Aya Nagaki

Noninvasive indices of arterial stiffness in hemodialysis patients

The purpose of this study was to evaluate the validity of brachial–ankle pulse wave velocity (baPWV) and the cardio–ankle vascular index (CAVI) as measures of arterial stiffness in hemodialysis (HD) patients. We studied 160 consecutively enrolled HD patients (mean age: 59±13 years; 91 male patients). We measured baPWV and CAVI using a VaSera VS-1000, maximum intima-media thickness (max IMT) of the carotid artery by ultrasonography and blood renal and lipid parameters. As a control, baPWV and CAVI were also measured in age- and gender-matched healthy volunteers. Both baPWV and CAVI were significantly higher in HD patients than in controls (baPWV: 1698±355 vs. 1454±263 cm s−1, P<0.0001; CAVI: 9.3±1.4 vs. 8.9±1.2, P<0.01). BaPWV correlated positively with age (r=0.549, P<0.0001), systolic blood pressure (SBP) (r=0.510, P<0.0001), diastolic blood pressure (r=0.203, P<0.0001), pulse pressure (PP) (r=0.499, P<0.0001), Kt V−1 (r=0.221, P<0.01), Brinkman index (r=0.186, P<0.05) and max IMT (r=0.285, P<0.001). CAVI also correlated positively with age (r=0.562, P<0.0001), SBP (r=0.395, P<0.0001), PP (r=0.490, P<0.0001), Kt V−1 (r=0.216, P<0.01), Brinkman index (r=0.238, P<0.01) and max IMT (r=0.280, P<0.001). Multiple regression analysis demonstrated baPWV and CAVI correlated independently with age and SBP. Receiver operating characteristics (ROC) curve analysis demonstrated that baPWV and CAVI had similar power to predict increases in max IMT. We also measured baPWV and CAVI immediately before and after HD, and showed CAVI was influenced by changes in water volume. Both baPWV and CAVI are therefore useful indices of arterial stiffness in HD patients.

Tacrolimus-eluting stent inhibits neointimal hyperplasia via calcineurin/NFAT signaling in porcine coronary artery model

AIMS The purpose is to elucidate the mechanism by which a newly developed tacrolimus-eluting stent (TES) prevents neointimal hyperplasia after stenting. METHODS AND RESULTS The three major coronary arteries in juvenile swine were randomized to implantation of either a TES or bare metal stent (BMS). Twelve weeks after stenting, the TES showed 29% less neointimal area than the BMS. Immunohistochemical staining showed that the expression of calcineurin was up-regulated in the neointima and media after stenting, and the TES inhibited this up-regulation. Western blotting demonstrated that the expression of calcineurin, nuclear factor of activated T cell (NFAT), and interleukin-2 (IL-2) was lower with the TES than with the BMS. To confirm the effect of tacrolimus on vascular smooth muscle cells (VSMCs) and its mechanism, cultured rat VSMCs were incubated with 12.5 microM of tacrolimus (tacrolimus group) or without tacrolimus (control group). The cell number of the tacrolimus group was significantly lower than that of the control group at 48 h of incubation. Western blotting demonstrated that tacrolimus decreased the expression of calcineurin, NFATc4, and IL-2 of cultured VSMCs. We confirmed that calcineurin small-interfering RNA (siRNA) decreased cell proliferation and the expression of NFATc4 and IL-2 in cultured VSMCs compared with negative control-siRNA. CONCLUSION The newly developed TES inhibited neointimal hyperplasia after stenting via the calcineurin/NFAT/IL-2 signaling pathway, which is one of several mechanisms through which TES inhibits restenosis. Calcineurin may be an important molecular target to prevent restenosis after stenting.