The effect of repeated exposure to particulate air pollution (PM10) on the bone marrow

Studies have shown that exposure to ambient particulate matter is related to an increased cardiopulmonary morbidity and mortality. The present study was designed to measure the effect of repeated exposure to urban air particles (PM10) on the rate of production and release of polymorphonuclear leukocytes (PMN) from the bone marrow into the peripheral blood. Rabbits exposed to PM10 (5 mg) twice a week for 3 wk, were given a bolus of 5'-bromo-2'-deoxyuridine (BrdU) to label dividing cells in the marrow that allows us to calculate the transit time of PMN in the bone marrow mitotic and postmitotic pools. The PM10 exposure (n = 8) causes a persistent increase in circulating band cells (p < 0.05) and a shortening of the transit time of PMN through the postmitotic pool in the marrow (64.4 +/- 2.2 h to 56.3 +/- 2.2 h, p < 0.05) if compared with vehicle-exposed control subjects (n = 6). PM10 exposure increases the bone marrow pool of PMN particularly the mitotic pool of PMN (p < 0.05). The PM10 were distributed diffusely in the lung and caused a mild mononuclear inflammation. The percentage of alveolar macrophages containing PM10 correlated significantly with the bone marrow PMN pool size (total pool r2 = 0.56, p < 0.012, mitotic pool r2 = 0.61, p < 0.007) and the transit time of PMN through the postmitotic pool (r2 = -0.42, p < 0.043). We conclude that repeated exposure to PM10 stimulates the bone marrow to increase the production of PMN in the marrow and accelerate the release of more immature PMN into the circulation. The magnitude of these changes was related to the amount of particles phagocytosed by alveolar macrophages.     

Left anterior descending coronary artery wall thickness measured by high-frequency transthoracic and epicardial echocardiography includes adventitia

High-frequency, 2-dimensional transthoracic echocardiography (HR-2DTTE) measurements of the left anterior descending (LAD) coronary artery wall thickness are larger than measurements obtained by intravascular ultrasound. We hypothesize that this difference is due to inclusion of the third vascular layer, which may represent adventitia by HR-2DTTE, and that this layer must be increasing in thickness with the development of atherosclerosis. We evaluated the contribution of this third layer to the wall thickness of the normal and atherosclerotic LAD artery imaged by HR-2DTTE using high-frequency epicardial echocardiography (HFEE) as the reference standard. Eighteen patients (10 men, mean age 62 years), 13 with coronary atherosclerosis and 5 with normal coronary arteries, referred for open-heart surgery, underwent preoperative HR-2DTTE evaluation of the LAD artery (SONOS 5500; 3- to 8-MHz transducer) and intraoperative HFEE of the LAD artery (SONOS 5500; 6- to 15-MHz transducer). Wall thickness was greater in patients with coronary atherosclerosis than in those with normal coronary arteries by both HR-2DTTE (1.9 +/- 0.3 vs 1.0 +/- 0.1 mm, p = <0.001) and HFEE (1.8 +/- 0.2 vs 1.0 +/- 0.2 mm, p = <0.001). On HFEE, the average intima plus media thickness was greater in patients with coronary atherosclerosis than in those with normal coronary arteries (0.78 +/- 0.3 vs 0.34 +/- 0.1 mm, p = 0.005). The average thickness of adventitia was also greater in patients with coronary atherosclerosis than in those with normal coronary arteries (0.92 +/- 0.2 vs 0.54 +/- 0.2 mm, p = 0.0005). HR-2DTTE and HFEE measurements of the wall thickness correlated well (r = 0.83 [reader 1], p <0.001; r = 0.61 [reader 2], p <0.01). A third vascular layer, which likely included adventitia, represents a significant portion of the LAD wall thickness imaged by HR-2DTTE and HFEE, and it significantly increases in thickness with the development of atherosclerosis.     

African Americans and Caucasians have a similar prevalence of coronary calcium in the Dallas Heart Study.

OBJECTIVES: We sought to compare the prevalence of coronary atherosclerosis in a cohort of middle-age African American (black) and non-Hispanic Caucasian (white) men and women from a population-based probability sample. BACKGROUND: Blacks have a higher mortality from coronary heart disease (CHD) than whites, particularly among younger individuals, and yet several studies have reported that coronary atherosclerosis is less prevalent in blacks than in whites. Data from population-based samples comparing coronary atherosclerotic burden between blacks and whites are limited. METHODS: The prevalence of coronary atherosclerosis in middle-aged blacks and whites was determined using coronary calcium measured by electron beam computed tomography in 1,289 men and women from a population-based probability sample from Dallas, Texas. RESULTS: The population estimates of the frequency of a positive scan for coronary artery calcium were not statistically different between black and white men (37% vs. 41%, p = 0.36) or between black and white women (29% vs. 23%, p = 0.21). Although the prevalence of most of the coronary risk factors varied significantly between blacks and whites, mean Framingham coronary risk factor scores were identical in black and white men (10 +/- 4) but significantly higher in black women (13 +/- 4) than in white women (12 +/- 4). CONCLUSIONS: Blacks in the general population have a prevalence of coronary atherosclerosis similar to whites. Factors other than coronary atherosclerotic burden, which are not reflected in the Framingham risk score, contribute significantly to the higher CHD mortality rate in blacks.     

Asymmetrical dimethylarginine: a novel risk factor for coronary artery disease

BACKGROUND: Asymmetrical dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and has been associated with systemic atherosclerosis; however, the role of ADMA in patients with coronary artery disease (CAD) has not been investigated. HYPOTHESIS: The present study was designed to determine whether the plasma ADMA level predicts the presence of CAD independently, and whether the plasma ADMA level correlates with the extent and severity of coronary atherosclerosis. METHODS: In all, 97 consecutive patients with angina and positive exercise stress test were enrolled prospectively for coronary angiography. According to the result of angiography, the subjects were divided into two groups: Group I (n = 46): patients with normal coronary artery or mild CAD (< 50% stenosis of major coronary arteries); Group 2 (n = 51): patients with significant CAD (> or = 50% stenosis of majorcoronary arteries). Plasma levels of ADMA and L-arginine were determined by high-performance liquid chromatography. In addition, we used coronary atherosclerotic score to assess the extent and severity of CAD. RESULTS: The plasma levels of ADMA in Group 2 patients were significantly higher than those in Group 1 patients (0.66 +/- 0.17 microM vs. 0.44 +/- 0.09 microM, p < 0.001); these were accompanied by significantly lower plasma L-arginine/ADMA ratio in patients with significant CAD (Group 1 vs. 2: 194.0 +/- 55.3 vs. 136.7 +/- 50.3, p < 0.001). In a multivariate stepwise logistic regression analysis, both plasma ADMA level and plasma L-arginine/ADMA ratio were identified as independent predictors for CAD. Moreover, there were significant positive and negative correlations between coronary atherosclerotic score and plasma ADMA level as well as plasma L-arginine/ADMA ratio, respectively (plasma ADMA level: r = 0.518, p < 0.001; L-arginine/ADMA ratio: r = -0.430, p < 0.001). CONCLUSIONS: Both plasma ADMA level and plasma L-arginine/ADMA ratio were useful in predicting the presence of significant CAD and correlated significantly with the extent and severity of coronary atherosclerosis. Our findings suggest that plasma ADMA level may be a novel marker of CAD.     

Assessment of coronary remodeling in stenotic and nonstenotic coronary atherosclerotic lesions by multidetector spiral computed tomography

OBJECTIVES: This study was designed to investigate whether contrast-enhanced multidetector spiral CT (MDCT) permits assessment of remodeling in coronary atherosclerotic lesions. BACKGROUND: With sufficient image quality, MDCT permits noninvasive visualization of the coronary arteries, but its ability to assess remodeling has not been evaluated. METHODS: Out of 102 patients in whom MDCT (16-slice scanner, intravenous contrast, 0.75-mm collimation, 420 ms rotation) was performed before invasive coronary angiography, 44 patients with high-quality MDCT data sets showing atherosclerotic plaque in a proximal coronary artery segment were chosen for evaluation. In multiplanar reconstructions orthogonal to the coronary artery, the cross-sectional vessel area was measured for the respective lesion and for a reference segment proximal to the lesion. The "Remodeling Index" was calculated by dividing the vessel area in the lesion by the reference segment. Results were correlated to the presence of stenosis (>50% diameter reduction) in invasive angiography. In a subset of 13 patients, MDCT measurements were verified by IVUS. RESULTS: Reference vessel area was not significantly different between nonstenotic versus stenotic lesions (20 +/- 8 mm(2), n = 23 vs. 22 +/- 8 mm(2), n = 21). The mean Remodeling Index was significantly higher in nonstenotic than in stenotic lesions (1.3 +/- 0.2 vs. 1.0 +/- 0.2, p < 0.001). In five stenotic lesions, "negative remodeling" (Remodeling Index < or = 0.95) was observed. Cross-sectional vessel areas and Remodeling Indices measured by MDCT correlated closely to IVUS (r(2) = 0.77 and r(2) = 0.82, respectively). CONCLUSIONS: Multidetector spiral CT may permit assessment of remodeling of coronary atherosclerotic lesions in selected data sets of sufficient quality.     

Oxidized low-density lipoprotein and high-density lipoprotein cholesterol modulate coronary arterial remodeling: an intravascular ultrasound study

BACKGROUND: Oxidized low-density lipoprotein (oxLDL) not only plays an important role in plaque formation, but also impairs the endothelium-dependent relaxation. Constrictive remodeling rather than intimal hyperplasia mainly contributes to restenosis after balloon angioplasty. Probucol (powerful antioxidant) reduced restenosis rate by improving constrictive remodeling. Thus, oxLDL may modulate coronary arterial remodeling. HYPOTHESIS: The study was designed for using intravascular ultrasound to test the hypothesis that arterial constrictive remodeling (CR) was associated with oxLDL in patients with coronary artery disease. METHODS: Intravascular ultrasound was performed in 36 patients with de novo atherosclerotic coronary. Remodeling was defined and evaluated as follows: remodeling index (RI) = lesion vessel area (VA)/(proximal reference VA + distal reference VA)/2. Constrictive remodeling (CR) was defined as remodeling index (RI) < 0.9. Neutral and expansive remodeling (NER) was defined as RI > or = 0.9. The level of plasma ox-LDL was measured by sandwich ELISA using the monoclonal antibody (DLH3)-recognized oxidatively modified lipoproteins and the antihuman apoprotein B monoclonal antibody. RESULTS: Neutral and expansive remodeling was found in 24 lesions, and CR in 12 lesions. Remodeling index was significantly lower in the CR group than in the NER group (0.8 +/- 0.1 vs. 1.0 +/- 0.1, p < 0.001). The level of oxLDL in the CR group was significantly higher than that in the NER group (24.0 +/- 12.1 vs. 16.4 +/- 6.2 U/ml, p < 0.05). The level of high-density lipoprotein-cholesterol (HDL-C) in the CR group was significantly lower than that in the NER group (40.5 +/- 4.8 vs. 46.2 +/- 10.6 mg/ml, p < 0.05). There was a statistically significant correlation between the value of HDL-C/ ox-LDL and the RI (r = -0.48, p < 0.005). CONCLUSIONS: Oxidized LDL and HDL-C were associated with arterial remodeling in de novo atherosclerotic lesions.     

Effects of intravenous dobutamine on coronary vasomotion in humans

OBJECTIVES: We sought to investigate the vascular mechanisms of dobutamine-induced myocardial ischemia. BACKGROUND: Dobutamine stress is often used as a surrogate for exercise. The effects of dobutamine on the epicardial arteries are incompletely understood and possibly different from those of physical exercise. METHODS: Intravenous (IV) dobutamine (40 microg/kg per min) was administered in 19 patients with normal, 23 patients with mildly atherosclerotic, and 12 patients with stenotic coronary arteries. In another two groups of patients with stenotic arteries, IV dobutamine was preceded by 1) an intracoronary (IC) bolus of the alpha-adrenergic blocker phentolamine (12 microg/kg, n = 12); and 2) an IC infusion of the nitric oxide substrate L-arginine (150 micromol/l per min for 20 min, n = 11). Intravenous saline instead of dobutamine was infused into eight patients with normal arteries. After dobutamine (or saline), an IC bolus of isosorbide dinitrate (ISDN, 0.2 mg) was given. Coronary vasomotion was evaluated by quantitative coronary angiography on angiograms obtained after each dose of dobutamine, saline, phentolamine, L-arginine, and ISDN. RESULTS: Dobutamine increased the rate-pressure product and heart rate similarly in all patients except those who received saline. Dobutamine induced vasodilation in normal (change in luminal diameter [DeltaLD] vs. baseline: 19 +/- 2%) and in mildly atherosclerotic arteries (DeltaLD: 8 +/- 2%, p < 0.05 vs. normal). In stenotic arteries, dobutamine did not induce significant vasomotion (DeltaLD: -3 +/- 3%); the latter was improved by L-arginine (DeltaLD: 10 +/- 3%, p < 0.05 vs. stenotic arteries) and fully restored by phentolamine (DeltaLD: 19 +/- 3%, p < 0.05 vs. stenotic arteries). CONCLUSIONS: Endothelial dysfunction and enhanced alpha-adrenergic tone contribute to the loss of dobutamine-induced vasodilation in coronary atherosclerosis. In contrast to physical exercise, dobutamine does not induce "paradoxical vasoconstriction" of atherosclerotic coronary arteries.     

Relationship of metabolic syndrome with quantum of coronary artery disease in Indian patients with chronic stable angina

Background: The current study was aimed to ascertain presence and severity of coronary artery lesions in patients of Type 2 diabetic mellitus (DM) with coronary artery disease (CAD), in our population, by using scoring system analysis of the coronary angiography. Methods: 147 consecutive patients with Type 2 DM of chronic stable angina (CSA) were enrolled in the study with 147 age- and sex-matched patients of CSA who did not have diabetes to serve as control. All of them underwent coronary angiography and were evaluated by using four scores to quantify the coronary artery lesions. The scores analyzed were coronary score, extent score, severity score, and atherosclerosis score. Other major risk factors such as smoking and hypertension lipid profile were also evaluated. Results: Type 2 diabetics with CAD had higher coronary score (0.91 +/- 0.63 in diabetics vs. 0.43 +/- 0.39, p < 0.001), extent score (4.91 +/- 3.1 vs. 2.3 +/- 1.8, p < 0.001), severity score (1.85 +/- 0.41 vs. 1.2 +/- 0.32, p < 0.001), and atherosclerosis score (0.52 +/- 0.31 vs. 0.21 +/- 0.26, p < 0.001) as compared to non-diabetics with CAD. Left main stem involvement, 2-vessel disease, and 3-vessel disease were also more frequent in the diabetics. These diabetes also had higher incidence of obesity, hypertension, and dyslipidemia. Conclusions: In our population, diabetics suffer from higher prevalence of diffuse and extensive coronary atherosclerosis. The grades of stenosis in coronary arteries are also higher in diabetic patients when compared with non-diabetics with CAD, as was the prevalence of other components of the metabolic syndrome.     

Increased serum leptin concentrations in patients with chronic stable angina pectoris and ST-elevated myocardial infarction

Leptin is an adipocytokine that is produced mainly by adipose tissue; it is also identified in atherosclerotic lesions in human coronary atherosclerosis. However, the relation of serum leptin concentrations to ischemic heart disease (IHD) is still obscure. The aims of the present study were to investigate serum leptin concentrations in patients with ST-elevated myocardial infarction (STEMI) and with chronic stable angina pectoris (CSAP) and to evaluate the possible correlations of leptin to other atherosclerotic risk factors; including serum high sensitive C-reactive protein (Hs-CRP), serum homocysteine, and fibrinogen concentrations. For this purpose, 35 patients with CSAP, 40 with acute STEMI, and 30 control subjects with normal findings from coronary angiography were taken into the study prospectively. Serum leptin concentrations were significantly higher in patients with CSAP and STEMI compared to the control group (7.74 +/-1.34 vs 6.37 +/-1.85 ng/mL, p=0.021 and 8.22 +/-3.13 vs 6.37 +/-1.85 ng/mL, p=0.023, respectively). In addition, serum homocysteine concentrations were significantly increased in patients with CSAP (15.23 +/-5.96 vs 11.40 +/-2.11 micromol/L, p=0.025) and patients with STEMI (15.90 +/-5.02 vs 11.40 +/-2.11 micromol/L, p=0.012) compared to the control group. Serum fibrinogen concentrations were significantly increased only in the CSAP group as compared to controls (4.15 +/-1.39 vs 3.45 +/-1.19 g/L, p=0.025). No significant correlation was found between leptin levels and selected risk factors. In conclusion, serum leptin concentrations were significantly higher in both the CSAP and STEMI groups. However, owing to the lack of correlation between the leptin levels and selected classical coronary risk factors, it may be considered that leptin can be evaluated as one of the independent risk factors for IHD. Further randomized and controlled studies will be required to determine the pathophysiological meaning of the increased leptin levels and the central role between adipocyte function and atherosclerosis.     

Cellular immunostaining of angiotensin-converting enzyme in human coronary atherosclerotic plaques.

OBJECTIVES: The aim of this study was to determine the cellular localization of angiotensin I-converting enzyme (ACE) in the atherosclerotic plaque and its correlation with inflammation and cellular proliferation. BACKGROUND: Angiotensin I-converting enzyme inhibitors reduce the incidence of vascular events; therefore, tissue ACE may play a determinant role in the pathophysiology of the atherosclerotic plaque. METHODS: Histology and immunocytochemistry of de novo coronary plaques retrieved with directional coronary atherectomy from 141 patients were analyzed: 87 with stable angina, 39 with subacute unstable angina, and 15 with acute unstable angina. RESULTS: Compared with stable patients, unstable patients showed more thrombotic lesions (72% vs. 27%, p < 0.0001), smaller areas of fibrous plaque (2.3 +/- 1.2 mm2 vs. 2.8 +/- 1.1 mm2, p = 0.02), higher cellular proliferative score (0.78 +/- 0.9 vs. 0.27 +/- 0.6, p = 0.003), larger content of ACE-stained cells (26.3 +/- 23% vs. 12.6 +/- 15%, p = 0.005) and larger areas of inflammation as identified by CD68 immunostaining (29.5 +/- 22% vs. 20.2 +/- 19%, p = 0.02). A significant linear correlation was found between CD68- and ACE-stained areas (mm2) among unstable patients (r = 0.6, p = 0.0001), but it was absent among stable patients (r = 0.006, p = 0.9). Co-localization of ACE, CD68, and alpha-actin was confirmed by double immunostaining. Patients with Ki-67-positive staining as an index of cell proliferation showed also significantly larger areas of ACE immunoactivity (p = 0.004). CONCLUSIONS: Our data demonstrate ACE immunoactivity in inflammatory and proliferative cells of coronary atherosclerotic plaques. In particular, patients with unstable angina showed larger areas of ACE immunoactive tissue and proliferating cells compared with stable patients. These observations support a role of the enzyme in the pathophysiology of coronary unstable plaques and suggest potentially different effects of ACE inhibitors according to clinical presentation.     

Plaque inflammation in restenotic coronary lesions of patients with stable or unstable angina

OBJECTIVES: To evaluate immunohistochemically various parameters of inflammation in coronary atherectomy specimens obtained from restenotic culprit lesions of patients presenting with either stable or unstable angina (UA). BACKGROUND: There is no information regarding the relationship between atherosclerotic plaque inflammation and the severity of the coronary syndromes in patients with restenotic coronary lesions. METHODS: A total of 37 patients with either stable angina or UA underwent directional coronary atherectomy for restenotic coronary lesions. Cryostat sections of atherectomy specimen were immunohistochemically stained with monoclonal antibodies CD68 (macrophages [MACs]), CD3 (T-lymphocytes) and alpha-actin (smooth muscle cells [SMCs]). Smooth muscle cell contents and MAC contents were planimetrically quantified as the percentage immunopositive tissue area of the total tissue area. T-lymphocytes were counted at 100-X magnification throughout the entire section and expressed as number of cells per mm2. RESULTS: Restenotic coronary lesions of patients with UA or stable angina showed no significant difference in SMC areas (31.9%+/-16.3% vs. 38.5%+/-18.8%, respectively; p = NS). However, restenotic coronary lesions of patients presenting with unstable angina contained significantly more MACs (24.4%+/-15.1% vs. 10.5%+/-5.8%, p = 0.001) and T-lymphocytes (18.8 cells/mm2+/-15.1 cells/mm2 vs. 8.6 cells/mm2+/-9.8 cells/mm2; p = 0.034) than patients with stable angina. CONCLUSIONS: These results suggested that inflammation appears to affect plaque instability in restenotic coronary lesions resulting in unstable coronary syndromes.     

Carotid atherosclerotic plaque instability in patients with acute myocardial infarction

The instability of atherosclerotic plaque is partly determined by local factors, but systemic factors such as infection, inflammation, autoimmunity or genes might also be important. We aimed to analyze whether patients with acute myocardial infarction (AMI) might have a higher proportion of unstable plaques in the carotid arteries compared with patients who had had no acute coronary events. METHODS: Sixty-nine consecutive patients with AMI (Group 1) and 95 patients without acute coronary events (Group 2) had carotid artery duplex ultrasounds. Carotid atherosclerosis was quantified by number of plaques in the two carotid arteries, intimal media thickening and degree of maximal stenosis. According to their morphology, plaques were divided into stable (fibrocalcific) and unstable (soft and/or not homogeneous). RESULTS: The two groups did not differ as regards age (66+/-8 vs. 68+/-19; p=0.3), female sex (13% vs. 21%; p=0.3), mean number of carotid plaques (2.8+/-1 vs. 2.5+/-2; p=0.2), degree of stenosis (59+/-2% vs. 36+/-1%; p=0.2) or intimal media thickening (1.04+/-0.2 vs. 1.06+/-0.2; p=0.8). However, Group 1 pts more frequently had unstable carotid plaques compared with Group 2 (43% vs. 15%; p=0.004), and had a greater number of unstable carotid plaques (0.51+/-0.6 vs. 0.16+/-0.4: p<0.0001) and a higher ratio of unstable to stable plaque (19% vs. 8%; p=0.005). In the overall population, logistic regression analysis showed that after adjustment for degree of maximal stenosis, the presence of coronary artery event (AMI pts) predicted the presence of unstable carotid plaque (OR: 4.3 95% CI: 2.0-9.2; p=0.0002). CONCLUSION: Patients with unstable coronary artery disease expressed clinically as AMI, frequently had unstable atherosclerotic plaques in other arterial sites such as carotid arteries. This finding supports the hypothesis that plaque instability might reflect a systemic process.     

Association between complex coronary artery stenosis and unstable angina and the extent of plaque inflammation

PURPOSE: Patients with unstable coronary syndromes often have complex morphology of coronary stenoses at angiography. We evaluated the association between qualitative assessment of coronary stenoses and plaque inflammation determined by immunohistochemistry. METHODS: A total of 79 patients with unstable (n = 46) or stable angina (n = 33) underwent directional coronary atherectomy for culprit lesions. Qualitative analysis of coronary angiograms was performed using a modified Ambrose classification. Coronary lesions were categorized as either simple (concentric and eccentric type I, n = 29) or complex (eccentric type II and multiple irregularities, n = 50). Cryostat sections of retrieved atherosclerotic specimens were stained immunohistochemically with monoclonal antibodies, alpha-actin (smooth muscle cells), CD68 (macrophages), and CD3 (T lymphocytes). The extent of atherosclerotic inflammation within each coronary lesion was determined by the percentage of immunopositive macrophages per total tissue area (including smooth muscle cells) and the number of T lymphocytes per mm(2). RESULTS: The mean (+/- SD) percentage of macrophages in atherectomy specimens from patients with unstable angina was greater than in specimens from patients with stable angina (21% +/- 14% vs. 13% +/- 10%, P = 0.01); similar results were seen when complex coronary lesions were compared with simple lesions (23% +/- 13% vs. 9% +/- 8%, P <0.001). In multivariate linear regression models, the combination of unstable angina and lesion complexity was strongly associated with the percentage of plaque macrophages. CONCLUSION: The extent of atherosclerotic plaque inflammation is associated with angiographic grading of coronary lesion complexity and unstable angina.     

Broad and specific caspase inhibitor-induced acute repression of apoptosis in atherosclerotic lesions evaluated by radiolabeled annexin A5 imaging.

OBJECTIVES: The purpose of this study was to evaluate the role of caspase inhibitors on acute resolution of apoptosis in atherosclerotic lesions as evaluated by imaging with annexin A5. BACKGROUND: Extensive apoptosis of macrophages has been reported at the site of plaque rupture in patients dying of acute coronary syndrome. METHODS: Of 31 New Zealand White atherosclerotic rabbits, 6 received broad caspase, 3 received caspase-1, 3 received caspase-3, 3 received caspase-8, and 4 received caspase-9 inhibitors; 12 animals did not receive any caspase inhibitors (treatment control group). Six unmanipulated rabbits were used for comparison (disease control group). Technetium-99m-labeled annexin A5 was used for imaging atherosclerotic lesions; 6 of the 12 uninhibited atherosclerotic rabbits received (99m)Tc-labeled mutant annexin A5 (radiotracer control group). Gamma images were obtained, and quantitative radiotracer uptake was compared with pathologic findings. RESULTS: Atherosclerotic lesions were best visible in untreated atherosclerotic rabbits. Quantitative annexin uptake, defined as the percent of injected dose per g of abdominal aorta tissue, was significantly higher in untreated atherosclerotic animals (mean +/- SD = 0.0515 +/- 0.0099) compared with the normal rabbits (0.0065 +/- 0.0008; p < 0.0001) or atherosclerotic rabbits receiving mutant annexin (0.014 +/- 0.0024; p < 0.0001). Among all caspase inhibitor-treated rabbits, uptake was 39% lower (0.0314 +/- 0.0151) than in untreated atherosclerotic animals (p < 0.01). Uptake was also significantly lower in rabbits receiving broad caspase (0.0206 +/- 0.0058; p < 0.0001) or caspase-1, -3, or -9 (0.0272 +/- 0.0088, p < 0.01; 0.0286 +/- 0.0095, p < 0.01; 0.0300 +/- 0.0021, p < 0.01, respectively) inhibitors. Caspase-8 inhibitor did not affect apoptosis (0.0618 +/- 0.0047; p = NS). Upon histologic characterization, a substantial decrease in macrophage apoptosis was observed in caspase-inhibited animals. CONCLUSIONS: Molecular imaging, using radiolabeled annexin A5, allows the detection of acute resolution of apoptosis as a result of caspase inhibition in experimental atherosclerosis. If proven clinically, this may allow development of novel intervention strategies in acute vascular events.     

Effect of Chlamydia pneumoniae infection on coronary flow reserve and intimal hyperplasia after stent implantation in patients with angina pectoris.

OBJECTIVES: Chlamydia pneumoniae (C. pneumoniae) has been detected in tissue from coronary atherosclerotic vascular lesions and may be involved in the pathogenesis of atherosclerosis. However, the effect of prior C. pneumoniae infection on coronary intimal hyperplasia after stent implantation and on coronary microvascular function is unknown. METHODS: Seventy-three patients with stable angina pectoris and a single de novo coronary lesion were studied prospectively. All patients underwent successful coronary angioplasty and stent implantation for the stenotic lesion. Blood samples were tested for prior C. pneumoniae infection before the procedure, and patients were divided into two groups: Seropositive and seronegative. Coronary flow reserve was measured in the non-stenotic coronary vessel before angioplasty, and quantitative coronary arteriography was performed at the stent implantation site before angioplasty and 6 months later in all patients. RESULTS: Coronary flow reserve in the non-stenotic vessel was significantly lower in the seropositive group than in the seronegative group (2.51 +/- 0.35 vs 2.76 +/- 0.43, p < 0.05). The minimum luminal diameter was smaller and late loss was greater in the seropositive group than in the seronegative group (minimum luminal diameter: 1.52 +/- 0.59 vs 1.91 +/- 0.79 mm, p < 0.05, late loss: 1.17 +/- 0.55 vs 0.76 +/- 0.67, p < 0.05). However, there was no significant difference in the restenosis rate or target lesion revascularization rate between the two groups. CONCLUSIONS: Prior C. pneumoniae infection may accelerate intimal hyperplasia after stent implantation and impair coronary microvascular function in the non-stenotic coronary vessels.     

Relation between coronary atherosclerotic plaque burden and cardiac enzyme elevation following percutaneous coronary intervention

Several studies have reported that elevation of cardiac creatine kinase (CK) enzymes after percutaneous coronary intervention (PCI) is associated with an increase in cardiac morbidity and mortality during follow-up. However, it remains unclear if enzyme elevation contributes to the adverse outcomes or is simply a marker for adverse events. We conducted a case-control study to determine if angiographically determined atherosclerotic plaque burden correlated with CK elevation. Patients (cases, n = 23) with CK elevation after PCI were identified along with 46 age- and gender-matched controls without CK elevation. Detailed angiographic analysis quantified the percentage of coronary artery length with any luminal irregularity, a surrogate for plaque burden. The CK elevation group was characterized by a greater number of smokers (65% vs 33%, p = 0.02), more thrombus-containing lesions (22% vs 2.2%, p = 0.014), and more frequent abrupt closure (13% vs 0%, p = 0.03). In addition, the case group had a 50% increase in atherosclerotic plaque burden compared with controls (30 +/- 14% vs 20 +/- 14%, p = 0.006). These data suggest that CK elevation after PCI is a marker for more extensive atherosclerosis, which may explain the worse prognosis of these patients.     

Long-term safety of intravascular ultrasound in nontransplant, nonintervened, atherosclerotic coronary arteries

OBJECTIVES: The goal of this study was to demonstrate that intravascular ultrasound (IVUS) examination of native coronary arteries does not result in an acceleration of the atherosclerotic process. BACKGROUND: Intravascular ultrasound is increasingly used to assess the effects of pharmacologic agents on atherosclerosis. METHODS: Intravascular ultrasound examinations of one coronary artery and coronary angiography were performed in 525 patients at baseline. Patients then underwent a follow-up angiogram 18 to 24 months later. All end points were evaluated in IVUS-related and non-IVUS arteries using quantitative coronary analysis. The study end points were the coronary change score (per-patient mean of minimum lumen diameter changes for all lesions measured), occurrence of new coronary lesions, and progression of preexistent lesions at follow-up. Acute angiographic and clinical complications were also analyzed. RESULTS: Coronary change score was -0.06 +/- 0.23 mm and -0.05 +/- 0.21 mm for IVUS-related and non-IVUS arteries, respectively (p = 0.35). The increase in percent diameter stenosis from baseline to follow-up was 0.8 +/- 6.7% and 1.2 +/- 7.0% in the IVUS-related and non-IVUS arteries (p = 0.29). New lesions occurred in 3.6% and 3.9% of IVUS-related and non-IVUS arteries, respectively (p = 0.84). When all coronary lesions were considered, the incidence of lesion progression was not significantly different between IVUS-related (11.6%) and non-IVUS (9.8%) arteries. Coronary spasm occurred in 1.9% of IVUS procedures, and there was one case of acute occlusion with no long-term sequelae. CONCLUSIONS: Intravascular ultrasound does not significantly accelerate atherosclerosis in native coronary arteries and can be used safely to assess progression/regression in clinical trials.     

Morphologic rather than functional or mechanical sonographic parameters of the brachial artery are related to angiographically evident coronary atherosclerosis

OBJECTIVES: The purpose of this study was to determine the relationship among coronary atherosclerosis and functional, morphologic, and mechanical parameters assessed noninvasively within the brachial artery (BA). BACKGROUND: Flow-mediated vasodilation (FMD) of the BA, intima-media thickness (IMT) of the carotid artery, and distensibility of the aorta have been correlated with the presence of coronary artery disease (CAD). METHODS: The BA was examined with high-resolution ultrasound (13 MHz) in 117 male patients, in whom coronary angiography was performed. Coronary artery disease (> or =30% diameter stenosis in > or =1 major branch) was found in 84 patients, and 33 patients had smooth coronary arteries (non-CAD). Wall cross-sectional area (WCSA) was calculated from resting diameter and IMT. RESULTS: The BA-WCSA (5.3 +/- 1.5 mm(2) vs. 4.4 +/- 1.4 mm(2), p = 0.002) and IMT (0.37 +/- 0.07 mm vs. 0.31 +/- 0.07 mm, p < 0.001) were significantly greater in patients with CAD compared with non-CAD patients. Flow-mediated vasodilation and distensibility were similar among groups. Using logistic regression analyses adjusting for age, positive family history, hypertension, hypercholesterolemia, smoking, FMD, and distensibility, only WCSA (p < 0.01) and IMT (p < 0.001) correlated independently with the presence of CAD. CONCLUSIONS: Morphologic but not functional and mechanical parameters of the BA are associated with the presence of CAD. Among BA sonographic parameters, IMT and WCSA seem to be the most accurate ones for the estimation of coronary atherosclerotic risk.     

Soluble CD154 is not associated with atherosclerosis in systemic lupus erythematosus

OBJECTIVE: Soluble CD154 (sCD154) is involved in the pathogenesis of systemic lupus erythematosus (SLE), as well as in the initiation and progression of atherosclerotic lesions. We determined the association of sCD154 with coronary calcium and carotid plaque at the baseline visit of the Lupus Atherosclerosis Prevention Study. METHODS: Serum samples were assayed for soluble CD154 by ELISA. Coronary calcium was measured by helical computed tomography. Carotid duplex was performed to measure carotid plaque. RESULTS: sCD154 was measured in 183 patients with SLE. Patients had a mean age of 48.8 +/- 10.5 yrs, and 92% were female. Ethnicity included 61% Caucasian, 34% African American, 2% Asian, and 2% Hispanic. sCD154 was not associated with carotid plaque (p = 0.45) nor with coronary calcium (p = 0.43). Indeed, those with carotid plaque had a trend toward lower levels of sCD154 (474 +/- 29.2 vs 526 +/- 5 pg/ml; p = 0.45). CONCLUSION: sCD154 is not associated with subclinical measures of atherosclerosis in SLE, including carotid plaque and coronary calcium.     

凝集素样氧化低密度脂蛋白受体1在兔自体静脉移植物及其粥样硬化病变中的分布表达

目的自体静脉移植物粥样硬化的产生机制有其特殊性,我们研究了一种新的氧化低密度脂蛋白(OXLDL)的受体,即凝集素样氧化低密度脂蛋白受体1(LOX1)在兔自体静脉移植物及其粥样硬化病变中的表达,探讨其在静脉移植物粥样硬化形成中的作用。方法将30只新西兰大白兔随机分为正常对照组、单纯移植组和高脂移植组3组,分别给予普通饲料喂养(N=10)、单纯自体颈外静脉移植(N=10)和自体颈外静脉移植加高脂饲料喂养(N=10)。在实验12周末处死动物,静脉移植段行免疫组化染色检测LOX1的表达及分布,用半定量逆转录聚合酶链反应(RTPCR)检测LOX1MRNA表达的情况,并且统计分析血清总胆固醇水平、内膜厚度与LOX1的表达之间的关系。结果正常对照组的颈外静脉组织中仅见极少量LOX1表达于静脉内皮细胞表面;而单纯移植组的静脉移植物的新生内膜和内皮细胞层,可见LOX1的表达明显升高(0.31±0.14比0.09±0.04,P<0.01),其中LOX1表达最强的是内皮细胞;高脂移植组静脉移植物的内皮和粥样硬化部位,可见LOX1的表达更加显著上调(0.93±0.34比0.31±0.14,P<0.01),在粥样硬化部位,内皮细胞和泡沫细胞LOX1染色均阳性,而表达最强的也是内皮细胞。并且LOX1的表达和血清总胆固醇水平、内膜厚度均显著正相关(P=0.00和0.02),偏相关系数分别为0.78和0.42。结论LOX1表达于兔自体静脉移植物的内皮和新生内膜,表达量较正常静脉组织明显上调,高胆固醇血症可以上调静脉移植物粥样硬化部位LOX1的表达,提示LOX1可能参与了静脉移植物粥样硬化的发生发展。