Optical coherence tomography (OCT) is a catheter-based imaging system that uses near-infrared light to produce cross-sectional images of the coronary arteries. With its extraordinarily high resolution (10-20 μm), OCT allows clinicians to observe various morphological features of coronary atherosclerosis in vivo. For example, intimal thickening presents as homogeneous, signal-rich regions on OCT, while fibroatheroma with a lipid-rich necrotic core is characterized by the presence of signal-poor regions with a diffuse border. Furthermore, plaque rupture is detected in 50〜70% of culprit lesions of acute coronary syndrome (ACS), and plaque erosion develops over areas of intimal thickening and/or thick-cap fibroatheroma. Meanwhile, calcified nodules are common in older patients with hypertension and chronic renal disease. Platelet-rich thrombi are visualized as low backscattering structures and often detected in patients with unstable angina, whereas red blood cell-rich thrombi exhibit a high backscattering structure with signal-free shadowing and are frequently noted in patients with acute myocardial infarction. Moreover, OCT-derived thin cap fibroatheroma has been shown to be a predictor of subsequent plaque progression and acute coronary events, while vasa vasorum and the macrophage density are associated with a thin fibrous cap and large necrotic core as well as increased serum levels of inflammatory biomarkers. One current challenge of OCT examinations is to detect morphologic characteristics capable of discriminating vulnerable from stable plaques. The ability to detect vulnerable plaques in vivo would allow physicians to identify patients at high risk for adverse coronary events, thus significantly helping to prevent ACS.
Aim: Vascular senescence, which is accelerated in individuals with chronic kidney disease (CKD), contributes to the development of cardio-renal syndrome, and various uremic toxins may play important roles in the mechanisms underlying this phenomenon. We recently reported that indoxyl sulfate (IS), a uremic toxin, directly activates aryl hydrocarbon receptor (AhR) and generates oxidative stress through NADPH oxidase-4 in human umbilical vein endothelial cells (HUVECs). In the current study, we sought to examine whether IS regulates sirtuin 1 (Sirt1) and affects endothelial senescence via AhR activation. Methods: HUVECs were incubated with 500 μmol/L of IS for the indicated time periods. In order to evaluate changes in the senescence of the HUVECs, the number of senescence-associated β-galactosidase (SA β-gal)-positive cells was determined using an image analysis software program. The intracellular nicotinamide phosphoribosyltransferase (iNampt) activity, cellular NAD＋/NADPH ratio and Sirt1 activity were analyzed according to a colorimetric assay to determine the mechanism of cellular senescence. Furthermore, we evaluated the involvement of AhR in the senescence-related changes induced by IS using AhR antagonists. Results: IS decreased the iNampt activity, NAD＋/NADPH ratio and Sirt1 activity, resulting in an increase in the percentage of SA β-gal-positive cells. On the other hand, the AhR antagonists restored the IS-induced decrease in the NAD＋ content in association with an improvement in the iNampt activity and ameliorated the senescence-related changes. Taken together, these results indicate that IS impairs the iNampt-NAD＋-Sirt1 system via AhR activation, which in turn promotes endothelial senescence. Conclusions: The IS-AhR pathway induces endothelial senescence. Therefore, blocking the effects of AhR in the endothelium may provide a new therapeutic tool for treating cardio-renal syndrome.
Aim: Vascular calcification is a critical problem in patients with chronic kidney disease (CKD). In this study, we examined the effects of a HMG Co-A reductase inhibitor (statin) and an angiotensin Ⅱ type 1 receptor blocker (ARB) on renal failure-induced vascular calcification. Method and Result: Severe renal failure was induced in rats by feeding a 0.75% adenine diet for six weeks. These rats had hyperphosphatemia, hypertension and hypercholesterolemia. A histological assessment showed extensive linear calcification in the aortic media and a significant increase in the aortic content of calcium and phosphorus. Oral administration of pravastatin (a statin; 1-10 mg/kg/day) or olmesartan (an ARB; 1-10 mg/kg/day) dose-dependently inhibited the aortic calcification in parallel with their renoprotective, lipid-lowering and blood pressure-lowering effects. Of note, the lowest dose of pravastatin inhibited aortic calcification with no influence on the renal function, BP and cholesterol, suggesting that it has direct vasoprotective properties. Intriguingly, the combined administration of pravastatin and olmesartan at the lowest doses synergistically ameliorated the aortic calcification, and the protective effect was at least partly attributable to the inhibition of RF-induced apoptosis in the aortic wall. An in vitro model of inorganic phosphate (Pi)-induced vascular smooth muscle cell calcification mimicked these effects of pravastatin and olmesartan, and the beneficial effect of the combination was attributable to the inhibitory effects on Pi-induced apoptosis via the restoration of the Gas6/Axl-mediated anti-apoptotic pathway. Conclusion: A statin and an ARB exerted potent protective effects against vascular calcification due to CKD, probably through their pleiotropic effects. In addition, combination therapy with pravastatin and olmesartan may provide a new therapeutic strategy for the prevention of vascular calcification.
Aim: Computed tomography angiography (CTA) is currently the most reliable imaging technique for evaluating and planning the treatment of atherosclerosis. The drawbacks of the technique are its low spatial resolution and challenging manual measurements. The purpose of this study was to develop a semi-automatic method to segment vessel walls, surrounding tissue, and the carotid artery lumen to measure the severity of stenosis. Methods: In vivo contrast CTA images from eight patients undergoing endarterectomy were analyzed using a tailored five-step process involving an adaptive segmentation algorithm and region growing to measure the maximum percent stenosis in the cross-sectional area of the carotid artery. The accuracy of this method was compared with that of manual measurements made by physicians. Results: There were no significant differences between the maximum percent stenosis value obtained using the semi-automatic tool and that obtained using manual measurements (6%; p=0.31). The data acquisition and analysis required an average of 145 seconds. Conclusion: This new semi-automatic segmentation method for CTA provides a fast and reliable tool to quantify the severity of carotid artery stenosis.
Aim: The composition of dietary fat affects various modifiable cardiovascular risk factors and cardiovascular outcomes in the general population. We investigated the effects of the regular consumption of fish meals on the fatty acid composition of red blood cell (RBC) membranes and the relationship of this parameter with the carotid intima-media thickness (IMT), an early marker of atherosclerosis. Methods: In 56 hypertensive patients, we measured the carotid IMT using ultrasound imaging and the RBC membrane fatty acid composition using gas-chromatography and calculated the polyunsaturated to saturated fatty acid (PUFA/SFA) ratio. The patients received intensive nutritional counseling and three weekly meals of fish containing elevated amounts of PUFA, in order to increase the membrane PUFA content. The RBC membrane fatty acid composition and IMT were reassessed after one year. Results: At baseline, the membrane PUFA/SFA ratio was inversely related to the carotid IMT, and the relationship was independent of all major cardiovascular risk factors. At follow-up, the PUFA/SFA ratio increased in the RBC membranes of 25 (45%) of 56 patients. The regular consumption of fish meals resulted in a decreased carotid IMT only in the patients with an increased membrane PUFA/SFA ratio. Changes in the PUFA/SFA ratio induced by the dietary intervention were inversely related to the changes in the IMT, independent of variations in body mass, blood pressure and plasma lipids. Conclusions: In hypertensive patients, a low RBC membrane PUFA/SFA ratio is associated with more prominent vascular damage, and the regular consumption of fish reduces the carotid IMT in patients in whom dietary intervention affects the membrane fatty acid composition.
Aim: Reactive hyperemia peripheral arterial tonometry (RH-PAT) can be used to noninvasively assess the vascular function with respect to the digital microcirculation. Abnormalities are associated with coronary endothelial dysfunction. We therefore investigated whether impaired digital reactive hyperemia is associated with restenosis after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS). Methods: This study included 86 patients with ACS who underwent successful primary PCI of native vessels for de novo lesions. The reactive hyperemia index (RHI) was calculated using RH-PAT at three weeks and eight months after ACS. The RHI was defined as the ratio of the digital pulse volume during reactive hyperemia to that observed at baseline. Restenosis was defined as diameter stenosis of ≥ 50% in the in-segment area based on the findings of quantitative coronary angiography performed at eight months. Results: Restenosis was detected in 17 patients (20%). There were no differences in the RHI at three weeks between the patients with and without restenosis (1.70 vs. 1.87; p=0.13); however, the RHI values at eight months were significantly attenuated in the patients with restenosis versus those without (1.75 vs. 2.12; p=0.03). A univariate logistic regression analysis showed that the eight-month RHI (＜2, obtained from a receiver operating characteristic analysis) was a significant risk factor for restenosis (odds ratio: 4.23, 95% confidence interval: 1.25 to 14.28, p=0.02). Conclusions: Impairment of the digital hyperemic response at eight months is associated with restenosis after primary intervention in patients with ACS, suggesting the potential of RH-PAT as a noninvasive test for identifying patients with a high risk of restenosis.
Aim: Peripheral artery disease (PAD), defined as a decreased ankle brachial index (ABI), is a risk factor for cardiovascular disease; however, few studies have assessed the relationship between a low ABI and cardiovascular risks in Asian populations. We herein examined the relationship between the ABI and the development of cardiovascular disease in a Japanese community. Methods: A total of 2,954community-dwelling Japanese individuals without prior cardiovascular disease ≥ 40years of age were followed up for an average of 7.1years. The subjects’ ABIs were categorized into the three groups: low (≤0.90), borderline (0.91-0.99) and normal (1.00-1.40). We estimated the relationship between the ABI and cardiovascular risk using a Cox proportional hazards model. Results: During the follow-up period, 134subjects experienced cardiovascular events. The incidence of cardiovascular disease across the ABI values was significantly different (p＜0.001). After adjusting for confounding factors, namely age, sex, systolic blood pressure, use of anti-hypertensive drugs, diabetes, total cholesterol, high-density lipoprotein cholesterol, obesity, smoking, alcohol intake and regular exercise, individuals with a low ABI were at 2.40-fold (95% confidence interval [CI] 1.14-5.06) greater risk of cardiovascular disease and 4.13-fold (95% CI 1.62-10.55) greater risk of coronary heart disease. Conclusions: Our findings suggest that individuals with an ABI of ≤ 0.90 have an increased risk of cardiovascular events, independent from traditional risk factors, in the general Japanese population.
Aim: Apolipoprotein B-48 (apoB-48) is a constituent of chylomicrons and their remnants (chylomicron remnants). A high concentration of serum apoB-48 is suspected to be a major risk factor for the development of atherosclerotic cardiovascular disease. Proteinuria and a reduced estimated glomerular filtration rate (eGFR) are independent risk factors for cardiovascular events and renal dysfunction. In the present study, we examined whether the serum apoB-48 concentration is associated with renal dysfunction. Methods: A total of 264 patients was enrolled and classified into four groups according to the eGFR and level of proteinuria: a high eGFR (＞60mL/min/1.73m2) without proteinuria (≥1＋ by urine dipstick) (n=50); a high eGFR with proteinuria (n=75); a low eGFR (＞60mL/min/1.73m2) without proteinuria (n=74); and a low eGFR with proteinuria (n=65). Biochemical markers of lipid metabolism, including the fasting serum apoB-48 concentration, were compared between the four groups. Results: The serum log-apoB-48 and log-apoB-48/TG levels were significantly higher in the patients with a high eGFR with proteinuria, low eGFR with proteinuria and low eGFR without proteinuria than in those with a high eGFR without proteinuria, with the most significant differences for these parameters. The eGFR was found to be significantly correlated with the log-apoB-48 and log-apoB-48/TG levels, whereas urinary protein was found to be significantly correlated with the log-apoB-48 level only. A multiple regression analysis indicated that the log-apoB-48/TG level was a significant determinant of a reduced eGFR. Conclusions: Both a low eGFR (＜60) and proteinuria (≥1＋) are independent determinants of a high apoB-48 concentration. Taken together, the present results suggest that an increased serum apoB-48 concentration contributes to an increased risk of cardiovascular events.
Aim: A patient with severe type III hyperlipoproteinemia and familial hypercholesterolemia (FH) was previously reported (Metabolism, 44,1995:460-465). In the current study, the patient’s apolipoprotein (apo) E gene was analyzed. Methods: An apo E isoform analysis was performed using isoelectric focusing and immunoblotting. In addition, after DNA preparation, a restriction fragment length polymorphism analysis and DNA sequence analysis were performed. Results: The patient’s apo E phenotype was E2/E1, and the genotype was ε2/ε2. The sequence analysis of the patient’s DNA revealed a new variant of apo E, which involves a single substitution of one serine (AGC) for one arginine (CGC) at position 142, thereby adding one negatively charged unit to apo E2. Therefore, the patient was compound heterozygous for apo E1 (Arg142Ser) and apo E2 (Arg158Cys). Conclusions: A novel mutation, apo E1 Nagoya (Arg142Ser) in a patient with severe type III hyperlipoproteinemia with heterozygous FH was characterized. Since the presence of arginine at the amino acid residue 142 of apo E is considered to play an important role in binding to LDL receptors, the mutation apo E1 Nagoya (Arg142Ser) likely contributed to the expression of severe type III hyperlipoproteinemia in this patient.
Sitosterolaemia is caused by mutations in either ABCG5 or ABCG8. Chinese and Japanese individuals usually have mutations in ABCG5. We herein report a known and a novel mutation in ABCG8 and their potential interaction with NPC1L1 polymorphisms in a Chinese family with sitosterolaemia. We sequenced ABCG5 and ABCG8 and measured the levels of plasma plant sterols in a 15-year-old Chinese girl with clinical sitosterolaemia (xanthomas with elevated low-density lipoprotein cholesterol (LDL-C) and plant sterols) and her apparently healthy family members. NPC1L1 was sequenced in the genetically affected sibling and other family members. A known mutation, c.490C＞T (p. Arg164＊), in exon 4 and a novel mutation, c.1949T＞G (p.Leu650Arg), in exon 13 of ABCG8 were detected in the proband and her sister, who had elevated sterols but low LDL-C levels and no xanthomas. The genetically affected sister, but not the proband, carried two additional heterozygous changes in NPC1L1 (rs2072183 C＞G, rs2301935 A＞C), which were inherited from the mother, who also had a low LDL-C level. In this study, we detected a known and a novel mutation in ABCG8 in a Chinese patient with sitosterolaemia. The same mutations were found in her clinically normal sister, suggesting that the contrasting features with the proband may be related to different variants in NPC1L1 and/or some other undetermined lipid-related genetic factors.