Association Between Endothelial Dysfunction and Left Ventricular Diastolic Stiffness　- Subanalysis of the Flow-Mediated Dilation Japan (FMD-J) Study.

BACKGROUND: Endothelial dysfunction and increased left ventricular (LV) stiffness are associated with the incidence of heart failure with preserved ejection fraction (HFpEF). This study evaluated the association between endothelial dysfunction and LV diastolic stiffness.Methods and Results: Endothelial dysfunction evaluated by flow-medicated vasodilation (FMD) and the reactive hyperemia index (RHI), which reflects endothelial dysfunction in the microvasculature, was measured in 112 subjects with hypertension in the Flow-Mediated Dilation Japan (FMD-J) study. Using transthoracic echocardiography, LV diastolic stiffness was evaluated by measuring diastolic wall strain (DWS) in the LV posterior wall. In this cross-sectional study, associations among FMD, RHI, and DWS were investigated using multiple regression analyses. The mean (±SD) age of the subjects 65±9 years, and 63% were men. DWS was significantly associated with RHI, but not FMD, on multivariate linear regression analysis (ß=0.39; P<0.0001). This association was preserved in subjects without LV hypertrophy (ß=0.46; P<0.0001). A DWS ≤median, suggesting increased LV diastolic stiffness, was significantly associated with RHI on multivariate logistic regression analysis (odds ratio 20.58; 95% confidence interval 4.83-87.63; P<0.0001). The receiver operating characteristic curve presented a cut-off value of 2.21 for RHI, with a sensitivity of 77% and a specificity of 71%, for DWS ≤median. CONCLUSIONS: RHI, rather than FMD, was associated with DWS. Endothelial dysfunction in the microvasculature may be associated with increased LV diastolic stiffness.

Association Between Insulin Resistance, Oxidative Stress, Sympathetic Activity and Coronary Microvascular Function in Patients With Early Stage Impaired Glucose Metabolism.

BACKGROUND: Although acute hyperglycemia and insulin resistance (IR) are risk factors for atherosclerosis development through oxidative stress and sympathetic activation in diabetes mellitus, the association of these factors with coronary microvascular function in the early diabetic stage remains controversial.Methods and Results: Using transthoracic echocardiography, coronary flow velocity (CFV) and its reserve (CFVR) as parameters of coronary microvascular function were measured before and 1 h after an oral glucose tolerance test (OGTT) in 40 patients (aged 59±12 years) without diagnosed diabetes mellitus or coronary artery disease. Plasma glucose, insulin and thiobarbituric acid reactive substance (TBARS; an oxidative stress marker) were measured during the OGTT. IR was evaluated as homeostasis model assessment of IR (HOMA-R). Sympathetic activity was evaluated by using plasma catecholamines after OGTT. CFVR decreased after an OGTT (P<0.0001) mainly because of an increased baseline CFV (P<0.0001). Although the change in CFVR was not associated with the change in TBARS and catecholamines, it was independently associated with HOMA-R on the multivariate regression analysis (ß=-0.40, P=0.01). Another multivariate regression analysis revealed that change in baseline CFV was independently associated with HOMA-R (ß=0.35, P=0.03). CONCLUSIONS: IR, rather than oxidative stress and sympathetic activity, was associated with an increase in baseline CFV and a decline in CFVR during acute hyperglycemia. IR might play an important role in increased myocardial oxygen demand and coronary microvascular dysfunction.

Effect of Novel Stratified Lipid Risk by "LDL-Window" and Flow-Mediated Dilation on the Prognosis of Coronary Artery Disease Using the FMD-J Study A Data.

BACKGROUND: Elevated levels of triglyceride (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) are regarded as a residual lipid risk in low-density lipoprotein cholesterol (LDL-C)-lowering therapy. This study investigated the association between lipid risk stratified by TG and non-HDL-C and the prognosis of patients with coronary artery disease (CAD), and the association between stratified lipid risk and flow-mediated dilatation (FMD) index.Methods and Results: The 624 CAD patients enrolled in flow-mediated dilation (FMD)-J study A were divided into 4 groups: low-risk group (n=413) with TG <150 mg/dL and non-HDL-C <170 mg/dL; hyper-TG group (n=180) with TG ≥150 mg/dL and non-HDL-C <170 mg/dL; hyper-non-HDL group (n=12) with TG <150 mg/dL and non-HDL-C ≥170 mg/dL; and high-risk group (n=19) with TG ≥150 mg/dL and non-HDL-C ≥170 mg/dL. Comparison of the groups showed the cumulative incidence of a 3-point major adverse cardiovascular event (MACE) was different and highest in the high-risk group in all the patients (P=0.009), and in patients with a FMD index ≥7.0% (P=0.021), but not in those with a FMD index <7.0%. Multivariable regression analysis showed that high lipid risk (P=0.019) and FMD <7.0% (P=0.040) were independently correlated with the incidence of a 3-point MACE. CONCLUSIONS: Novel stratification of lipid risk, simply using TG and non-HDL-C levels, combined with FMD measurement, is useful for predicting cardiovascular outcomes in patients with CAD.

Efficacy and Safety of Ivabradine in Japanese Patients With Chronic Heart Failure　- J-SHIFT Study.

BACKGROUND: Increased heart rate (HR) is an independent risk factor for cardiovascular outcomes in chronic heart failure (HF). Ivabradine, anIfinhibitor, improved outcomes in patients with HF and reduced ejection fraction (HFrEF) in the SHIFT study. We evaluated its efficacy and safety in Japanese HFrEF patients in a randomized, double-blind, placebo-controlled phase III study: the J-SHIFT study. The main objective was to confirm a hazard ratio of <1 in the primary composite endpoint of cardiovascular death or hospital admission for worsening HF.Methods and Results:Patients with NYHA functional class II-IV, left ventricular EF ≤35%, and resting HR ≥75 beats/min in sinus rhythm under optimal medical therapy received ivabradine (n=127) or placebo (n=127). Mean reduction in resting HR was significantly greater in the ivabradine group (15.2 vs. 6.1 beats/min, P<0.0001). However, symptomatic bradycardia did not occur. A total of 26 (20.5%) patients in the ivabradine group and 37 (29.1%) patients in the placebo group had the primary endpoint event (hazard ratio 0.67, 95% CI 0.40-1.11, P=0.1179) during median follow-up of 589 days. Mild phosphenes were reported in 8 (6.3%) patients in the ivabradine group and 4 (3.1%) patients in the placebo group (P=0.3760). CONCLUSIONS: The J-SHIFT study supported the efficacy and safety of ivabradine for Japanese HFrEF patients, in accord with the SHIFT study.

Target of Triglycerides as Residual Risk for Cardiovascular Events in Patients With Coronary Artery Disease　- Post Hoc Analysis of the FMD-J Study A.

BACKGROUND: Circulating triglyceride (TG) levels are a current focus as a residual risk for cardiovascular (CV) events. We evaluated the relationship between circulating TG levels and future CV events in patients with coronary artery disease (CAD) who were treated with conventional therapy. Methods and Results: We analyzed data for 652 patients who were enrolled in the FMD-J Study A. We investigated the associations between serum TG levels and first major CV events (death from CV cause, nonfatal acute coronary syndrome (ACS), nonfatal stroke, and CAD) for a 3-year follow-up period. Patients were divided into 4 groups based on serum TG level: low-normal (<100 mg/dL), high-normal (100-149 mg/dL), borderline hypertriglyceridemia (150-199 mg/dL), and moderate hypertriglyceridemia (≥200 mg/dL). During a median follow-up period of 46.6 months, 14 patients died (9 from CV causes), 16 had nonfatal ACS, 6 had nonfatal stroke, and 54 had CAD. The Kaplan-Meier curves for first major CV event among the 4 groups were significantly different (P=0.04). After adjustment for various confounders, serum TG level ≥100 mg/dL were significantly associated with an increased risk of first major CV events compared with serum TG level <100 mg/dL. CONCLUSIONS: Serum TG level may be a surrogate marker for predicting CV events in patients with CAD.

Difference in immunohistochemical characteristics between Takayasu arteritis and giant cell arteritis: It may be better to distinguish them in the same age.

Objectives: This study aimed to compare Takayasu arteritis (TAK) with giant cell arteritis (GCA) through immunohistochemistry principally of inflammatory cells; these two disorders may be on the spectrum within a single disease state.Methods: Nine TAK and 5 GCA surgically resected vessel specimens were selected. TAK specimen was divided into each three acute-, chronic-, and healed-phase samples based on intimal and adventitial thickening. Immunohistochemical analysis was performed of smooth muscle cells and inflammatory cells including lymphocytes, plasma cells, macrophages, and dendritic cells, where three healed-phase TAK specimens were excluded due to paucity of inflammation. Immunopositive cells per three different fields in intima, media, and adventitia were counted in each specimen, and their numbers in these three layers along with total 3 layers were compared between the two disorders.Results: Intimal smooth muscle maturity estimated by ratio of h-Caldesmon+ cells to α-SMA+ cells significantly increased in chronic- and healed- over acute-phase increases in TAK. Mann-Whitney tests demonstrated significantly more adventitial lymphoplasmacytic infiltration and less intimal fascin+ dendritic cells, as well as overall more CD8+ T-cells, more CD20+ B-cells and lower CD4/8 ratio in TAK than in GCA.Conclusion: Different inflammatory involvement is suggested in the pathogenesis of TAK and GCA.

Time Trend in Interest and Satisfaction Towards Clinical Training and Academic Activities Among Early-Career Cardiologists　- The Japanese Circulation Society Post-Graduate Training Survey.

BACKGROUND: Satisfaction among early-career cardiologists is a key performance metric for cardiovascular (CV) educational programs. To assess the time trend in the interest and activities of early-career cardiologists regarding their training, we conducted web-based surveys in 2011 and 2015.Methods and Results:Early-career cardiologists were defined as physicians who planned to attend Japanese Circulation Society (JCS) annual meetings within 10 years of graduation. A total of 272 and 177 participants completed the survey for the years 2011 and 2015, respectively. Survey questions were designed to obtain core insights into the workplace, research interests, and demographic profile of respondents. Main outcome measures were satisfaction levels with their training program. The overall satisfaction rate for training was lower in 2015 than 2011; this was largely affected by decreases in the rates of satisfaction for valvular heart disease, ischemic heart disease, advanced heart failure, and congenital heart disease. Moreover, satisfaction with CV training was associated with the volume of invasive procedures such as coronary angiography and percutaneous coronary interventions in 2011 but not 2015. CONCLUSIONS: Early-career cardiologists' satisfaction with their training decreased during the study period, especially in the field of evolving subspecialties (e.g., valvular heart disease or advanced heart failure), suggesting that prompt reevaluation of the current educational curriculum is needed to properly adapt to progress in cardiology.

Proposed Cutoff Value of Brachial-Ankle Pulse Wave Velocity for the Management of Hypertension.

BACKGROUND: The optimal cutoff values of the brachial-ankle pulse wave velocity (baPWV) for predicting cardiovascular disease (CVD) were examined in patients with hypertension.Methods and Results:A total of 7,656 participants were followed prospectively. The hazard ratio for the development of CVD increased significantly as the baPWV increased, independent of conventional risk factors. The receiver-operating characteristic curve analysis showed that the optimal cutoff values for predicting CVD was 18.3 m/s. This cutoff value significantly predicted THE incidence of CVD. CONCLUSIONS: The present analysis suggests that the optimal cutoff value for CVD in patients with hypertension is 18.3 m/s.

Association Between Waist-to-Height Ratio and Endothelial Dysfunction in Patients With Morbidity　- A Report From the FMD-J Study.

BACKGROUND: Waist circumference (WC), waist-to-height ratio (WHtR) and body mass index (BMI) are known as easy anthropometric markers of abnormal obesity and screening tools for predicting cardiovascular outcomes, but which indices are best is unclear. We therefore investigated the superiority and association between each index and low flow-mediated dilatation (FMD) as a surrogate marker for cardiovascular outcomes in patients with morbidity in a large Japanese prospective cohort.Methods and Results:A total of 1,645 Japanese patients who had coronary artery disease and hypertension or diabetes mellitus were enrolled, and 1,087 of them were analyzed. The high-WHtR group (≥0.5) showed greater morbidity and increased inflammation in association with atherosclerosis compared with the low-WHtR group. High WHtR and advanced age were identified as predictors of low FMD (odds ratio (OR) 1.39, 95% confidence interval (CI) 1.02-1.88, P=0.037 and OR 1.55, 95% CI 1.19-2.01, P=0.001, respectively). However, WC was not associated with that risk in either sex (male: OR 1.37, 95% CI 0.97-1.93, P=0.076; female: OR 1.08, 95% CI 0.68-1.73, P=0.74), and no association was evident between high BMI and low FMD (OR 0.92, 95% CI 0.71-1.19, P=0.54). CONCLUSIONS: WHtR offers a superior predictor of decreased FMD than other anthropometric indices, and progression of arteriosclerosis might be detected more sensitively. Further study is needed to investigate the relationship between cardiovascular mortality and WHtR.

Measurement of Flow-Mediated Vasodilatation.

The FMDJ study, a multicenter prospective observational study conducted in Japan, demonstrated the acceptable reliability of measurement of flow-mediated vasodilatation (FMD) using a semi-automatic device in individual institutions. However, in about 10% of Japanese subjects, adequate scans to determine the brachial arterial diameter failed to be obtained. The prevalence of inadequate scans was higher in women than in men, while obesity had no influence on the inadequate scan rate. The FMDJ study also proposed that attending periodic refresher courses on the measurement of FMD is needed for maintaining competency. Finally, the FMDJ study proposed reference values for FMD. Thus, FMD measurement may be categorized as a clinically applicable tool on the basis of class IIb (exploratory cohort study with good reference standards) evidence.

Rationale and design of a randomized trial to test the safety and non-inferiority of canagliflozin in patients with diabetes with chronic heart failure: the CANDLE trial.

BACKGROUND: Because type 2 diabetes mellitus is associated strongly with an increased risk of cardiovascular diseases, the number of patients with diabetes with chronic heart failure is increasing steadily. However, clinical evidence of therapeutic strategies in such patients is still lacking. A recent randomized, placebo-controlled trial in patients with type 2 diabetes with high cardiovascular risk demonstrated that the SGLT2 inhibitor, empagliflozin, reduced the incidence of hospitalization for heart failure. Because SGLT2 inhibitors cause a reduction in body weight and blood pressure in addition to improving glycemic control, they have the potential to exert beneficial effects on the clinical pathophysiology of heart failure. The aim of the ongoing CANDLE trial is to test the safety and non-inferiority of canagliflozin, another SGLT2 inhibitor, compared with glimepiride, a sulfonylurea agent, in patients with type 2 diabetes mellitus and chronic heart failure. METHODS: A total of 250 patients with type 2 diabetes who are drug-naïve or taking any anti-diabetic agents and suffering from chronic heart failure with a New York Heart Association classification I to III will be randomized centrally into either canagliflozin or glimepiride groups (1: 1) using the dynamic allocation method stratified by age (<65, ≥65 year), HbA1c level (<6.5, ≥6.5 %), and left ventricular ejection fraction (<40, ≥40 %). After randomization, all the participants will be given the add-on study drug for 24 weeks in addition to their background therapy. The primary endpoint is the percentage change from baseline in NT-proBNP after 24 weeks of treatment. The key secondary endpoints after 24 weeks of treatment are the change from baseline in glycemic control, blood pressure, body weight, lipid profile, quality of life score related to heart failure, and cardiac and renal function. DISCUSSION: The CANDLE trial is the first to assess the safety and non-inferiority of canagliflozin in comparison with glimepiride in patients with type 2 diabetes with chronic heart failure. This trial has the potential to evaluate the clinical safety and efficacy of canagliflozin on heart failure. Trial registration Unique trial Number, UMIN000017669.

Association of moderate chronic kidney disease with insufficient improvement of fractional flow reserve after stent implantation.

OBJECTIVES: This study aims to investigate the association of moderate chronic kidney disease (CKD) with fractional flow reserve (FFR) after stent implantation. BACKGROUND: Patients with moderate CKD have a higher prevalence of severe and diffuse coronary artery disease, and have increased risk of cardiovascular events even after stent implantation. On the other hand, in some patients, FFR could not be sufficiently improved even after stent implantation. However, the association between these pathophysiological processes is unclear. METHODS AND RESULTS: A total of 102 patients with stable angina, in whom a stent was implanted for the left anterior descending coronary artery (LAD) lesion, were included. Patients with a severely decreased glomerular filtration rate (GFR; > CKD stage 4) were excluded. Patients were stratified into 3 groups: those with an estimated GFR (eGFR) ≥ 60 mL per min per 1.73 m(2) (stage 0-2), 45 to 59 mL per min per 1.73 m(2) (stage 3a), and 30 to 44 mL per min per 1.73 m(2) (stage 3b). FFR after stent implantation (post-stent FFR) was significantly lower in the stage 3b group than in both the stage 0-2 group and the stage 3a group (P < 0.01). Post-stent FFR had a significant positive correlation with eGFR (r = 0.223, P = 0.024). Multivariate analysis demonstrated that eGFR was an independent predictor of post-stent FFR. CONCLUSIONS: Moderate CKD was independently associated with insufficient improvement of FFR after stent implantation. This can partly explain the poor prognosis of patients with CKD. © 2015 Wiley Periodicals, Inc.

Obstructive Sleep Apnea as Possible Causal Factor for Visit-to-Visit Blood Pressure Variability.

BACKGROUND: Recent studies have shown that visit-to-visit blood pressure variability (BPV) is an independent risk factor for cardiovascular disease. However, it has not been clarified whether obstructive sleep apnea (OSA) is associated with visit-to-visit BPV. METHODS AND RESULTS: The 56 subjects with OSA and 26 control subjects without OSA were examined. Office BP was measured on 5 separate consecutive occasions prior to a polysomnography examination. The visit-to-visit BPV was expressed as the standard deviation and the coefficient of variation of the 5 systolic BP measurements. In subjects with an apnea-hypopnea index (AHI) of more than 20 episodes per hour, the visit-to-visit BPV was also measured after the start of continuous positive airway pressure (CPAP) therapy. Overall, the AHI positively correlated with the standard deviation and the coefficient of variation of systolic BP. In a multivariate analysis, the plasma noradrenaline level and the AHI were independently and positively correlated with the standard deviation and the coefficient of variation of the systolic BP. Among the patients who underwent CPAP therapy, good adherence with CPAP therapy significantly reduced the visit-to-visit BPV. CONCLUSIONS: OSA is associated with abnormal visit-to-visit BPV and sympathetic activation seems to be related in some way. (Circ J 2016; 80: 1787-1794).

Diagnostic Performance of a Cadmium-Zinc-Telluride Single-Photon Emission Computed Tomography System With Low-Dose Technetium-99m as Assessed by Fractional Flow Reserve.

BACKGROUND: Although stress single-photon emission computed tomography (SPECT) using a cadmium-zinc-telluride (CZT) camera facilitates radiation dose reduction, only a few studies have evaluated its diagnostic accuracy in Japanese patients by applying fractional flow reserve (FFR) measurements. METHODS AND RESULTS: We prospectively evaluated 102 consecutive patients with suspected or known coronary artery disease with a low-dose stress/rest protocol ((99m)Tc radiotracer 185/370 MBq) using CZT SPECT. Within 3 months, coronary angiography was performed and a significant stenosis was defined as ≥90% diameter narrowing on visual estimation, or as a lesion of <90% and ≥ 50% stenosis with FFR ≤0.80. To detect individual coronary stenosis, the respective sensitivity, specificity, and accuracy were 86%, 75%, and 82% for left anterior descending artery stenosis, 76%, 81%, and 79% for left circumflex artery stenosis, and 87%, 92%, and 90% for right coronary artery stenosis. When limited to 92 intermediate stenotic lesions in which FFR was measured, stress SPECT showed 77% sensitivity, 91% specificity, and 84% accuracy, whereas the diagnostic value decreased to 52% sensitivity, 68% specificity, and 58% accuracy based only on visual estimation of ≥75% diameter narrowing. CONCLUSIONS: CZT SPECT demonstrated a good diagnostic yield in detecting hemodynamically significant coronary stenoses as assessed by FFR, even when using a low-dose (99m)Tc protocol with an effective dose ≤5 mSv. (Circ J 2016; 80: 1217-1224).

Heart Rate Control With If Inhibitor, Ivabradine, in Japanese Patients With Chronic Heart Failure　- A Randomized, Double-Blind, Placebo-Controlled Phase II Study.

BACKGROUND: Elevated heart rate (HR) is an independent risk factor for cardiovascular outcomes in various cardiac diseases, including heart failure (HF). METHODS AND RESULTS: Randomized placebo-controlled study was conducted to evaluate the effects of ivabradine, an Ifinhibitor, on the resting HR in 126 Japanese symptomatic HF patients with left ventricular ejection fraction ≤35%, resting HR ≥75 beats/min in sinus rhythm, and stable, optimal background treatment. Patients were randomly allocated into 3 groups: placebo; starting dose of ivabradine 2.5 mg twice daily (BID; 2.5 mg group); 5 mg BID group. The dose was increased up to 7.5 mg BID according to dose-adjustment criteria. After the 6-week treatment, the reductions in resting HR were significant in both the 2.5-mg (16.6±8.1 beats/min) and 5-mg (16.4±9.6 beats/min) groups (P<0.0001 for both groups) compared with placebo (1.7±8.7 beats/min). The most frequent side effect of ivabradine was phosphenes, but all were mild. Treatment was discontinued in 1 patient due to HF in the 5 mg group. CONCLUSIONS: Ivabradine starting at 2.5 or 5 mg BID effectively reduced resting HR in Japanese HF patients. Ivabradine at the starting dose of 2.5 mg BID could be safer than 5 mg BID. (Circ J 2016; 80: 668-676).

Older age is associated with greater central aortic blood pressure following the exercise stress test in subjects with similar brachial systolic blood pressure.

Brachial systolic pressure (BSP) is often monitored during exercise by the stress test; however, central systolic pressure (CSP) is thought to be a more direct measure of cardiovascular events. Although some studies reported that exercise and aging may play roles in changes of both BSP and CSP, the relationship between BSP and CSP with age following the exercise stress test remains unclear. The aim of this study was to evaluate the effect of age on the relationship between BSP and CSP measured after exercise. Ninety-six subjects underwent the diagnostic treadmill exercise stress test, and we retrospectively divided them into the following 3 groups by age: the younger age group (43 ± 4 years), middle age group (58 ± 4 years), and older age group (70 ± 4 years). Subjects exercised according to the Bruce protocol, to achieve 85 % of their age-predicted maximum heart rate or until the appearance of exercise-associated symptoms. BSP, CSP, and pulse rate (PR) were measured using a HEM-9000AI (Omron Healthcare, Japan) at rest and after exercise. BSP, CSP, and PR at rest were not significantly different among the 3 groups (p = 0.92, 0.21, and 0.99, respectively). BSP and PR immediately after exercise were not significantly different among the groups (p = 0.70 and 0.38, respectively). However, CSP immediately after exercise was 144 ± 18 mmHg (younger age), 149 ± 17 mmHg (middle age), and 158 ± 19 mmHg (older age). CSP in the older age group was significantly higher than that in the younger age group (p < 0.01). Despite similar BSPs in all age groups after exercise, CSP was higher in the older age group. Therefore, older subjects have a higher CSP after exercise, which is not readily assessed by conventional measurements of BSP.

Different characteristics of cardiac biomarkers to decide and predict the culprit lesions in patients with suspicious acute coronary syndrome.

This multicenter prospective study was conducted to assess high-sensitivity troponin T (hs-TnT) and other biomarkers to decide and predict culprit lesions indicated for emergency percutaneous coronary intervention (PCI) in patients with suspicious acute coronary syndrome (ACS). We have reported Hs-TnT is the most sensitive biomarker for earlier diagnosis and decision making in patients with suspected ACS. In this study, we had conducted subanalysis investigating the usefulness for prediction of ACS culprit lesion. The patients with suspicious ACS and initially negative whole-blood rapid troponin T test, who underwent coronary angiogram (CAG), were enrolled (n = 74). Hs-TnT, quantitative assay for conventional troponin T (c-TnT), creatine kinase MB isozyme (CK-MB), and heart-type fatty acid-binding protein (H-FABP) were simultaneously measured. ACS culprit lesion was described as total occlusion, subtotal occlusion, and/or angiographical unstable lesion such as thrombosis, ulceration or irregularity. The CAG revealed that 49 cases had ACS lesions to be indicated for emergency PCI. The areas under the ROC curves and ROC-optimized cut-off of hs-TnT, c-TnT, CK-MB, and H-FABP were 0.75, 0.67, 0.68, and 0.75, respectively, and 18, 11, 2.0, and 4.6 ng/ml, respectively. In patients with total occlusion and 90-99 % of diameter stenosis (TIMI 2 or 3), hs-TnT could predict emergency PCI with significantly higher sensitivity compared with H-FABP (hs-TnT >14 ng/ml; 71 %, and H-FABP >6.2 ng/dl; 51 %, p = 0.021) and other biomarkers. Meanwhile, H-FABP displayed significant correlations with number of diseased vessels and presence of thrombotic lesion. The present study first revealed different characteristics of correlation between the angiographic culprit lesions and each cardiac biomarker. For prediction of ACS lesions requiring emergency PCI, hs-TnT had the highest sensitivity with satisfied analytical precision.

Papaverine-induced polymorphic ventricular tachycardia during coronary flow reserve study of patients with moderate coronary artery disease.

BACKGROUND: Papaverine is useful for evaluating the functional status of a coronary artery, but it may provoke malignant ventricular arrhythmia (VA). The aim of this study was to investigate the incidence, and clinical and ECG characteristics of patients with papaverine-induced VAs. METHODS AND RESULTS: The 182 consecutive patients underwent fractional flow reserve (FFR) measurement of 277 lesions. FFR was determined after intracoronary papaverine administration by standard procedures. The clinical and ECG characteristics were compared between patients with and without ventricular tachycardia (VT: ≥3 successive premature ventricular beats (PVBs), or ventricular fibrillation (VF)). After papaverine administration, the QTc interval, QTUc interval, and T-peak to U-end interval were prolonged significantly. Single PVBs on the T-wave or U-wave type developed in 29 patients (15.9%). Polymorphic VT (torsade de pointes) occurred in 5 patients (2.8%), and of those, VF developed in 3 patients (1.7%). No clinical and baseline ECG parameters were predictors for VT or VF except for sex and administration of papaverine into the left coronary artery. Excessive prolongation of QT (or QTU), T-peak to U-end intervals and giant T-U waves were found immediately prior to the ventricular tachyarrhythmias (VTAs), which were unpredictable from the baseline data. CONCLUSIONS: Intracoronary administration of papaverine induced fatal VTAs, although the incidence is rare. Excessive prolongation of the QT (and QTU) interval appeared prior to VTAs; however, they were unpredictable.

Rationale and Design of the Double-Blind, Randomized, Placebo-Controlled Multicenter Trial on Efficacy of Early Initiation of Eplerenone Treatment in Patients with Acute Heart Failure (EARLIER).

BACKGROUND AND AIMS: Aldosterone is one of the major factors to cause organ damage during an acute phase of heart failure (HF), and many reports have demonstrated that patients with acute decompensated HF (ADHF) have high blood aldosterone concentrations, and the high aldosterone concentrations predict poor prognosis in patients with HF. These findings suggest that eplerenone, an antagonist of aldosterone receptors may provide a new concept and strategy for the treatment of ADHF, protecting the heart and other organs during chronic phases, depending on the restoration of hemodynamic abnormalities. METHODS: EARLIER is an event-driven clinical trial with an estimated enrolment of 300 patients hospitalized with ADHF with reduced left ventricular ejection fraction. ADHF includes ischemic or non-ischemic HF, and patients can be enrolled within 72 h after the visit to the hospital. We randomize the patients taking standard therapies for ADHF to the eplerenone and placebo groups. Eplerenone, either 25 or 50 mg, is administered for 6 months in the eplerenone group, and the corresponding placebo is administered in the placebo group on top of the standard care. We set the primary endpoint as the incidence of the composite endpoint (cardiac death or first re-hospitalization due to cardiac disease) 6 months after the enrollment, and also check the quality of life, i.e., exercise capacity and safety features of eplerenone. CONCLUSION AND PERSPECTIVES: EARLIER is a clinical trial of eplerenone targeting ADHF and also the first multicenter investigator-initiated phase III trial in the cardiovascular field in Japan, funded by the Japanese government.