Platelet factor 4 release during exercise in patients with coronary artery disease

Many recent studies provide evidence that increased platelet activation occurs in a significant number of patients with atherosclerotic coronary artery disease. The mechanisms responsible for this activation are unknown, although there have been studies suggesting a correlation with abnormal lipoproteinemia, acute myocardial infarction, unstable angina, and exercise-induced myocardial ischemia. We studied 84 patients undergoing standardized treadmill exercise using either a Bruce [N = 63] or symptom-limited Naughton protocol [N = 21]. In contrast to ten healthy volunteer subjects, the patient group demonstrated a significant increase in plasma concentrations of platelet factor 4 [PF4] between pre- and postexercise blood samples confirming earlier reports of exercise-induced platelet activation and secretion. As with previous studies, however, only a subset of patients demonstrated this response. When the entire group was analyzed for the presence or absence of electrocardiographic ischemic changes and the presence of documented versus suspected coronary artery occlusions, there were no differences noted between groups that explained the variable responses measured. However, there was a significant difference between patient groups when analyzed by whether or not they were being treated with β-blocking agents. Patients who were being treated with propranolol or one of the longer-acting β-blocking agents did not have a significant increase in plasma PF4 following exercise, in contrast to patients who were not β-blocked. Plasma concentrations of epinephrine, norepinephrine, and lactic acid were measured in 49 patients and all normal subjects. There was no correlation between the changes in plasma PF4 concentrations and any of these three variables, suggesting that platelet activation was not occurring through direct platelet activation by circulating catecholamines. This study provides further evidence that there is a subset of CAD patients with platelet hyperactivity. This is the first time that β-blockade has been demonstrated to modify this platelet response. The effectiveness of β-blocking agents in CAD may be in part related to their antiplatelet effect.     

Heparin-releasable platelet factor 4 in patients with coronary artery disease.

Recently, platelet factor 4 (PF4) release by heparin (heparin-releasable PF4) has been examined as a useful marker of the interaction between the substances liberated from circulating platelets and the vascular endothelium. We compared the plasma levels of PF4 and beta-thromboglobulin (beta-TG) after intravenous heparin injection in patients with coronary artery disease (CAD) and normal control subjects. We also studied the effects of low-dose aspirin (81 mg/day) on the plasma level of heparin-releasable PF4 in the CAD patients. Blood samples were obtained before and 5 min after the intravenous injection of heparin (1,000 IU) from 23 patients with CAD and 15 normal control subjects. Although the plasma beta-TG level remained unchanged after heparin injection, the plasma PF4 level markedly increased in both groups. There was a significant difference in plasma PF4 levels at 5 min after heparin injection between the CAD group (100.1 +/- 38.1) and the control group (61.0 +/- 24.0) (p less than 0.01). The PF4/beta-TG ratio after heparin injection was also higher in the CAD group than in the control group (p less than 0.01). There was a correlation between the PF4/beta-TG ratio after heparin and the Gensini CAD score, which defines the severity of coronary atherosclerosis (r = 0.489, n = 23, p less than 0.01). Low-dose aspirin was administered to 11 CAD patients for 246.0 +/- 28.8 days. Blood samples for the assay of PF4 and beta-TG were obtained as stated above, and platelet aggregation, thromboxane B2 (TxB2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) levels were also measured before and during aspirin administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Platelet aggregability to platelet activating factor at rest and after exercise in patients with coronary artery disease

The platelet response to the aggregatory effect of platelet-activatingfactor (PAF) in relation to blood PAF levels, serum PAF-acetylhydrolase(PAF-AH) activity and to their lipidoemic profile, was studiedin 44 patients with coronary artery disease undergoing exercisetests. The PAF EC₅₀ values in 21 patients with positive exercisetest results were found to be significantly decreased at restcompared with 21 normal subjects (126±3•9 nM and24•9±11•7 nM respectively) (P<0•0001).Moreover, the maximal percentage of aggregation to 50 nM PAFwas found to be significantly increased (20•0±4•3%vs 13•5±3•6% respectively) (P<0•0001).By contrast, the PAF EC₅₀ values and the maximal percentageof aggregation in 23 patients with negative exercise test resultswere not statistically significantly different from the controlgroup (25•2±11•4 nM and 14•1±4•7%,respectively). At the end of exercise, the PAF EC₅₀ values and the maximalpercentage of aggregation did not change in any group, and therewere no significant differences in the whole-blood PAF levelseither at rest or at the end of exercise. In patients with positiveexercise test results, the PAF-AH activity at rest was significantlyhigher compared with the control group (37•2±8•0nmol. ml^–1. min^–1 vs 32•4±4•3 nmol.ml^–1. min^–1), (P<0•03), whereas the enzymeactivity did not differ in patients with negative exercise testresults compared to controls (33•6±6•1 nmol.ml^–1. min^–1). There was no change in PAF-AH activity during exercise in anygroup. The enzyme activity was positively correlated to theserum total and low density lipoprotein (LDL) cholesterol levelsin the control group and in patients with negative exercisetest results, whereas no correlation was found between PAF-AHactivity and total or LDL cholesterol levels in patients withpositive exercise test results. Our results suggest that platelethyper-reactivity to PAF may play a pathophysiological role inmyocardial ischaemia observed during exercise in coronary arterydisease patients.     

Beta thromboglobulin and platelet factor 4 in bronchoalveolar lavage fluid of patients with systemic sclerosis

OBJECTIVE: To evaluate concentrations of the platelet activation markers beta thromboglobulin (BTG) and platelet factor 4 (PF4) in bronchoalveolar lavage fluid (BALF) from patients with systemic sclerosis with and without scleroderma interstitial lung disease (SLD). METHODS: BTG and PF-4 were measured by enzyme immunoassay in BALF from 37 patients with systemic sclerosis. Controls were 10 healthy subjects. BALF was collected during routine bronchoscopy from the right middle lobe. SLD was diagnosed by high resolution computed tomography of the lungs. RESULTS: BTG was detected in 11 of the patients with systemic sclerosis (29.7%) and PF4 was found in eight (21.6%). Mean (SD) concentrations of BTG and PF4 in BALF from patients with detectable levels of these platelet activation markers were 106.9 (69.8) and 35.2 (17.4) IU/ml, respectively. The BTG:PF4 ratio was more than 2:1, indicating in vivo release. Both markers were found exclusively in patients with SLD. SLD patients with detectable platelet activation markers had a significantly shorter disease duration than those with undetectable BTG/PF4. CONCLUSIONS: The study provides evidence that activation of blood platelets takes place within the lungs of patients with SLD and may contribute to the development of lung fibrosis.     

Maximal cardiac output during exercise in patients with coronary artery disease

Cardiac output, determined by the direct Fick method, was measured each minute during multistage treadmill testing in which patients exercised to the point of exhaustion. Twenty-nine tests and 183 measurements of cardiac output during exercise were performed in 16 patients with coronary artery disease. Maximal cardiac output paralleled the maximal oxygen intake and was reflected by a plateau during the final minutes of exercise. Significant decreases in stroke volume and increases in mean pulmonary arterial pressure suggest that acute left ventricular dysfunction is the mechanism limiting the maximal cardiac output in these patients. Maximal cardiac output is a sensitive and fundamental indicator of the degree of impairment resulting from coronary disease, and has potential value in defining the role of various methods of treating this disease.     

Reversal of rest asynergy during exercise in patients with coronary artery disease

The diagnosis of ischemic heart disease by radionuclide ventriculography (RNV) is performed on the basis of an abnormal response of the left ventricular ejection fraction and the occurrence, or aggravation, of regional wall motion abnormality during exercise. However, the abnormal wall motion observed by RNV at rest is improved in some patients with coronary artery disease during exercise. We examined the clinical features of such patients who showed a paradoxical response of regional wall motion. The left ventricle was divided into 4 segments: anteroseptal, apical, inferior and posterolateral. The degree of wall motion of each segment was classified into 5 grades and scored according to a 5 point system: 4 = normokinesis, 3 = hypokinesis, 2 = severe hypokinesis, 1 = akinesis and 0 = dyskinesis. The wall motion score (WMS) was calculated as the sum of each segment score. If the WMS increased by 2 points or more during exercise, the case was defined as having shown significant improvement of wall motion. Improvement in WMS was found in 26 (12%) of 209 serial patients who underwent exercise RNV, exercise thallium myocardial scintigraphy and coronary angiography. Clinically, half of these patients had a variant form of angina pectoris. With respect to coronary lesions in the segments with reversible asynergy, 12 patients had 0 vessel disease, 8 had lesions with stenosis of less than 75% and 3 showed an adequate collateral circulation. Redistribution found on the exercise thallium myocardial scintigram at the same sites of improved wall motion was identified in only 1 patient. An analysis of patients with paradoxical improvement of wall motion during exercise suggests the involvement of coronary spasm, an improvement of coronary flow reserve, such as could be produced by regression or recanalization of the main lesions, or establishment of significant collateral circulation.     

Serial pulmonary blood volume changes with supine exercise in normal subjects and in coronary artery disease patients

Relative changes in pulmonary blood volume (PBV) were assessedserially at first stage, peak and post-supine exercise in 13young normal volunteers and 33 coronary artery disease (CAD)patients.Gatedblood pool imaging was used with time correced count calculationof a region over the lung and comparison to he rest image. Innormal subjects, the PBV ratio did not change with exercisebut dropped significally immediately post-exercise. In CAD patients,the PBV ratio increased in the first exercise stage, increasedfurther at peak exercise, and fell significantly following exercisecessation. In the three stages studied, significantly higherPBV ratios were demonstrated in the CAD patients compared tonormal subjects, but with significant overlap between he twogroups. No significant relation was found between PBV changesand the number of diseased vessels, severity score (Gensini),left ventricular end-diastolic pressure, exercise-limiting symptoms,andleft and right ventricular ejection fraction at rest and withexercise. Despite the different response of the PBV ratio toexercise between normals and CAD patients, a significant overlaplimits the value of this ratio as a discriminator of the presence,severity or location of CAD.     

Prevention of coronary vasoconstriction by diltiazem during dynamic exercise in patients with coronary artery disease

Whether exercise-induced vasoconstriction of coronary artery stenoses is modified by the administration of calcium antagonists was examined in 14 patients with classic angina pectoris. In this group the effect of intracoronary diltiazem (2 to 3 mg) on luminal area was evaluated in normal and stenotic segments of epicardial coronary arteries during symptom-limited supine exercise. The luminal area of a normal and a stenotic coronary artery segment was determined by quantitative coronary arteriography with a computer-assisted system. Patients were studied at rest, 6 min after 2 to 3 mg of intracoronary diltiazem, during supine bicycle exercise (96 W) and 5 min after sublingual administration of 1.6 mg nitroglycerin. Heart rate, mean pulmonary and aortic pressure as well as the percent change of both normal and stenotic luminal area were determined. Intracoronary administration of diltiazem was associated with mild dilation of both normal (19%, p less than 0.01) and stenotic coronary luminal area (11%, p less than 0.05). During subsequent exercise, luminal area of the stenotic vessel segment increased by 23% (p less than 0.001) and that of the normal vessel segment by 24% (p less than 0.001), whereas in a previously reported control group, luminal area of the stenotic vessel segment decreased by 29% during exercise. After sublingual administration of nitroglycerin, the luminal area of both the normal and the stenotic vessel segment increased further by 19% (p less than 0.01) and 22% (p less than 0.01), respectively, compared with the values after intracoronary administration of diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical significance of cerebral oxygenation during exercise in patients with coronary artery disease

BACKGROUND: Recent investigations have demonstrated that cerebral oxyhemoglobin (O(2)Hb) decreases during exercise in patients with left ventricular dysfunction, reflecting a cerebral hypoxia. We sought to establish a prognostic value of decreased cerebral O(2)Hb during exercise in cardiac patients, and to compare it with those of indexes obtained from cardiopulmonary exercise testing (CPX). METHODS AND RESULTS: A total of 344 consecutive patients with coronary artery disease were enrolled in the study. All the patients performed CPX, during which cerebral O(2)Hb was continuously monitored using near-infrared spectroscopy. There were 13 cardiac deaths and 78 cardiovascular events during the prospective follow-up period of 1,231+/-538 days. The change of O(2)Hb measured at the forehead from rest to peak exercise (DeltaO(2)Hb) was significantly lower in non-survivors than in survivors (-1.5+/-3.3 vs 1.7+/-3.2 micromol/L, p=0.0004). By multivariate Cox proportional hazards analysis, DeltaO(2)Hb and left ventricular ejection fraction (LVEF) were found to be independent prognostic markers for cardiac deaths. The DeltaO(2)Hb, LVEF and peak oxygen uptake were found to be significant prognostic markers for cardiovascular events, mainly for heart failure worsening and sudden cardiac death. CONCLUSION: The present findings suggest that a decrease in cerebral O(2)Hb during exercise predicts future cardiovascular events in patients with coronary artery disease.     

Variations in lymphocyte activation during exercise testing in patients with coronary artery disease

BACKGROUND: Several studies have shown that strenuous exercise induces changes in the immune system. Soluble interleukin-2 receptor (sIL-2R) is a marker of immune system activation and is known to increase in association with cardiac disease. The aim of the present study was to assess sIL-2R levels in patients with coronary artery disease (CAD) in conjunction with exercise testing. METHODS: Blood levels of sIL-2R were determined in 10 healthy control individuals and 21 patients with CAD before exercising, at maximal exercise testing (Bruce) and at 0.5 h and 3-4 h after exercise (T1-T4). The study group had stable angina and normal or near-normal left ventricular function. Patients at risk of abnormal cytokine levels were excluded. RESULTS: The patients were divided into two groups: those with mild to moderate ischemia (according to a thallium scan) (n = 14, group 1a) and those with severe exercise-induced ischemia (n = 7, group 1b). The prevalence of anginal pain at exercise and mean ST depression were similar in both groups, however, signs of left ventricular dysfunction during exercise were significantly more frequent in group 1b. Mean sIL-2R levels (units per ml) showed no significant difference between group 1a and the control group at all time points (503 +/- 122, 518 +/- 140, 489 +/- 164, 461 +/- 131 mu/ml compared with 505 +/- 135, 509 +/- 112, 469 +/- 126, 416 +/- 103 mu/ml, respectively, P = NS), while a significant increase in group 1b compared with the control group was found at 0.5-h after exercise (T3) (1147 +/- 510 mu/ml, P = 0.03). DISCUSSION: This study demonstrated immunological involvement in some patients with severe exercise-induced ischemia shortly after exercise, suggesting an association with heart failure.     

Diastolic pressure-volume relationship during handgrip exercise in patients with coronary artery disease.

There is some controversy regarding the mechanisms of an upward shift in the left ventricular diastolic pressure-volume curve during ischemia. The effects of handgrip exercise on the pressure-volume curve were examined in 21 patients with coronary artery disease and in 6 control subjects. Pressure-volume curves were constructed from digitized left ventricular pressure and volume derived from biplane left ventriculogram. Diastolic pressure-volume curve shifted upward in 12 patients with coronary artery disease during handgrip exercise (Group 1), but not in the other 9 patients who were similarly afflicted (Group 2). The upward shift did not occur in any control subject. No difference was observed in rate-pressure product gain during exercise. In Group 1, left ventricular end-diastolic pressure increased (p less than 0.01) and ejection fraction was reduced (p less than 0.01), although it did not change in Group 2. In Group 1, the time constant was prolonged (p less than 0.01) with no change in the coefficient for elastic modulus. In Group 2, these parameters remained unchanged. Group 1 was accompanied by more extensive asynergy than Group 2. Thus, isometric handgrip exercise resulted in an upward shift in the diastolic pressure-volume curve in patients with coronary artery disease. Incomplete relaxation and/or the viscoelastic properties of the left ventricle associated with ischemia could be responsible for this phenomenon.     

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.     

Acute haemodynamic effects of felodipine during beta blockade in patients with coronary artery disease

The acute effects of felodipine on left ventricular function and haemodynamics were studied in 11 patients with coronary artery disease. To block reflex sympathetic activation due to peripheral vasodilatation and to avoid effects secondary to changes in heart rate all patients received a standard regimen of beta adrenoceptor blockade and all measurements were made during sinus rhythm and right atrial pacing. At 30 minutes after an oral dose (0.075 mg/kg in solution) felodipine plasma concentration were 16.4 (3.5) nmol/l. A significant fall in systemic vascular resistance (30%) and increase in cardiac index (30%) occurred, whereas pulmonary vascular resistance was unchanged. Felodipine increased left ventricular ejection fraction and mean velocity of circumferential fibre shortening but had no effect on derivates of left ventricular pressure (dP/dt or dP/dt P-1) during sinus rhythm or pacing. Thus at the dosage used felodipine was a potent dilator of systemic arterioles but had no direct effect on left ventricular function.