Association between adiponectin production in coronary circulation and future cardiovascular events in patients with coronary artery disease.

Adiponectin has antiatherosclerotic properties and is also produced in the local coronary circulation. We previously reported that significantly less adiponectin was produced in the coronary circulation of patients with than without coronary artery disease (CAD). The goal of this study was to determine whether adiponectin production in the coronary circulation could predict future cardiovascular events in patients with CAD.Forty-eight CAD patients whose left anterior descending coronary arteries required percutaneous coronary intervention (PCI) were enrolled. The amount of adiponectin production in the coronary circulation was defined as the plasma adiponectin level at the great cardiac vein minus that at the orifice of the left coronary artery. All patients were divided by adiponectin production level in the coronary circulation into the adiponectin-positive production group (> 0 µg/ mL) and adiponectin-negative production group (≤ 0 µg/mL). Median follow-up period was 66 months (maximum, 108 months). The primary endpoint was the combined occurrence of major adverse cardiovascular events (MACE), including rehospitalization due to unstable angina, heart failure, nonfatal myocardial infarction, revascularization with PCI or coronary artery bypass grafting, ischemic stroke, and cardiovascular death.Sixteen MACE occurred. The incidence of MACE was significantly higher in the adiponectin-negative production group than in the adiponectin-positive production group (P = 0.02). In multivariate analysis, adiponectin-negative production was a predictor of MACE (P = 0.03). Kaplan-Meier analysis revealed that the MACE-free rate was significantly lower in the adiponectin-negative production group than in the adiponectin-positive production group.Adiponectin production in the coronary circulation with CAD may be associated with MACE.

Adiponectin produced in coronary circulation regulates coronary flow reserve in nondiabetic patients with angiographically normal coronary arteries.

BACKGROUND: Epicardial adipose tissue expresses adiponectin protein, and its expression is significantly lower in patients with severe coronary artery disease (CAD) than in those without CAD. Transcoronary adiponectin levels are significantly decreased in nondiabetic but not in diabetic patients with CAD. Adiponectin is also an important adipocytokine that is linked to insulin resistance and reduces coronary microvascular function. HYPOTHESIS: Adiponectin may play a significant role in the localized coronary circulation. The present study examines the local dynamics of adiponectin in the coronary circulation in nondiabetic individuals with normal coronary arteries and the relationship between adiponectin and coronary microvasculature function. METHODS: We examined 22 consecutive nondiabetic patients whose coronary arteries were angiographically normal. Plasma levels of adiponectin were measured in blood samples that were simultaneously collected from the orifice of the left coronary artery (LCA) and the great cardiac vein (GCV). To evaluate the function of the coronary microcirculation, we measured coronary flow velocity at maximal hyperemia using a Doppler wire. Coronary flow reserve (CFR) was obtained from the ratio of hyperemia to the baseline coronary flow velocity. RESULTS: Plasma adiponectin levels in the GCV (median 6.95 microg/ml) were significantly higher than those in the LCA (median 6.60 microg/ml, p < 0.0005). The difference in plasma adiponectin levels between GCV and LCA significantly correlated with CFR (R = 0.451, p < 0.05). CONCLUSIONS: Adiponectin is locally produced in the coronary circulation. This protein may participate in modulating the coronary circulation of nondiabetic patients with angiographically normal coronary arteries.

Increased expression of interleukin-10 in unstable plaque obtained by directional coronary atherectomy.

AIMS: The present study investigates the expression and localization of interleukin (IL)-10, an important anti-inflammatory cytokine, in atherectomy specimens from patients with stable and unstable angina. METHODS AND RESULTS: Twenty-two patients with stable angina and 21 with unstable angina who underwent directional coronary atherectomy for de novo lesions were studied. The atherectomy specimens were morphologically assessed and immunohistochemically stained with antibodies for IL-10, macrophages, smooth muscle cells, and endothelial cells. The localization and immunopositive areas were evaluated using an image analysing system. Immunoreactivity for IL-10 was detected in coronary plaques, especially in macrophages. Immunopositive areas of macrophages and IL-10, as well as the incidence of thrombus formation, were significantly greater in specimens from patients with unstable angina than in those from patients with stable angina (macrophages, P<0.001; IL-10, P<0.05; thrombus formation, P<0.05; respectively). Even after adjustment, IL-10 expression and the incidence of thrombus formation were significantly greater in the unstable angina group (P<0.05, each). The immunoreactivities for smooth muscle cells and endothelial cells did not differ between the two groups. CONCLUSION: IL-10 was more frequently expressed in specimens from patients with unstable angina. This finding might contribute to a better understanding of plaque instability.

Detection of von Willebrand factor and tissue factor in platelets-fibrin rich coronary thrombi in acute myocardial infarction.

The rapid closure of coronary arteries due to occlusive thrombi is the major cause of acute myocardial infarction. However, the mechanisms of coronary thrombus formation have not been elucidated. We immunohistochemically assessed the localizations and their changes over time of glycoprotein IIb/IIIa, fibrin, von Willebrand factor (vWF), and tissue factor (TF), after the onset of chest pain (<4, 4 to 6, or 6 to 12 hours), in fresh coronary thrombi causing acute myocardial infarction. The occlusive thrombi were consistently composed of platelets, fibrin, vWF, and TF from the early phase of onset, and glycoprotein IIb/IIIa and fibrin were closely associated with vWF and TF, respectively. vWF and/or TF may contribute to occlusive thrombus formation and be novel therapeutic candidates for treating patients with coronary thrombosis.

Effects of interleukin-6 produced in coronary circulation on production of C-reactive protein and coronary microvascular resistance.

We measured plasma levels of interleukin-6 and C-reactive protein at the orifice of the left coronary artery and at the great cardiac vein in patients who had coronary artery disease and those who had angiographically normal coronary arteries (controls). We also measured coronary microvascular resistance in the control group. We found increased levels of interleukin-6 in the coronary circulation of patients who had coronary artery disease compared with controls. This increase correlated with C-reactive protein production in the coronary circulation and coronary microvascular resistance. These findings suggest that a localized cytokine/inflammatory pathway functions in the coronary circulation and that interleukin-6 is involved in modulating coronary vascular tone.

Cerebral sinus thrombosis associated with severe active ulcerative colitis.

A 19-year-old man with severe active ulcerative colitis was admitted to our hospital where he was prescribed 80 mg prednisolone and underwent leukocytapheresis (LCAP). Two weeks after initiating therapy, his symptoms had not recovered. We administered cyclosporin via continuous intravenous infusion for 12 days. Although his clinical symptoms improved, he complained of severe headache. Immediate plain computed tomography (CT) and magnetic resonance imaging angiography (MRA) revealed extensive thrombosis in the superior sagittal sinus and right transverse sinus. We treated this condition with the anticoagulant agent, heparin, which prevents and can treat venous thrombosis. We report an occurrence of cerebral sinus thrombosis accompanying ulcerative colitis, where active anticoagulant therapy was useful.

Relation of C-reactive protein to restenosis after coronary stent implantation and to restenosis after coronary atherectomy.

To determine whether the inflammatory response is equally involved in the pathogenesis of restenosis after coronary stenting and directional coronary atherectomy, we assessed restenotic lesions with immunohistochemical methods. Levels of C-reactive protein and macrophages were greater in patients with in-stent restenosis than in those with restenosis after directional coronary atherectomy. This suggests that the inflammatory response is more involved in the pathogenesis of in-stent restenosis than in restenosis after directional coronary atherectomy.

Possible contribution of C-reactive protein within coronary plaque to increasing its own plasma levels across coronary circulation.

C-reactive protein (CRP) mRNA was detected in coronary plaque. Plasma CRP levels across the coronary circulation were increased much more in patients with unstable angina pectoris and somewhat more in those with stable angina pectoris compared with controls whose coronary arteries were angiographically normal. Thus, CRP within coronary plaque might contribute to increased plasma CRP levels across coronary circulation, particularly among patients with unstable angina pectoris.

Differential increase in natriuretic peptides in elite dynamic and static athletes.

The echocardiographic measures and plasma concentrations of either atrial natriuretic peptide (ANP) or brain natriuretic peptide (BNP) were compared in elite judo practitioners (static athletes), elite marathon runners (dynamic athletes) and healthy controls to investigate the relationship between the different types of left ventricular (LV) hypertrophy and plasma concentrations of natriuretic peptides in athletes. The LV mass and LV wall thickness of marathon runners and judo practitioners were significantly greater than those of controls. The LV end-diastolic dimension index was significantly larger in the marathon group, but smaller in the judo group. The left atrial dimension (LAD) index was significantly larger only in marathon runners. Plasma BNP concentrations were higher in both the judo and marathon groups than in controls, and positively correlated with LV mass as well as with deceleration time. Plasma ANP concentrations were significantly higher in marathon runners than in the controls and judo groups, and positively correlated with the LAD index, but negatively correlated with ejection fraction. Multivariate analyses showed that the type of athlete and LAD index were independent predictors of plasma BNP and ANP concentrations, respectively. Thus, there is an intimate link between plasma concentrations of natriuretic peptides and cardiac morphology in different types of athletes.

Two cases of pheochromocytoma associated with tetralogy of Fallot.

We report two cases of pheochromocytoma combined with tetralogy of Fallot who showed different clinical courses. Case 1 was a 45-year-old woman with a history of radical operation for tetralogy of Fallot at 20 years of age. She presented with sudden hypertensive attack, and was diagnosed with pheochromocytoma of the left adrenal gland. She was treated surgically, and her high plasma noradrenaline level normalized. Case 2 was a 41-year-old woman who had been suffering from severe cyanosis due to tetralogy of Fallot throughout her life. A palliative operation had been performed at 7 years of age, but a radical operation had not been performed. She has had resistant hypertension since 38 years of age. She was diagnosed as having pheochromocytoma of the left adrenal gland at 41 years of age, but surgery was not performed. She was pharmacologically treated with doxazosin, followed by bisoprolol. Her symptoms somewhat improved, although she continued to have high plasma levels of noradrenaline and adrenomedullin. The combination of pheochromocytoma with tetralogy of Fallot or cyanotic congenital heart disease is rare; however, pheochromocytoma and congenital heart disease might be related through chronic hypoxia and/or gene abnormalities. The presence of pheochromocytoma worsens the hemodynamic state in patients with congenital heart disease regardless of whether radical surgery for congenital heart disease had been performed. Differential diagnosis of pheochromocytoma could be paramount in congenital heart disease patients who show unexpected or unusual symptoms.

Hyperkalemia induced by the calcium channel blocker, benidipine.

A 73-year-old hypertensive, non-diabetic woman without obvious renal dysfunction had frequently been hyperkalemic over four years after receiving antihypertensive drugs including the calcium channel blocker (CCB) benidipine. One week after all medications were accidentally discontinued, the serum potassium level returned to normal. After we obtained the informed consent of the patient, benidipine alone was administered again for over two weeks and hyperkalemia developed once more. This previously uncommon side effect of hyperkalemia induced by benidipine is not very serious but it is apt to be overlooked. Since CCBs are now widely prescribed, the development of hyperkalemia should be considered.

Involvement of C-reactive protein obtained by directional coronary atherectomy in plaque instability and developing restenosis in patients with stable or unstable angina pectoris.

We investigated whether positive immunohistochemical staining of C-reactive protein (CRP) in initial culprit lesions is related to coronary plaque instability and whether it could affect the outcome of directional coronary atherectomy (DCA). The plasma level of CRP is a reliable marker of the risk of coronary events and restenosis after percutaneous coronary intervention. However, the influence of tissue CRP in atheromatous plaque on plaque vulnerability and restenosis remains unknown. Samples of DCA obtained from 12 patients with stable angina pectoris and 15 patients with unstable angina pectoris were immunohistochemically stained with a monoclonal antibody against CRP. We performed follow-up coronary angiography on 22 of 27 patients to evaluate the presence of restenosis after DCA. Immunoreactivity to CRP was localized to macrophages, smooth muscle cells, and necrotic areas. The ratio of CRP positive cells to total cells was significantly higher in DCA samples from patients with unstable (17.9 +/- 2.0%) than with stable angina (11.0 +/- 2.5%) (p <0.05). Follow-up coronary angiography showed that 12 of 22 patients developed restenosis after DCA. The ratio was also significantly higher in DCA specimens from patients with restenosis (19.3 +/- 2.8%) compared with those without restenosis (11.0 +/- 2.0%) (p <0.05). In addition, the ratio significantly correlated with late luminal loss (r = 0.428, p <0.05) and loss index (r = 0.636, p = 0.0011) after DCA. Immunoreactivity to CRP in coronary atheromatous plaque increases in culprit lesions of unstable angina, and it affects restenosis after DCA. These findings suggest that CRP in atheromatous plaque plays an important role in the pathogenesis of unstable angina and restenosis after coronary intervention.

Interstitial pneumonia induced by ticlopidine.

A 67-year-old female non-smoker, who had been diagnosed with familial hypercholesterolemia associated with severe atherosclerosis of the coronary, carotid and vertebral arteries, developed interstitial pneumonia 4 months after initiating ticlopidine to inhibit platelet aggregation. The lymphocyte stimulation test by ticlopidine was positive and bronchoalveolar lavage fluid showed an increase in lymphocytes and a decrease in the CD4+/8+ ratio, suggesting potentially undesirable side effects of ticlopidine. Two months after ticlopidine therapy was discontinued and prednisolone therapy started, the interstitial pneumonia had almost completely resolved. Two patients, one with ticlopidine-associated bronchiolitis obliterans organizing pneumonia and the other with pneumonia with multiple nodules, have been reported to date and the present patient is the third reported case of ticlopidine-induced pneumonia. The incidence of this side effect may not be so high because approximately 20 years have passed since ticlopidine was first marketed in Japan, but because the drug is now widely prescribed, this serious clinical side effect should be considered.