Daiji Yoshikawa

Comparison of Atorvastatin 5 and 20 mg/d for Reducing F-18 Fluorodeoxyglucose Uptake in Atherosclerotic Plaques on Positron Emission Tomography/Computed Tomography: A Randomized, Investigator-Blinded, Open-Label, 6-Month Study in Japanese Adults Scheduled for Percutaneous Coronary Intervention

BACKGROUND F-18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) is a useful tool for the detection of local inflamed atherosclerotic lesions. OBJECTIVE This study used hybrid PET/computed tomography (CT) to examine the effects of 2 doses of atorvastatin on (18)F-FDG uptake in atherosclerotic plaques in Japanese adults with stable angina pectoris who were scheduled to undergo percutaneous coronary intervention (PCI). METHODS This was a prospective, randomized, investigator-blinded, open-label study in patients with dyslipidemia (total cholesterol ≥ 220 mg/dL and/or LDL-C ≥ 140 mg/dL) who were scheduled to undergo PCI for stable angina pectoris and had not received any lipid-lowering drugs within 1 year before enrollment. Patients were randomly allocated to receive atorvastatin 5 or 20 mg/d for 6 months. At baseline (the day after PCI), (18)F-FDG uptake in the ascending aorta and femoral artery was determined using PET/CT imaging, and the mean target-to-background ratio (TBR) was calculated in individual plaques. The same regions were assessed by PET/CT after 6 months of treatment. Changes from baseline to follow-up in the lipid profile, serum malondialdehyde-modified LDL-C (MDA-LDL-C), and serum high-sensitivity C-reactive protein (hs-CRP) were also examined. Drug adherence, adverse events, and changes in medications were monitored at monthly outpatient visits. RESULTS Of 32 patients initially screened, 2 were excluded due to newly diagnosed cancer; thus, 30 patients were randomly assigned to treatment, 15 in each group. Patients were predominantly male (18 [60%]), with a mean (SD) age of 54 (11) years, mean body weight of 65 (12) kg, and mean total cholesterol, HDL-C, and triglyceride concentrations of 240 (29), 48 (14), and 180 (102) mg/dL, respectively. After 6 months, the 20-mg group had significant reductions from baseline in mean (SD) TBR in the ascending aorta (from 1.15 [0.14] to 1.05 [0.12]; percent change, -7.9% [9.4%]; P = 0.007) and the femoral artery (from 1.12 [0.11] to 1.02 [0.11]; percent change, -9.9% [13.8%]; P = 0.012). The corresponding changes from baseline were not statistically significant in the 5-mg group. The differences in percent change in TBR in the 2 locations were not significant between groups. When data from the 2 groups were combined, the overall reduction in TBR from baseline to 6 months was significant in both the ascending aorta (P = 0.003) and the femoral artery (P = 0.021). The decreases in TBR in both arteries were significantly correlated with reductions in LDL-C (ascending aorta: r(2) = 0.230 [P = 0.012]; femoral artery: r(2) = 0.338 [P = 0.003]), MDA-LDL-C (ascending aorta: r(2) = 0.183 [P = 0.028]; femoral artery: r(2) = 0.247 [P = 0.010]), and hs-CRP (ascending aorta: r(2) = 0.132 [P = 0.048]; femoral artery: r(2) = 0.271 [P = 0.007]). One patient in the 5-mg group and 2 patients in the 20-mg group had ∼2-fold increases in serum aminotransferases on a single occasion; however, no specific musculoskeletal or hepatic adverse events were observed, and aminotransferase values decreased to within normal ranges without changes in the atorvastatin dose. CONCLUSION Six months of treatment with atorvastatin 20 mg, but not 5 mg, was associated with a significant reduction in TBR in the ascending aorta and femoral artery in these Japanese adults with dyslipidemia undergoing PCI for stable angina pectoris. University Hospital Medical Information Network Clinical Trials Registry identifier: C000000371.

Impact of renal function on coronary plaque composition

BACKGROUND Recent studies have demonstrated that patients with chronic kidney disease are at high risk of atherosclerosis. Recently it has been found that coronary plaque components can be evaluated by integrated backscatter intravascular ultrasound (IB-IVUS), and lipid-rich plaque is associated with vulnerable plaque. The aim of the study was to investigate the relationship between renal function and tissue characterization of coronary plaque composition at the target stenotic site for percutaneous coronary intervention (PCI). METHODS We prospectively performed IB-IVUS before elective PCI in 89 consecutive patients with stable angina. According to estimated glomerular filtration rate (eGFR), they were divided into two groups (eGFR <60 ml/min/ 1.73 m(2) or eGFR > or =60 ml/min/1.73 m(2)). The tissue characteristics of the coronary plaque at each target stenotic site were evaluated by three-dimensional (3D) IB-IVUS just before PCI procedure. RESULTS The patients with eGFR <60 ml/min/1.73 m(2) had higher percentage of lipid volume and lower percentage of fibrous volume compared to the patients with eGFR > or = 60 ml/min/1.73 m(2) on the 3D IB-IVUS images (36.7 +/- 10.6% versus 28.7 +/- 9.3%, P < 0.001 and 59.1 +/- 8.7% versus 66.3 +/- 8.3%, P < 0.001, respectively). eGFR showed a significant negative correlation with lipid volume and had a significant positive correlation with fibrous volume in coronary plaques (r = -0.44, P < 0.0001, and r = 0.46, P < 0.0001, respectively). CONCLUSIONS Impaired renal function was related to higher percentage of lipid volume and lower percentage of fibrous volume in coronary plaque. Our findings may explain the increasing risk of cardiovascular events in patients with renal dysfunction.

Circulating cathepsin K as a potential novel biomarker of coronary artery disease.

BACKGROUND Cathepsin K (CatK) is one of the most potent mammalian collagenases involved in atherosclerosis-based vascular disease. We investigated whether circulating CatK is associated with the prevalence of coronary artery disease (CAD). METHODS Two-hundred fifty-two consecutive subjects were enrolled from among patients who underwent coronary angiography and intravascular ultrasound analyses. One-hundred thirty-two age-matched subjects served as controls. Plasma CatK, intact procollagen type I N-terminal propeptide (I-PINP), and linked carboxy-terminal telopeptide of collagen type I (ICTP) were measured. RESULTS Patients with CAD had higher CatK levels (44.0 ± 31.2 versus 15.5 ± 8.3 ng/mL, P < 0.001) and ICTP/I-PINP ratios (0.2 ± 0.1 versus 0.04 ± 0.03, P < 0.001) than the controls. Patients with acute coronary syndrome had higher CatK levels than those with stable angina pectoris. Overall, linear regression analysis showed that the CatK levels correlated positively with ICTP/I-PINP ratios (r = 0.41, P < 0.001). Multiple logistic regression analysis showed that CatK levels were independent predictors of CAD (odds ratio, 1.15; 95% CI, 1.07 to 1.23; P < 0.01). Furthermore, CatK levels were also correlated positively with percent plaque volumes and inversely with percent fibrous volumes by intravascular ultrasound. CONCLUSIONS These data indicated that high levels of CatK are closely linked with the presence of CAD and that CatK serves as a novel biomarker for CAD.

Atorvastatin 10 mg plus ezetimibe 10 mg compared with atorvastatin 20 mg: Impact on the lipid profile in Japanese patients with abnormal glucose tolerance and coronary artery disease

BACKGROUND Oxidized low-density lipoprotein (LDL) cholesterol is a sensitive lipid marker for predicting atherosclerosis. Ezetimibe and statins are reported to decrease both LDL cholesterol and oxidized LDL cholesterol. This prospective randomized open-label crossover study compared combination therapy with atorvastatin plus ezetimibe versus high-dose atorvastatin monotherapy. Changes in serum lipids, including malondialdehyde-modified LDL (MDA-LDL) as a representative form of oxidized LDL cholesterol, and glucose metabolism were assessed. METHODS AND RESULTS The subjects were 39 Japanese patients with coronary artery disease and type 2 diabetes or impaired glucose tolerance who were taking 10 mg/day of atorvastatin (30 men and 9 women with a mean age of 67.8 years). They were randomized to a group that first received add-on ezetimibe (10 mg/day) or a group that first received atorvastatin monotherapy at a higher dose of 20 mg/day. Both treatments were given for 12 weeks each in a crossover fashion. Add-on ezetimibe significantly decreased MDA-LDL (109.0 ± 31.9 mg/dl to 87.7 ± 29.4 mg/dl, p=0.0009), while up-titration of atorvastatin did not. The decrease with add-on ezetimibe was significantly greater than with up-titration of atorvastatin (p=0.0006). Total cholesterol and LDL cholesterol were significantly decreased by both treatments, but the percent reduction with add-on ezetimibe was significantly greater (p<0.05). High-density lipoprotein cholesterol was significantly increased by both treatments and there was no significant difference between them. The apolipoprotein B/apolipoprotein A-I ratio and remnant-like particle cholesterol were only significantly decreased by add-on ezetimibe. Both treatments caused similar elevation of hemoglobin A(1c). CONCLUSION In Japanese patients with type 2 diabetes or impaired glucose tolerance and coronary artery disease, adding ezetimibe (10 mg/day) to atorvastatin (10 mg/day) significantly improved the lipid profile compared with atorvastatin monotherapy at 20 mg/day.

Ankle brachial pressure index but not brachial-ankle pulse wave velocity is a strong predictor of systemic atherosclerotic morbidity and mortality in patients on maintenance hemodialysis

BACKGROUND Ankle brachial pressure index (ABPI) and pulse wave velocity (PWV) have been widely recognized as a marker of systemic atherosclerosis. We examined whether ABPI and brachial-ankle PWV (baPWV) predict individual cardiovascular events in patients on maintenance hemodialysis (HD). METHODS We prospectively followed-up 445 HD patients undergoing both ABPI and baPWV measurements for up to 5 years. They were divided into 2 groups [group with ABPI > 0.9 to ≤ 1.3 (n = 328) and group with ABPI ≤ 0.9 or >1.3 (n = 117)] and were also divided into tertiles according to the baPWV level (T1: <1850 cm/s; T2: 1850-2310 cm/s and T3: ≥ 2310 cm/s). RESULTS During the follow-up period (mean 43 ± 17 months), 206 cardiovascular events [cardiac event: 125 (28.1%), cerebrovascular events: 39 (8.8%), and peripheral arterial events: 42 (9.4%)] occurred, and 36 (8.1%) and 42 (9.4%) patients experienced cardiovascular and non-cardiovascular deaths, respectively. Cox multivariable analysis showed that presence of ABPI ≤ 0.9 or >1.3 was a significant predictor of cardiac events [hazard ratio (HR) 1.78, 95% confidential interval (CI) 1.27-2.49, p = 0.0008], cerebrovascular event (HR 1.95, 95%CI 1.13-3.36, p = 0.017), peripheral arterial event (HR 3.64, 95%CI 2.10-6.29, p < 0.0001), composite endpoint of cardiovascular events (HR 2.22, 95%CI 1.64-2.99, p < 0.0001), cardiovascular mortality (HR 2.42, 95%CI 1.44-4.06, p = 0.0008) and all-cause mortality (HR 1.52, 95%CI 1.03-2.25, p = 0.037). However, baPWV did not predict cardiovascular events on multivariate analysis. CONCLUSION ABPI but not baPWV is useful for risk stratification of systemic atherosclerotic morbidity and mortality in HD patients. Furthermore, ABPI could predict not only individual peripheral arterial events but also cardiac and cerebrovascular events.

Relation of Plasma Indoxyl Sulfate Levels and Estimated Glomerular Filtration Rate to Left Ventricular Diastolic Dysfunction

The prognosis of patients with diastolic heart failure (HF) is as poor as that of patients with systolic HF. Greater chronic kidney disease-associated mortality occurs in patients with left ventricular (LV) diastolic HF than in those with systolic HF. Indoxyl sulfate (IS), a uremic toxin, directly affects cardiac cells adversely in in vitro experiments. We investigated the association of IS, a uremic toxin, and chronic kidney disease with LV diastolic dysfunction in the clinical setting. The present study included 204 consecutive patients with preserved LV systolic function. To evaluate LV function, all patients underwent echocardiography. To measure the plasma IS levels and estimated glomerular filtration rate (eGFR), blood samples were obtained. Of the 204 patients, 75 (37%) had LV diastolic dysfunction. A significantly lower prevalence of LV diastolic dysfunction was present in patients with lower plasma IS levels (≤1.0 μg/ml) than those with greater plasma IS levels (38 [29%] vs 37 [51%], p <0.001). Furthermore, a significantly lower prevalence of LV diastolic dysfunction was present in patients with lower plasma IS levels and preserved eGFR than those with greater plasma IS levels and preserved eGFR, those with lower plasma IS levels and a reduced eGFR, or those with greater plasma IS levels and reduced eGFR (20 [21%] vs 18 [53%], p = 0.001; 20 [21%] vs 18 [46%], p = 0.004; and 20 [21%] vs 19 [56%], p <0.001, respectively). In conclusion, greater plasma IS levels or a reduced eGFR, or both, represent an increased risk of LV diastolic dysfunction.

Association of Cardiac Valvular Calcifications and C-Reactive Protein With Cardiovascular Mortality in Incident Hemodialysis Patients: A Japanese Cohort Study

BACKGROUND Cardiac valve calcification is seen frequently in patients undergoing dialysis. Serum C-reactive protein (CRP) level also is reported to predict future cardiovascular events. We investigated the association among valve calcification, CRP level, and mortality in patients with end-stage renal disease who were just beginning hemodialysis (HD) therapy. STUDY DESIGN Observational cohort. SETTING & PARTICIPANTS 1,290 consecutive patients who just started HD therapy were enrolled and were followed up to 10 years. PREDICTOR Patients were divided into 3 groups according to number of calcified valves: those without valve calcification, those with calcification in a single (aortic or mitral) valve, and those with calcification in both valves. They also were divided into tertiles according to CRP level. OUTCOMES Cardiovascular and all-cause mortality. MEASUREMENTS Echocardiography and CRP measurement were performed within 1 month after beginning HD therapy. RESULTS During follow-up (median, 51 months), 335 (25.9%) patients died, including 156 (12.1%) of cardiovascular disease. The adjusted HR for cardiovascular mortality was 2.80 (95% CI, 1.63-4.81) for 2 calcifications versus 0 (P < 0.001). Furthermore, the risk of cardiovascular mortality was 3.66-fold higher in patients with calcifications in both valves (highest tertile of CRP) compared with patients without valve calcification (lowest tertile of CRP; P < 0.001). LIMITATIONS Precise medical treatments or therapeutic interventions were not evaluated. CONCLUSIONS Valve calcification and elevated CRP levels were not only related to additively increased risk of mortality, but also improved the prediction of mortality in patients with end-stage renal disease who had just begun HD therapy.

Importance of oral fluid intake after coronary computed tomography angiography: An observational study

BACKGROUND The prevention of contrast-induced acute kidney injury (AKI) after coronary computed tomography angiography (CCTA) is important because patients referred for CCTA often need further contrast exposure such as an invasive coronary angiography. We aimed to examine the effects of oral volume intake on renal function in patients with preserved renal function referred for CCTA. METHODS We enrolled 180 patients who were referred for CCTA. The serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) levels were measured before, 24h, and a mean of 4.8 days after CCTA. The amount of unrestricted oral fluid intake for 24h was checked. The patients were divided into two groups: 106 subjects with a rise in SCr after CCTA (group A); and 74 without (group B). RESULTS Significant correlations were observed between the amount of oral fluid intake and the percentage changes in SCr (%SCr) (r=-0.66, p<0.0001) as well as the absolute changes in eGFR (ΔeGFR) (r=0.65, p<0.0001). The percentage of patients showing hemoglobin-A1c (HbA1c)≥6.5% was greater in group A than in group B (29% vs. 18%, p<0.001). Patients with HbA1c≥6.5% showed higher %SCr and lower ΔeGFR compared to those without it. Multiple regression analysis revealed that the amount of oral fluid intake was the only independent predictor for a rise in SCr (β=-0.731, p<0.0001). CONCLUSION Oral volume intake after CCTA is a very simple but important prophylactic procedure for contrast-induced AKI especially in diabetic patients.

Association of cardiorespiratory fitness with characteristics of coronary plaque: Assessment using integrated backscatter intravascular ultrasound and optical coherence tomography

BACKGROUND Cardiorespiratory fitness (CRF) can predict future cardiovascular disease. Rupture of vulnerable plaque which often has a large lipid core with a thin fibrous cap causes acute coronary syndrome including sudden cardiac death. We tested our hypothesis that preserved CRF is associated with low lipid composition and thick fibrous cap thickness of coronary lesions. METHODS We prospectively performed both integrated backscatter intravascular ultrasound (IB-IVUS) and optical coherence tomography (OCT) for 77 non-culprit coronary lesions in 77 consecutive angina pectoris patients who underwent percutaneous coronary intervention (PCI). Percentage of achieved of predicted peak oxygen consumption (%PPeak Vo(2)) calculated based on measured peak Vo(2) using a cardiopulmonary exercise test performed post PCI was adapted as an indicator of patient CRF. RESULTS Patients were divided into two groups [those with preserved CRF (%PPeak Vo(2) >82%) (Group I) or others (Group II)]. Coronary plaques of Group I patients had significantly smaller lipid volume, greater fibrous volume, and thicker fibrous cap thickness than those of Group II (32 ± 14% vs. 45 ± 13%, p<0.001; 57 ± 11% vs. 49 ± 11%, p<0.001; and 177.7 ± 20.9 μm vs. 143.7 ± 36.9 μm, p<0.001). In multivariate linear regression analysis, %PPeak Vo(2) showed a significantly negative correlation with lipid volume and a positive correlation with fibrous volume and fibrous cap thickness (β=-0.418, p=0.001; β=0.361, p=0.006; and β=0.339, p=0.008). CONCLUSIONS High %PPeak Vo(2) was associated with low lipid volume, high fibrous volume and thick fibrous cap thickness in coronary lesions. These results may well suggest an attenuated risk of cardiovascular events in patients with preserved CRF.

Indoxyl sulfate, a uremic toxin, and carotid intima-media thickness in patients with coronary artery disease

coronary artery disease☆ Bummei Sato , Daiji Yoshikawa ⁎, Hideki Ishii , Ryosuke Kikuchi , Takeshi Arima , Kyosuke Takeshita , Yosuke Inoue , Susumu Suzuki , Miho Tanaka , Soichiro Kumagai , Masaya Matsumoto , Mutsuharu Hayashi , Hirohiko Ando , Tetsuya Amano , Tatsuaki Matsubara , Toshimitsu Niwa , Toyoaki Murohara a a Department of Cardiology, Nagoya University Graduate School of Medicine, Japan b Department of Clinical Laboratory, Nagoya University Hospital, Japan c Department of Cardiology, Aichi Medical University, Japan d Department of Internal Medicine, School of Dentistry, Aichi-Gakuin University, Japan e Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, Japan