Seiya Tanaka

Simvastatin increases plasma NO2− and NO3− levels in patients with hypercholesterolemia

In this study, plasma NO2- and NO3- (NOx-) levels were studied after lowering cholesterol with simvastatin in 26 outpatients with hypercholesterolemia (male, 9; female, 17; mean age, 59 +/- 12 years; cholesterol level > 220 mg/dl). Simvastatin (5 mg) was orally administered once daily, and blood samples were collected before, and after 4 and 12 weeks of treatment. Total, very-low-density lipoprotein (VLDL), and low-density lipoprotein (LDL) cholesterol were lowered (total, 254 +/- 44 mg/dl to 209 +/- 34 mg/dl; VLDL, 48 mg/dl [5-126 mg/dl] to 34 mg/dl [10-67 mg/dl]; LDL, 171 +/- 41 mg/dl to 133 +/- 37 mg/dl), but high-density lipoprotein (HDL) cholesterol was elevated (33 +/- 9.5 mg/dl to 39 +/- 11 mg/dl) at 12 weeks after starting simvastatin. Although the effects of simvastatin on the lipid levels nearly reached their maximum levels at 4 weeks, NOx- was elevated in a linear fashion with simvastatin (before; 8 +/- 17 mumol/l, at 12 weeks; 57 +/- 32 mumol/l). The % changes in the NOx- correlated directly with those in HDL-cholesterol at 12 weeks (P < 0.002) but not with other lipoprotein cholesterol fractions. These results suggest that simvastatin lowers cholesterol levels and elevates HDL while increasing the plasma NOx- levels.

ENHANCED MACROPHAGE UPTAKE OF LIPOPROTEIN(A) AFTER CA2+-INDUCED AGGREGATE-FORMATION

We tested the hypothesis that aggregated lipoprotein(a) [Lp(a)] is avidly taken up by macrophages. Lp(a) was isolated by sequential centrifugations and gel chromatography from a patient with high plasma levels of Lp(a) who was being treated with low density lipoprotein (LDL)-apheresis. Aggregated Lp(a) was prepared by mixing native Lp(a) with 2.5 mmol/L CaCl2, and 54% of the 125I-Lp(a) aggregated after interacting with CaCl2. The binding and degradation of aggregated Lp(a) in macrophages were 4.6- and 4.7-fold higher than those of native Lp(a), respectively. An excess amount of LDL did not inhibit either increase. Cholesterol esterification in macrophages was markedly stimulated by aggregated Lp(a), and macrophages were transformed into foam cells. Cytochalasin B, a phagocytosis inhibitor, strongly inhibited the degradation and cholesterol esterification (78 and 83%, respectively). These findings suggested that aggregation may be partially involved in Lp(a) accumulation, thereby contributing to the acceleration of atherosclerosis.

Comparative effects of dobutamine and amrinone on coronary blood flow in patients with idiopathic dilated cardiomyopathy.

Although amrinone has favorable hemodynamic effects in patients with congestive heart failure, little is known about its effects on coronary blood flow (CBF). We compared the effects of intravenous low-dose dobutamine and amrinone on CBF in 10 patients with dilated cardiomyopathy using a Doppler guidewire. We infused dobutamine at a dose of 5 and 10 microg/kg/min for 5 min. After the end of each stage, coronary flow velocity (CFV) and coronary arterial diameter (CAD) in the proximal left anterior descending coronary artery, and hemodynamic variables were obtained. After the CFV and hemodynamics returned to baseline, we infused 1 mg/kg of amrinone over 5 min, and obtained these variables at 5 and 10 min after the cessation of the infusion. CAD did not increase with dobutamine, but significantly increased after amrinone (% increase: 10 +/- 7%; P < 0.001 vs. baseline). CFV progressively increased with dobutamine (5 microg/kg/min: 21 +/- 26%; P < 0.05 vs. baseline; 10 microg/kg/min: 53 +/- 42%; P < 0.005 vs. baseline and 5 microg/kg/min), but slightly decreased after amrinone (-4 +/- 17%; P = not significant vs. baseline). CBF increased during dobutamine (5 microg/kg/min: 25 +/- 29%; P < 0.05; 10 microg/kg/min: 66 +/- 55%; P < 0.005) and after amrinone (19 +/- 22%; P < 0.05) compared to that at baseline. Although there was a significant correlation between the percent increase in CFV and that in dP/dt during dobutamine infusion (r = 0.82, P < 0.001), this correlation was not observed after amrinone (r = 0.23). In conclusion, although both agents significantly increased CBF in patients with dilated cardiomyopathy, they do so by different mechanisms. Amrinone mainly increases CBF by causing dilatation of epicardial coronary arteries. These results suggest that amrinone has beneficial effects on coronary flow dynamics in dilated cardiomyopathy.

The Correlation between Post-Procedural Plasma Fractalkine and Lipid Plaque Volume in Target Lesion after Coronary Stent Implantation

Several reports suggest that fractalkine (FKN) and its cognate receptor, CX3CR1, play a role in atherogenesis. Recent data showed that plasma FKN is elevated in patients with unstable angina pectoris and is more elevated with patients with plaque rapture. We assessed the hypothesis that plasma FKN might be elevated after stentimplantation and related to the plaque-characteristics. First of all we tested the time course of plasma FKN level 30-min., 3-hour, 6-hour and 12-hour after coronary stenting. Their levels are elevated at 30 min. after percutaneous coronary intervention (PCI) and maintained the level until 12-hour after PCI. Then we examined the plasma levels of FKN, IL-8 and IL-6 in fifty consecutive patients before and 12-hour after coronary stenting following in integrated backscatterintravascular ultrasound (IB-IVUS) analysis. The plasma IL-8 did not change 12-hour after stenting. Those of FKN and IL-6, however, were significantly elevated 12-hour after stenting (FKN: from 656 ± 122 pg/mL to 811 ± 177 pg/ mL, p<0.0001, IL-6: from 3.15 ± 3.42 pg/mL to 16.0 ± 15.0 pg/mL, p<0.0001). In IB-IVUS analysis the lipid volume and volume fraction were correlated with post-procedural FKN level (R2=0.29, p<0.0001; R2=0.22, p<0.0001), while they were not related with post-procedural IL-6 level. In conclusion, a local release of FKN and IL-6 occurs shortly after PCI, which is possibly related to plaque rapture and/or endothelial traumatism following stent-implantation. We have further shown that local release of FKN is evoked proportionally to the volume of the lipid-rich plaques which are prone to be ruptured. These suggested that anti-FKN treatment could be of benefit to decrease the amount of lipid-rich plaque.

Pulmonary Tumor Thrombotic Microangiopathy by Lung Adenocarcinoma

Ikutarou Furuno1,2, Seiya Tanaka1, Hiromichi Ueno2, Hisaharu Ooe2, Yugo Yoshida3, Takashi Harada1, Yukikazu Awaya3, Hiromi Tasaki1, Tatsuro Shimokama4 From the Department of Cardiology1and Respirology3, Kitakyushu Municipal Yahata Hospital, 4-18-1 Nishihon-machi, Yahatahigashi-ku, Kitakyushu, Japan; The Second Department of Internal Medicine2, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan; and Department of Pathology4, Steel Memorial Yawata Hospital, Kitakyushu, Japan. Pulmonary Tumor Thrombotic Microangiopathy by Lung Adenocarcinoma