Kazumasa Sugimoto

Effects of stem cell mobilization by granulocyte colony-stimulating factor on endothelial function after sirolimus-eluting stent implantation: A double-blind, randomized, placebo-controlled clinical trial

BACKGROUND Stem cell mobilization by granulocyte colony-stimulating factor (G-CSF) has been shown to enhance endothelial healing after spontaneous or iatrogenic arterial disruption. Granulocyte colony-stimulating factor treatment might attenuate endothelial dysfunction after sirolimus-eluting stent (SES) implantation that may be associated with adverse cardiac events during follow-up. This prospective, double-blind, randomized, placebo-controlled study investigated whether G-CSF improved endothelial dysfunction after SES implantation. METHODS One hundred patients who underwent SES implantation were randomly assigned to the G-CSF (n = 50) or the placebo group (n = 50). They received daily subcutaneous injection of 300 μg G-CSF or saline for 5 days. Endothelial function was estimated by measuring the coronary vasoreactivity in the segments 15 mm proximal and distal to SES in response to intracoronary infusion of acetylcholine (10(-8) and 10(-7) mol/L) at 9-month follow-up. RESULTS Follow-up angiography was performed in 41 G-CSF patients (82%) and 46 placebo patients (92%) (P = .14). Changes in coronary diameter in response to acetylcholine infusion in the proximal segment were not significantly different between the 2 groups. However, vasoconstriction in the distal segment in response to 10(-8) mol/L (-3.9% ± 6.4% vs -7.0% ± 8.1%, P < .05) and 10(-7) mol/L (-8.8% ± 11.0% vs -15.2% ± 7.6%, P < .01) acetylcholine infusion was attenuated in the G-CSF group. Endothelium-independent vasodilatation after nitrate infusion did not differ between the 2 groups. CONCLUSION Granulocyte colony-stimulating factor attenuates endothelial dysfunction after SES implantation.

Increased platelet inhibition after switching from maintenance clopidogrel to prasugrel in Japanese patients with stable coronary artery disease.

BACKGROUND The pharmacodynamic effects of changing from standard-dose clopidogrel to low-dose (3.75 mg) prasugrel in Japanese patients are largely unknown. METHODSANDRESULTS A total of 53 consecutive Japanese patients with stable coronary artery disease (CAD) who received aspirin and clopidogrel were enrolled. Clopidogrel was switched to 3.75 mg prasugrel. At day 14, prasugrel was switched to 75 mg clopidogrel. Platelet reactivity was measured using the VerifyNow assay at baseline, day 14, and day 28. VerifyNow P2Y12 reaction units (PRU) >208 was defined as high on-treatment platelet reactivity (HPR). The prevalence of HPR (18.9% vs. 41.5% vs. 44.2%, P<0.001) and the PRU level (154.3±54.2 vs. 196.2±55.5 vs. 194.6±55.8, P<0.001) were significantly lower on prasugrel maintenance therapy compared with the clopidogrel therapy before and after switching. The CYP2C19 genotypes that account for the 3 phenotypes (ie, extensive metabolizer, intermediate metabolizer, and poor metabolizer) had a significant impact on platelet reactivity with clopidogrel (174.9±54.0 vs. 193.1±56.5 vs. 240.6±25.4 PRU, P<0.001) but not prasugrel (147.0±51.9 vs. 147.5±58.3 vs. 184.4±38.3 PRU, P=0.15). CONCLUSIONS Low-dose prasugrel achieves stronger platelet inhibition than clopidogrel in Japanese patients with stable CAD.

Efficacy and safety of low-dose clopidogrel in Japanese patients after drug-eluting stent implantation: a randomized pilot trial

In Japan, a lower maintenance dose of ticlopidine is used than in the United States and Europe. Therefore a lower maintenance dose of clopidogrel may also be considered appropriate in Japanese patients. The present randomized pilot study evaluated the efficacy and safety of 50 mg clopidogrel in Japanese patients who underwent drug-eluting stent (DES) implantation. A total of 200 patients with 277 lesions who underwent intravascular ultrasound-guided DES implantation were enrolled. The subjects were allocated to the 50- or 75-mg clopidogrel group. All patients received 100 mg aspirin daily before the procedure, and this continued indefinitely. The duration of clinical follow-up was 21.8 ± 5.7 months in the 75-mg group and 21.9 ± 6.1 months in the 50-mg group (P = 0.96). During follow-up, no cardiac death, myocardial infarction, or stent thrombosis was observed in either group. Side effects of clopidogrel were observed in 4 patients (4.0 %) in the 75-mg group and in 4 patients (4.0 %) in the 50-mg group. Following this randomized pilot study, it may be justified to perform a large-scale randomized study comparing 50- and 75-mg dosing of clopidogrel in Japanese patients undergoing coronary stent implantation.

Intracoronary Acetylcholine Provocation Testing - Omission of the 20-µg Dose Is Feasible in Patients Without Coronary Artery Spasm in the Other Coronary Artery.

BACKGROUND Based on the Japanese Circulation Society guideline of vasospastic angina, incremental doses of acetylcholine (ACh) are prescribed for coronary spasm provocation: 20 and 50 μg for the right coronary artery (RCA), and 20, 50 and 100 μg for the left coronary artery (LCA). However, the requirement for each dose of ACh has not been fully evaluated. METHODSANDRESULTS A total of 249 patients who underwent ACh provocation test for both the RCA and LCA were included. The positive diagnosis of intracoronary ACh provocation test was defined as total or subtotal coronary artery narrowing accompanied by chest pain and/or ischemic ECG changes. Positive ACh provocation test was observed in 116 patients (47%). Patients without vasospasm in the LCA had a lower incidence of vasospasm in the RCA induced by 20 μg of ACh compared with those with vasospasm in LCA (0.8% vs. 27.5%, P<0.001). Similarly, vasospasm in the LCA induced by 20 μg of ACh was observed less frequently in patients without than with vasospasm in the RCA (6.1% vs. 26.7%, P<0.001). In all patients without vasospasm in the other coronary artery, intracoronary administration of 50 μg of ACh was performed without any complications. CONCLUSIONS Skipping the provocation test with 20 μg of ACh in patients without coronary artery spasm in the other coronary artery may be possible. (Circ J 2016; 80: 1820-1823).

Comparison of 3-dimensional and 2-dimensional quantitative coronary angiography and intravascular ultrasound for functional assessment of coronary lesions

BACKGROUND Three-dimensional quantitative coronary angiography (3D-QCA) reportedly allows more accurate delineation of true vessel geometry when compared with standard two-dimensional (2D) QCA and has been validated by intravascular ultrasound (IVUS). This study sought to compare diagnostic efficiency of 2D- and 3D-QCA, and IVUS in identifying hemodynamically significant coronary stenoses as determined by fractional flow reserve (FFR). METHODS Forty-two lesions in 40 patients were assessed by FFR, IVUS, and 2D- and 3D-QCA. Correlations between FFR values and anatomical parameters obtained by 2D- and 3D-QCA and IVUS were analyzed. The receiver operating characteristic (ROC) curves were used to compare the diagnostic accuracy of the parameters for predicting FFR≤0.80. RESULTS Mean FFR value was 0.75±0.13. FFR≤0.80 was observed in 28 lesions (67%). Of IVUS measurements, minimum lumen area (MLA) well correlated with FFR values (r=0.71, p<0.001). Of 3D- and 2D-QCA measurements, minimum lumen diameter (MLD) correlated best with FFR values (r=0.79, p<0.01; r=0.68, p<0.01, respectively), followed by MLA (r=0.76, p<0.01; r=0.67, p<0.01, respectively). The area under the ROC curve for 3D-QCA MLD was greater than those for 2D-QCA MLD (p=0.03) and 2D-QCA MLA (p=0.03). On the other hand, the AUC for 3D-QCA MLD, 3D-QCA MLA, and IVUS MLA were not significantly different. CONCLUSIONS 3D-QCA is more useful than 2D-QCA and possibly comparable to IVUS in the assessment of functional stenosis severity. When FFR is not available, 3D-QCA MLA and MLD may assist in the assessment of functional severity of intermediate lesions.

Impact of chronic kidney disease on platelet inhibition of clopidogrel and prasugrel in Japanese patients

BACKGROUND The impact of chronic kidney disease (CKD) on the antiplatelet effect of clopidogrel and low-dose (3.75mg) prasugrel in Japanese patients is largely unknown. METHODS A total of 53 consecutive Japanese patients with stable coronary artery disease who received aspirin and clopidogrel were enrolled, and categorized by estimated glomerular filtration rate (eGFR): CKD group (n=15, eGFR<60ml/min/1.73m2) and non-CKD group (n=38, eGFR≥60ml/min/1.73m2). Clopidogrel was switched to 3.75mg prasugrel. Platelet reactivity measurement using the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA, USA) was performed at baseline (on clopidogrel) and day 14 (on prasugrel). RESULTS The VerifyNow P2Y12 reaction units (PRU) during clopidogrel therapy was significantly higher in the CKD group than that in the non-CKD group (185.2±51.1 PRU vs. 224.3±57.0 PRU, p=0.02), whereas, the PRU with the prasugrel therapy in the CKD group and non-CKD group were not significantly different (149.9±51.1 PRU vs. 165.3±61.8 PRU, p=0.36). The PRU was significantly lower with the prasugrel therapy compared to that with the clopidogrel therapy both in the CKD group and in the non-CKD group. CONCLUSIONS Antiplatelet effect of clopidogrel but not prasugrel is attenuated in patients with CKD. Prasugrel achieves a consistently lower platelet reactivity compared with clopidogrel regardless of the presence of mild to moderate CKD.

Recovery of endothelial function after sirolimus-eluting stent implantation: a pilot study.

Whether endothelial dysfunction after sirolimus-eluting stent (SES) implantation is persistent has not been fully evaluated. Endothelial function was evaluated in 152 lesions that underwent follow-up coronary angiography after SES implantation. Lesions were classified into 2 groups according to the duration between SES implantation and follow-up: ≤12 months (n = 95) and >12 months (n = 57). Changes in coronary diameter in response to 10−8 mol/L (−2.4% ± 6.3% vs −4.9% ± 3.8%, P < .01) and 10−7 mol/L acetylcholine (Ach; −4.6% ± 7.6% vs −10.7% ± 9.1%, P < .001) in segment proximal to SES were significantly attenuated in the >12-month group than in the ≤12-month group. There were less changes in coronary diameter in response to 10−8 mol/L (−2.3% ± 4.6% vs −6.9% ± 5.0%, P < .001) and 10−7 mol/L Ach (−6.5% ± 11.4% vs −16.8% ± 10.5%, P < .001) in segment distal to SES in the >12-month group. Endothelial dysfunction may diminish long after SES implantation.

Efficacy of intravenous nicorandil for fractional flow reserve assessment: study protocol for a crossover randomised trial

Introduction Nicorandil has vasodilatory effects on both the epicardial coronary arteries and the coronary microvasculature, thereby increasing coronary blood flow. Intravenous administration of nicorandil can be applicable for fractional flow reserve (FFR) measurement as a hyperaemic agent and a possible alternative to adenosine. However, the effectiveness of intravenous nicorandil infusion for FFR measurement is largely unclear. Methods and analysis This crossover randomised study is being performed to investigate the efficacy of intravenous administration of nicorandil for FFR measurement. Patients with an intermediate coronary artery stenosis who satisfy the eligibility criteria undergo FFR measurement with a consecutive randomised order of patient-blind infusions of continuous intravenous administration of adenosine and a single bolus intravenous administration of nicorandil. The primary end point of the study is the agreement between the FFR values obtained by the intravenous nicorandil and those obtained by the intravenous adenosine. Recruitment of this trial started in November 2015 and will end in March 2017, or until a total of 50 participants have been recruited. Ethics and dissemination The protocol was approved by the Institutional Review Board at Chiba University Hospital. Study findings will be published in peer-reviewed journals. Trial registration number UMIN000019309; Pre-results.

Relation between severity of myocardial bridge and vasospasm

BACKGROUND Myocardial bridge (MB) has been reported to induce cardiac complications including coronary vasospasm. Although MB has some anatomical and morphological variations, the association of these variations with vasospasm is unclear. The aim of this study was to investigate the relation between morphological severity of MB and vasospasm induced by acetylcholine (ACh) provocation test. METHODS A total of 392 patients without coronary stent in the left anterior descending artery (LAD) undergoing intracoronary ACh provocation test were included. Angiographic coronary artery vasospasm was defined as total or subtotal occlusion induced by ACh provocation. MB was identified on coronary angiography as a milking effect. Total bridged length and maximum percent systolic compression of MB in the LAD were analyzed quantitatively. RESULTS MBs in the LAD were identified in 140 patients (36%), mostly in the mid segment. Patients with MB in the LAD had greater number of provoked vasospasm in the LAD and positive ACh provocation test compared to those without. The bridged length positively correlated with percent systolic compression of MB (r=0.37, p<0.001). In the receiver operating characteristic curve analysis, both bridged length and percent systolic compression of MB significantly predicted the provoked LAD spasm (AUC 0.74, p<0.001, and AUC 0.68, p<0.001). Multivariate regression analysis demonstrated these factors as independent predictors for provoked LAD spasm. CONCLUSION MB, especially morphologically severe MB, may induce greater coronary vasospasm.

Protective effect of angiotensin II receptor blocker and calcium channel blocker on endothelial vasomotor function after everolimus-eluting stent implantation

BACKGROUND Endothelial dysfunction after drug-eluting stent implantation has been demonstrated. It may be associated with adverse cardiovascular events during follow-up. Olmesartan, an angiotensin II receptor antagonist, ameliorates endothelial dysfunction. The present study evaluated the protective effect of olmesartan on endothelial function after everolimus-eluting stent (EES) implantation. METHODS A total of 40 patients who underwent EES implantation were randomly assigned to the olmesartan group (20 patients with 30 lesions) or the non-olmesartan group (20 patients with 32 lesions). Endothelial function was estimated by measuring the coronary vasoreactivity in the segments 15mm proximal and distal to EES in response to intracoronary infusion of acetylcholine (Ach; 10(-8) and 10(-7)mol/L) at 9-month follow-up. Endothelium-independent vasomotion was assessed after an intracoronary bolus of isosorbide dinitrate. RESULTS In both groups, Ach infusion did not induce significant vasoconstriction in the segment either proximal or distal to the EES. The changes in coronary diameter in response to 10(-8)mol/L (-2.0±4.4% vs. -0.6±4.1%, p=0.33) and 10(-7)mol/L (-1.8±7.9% vs. -0.3±7.6%, p=0.57) Ach infusion in the segment proximal to EES were not significantly different between the olmesartan group and the non-olmesartan group. There were no significant differences in vasoconstriction in response to 10(-8)mol/L (-0.8±5.8% vs. -0.9±7.0%, p=0.96) and 10(-7)mol/L (1.8±9.7% vs. -1.8±9.7%, p=0.16) Ach infusion in the segment distal to EES between the 2 groups. Endothelium-independent vasodilation after nitrate infusion did not differ between the 2 groups. CONCLUSIONS Endothelial dysfunction is not observed after EES implantation. Olmesartan does not improve endothelial function after EES implantation.