a small elevation in coronary plasma levels of FPA 10 minutes post-PTCA (median 3.2 ng/ml, 95% CI 2.4Ð5.8 ng/ml) in comparison to the levels measured proximal to the lesion pre-PTCA (median 2.1 ng/ml, 95% CI 1.6Ð3.5 ng/ml; p=0.05). In contrast, in the group of patients with simple lesion morphologies, the plasma FPA levels proximal to the lesion pre-PTCA (median 2.1 ng/ml, 95% CI 1.5 to 3.9 ng/ml) were similar to those measured 10 minutes after the procedure (median 2.0 ng/ml, 95% CI 1.5 to 6.3 ng/ml; p=NS). CONCLUSIONS: In comparison to patients with angiographically complex lesions, patients with angiographically simple lesions demonstrate a similar incidence (~33%) of elevated coronary plasma thrombin generation (F1+2) and activity (FPA) after PTCA. As a group, patients with angiographically complex lesions (irregular borders, overhanging edges, filling defects) demonstrate a slightly greater increase in thrombin activity in comparison to patients with simple lesion morphologies. Percutaneous coronary interventions of lesions with a wide variety of angiographic morphologies are prone to result in activation of the coagulation cascade.

Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise.

BACKGROUND: Carvedilol has improved the symptomatic status of patients with moderate to severe heart failure in single-center studies, but its clinical effects have not been evaluated in large, multicenter trials. METHODS AND RESULTS: We enrolled 278 patients with moderate to severe heart failure (6-minute walk distance, 150 to 450 m) and a left ventricular ejection fraction < or = 0.35 at 31 centers. After an open-label, run-in period, each patient was randomly assigned (double-blind) to either placebo (n = 145) or carvedilol (n = 133; target dose, 25 to 50 mg BID) for 6 months, while background therapy with digoxin, diuretics, and an ACE inhibitor remained constant. Compared with placebo, patients in the carvedilol group had a greater frequency of symptomatic improvement and lower risk of clinical deterioration, as evaluated by changes in the NYHA functional class (P = .014) or by a global assessment of progress judged either by the patient (P = .002) or by the physician (P < .001). In addition, treatment with carvedilol was associated with a significant increase in ejection fraction (P < .001) and a significant decrease in the combined risk of morbidity and mortality (P = .029). In contrast, carvedilol therapy had little effect on indirect measures of patient benefit, including changes in exercise tolerance or quality-of-life scores. The effects of the drug were similar in patients with ischemic heart disease or idiopathic dilated cardiomyopathy as the cause of heart failure. CONCLUSIONS: These findings indicate that, in addition to its favorable effects on survival, carvedilol produces important clinical benefits in patients with moderate to severe heart failure treated with digoxin, diuretics, and an ACE inhibitor.

Dose-response of chronic beta-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy. Bucindolol Investigators.

BACKGROUND: Small-scale clinical investigations have demonstrated that single doses of beta-blocking agents can improve left ventricular function in heart failure from idiopathic dilated cardiomyopathy (IDC). The purpose of this multicenter clinical trial was to determine the dose-effect characteristics of beta-blockade in a heart failure population that includes ischemic dilated cardiomyopathy (ISCD). METHODS AND RESULTS: Bucindolol is a nonselective beta-blocking agent with mild vasodilatory properties. One hundred forty-one subjects with class II or III heart failure, left ventricular ejection fraction (LVEF) < or = 0.40, and background therapy of angiotensin-converting enzyme inhibitors, digoxin, and diuretics were given an initial challenge dose of bucindolol 12.5 mg. One hundred thirty-nine subjects (99 with IDC, 40 with ISCDC) tolerated challenge and were randomized to treatment with placebo or bucindolol 12.5 mg/d (low dose), 50 mg/d (medium dose), or 200 mg/d (high dose). At the end of 12 weeks, left ventricular function and other parameters were measured and compared with baseline values. There was a dose-related improvement in left ventricular function in bucindolol-treated subjects. In the high-dose bucindolol group, radionuclide-measured LVEF improved by 7.8 EF units (%) compared with 1.8 units in the placebo group (P < .05), and compared with the placebo group, a greater percentage of subjects had an increase in LVEF by > or = 5 units. In contrast, all three bucindolol doses prevented deterioration of myocardial function as defined by an LVEF decline of > or = 5 units. CONCLUSIONS: In heart failure from systolic dysfunction, beta-blockade with bucindolol produces a dose-related improvement in and prevents deterioration of left ventricular function.

Neutrophil-endothelial cell interaction in critical illness.

Sepsis syndrome frequently results in endothelial injury in many organ systems. To evaluate neutrophil-pulmonary endothelial cell interaction in the sepsis syndrome, we studied 39 critically ill patients prospectively and 20 normal volunteers. Thirteen patients with sepsis (mean age, 71.4 years), 14 patients in an intensive care unit control group (mean age 65.4 years), and 12 patients admitted with acute myocardial infarction (mean age, 66.8 years) were evaluated. Blood samples were drawn from septic patients within 24 hours and from ICU and MI patients within 72 hours of admission. All sepsis patients were culture positive, 6 of 13 from the blood. Both renal failure and ARDS developed in 54 percent of septic patients. 51Cr-labelled neutrophils were prepared and added to bovine pulmonary endothelial cell monolayers with and without added phorbol myristate acetate. Endothelial cells with adherent PMA and nonadherent PMN's, were harvested and radioactivity in each fraction measured with a gamma scintillation counter. Baseline and maximally stimulated (PMA, 3.0 ng/ml) neutrophil adherence to endothelial cells were similar in all patients groups. However, in septic patients, PMA-stimulated PMN adherence was reduced at lower doses, most significantly in those who developed ARDS within 24 to 48 hours of admission (p less than 0.05). Seventy-one percent of patients who developed ARDS had reduced stimulated adherence (PMA 1.0 ng/ml) compared to 22 percent of critically ill patients who did not. We conclude that diminished adherence of neutrophils to endothelium in response to low-level PMA stimulation is significantly more common in patients with sepsis who develop ARDS. Our findings suggest that PMN-endothelial cell interaction is altered by the time sepsis is clinically recognized but before the development of ARDS. We speculate that the observed reduction in adherence of the PMN to endothelial cells may be a consequence of down-regulation by mediators generated in the inflammatory response to sepsis and/or the need for active participation of septic endothelium in this interaction.

Histamine mediates myocardial damage by an H1 mechanism independent of coronary blood flow.

Administration of histamine to rabbits may result in myocardial damage similar to that produced by catecholamines and the anthracycline antibiotics. To explore the mechanisms involved in histamine-mediated myocardial damage, conscious New Zealand white rabbits were pretreated with H1 and H2 receptor blocking agents, alone and in combination, and then administered histamine. Coronary artery blood flow was measured with radiolabeled microspheres in rabbits that received histamine alone, and in those that received an H1 blocking agent and histamine. Rabbits that received an H1 blocking agent had a significant reduction in morphological injury which was scored as follows: grade 1, minimal or no injury; grade 2, moderate; and grade 3, severe injury (mean pathology score = 1.1 +/- 0.28 for histamine alone vs. 0.06 +/- 0.06 with H1 receptor blockade, p less than 0.05). Animals pretreated with H2 receptor blockade (mean pathology score = 1.2 +/- 0.49) were not protected against morphological injury. Coronary blood flow decreased in animals that received histamine alone: control = 2.61 +/- 0.38 vs. 1.80 +/- 0.30 ml/min/g (p less than 0.05), and in animals pretreated with H1 blockade; control = 3.29 +/- 0.34 vs. 1.91 +/- 0.28 ml/min/g (p less than 0.01). We conclude that histamine-mediated myocardial damage appears to be mediated by the H1 receptor system and that this appears to be independent of initial changes in global coronary blood flow.

Effects of intravenous metoprolol on global and regional left ventricular function after coronary arterial reperfusion in acute myocardial infarction.

Coronary reperfusion in myocardial infarction improves infarct zone motion, but its effect on the global ejection fraction has been less consistent. The directional movement of the ejection fraction is determined by the opposing influences of improved infarct zone motion and diminishing hyperkinesia in the noninfarct zone. Noninfarct zone hyperkinesia has been attributed to catecholamine stimulation, the Frank-Starling mechanism or intraventricular interactions that unload noninfarcted segments. To investigate the influence of catecholamine stimulation, 9 men presenting with a first myocardial infarction (mean age 53 +/- 13 years) were studied. Coronary reperfusion was accomplished less than 4 hours after the onset of myocardial infarction. Radionuclide ventriculography was then performed before and immediately after the intravenous administration of 15 mg of metoprolol. End-diastolic volume did not change, but end-systolic volume increased 28% after metoprolol (p = 0.041). The ejection fraction decreased from 55 +/- 13% before metoprolol to 45 +/- 14% after its administration (p = 0.002). There was no effect of intravenous metoprolol on infarct zone motion, whereas motion in the noninfarcted segment decreased (p = 0.002). The patients underwent repeat ventriculography after receiving metoprolol, 100 mg orally twice a day for 9 days. Infarct zone motion improved (p less than 0.002) and the ejection fraction increased to 55 +/- 12% (p less than 0.02). Normal zone motion did not change. Thus, compensatory hyperkinesia is at least in part caused by catecholamine stimulation. Conclusions regarding the effects of reperfusion on global ventricular performance can be influenced by the timing of ejection fraction determinations relative to metoprolol therapy.

A new method for assessing right-sided heart pressures using encapsulated microbubbles--a preliminary report.

A new noncatheter method for measuring pressures of the right side of the heart uses specially manufactured microbubbles of carbon dioxide injected into the peripheral venous system. Sudden expansion of these bubbles in the cardiac chambers causes bubble oscillations at a frequency that is primarily a function of surrounding pressure. The oscillations are recordable by a microphone on the chest wall. The preliminary experience has been in dogs and further development is needed before we can begin clinical testing of the method. In its current form, the potential for measuring higher systolic pressures seems better than that for lower diastolic pressures.

Beta-adrenergic function in heart muscle disease and heart failure.

Using data derived from clinical and experimental observations, we examine the role of the myocardial beta-adrenergic receptor system in pathophysiologic processes involved in heart muscle disease and heart failure. The available data suggest that the sympathetic nervous system exerts important influences on myocardial structure and function. As such the beta-adrenergic pathways represents an obvious locus for therapeutic intervention in evolving cardiomyopathic states.

Mediation of subacute anthracycline cardiotoxicity in rabbits by cardiac histamine release.

We tested the hypothesis that cardiac histamine release mediates subacute doxorubicin (DXR) cardiotoxicity in rabbits. New Zealand white rabbits given DXR 20 mg/kg i.v. over 30 min developed myocardial damage 24 h later that was similar to that observed in humans. In isolated heart preparations, DXR produced dose-related cardiac histamine release at DXR concentrations of 1, 5, and 25 micrograms/ml given as 1-min exposures. Prior exposure of isolated hearts to 10 microM cromolyn sodium completely prevented histamine release from 5 micrograms/ml DXR. Pretreatment of animals with cromolyn produced significant protection against DXR-mediated subacute cardiotoxicity. We conclude that the release of cardiac histamine may be involved in the pathogenesis of anthracycline cardiotoxicity.

Rapid, semiautomated technique for estimating left ventricular volume.

A new system for rapidly quantitating left ventricular volume using two-dimensional echocardiography is tested. This system relies on a microprocessor built into a sector scanner that immediately calculates the length, area, and volume of the chamber being imaged using the mathematical model of an ellipsoid of revolution. The calculations are made after the observer superimposes a smooth calibrated ellipse outline on the endocardium imaged with the sector scanner. We report our experience with this system in 50 patients with a variety of cardiac disorders and compare the left ventricular volumes measured with those obtained using cineangiography, M-mode, and more detailed light pen tracing techniques. Correlations between volumes measured with the elliptical calipers and angiography were good (r = 0.820, SEE +/- 38.8 ml) (n = 100), but not as good as that between light pen tracing of the echo images and angiography (r = 0.847, SEE +/- 27.8 ml) (n = 22). M-mode correlated less well with angiography (r = 0.789; SEE +/- 42.1 ml) (n = 90). We conclude that the calibrated ellipse system is rapid and simple to use, while its accuracy matches previous studies using two-dimensional echocardiography to quantitate left ventricular volume.

Coronary spasm associated with urticaria: report of a case mimicking anaphylaxis.

Recent investigations suggest that the vasoactive substances, histamine, prostaglandin E2, and thromboxane A2 are mediators of coronary artery spasm. These substances may be released during a episode of urticaria. We report here a case of coronary artery spasm associated with an episode of acute urticaria. The coronary spasm may have been mediated by the vasoactive substances released from basophils and secondary platelet aggregation, known to occur with urticaria.

Histamine provocation of clinical coronary artery spasm: implications concerning pathogenesis of variant angina pectoris.

Twelve patients with nonexertional chest pain and nonobstructive fixed coronary disease (less than 50% luminal diameter narrowing) were given histamine to investigate the potential role (coronary artery H1 receptor agonism) of the endogenous agent in producing coronary artery spasm (CAS). Histamine, at intravenous dose of 0.5 to 1.0 microgram/kg/min, provoked CAS in four patients. In six patients neither histamine nor ergonovine provoked spasm, and these patients were considered by chronic follow-up evaluation to have noncardiac etiology for their chest pain syndrome. In one patient CAS was provoked with ergonovine but not by histamine, and one ergonovine-positive patient had an equivocally positive histamine result. Pretreatment with cimetidine (H2 receptor antagonism) was necessary to avoid unpleasant side effects of histamine. Thus these observations indicate that histamine should be included among the specific agents capable of inducing CAS and provide new insight concerning the mechanism(s) causing variant angina pectoris.