C-reactive protein contributes to the hypercoagulable state in coronary artery disease.

OBJECTIVES: Elevated plasma C-reactive protein (CRP) levels predict coronary events, but it is unclear whether CRP plays a role in thrombosis associated with these events. We investigated tissue factor (TF) induction by CRP on peripheral blood mononuclear cells (PBMC) from patients with coronary disease. PATIENTS AND METHODS: PBMC from 35 patients with stable angina (SA) in study 1, 10 male patients with SA, 10 with unstable angina (UA) and 10 matched controls in study 2, and 25 patients with inflammatory disorders (ID) and 24 normal controls in study 3 were stimulated with CRP, interferon-gamma (IFN) or lipopolysaccharide (LPS), or their combination. PBMC from additional normal donors were also stimulated with CRP in adherent and non-adherent conditions, and TF activity, antigen and mRNA expression detected. RESULTS: CRP (5-25 microg mL(-1)) dose dependently induced more TF on PBMC from SA patients than 42 contemporary controls (P = 0.001, study 1). Compared with controls, patients with SA or UA had higher basal, and much higher CRP- or CRP/LPS-induced monocyte TF activity although serum CRP levels were similar (study 2). IFN induced monocyte TF activity in patients with angina, but not in controls. Basal or CRP-induced TF levels did not differ between controls and ID, even though ID patients had much higher serum CRP levels (study 3). CRP-induced monocyte TF activity correlated with serum CRP levels in controls (P = 0.005) and ID (P = 0.007) in study 3, but not in patients with angina (P =0.84) in study 2. CRP induced more TF activity, protein and mRNA under adherent than non-adherent conditions implying that it may mainly target macrophages in lymphocyte-rich lesions. CONCLUSIONS: Our results indicate that monocytes from patients with angina are preactivated and express TF but CRP is unlikely to be a major priming factor in vivo. IFN and CRP further increase TF levels that may contribute to the hypercoagulable state in coronary disease.

Interferon-gamma and lipopolysaccharide potentiate monocyte tissue factor induction by C-reactive protein: relationship with age, sex, and hormone replacement treatment.

BACKGROUND: Elevated plasma levels of C-reactive protein (CRP) in population studies and in patients with unstable coronary syndromes are predictive of future adverse events, including cardiac death and myocardial infarction, implicating inflammation in pathogenesis. Although CRP is considered a marker of inflammation, it induces monocyte tissue factor (TF) and may play a prothrombotic role in atherosclerosis and its complications. METHODS AND RESULTS: Peripheral blood mononuclear cells (PBMCs) from 79 healthy men and women aged 26 to 83 years and 21 healthy postmenopausal women taking hormone replacement therapy (HRT) were stimulated with CRP, lipopolysaccharide (LPS), interferon-gamma (IFN), or their combination. Levels of CRP in the normal range (1 to 5 microg/mL) increased basal monocyte TF 4- to 6-fold and 40-fold at higher concentrations (25 microg/mL). Coincubation of LPS with CRP produced a greater-than-additive response. IFN did not induce TF but synergized with CRP to approximately double activity. There was a striking positive correlation between age and monocyte TF induction, with a dramatic rise on monocytes from postmenopausal women that was not apparent on cells from women taking HRT. CONCLUSIONS: Synergy between CRP and inflammatory mediators may play a direct prothrombotic role in the pathogenesis of coronary atherosclerosis and its acute complications by increasing monocyte/macrophage TF. This may contribute to age and sex differences in coronary events and to the protective effects of HRT.

Vascular risk factors correlate to the extent as well as the severity of coronary atherosclerosis.

BACKGROUND: Because most acute coronary events result from thrombosis at sites of minor plaque, the extent of non-obstructive coronary artery disease (CAD), rather than simply the number of severe stenoses, might be clinically relevant. OBJECTIVE: To examine the relationship between vascular risk factors and a novel extent score for CAD that measures the percentage of the coronary tree involved with atheromatous plaque, as judged by coronary angiography. METHODS: We assessed the extent and severity of CAD and the presence of vascular risk factors of 429 consecutive eligible patients (296 men, aged 61 +/- 11 years) who presented for elective coronary angiography. Detailed analyses of lipid levels were performed for 126 subjects. RESULTS: The mean extent score was 54 (range 0-100). The presence of diabetes (P < 0.001), current or former smoking (P < 0.005) and a history of hypertension (P < 0.001) were all strongly associated with the CAD extent score, as was severity of disease. For the 283 patients with one or no severe stenosis, diabetes was associated with a greater extent score (57 versus 41%, P < 0.005), as was smoking (49 versus 34%, P < 0.005). For the 126 patients with detailed data on lipid levels, extent of coronary artery disease was independently correlated to age (P < 0.005), male sex (P < 0.05), presence of diabetes (P < 0.05), hypertension (P < 0.05), level of lipoprotein (a) (P < 0.005) and low-density:high-density lipoprotein ratio (P < 0.01) in multivariable analysis. CONCLUSIONS: Extent of CAD, as well as its severity, is significantly associated with traditional vascular risk factors. Because most acute coronary events occur at sites of minor plaque, this might explain the mechanism whereby risk factors confer adverse prognostic significance.

Angiographic severity of coronary narrowing is a surrogate marker for the extent of coronary atherosclerosis.

Most acute coronary events occur because of narrowings at sites of angiographically minor plaque. Despite this, angiograms are reported in terms of the number of coronary arteries with severe narrowings. Disease severity is correlated with prognosis, but this may simply be due to a strong positive correlation between the severity and extent of coronary atheroma. We therefore aimed to assess the relation between the severity and the extent of coronary atherosclerosis. Coronary angiograms of 350 consecutive patients referred for elective cardiac catheterization were analyzed. Two independent observers calculated the number of arteries with > or = 70% stenosis, a disease severity score, and an extent score (percentage of the coronary artery length with any luminal irregularity). There were no obstructive stenoses in 123 patients (35%); 91 (26%) had 1-vessel disease, 81 (23%) had 2-vessel disease, and 55 (16%) had 3-vessel coronary artery disease. The median severity score was 1 (lower, upper quartile 0, 3; range 0 to 8), and the median extent score was 66% (lower, upper quartile 32, 83; range 0% to 100%). There was a strong linear relation between severity score and extent score (r = 0.62, p < 0.001); however, the data were better described by 2 intersecting straight lines, with a steeper increase in disease severity when the extent score was between 80% and 90% (F1;121 = 6.9, p = 0.001). The severity of coronary disease is therefore significantly correlated with disease extent. This may explain the observed relation between the number of arteries with obstructive stenoses and subsequent risk, even though most events occur at sites of minor plaque.

Carotid intima-media thickness is only weakly correlated with the extent and severity of coronary artery disease.

BACKGROUND: Intima-media thickness (IMT) of the common carotid artery (CCA), measured with external vascular ultrasound, has been widely used in clinical trials as a surrogate marker for coronary atherosclerosis. Despite this, the degree of correlation between carotid IMT and the extent and severity of coronary artery disease (CAD) is not known. METHODS AND RESULTS: Common carotid IMT was measured by ultrasound in 350 consecutive subjects of age 60 +/- 10 years (range, 30 to 85 years) on the day of coronary angiography. Carotid mean IMT was 0.83 +/- 0.20 mm (range, 0.43 to 1.80 mm), and maximum IMT was 1.04 +/- 0.27 mm (range, 0.49 to 2.19 mm). Coronary angiograms were analyzed by independent observers for disease severity (number of vessels with > or = 70% stenosis), extent score, and a modified Gensini score. Mean carotid IMT was weakly but significantly correlated with CAD severity (r = .26), extent (r = .23), and modified Gensini score (r = .29, P < .0001 for all correlations). Carotid IMT was not clinically useful, however, because it was not specific or sensitive enough to identify patients with or without significant CAD. Increasing age, male sex, and presence of diabetes were all associated with a significantly (P < .01) higher CAD score than the average for any level of carotid IMT, suggesting differential effects of these traditional risk factors on the coronary and common carotid arteries. CONCLUSIONS: Although carotid IMT is significantly correlated with extent and severity of CAD, the relationship is weak. This relatively poor correlation (r2 < .10) should be considered in the interpretation of clinical trials that use carotid IMT as a surrogate end point for coronary atherosclerosis.

Altered electrical and metabolic response of reperfused myocardium to ischaemia after recovery from preceding ischaemia: evidence for ischaemia sensitised myocardium.

OBJECTIVE: The aim was to examine electrical and metabolic responses of myocardium to ischaemia after recovery from preceding ischaemia. METHODS: In 23 open chest dogs (5 min occlusion group), the left anterior descending coronary artery was occluded three times in the following order: 2 min occlusion (Trial 1) followed by 15 min reperfusion; then 5 min occlusion followed by 90 min reperfusion and 2 min occlusion (Trial 2). In 15 control dogs, the 2 min occlusion was performed twice at a 110 min reperfusion interval; the former occlusion was also referred to as Trial 1 and the latter as Trial 2. The dogs were monitored by epicardial surface ECG, while regional myocardial function was estimated by sonomicrometry. Continuous measurements of myocardial tissue PCO2, pH, and extracellular K+ concentration were made concurrently. RESULTS: Both trial occlusions produced a biphasic change in R wave amplitude characterised by a transient initial decrease succeeded by an increase with ST elevation. This biphasic change in R wave amplitude was indistinguishable between Trial 1 and Trial 2 in the control group. By contrast, in the 5 min group, the R wave amplitude initially decreased to a greater degree in Trial 2 than in Trial 1. More rapid contractile failure was also noticed in Trial 2, suggesting the possible involvement of mechanically induced electrical changes in the genesis of decreased R wave amplitude. After 45-60 s of occlusion, however, the R wave amplitude increased to a level much beyond the initial amplitude in Trial 1 [124.9(SEM 8.4)% at 120 s], whereas this level of increase was not observed in Trial 2 [106.5(7.8)%, p < 0.05 v Trial 1]. There was also reduced elevation of the ST segment in Trial 2: 3.6(0.8) mV v 6.5(0.8) mV in Trial 1 at 120 s (p < 0.05). This reduction in ST elevation was concomitant with decreased changes in PCO2, pH, and extracellular K+ concentration in Trial 2. These reduced changes in the ST segment and the metabolic variables were absent in the control group. CONCLUSIONS: These altered electrical responses of the myocardium may be the result of more rapid early contractile failure and attenuated metabolic changes during ischaemia occurring after recovery from preceding ischaemia.

Augmented contractile response to endothelin and blunted endothelium-dependent relaxation in post-ischemic reperfused coronary arteries.

To elucidate the pathogenesis of the post-ischemic vascular injury in reperfused coronary arteries, the left anterior descending coronary artery (LAD) was occluded for 30 min or 60 min in 26 dogs. After 120 min of reperfusion, vascular strips were prepared from LAD and the left circumflex coronary artery (LCX) as control, and suspended in organ chambers containing Krebs-Henseleit solution and vascular reactivity was evaluated pharmacologically. In a separate experiment, LCX-strips from 12 dogs were subjected ex vivo to blood cell-free simulated ischemia by the substitution of perfusate to hypoxic, low pH and high K+ for 60 min and the following 60 min of reoxygenation. Vascular responses to various agents were compared prior to and after simulated ischemia. Vascular injury was also investigated histologically with electron microscopy. As the results; significantly blunted endothelium-dependent relaxations to acetylcholine (10(-6) M) and Ca-ionophore (A-23187: 10(-6) M) in LAD-strips compared to LCX were noticed (43.7 +/- 4.8 vs 61.6 +/- 7.3%, 22.7 +/- 5.2 vs 47.9 +/- 8.4% in % relaxation, respectively). Augmented contractile response selective to endothelin was also observed in reperfused vessels (LAD) compared to control vessels (10(-9) M: 105.4 +/- 19.5 vs 42.4 +/- 12.3% of 20 mM-KCl induced contraction, p less than 0.01). Electron microscopy revealed partial detachment and blebbing of endothelial cells in reperfused coronary arteries. Similar changes were also observed in the simulated ischemia and reoxygenation study, but the augmented response to endothelin was seen only when polymorphonuclear leukocytes (PMN) activated with phorbol myristate acetate were added. Our results suggest that endothelial injury does not essentially depend on PMN, but PMN promote augmented response to endothelin. These changes indicate that enhanced spasmogeneity is present in reperfused arteries, which may contribute to post-infarction angina and prolonged myocardial dysfunction after reperfusion.

[Secretion of atrial natriuretic peptide during artificial pacing: assessments including the influence of ventriculoatrial conduction].

Secretion of atrial natriuretic peptide (ANP) depends on the atrial wall distension which may be caused by ventricular pacing. This study was designed to assess the differences in plasma ANP level between DDD and VVI pacing. We measured ANP from venous blood samples using radio-immunoassay in patients with the sick sinus syndrome (n = 8) and atrioventricular block (n = 2) following DDD implantation. Measurement was made under control conditions during DDD and 15-180 min after the pacing mode was changed to VVI and 60 min after returning to DDD. Serum epinephrine (E), norepinephrine (NE), renin (R) and aldosterone (A) levels were also measured prior to and every 30 min after pacing mode changes. The plasma ANP concentration changed from 71.3 pg/ml (normal value) with DDD to 126.8 (15 min), 180.6 (30 min), 221.8 (60 min), 219.2 (90 min), 270.1 (120 min), 145.4 (150 min) and 115.1 pg/ml (180 min) with VVI. It increased markedly, then gradually decreased. It returned to the control value (66.6 pg/ml) in 60 min with DDD, and it reached the peak level with VVI within 60-120 min, and the peak was significantly higher than that for DDD. The increase related to the retrograde ventriculoatrial conduction during VVI pacing. There was no significant change in the NE, E, R and A concentrations. Systolic blood pressure decreased 15 mmHg in VVI and returned to normal by DDD. These results indicated that plasma ANP levels is elevated by VVI pacing, though it was not explained by ventricular pacing alone.

[Recovery of left ventricular wall motion in early periods by successful reperfusion following myocardial infarction].

To study the time course and recovery of left ventricular (LV) function after reperfusion therapy (PTCR or PTCA), we recorded 2 D E in 1, 3, 5, 7, 14, 28 days following myocardial infarction in 41 cases with complete occlusion of left anterior descending artery. LV volumes and regional wall motion were analyzed by the centerline method (100 chords) between a reperfused (R) and a non-R group. LV end-diastolic volumes of R increased from 3 to 7 days were smaller than those in non-R. LV end-systolic volume of R decreased during the same periods were also smaller than those of non-R. Besides global ejection fractions of R were larger significantly (p less than 0.05) than those of non-R. Moreover mean percent fractional shortening of infarct-related chords from anteroseptum (-15) to lateral wall (61-80) in R improved more than those in non-R. In conclusion, LV function following myocardial infarction can be assessed by quantitative 2D echo and improved early, and become constant 7 days after successful reperfusion therapy.

[Evaluation of aortic regurgitation by Doppler echocardiography].

To establish a method for evaluating aortic regurgitation (AR) using Doppler echocardiography, we studied 104 patients who were classified according to aortographic grading (Sellers). The severity of the AR was graded by measuring the length of AR jet within the left ventricle by pulsed Doppler mapping (mapping method) or by two-dimensional color Doppler echocardiography (length method). Also, color Doppler echocardiography was used to measure the width of AR jet just below the aortic valve (width method), and pulsed Doppler echocardiography to determine the fraction of integral of forward flow and reverse flow in the abdominal aorta (abdominal method). Although the diagnostic accuracy of grading by these Doppler techniques only ranged between 52% and 68%, the length method combined with the abdominal one enhanced the diagnostic accuracy to 89% in retrospective study and 80% in prospective study. In conclusion, the length method combined with the abdominal method appeared to be useful and reliable in evaluating AR.

[A case of mitral stenosis developing infective endocarditis 18 months after PTMC].

We presented here a case of mitral stenosis developing infective endocarditis 18 months after PTMC. A 33-year-old male was admitted to our hospital for the evaluation of mitral stenosis with signs of congestive heart failure. The use of PTMC was adequately indicated based on the data of previous cardiac catheterization and was successfully performed. The post-operative clinical course was good leaving only slight mitral regurgitation demonstrated by post-valvuloplasty LVG. About 18 months after PTMC, the patient developed a high fever and erythema with tenderness on his leg, so he was admitted again. Blood culture was positive for streptococcus viridans. Moreover, echocardiogram revealed valvular vegetation on the anterior mitral leaflet, which is the characteristic finding of infective endocarditis. Antibiotics were so effective that his clinical course was relatively good with minor cerebral infarction during chemotherapy. Little is known about the prognosis and late complication of PTMC. However, our reported case may suggest that prophylactic chemotherapy might be recommended at least in some cases showing mitral regurgitation after PTMC.

Combination of ambulatory electrocardiographic monitoring and psychological testing in coronary artery disease patients.

Ambulatory electrocardiographic monitoring and psychological testing were performed in 100 patients with chronic stable myocardial infarction. These patients were divided into four groups according to their chest pain and transient ST-segment depression by Holter monitoring during the follow-up period: group A, 40 patients without complications; group B, 20 patients with silent myocardial ischemia; group C, 14 patients with episodes of chest pain alone; and group D, 26 patients with postinfarction angina. Whereas group B had silent myocardial ischemia and extroversion, groups C and D were characterized by introversion and neuroticism. The frequency of multi-vessel disease was 41% for group A, 53% for group B, 8% for group C and 70% for group D. The patients of group B not only received treatment for coronary artery disease but also behavioral counseling and those of group C received psychotherapy. The results support the view that a combination of Holter monitoring and psychological testing is clinically useful for the development of therapeutic strategies for coronary artery disease.

[A case of rupture of a posterior pancreaticoduodenal artery aneurysm].

A 75 year old man complaining of right upper abdominal pain was admitted to our hospital. He became shocked with hypotension and cold sweat, and immediately underwent operation. Laparotomy revealed massive hemorrhage in the retroperitoneal region, particularly in the right upper space. It was derived from the rupture of the posterior pancreaticoduodenal artery aneurysm. The arterial trunk was ligated above and below the aneurysm and the aneurysmectomy was carried out. The patient recovered and was discharged from the hospital 56 days after operation. There was no other visceral artery aneurysm and the etiology of this aneurysm was unknown. Four cases of pancreaticoduodenal artery aneurysm have been reported in Japan and three of them were operated, but this is the first surgically resected case for the rupture of pancreaticoduodenal artery aneurysm with success.

Factors influencing the clinical course and the long-term prognosis of patients with variant angina.

The purpose of this study was to clarify the factors influencing the clinical course and prognosis in variant angina. Also, the mechanism of acute myocardial infarction in variant angina is reviewed. The subjects were 110 patients with variant angina who, after the initial visit or admission, were observed for a period of at least 2 months, the average observation period being 68 +/- 49 months (range: 2 months-16 years). The incidence of acute myocardial infarction was 21.8% of these patients and 87.5% of the infarctions occurred within 1 month of the initial visit or admission. In variant angina, the average rate over 1 year was 2.2%; however, in classical angina the rate was 3.7% and in postinfarction angina 5.0%. The mortality rate was 5.5%, with death in the majority of cases occurring within 1 month, as in myocardial infarction. When treatment was stopped, spontaneous remission occurred in at least 26 of the 110 cases (23.6%). Beyond 3 months, the remission continued in 19 of these 26 cases. Seven cases had acute myocardial infarction in spite of the suppression of anginal attacks with administration of calcium antagonists. Apparently coronary spasm is the cause of anginal attacks, and the cause of acute myocardial infarction in patients with variant angina appears to be coronary thrombus formation.