Satomi Iwashita

Digital assessment of endothelial function and ischemic heart disease in women.

OBJECTIVES We investigated the utility of digital reactive hyperemia peripheral arterial tonometry (RH-PAT) in predicting ischemic heart disease (IHD), including obstructive coronary artery disease (CAD) and nonobstructive coronary artery disease (NOCAD), in women. BACKGROUND IHD is the leading cause of mortality, and its pathogenesis is diverse in women. Fingertip RH-PAT is a new device that provides noninvasive, automatic, and quantitative evaluation of endothelial dysfunction. METHODS RH-PAT was measured using Endo-PAT2000 (Itamar Medical, Caesarea, Israel) before cardiac catheterization in 140 stable women scheduled for hospitalization to examine chest pain. NOCAD was diagnosed by angiography with measurement of coronary blood flow and cardiac lactate production during intracoronary acetylcholine provocation test and cardiac scintigraphy with stress tests. RESULTS Sixty-eight women (49%) had obstructive CAD and 42 women (30%) had NOCAD. RH-PAT indexes were significantly attenuated in both obstructive CAD and NOCAD as compared with non-IHD (n = 30) (obstructive CAD: median 1.57, interquartile range [IQR] 1.42 to 1.76; NOCAD: median 1.58, IQR 1.41 to 1.78; non-IHD: median 2.15, IQR 1.85 to 2.48, p < 0.001). By multivariate logistic regression analysis, only RH-PAT index was significantly associated with IHD, including obstructive CAD and NOCAD (odds ratio 0.51; 95% confidence interval: 0.38 to 0.68; p < 0.001). In receiver-operating characteristic analysis, RH-PAT index was a significant predictor of IHD (area under the curve 0.86; p < 0.001). Furthermore, only RH-PAT was useful for the prediction of NOCAD after excluding obstructive CAD (area under the curve 0.85; p < 0.001; RH-PAT index of <1.82 had 81% sensitivity and 80% specificity). CONCLUSIONS RH-PAT indexes were significantly attenuated in women with IHD. Digital RH-PAT can predict patients with IHD, especially NOCAD before angiography. RH-PAT is potentially useful for identifying high-risk women for IHD. (Endothelial Dysfunction and Coronary Artery Spasm; NCT00619294).

Peripheral Endothelial Function and Cardiovascular Events in High-Risk Patients

Background Endothelial dysfunction is a key component of vascular vulnerability. Reactive hyperemia index (RHI), as assessed by the peripheral arterial tonometry, can noninvasively evaluate endothelial function. This study was designed to determine the additional prognostic value of endothelial function to the Synergy Between PCI With Taxus and Cardiac Surgery Score (SYNTAXsc) and the Framingham Risk Score (FRS) in predicting cardiovascular events in high‐risk patients. Methods and Results We undertook a two‐center prospective study in 528 stable patients at high‐risk for cardiovascular events from the years 2006–2011. The RHI was measured before coronary angiography and coronary complexity was assessed by SYNTAXsc. After optimal therapies including coronary revascularization, there was follow‐up with patients until August 2012. Cardiovascular events consist of cardiovascular death, myocardial infarction, unstable angina, ischemic stroke, coronary revascularization, heart failure‐induced hospitalization, aortic disease, and peripheral arterial disease. During 1468 person‐years of follow‐up, 105 patients developed cardiovascular events. Multivariate Cox proportional hazards analysis identified B‐type natriuretic peptide (BNP), SYNTAXsc, and RHI as independent cardiovascular event predictors (hazard ratio [95% confidence interval]: natural logarithm of BNP per 0.1: 1.019 [1.002 to 1.037]; P=0.023, SYNTAXsc per tertile: 2.426 [1.825 to 3.225]; P<0.0001, RHI per 0.1: 0.761 [0.673 to 0.859]; P<0.0001). When RHI was added to the FRS, BNP, and SYNTAXsc, net reclassification index was significantly improved (27.5%; P<0.0001), with a significant increase in the C‐statistic (from 0.728 [0.679 to 0.778] to 0.766 [0.726 to 0.806]; P=0.031). Conclusions Advanced endothelial dysfunction significantly correlated with near future cardiovascular events in high‐risk patients. This physiological vascular measurement improved risk discrimination when added to the FRS, BNP, and SYNTAXsc. Clinical Trial Registration URL: clinicaltrials.gov (http://www.clinicaltrials.gov). Unique identifier: NCT00737945.

Endothelial function and cardiovascular events in chronic kidney disease

BACKGROUND As patients with chronic kidney disease (CKD) are at high risk of developing coronary artery disease (CAD), it is important to stratify their cardiovascular risk. We investigated whether peripheral endothelial dysfunction is associated with the presence of CAD in patients with CKD and is a predictor of cardiovascular events. METHODS We enrolled 383 CKD patients with at least one coronary risk factor. Peripheral endothelial function was assessed by reactive hyperemia peripheral arterial tonometry index (RHI). The presence of CAD was determined by coronary angiography. Cardiovascular events were assessed during follow-up. RESULTS Ln-RHI was significantly lower in risk factor-matched CKD patients (n=323) than risk factor-matched non-CKD patients (n=323) (0.527 ± 0.192 vs. 0.580 ± 0.218, p=0.001). In CKD patients (n=383), Ln-RHI was significantly lower in CAD (0.499 ± 0.183, n=262) than non-CAD (0.582 ± 0.206, n=121) (p<0.001) patients. Multivariate logistic regression analysis identified Ln-RHI as an independent factor associated with the presence of CAD (p=0.001). During a mean follow-up period of 30 months, 90 cardiovascular events were recorded in CKD patients. Multivariate Cox hazard analysis identified low-Ln-RHI as an independent predictor of cardiovascular events (hazard ratio=2.70, 95% confidence interval=1.62-4.51, p<0.001). The predictive value of combined Ln-RHI and Framingham risk score (FRS) was evaluated by net reclassification index (NRI) and C-statistics, which showed significant improvement (NRI=22%, p<0.001) (C-statistics: FRS=0.49, FRS+Ln-RHI=0.62, p=0.005). CONCLUSIONS Endothelial function was significantly impaired in CKD patients and correlated with the presence of CAD. Severe endothelial dysfunction was an independent and incremental predictor of cardiovascular events in CKD.

Determination of cut-off levels for on-clopidogrel platelet aggregation based on functional CYP2C19 gene variants in patients undergoing elective percutaneous coronary intervention

INTRODUCTION Carriers of reduced-function CYP2C19 allele on antiplatelet therapy show diminished platelet inhibition and higher rate of clinical risk. The purpose of this study was to determine cut-off levels of VerifyNow P2Y12 system associated with effective inhibition of on-clopidogrel platelet aggregation to predict carriers of CYP2C19 reduced-function allele among patients undergoing percutaneous coronary intervention (PCI). MATERIALS AND METHODS We enrolled 202 consecutive patients with stable coronary artery disease (CAD) undergoing PCI and treated with clopidogrel. All patients underwent CYP2C19 genotyping and measurement of residual platelet aggregation by VerifyNow system. RESULTS Carriers of CYP2C19 reduced-function allele constituted 131 (65%) of 202 CAD patients. Platelet inhibition measured by P2Y12 reaction units (PRU) and %inhibition was diminished in carriers compared with noncarriers (PRU: 290.0±81.2 vs 217.6±82.4, p<0.001, %inhibition: 17.9±17.8 vs 35.5±22.8, p<0.001, respectively). Multiple logistic regression analysis identified PRU and %inhibition as significant predictors of carrier state [odds ratio (OR) 4.95; 95% confidence interval (95%CI): 2.49 to 9.85; p<0.001, OR 5.55; 95%CI: 2.80 to 10.99; p<0.001, respectively]. Receiver-operating characteristic analysis showed that PRU and %inhibition were significant predictors of carrier state [area under the curve (AUC) 0.736 (95%CI: 0.664 to 0.808; p<0.001), AUC 0.727 (95%CI: 0.651 to 0.803; p<0.001), respectively]. The cut-off levels of PRU and %inhibition were 256 and 26.5% for the identification of carriers. CONCLUSIONS Our results suggested that the cut-off levels of PRU and %inhibition to discriminate carriers of CYP2C19 reduced-function allele from noncarriers are potentially useful clinically to provide optimal clopidogrel therapy in patients with stable CAD undergoing PCI.

Improvement effect on endothelial function in patients with congestive heart failure treated with cardiac resynchronization therapy

BACKGROUND AND PURPOSE Cardiac resynchronization therapy (CRT) is a beneficial strategy to improve severe cardiac dysfunction in patients with congestive heart failure (CHF). The improvement of endothelial function in CHF patients treated with CRT is reflected in the mortality risk reduction. However the precise mechanisms of the relationship between CRT and vascular endothelial function have not been well discussed. METHODS AND SUBJECTS Twenty-two severe consecutive CHF patients associated with dilated cardiomyopathy [New York Heart Association (NYHA) class 3.3 ± 0.5, left ventricular ejection fraction (LVEF) 24.4 ± 5.9%] were included in this study. We evaluated endothelial function, measured by reactive hyperemia peripheral arterial tonometry (RH-PAT), between optimal medical therapy alone group (medical therapy group: n = 10) and CRT group (n = 12) at the study enrolment and 12 weeks later. Furthermore we analyzed the association between the RH-PAT and cardiac function. ESSENTIAL RESULTS Both therapies significantly and equally improved NYHA class, LVEF, end-diastolic left ventricular dimension and plasma levels of brain natriuretic peptide (BNP). CRT significantly increased RH-PAT index (medical therapy group: 1.5 ± 0.2 to 1.5 ± 0.3, p = 0.824; CRT group: 1.4 ± 0.2 to 1.7 ± 0.4, p = 0.003) and cardiac output (medical therapy group: 3.3 ± 1.1 to 3.5 ± 1.0, p = 0.600; CRT group: 2.7 ± 0.6 to 4.3 ± 1.5, p = 0.001), compared to the medical therapy group. There was significant positive correlation between the change in RH-PAT index and cardiac output (r = 0.600, p = 0.003). CONCLUSIONS CRT significantly improved endothelial function through the improvement of cardiac output in CHF patients, compared to optimal medical therapy.

Effects of Endothelial Dysfunction on Residual Platelet Aggregability After Dual Antiplatelet Therapy With Aspirin and Clopidogrel in Patients With Stable Coronary Artery Disease

Background—Dual antiplatelet therapy with aspirin and clopidogrel is widely used in patients with coronary stents. High residual platelet reactivity (high RPR) after dual antiplatelet therapy is associated with increased cardiovascular events. Endothelial function could affect platelet reactivity in vivo. We hypothesized that endothelial dysfunction could be associated with high RPR after dual antiplatelet therapy in patients with stable coronary artery disease. Methods and Results—We screened patients with stable coronary artery disease for cytochrome P450 (CYP) 2C19 genotypes and enrolled 103 patients who lacked CYP2C19*2 or *3 loss-of-function allele to minimize the effect of this gene on high RPR. All patients received aspirin (100 mg/d) and clopidogrel (75 mg/d for long-term treatment or a loading dose of 300 mg) before the following tests. Platelet aggregability was assessed as P2Y12 reaction unit using the VerifyNow System. High RPR was defined as P2Y12 reaction unit ≥230. Peripheral endothelial function was expressed as reactive hyperemia index using reactive hyperemia peripheral arterial tonometry. Fifty-three patients exhibited high RPR. High RPR patients were significantly older, had higher levels of B-type natriuretic peptide, and were predominantly hypertensive compared with non–high RPR patients. Reactive hyperemia index was significantly lower in high RPR patients (0.46±0.15) compared with non–high RPR patients (0.61±0.18; P<0.001). Linear regression analysis demonstrated significant negative correlation between reactive hyperemia index and P2Y12 reaction unit (r=−0.32; P=0.001). Multivariable logistic regression analysis identified reactive hyperemia index as an independent and significant determinant of high RPR (odds ratio, 0.55; 95% confidence interval, 0.39–0.78; P=0.001). Conclusions—In patients with stable coronary artery disease, endothelial function was significantly impaired in high RPR patients. Endothelial dysfunction is independently correlated with high RPR after dual antiplatelet therapy. Clinical Trial Registration—URL: http://www.umin.ac.jp/ctr. Unique identifier: UMIN000008239.

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

Prognostic significance of peripheral microvascular endothelial dysfunction in heart failure with reduced left ventricular ejection fraction

BACKGROUND Endothelial dysfunction plays a crucial role in heart failure (HF), but the association between peripheral microvascular endothelial function assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) and prognosis remains unknown in HF with reduced left ventricular (LV) ejection fraction (HFREF). We prospectively investigated the association between peripheral microvascular endothelial function and HF-related near-future cardiovascular outcomes in HFREF patients. METHODSANDRESULTS The 362 HFREF patients (LVEF <50%) were followed for HF-related events (composite of cardiovascular death and HF hospitalization) up to 3 years. A natural logarithmic-scaled RH-PAT index (Ln-RHI) was obtained for each patient. A total of 82 HF-related events were recorded. The lower-RHI group (Ln-RHI ≤0.49, median) experienced a higher rate of HF-related events compared with the higher-RHI group by Kaplan-Meier analysis (30.9% vs. 14.4%, log-rank test: P<0.001). Multivariable Cox hazard analysis identified Ln-RHI as an independent predictor for HF-related events (per 0.1, hazard ratio: 0.84, 95% confidence interval: 0.75-0.95, P=0.005). Adding Ln-RHI to the Meta-analysis Global Group in Chronic HF risk score (MAGGICs) and Seattle Heart Failure Model (SHFM), powerful prognostic predictors of HF, significantly improved the net reclassification index (MAGGICs: 20.11%, P=0.02, SHFM: 24.88%, P<0.001), and increased the C-statistics for prediction of HF-related events (MAGGICs+Ln-RHI: from 0.612 to 0.670, SHFM+Ln-RHI: from 0.662 to 0.695). CONCLUSIONS Peripheral microvascular endothelial dysfunction assessed by RH-PAT was associated with future HF-related events in HFREF.

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.

Intravascular ultrasound morphology of culprit lesions and clinical demographics in patients with acute coronary syndrome in relation to low-density lipoprotein cholesterol levels at onset

Despite current standards of care aimed at achieving targets for low-density lipoprotein cholesterol (LDL-C), many patients remain at high residual risk of cardiovascular events. We sought to assess the LDL-C-dependent differences in culprit intravascular ultrasound (IVUS) morphologies and clinical characteristics in patients with acute coronary syndrome (ACS). Eighty-six consecutive ACS patients whose culprit lesions imaged by preintervention IVUS were divided into two groups based on the fasting LDL-C level on admission: a low-LDL-C group (LDL-C <2.6 mmol/l, n = 45) and a high-LDL-C group (LDL-C ≥2.6 mmol/l, n = 41). Patients with stable angina with LDL-C <2.6 mmol/l (n = 30) were also enrolled as an age- and gender-matched control. The low-LDL-C ACS group was significantly older (72 ± 12 vs 64 ± 14 years, P = 0.007) and more diabetic (47 % vs 15 %, P = 0.001). Importantly, IVUS morphologies were comparable between low- and high-LDL-C ACS groups (all P not significant), whereas culprit plaque was more hypoechoic and less calcified in the low-LDL-C ACS group than in the low-LDL-C stable angina group. Furthermore, compared with the low-LDL-C ACS nondiabetic group, the low-LDL-C ACS diabetic group was more obese, more triglyceride rich (1.3 ± 0.6 vs 0.9 ± 0.4 mmol/l, P = 0.003), and more endothelially injured, but no different for the culprit IVUS morphologies. In multivariate analysis, diabetes was independently associated with a low LDL-C level on admission in patients with ACS. There was no relationship between the LDL-C level at onset and culprit-plaque IVUS morphologies in ACS patients, although culprit plaque in the low-LDL-C ACS group was more vulnerable than in the low-LDL-C stable angina group. In patients with low-LDL-C levels, diabetes with atherogenic dyslipidemia might be the key residual risk.