Toshihiko Uchida

Comparison of Serum High-Molecular Weight (HMW) Adiponectin With Total Adiponectin Concentrations in Type 2 Diabetic Patients With Coronary Artery Disease Using a Novel Enzyme-Linked Immunosorbent Assay to Detect HMW Adiponectin

Adiponectin (Acrp30), an adipocyte-derived protein, exists in serum as a trimer, a hexamer, and a high–molecular weight (HMW) form, including 12–18 subunits. Because HMW adiponectin may be biologically active, we measured it in serum using a novel enzyme-linked immunosorbent assay (ELISA) confirmed by gel filtration chromatography that the ELISA detected mainly adiponectin with 12–18 subunits, and we compared HMW with total adiponectin concentration in patients with type 2 diabetes. We next investigated the relationship between serum HMW and coronary artery disease (CAD) in 280 consecutive type 2 diabetic patients, including 59 patients with angiographically confirmed CAD. Total adiponectin was measured in serum by a commercially available ELISA. Like serum total adiponectin, HMW adiponectin correlated positively with HDL cholesterol and negatively with triglyceride, insulin sensitivity, creatinine clearance, and circulating inflammatory markers. Total and HMW adiponectin were significantly higher in women than in men, as was the HMW-to-total adiponectin ratio. Serum HMW and the HMW-to-total adiponectin ratio were significantly lower in men with than without CAD (P < 0.05, respectively). In women, the ratio, but neither total nor HMW adiponectin, tended to be lower when CAD was present. In conclusion, determination of HMW adiponectin, especially relative to total serum adiponectin, is useful for evaluating CAD in type 2 diabetic patients.

Mobilization of CD34-Positive Bone Marrow–Derived Cells After Coronary Stent Implantation Impact on Restenosis

Background— Recently, accumulating evidence has indicated that bone marrow–derived stem cells are capable of differentiating into vascular cells. It has been hypothesized that the inflammatory response after vascular injury triggers the mobilization of endothelial and smooth muscle progenitor cells from bone marrow. Methods and Results— We measured circulating CD34-positive mononuclear cells, activation of integrin Mac-1 on the surface of neutrophils, and plasma granulocyte-colony stimulating factor levels in 40 patients undergoing coronary stenting. After bare-metal stenting, CD34-positive cells increased, reaching a maximum on day 7 after stenting. The maximum change compared with baseline before stenting was more striking in patients with restenosis than without restenosis (332±108% versus 148±49%; P<0.05). In contrast, CD34-positive cells decreased after sirolimus-eluting stenting (72±21% on day 7). The change in CD34-positive cells on day 7 relative to baseline was closely correlated with that in activated Mac-1 at 48 hours (R=0.52, P<0.01) and that in granulocyte-colony stimulating factor levels at 24 hours (R=0.42, P<0.05). Cell culture assay on day 7 showed that mononuclear cells differentiated into CD31-positive endothelium-like cells after bare-metal stenting. In patients with restenosis, mononuclear cells differentiating into α-smooth muscle actin–positive smooth muscle–like cells also were observed. Implantation of sirolimus-eluting stents suppressed both types of differentiation. Conclusions— Stent implantation may induce differentiation of bone marrow cells into endothelial or smooth muscle cells. Endothelial cells may participate in reendothelialization, a protective reaction against vascular injury, whereas smooth muscle cells may participate in neointimal thickening and restenosis. Sirolimus-eluting stents appear to inhibit the mobilization and differentiation of bone marrow cells.

Stent-induced expression and activation of the leukocyte integrin Mac-1 is associated with neointimal thickening and restenosis.

Background—Increased expression of the &bgr;2 integrin Mac-1 (CD11b/CD18, &agr;M&bgr;2), which is responsible for firm leukocyte adhesion to platelets and fibrinogen at injured vessels, is found in association with neointimal hyperplasia after coronary interventions. The role of Mac-1 in the pathophysiology of restenosis is incompletely defined. To clarify further the role of Mac-1, we determined whether coronary stenting induced activation of Mac-1, which is required for high-affinity receptor-ligand interactions. Methods and Results—Expression of CD11b (&agr;-subunit of Mac-1) and binding of 8B2 (monoclonal antibody against an activation-dependent neoepitope of Mac-1) on the surface of polymorphonuclear leukocytes were analyzed in 62 patients undergoing coronary stenting using flow cytometric analysis of whole blood obtained from the coronary sinus and femoral vein. Transcardiac CD11b expression increased significantly at 24 hours and maximally at 48 hours after stenting; 8B2 began to increase at 10 minutes and was maximally increased at 48 hours after stenting. These changes were more prominent in patients with subsequent restenosis. Multiple regression analysis showed that the late lumen loss by quantitative coronary angiographic analysis was independently correlated with the CD11b increase (R =0.42, P <0.01) and the 8B2 increase (R =0.55, P <0.001) 48 hours after the procedure. Mac-1 activation, as assessed by 8B2 binding, was the most powerful predictor of late lumen loss. Conclusion—Coronary stenting produced upregulation and early activation of the leukocyte integrin Mac-1, which is associated with late lumen loss and restenosis. These data support a role for inflammation in neointimal thickening and suggest the validity of targeting leukocyte recruitment for preventing clinical restenosis.

Clinical significance of antibody against oxidized low density lipoprotein in patients with atherosclerotic coronary artery disease

OBJECTIVES This study was designed to establish the clinical significance of antibodies against oxidized low density lipoprotein (anti-Ox-LDL) titer in atherosclerotic coronary artery disease (CAD). BACKGROUND Oxidative modification of LDL, which plays a key role in the development of atherosclerosis, induces immunogenic epitopes in the LDL molecule, and the presence of anti-Ox-LDL has been demonstrated in human sera. METHODS Anti-Ox-LDL titer was measured by enzyme-linked immunosorbent assay in 108 patients who had angiographically verified CAD, and 31 patients who had chest pain but no significant CAD, as controls. RESULTS The anti-Ox-LDL titer was higher (p < 0.01) in patients with multivessel CAD (19.4 +/- 10.1 AcU/ml, n = 68) than in the controls (9.8 +/- 4.1). However, no significant difference was shown between the single-vessel CAD group (15.1 +/- 6.4, n = 40) and the controls, or between the multivessel CAD group and the single-vessel CAD group. The titer was higher in patients with unstable angina (21.5 +/- 11.8 AcU/ml, n = 20, p < 0.01), or in patients with acute myocardial infarction (23.1 +/- 12.0, n = 20, p < 0.01) than in patients with stable-effort angina or old myocardial infarction (12.2 +/- 8.6, n = 68). Multiple logistic regression analysis indicated that the anti-Ox-LDL titer most powerfully discriminated CAD patients from controls (odds ratio [OR]: 1.20, 95% confidence interval [CI]: 1.07-1.33, p = 0.0006) and acute coronary syndrome from chronic CAD (OR: 1.09, 95% CI: 1.04-1.14, p = 0.0008). CONCLUSIONS Serum anti-Ox-LDL titer not only can predict a presence of atherosclerotic CAD but also may be a marker of plaque instability. Low density lipoprotein oxidation may play an important role in the development of plaque instability.

Antibody against oxidized low density lipoprotein may predict progression or regression of atherosclerotic coronary artery disease.

OBJECTIVES This study aimed to elucidate whether an antibody against oxidized low density lipoprotein (anti-Ox-LDL) could predict short-term coronary artery atherosclerotic lesion progression. BACKGROUND It is still controversial whether higher levels of the anti-Ox-LDL titer are associated with atherosclerotic coronary artery disease. METHODS In 52 patients undergoing coronary angioplasty and six-month follow-up angiography, we performed quantitative coronary angiographic analysis of a lesion on a branch away from the intervention site vessel and assessed lesion progression or regression using the Progression-Regression score calculated as the baseline minimal lumen diameter minus the follow-up minimal lumen diameter. The serum anti-Ox-LDL titer was measured using an enzyme-linked immunosorbent assay method just before the initial angiography in all patients. RESULTS The anti-Ox-LDL titer was 16.6+/-1.5 AcU/ml in the progression group (Progression-Regression score >0.15 mm; n = 20), which was significantly higher (p < 0.001) than the value of 9.5+/-1.2 in the regression group (< or =-0.15 mm; n = 14) and also higher (p < 0.01) than the value of 11.4+/-1.3 in the no-change group (-0.15 to 0.15 mm; n = 18). The Progression-Regression score was correlated with the antibody titer in all patients (r = 0.56, p < 0.001). Multiple regression analysis showed that the Progression-Regression score was independently correlated with the antibody titer (r = 0.44, p < 0.01) as well as lipoprotein (a) (r = 0.33, p < 0.05). CONCLUSIONS Anti-Ox-LDL may be an independent predictor of coronary atherosclerotic lesion progression in the short term.

Clinical Significance of the Antibody against Oxidized Low-Density Lipoprotein in Acute Myocardial Infarction

To establish the clinical significance of the antibody against oxidized low-density lipoprotein (anti-Ox-LDL) titer in patients with acute myocardial infarction (AMI), we measured the anti-Ox-LDL titer in 39 patients with AMI and 25 controls. In all AMI patients, the anti-Ox-LDL titer on admission was higher (p < 0.05) than the value in the controls. One month after admission, the titer decreased significantly (p < 0.001) reaching control levels. In patients who underwent thrombolytic therapy, the anti-Ox-LDL titer on admission was identical in patients with occluded infarct-related arteries (IRA) and patients with patent IRA during emergency coronary angiography. In patients who did not undergo thrombolytic therapy, the anti-Ox-LDL titer on admission was higher in patients with occluded IRA than in patients with patent IRA. An increased anti-Ox-LDL titer may be a risk factor for the onset of AMI. Spontaneous recanalization of the IRA may be associated with increased anti-Ox-LDL titers, while thrombolysis-induced recanalization may be independent of it.

Effects of losartan on serum total and high-molecular weight adiponectin concentrations in hypertensive patients with metabolic syndrome

High-molecular weight (HMW) adiponectin may have the most biologic activity among several isoforms. We investigated long-term effects of losartan on serum concentrations of total and HMW adiponectin in hypertensive patients with metabolic syndrome (MS) by serial measurements over 6 months. Forty hypertensive patients first received 50 mg of losartan. Upward titration of the losartan dose was implemented to reach a target blood pressure of less than 140/90 mm Hg. Serum total adiponectin and HMW adiponectin were measured at study entry (baseline), the 3-month treatment time point, and the end of the 6-month period. Non-HMW adiponectin (ie, medium- and low-molecular weight adiponectin) was calculated as total adiponectin--HMW adiponectin. Diagnosis of MS was done by current standard criteria. In hypertensive patients without MS (n = 21), the serum total adiponectin increased from 9.8 +/- 5.4 microg/mL at baseline to 11.1 +/- 6.2 microg/mL at 6 months (P < .01). Furthermore, the serum total adiponectin was significantly higher at 6 months than at 3 months (P < .01). Serum HMW adiponectin also increased from 5.7 +/- 3.9 microg/mL at baseline to 6.6 +/- 4.4 microg/mL at 6 months (P < .01). In hypertensive patients with MS, the serum total adiponectin increased from 6.0 +/- 2.7 mug/mL at baseline to 6.7 +/- 3.3 microg/mL at 3 months and to 7.0 +/- 3.1 microg/mL at 6 months (P < .01 for both). Furthermore, the serum HMW adiponectin concentration was significantly higher at 6 months than at 3 months (P < .001). However, the serum non-HMW adiponectin concentration did not change during treatment in either group. In conclusion, serum total and HMW adiponectin concentrations increase after 6 months of losartan treatment in hypertensive patients, irrespective of the presence or absence of MS.

Unusual coronary artery aneurysm and acute myocardial infarction in a middle-aged man with systemic lupus erythematosus

A 55-year-old man developed acute myocardial infarction (AMI) related to a large coronary artery aneurysm and a distal coronary stenotic lesion after steroid therapy for systemic lupus erythematosus (SLE). Only 13 SLE patients with AMI caused by coronary artery aneurysms have been reported, 11 of whom were young or middle-aged women and the 2 remaining were young men. This is the first report of a middle-aged man with multiple coronary lesions.

Significance of platelet aggregability immediately after blood sampling and effect of cigarette smoking

A novel type platelet aggregometer, a WBA Analyzer, has enabled us to obtain the platelet aggregability data immediately after blood sampling, which is considered to closely reflect in vivo platelet function. Using this analyzer, we measured the platelet aggregatory threshold index (PATI) 5 min after blood sampling and compared it with that 60 min after blood sampling in 20 healthy male volunteers (10 smokers and 10 non-smokers). In the non-smokers, PATI was 10.3 - 2.3 w M 5 min after blood sampling, and it decreased to 4.7 - 1.5 ( P <0.001) 60 min after blood sampling. In the smokers, the PATI was 7.7 - 2.9 w M 5 min after blood sampling, and it decreased to 3.8 - 1.5 ( P <0.001) at 60 min after blood sampling. In the smokers, the PATI 5 min after blood sampling increased after a 4-week cessation of smoking (10.4 - 2.9, P <0.01), although the PATI 60 min after blood sampling did not change (4.2 - 1.6 w M). The measurement of platelet aggregability immediately after blood sampling using a WBA Analyser may be useful to evaluate not only platelet function in various thrombotic disorders, but also the effects of various anti-platelet drugs. Cessation of smoking should also be encouraged in the light of the adverse effects on platelet function.

Prediction of short-term progression or regression of atherosclerotic coronary artery disease by lipoprotein (a): a quantitative coronary angiographic study.

This study assessed whether progression of coronary artery atherosclerotic lesions could be predicted in the short term using various lipid profiles. In 37 patients (61.9 ±9.5 years) under going coronary angioplasty and with 6-month follow-up angiography, quantitative coronary angiography of a new or changed lesion was performed in the follow-up examination, except for intervention vessels. The progression-regression score of the assessed lesion was calcu lated as the baseline minus the follow-up minimal lumen diameter. The serum lipoprotein (a) level was higher in the progression group (progression-regression score >0.15 mm), than in the regression group (≤ -0.15 mm; p<0.01) and the no change group (within ±0.15 mm; p < 0.05). Remnant-like lipoprotein particle-cholesterol and apolipoprotein-B levels were also higher in the progression group. However, multiple regression analysis of the progression showed that the progression-regression score was independently correlated with lipoprotein (a) alone (R = 0.50, p < 0.05). This shows that lipoprotein (a) is an independent predictor of coronary atherosclerotic lesion progression over the short term.