Improvement of Vascular Endothelial Function Reflects Nonrecurrence After Catheter Ablation for Atrial Fibrillation.

Background The clinical implication of vascular endothelial dysfunction in patients with atrial fibrillation (AF) remains unclear. This study aimed to elucidate the correlation between changes in vascular endothelial function assessed by reactive hyperemia-peripheral arterial tonometry and the effect of sinus rhythm restoration after catheter ablation (CA) for AF. Methods and Results Consecutive 214 patients who underwent CA for AF were included in this single center, retrospective study. The natural logarithmic transformed reactive hyperemia-peripheral arterial tonometry index (LnRHI) of all patients was measured before CA as well as 3 and 6 months after CA. LnRHI in sinus rhythm was significantly higher than that in AF before CA. Multivariate logistic regression analysis revealed that the presence of AF was an independent risk factor for lowering of LnRHI (odds ratio, 4.092; P=0.002) before CA. The LnRHI was significantly improved 3 and 6 months after CA in patients without AF recurrence. Multivariate Cox hazard analysis revealed that changes in LnRHI from before to 3 months after CA independently correlated with recurrence of AF (hazard ratio, 0.106; P=0.001). Receiver operating characteristic analysis showed the decrease in LnRHI levels from before to 3 months after CA as a significant marker that suspects AF recurrence (area under the curve, 0.792; log-rank test, P<0.001). Conclusions The presence of AF was independently correlated with the impaired vascular endothelial function assessed by the reactive hyperemia-peripheral arterial tonometry. Long-term sinus rhythm restoration after CA for AF might contribute to the improvement of vascular endothelial function, which may reflect the nonrecurrence of AF.

Total Thrombus-Formation Analysis System can Predict 1-Year Bleeding Events in Patients with Coronary Artery Disease.

AIMS: The assessment of bleeding risk in patients with coronary artery disease (CAD) is clinically important. We recently developed the Total Thrombus-Formation Analysis System (T-TAS) for the quantitative analysis of thrombus formation using microchips with thrombogenic surfaces. Here, we assessed the utility of T-TAS parameters in predicting 1-year bleeding events in patients with CAD. METHODS: The study subjects were 561 consecutive patients who underwent coronary angiography (CAG) between August 2013 and September 2016 for suspected CAD. Blood samples collected at the time of CAG were used for T-TAS to compute the area under the curve (AUC) (AR10-AUC30) in the AR chip. Patients were divided into three groups according to AR10-AUC30 (low: ≤ 1603, intermediate, and high: ＞1765, n=187 each). One-year bleeding events were defined by the Platelet Inhibition and Patient Outcomes criteria. RESULTS: Bleeding occurred in 21 (3.7%) patients and was classified as major (8 [1.4%]) and minor (13 [2.3%]). The AR10-AUC30 levels were significantly lower in the bleeding group than the non-bleeding group (median [interquartile range] 1590 [1442-1734] vs. 1687 [1546-1797], p=0.04). Univariate Cox regression analysis demonstrated that low AR10-AUC30 , high prothrombin time-international normalized ratio levels, and diabetes correlated with bleeding events. Multivariate Cox regression analysis identified low AR10-AUC30 levels as a significant determinant of bleeding events. Kaplan-Meier survival curves showed a higher rate of bleeding events in the low than the high AR10-AUC30 group (p=0.007). CONCLUSIONS: The results highlight the potential usefulness of the AR10-AUC30 levels in the prediction of 1-year bleeding events in patients with CAD treated with various antithrombotic therapies.

Edoxaban Enhances Thromboprophylaxis by Physiotherapy After Total Knee Arthroplasty　- The Randomized Controlled ESCORT-TKA Trial.

BACKGROUND: The pharmacological advantage of combining physiotherapy with anticoagulants for the prevention of venous thromboembolism (VTE) after total knee arthroplasty (TKA) is not fully known. Herein we investigated the potential benefit of this combination therapy in patients undergoing TKA.Methods and Results:The 38 patients were randomly assigned to a physiotherapy group (n=19) or a physiotherapy plus 30 mg/day edoxaban group (n=19). The occurrence of VTE was evaluated, as were serial changes in parameters measured by the Total Thrombus-formation Analysis System, a novel system for quantitatively analyzing thrombus formation using microchips with thrombogenic surfaces (collagen plus tissue factor, atheroma [AR]-chip). Combination therapy significantly reduced the incidence of VTE after TKA compared with monotherapy (P=0.038). The area under the curve (AUC) of thrombus formation for the AR-chip (AR10-AUC30) was significantly lower in the combination group (P=0.001) on Day 7 after TKA than before TKA, but no significant change was observed with monotherapy (P=0.809). In 13 VTE-positive patients, AR10-AUC30was significantly lower in the combination group (n=3) than in the monotherapy group (n=10) on Day 7 (P=0.045). CONCLUSIONS: The combination of physiotherapy and edoxaban significantly reduced the incidence of VTE after TKA compared with physiotherapy alone. However, it is possible that VTE occurrence after TKA is not only associated with thrombogenicity, but also rheological factors.

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.

Pre-procedural peripheral endothelial function is associated with increased serum creatinine following percutaneous coronary procedure in stable patients with a preserved estimated glomerular filtration rate.

BACKGROUND: Worsening renal function, indicated by increased serum creatinine (SCr), is a common complication of percutaneous coronary procedures. Risk factors for increased SCr overlap with coronary risk factors involved in endothelial dysfunction. We hypothesized that endothelial dysfunction, measured using the reactive hyperemia peripheral arterial tonometry index (RHI), can predict periprocedure-increased SCr. METHODS: RHI was assessed before elective coronary procedures in 316 consecutive stable patients with a preserved estimated glomerular filtration rate (eGFR, >60mL/min/1.73m2). SCr was measured before and 2 days after procedures. RESULTS: There was no significant correlation between natural logarithmic transformations of RHI (Ln-RHI) and basal Ln-eGFR. Periprocedure increase in SCr was observed in 148 (47%) patients. The increased SCr group had significantly lower Ln-RHI [0.48 (0.36, 0.62) vs. 0.59 (0.49, 0.76), p<0.001]. Multivariate linear regression analysis identified body mass index (BMI) (ß=0.148, p=0.005) and Ln-RHI (ß=-0.365, p<0.001) as significant determinants of percent changes in SCr. Multivariate logistic regression analysis identified Ln-RHI (per 0.1) [odds ratio (OR) 0.672, 95% confidence interval (95% CI) 0.586-0.722; p<0.001], Ln-B-type natriuretic peptide (OR: 1.484, 95% CI: 1.130-1.974; p=0.004), current smoking (OR: 2.563, 95% CI: 1.379-4.763, p=0.003), BMI (OR: 1.113, 95% CI: 1.031-1.203; p=0.007), coronary intervention (OR: 1.736, 95% CI: 1.036-2.909; p=0.036), and Ln-hemoglobin A1c (OR: 6.728, 95% CI: 1.093-41.392, p=0.040) as independent determinants of increased SCr. Receiver-operating characteristics curve analysis showed that Ln-RHI correlated significantly with increased SCr (area under the curve, 0.684, 95% CI: 0.626-0.742, p<0.001). The optimum cut-off point of Ln-RHI for the periprocedure increased SCr was 0.545. CONCLUSIONS: Pre-procedure measurement of endothelial function by RHI is an effective strategy to assess the patient's risk conditions for worsening renal function after percutaneous coronary procedures.

Impaired Peripheral Endothelial Function Assessed by Digital Reactive Hyperemia Peripheral Arterial Tonometry and Risk of In-Stent Restenosis.

BACKGROUND: Drug-eluting stents are replacing bare-metal stents, but in-stent restenosis (ISR) remains a problem. Reactive hyperemia index (RHI) assessed by peripheral arterial tonometry evaluates endothelial function noninvasively. We prospectively assessed the prognostic value of RHI in predicting ISR after percutaneous coronary intervention. METHODS AND RESULTS: RHI was measured before percutaneous coronary intervention and at follow-up (F/U) angiography (F/U RHI; 6 and 9 months post bare-metal stents- and drug-eluting stents- percutaneous coronary intervention, respectively) in 249 consecutive patients. At F/U, ISR (stenosis >50% of diameter) was seen in 68 patients (27.3%). F/U natural logarithm (RHI) was significantly lower in patients with ISR than in those without (0.52±0.23 versus 0.65±0.27, P<0.01); no between-group difference in initial natural logarithm (RHI) (0.60±0.26 versus 0.62±0.25, P=0.56) was seen. By multivariate logistic regression analysis, even after adjusting for other significant parameters in univariate analysis, F/U natural logarithm (RHI) independently predicted ISR (odds ratio: 0.13; 95% CI: 0.04-0.48; P=0.002). In receiver operating-characteristic analysis, F/U RHI was the strongest predictor of ISR (area under the curve: 0.67; 95% CI: 0.60-0.75; P<0.01; RHI <1.73 had 67.6% sensitivity, 64.1% specificity); area under the curve significantly improved from 0.62 to 0.70 when RHI was added to traditional ISR risk factors (P=0.02). Net reclassification index was significant after addition of RHI (26.5%, P=0.002). CONCLUSIONS: Impaired RHI at F/U angiography independently correlated with ISR, adding incremental prognostic value to the ISR-risk stratification following percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02131935.

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 [PL24-AUC10]; AUC for the first 30 minutes for AR tested at flow rate of 10 µL/min [AR10-AUC30]). AR10-AUC30 and PL24-AUC10 levels were similar in the 2 groups on the day of CA. Levels of AR10-AUC30, but not PL24-AUC10, were significantly lower in the 2 groups at days 3 and 30 after CA. Multiple logistic regression analyses identified the AR10-AUC30 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 AR10-AUC30 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 AR10-AUC30 level was 1648 for identification of periprocedural bleeding events. CONCLUSIONS: These results suggested that the AR10-AUC30 level determined by T-TAS is a potentially useful marker for prediction of bleeding events in atrial fibrillation patients undergoing CA.

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. METHODS AND RESULTS: 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.

Lack of association between peri-procedural myocardial damage and CYP2C19 gene variant in elective percutaneous coronary intervention.

Peri-procedural myocardial damage (MD) is associated with increased risk of major in-hospital complications and adverse clinical events. The aim of this study was to evaluate the effects of on-clopidogrel platelet aggregation and CYP2C19-reduced-function gene variants on elective percutaneous coronary intervention (PCI)-related MD. We measured changes in serum high-sensitive troponin T (hs-TnT) levels, CYP2C19 genotype, and on-clopidogrel platelet aggregation (PA) using VerifyNow(®) P2Y12 system in 91 patients who received stent implantation (stent group). The control group comprised 30 patients who did not receive PCI. Blood samples were obtained before and 24 h after PCI or coronary angiography (CAG). Patients of the stent group were divided into high and low MD groups based on the median value of hs-TnT level at 24 h after PCI. Serum hs-TnT levels were significantly higher 24 h after PCI (86.8 ± 121.5 pg/ml) compared with before PCI (9.4 ± 5.3, p < 0.001), whereas the levels were identical before and 24 h after CAG in the control group. Simple logistic regression analysis demonstrated that MD correlated with age (p = 0.014), estimated GFR (p = 0.003), hemoglobin A1c (p = 0.015), baseline serum hs-TnT (p = 0.049), and stent length (p < 0.001). Multiple logistic regression analysis identified old age, high hemoglobin A1c level, and long stent, but not CYP2C19 reduced-function allele or high on-clopidogrel PA, as independent predictors of elective PCI-related MD. The present study demonstrated no significant relation between peri-procedural MD and high on-clopidgrel PA associated with CYP2C19 reduced-function allele in patients undergoing elective PCI.

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.

Impact of CYP3A5 polymorphism on platelet reactivity at percutaneous coronary intervention and after 9 months of aspirin and clopidogrel therapy in Japanese patients with coronary artery disease.

BACKGROUND: High residual platelet reactivity in patients receiving clopidogrel is associated with an increased risk of a cardiovascular event after coronary stenting. The aim of our study was to evaluate the impact of the cytochrome P450 (CYP) 3A5 and CYP2C19 polymorphisms on platelet reactivity during dual antiplatelet therapy. METHODS: We determined the CYP2C19 and CYP3A5 genotypes of 101 angina patients (65 male patients, mean age 64 years) receiving dual antiplatelet therapy with aspirin and clopidogrel and evaluated the effect of these polymorphism on platelet reactivity at the early and late phases of treatment using a conventional light transmission aggregometry. Early and late phases were defined as 24 h after the loading dose and after 9 months on a maintenance dose of 75 mg daily, respectively. RESULTS: The distribution of the CYP2C19 genotype was 30 % in extensive metabolizers (EM; CYP2C19*1/*1), 46 % in intermediate metabolizers (IM; *1/*2, *1/*3), and 25 % in poor metabolizers (PM; *2/*2, *2/*3, *3/*3). Platelet reactivity levels in during the early and late phases were 3,793 ± 1,476 and 2,960 ± 1,410, respectively, in EM, 4,706 ± 1,417 and 3,239 ± 1,479, respectively, in IM, and 5,402 ± 776 and 4,736 ± 1,356 aggregation units (AU)•min, respectively in EM. The distribution of the CYP3A5 genotype was 33 % in patients carrying the wild-type or one loss-of-function allele (Expressor phenotype; *1/*1 and *1/*3, respectively) and 67 % in those carrying two loss-of-function alleles (Non-expressor; *3/*3). In total, eight patients were EM+Expressor, 22 were EM+Non-expressor, 18 were IM+Expressor, 28 were IM+Non-expressor, eight were PM+Expressor, and 17 were PM+Non-expressor. In the late phase of PM with the CYP2C19 polymorphism, the levels of platelet reactivity according to CYP3A5 genotype were 3,963 ± 1,436 and 5,100 ± 1,190 AU•min in Expressor and Non-expressor, respectively (P < 0.05), however, there was no difference in platelet reactivity between Expressor and Non-expressor in EM and IM. CONCLUSIONS: Our results suggest that antiplatelet response to clopidogrel in the late phase depends on the CYP3A5 polymorphism in PM with CYP2C19.

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.

Impact of CYP2C19 polymorphism on platelet function tests and coagulation and inflammatory biomarkers in patients undergoing percutaneous coronary intervention.

AIM: Carriers of the reduced-function CYP2C19 allele receiving dual antiplatelet therapy (DAPT) with aspirin and clopidogrel exhibit diminished platelet inhibition and an increased risk of events. The purpose of this study was to investigate the effects of CYP2C19 gene variants on platelet function tests and coagulation and inflammatory biomarkers in patients undergoing elective percutaneous coronary intervention (PCI). METHODS: This prospective, observational, multicenter study enrolled 104 consecutive Japanese patients undergoing elective PCI. We examined the CYP2C19 genotype, platelet function tests, the levels of coagulation and inflammatory biomarkers and the serum levels of high-sensitivity troponin T (hs-TnT) before, immediately after and one, two and 28 days after PCI. RESULTS: A total of 68 (65%) of the 104 enrolled patients were carriers of the CYP2C19 reducedfunction allele. On-clopidogrel platelet aggregation (PA), measured using light transmittance aggregometry and the VerifyNow(®) P2Y12 system, and the platelet reactivity index (PRI) were significantly higher at all time points in the carriers than in the noncarriers (p＜0.05), whereas there were no differences in the levels of the coagulation and inflammatory biomarkers or serum hs-TnT. Simple and multiple logistic regression analyses identified on-clopidogrel PA and PRI as being significant predictors of carriers of the CYP2C19 reduced-function allele. CONCLUSIONS: The present study suggests that platelet function tests, but not coagulation, inflammatory or cardiac biomarkers, are useful for identifying carriers of CYP2C19 reduced-function gene variants and monitoring the efficacy of DAPT in patients undergoing elective PCI.

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.

Successful diet and exercise therapy as evaluated on self-assessment score significantly improves endothelial function in metabolic syndrome patients.

BACKGROUND: Simple office-based counseling for diet and exercise does not appear to positively affect success rates in metabolic syndrome (MetS) patients. The utility of the lifestyle modification self-assessment score (Self-AS) in the improvement of endothelial function by office-based counseling for patients with MetS was investigated. METHODS AND RESULTS: Patients with MetS (n=207) and age- and sex-matched individuals without MetS (n=124) were enrolled in this cross-sectional study. Endothelial function was assessed using reactive hyperemia-peripheral arterial tonometry index (RHI). Patients with MetS had significant endothelial dysfunction compared with those without MetS (RHI, 0.502±0.178 vs. 0.614±0.229; P<0.001). Seventy MetS patients participating in the prospective interventional study received simple office-based lifestyle modification counseling that was accompanied by Self-AS questionnaire after 10 months. RHI was significantly improved following lifestyle modifications (from 0.452±0.136 to 0.547±0.202, P<0.001). Reductions in waist circumference (R(2)=0.094, P=0.01) and increased high-density lipoprotein cholesterol (R(2)=0.227, P<0.001) independently correlated with improved RHI. Self-AS significantly correlated with changes in waist circumference (r=-0.57, P<0.001) and RHI (r=0.30, P=0.02). Patients with a good achievement of lifestyle modifications (higher Self-AS) had significant improvement in endothelial function compared with those with lower scores (% change in RHI, +48.7±61.6 vs. +7.8±35.1, P=0.001). CONCLUSIONS: Good achievement of lifestyle modifications as evaluated on Self-AS significantly improved endothelial function with concomitant reductions in waist circumferences in MetS patients.

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.

Dipeptidyl peptidase-4 inhibitor, sitagliptin, improves endothelial dysfunction in association with its anti-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes.

BACKGROUND: Dipeptidyl peptidase 4 (DPP4) inhibitors are used for treatment of diabetes mellitus (DM). We hypothesized that sitagliptin, a DPP4-inhibitor, could improve endothelial dysfunction in DM patients with coronary artery disease (CAD). METHODS AND RESULTS: The 40 patients with CAD and uncontrolled DM, aged 68.7±9.4 years (mean±standard deviation) (50% males, hemoglobin A1c [HbA1c] 7.4±1.0%) were assigned to either additional treatment with sitagliptin (50 mg/day, n=20) or aggressive conventional treatment (control, n=20) for 6 months. Endothelial function was assessed by the reactive hyperemia peripheral arterial tonometry index (RHI). The clinical characteristics at baseline were not different between the groups. After treatment, fasting blood glucose and insulin levels, and lipid profiles were not different between the groups. HbA1c levels significantly improved similarly in both groups. The percent change in RHI was greater in the sitagliptin group than in the control group (62.4±59.2% vs. 15.9±22.0%, P<0.01). Furthermore, treatment with sitagliptin resulted in a significant decrease in the high-sensitivity C-reactive protein (hsCRP) level, but no such change was noted in the control group. Linear regression analysis demonstrated a significant negative relation between changes in RHI and hsCRP, but not between RHI and HbA1c. CONCLUSIONS: Sitagliptin significantly improved endothelial function and inflammatory state in patients with CAD and uncontrolled DM, beyond its hypoglycemic action. These findings suggest that sitagliptin has beneficial effects on the cardiovascular system in DM patients.

Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction.

OBJECTIVES: The purpose of this study was to investigate whether peripheral endothelial dysfunction could predict the occurrence of cardiovascular events in patients with heart failure (HF) with normal left ventricular ejection fraction (HFNEF). BACKGROUND: Endothelial dysfunction plays an important role in HF, but the relation between peripheral endothelial dysfunction and prognosis in HFNEF remains unknown. METHODS: We conducted a prospective cohort study of 321 patients with HFNEF. We evaluated cardiac function by echocardiography measuring the ratio of early transmitral flow velocity to tissue Doppler early diastolic mitral annular velocity (E/e'), noninvasively assessed peripheral endothelial function by reactive hyperemia-peripheral arterial tonometry (RH-PAT) as the RH-PAT index (RHI), and followed cardiovascular events. RESULTS: A total of 59 patients had a cardiovascular event. Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events in the low RHI group than in the high RHI group (mean follow-up: 20 months; log-rank test: p < 0.001). Multivariate Cox hazard analysis identified RHI (per 0.1) (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.67 to 0.94; p = 0.007), E/e' (Ln[E/e'] [per 0.1]) (HR: 1.15; 95% CI: 1.04 to 1.26; p = 0.006), and B-type natriuretic peptide (BNP) (Ln[BNP] [per picogram/milliliter]) (HR: 1.81; 95% CI: 1.44 to 2.28; p < 0.001) as independent predictors of cardiovascular events. The C-statistics for cardiovascular events substantially increased when the RHI was added to the HFNEF prognostic 5 factors (PF5)-age, diabetes, New York Heart Association classification, HF hospitalization history, and left ventricular ejection fraction-which were identified in the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction Study) (PF5 alone: 0.671; PF5 + RHI: 0.712). The net reclassification index was significant after addition of the RHI (19.0%, p = 0.01). CONCLUSIONS: Peripheral endothelial dysfunction independently correlated with future cardiovascular events, adding incremental clinical significance for risk stratification in patients with HFNEF. (Endothelial Dysfunction Assessed by Reactive Hyperemia Peripheral Arterial Tonometry and Heart Failure with Preserved Left Ventricular Ejection Fraction; UMIN000002640).