Tsuyoshi Nozue

Statin treatment for coronary artery plaque composition based on intravascular ultrasound radiofrequency data analysis

BACKGROUND Systemic therapy with statin has been shown to lower the risk of coronary events; however, the in vivo effects of statin therapy on plaque volume and composition are less understood. METHODS We conducted a prospective, open-labeled, randomized, multicenter study in 11 centers in Japan. A total of 164 patients were randomized to receive either 4 mg/d of pitavastatin (intensive lipid-lowering therapy) or 20 mg/d of pravastatin (moderate lipid-lowering therapy). Analyzable intravascular ultrasound data were obtained for 119 patients at baseline and at 8-month follow-up. The primary end point was the difference of volume changes in each of the 4 main plaque components (fibrosis, fibrofatty, calcium, and necrosis), assessed by virtual histology intravascular ultrasound, between the 2 groups. RESULTS The mean low-density lipoprotein cholesterol level at follow-up was significantly lower in the pitavastatin than in the pravastatin group (74 vs 95 mg/dL, P < .0001). During the 8-month follow-up period, statin therapy reduced the absolute and relative amount of fibrofatty component (pitavastatin: from 1.09 to 0.81 mm(3)/mm, P = .001; pravastatin: from 1.05 to 0.83 mm(3)/mm, P = .0008) and increased in the amount of calcium (pitavastatin: from 0.42 to 0.55 mm(3)/mm, P < .0001; pravastatin: from 0.44 to 0.55 mm(3)/mm, P = .005), whereas volume changes in both plaque components were not statistically different between the 2 groups. CONCLUSIONS Both pitavastatin and pravastatin altered coronary artery plaque composition by significantly decreasing the fibrofatty plaque component and increasing the calcified plaque component.

Effects of serum n-3 to n-6 polyunsaturated fatty acids ratios on coronary atherosclerosis in statin-treated patients with coronary artery disease.

A low ratio of n-3 to n-6 polyunsaturated fatty acids has been associated with cardiovascular events. However, the effects of this ratio on coronary atherosclerosis have not been fully examined. The purpose of the present study was to evaluate the correlations between the n-3 to n-6 polyunsaturated fatty acid ratio and coronary atherosclerosis. Coronary atherosclerosis in nonculprit lesions in the percutaneous coronary intervention vessel was evaluated using virtual histology intravascular ultrasound in 101 patients at the time of percutaneous coronary intervention and 8 months after statin therapy. Forty-six patients (46%) showed atheroma progression and the remaining 55 patients (54%) showed atheroma regression at 8-month follow-up. Significant negative correlations were observed between percentage change in plaque volume and change in the eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio (r = -0.190, p = 0.05), docosahexaenoic acid (DHA)/AA ratio (r = -0.231, p = 0.02), and EPA+DHA/AA ratio (r = -0.240, p = 0.02). Furthermore, percentage change in the fibrous component volume was negatively and significantly correlated with change in the EPA/AA ratio (r = -0.206, p = 0.04) and EPA+DHA/AA ratio (r = -0.217, p = 0.03). Multivariate regression analysis showed that change in the EPA+DHA/AA ratio was a significant predictor of percentage change in plaque volume and fibrous component volume (β = -0.221, p = 0.02, and β = -0.200, p = 0.04, respectively). In conclusion, decreases in serum n-3 to n-6 polyunsaturated fatty acid ratios are associated with progression in coronary atherosclerosis evaluated using virtual histology intravascular ultrasound in statin-treated patients with coronary artery disease.

Effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance

AIM To evaluate the effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance. METHODS Seventy-six patients with diabetes and glucose intolerance were enrolled in this study. At baseline and 12 weeks after treatment with ezetimibe 10mg/day, we measured the levels of lipid and glucose parameters. RESULTS Ezetimibe reduced the mean levels of low-density lipoprotein cholesterol (LDL-C) (-20%, P<0.001), remnant-like particle cholesterol (-22%, P<0.001), small dense-LDL (-19%, P<0.001), apolipoprotein B-48 (-2%, P<0.01), malondialdehyde modified-LDL (-15%, P<0.001), and serum immunoreactive insulin (IRI) (-4%, P<0.01). In the insulin resistance subgroup, ezetimibe reduced the abdominal circumference (-1%, P<0.05) and mean levels of fasting plasma glucose (-7%, P<0.05), IRI (-36%, P<0.01), s-CPR (-27%, P<0.01), HOMA-IR (-39%, P<0.01) and HbA1c tended to decrease (-2%, P=0.06). CONCLUSIONS Ezetimibe reduced atherogenic lipoproteins in patients with diabetes and glucose intolerance; besides, it improved glucose metabolism in patients with insulin resistance.

Comparison of Arterial Remodeling and Changes in Plaque Composition Between Patients With Progression Versus Regression of Coronary Atherosclerosis During Statin Therapy (from the TRUTH Study)

Statin therapy produces regression of coronary artery plaques and reduces the incidence of coronary artery disease. However, not all patients show regression of coronary atherosclerosis after statin therapy. The purpose of the present study was to identify differences in clinical characteristics, serum lipid profiles, arterial remodeling, and plaque composition between patients with progression and those with regression of coronary atherosclerosis during statin therapy. The effects of 8-month statin therapy on coronary atherosclerosis were evaluated in the Treatment With Statin on Atheroma Regression Evaluated by Intravascular Ultrasound With Virtual Histology (TRUTH) study using intravascular ultrasound-virtual histology. One hundred nineteen patients were divided into 2 groups according to atheroma volume increase (progressors) or decrease (regressors) during an 8-month follow-up period. Fifty-one patients (43%) were categorized as progressors and the remaining 68 (57%) as regressors. External elastic membrane volume increased, although not significantly (0.8%, p = 0.34), and luminal volume decreased significantly (-5.3%, p = 0.0003) in progressors, while external elastic membrane volume decreased significantly (-3.2%, p <0.0001) and luminal volume increased (2.2%, p = 0.13) in regressors. The fibrous component increased significantly in progressors, while this component decreased in regressors. A strong positive correlation was observed between change in atheroma volume and change in fibrous volume (r = 0.812, p <0.0001). In conclusion, coronary arteries showed negative remodeling during statin-induced plaque regression. The difference in plaque composition between patients with progression and those with regression of coronary atherosclerosis during statin therapy arose from the difference in the change in fibrous component.

Comparison of Change in Coronary Atherosclerosis in Patients With Stable Versus Unstable Angina Pectoris Receiving Statin Therapy (from the Treatment With Statin on Atheroma Regression Evaluated by Intravascular Ultrasound With Virtual Histology [TRUTH] Study)

Although statin-induced regression in coronary atherosclerosis seems to be greater in patients with acute coronary syndrome than in those with stable coronary artery disease, no reports have examined this. The purpose of the present study was to compare the changes in coronary atherosclerosis in patients with stable versus unstable angina pectoris (AP). The effects of 8-month statin therapy on coronary atherosclerosis were evaluated using virtual histology intravascular ultrasound, and analyzable intravascular ultrasound data were obtained from 119 patients (83 patients with stable AP and 36 with unstable AP). A significant decrease in plaque volume was observed in patients with unstable AP (-2.2%, p = 0.02) but not in patients with stable AP. A significant increase in the necrotic-core component (0.30 mm(3)/mm, p = 0.009) was observed only in patients with unstable AP. Significant positive correlations were observed between the percentage of change in platelet-activating factor acetylhydrolase and the percentage of change in plaque volume (r = 0.346, p = 0.05) in patients with unstable AP. No significant correlations were observed in patients with stable AP. Multivariate regression analyses showed that a reduction in platelet-activating factor acetylhydrolase was associated with regression in coronary atherosclerosis, particularly of the fibrous component (β = 0.443, p = 0.003), in patients with unstable AP. In conclusion, regression of the coronary artery plaque volume was greater, although statin therapy did not halt the increases in plaque vulnerability, in patients with unstable AP compared to those with stable AP. A reduction in the serum platelet-activating factor acetylhydrolase level was associated with regression in coronary atherosclerosis, particularly the fibrous plaque volume, in patients with unstable AP.

Contrast medium volume to estimated glomerular filtration rate ratio as a predictor of contrast-induced nephropathy developing after elective percutaneous coronary intervention

BACKGROUND Contrast-induced nephropathy (CIN) has been recognized as a serious complication of diagnostic coronary angiography and percutaneous coronary intervention (PCI), and has been associated with prolonged hospitalization and adverse clinical outcomes. A key step to minimize the risk for developing CIN is to identify patients at risk for CIN. METHODS AND RESULTS We retrospectively investigated clinical factors associated with the development of CIN in 60 stable angina patients who had undergone elective PCI. The frequency of CIN was 13% (8/60). There were neither any significant differences in age, gender, baseline serum creatinine or hemoglobin levels, nor in the rate of diabetes mellitus between the CIN and the non-CIN group. However, the estimated glomerular filtration rate (eGFR) was significantly lower (40.4+/-11.4 mL/min/1.73 m(2) vs. 57.4+/-22.6 mL/min/1.73 m(2), p=0.044), and number of treated vessels (1.5+/-0.8 vs. 1.2+/-0.4, p=0.039) and stents used (2.1+/-0.6 vs. 1.4+/-0.6, p=0.007) were significantly higher in the CIN group. In addition, the amount of contrast medium was significantly larger (272+/-37 mL vs. 201+/-62 mL, p=0.003) and the contrast medium volume (CMV) to eGFR ratio (CMV/eGFR) was significantly greater (7.4+/-2.9 vs. 4.0+/-2.0, p=0.0001) in the CIN group. Stepwise regression analysis showed that the CMV/eGFR ratio was a significant independent predictor of CIN (p=0.035). At a cut-off point of >5.1, the CMV/eGFR ratio exhibited 87.5% sensitivity and 74.5% specificity for detecting CIN. CONCLUSION The CMV/eGFR ratio could be a useful predictor of CIN developing after elective PCI.

Apolipoprotein B gene mutations and fatty liver in Japanese hypobetalipoproteinemia

BACKGROUND Familial hypobetalipoproteinemia (FHBL) is a hereditary disorder characterized by decreased plasma concentrations of low-density lipoprotein cholesterol. The best-characterized causes of FHBL are apolipoprotein B (apoB) gene mutations, which produce truncated apoB proteins. Fatty liver is thought to be frequent in FHBL, owing to impaired secretion of very-low-density lipoprotein from the liver. Homozygotes for FHBL present with extremely low concentrations of plasma lipids, and may suffer from deficiencies of fat-soluble vitamins. The objectives of this study were to identify apoB-defective FHBL subjects and investigate fatty liver in Japanese population. METHODS We screened 14 hypocholesterolemic subjects for apoB gene mutations by PCR-SSCP and performed liver ultrasonography in a Japanese population. RESULTS We identified an apoB-82 homozygote in one subject and an apoB-13.7 heterozygote in another subject. Four of 6 individuals with FHBL presented with fatty liver in those 2 FHBL families. Liver biopsy of the apoB-13.7 heterozygote, which had obesity and insulin resistance, showed severe fatty liver. The apoB-82 homozygote was asymptomatic with fat-soluble vitamin concentrations being normal, possibly due to spared secretion of apoB-48 from the intestine and increased plasma concentrations of high-density lipoprotein cholesterol. CONCLUSION ApoB gene mutations might not be rare and that fatty liver might be frequent in Japanese FHBL.

Low serum docosahexaenoic acid is associated with progression of coronary atherosclerosis in statin-treated patients with diabetes mellitus: results of the treatment with statin on atheroma regression evaluated by intravascular ultrasound with virtual histology (TRUTH) study

BackgroundDiabetes mellitus (DM) accelerates plaque progression despite the use of statin therapy. The purpose of the present study was to evaluate the determinants of atheroma progression in statin-treated patients with DM.MethodsCoronary atherosclerosis in nonculprit lesions in a vessel undergoing percutaneous coronary intervention (PCI) was evaluated using virtual histology intravascular ultrasound. The study included 50 patients with DM who had been taking statin therapy for 8 months at the time of PCI.ResultsTwenty-six patients (52%) showed atheroma progression (progressors) and the remaining 24 patients (48%) showed atheroma regression (regressors) after 8 months of follow-up. Fewer progressors than regressors received intensive lipid-lowering therapy with pitavastatin (31% vs. 50%, p = 0.17) and the frequency of insulin use was higher in progressors (31% vs. 13%, p = 0.18). However, neither of these differences reached statistical significance. Risk factor control at baseline and at the 8-month follow-up did not differ between the 2 groups except for serum levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Univariate regression analysis showed that serum EPA (r = -0.317, p = 0.03) and DHA (r = -0.353, p = 0.02) negatively correlated with atheroma progression. Multivariate stepwise regression analysis showed that low serum DHA and pravastatin use were significant independent predictors for atheroma progression during statin therapy (DHA: β = -0.414, type of statin: β = -0.287, p = 0.001).ConclusionsLow serum DHA is associated with progression of coronary atherosclerosis in statin-treated patients with DM.Trial registrationUMIN Clinical Trials Registry, UMIN ID: C000000311.

Effects of Statin Therapy on Plasma Proprotein Convertase Subtilisin/kexin Type 9 and Sortilin Levels in Statin-Naive Patients with Coronary Artery Disease

AIM Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of serum low-density lipoprotein (LDL) cholesterol levels, and sortilin is linked to lipoprotein metabolism. Although statin therapy increases PCSK9 levels, effects of this therapy on plasma sortilin levels have not been evaluated. The purpose of the present study was to examine the effects of statins on plasma PCSK9 and sortilin levels, and association of statin-induced increase in PCSK9 levels with sortilin. METHODS Serum lipid levels and plasma PCSK9 and sortilin levels were measured at baseline and 8 months after statin therapy in 90 statin-naive patients with coronary artery disease (CAD). Pitavastatin 4 mg/day was used to treat 44 patients and pravastatin 20 mg/day to treat the remaining 46 patients. RESULTS For both statin groups, significant increases in hetero-dimer PCSK9 levels (pitavastatin: 31%, p＜0.0001; pravastatin: 34%, p=0.03) and decreases in sortilin levels (pitavastatin: －8%, p=0.02; pravastatin: －16%, p=0.002) were observed. Although a reduction in LDL cholesterol was greater in the pitavastatin group than in the pravastatin group, no significant differences were observed in percentage changes in hetero-dimer PCSK9 and sortilin levels. A significant positive correlation was observed between percentage changes in hetero-dimer PCSK9 levels and those in sortilin levels (pitavastatin: r=0.359, p=0.02; pravastatin: r=0.276, p=0.06). CONCLUSIONS Use of pitavastatin and pravastatin increased plasma PCSK9 and decreased sortilin levels. Statin-induced increases in PCSK9 were associated with changes in sortilin in statin-naive patients with CAD.

Elevation of urinary liver-type fatty acid-binding protein as predicting factor for occurrence of contrast-induced acute kidney injury and its reduction by hemodiafiltration with blood suction from right atrium

Although contrast-induced acute kidney injury (CI-AKI) has a great impact on patients’ prognosis, few data exist regarding predictors of CI-AKI in patients with severe renal dysfunction who have undergone contrast angiography. Therefore, we prospectively studied 25 patients with renal dysfunction, which was defined as the estimated glomerular filtration rate (eGFR) level <45 ml/min/1.73 m2, undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI). We performed hemodiafiltration with blood suction from the right atrium (RA-HDF). The mean level of urinary liver-type fatty acid-binding protein (L-FABP) at baseline was significantly higher in the CI-AKI group than in the non-CI-AKI group (59.8 ± 45.6 vs 13.4 ± 11.9 μg/gCr, P = 0.0003). Multivariate regression analysis demonstrated that baseline urinary L-FABP was an independent significant predictor of CI-AKI (β = 0.741, P = 0.013). Receiver-operating characteristic analysis showed that baseline urinary L-FABP exhibited 100 % sensitivity and 81.8 % specificity for predicting CI-AKI when the cutoff value was defined as 19.0 μg/gCr. Interestingly, the incidence of CI-AKI after CAG or PCI was reduced in the RA-HDF group in a comparison with 41 control patients (12 % vs 27 %) with eGFR level <45 ml/min/1.73 m2 who underwent PCI before the introduction of RA-HDF. In conclusion, baseline L-FABP levels can be a predictor for occurrence of CI-AKI. We suggest that RA-HDF may prevent the development of CI-AKI in patients with severe renal dysfunction undergoing coronary procedures, although further large-scale prospective study is necessary to confirm our conclusions.