Increases in interleukin-6 and matrix metalloproteinase-9 in the infarct-related coronary artery of acute myocardial infarction.

BACKGROUND: To elucidate the involvement of inflammation in coronary artery occlusion, the regional changes in cytokines and matrix metalloproteinases (MMPs) in the infarct-related coronary artery were determined in patients with acute myocardial infarction. METHODS AND RESULTS: Cardiac catheterization was carried out within 24 h of the onset of infarction in 36 patients. Blood samples were collected from the infarct-related coronary artery, the ascending aorta and the peripheral vein. Plasma interleukin (IL)-6 concentrations were elevated in all 3 samples. Particularly, the plasma IL-6 concentrations were 14.4 pg/ml in the infarct-related coronary artery, a value significantly greater than the respective 8.0 pg/ml and 6.5 pg/ml in the ascending aorta and peripheral vein. Plasma IL-6 concentrations in the infarct-related coronary artery had positive correlation with all of the following references measured by intravascular ultrasound: external elastic membrane cross-sectional area (EEM-CSA) (r=0.47, p<0.01), lesion EEM-CSA (r=0.51, p<0.01) and plaque area (r=0.48, p<0.01). MMP-9 was increased regionally in the infarct-related coronary artery, at 11.8 ng/ml vs 8.2 ng/ml in the ascending aorta (p<0.001). CONCLUSIONS: The present findings suggest that IL-6 at least is released from the ruptured vulnerable atherosclerotic plaque and that regional activation of macrophages is involved in the occlusive process of coronary artery in acute myocardial infarction.     

Immunodetection of human atherosclerotic plaque with I-labeled monoclonal antifibrin antibodies

To test the affinity of a new F(ab′)₂ monoclonal antibody (TRF1) against human fragment D dimer of cross-linked fibrin for atherosclerotic plaques free of detectable thrombi, 6 atherosclerotic segments of carotid and femoral artery, and as a control 5 segments of atherosclerosis-free internal mammary artery, were drawn from 11 male patients undergoing bypass surgery. All segments were carefully washed in order to remove possible endoluminal thrombi, and cut to obtain pairs of intimal fragments of similar weight, containing either plaques (n = 16), or fatty streaks (n = 12), or normal endothelium (n = 20). Each fragment underwent a direct binding test to TRFI, or to a non-specific antibody, both labeled with ¹²⁵I. The activity in each fragment was measured after 3 h of incubation at 37°C, and after washing the fragments every hour for 3 h. TRF1 binding (as percentage of initial activity) was significantly higher (P < 0.001) in atherosclerotic than in normal fragments (26% ± 11.5%, vs. 9.2% ± 3.9% in fatty streaks, and 1.9% ± 0.6% in normal endothelium), and indirect immunofluorescence confirmed TRF1 uptake within the plaque wall. By contrast, the non-specific antibody did not show any significant binding. These preliminary results demonstrate the high specific affinity of TRF1 for atherosclerotic plaques, probably due to the hemorheologic phenomena that activate platelets and provoke the formation of fragment D dimers of cross-linked fibrin on the plaque surface.     

Dynamic change in collateral flow associated with myocardial ischemia in humans

Background: This study sought to investigate how collateral flow changes during myocardial ischemia in patients. Methods: Myocardial contrast echocardiography (MCE) and rapid atrial pacing were performed in 20 patients with angiographically evidenced coronary collaterals from the right coronary artery (RCA) to the occluded left anterior descending coronary artery. Sonicated contrast medium was injected into the RCA before and immediately after atrial pacing to determine the peak background-subtracted contrast intensity (PI) in the collateral territory (PIA) and its ratio to PI in the control territory (PI ratio) as parameters of collateral blood flow. Lactate production in the coronary circulation during pacing was determined to assess myocardial ischemia in the collateral territory. Results: PIA showed a significant correlation with regional wall motion either before (r(squared)=−0.64, P<0.01) or after pacing (r(squared)=−0.65, P<0.01). Similarly, PI ratio was significantly correlated with regional wall motion either before (r(squared)=−0.54, P<0.05) or after pacing (r(squared)=−0.64, P<0.01). Rapid atrial pacing decreased both PIA and PI ratio significantly greater in patients with lactate production than in those without (PIA: −67±53 vs. −15±34%, P<0.05; PI ratio: −68±49 vs. −8.2±32%, P<0.05, respectively), while neither PIA nor PI ratio differ between the two groups of patients before pacing (PIA: 13.8±19. vs. 16.2±13.3U, P=0.75; PI ratio: 0.70±0.71 vs. 0.87±0.65, P=0.58, respectively). Conclusions: We concluded that (1) collateral flow determined by MCE was closely associated with regional cardiac function, and (2) not the amount of collateral flow at rest, but pacing-induced change of collateral flow seemed to be a determinant of regional ischemia in patients with coronary collaterals.     

Abnormal diurnal changes in in-vivo platelet activation in patients with atherosclerotic diseases

We measured the urinary excretion of beta-thromboglobulin in timed urine samples collected by 2 groups of healthy volunteers, (group I, N = 20, mean age 34 years, group II, N = 15, mean age 64 years) and by patients (n = 40) with symptomatic atherosclerotic diseases. Older healthy subjects were found to excrete high amounts of BTG in comparison to young subjects (302.25 ± 50.61 vs 219.65 ± 59.31 ng/day, P < 0.05). Higher (P < 0.01) levels of urinary BTG were observed in patients with coronary (427.61 ± 179.96 ng/day), cerebral (422.13 ± 223.2 ng/day) and peripheral (454.16 ± 269.05 ng/day) arterial diseases and in diabetic patients with diffuse vascular complications (613.71 ± 253.07 ng/day). The diurnal variability of BTG excretion, measured as coefficient of variation (C.V. %) of the mean daily excretion rate, was higher (P < 0.001) in atherosclerotic patients (70.59 ± 26.57) as compared with the similar values observed in the control groups of young (32.05 ± 14.54) and older subjects (26.38 ± 8.4). Comparable diurnal variabilities of the creatinine excretion rate were observed in the control groups and in patients. These data indicated that in vivo platelet activation may occur in atherosclerotic patients with a distinctive high fluctuation rate.     

Effects of the angiotensin II antagonist losartan on endothelin-1 and norepinephrine plasma levels during cold pressor test in patients with chronic heart failure

We evaluate the acute hemodynamic and neurohormonal effects of losartan in 15 patients with symptomatic chronic heart failure (CHF), mean age 72 ± 8 years, which were classified in two subgroups: (A) Patients with left ventricular ejection fraction (LVEF) ≤0.35 (n = 7); (B) subjects with LVEF >0.35 (n = 8). Sympathetic reactivity (blood pressure, heart rate and plasma norepinephrine) and plasma endothelin-1 (ET-1) were evaluated by a cold pressor test (CPT). Single doses of losartan (50 mg p.o.) lowered delta DBP in both subgroups (A, 8 ± 9 to 0 ± 5 mmHg, P < 0.05; B, 10 ± 6 to 3 ± 4 mmHg, P < 0.05) and attenuated the rise of HR in patients with mild (4 ± 6 to −1 ± 2 bpm, P < 0.05) but not with severe (4 ± 5 to 2 ± 5 bpm, n.s.) impairment of left ventricular function. Losartan blunted the response (delta) of PNE during CPT (A, 142 ± 131 to 10 ± 74 pg/ml, P < 0.05; B, 129 ± 72 to 1 ± 144 pg/ml, P < 0.01). A significant rise in plasma ET-1 was observed during CPT in patients from subgroup B (0.64 ± 0.40 to 0.81 ± 0.40 fmol/ml, P < 0.05) but not in patients with LVEF ≤0.35 (1.79 ± 0.44 to 1.51 ± 0.66 fmol/ml, n.s.). Losartan attenuated the rise in ET-1 during CPT in patients with LVEF >0.35 (delta ET-1 0.17 ± 0.86 to 0.03 ± 0.11 fmol/ml, P < 0.05), with no significant changes in subgroup A. Acute effects of losartan were characterized by a more favorable hemodynamic and neurohumoral response in patients with chronic heart failure and preserved systolic ventricular function related to subjects with lower ejection fractions.     

Tenascin C upregulates interleukin-6 expression in human cardiac myofibroblasts via toll-like receptor 4

AIM:To investigate the effect of Tenascin C(TNC)on the expression of pro-inflammatory cytokines and matrixmetalloproteinases in human cardiac myofibroblasts(CMF).METHODS:CMF were isolated and cultured from patients undergoing coronary artery bypass grafting.Cultured cells were treated with either TNC(0.1μmol/L,24 h)or a recombinant protein corresponding to different domains of the TNC protein;fibrinogen-like globe(FBG)and fibronectin typeⅢ-like repeats(TNⅢ5-7)(both 1μmol/L,24 h).The expression of the proinflammatory cytokines;interleukin(IL)-6,IL-1β,TNFαand the matrix metalloproteinases;MMPs(MMP1,2,3,9,10,MT1-MMP)was assessed using real time RT-PCR and western blot analysis.RESULTS:TNC increased both IL-6 and MMP3(P0.01)mR NA levels in cultured human CMF but had no significant effect on the other markers studied.The increase in IL-6 mR NA expression was mirrored by an increase in protein secretion as assessed by enzymelinked immunosorbant assay(P0.01).Treating CMF with the recombinant protein FBG increased IL-6mR NA and protein(P0.01)whereas the recombinant protein TNⅢ5-7 had no effect.Neither FBG nor TNⅢ5-7 had any significant effect on MMP3 expression.The expression of toll-like receptor 4(TLR4)in human CMF was confirmed by real time RT-PCR,western blot and immunohistochemistry.Pre-incubation of cells with TLR4neutralising antisera attenuated the effect of both TNC and FBG on IL-6 mR NA and protein expression.CONCLUSION:TNC up-regulates IL-6 expression in human CMF,an effect mediated through the FBG domain of TNC and via the TLR4 receptor.     

IL-6 is produced by splenocytes derived from CMV-infected mice in response to CMV antigens, and induces MCP-1 production by endothelial cells: a new mechanistic paradigm for infection-induced atherogenesis

Atherosclerosis is an inflammatory disease. One of the candidate inflammatory triggers is infection. To further characterize the interaction between infection, cytokine induction, and atherosclerosis, we tested the hypothesis that cytomegalovirus (CMV) infection induces the pro-inflammatory cytokine interleukin-6 (IL-6), which in turn induces “pro-atherosclerotic” changes in vascular endothelial cells (ECs). ELISA was used to determine the levels of monocyte chemoattractant protein-1 (MCP-1) in the supernatant of mouse and human ECs incubated with IL-6, and IL-6 levels in supernatants of splenocytes, derived from CMV-infected and uninfected mice, stimulated with mice CMV antigens. IL-6 induced, in a dose response fashion, MCP-1 expression in human ECs: 0, 2, 10, and 50 pg/ml IL-6 increased MCP-1 levels in EC conditioned medium from 1120±65 to 1148±105, 1395±40, and 2119±130 pg/ml, respectively (P<0.001). IL-6 also induced MCP-1 expression in mouse ECs (P<0.002). Importantly, IL-6 concentration in the supernatants of splenocytes stimulated with CMV antigens rose from undetectable levels in uninfected mice to 14.9±5 pg/ml in the infected mice (P<0.04). These results suggest a previously unrecognized, but potentially important mechanism whereby CMV, and other pathogens, contribute to atherogenesis: T lymphocytes, clonally expanded in response to antigens presented by CMV infection, home to sites of vascular injury and locally release IL-6 when presented with either pathogen antigens that may be present in the plaque, or when they cross-react with host peptides homologous to the relevant pathogen antigens; IL-6 then triggers ECs to release MCP-1, which recruits more monocytes and T-cells into the vessel wall and thereby exacerbates local inflammation, and thus atherogenesis.     

Influence of cigarette smoking on rate of reopening of the infarct-related coronary artery after myocardial infarction: A multivariate analysis

Objectives. This study sought to determine whether the reopening of the infarct-related vessel is related to clinical characteristics or cardiovascular risk factors, or both.

Background. In acute myocardial infarction, thrombolytic therapy reduces mortality by restoring the patency of the infarct-related vessel. However, despite the use of thrombolytic agents, the infarct-related vessel remains occluded in up to 40% of patients.

Methods. We studied 295 consecutive patients with an acute myocardial infarction who underwent coronary angiography within 15 days (mean [±SD] 6.7 ± 3.2 days) of the onset of symptoms. Infarct-related artery patency was defined by Thrombolysis in Myocardial Infarction trial flow grade ≥ 2. Four cardiovascular risk factors—smoking, hypertension, hypercholesterolemin and diabetes mellitus—and eight different variables—age, gender, in-hospital death, history of previous myocardial infarction, location of current myocardial infarction, use of thrombolytic agents, time interval between onset of symptoms, thrombolytic therapy and coronary angiography—were recorded in all patients.

Results. Thrombolysis in current smokers and anterior infarct location on admission were the three independent factors highly correlated with the patency of the infarct-related vessel (odds ratios 3.2, 3.0 and 1.9, respectively). In smokers, thrombolytic therapy was associated with a higher reopening rate of the infarct vessel, from 35% to 77% (p < 0.001). Nonsmokers did not benefit from thrombolytic therapy, regardless of infarct location.

Conclusions. These observational data, if replicated, suggest that in patients with acute myocardial infarction, thrombolytic therapy may be most effective in current smokers, whereas non-smokers and ex-smokers may require other management strategies, such as emergency percutaneous transluminal coronary angioplasty.     

Comparison between warm blood and crystalloid cardioplegia during open heart surgery

Objective: This study was designed to compare the degree of myocardial protection afforded by warm blood and cold crystalloid cardioplegia in a group of patients undergoing elective coronary artery bypass surgery. Methods: Seventeen patients, were randomly assigned to Group A (n=9), who received crystalloid cardioplegic solution, and Group B who received warm blood cardioplegic solution (n=8). Before the aorta was clamped, and 10 min after reperfusion, blood samples from the coronary sinus were obtained to assay -tocopherol, β-carotene, ubiquinol, and thiobarbituric acid reactive substances (TBARS). At the same intervals, biopsies from the left ventricle were obtained to determine ultrastructural alterations. Results: No significant changes were observed between preischemia and reperfusion values for both blood and crystalloid groups concerning -tocopherol, β-carotene, and ubiquinol, and no differences between groups were detected. Values for TBARS in group A were 3.49±0.3 and 5.27±0.45 μM for presichemia and reperfusion samples, respectively (P<0.01). In group B values were 2.6±0.3 and 3.54±0.3 μM, respectively (P=NS). For electron microscopy studies, semiquantitative analysis showed a significant mitochondrial damage in reperfusion biopsies from group A (grades 0, 3 and 4). In group B, no significant changes were observed in mitochondrial damage between preischemia and repefusion biopsies (except for grade 0). Conclusion: These results indicate that blood cardioplegia affords better protection to the myocyte than crystalloid cardioplegia.     

Serum tumour necrosis factor-alpha,interleukin-2 and interleukin-10 activation in stable angina and acute coronary syndromes

BACKGROUND: Dynamic instability of coronary atherosclerotic plaque results in the development of both unstable angina and myocardial infarction. The aim of the study was to investigate the dynamics of serum concentrations of tumour necrosis factor (TNF)alpha, interleukin (IL)-10, and IL-2 in patients with myocardial infarction (MI) and unstable angina (UA) as compared to stable angina (SA) patients and healthy volunteers. METHODS: A total of 189 patients with coronary artery disease (CAD) were studied: 100 patients with SA (class II/III according to CCS), 57 patients with UA (Braunwald class IIIB; determinations at 6, 24, and 48 h after chest pain), and 32 patients with MI (determinations at admission, on the 7th and 30th days after MI). Twenty healthy volunteers acted as controls. RESULTS: Serum TNFalpha levels were elevated in all CAD groups (SA: 17.3+/-4; UA: 18.7+/-4; MI: 22.0+/-3 pg/ml; p<0.001) in comparison to the controls (8.3+/-1.4 pg/ml). However, the highest values were characteristic of MI patients, especially values obtained at admission (p<0.01 versus SA and UA). Mean serum concentrations of IL-2 were significantly higher in patients with MI and UA (89.6+/-40; 87.0+/-24 pg/ml, respectively; p<0.01) when compared to SA and the control group (58.3+/-49; and 51.5+/-39, respectively). Serum IL-10 levels were also higher in MI and UA patients. Levels of IL-2 and IL-10 measured following chest pain in unstable patients, as well as their consecutive determinations in MI patients did not show any change dynamics, that is, they were persistently elevated. CONCLUSIONS: When compared to stable CAD and healthy subjects, acute coronary syndromes are associated with long-term increase of serum concentrations of pro- and anti-inflammatory cytokines. It seems likely that sudden CAD progression leading to acute coronary syndromes is triggered/accompanied by prolonged immune activation.     

Characteristics of the pathological images of coronary artery thrombi according to the infarct-related coronary artery in acute myocardial infarction.

BACKGROUND: Unstable plaque and coronary arterial thrombi sometimes induce a no-reflow phenomenon after intervention whereby there is sufficient reperfusion. The greater susceptibility of the right coronary artery to development of large thrombi makes successful reperfusion more difficult, therefore the characteristics of the pathological images of coronary arterial thrombi according to the infarct-related coronary artery were investigated. METHODS AND RESULTS: Coronary arterial thrombi were extracted from 77 patients with acute myocardial infarction (AMI) using a thrombectomy catheter. The 36 patients had a thrombus containing atherosclerotic cells. Platelets, fibrin, and neutrophils were seen in all cases. The mean ratios of structural components of thrombi were 51.0 +/- 29.5% (mean +/- SD) of the platelet component, 19.9 +/- 25.7% of the erythrocyte component and 11.9 +/- 22.5% of atherosclerosis component. Erythrocyte-rich thrombi and mixed thrombi mainly composed of erythrocytes were seen in 14 of the 30 cases involving the right coronary artery, 6 of the 35 cases in the left anterior descending artery, 2 of the 11 cases of the left circumflex artery, and in the 1 case of saphenous vein bypass graft. There was significantly more erythrocyte component in the thrombi from the right coronary artery (28.7 +/- 30.1%) than in those from the left coronary artery (12.1 +/- 18.4%). CONCLUSION: Coronary artery thrombi in AMI are composed principally of platelets. Atherosclerotic cells were identified within thrombi from some patients. In the right coronary artery there were many more thrombi that were rich in erythrocytes than in thrombi from the left coronary artery.     

Coronary Flow Reserve During Coronary Angioplasty in Patients With a Recent Myocardial Infarction: Relation to Stenosis and Myocardial Viability

Objectives. In the present study, we examined post-stenotic coronary flow before and after percutaneous transluminal coronary angioplasty (PTCA) in patients with and without a recent myocardial infarction (MI) and related it to stenosis severity and residual viability.

Background. Post-stenotic coronary blood flow velocity reserve (CFVR) has been used with success to estimate functional stenosis severity in patients with stable angina. However, in patients with a recent MI, the impaired coronary vasodilator response of the reperfused myocardium may substantially alter the flow dynamics of the infarct-related artery.

Methods. Distal coronary flow velocities were recorded before and after PTCA in 36 patients at day 13 ± 7 (mean ± SD) after acute MI and in 38 patients without MI. The CFVR was assessed by the ratio of distal hyperemic to baseline average peak velocity, using a 0.014-in. Doppler guide wire. Stenosis severity was analyzed by quantitative coronary angiography, and infarct size was assessed scintigraphically.

Results. For similar angiographic stenosis severity, pre- and post-PTCA values of CFVR were significantly lower in patients with than without MI: 1.22 ± 0.26 versus 1.50 ± 0.45 before PTCA (p < 0.05) and 1.72 ± 0.43 versus 2.21 ± 0.74 after PTCA, respectively (p < 0.01). Although CFVR increased significantly (p < 0.0001) after angiographically successful PTCA in both study groups, abnormal CFVR (≤2.0) was still observed in 80% of patients with MI and in 44% of those without MI (MI vs. no MI, p = 0.001). Patients with an extensive infarction (relative infarct size ≥50%) and those with a small infarction (relative infarct size <50%) had comparable levels of post-PTCA CFVR (1.6 ± 0.3 vs. 1.8 ± 0.5, p = NS). Among a variety of factors, angiographic stenosis severity was the most important determinant of CFVR in both study groups.

Conclusions. In patients with a recent MI, CFVR was significantly lower than in those without MI, both before and after PTCA. Besides the presence of this postreperfusion-related impairment of the coronary vasodilating response, CFVR was mainly influenced by stenosis severity and not by residual viability.

(J Am Coll Cardiol 1996;28:1712–9)>     

血管内超声评价斑块稳定性及其与血清高敏C反应蛋白和白细胞介素6的关系

目的 应用血管内超声技术探讨不稳定型心绞痛患者不稳定性斑块与血清高敏C反应蛋白和白细胞介素6的关系.方法 38例拟诊为冠心病患者行血管内超声检查,其中8例患者经血管内超声检查未发现冠状动脉有明显狭窄病变为对照组;30例经血管内超声检查发现冠状动脉有明显狭窄病变为冠心病组,其中不稳定型心绞痛18例,稳定型心绞痛组12例.检测所有患者血清高敏C反应蛋白和白细胞介素6水平.结果 38例患者均有不同程度的内膜增厚;8例对照组无动脉粥样硬化斑块;30例冠心病患者有不同类型的动脉粥样硬化斑块.不稳定型心绞痛患者血清高敏C反应蛋白和白细胞介素6水平显著高于稳定型心绞痛组和对照组;不稳定性斑块组高敏C反应蛋白和白细胞介素6水平高于稳定性斑块组.结论 不稳定型心绞痛患者血清高敏C反应蛋白和白细胞介素6水平明显增高,提示高敏C反应蛋白和白细胞介素6水平升高与动脉粥样硬化斑块不稳定性有关.     

Effects of sympathetic nerves on collateral vessels in the limb of atherosclerotic primates

This study was performed to examine effects of sympathetic nerves on collateral vessels in the limb. We studied normal (N) and atherosclerotic (AS) cynomolgus monkeys that were fed atherogenic diet for 21 months. A common iliac artery was ligated 13 months before hemodynamic measurements. Using histofluorescence microscopy, a plexus of noradrenergic nerves was identified in the adventitia of collateral vessels. We measured blood flow to the limb with microspheres, and the pressure gradient from aorta to the iliac artery beyond the occlusion. The lumbar sympathetic chain was stimulated electrically at 3 Hz (SNS-3) and 15 Hz (SNS-15). In normal monkeys, conductance of collateral vessels (in ml/min per 100 g per 100 mm Hg) was 19 ± 3.6 (mean ± SE) during control, 14 ± 1.6 during SNS-3, and 9.8 ± 0.9 during SNS-15 (P < 0.05 vs control). In AS monkeys, collateral conductance was 12 ± 2.9 during control, 7.5 ± 1.7 during SNS-3 and 3.9 ± 1.8 during SNS-15 (P < 0.05). In summary, collateral vessels in the limb are innervated and sympathetic stimulation produces pronounced constriction of collateral vessels in both normal and atherosclerotic monkeys. Thus, the effectiveness of collateral vessels in maintaining blood flow to the limb may be compromised by increased activity of sympathetic nerves.     

Post-exercise response of the systolic blood pressure in the diagnosis of coronary artery disease: comparison of two exercise methods

We studied 81 angiographically documented coronary artery disease patients and 28 with normal coronary arteries, having paired exercise tests (the Bruce treadmill protocol and the jogging in place test) in order to investigate the value of the ratio of recovery systolic blood pressure to peak exercise systolic blood pressure (postexercise pressure ratio) compared to the classic ST depression. The postexercise pressure ratio was significantly higher in patients with coronary artery disease than in patients with normal coronary arteries for each of the 2 exercise tests (P < 0.001 − P < 0.00001). On the contrary, we obtained significantly lower sensitivities for the pathologic (> ± 2 SD of patients with normal coronary arteries) values of the post-exercise pressure ratio than for the positive electrocardiographic outcome 30% vs 58% (P < 0.00002) and 37% vs 64% (P < 0.0001) as well as lower accuracies 48% vs 63% (P < 0.03) and 52% vs 71% (P < 0.005), respectively.

Thus, we proved that the classic ST depression has much more diagnostic value than the post-exercise pressure ratio and this result is independent of the exercise methodology. Consequently this ratio is not recommended to replace the electrocardiographic exercise criteria.     

Plasma homocysteine and the extent of atherosclerosis in patients with coronary artery disease

Homocysteine is a graded risk factor for the incidence of stroke and for the degree of carotid atherosclerosis. Homocysteine is also a graded risk factor for the incidence of myocardial infarction but we do not know its precise relations to the severity of atherosclerosis in coronary patients. Seventy five symptomatic coronary patients were recruited for the study. Fifty of these patients had coronary artery disease only and were compared in a case-control manner to 50 healthy controls matched for age and sex. The 25 other coronary patients had also symptoms in another atherosclerotic territory (cerebral, peripheral or both) and were also compared to 25 matched controls. Mean plasma homocysteine level was significantly higher in coronary patients than in controls (11.7±0.7μmol l⁻¹, n=50 versus 9.9±0.5μmol l⁻¹, n=50, p<0.05). Homocysteine in patients with symptomatic atherosclerosis in two or three arterial sites was 15.7±1.5μmol l⁻¹ which differed significantly from matched controls and from patients with coronary artery disease only (p=0.01). The extent of coronary atherosclerosis evaluated by an angiographic coronary score correlated weakly to plasma homocysteine levels (r=0.25, p<0.05). The patients with both hypertension and high levels of homocysteine (>11.3μmol l⁻¹, median value) had more severe coronary atherosclerosis (coronary score of 16.3±2.3 versus 11.9±0.9, p<0.05) and more diffuse atherosclerosis (number of atherosclerotic territories of 1.5±0.2 versus 1.2±0.7, p=0.08) than the coronary patients without this association. There were no other high risk association when considering the other classical risk factors.

Thus, the highest levels of homocysteine were present in patients with coronary disease and another symptomatic localisation of atherosclerosis. A small gradient in the extent of coronary atherosclerosis was found with increasing levels of homocysteine. The presence of both hypertension and hyperhomocysteinemia was associated with more severe coronary atherosclerosis.     

Response of the left anterior descending coronary artery to acetylcholine in patients with chest pain and angiographically normal coronary arteries

Because atherosclerotic plaque burden affects the likelihood of plaque rupture, it is important to determine the presence and extent of atherosclerotic plaque. We hypothesized that endothelial dysfunction becomes more prominent with development of atherosclerotic plaque; therefore, we examined the relation between coronary endothelial dysfunction and the presence of atherosclerotic plaque. In 36 patients with normal coronary arteries, acetylcholine (ACh; 3 and 30 μg/min) and nitroglycerin were infused into the left coronary ostium, and the diameter of the left anterior descending (LAD) coronary artery was quantitatively measured in response to each drug. The plaque burden was measured in the same segment using intravascular ultrasonography. The plaque burden was 31.2 ± 2.1% and correlated inversely with changes in coronary diameter induced by 3 μg/min of ACh (r = −0.754, p <0.0001), 30 μg/min of ACh (r = −0.552, P = 0.0005), and nitroglycerin (r = −0.531, P = 0.0009). Multivariate regression analysis showed that the change in coronary diameter induced by 3 μg/min of ACh was associated with plaque burden, independent of the effects of nitroglycerin-induced dilation. Receiver-operating characteristics analysis demonstrated that a cut-off value for the change in coronary diameter induced by 3 μg/min of ACh for predicting a plaque burden of>30% was 0%, with a sensitivity of 0.82 and a specificity of 0.95. These findings suggest that coronary endothelial dysfunction is correlated with atherosclerotic plaque burden, indicating that atherosclerotic plaque may be detected based on coronary endothelial function as assessed by low-dose ACh infusion.     

Simultaneous assessment of myocardial perfusion and left ventricular function during transient coronary occlusion

Objectives. We used technetium-99m sestamibi imaging to evaluate the magnitude of changes in left ventricular function and perfusion and to investigate their interdependence during transient coronary occlusion.

Background. Transient coronary occlusion during coronary angioplasty provides a unique opportunity for examining the effects of acute myocardial ischemia on left ventricular function and perfusion.

Methods. Thirty-five patients with normal left ventricular function underwent first-pass radionuclide angiography with technetium-99m sestamibi using a multicrystal gamma camera during balloon occlusion of a coronary artery. Single-photon tomography was performed 2.1 ± 1.7 h later. Subsequently, all scans were repeated at rest.

Results. The mean size ± SD of the perfusion defect during coronary occlusion was 23 ± 18%, with significantly larger defects observed for occlusions of the left anterior descending coronary artery (39 ± 20%) than for occlusions of the left circumflex (15 ± 11%) or right (15 ± 9%) coronary artery (p < 0.05). The mean change in ejection fraction from recovery to occlusion was −17 ± 17% and was significantly larger for left anterior descending (−26 ± 21%) and left circumflex (−15 ± 11%) than for right (−8 ± 10%) coronary artery occlusions (p < 0.05). For the entire group, ejection fraction during occlusion correlated significantly with perfusion defect size ( r= 0.63, p = 0.0004), whereas the extent of ischemic myocardium correlated with the decrease in ejection fraction (r = 0.69, p = 0.0001). The defects present during occlusion reversed within a few hours.

Conclusions. Changes in left ventricular function and perfusion develop pari passu during coronary occlusion and are more severe when the left anterior descending artery is occluded. Although a significant correlation exists between the extent of the perfusion defect and the severity of the decrease in ejection fraction, there is a substantial individual variation with respect to changes in both myocardial perfusion and ventricular function during acute coronary occlusion.     

Plasma osteopontin levels are associated with the presence and extent of coronary artery disease

Recently, osteopontin (OPN) mRNA was reported to be highly expressed in atherosclerotic plaques, most strikingly in calcified plaques. We examined if plasma OPN levels are associated with coronary stenosis and calcification in patients with coronary artery disease (CAD). We measured plasma OPN levels in 178 patients undergoing coronary angiography. Compared with 71 patients without CAD, 107 with CAD had higher OPN levels (616±308 ng/ml versus 443±237 ng/ml, P<0.001). A stepwise increase in OPN levels was found depending on the number of >50% stenotic coronary vessels: 540±293 ng/ml in 1-vessel, 615±230 ng/ml in 2-vessel, and 758±416 ng/ml in 3-vessel disease. OPN levels also correlated with the numbers of >50% and >25% stenotic segments (r=0.35 and 0.43, respectively, P<0.001). In multivariate analysis, OPN levels were significantly associated with CAD (odds ratio=1.21, 95% CI=1.05–1.39 for a 100 ng/ml increase) independent of traditional risk factors. Coronary calcification was found in 86 patients. OPN levels were higher in patients with calcification than in those without calcification (608±328 ng/ml versus 490±246 ng/ml, P<0.01) and correlated with the number of calcified segment (r=0.26, P<0.001). However, OPN levels were not independently associated with coronary calcification. Thus, plasma OPN levels were found to be associated with the presence and extent of CAD.