Masanobu Ishii

Acetylcholine-Provoked Coronary Spasm at Site of Significant Organic Stenosis Predicts Poor Prognosis in Patients With Coronary Vasospastic Angina

BACKGROUND Coronary artery spasm contributes to the pathogenesis of variant angina and ischemic heart disease and may play a role in the progression of atherosclerosis. It is unclear whether the location of spasm is related to outcome. OBJECTIVES This study compared the clinical features and prognosis of patients with coronary spasm at the site of significant atherosclerotic stenosis with patients with spasm at sites without stenosis or nonsignificant stenosis. METHODS This was a retrospective, observational study of 1,877 consecutive patients with typical or atypical angina-like chest pain undergoing acetylcholine (ACh)-provocation testing. A total of 1,760 patients were eligible for analysis. ACh-provoked coronary spasm and significant organic stenosis were observed in 873 and 358 patients, respectively. RESULTS In patients with significant atherosclerotic stenosis, ACh-positive patients (n = 233) were younger and without diabetes mellitus compared with nonspasm patients (n = 125). In patients without organic stenosis, ACh-positive patients (n = 640) were older, had dyslipidemia, and were more likely to have a family history of ischemic heart disease than nonspasm patients (n = 762). Multiple logistic regression analysis identified ST-segment elevation during anginal attacks, organic stenosis of the left anterior descending artery, and multivessel spasm as correlates of spasm at sites of significant organic stenosis (n = 192). Multivariate analysis identified ACh-provoked spasm at the site of significant stenosis and use of nitrates as the 2 prognostic factors for major adverse cardiac events. CONCLUSIONS The clinical features and prognosis of patients with ACh-provoked coronary spasm were different when it occurred at the site of significant atherosclerotic stenosis compared with patients with spasm elsewhere. Both spasm at the site of significant organic stenosis and nitrate use were significant predictors of major adverse cardiac events.

A novel quantitative assessment of whole blood thrombogenicity in patients treated with a non-vitamin K oral anticoagulant

Non-vitamin K oral anticoagulants(NOAC) negate complex patient management issues, such as frequent blood sampling, diet restriction, and drug interactions, that had to be dealt with during the warfarinonly era. However, there is no definite tool tomonitor the anticoagulant effects of NOACs, although some patients suffer from bleeding complications related to exceedingly high blood concentrations of NOACs. [1, 2] Routine tests, such as prothrombin time-international normalized ratio (PT-INR) and activated partial thromboplastin time (APTT), can be problematic formonitoring the anticoagulant effects of all NOACs because each individual NOAC has a different characteristic chemical structure and different pharmacokinetic profile (e.g., plasma half-life and tissue penetration rate) [3]. Recently, the Total Thrombus-formation Analysis System (T-TASTM) [4,5], a microchip-based flow chamber system capable of evaluating whole blood thrombogenicity, was developed as an easy-to-use system for quantitative analysis of thrombus formation (Fig. 1A,B). In the present study, we sought to examine whether the T-TASTM was useful for the quantitative analysis of thrombogenicity in patients treated with the NOAC edoxaban (Fig. 1C, D). We recruited 20 consecutive patients (male: n = 8 [40%] and female: n=12 [60%], average age: 75.2±8.7 years)whowere scheduled

Total Thrombus‐Formation Analysis System (T‐TAS) Can Predict Periprocedural Bleeding Events in Patients Undergoing Catheter Ablation for Atrial Fibrillation

Background Non–vitamin K antagonist oral anticoagulants are used to prevent thromboembolism in patients with atrial fibrillation. The T‐TAS “Total Thrombus‐formation Analysis System” (Fujimori Kogyo Co Ltd) was developed for quantitative analysis of thrombus formation using microchips with thrombogenic surfaces (collagen, platelet chip [PL] ; collagen plus tissue factor, atheroma chip [AR]). We evaluated the utility of T‐TAS in predicting periprocedural bleeding in atrial fibrillation patients undergoing catheter ablation (CA). Methods and Results After exclusion of 20 from 148 consecutive patients undergoing CA, the remaining 128 patients were divided into 2 treatment groups: the warfarin group (n=30) and the non–vitamin K antagonist oral anticoagulants group (n=98). Blood samples obtained on the day of CA (anticoagulant‐free point) and at 3 and 30 days after CA were used in T‐TAS to compute the thrombus formation area under the curve (AUC; AUC for the first 10 minutes for PL tested at flow rate of 24 μL/min [PL 24‐AUC 10]; AUC for the first 30 minutes for AR tested at flow rate of 10 μL/min [AR 10‐AUC 30]). AR 10‐AUC 30 and PL 24‐AUC 10 levels were similar in the 2 groups on the day of CA. Levels of AR 10‐AUC 30, but not PL 24‐AUC 10, were significantly lower in the 2 groups at days 3 and 30 after CA. Multiple logistic regression analyses identified the AR 10‐AUC 30 level on the day of CA as a significant predictor of periprocedural bleeding events (odds ratio 5.7; 95% CI 1.54–21.1; P=0.009). Receiver operating characteristic analysis showed that the AR 10‐AUC 30 level on the day of CA significantly predicted periprocedural bleeding events (AUC 0.859, 95% CI 0.766–0.951; P<0.001). The cutoff AR 10‐AUC 30 level was 1648 for identification of periprocedural bleeding events. Conclusions These results suggested that the AR 10‐AUC 30 level determined by T‐TAS is a potentially useful marker for prediction of bleeding events in atrial fibrillation patients undergoing CA.

Differential Effects of Strong and Regular Statins on the Clinical Outcome of Patients With Chronic Kidney Disease Following Coronary Stent Implantation – The Kumamoto Intervention Conference Study (KICS) Registry –

BACKGROUND The aim of this study was to examine the effects of different statins on the clinical outcomes of Japanese patients with coronary stent implants. METHODS AND RESULTS This study included 5,801 consecutive patients (males, 4,160; age, 69.7±11.1 years, mean±SD) who underwent stent implantation between April 2008 and March 2011. They were treated with a strong statin (n=3,042, 52%, atorvastatin, pitavastatin, or rosuvastatin), a regular statin (n=1,082, 19%, pravastatin, simvastatin, or fluvastatin) or no statin (n=1,677, 29%). The patients with chronic kidney disease (CKD) were divided into mild-to-moderate CKD (30≤eGFR<60, n=1,956) and severe CKD (eGFR <30, n=559). Primary endpoints included cardiovascular death and nonfatal myocardial infarction, including stent thrombosis and ischemic stroke. The clinical outcome for the primary endpoint in mild-to-moderate CKD patients treated with a strong statin (hazard ratio 0.50, 95% confidence interval 0.31-0.81; P=0.005) was significantly lower than in those on no statins, but that in the patients treated with a regular statin was not (P=0.160). The clinical outcome for the primary endpoint in severe CKD patients treated with a strong or regular statin was no different than not being on statin therapy (P=0.446, P=0.194, respectively). CONCLUSIONS In patients with mild-to-moderate CKD, only strong statins were associated with lower risk compared with no statin, but regular statins were not. It is possible that taking a strong statin from the early stage of CKD is useful for suppression of cardiovascular events.

Colchicine Improves Survival, Left Ventricular Remodeling, and Chronic Cardiac Function After Acute Myocardial Infarction

BACKGROUND Several studies have reported that colchicine attenuated the infarct size and inflammation in acute myocardial infarction (MI). However, the sustained benefit of colchicine administration on survival and cardiac function after MI is unknown. It was hypothesized that the short-term treatment with colchicine could improve survival and cardiac function during the recovery phase of MI.Methods and Results:MI was induced in mice by permanent ligation of the left anterior descending coronary artery. Mice were then orally administered colchicine 0.1 mg/kg/day or vehicle from 1 h to day 7 after MI. Colchicine significantly improved survival rate (colchicine, n=48: 89.6% vs. vehicle, n=51: 70.6%, P<0.01), left ventricular end-diastolic diameter (5.0±0.2 vs. 5.6±0.2 mm, P<0.05) and ejection fraction (41.5±2.1 vs. 23.8±3.1%, P<0.001), as assessed by echocardiogram compared with vehicle at 4 weeks after MI. Heart failure development as pulmonary edema assessed by wet/dry lung weight ratio (5.0±0.1 vs. 5.5±0.2, P<0.01) and B-type natriuretic peptide expression in the heart was attenuated in the colchicine group at 4 weeks after MI. Histological and gene expression analysis revealed colchicine significantly inhibited the infiltration of neutrophils and macrophages, and attenuated the mRNA expression of pro-inflammatory cytokines and NLRP3 inflammasome components in the infarcted myocardium at 24 h after MI. CONCLUSIONS Short-term treatment with colchicine successfully attenuated pro-inflammatory cytokines and NLRP3 inflammasome, and improved cardiac function, heart failure, and survival after MI.

Impact of Statin Therapy on Clinical Outcome in Patients With Coronary Spasm

Background Statin therapy reduces the risk of cardiovascular events in patients with obstructive coronary artery disease. The aim of the present study was to determine the effects of statins on the prognosis of patients with coronary vasospastic angina (VSA) free of significant atherosclerotic stenosis. Methods and Results After exclusion of 475 from 1877 consecutive patients who underwent an acetylcholine‐provocation test between January 1991 and December 2010, data of 640 VSA patients without significant organic stenosis of the remaining 1402 were analyzed retrospectively. Propensity score matching was performed to reduce the effect of treatment‐selection bias and possible confounders. The primary endpoint was major adverse cardiac events (MACE), including cardiac death, nonfatal myocardial infarction, and unstable angina. Among the study population, dyslipidemia on admission was identified in 160 of 168 (95.2%) patients of the statin group compared with only 125 of 472 (26.5%) of the no‐statin group. Of the 640 patients, 24 (3.8%) developed MACE. Multivariate Cox hazard regression analysis identified statin therapy as a significant negative predictor of MACE (hazard ratio, 0.11; 95% CI, 0.02–0.84; P=0.033). In the propensity‐score matched cohorts (n=128 each), Kaplan–Meier survival curve showed a better 5‐year MACE‐free survival rate for patients of the statin group compared to the no‐statin group (100% vs 91.7%, respectively; P=0.002). Conclusions Statin therapy correlated with a lower rate of cardiovascular events in VSA patients free of significant organic stenosis. Statins seems to improve the prognosis of VSA patients free of significant organic stenosis.

Total Thrombus‐formation Analysis System Predicts Periprocedural Bleeding Events in Patients With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention

Background Periprocedural bleeding events are common after percutaneous coronary intervention. We evaluated the association of periprocedural bleeding events with thrombogenicity, which was measured quantitatively by the Total Thrombus‐formation Analysis System equipped with microchips and thrombogenic surfaces (collagen, platelet chip [PL]; collagen plus tissue factor, atheroma chip [AR]). Methods and Results Between August 2013 and March 2016, 313 consecutive patients with coronary artery disease undergoing elective percutaneous coronary intervention were enrolled. They were divided into those with or without periprocedural bleeding events. We determined the bleeding events as composites of major bleeding events defined by the International Society on Thrombosis and Hemostasis and minor bleeding events (eg, minor hematoma, arteriovenous shunt and pseudoaneurysm). Blood samples obtained at percutaneous coronary intervention were analyzed for thrombus formation area under the curve (PL24‐AUC10 for PL chip; AR10‐AUC30 for AR chip) by the Total Thrombus‐formation Analysis System and P2Y12 reaction unit by the VerifyNow system. Periprocedural bleeding events occurred in 37 patients. PL24‐AUC10 levels were significantly lower in patients with such events than those without (P=0.002). Multiple logistic regression analyses showed association between low PL24‐AUC10 levels and periprocedural bleeding events (odds ratio, 2.71 [1.22–5.99]; P=0.01) and association between PL24‐AUC10 and periprocedural bleeding events in 176 patients of the femoral approach group (odds ratio, 2.88 [1.11–7.49]; P=0.03). However, PL24‐AUC10 levels in 127 patients of the radial approach group were not significantly different in patients with or without periprocedural bleeding events. Conclusions PL24‐AUC10 measured by the Total Thrombus‐formation Analysis System is a potentially useful predictor of periprocedural bleeding events in coronary artery disease patients undergoing elective percutaneous coronary intervention.

Assessment of platelet-derived thrombogenicity with the total thrombus-formation analysis system in coronary artery disease patients receiving antiplatelet therapy.

Essentials Total thrombus‐formation analysis system (T‐TAS) quantitatively measures platelet thrombus formation. We examined the utility of T‐TAS in patients with coronary artery disease. T‐TAS can discriminate different types of the antiplatelet therapy in the same measuring method. Genetic background, cytochrome P‐450 2C19 genotypes, also influenced T‐TAS parameters.

Determinants of Myocardial Lactate Production During Acetylcholine Provocation Test in Patients With Coronary Spasm

Background Myocardial lactate production in the coronary circulation during acetylcholine (ACh)‐provocation test (abbreviated as lactate production) provides supporting evidence for coronary spasm–induced myocardial ischemia. The purpose of this study was to examine the clinical features, predictive factors, and prognosis of patients with coronary vasospastic angina (VSA) and lactate production. Methods and Results We examined all 712 patients who underwent both myocardial lactate measurement during ACh‐provocation test in the left coronary artery and genetic screening test of a –786T/C polymorphism in the 5′‐flanking region of the endothelial nitric oxide synthase (eNOS) gene between January 1991 and December 2010. Lactate production was observed in 252 of the 712 patients and in 219 of 356 VSA patients diagnosed by ACh‐provocation test. Compared with lactate production–negative VSA patients, the lactate production–positive counterparts were more likely to be nonsmoker female diabetics with –786T/C eNOS polymorphism (61% vs 31%, P<0.001, 62% vs 34%, P<0.001, 24% vs 14%, P=0.016, and 25% vs 15%, P=0.018, respectively). Multivariable logistic regression analysis identified female sex, diabetes mellitus, and –786T/C eNOS polymorphism to correlate with lactate production (odds ratio 3.51, 95% CI 2.16 to 5.70, P<0.001; odds ratio 2.53, 95% CI 1.38 to 4.65, P=0.003; and odds ratio 1.85, 95% CI 1.02 to 3.35, P=0.044, respectively). Kaplan–Meier survival curve showed no difference in 5‐year survival rate free from major adverse cardiac events between lactate production–positive and –negative VSA patients (P=0.319). Conclusions The results indicated that female sex, diabetes, and mutation in –786T/C eNOS gene correlate with ACh‐provoked myocardial ischemia in patients with coronary spasm.

Impact of left ventricular hypertrophy on impaired coronary microvascular dysfunction

Impact of left ventricular hypertrophy on impaired coronary microvascular dysfunction Kenichi Tsujita ⁎, Kenshi Yamanaga , Naohiro Komura , Kenji Sakamoto , Takashi Miyazaki , Masanobu Ishii , Noriaki Tabata , Tomonori Akasaka , Daisuke Sueta , Yuichiro Arima , Sunao Kojima , Eiichiro Yamamoto , Megumi Yamamuro , Tomoko Tanaka , Yasuhiro Izumiya , Shinji Tayama , Sunao Nakamura , Koichi Kaikita , Seiji Hokimoto , Hisao Ogawa a