The waveform index of the ophthalmic artery predicts impaired coronary flow reserve.

BACKGROUND: Coronary flow reserve (CFR) can decrease with impairment in coronary microcirculation, even in the absence of epicardial conduit obstruction. Recently, the ophthalmic artery (OA), which is the first major branch of the internal carotid artery and is representative of microarterioles, has been identified using color Doppler sonography. However, the features of ultrasound waveform indices suggestive of impaired OA microcirculation and the relationships between these indices and CFR have not been elucidated. The present study aimed to assess the features of ultrasound waveform indices suggestive of impaired OA microcirculation and the relationships between these indices and CFR. METHODS AND RESULTS: A total of 30 consecutive patients with a normal coronary angiogram and normal left ventricular function were studied. Patients with ≥ 25% stenosis of the right common or internal carotid artery were excluded. The CFR was defined as the ratio of adenosine-induced hyperemic to baseline blood flow velocity with an intracoronary Doppler guidewire. Color Doppler imaging was used to determine the blood flow velocity of the right OA, and the indices of peripheral resistance (resistance index [RI], pulsatility index [PI], and systolic mean velocity to diastolic mean velocity [Sm/Dm] ratio) were calculated. The ultrasound form showed a distinctive biphasic wave during systole followed by a monophasic wave during diastole. The velocity component in the early-systolic wave was higher than that in the mid-systolic wave or the diastolic wave (31.4 ± 5.1 vs. 26.1 ± 5.4 vs. 15.9 ± 4.0 cm/s, P<0.0001). The RI and PI were not related to the CFR, and the Sm/Dm ratio was negatively correlated with the CFR (ß=-0.415, P=0.022). However, the relationship was attenuated by clinical variables closely associated with the Sm/Dm ratio or CFR, and hemoglobin A1c was a common mediator. The best Sm/Dm ratio cutoff for predicting an impaired CFR was 2.5 based on a receiver operating characteristic curve analysis. CONCLUSIONS: An increase in the Sm/Dm ratio, which reflects a characteristic waveform, indicates impaired OA microcirculation. The ratio is negatively correlated with CFR, and therefore, it may be applied for the noninvasive evaluation of coronary physiology. Furthermore, hemoglobin A1c may be a common mediator for the OA and coronary microcirculation.

Coronary plaque component in patients with vasospastic angina: a virtual histology intravascular ultrasound study.

BACKGROUND: Coronary spasm plays an important role in the pathogenesis of ischemic heart disease. However, tissue components of coronary plaque in patients with vasospastic angina (VSA) have been unknown. This study used virtual histology (VH)-intravascular ultrasound (IVUS) to elucidate the tissue component of spastic coronary arteries and its gender differences in patients with VSA. METHODS: According to acetylcholine provocation tests, the study subjects (42 patients [19 men, 23 women, 61 ± 13 years]) were divided into 2 groups: the VSA group of 26 patients and the non-VSA group of 16 patients. After nitrate injection, IVUS volumetric analysis was done, and the parameters were compared between the groups. RESULTS: Although clinical demographics were almost identical between the groups, VSA group had lower plasma adiponectin level (5.9 ± 3.3 µg/ml vs. 11.2 ± 7.6 µg/ml, p=0.007) and tended to have higher high-sensitivity C-reactive protein (0.15 ± 0.24 mg/dl vs. 0.06 ± 0.04 mg/dl, p=0.1) than non-VSA group. VSA group had diffusely thickened intima (% plaque volume, 34 ± 11% vs. 27 ± 7%, p=0.01) compared with non-VSA group. However, plaque components of patients with VSA were similar with that of non-VSA patients (dense calcium, 4 ± 6% vs. 3 ± 4%; necrotic core, 10 ± 9% vs. 8 ± 6%; fibrofatty, 19 ± 16% vs. 22 ± 11%; and fibrous, 67 ± 16% vs. 67 ± 9%). Although male patients with VSA had atherogenic lipid and metabolic profiles than female VSA patients, there were no significant gender differences in the volumetric IVUS parameters and plaque components. CONCLUSIONS: Compared with non-VSA patients, VSA patients had diffusely thickened fibrous-dominant coronary plaque without gender difference, and that might suggest the role of vasospasm in the development of atherosclerosis.

Long-term use of oral nicorandil stabilizes coronary plaque in patients with stable angina pectoris.

OBJECTIVE: The Impact of Nicorandil in Angina (IONA) trial demonstrated that the use of nicorandil, an anti-anginal drug, reduced future cardiovascular events in patients with stable angina. We hypothesized that nicorandil has beneficial effects on coronary arterial plaque characteristics and atherosclerogenesis. METHODS AND RESULTS: Preintervention intravascular ultrasound-virtual histology was performed prospectively in 65 consecutive patients with stable angina pectoris. There were no differences in coronary risk factors between the nicorandil (n = 16) and non-nicorandil (n = 49) groups. However, the nicorandil group demonstrated a larger %fibrous tissue (68 ± 10 vs. 62 ± 11%, P = 0.049) and a smaller %necrotic core tissue (11 ± 7 vs. 16 ± 10%, P = 0.049) compared with the non-nicorandil group. Multiple regression analysis showed that %necrotic core tissue (P = 0.045) was negatively and %fibrous tissue (P = 0.026) was positively associated with the use of nicorandil independent of statin use. We also analyzed the effect of nicorandil on atherosclerotic lesion formation in a mouse model of atherosclerosis. Lipid profiles were unaffected, but the area of atherosclerotic lesion and plaque necrosis were significantly reduced following 8-week nicorandil treatment in ApoE-deficient mice fed an atherogenic diet. Nicorandil significantly reduced the expression levels of endoplasmic reticulum stress markers, C/EBP homologous protein (CHOP) and glucose regulated protein/BiP (GRP78) in atherosclerotic lesions. Nicorandil significantly attenuated tunicamycin-induced CHOP upregulation in cultured THP-1 macrophages. CONCLUSIONS: Nicorandil exerts its anti-atherogenic effect by mechanisms different from those of statins. Long-term nicorandil treatment is a potentially suitable second-line prevention therapy for patients with coronary artery disease.

Hypercholesterolemia and hypoadiponectinemia are associated with necrotic core-rich coronary plaque.

BACKGROUND: Hypercholesterolemia is a risk factor for coronary artery disease and closely linked to unstable plaque. Hypoadiponectinemia is frequently observed in patients with metabolic syndrome complicated with macroangiopathy and predicts poor clinical outcome. Spectral analysis of intravascular ultrasonography radiofrequency (IVUS-Virtual Histology [VH]) allows quantitative analysis of plaque composition. The purpose of this study was to verify the effects of low-density lipoprotein (LDL) cholesterol level on plaque morphology, and test the hypothesis that adiponectin influences coronary plaque volume and composition. METHODS: Preintervention IVUS-VH using a continuous pullback was performed in 92 coronary vessels in 92 patients with coronary artery disease. The morphological distribution of plaque was evaluated prospectively in a 60-mm segment of coronary vessels containing the culprit lesion. RESULTS: Serum LDL cholesterol levels correlated positively with necrotic core volume (r = 0.217, P = 0.037) and percent necrotic core tissue (r = 0.308, P = 0.003), while plasma adiponectin levels correlated negatively with plaque volume (r = -0.297, P = 0.004) and necrotic core volume (r = -0.306, P = 0.003). Multiple regression analyses showed close association between necrotic core volume and statin-use (ß = -21.68, P = 0.004) and adiponectin levels (ß = -31.25, P = 0.038), and that percent necrotic core tissue was influenced by statin-use (ß = -4.595, P = 0.026) and LDL cholesterol levels (ß = 0.092, P = 0.031). CONCLUSIONS: Adiponectin is closely linked to coronary plaque volume. Hypercholesterolemia and hypoadiponectinemia correlate with necrotic core lesions and may contribute to increased risk of coronary plaque vulnerability. Statins can affectively prevent necrotic core plaque formation associated with hypercholesterolemia and hypoadiponectinemia.

Waveform of ophthalmic artery Doppler flow predicts the severity of systemic atherosclerosis.

BACKGROUND: Doppler imaging of ophthalmic artery (OA), the first major branch of the internal carotid artery, provides anatomical advantages due to the vertical angle to the body surface and absence of ultrasonic obstacles. It was hypothesized that the Doppler waveform indices of OA correlate with severity of systemic atherosclerosis. METHODS AND RESULTS: The study subjects were 180 patients who underwent cardiac catheterization and OA Doppler imaging (90 patients with coronary artery disease (CAD) and 90 control patients). The ratio of stroke volume to pulse pressure, an index of arterial compliance, was closely associated with the ratio of systolic to diastolic mean velocity (Sm/Dm) in OA. The level of Sm/Dm increased in proportion with the increase in number of stenosed coronary arteries (0-vessel disease 2.1+/-0.3, 1-vessel disease 2.3+/-0.3, multi-vessel disease 2.6+/-0.5, P<0.0001). The Sm/Dm level in OA correlated positively with age, pulse pressure, pulse wave velocity, resistive index and pulsatility index in OA. The best Sm/Dm cut-off to predict CAD was 2.3, and patients with Sm/Dm >2.3 had 8.0-fold risk for CAD. CONCLUSIONS: The waveform indices of OA are clinically useful for evaluating the severity of CAD and may help explain the missing link between OA circulation and systemic arterial compliance.

Increased density of the liver and amiodarone-associated phospholipidosis.

This is a case report in which a 60-year-old man who suffered from ventricular tachycardia with dilated cardiomyopathy was prescribed amiodarone. After taking amiodarone, liver enzymes were increased and computed tomographic (CT) scanning of the abdomen showed a significant increase in the density of the liver without contrast medium. He was suspected as hemochromatosis and liver biopsy was performed. An abnormal high density of liver tissue may be observed in an unenhanced CT in patients treated with amiodarone and we suggest that periodic monitoring of liver function and/or liver biopsy is warranted before an irreversible stage is reached.

[Clinical effects of Hange-shashin-to on combination therapy of S-1/irinotecan against the for patients with metastatic gastric and colorectal cancer].

From July, 2007 to June, 2008, we prospectively investigated the influence of Hange-shashin-to on the therapeutic and adverse effects of chemotherapy and the changes in quality of life(QOL)scores of the patients with metastatic gastric and colorectal cancer. Twenty patients receiving S-1/Irinotecan (CPT-11) therapy were randomly allocated into group A (with Hange-shashin-to) and B (without Hange-shashin-to). While the anti-tumor effects did not differ significantly between these two groups, severe side effects of more than grade 3 occurred less frequently in group A. Our results suggested that the decrease in QOL scores on day 15 might be alleviated in group A, compared to group B. Therefore, Hange-shashin-to can be one of the useful supportive medicines in the combination therapy of S-1/CPT- 11.

Smoking cessation is associated with increased plasma adiponectin levels in men.

OBJECTIVES: Low levels of adiponectin, an adipocytokine with anti-diabetic and anti-atherogenic properties, are associated with increased risk of future myocardial infarction in men. Previous studies have demonstrated that cigarette smoking is involved in the development of insulin resistance, and current smokers have been shown to have reduced plasma adiponectin levels. However, the influence of smoking cessation on adiponectin levels remains unknown. We sought to assess whether smoking cessation is associated with increased plasma adiponectin levels in men. METHODS: The study includes 72 men (47 non-smokers and 25 current smokers at baseline) with stable angina pectoris who underwent percutaneous coronary intervention and follow-up coronary angiography 6 months later. During the 6-month follow-up period, all 47 non-smokers remained non-smokers, while 15 men of the 25 baseline current smokers successfully quit smoking. We evaluated plasma adiponectin levels at coronary intervention and 6 months later. RESULTS: Plasma adiponectin levels at coronary intervention were comparable to those after 6 months in non-smokers (4.22 [3.15-6.43] vs. 4.58 [3.03-6.26] microg/mL, P=0.124) and in persistent smokers (4.77 [4.25-10.53] vs. 5.16 [4.11-8.10] microg/mL, P=0.721). Meanwhile, an increase in adiponectin level was observed in patients who quit smoking for 6 months (4.24 [3.30-5.70] vs. 5.50 [4.03-8.00] microg/mL, P=0.002). Univariate analysis revealed that the percent increase in adiponectin levels correlated positively with smoking cessation (P=0.003) and negatively with additional use of beta-blockers (P=0.049). In addition, increases in adiponectin levels were closely associated with increase in high-density lipoprotein cholesterol (P=0.148), decrease in triglycerides (P=0.140), and additional use of renin-angiotensin system inhibitors (P=0.069). Multivariate analysis demonstrated that smoking cessation was an independent determinant of the increase in adiponectin (P=0.036). CONCLUSIONS: Smoking cessation is associated with increased plasma adiponectin levels in men with stable angina, suggesting that the significance of smoking cessation may be partly explained by the increase in adiponectin level.

[A case of interstitial pneumonia induced by S-1/irinotecan combination therapy].

A 67-year-old man with multiple liver metastases of colonic cancer was treated with combination therapy of S-1 and irinotecan (CPT-11): S-1 (120 mg/day) administered orally for 14 consecutive days followed by 14 days rest. CPT-11 (100 mg/m(2)) was given as a 2-hour infusion on day 1 and 15. The patient complained of high fever and subsequent exertional dyspnea in the middle of the second course of S-1/CPT-11 therapy. He was hospitalized with severe hypoxemia. CT scan showed extensive ground glass and consolidative changes in bilateral lungs. Steroid pulse therapy with oxygen therapy remarkably improved his symptoms, and abnormal findings on CT scan also resolved. Drug-induced pneumonia needs to be considered in the differential diagnosis when patients treated with S-1/CPT-11 combination therapy present high fever and dyspnea.

[A phase I study of modified FOLFOX 6 therapy for advanced colorectal cancer].

Oxaliplatin (L-OHP) has been established as a key drug for advanced colorectal cancer, and combination therapy with 5-FU/Leucovorin (LV)(FOLFOX regimen) is commonly used in Europe and the US. A phase I study of modified (m) FOLFOX 6 therapy was conducted to determine the recommended dose (RD) of 5-FU infused for 46 hours. Inclusion criteria were unresectable advanced colorectal cancer,measurable lesions, performance status (PS; ECOG) 0-2, age 20-75 years, and adequate organ functions. L-OHP and l-LV was administered over 2 hours and followed by bolus injection and continuous infusion of 5-FU for 46 hours every 2 weeks. Two cycles of mFOLFOX 6 therapy were performed. Doses of L-OHP, l-LV, and bolus injection of 5-FU were fixed at 85 mg/m(2), 200 mg/m(2), and 400 mg/m(2), respectively. The dose of continuous infused 5-FU was escalated from 1,600 mg/m(2), (level 1), 2,000 mg/m(2), (level 2), 2,400 mg/m(2), (level 3), and 2,800 mg/m(2), (level 4). RD was determined in a dose escalation manner, and safety was evaluated according to NCI-CTC Ver 2.0. A total of 13 patients were enrolled. Male/female=7/6, PS 0/1/2=2/4/7, mean age 64 years (range 55-75). Thrombocytopenia was not observed, and grade 2 of neutropenia and peripheral neuropathy was observed in 4 and 6 out of 13 patients. No dose-limiting toxicity (DLT) was observed at level 1 (n=3), 2 (n=4), and 3 (n=4), but at level 4 (n=2), 2 patients experienced DLT; grade 3 easy fatigue and anorexia required treatment delay over 7 days. Level 3 was therefore determined as RD. A phase II study is ongoing to evaluate the efficacy of mFOLFOX 6 therapy.