YUKIO OZAKI

OBJECTIVES: We sought to examine associations between plaque characteristics by intravascular ultrasound (IVUS) and detectability of external elastic lamina (EEL) by optical frequency domain imaging (OFDI) in human coronary arteries. BACKGROUND: It is often challenging to detect EEL which represents vessel size by light-based imaging modalities due to light intensity attenuation through atherosclerotic plaque. METHODS: IVUS and OFDI prior to stent implantation were sequentially investigated per protocol. We identified corresponding cross-sections by minimum lumen area (MLA) or just distally to side branches as anatomical landmarks. Plaque characterization was determined by integrated backscatter IVUS analysis. We categorized detectable EEL arc by OFDI into four groups: 0≤ and <1 quadrant (group 1), 1≤ and <2 quadrants (group 2), 2≤ and <3 quadrants (group 3), or 3≤ and <4 quadrants (group 4). RESULTS: We prospectively studied 103 vessels in 93 patients with stable coronary artery disease. Corresponding 711 cross-sections were analyzed. Cross-sections with detectable EEL arc <2 quadrants (group 1 or 2) were observed in 86.1% of MLA sites but only in 29.3% of non-MLA sites (p < .05). Percentage plaque area (%PA) appeared to be the strongest predictor to detect EEL arc <2 quadrants with the cut-off of 60.3% (AUC 0.90; sensitivity 79.8%, specificity 85.5%). Lipid pool and calcification remained statistically significant in predicting detectable EEL arc <2 quadrants after adjustment with %PA. CONCLUSIONS: Presence of large plaque burden, lipid pool, and calcification significantly predicts the detectability of EEL by OFDI assessment. Locations with detectable EEL arc <2 quadrants should thus be avoided for optimal stent landing zone.

BACKGROUND: Beta-blockers are standard therapy for acute myocardial infarction (AMI). However, despite current advances in the management of AMI, it remains unclear whether all AMI patients benefit from β-blockers. We investigated whether admission heart rate (HR) is a determinant of the effectiveness of β-blockers for AMI patients. Methods and Results: We enrolled 3,283 consecutive AMI patients who were admitted to 28 participating institutions in the Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition (J-MINUET) study. According to admission HR, we divided patients into 3 groups: bradycardia (HR <60 beats/min, n=444), normocardia (HR 60 to ≤100 beats/min, n=2,013), and tachycardia (HR >100 beats/min, n=342). The primary endpoint was major adverse cardiac events (MACE), including all-cause death, non-fatal MI, non-fatal stroke, heart failure (HF), and urgent revascularization for unstable angina, at 3-year follow-up. Beta-blocker at discharge was significantly associated with a lower risk of MACE in the tachycardia group (23.6% vs. 33.0%; P=0.033), but it did not affect rates of MACE in the normocardia group (17.8% vs. 18.4%; P=0.681). In the bradycardia group, β-blocker use at discharge was significantly associated with a higher risk of MACE (21.6% vs. 12.7%; P=0.026). Results were consistent for multivariable regression and stepwise multivariable regression. CONCLUSIONS: Admission HR might determine the efficacy of β-blockers for current AMI patients.

Previous studies have demonstrated that use of intravascular ultrasound (IVUS) during percutaneous coronary intervention (PCI) was associated with lower incidence of death, myocardial infarction, and target vessel revascularization. Recently, optical coherence tomography (OCT) has emerged as an alternative intravascular imaging device with better resolution. The aim of this study was to investigate frequency and prognostic impact of IVUS or OCT-guided PCI during urgent revascularization for acute myocardial infarction diagnosed by the universal definition. A total of 2788 patients who underwent urgent PCI were selected from a multicenter, Japanese registry of acute myocardial infarction diagnosed by universal definition (J-MINUET). Frequency, clinical characteristics and prognostic impact of the IVUS-, or OCT- guided PCI were investigated. Clinical endpoint was in-hospital death. Angiography-, IVUS-, and OCT-guided urgent PCI were performed in 689 (24.7%), 1947 (69.8%), and 152 (5.5%) patients. In-hospital death in each group was 10.4%, 5.1%, and 3.3%, respectively (P < 0.01). By univariate and multivariate logistic regression analysis, IVUS-guided PCI (vs. angiography-guided PCI, OR 0.49, 95% CI 0.30-0.81, P = 0.006) was a significant independent predictor of in-hospital death. Intravascular imaging guided-PCI was frequently adopted during urgent PCI for acute myocardial infarction diagnosed by universal definition and was associated with better in-hospital survival.

Implantable cardioverter-defibrillators (ICDs) improve survival in patients who are at risk of sudden death. However, inappropriate therapy is commonly given to ICD recipients, and this situation may be associated with an increased risk of death. This study aimed to construct a risk stratification scheme by using decision tree analysis in patients who received inappropriate ICD therapy.Mortality was calculated from a retrospective data analysis of a multicenter cohort involving 417 ICD recipients. Inappropriate therapy was defined as therapy for nonventricular arrhythmias, including sinus tachycardia, supraventricular tachycardia, atrial fibrillation/flutter, oversensing, and lead failure. Inappropriate therapy included antitachycardia pacing, cardioversion, and defibrillation. The prognostic factors were identified by a Cox proportional hazards regression analysis, and we constructed a decision tree.During an average follow-up of 5.2 years, 48 patients (12%) had all-cause death. A multivariate Cox hazard model revealed that the age (hazard ratio [HR] 1.06, P < 0.001), ln B-type natriuretic peptide (BNP) (HR 1.47, P = 0.02), nonsinus rhythm at implantation (HR 2.70, P < 0.05), and inappropriate therapy occurring during sedentary/awake conditions (HR 3.51, P = 0.001) correlated with an increased risk of mortality. An inappropriate therapy due to abnormal sensing (HR 0.16, P = 0.04) decreased the risk of mortality. Furthermore, a decision tree analysis stratified the patients well by using 4 covariates: BNP, activity at the time of inappropriate therapy, mechanism of inappropriate therapy, and baseline rhythm at ICD implantation (log-rank test, P < 0.0001).We identified the predictors of mortality in inappropriate ICD therapy recipients and constructed a risk stratification scheme by using decision tree analysis.

Background Scarce data exist about the outcomes after percutaneous coronary intervention ( PCI ) in old patients. This study sought to provide an overview of PCI in elderly patients, especially nonagenarians, in a Japanese large prospective nationwide registry. Methods and Results We analyzed 562 640 patients undergoing PCI (≥60 years of age) from 1018 Japanese hospitals between 2014 and 2016 in the J-PCI (Japanese percutaneous coronary intervention) registry. Among them, 10 628 patients (1.9%), including 6780 (1.2%) with acute coronary syndrome ( ACS ) and 3848 (0.7%) with stable coronary artery disease, were ≥90 years of age. We investigated differences in characteristics and in-hospital outcomes among sexagenarians, septuagenarians, octogenarians, and nonagenarians. Older patients were more frequently women and had a greater frequency of heart failure and chronic kidney disease than younger patients. In addition, older patients had a higher rate of in-hospital mortality, cardiac tamponade, cardiogenic shock after PCI , and bleeding complications requiring blood transfusion. Nonagenarians had the highest risk of in-hospital mortality (odds ratio, 3.60; 95% CI , 3.10-4.18 in ACS ; odds ratio , 6.24; 95% CI, 3.82-10.20 in non- ACS ) and bleeding complications ( odds ratio, 1.79; 95% CI, 1.35-2.36 in ACS ; odds ratio , 2.70; 95% CI, 1.68-4.35 in non- ACS ) when referenced to sexagenarians. More important, transradial intervention was an inverse independent predictor of both in-hospital mortality and bleeding complications. Conclusions Older patients, especially nonagenarians, carried a greater risk of in-hospital death and bleeding compared with younger patients after PCI . Transradial intervention might contribute to risk reduction for periprocedural complications in elderly patients undergoing PCI .

Background: Since warfarin is primarily bound to serum albumin, hypoalbuminemia is likely to increase the free fraction of warfarin and to increase the risk of bleeding. We prospectively evaluated the impact of serum albumin levels (ALB) on international normalized ratio of prothrombin time (PT-INR) control and hemorrhagic events in atrial fibrillation (AF) patients treated with warfarin. Methods: Seven hundred fifty-five non-valvular AF patients on warfarin were enrolled. PT-INR control and major bleeding events (MB, International Society on Thrombosis and Haemostasis) were prospectively followed and were related to ALB at enrollment. Results: Twenty-seven patients developed MB during 1-year follow-up. In univariate/multivariate analyses, ALB (OR = 0.49, 95% CI 0.26-0.99, p = 0.04) and hemoglobin levels (OR = 0.78, 95% CI 0.65-0.92, p = < 0.01) were predictive for the annual risk of MB. In Spearman's rank correlation analysis, the baseline ALB was inversely correlated with the percentage of the time in PT-INR > 3.0 (ρ = -0.15, p < 0.0001), but neither 2.0 ≤ PT-INR ≤ 3.0 (ρ = 0.056, p = 0.13) nor PT-INR < 2.0 (ρ = -0.008, p = 0.82) during 1-year follow-up, suggesting that patients with low ALB had a directional tendency to be supratherapeutic control of PT-INR. The ROC curve showed that a cutoff of ALB was 3.6 g/dl to identify MB (AUC = 0.65). In Kaplan-Meier analysis, patients with ALB <3.6 g/dl (23/80, 29%) had more MB than those with ALB ≥3.6 g/dl (87/675, 13%, log-rank = 16.80, p < 0.0001) during long-term follow-up (3.8 ± 2.0 years). Conclusions: Hypoalbuminemia increases the likelihood of supratherapeutic PT-INR control and the risk of MB. ALB can be a practical surrogate marker to prevent excessive warfarin control and warfarin-related MB.

We have previously demonstrated that cardiac shock wave therapy (CSWT) effectively improves myocardial ischemia through coronary neovascularization both in a porcine model of chronic myocardial ischemia and in patients with refractory angina pectoris (AP). In this study, we further addressed the efficacy and safety of CSWT in a single-arm multicenter study approved as a highly advanced medical treatment by the Japanese Ministry of Health, Labour and Welfare. Fifty patients with refractory AP [mean age 70.9 ± 12.6 (SD) years, M/F 38/12] without the indications of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) were enrolled in 4 institutes in Japan. Ischemic myocardial regions in the left ventricle (LV) were identified by drug-induced stress myocardial perfusion imaging (MPI). Shock waves (200 shots/spot at 0.09 mJ/mm2) were applied to 40-60 spots in the ischemic myocardium 3 times in the first week. The patients were followed up for 3 months thereafter. Forty-one patients underwent CSWT and completed the follow-up at 3 months. CSWT markedly improved weekly nitroglycerin use [from 3.5 (IQR 2 to 6) to 0 (IQR 0 to 1)] and the symptoms [Canadian Cardiovascular Society functional class score, from 2 (IQR 2 to 3) to 1 (IQR 1 to 2)] (both P < 0.001). CSWT also significantly improved 6-min walking distance (from 384 ± 91 to 435 ± 122 m, P < 0.05). There were no significant changes in LV ejection fraction evaluated by echocardiography and LV stroke volume evaluated by cardiac magnetic resonance imaging (from 56.3 ± 14.7 to 58.8 ± 12.8%, P = 0.10, and from 52.3 ± 17.4 to 55.6 ± 15.7 mL, P = 0.15, respectively). Percent myocardium ischemia assessed by drug-induced stress MPI tended to be improved only in the treated segments (from 16.0 ± 11.1 to 12.1 ± 16.2%, P = 0.06), although no change was noted in the whole LV. No procedural complications or adverse effects related to the CSWT were noted. These results of the multicenter trial further indicate that CSWT is a useful and safe non-invasive strategy for patients with refractory AP with no options of PCI or CABG.

BACKGROUND: Although cardiac sarcoidosis is associated with poor prognosis, diagnosis of the disease is challenging and the sensitivity and specificity of diagnostic modalities are limited. This study was performed to evaluate the potential of serum microRNAs (miRNAs) as diagnostic biomarkers for cardiac sarcoidosis. METHODS: We performed genome-wide expression profiling for 2565 miRNAs (Human-miRNA ver.21) using peripheral blood samples from 5 patients with cardiac sarcoidosis (61±9 years) and 3 healthy controls (54±7 years). From this screening study, we selected 12 miRNAs that were significantly related to cardiac sarcoidosis. Next, we performed real-time polymerase chain reaction (PCR) on blood samples from 15 new patients with cardiac sarcoidosis and 4 healthy controls to quantify the expression of these 12 miRNAs. RESULTS: In the screening study, 12 miRNAs were differentially expressed (p<0.01) in all 5 patients with cardiac sarcoidosis, showing greater fold-change values (>4 or <0.25) compared with the expression in the 3 healthy controls. Analysis of the real-time PCR for blood samples from the other 15 patients and 4 controls using Mann-Whitney U tests revealed that the expression of miR-126 and miR-223 was significantly higher in the patients than in the healthy individuals. However, there were no differences in the expressions of miRNA-126 and miR-223 between patients with only cardiac lesions and those with extra-cardiac lesions. CONCLUSIONS: Our results demonstrate the potential of serum miR-126 and miR-223 as new-generation biomarkers for the differential diagnosis of cardiac sarcoidosis in patients with heart failure.

BACKGROUND: Cardiac wall motion abnormality (WMA) is a common complication in patients with subarachnoid hemorrhage (SAH) and is one determinant of their prognosis. The aim of this study was to examine whether the electrocardiography (ECG) findings at admission could predict WMA commonly observed after SAH. MATERIALS AND METHODS: We studied 161 SAH patients with SAH who were hospitalized in our institution between April 2007 and November 2010. We performed bedside 2-dimensional transthoracic echocardiography and 12-lead surface ECG within 24hours of SAH onset. Each of the following ECG changes was scored as having 1 point: ST elevation, ST depression and T wave inversion. We summed up the points in every patient and compared with WMA evaluated by echocardiography. RESULTS: The study subjects were classified into 2 groups based on the presence of WMA. Multivariate analysis revealed that ST elevation, ST depression and T wave inversion were strong independent predictors of WMA. Receiver operating characteristic curve determined that the threshold value to predict WMA was 4 points (sensitivity 86.5%, specificity 83.1%, AUC 0.94, P < .0001). CONCLUSIONS: In conclusion, a novel ECG score may well predict WMA after SAH which may associate with an increased risk of mortality.

BACKGROUND: In atrial fibrillation (AF) patients, the effect of direct oral anticoagulant (DOACs) therapy on the incidence of left atrial appendage thrombus (LAT) remains poorly investigated. This study examined the prevalence and risk factors of LAT in AF patients on DOACs undergoing catheter ablation, and sought an anticoagulation strategy for LAT. Methods and Results: In 407 AF patients on DOACs, transesophageal echocardiography (TEE) was performed 1 day before ablation. If patients had LAT, initial DOACs were switched to dabigatran (300 mg) or warfarin based on their renal function; TEE was repeated after treatment for ≥4 weeks. LAT was detected in 18 patients (4.4%). The prevalence of persistent AF and low-dose treatment/inappropriate dose reduction of DOACs, CHADS2/CHA2DS2-VASc scores, serum N-terminal pro-brain natriuretic peptide levels, and LA dimension/LA volume index significantly increased in patients with LAT vs. those without LAT. AF rhythm on TEE and spontaneous echo contrast also increased in patients with LAT; LA appendage flow velocity decreased. In the multivariate analysis, persistent AF and inappropriately reduced DOAC dose were risk factors for LAT. On repeat TEE, LAT had disappeared in 13 of 16 patients treated with dabigatran and in 2 of 2 patients treated with warfarin. CONCLUSIONS: DOACs still carry a finite risk of LAT in AF patients. Inappropriately reduced DOAC dose should be avoided to minimize the thromboembolic risk. Regular-dose dabigatran may have therapeutic efficacy against LAT.

It has been shown that the patency of an infarct-related artery (IRA) before primary percutaneous coronary intervention determines post-procedural success, better preservation of left ventricular function, and lower in-hospital mortality. However, the factors associated with pre-procedural Thrombolysis In Myocardial Infarction (TIMI) flow have not been fully investigated.The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET) is a prospective multicenter registry conducted at 28 Japanese medical institutions between July 2012 and March 2014. We enrolled 3,283 consecutive patients with acute myocardial infarction who were admitted to a participating institution within 48 hours of symptom onset. There were 2,262 patients (68.9%) with ST-elevation myocardial infarction (STEMI), among whom 2,182 patients underwent emergent or urgent coronary angiography.Pre-procedural TIMI flow grade 3 was related to post-procedural TIMI flow grade 3 (P < 0.001), lower enzymatic infarct size (P < 0.001), lower ventricular tachycardia and ventricular fibrillation (P = 0.049), and lower in-hospital mortality (P = 0.020). A history of antiplatelet drug use was associated with pre-procedural TIMI flow.Antiplatelet drug use on admission was associated with pre-procedural TIMI flow. The patency of the IRA in patients with STEMI was related to procedural success and decreased enzymatic infarct size, fatal arrhythmic events, and in-hospital mortality.

BACKGROUND: The early prediction of acute kidney injury (AKI) can facilitate timely intervention and prevent complications. We aimed to understand the predictive value of urinary liver-type fatty-acid binding protein (L-FABP) levels on admission to medical (non-surgical) cardiac intensive care units (CICUs) for AKI, both independently and in combination with serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. METHODS: We prospectively investigated the predictive value of L-FABP and NT-proBNP for AKI in a large, heterogeneous cohort of patients treated in medical CICUs. Baseline urinary L-FABP and serum NT-proBNP were measured on admission. AKI was diagnosed according to the Kidney Disease: Improving Global Outcomes criteria. We studied 1273 patients (mean age, 68 years), among whom 46% had acute coronary syndromes, 38% had acute decompensated heart failure, 5% had arrhythmia, 3% had pulmonary hypertension, 2% had acute aortic syndrome, 2% had infective endocarditis, and 1% had Takotsubo cardiomyopathy. RESULTS: Urinary L-FABP levels correlated with serum NT-proBNP levels (r = 0.17, p < 0.0001). AKI occurred in 224 patients (17.6%), including 48 patients with stage 2 or 3 disease. Patients who developed AKI had higher one-week and 6-month mortality than those who did not develop AKI (p = 0.0002 and p = 0.003, respectively). In the multivariate logistic analysis, both L-FABP (p < 0.0001) and NT-proBNP (p = 0.006) were independently associated with the development of AKI. Adding L-FABP and NT-proBNP to a baseline model that included established risk factors further improved reclassification (p < 0.001) and discrimination (p < 0.01) beyond that of the baseline model or any single biomarker individually. CONCLUSIONS: Urinary L-FABP and serum NT-proBNP levels on admission are independent predictors of AKI, and when used in combination, improve early prediction of AKI in patients hospitalized at medical CICUs.

BACKGROUND: Previous studies suggest that the pathophysiology of heart failure with preserved ejection fraction (HFpEF) is characterized not only by high ventricular stiffness, but also by vascular stiffness. Azilsartan has higher vascular affinity compared with other angiotensin II receptor blockers (ARBs), which were proven to have no beneficial effects on clinical outcomes in patients with HFpEF in earlier clinical trials. We aimed to test the hypothesis that azilsartan may improve left ventricular diastolic function in HFpEF patients with hypertension in this trial. METHODS: The Effects of Angiotensin Receptor Blockers on Diastolic Function in Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE trial is a multicenter, randomized, open-labeled, and assessor(s)-blinded, active controlled using candesartan, parallel-group clinical trial, to compare changes in left ventricular (LV) diastolic dysfunction between HFpEF patients with hypertension who have received candesartan or azilsartan for 48 weeks. The primary endpoint is the change in early diastolic wave height/early diastolic mitral annulus velocity (E/e') assessed by echocardiography from the baseline to the end of the study (48 weeks). A total of 190 patients will be recruited into the study. CONCLUSIONS: The design of the J-TASTE trial will provide data on whether differences between the effects of the two tested drugs on LV diastolic function exist in HFpEF patients with hypertension and will improve understanding of the pathophysiological role of vascular stiffness on diastolic function.

© 2018 The Society of Thoracic Surgeons Aortic annular rupture is a potentially fatal complication after transcatheter aortic valve implantation with high mortality. Although it is quite rare and difficult to identify the mechanisms and predictors, prosthesis oversizing and massive calcification of the aortic annulus are thought to be a potential risk of this complication. A case presented here is an aortic annular rupture after transcatheter aortic valve implantation. Although the valve was not oversized, there were 2 severe calcifications of aortic annulus at nearby areas like “twin icicles,” thought to be a trigger of this potentially fatal complication.

© 2018 Author(s) (or their employer(s)). Purpose The ratio of the left atrial volume index (LAVI) and late diastolic mitral annular velocity (A′) is a useful echocardiographic index for identifying advanced left ventricular (LV) diastolic dysfunction in patients with dyspnoea. We investigated the clinical implications and prognostic value of the aforementioned ratio (LAVI/A′) in patients with ST elevation (STE) or non-STE (NSTE) acute coronary syndrome (ACS). Methods We studied 212 patients with ACS. All patients underwent electrocardiography, echocardiography and measurement of plasma B-type natriuretic peptide (BNP) level on admission. The study endpoints were hospitalisation and mortality because of heart failure (HF). Results There was a significant, moderate positive correlation between LAVI/A′ and natural logarithm (Ln) BNP level among the participants (r=0.48, p&lt;0.0001). During a mean follow-up of 17 months, eight patients died and nine patients were hospitalised because of HF. The receiver operating characteristics curve indicated that LAVI/A′≥3.0 predicted these events (log-rank, p=0.0021). A significant and moderate positive correlation existed between LAVI/A′ and Ln BNP level in the NSTE-ACS group (n=128; r=0.58, p&lt;0.0001). However, the correlation between LAVI/A′ and Ln BNP level was weaker in the STE-ACS group (n=84; r=0.33, p=0.0017). Conclusion LAVI/A′ was related to plasma BNP levels in patients with ACS, particularly in those with NSTE-ACS. This index was useful for predicting cardiac events in patients with ACS.

BACKGROUND: Prediction of thrombotic and bleeding risk is important to optimize antithrombotic therapy after percutaneous coronary intervention. METHODS AND RESULTS: We developed the prediction rules for thrombotic and bleeding events separately in Japanese patients. Derivation and validation cohorts consisted of 4778 patients from CREDO-Kyoto (Coronary Revascularization Demonstrating Outcome Study in Kyoto) registry cohort 2 and 4669 patients from RESET (Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial) and NEXT (Nobori Biolimus-Eluting Versus Xience/Promus Everolimus-Eluting Stent Trial). Primary thrombotic and bleeding events were a composite of myocardial infarction, definite or probable stent thrombosis or ischemic stroke, and GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) moderate or severe bleeding. The prediction rule for thrombosis assigned 2 points for severe chronic kidney disease, atrial fibrillation, peripheral vascular disease, and anemia and 1 point for age ≥75 years, heart failure, diabetes mellitus, and chronic total occlusion. The prediction rule for bleeding assigned 2 points for thrombocytopenia, severe chronic kidney disease, peripheral vascular disease, and heart failure and 1 point for prior myocardial infarction, malignancy, and atrial fibrillation. In derivation and validation cohorts, area under the curve was 0.68 and 0.64, respectively, for thrombosis and 0.66 and 0.66, respectively, for bleeding. In the validation cohort, a high thrombosis risk score (≥4, n=682) was associated with higher 3-year incidence of thrombotic events than a score that was intermediate (2-3, n=1178) or low (0-1, n=2809) (7.6%, 3.7%, versus 2.4%, respectively; P<0.0001). A high bleeding risk score (≥3, n=666) was associated with higher incidence of bleeding than scores that were intermediate (1-2, n=1802) or low (0, n=2201) (8.8%, 4.1%, versus 2.3%, respectively; P<0.0001). Among 682 patients at high thrombotic risk, only 39 (5.7%) had low bleeding risk, whereas 401 (58.8%) had high bleeding risk with very high incidence of bleeding (11.6%). CONCLUSIONS: CREDO-Kyoto thrombotic and bleeding risk scores demonstrated modest accuracy in stratifying thrombotic and bleeding risks; however, a large proportion of patients at high thrombotic risk also had high bleeding risk.

BACKGROUND: Current guidelines call for high-intensity statin therapy in patients with cardiovascular disease on the basis of several previous "more versus less statins" trials. However, no clear evidence for more versus less statins has been established in an Asian population. METHODS: In this prospective, multicenter, randomized, open-label, blinded end point study, 13 054 Japanese patients with stable coronary artery disease who achieved low-density lipoprotein cholesterol (LDL-C) <120 mg/dL during a run-in period (pitavastatin 1 mg/d) were randomized in a 1-to-1 fashion to high-dose (pitavastatin 4 mg/d; n=6526) or low-dose (pitavastatin 1 mg/d; n=6528) statin therapy. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. The secondary composite end point was a composite of the primary end point and clinically indicated coronary revascularization excluding target-lesion revascularization at sites of prior percutaneous coronary intervention. RESULTS: The mean age of the study population was 68 years, and 83% were male. The mean LDL-C level before enrollment was 93 mg/dL with 91% of patients taking statins. The baseline LDL-C level after the run-in period on pitavastatin 1 mg/d was 87.7 and 88.1 mg/dL in the high-dose and low-dose groups, respectively. During the entire course of follow-up, LDL-C in the high-dose group was lower by 14.7 mg/dL than in the low-dose group (P<0.001). With a median follow-up of 3.9 years, high-dose as compared with low-dose pitavastatin significantly reduced the risk of the primary end point (266 patients [4.3%] and 334 patients [5.4%]; hazard ratio, 0.81; 95% confidence interval, 0.69-0.95; P=0.01) and the risk of the secondary composite end point (489 patients [7.9%] and 600 patients [9.7%]; hazard ratio, 0.83; 95% confidence interval, 0.73-0.93; P=0.002). High-dose pitavastatin also significantly reduced the risks of several other secondary end points such as all-cause death, myocardial infarction, and clinically indicated coronary revascularization. The results for the primary and the secondary composite end points were consistent across several prespecified subgroups, including the low (<95 mg/dL) baseline LDL-C subgroup. Serious adverse event rates were low in both groups. CONCLUSIONS: High-dose (4 mg/d) compared with low-dose (1 mg/d) pitavastatin therapy significantly reduced cardiovascular events in Japanese patients with stable coronary artery disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01042730.

The ratio of serum eicosapentaenoic acid (EPA) to arachidonic acid (AA) is significantly associated with long-term clinical outcomes in patients with acute myocardial infarction (AMI). However, it has not been conclusively demonstrated that higher serum EPA/AA ratio fares better clinical outcomes in the early phase of AMI. The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET) is a prospective multicenter registry conducted in 28 Japanese medical institutions between July 2012 and March 2014. We enrolled 3,283 consecutive AMI patients who were admitted to participating institutions within 48 h of symptom onset. A serum EPA/AA ratio was available for 629 of these patients. The endpoints were in-hospital mortality and major adverse cardiac events (MACE), defined as a composite of all cause death, cardiac failure, ventricular tachycardia (VT) and/or ventricular fibrillation (VF) and bleeding during hospitalization. Although similar rates of in-hospital mortality, cardiac failure, bleeding, and MACE were found in the lower serum EPA/AA group and higher serum EPA/AA group, the incidence of VT/VF during hospitalization was significantly higher in the low ratio group (p = 0.008). Receiver operating characteristic curve analysis showed that an EPA/AA ratio &lt  0.35 could predict the incidence of VT/VF with 100% sensitivity and 64.0% specificity. A lower serum EPA/AA ratio was associated with a higher frequency of fatal arrhythmic events in the early phase of AMI.

© The Author(s) 2018. Introduction: Ventricular assist device is used in the patients with severe heart failure due to cardiotoxicity of anthracyclines, which are widely used chemotherapeutic agents for a wide range of malignant tumors. However, recovery of cardiac function is rare. Methods: We present the clinical course of a 43-year-old woman in remission from diffuse large B-cell lymphoma after the chemotherapy including anthracyclines, who presented in cardiogenic shock 8 months after the end of chemotherapy. Results: The patient was initially treated with intra-aortic balloon pumping, followed by conversion to left ventricular assist device with an Abiomed AB5000 (Abiomed, Inc, Danvers, MA) and right ventricular assist device with a centrifugal pump and a membrane oxygenator, in addition to tricuspid annuloplasty, due to rapid deterioration to cardiogenic shock. With intensive medical treatments during biventricular support, her cardiac and respiratory functions gradually improved, although moderate mitral regurgitation persisted despite of left ventricular unloading. At 64 days of biventricular support, she underwent mitral valve annuloplasty to correct regurgitation under cardiopulmonary bypass. She was consequently weaned from biventricular assist successfully 8 days after mitral surgery (72 days of biventricular support). The patient discharged uneventfully from our hospital and survives at home 12 months after weaning from the ventricular assist devices. Conclusion: Our case and the literature review highlight potential usefulness of aggressive mechanical biventricular support for cardiac recovery in patients with anthracycline-induced cardiomyopathy. Additional valve surgery and neurohormonal medications may be also promising in such patients with cancer, who are contraindicated for heart transplantation.

Heart failure (HF) is classified into three clinical subtypes: HF with a preserved ejection fraction (HFpEF: EF ≥ 50%), HF with a mid-range ejection fraction (HFmrEF: 40 ≤ EF < 49%), and HF with a reduced ejection fraction (HFrEF: EF < 40%). These types often coexist with atrial fibrillation (AF). We investigated the rate of strokes/systemic embolisms (SSEs) in AF patients with HFpEF (AF-HFpEF) compared to that in those with HFrEF (AF-HFrEF: HFmrEF and HFrEF), and examined the independent predictors. We prospectively enrolled 1350 patients admitted to our hospital for worsening HF. We identified 301 patients with either AF-HFpEF (n = 129, 43%) or AF-HFrEF (n = 172, 57%). Compared to the patients with AF-HFrEF, those with AF-HFpEF were older and more likely to be female. Oral anticoagulant use was 63 vs. 66%, respectively. During a mean follow-up period of 26 months, 21 (7%) and 66 (22%) patients had SSEs and all-cause death, respectively. The crude annual rates of SSEs (3.9 vs. 2.7%, P = 0.47) were similar between the groups. In a multivariate Cox regression analysis, an age ≥ 75 years (hazard ratio 2.14, 95% confidence interval 1.32-3.58, P < 0.01) and the plasma B-type natriuretic peptide (BNP) level ≥ 341 pg/ml (hazard ratio 1.60, 95% confidence interval 1.07-2.39, P < 0.05) were associated with SSEs. The EF was not an independent predictor of SSEs (hazard ratio 1.01, 95% confidence interval 0.98-1.04, P = 0.51). There were no significant differences in the rates of SSEs between AF-HFpEF and AF-HFrEF. Patients with HF and concomitant AF should be treated with anticoagulants irrespective of EF.

While primary percutaneous coronary intervention (PCI) has significantly contributed to improve the mortality in patients with ST segment elevation myocardial infarction even in cardiogenic shock, primary PCI is a standard of care in most of Japanese institutions. Whereas there are high numbers of available facilities providing primary PCI in Japan, there are no clear guidelines focusing on procedural aspect of the standardized care. Whilst updated guidelines for the management of acute myocardial infarction were recently published by European Society of Cardiology, the following major changes are indicated; (1) radial access and drug-eluting stent over bare metal stent were recommended as Class I indication, and (2) complete revascularization before hospital discharge (either immediate or staged) is now considered as Class IIa recommendation. Although the primary PCI is consistently recommended in recent and previous guidelines, the device lag from Europe, the frequent usage of coronary imaging modalities in Japan, and the difference in available medical therapy or mechanical support may prevent direct application of European guidelines to Japanese population. The Task Force on Primary Percutaneous Coronary Intervention of the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT) has now proposed the expert consensus document for the management of acute myocardial infarction focusing on procedural aspect of primary PCI.

Large-scale clinical trials in patients in Western countries with coronary artery disease (CAD) have found that aggressive lipid-lowering therapy using high-dose statins reduces cardiovascular (CV) events further than low-dose statins. However, such evidence has not yet been fully established in Asian populations, including in Japan. The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study addresses whether intensification of statin therapy improves clinical outcomes in Japanese patients with CAD.REAL-CAD is a prospective, multicenter, randomized, open-label, blinded-endpoint, physician-initiated phase 4 trial in Japan. The study will recruit up to 12,600 patients with stable CAD. Patients are assigned to receive either pitavastatin 1 mg/day or pitavastatin 4 mg/day. LDL-C levels are expected to reach approximate mean values of 100 mg/dL in the low-dose pitavastatin group and 80 mg/dL in the high-dose group. The primary endpoint is the time to occurrence of a major CV event, including CV death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization during an average of 5 years. The large number of patients and the long follow-up period in the REAL-CAD study should ensure that there is adequate power to definitively determine if reducing LDL-C levels to approximately 80 mg/dL by high-dose statin can provide additional clinical benefit.After the study is completed, we will have categorical evidence on the optimal statin dose and target LDL-C level for secondary prevention in Japanese patients.

Aims: The aim of this study was to assess in vitro the diagnostic accuracy of computed tomography angiography (CTA) for the evaluation of complex coronary lesions. Methods and results: Five Plexiglas phantoms with three bifurcation lesions each were designed to mimic the anatomic variations and fractal phenomena of the coronary tree. In addition, luminal stenoses were scaled up with increases of 10% from 40% to 80%, corresponding to luminal areas ranging from 3.0 mm2 to 0.22 mm2. Third-generation dual-source computed tomography was used. Automated quantitative CTA analysis was performed according to the bifurcation segment model. The primary objective was to determine the diagnostic accuracy of quantitative CTA in assessing bifurcation lesions with the phantoms as a reference. The accuracy of CTA for the assessment of minimal luminal diameter was-0.07 mm (limits of agreement-0.75 to 0.61), for reference vessel diameter 0.19 mm (limits of agreement-0.25 to 0.63) and diameter stenosis 8.2% (limits of agreement-13.2 to 29.5) with no difference regarding the location within the bifurcation (i.e., proximal and distal main vessel and side branch). In stenosis with minimal luminal diameter ≥1 mm, CTA overestimated the lesion severity (bias 0.19 mm, limits of agreement-0.09 to 0.47), whereas in lesions with severe stenosis and minimal luminal diameter ≤1 mm, CTA underestimated the lesion severity (bias-0.48 mm, limits of agreement-0.55 to-0.41). CTA was able to identify the contrastfilled lumen in all degrees of lesion severity. Conclusions: In vitro, CTA is accurate for the evaluation of bifurcation lesions. CTA was able to distinguish contrast-filled lumen even in severe obstructive lesions. These findings require further validation in the clinical setting.

© 2018 Elsevier Ltd Background: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease. Methods: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants. Findings: Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65–0·86, p&lt;0·0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8250 vs 460 [6%] of 8261; HR 0·89, 95% CI 0·78–1·02, p=0·094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8313 vs 158 [2%] of 8261; HR 1·66, 95% CI 1·37–2·03, p&lt;0·0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8250 vs 158 [2%] of 8261; HR 1·51, 95% CI 1·23–1·84, p&lt;0·0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8313 vs 339 [4%] of 8261; HR 0·77, 95% CI 0·65–0·90, p=0·0012). Interpretation: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide. Funding: Bayer AG.

© 2018 Elsevier Ltd Background: Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications. Methods: This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle–brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants. Findings: Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·57–0·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·35–0·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·69–1·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·45–1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12–2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17–2·40; p=0·0043). Interpretation: Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding. Funding: Bayer AG.

Vascular reparative therapy has become a reality with bioresorbable scaffolds (BRSs). To assess acute and long-term performance of the device, multimodality imaging would be essential. Radiopacity of metal hinders the imaging assessment, whereas radiolucent polymeric scaffolds allow for a precise imaging assessment with either invasive or non-invasive modality at baseline and at follow-up, which is one of the advantages of polymeric BRSs. Recent large trials evaluating clinical results of the first-generation BRS technology raised concerns about the safety and efficacy of these devices, namely, scaffold thrombosis. Intensive research with multimodality imaging in the field is being conducted to have in-depth understanding of the issues, which will facilitate the improvement of implantation techniques and the development of the next-generation BRSs. The current review focuses on the clinical application of the imaging modalities to assess the short- and long-term performance of the Absorb BVS.

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.

Background: Cardiac recovery and prevention of end-organ damage are the cornerstones of establishing successful bridge to recovery (BTR) in patients with fulminant myocarditis (FM) supported with percutaneous venoarterial extracorporeal membrane oxygenation (VA-ECMO). However, the timing and method of successful BTR prediction still remain unclear. We aimed to develop a prediction model for successful BTR in patients with FM supported with percutaneous VA-ECMO. Methods and Results: This was a retrospective multicenter chart review enrolling 99 patients (52±16 years female, 42%) with FM treated with percutaneous VA-ECMO. The S-group comprised patients who experienced percutaneous VA-ECMO decannulation and subsequent discharge (n=46), and the F-group comprised patients who either died in hospital or required conversion to other forms of mechanical circulatory support (n=53). At VA-ECMO initiation (0-h), the S-group had significantly higher left ventricular ejection fraction (LVEF) and lower aspartate aminotransferase (AST) concentration than the F-group. At 48 h, the LVEF, increase in the LVEF, and reduction of AST from 0-h were identified as independent predictors in the S-group. Finally, we developed an S-group prediction model comprising these 3 variables (area under the curve, 0.844 95% confidence interval, 0.745–0.944). Conclusions: We developed a model for use 48 h after VA-ECMO initiation to predict successful BTR in patients with FM.

Background: The results of previous clinical trials on the effects of ezetimibe-statin combination therapy on atherosclerosis are inconsistent, and the anti-atherosclerotic effect of ezetimibe remains controversial. Methods and Results: We conducted a prospective, randomized open-label study at 10 centers. One hundred and twenty-eight statin-naïve patients with acute coronary syndrome (ACS) undergoing intravascular ultrasound (IVUS)-guided percutaneous coronary intervention were randomized to receive either 2 mg/day pitavastatin plus 10 mg/day ezetimibe, or 2 mg/day pitavastatin. One hundred and 3 patients had evaluable IVUS of non-culprit coronary lesions at baseline and at follow-up. The primary endpoint was the percentage change in non-culprit coronary plaque volume (PV) and lipid PV on integrated backscatter IVUS. Mean low-density lipoprotein cholesterol was reduced from 123 mg/dL to 64 mg/dL in the combination therapy group (n=50) and 126 mg/dL to 87 mg/dL in the statin alone group (n=53 between-group difference, 16.9%, P&lt 0.0001). The percent change in PV was −5.1% in the combination therapy group and −6.2% in the statin alone group (P=0.66), although both groups had reduction of PV compared with baseline (both P&lt 0.01). The percent change in lipid PV did not differ between the groups (4.3 vs. −3.0%, P=0.37). Conclusions: In statin-naïve patients with ACS, combined therapy with ezetimibe and statin did not result in a significant change in coronary plaque regression or tissue component compared with statin alone.

High levels of blood urea nitrogen (BUN) have been demonstrated to significantly predict poor prognosis in patients with acute decompensated heart failure. However, this relationship has not been fully investigated in patients with acute myocardial infarction (AMI). We investigated whether a high level of BUN is a significant predictor for in-hospital mortality and other clinical outcomes in patients with AMI. The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET) is a prospective, observational, multicenter study conducted in 28 institutions, in which 3,283 consecutive AMI patients were enrolled. We excluded 98 patients in whom BUN levels were not recorded at admission and 190 patients who were undergoing hemodialysis. A total of 2,995 patients were retrospectively analyzed. BUN tertiles were 1.5-14.4 mg/dL (tertile 1), 14.5-19.4 mg/dL (tertile 2), and 19.5-240 mg/dL (tertile 3). Increasing tertiles of BUN were associated with stepwise increased risk of in-hospital mortality (2.5, 5.1, and 11%, respectively P &lt 0.001). These relationships were also observed after adjusting for reduced estimated glomerular filtration rate (estimated GFR &lt 60 mL/ minute/1.73 m2) or Killip classifications. In multivariable analysis, high levels of BUN significantly predicted in-hospital mortality, after adjusting for creatinine and other known predictors (BUN tertile 3 versus 1, adjusted odds ratio [OR]: 2.59, 95% confidence interval [95% CI]: 1.57-4.25, P &lt 0.001 BUN tertile 2 versus 1, adjusted OR: 1.60, 95% CI: 0.94-2.73, P = 0.081). A high level of BUN could be a useful predictor of in-hospital mortality in AMI patients.

Background: Limitations of coronary computed tomography (CTA) include false-positive stenosis at calcified lesions and assessment of in-stent patency. A prototype of ultra-high resolution computed tomography (U-HRCT: 1,792 channels and 0.25-mm slice thickness×128 rows) with improved spatial resolution was developed. We assessed the diagnostic accuracy of coronary artery stenosis using U-HRCT. Methods and Results: Seventy-nine consecutive patients who underwent CTA using U-HRCT were prospectively included. Coronary artery stenosis was graded from 0 (no plaque) to 5 (occlusion). Stenosis grading at 102 calcified lesions was compared between U-HRCT and conventional-resolution CT (CRCT: 896 channels and 0.5-mm slice thickness×320 rows). Median stenosis grading at calcified plaque was significantly improved on U-HRCT compared with CRCT (1 IQR, 1–2 vs. 2 IQR, 1–3, P&lt 0.0001). Assessability of in-stent lumen was evaluated on U-HRCT in 79 stents. Stent strut thickness and luminal diameter were quantitatively compared between U-HRCT and CRCT. Of 79 stents, 83.5% were assessable on U-HRCT 80% of stents with diameter 2.5 mm were regarded as assessable. On U-HRCT, stent struts were significantly thinner (median, 0.78 mm IQR, 0.7–0.83 mm vs. 0.83 mm IQR, 0.75–0.92 mm, P=0.0036), and in-stent lumens were significantly larger (median, 2.08 mm IQR, 1.55–2.51 mm vs. 1.74 mm IQR, 1.31–2.06 mm, P&lt 0.0001) than on CRCT. Conclusions: U-HRCT with improved spatial resolution visualized calcified lesions with fewer artifacts. The in-stent lumen of stents with diameter ≥2.5 mm was assessable on U-HRCT.

© 2018, Japanese Circulation Society. All rights reserved. Background: Fulminant myocarditis (FM) presents various abnormal findings on ECG, the prognostic impact of which has not been not fully elucidated. The aim of this study was therefore to clarify the prognostic value of ECG data in FM patients supported by venoarterial extracorporeal membrane oxygenation (VA-ECMO). Methods and Results: In this multicenter chart review, we investigated 99 patients with FM supported by VA-ECMO. The final cohort consisted of 87 patients (mean age, 52±16 years; female, 42%) after 12 patients who required conversion to other forms of mechanical circulatory support were excluded. The median LVEF was 14.5%. At the time of VA-ECMO initiation, 38 patients (44%) had arrhythmias including atrial fibrillation (6%), complete atrioventricular block (CAVB; 17%), and ventricular tachycardia or fibrillation (VT/VF; 15%). Of the 49 patients with sinus rhythm (SR), 26 had QRS duration ≥120 ms (wide QRS). On logistic regression analysis, wide QRS predicted in-hospital death in patients with SR (OR, 3.6; 95% CI: 1.07–13.61, P=0.04). Compared with SR with narrow QRS (QRS duration &lt;120 ms), CAVB and VT/VF had a higher risk of in-hospital death (CAVB: OR, 7.20; 95% CI: 1.78–34.15, P=0.005; VT/VF: OR, 8.10; 95% CI: 1.86–42.31, P=0.005). Conclusions: In patients with FM, CAVB and VT/VF carried a higher risk of in-hospital death. Wide QRS also predicted a higher risk of in-hospital death in patients with SR.

© 2018 Japan Atherosclerosis Society. Aims: Coronary artery atherosclerosis in patients needing carotid revascularization has not been fully clarified. The aim of this study was to evaluate the stenotic severity and plaque characteristics of coronary arteries by coronary computed tomography angiography (CTA) in patients scheduled for carotid-artery stenting (CAS) or carotid endarterectomy (CEA). Methods: We performed coronary CTA after carotid ultrasound (US) in 164 patients (81.7% male, aged 68.1± 12.2 years) from 2014 to 2016. Of all, 70 were scheduled for CAS or CEA (CAS/CEA group) and 94 were not (non-CAS/CEA group). Carotid US and coronary CTA were compared for the evaluation of stenotic severity and plaque characteristics of each vessel between CAS/CEA and non-CAS/CEA groups. Results: Between the two groups, there were significant differences in the presence of significant stenosis (SS: ≥ 70% stenosis of coronary artery) (55.7% vs. 39.4%, P =0.038), triple-vessel disease (TVD)/left main trunk (LMT) (SS in each of three epicardial vessels and/or LMT) (24.3% vs. 7.5%, P = 0.0025), and high-risk plaque (HRP: positive remodeling and/or low attenuation) (55.7% vs. 24.5%, P ＜0.0001). CAS/CEA was independently associated with TVD/LMT (OR = 2.30, 95%CI: 1.14 – 8.59, P = 0.026) and HRP (OR = 3.17, 95%CI: 1.57 – 6.54, P = 0.0012) in multivariable logistic regression analysis. Similarly, vulnerable plaque (78.6% vs. 2.1%, P ＜0.0001) as well as severe stenosis of carotid artery (98.6% vs. 0%, P ＜0.0001) was seen more often in CAS/CEA than in non-CAS/CEA group. Conclusions: The prevalence of TVD/LMT and HRP determined by coronary CTA is higher in patients needing CAS/CEA than in those without. Management of systemic atherosclerosis is required in the perioperative period of CAS/CEA.

Background: The association between patients with acute myocardial infarction (AMI) who present during off-hours and clinical outcomes has not been fully elucidated. Methods: We investigated 3283 consecutive patients with AMI who were selected from a prospective, nationwide, multicenter registry (J-MINUET) database comprising 28 institutions in Japan between July 2012 and March 2014 to determine the current impact of off-hours presentation on in-hospital mortality among Japanese patients with AMI. Results: Among the patients, 52% presented in off-hours. Baseline characteristics were comparable, although those who presented during off-hours were younger and had a higher incidence of ST-elevation myocardial infarction and advanced Killip Class. The time from symptom onset to presentation time was shorter in off-hour patients (120 min, interquartile range 60 to 256 vs. 215 min, interquartile range 90 to 610, p &lt; 0.0001). In contrast, 85% of patients underwent primary percutaneous coronary intervention (PCI) and door to balloon time was comparable between the groups (74 min, interquartile range 52 to 113 vs. 75 min, interquartile range 52 to 126, p = 0.34). The rates of in-hospital mortality were comparable (6.2% vs 6.8%, p = 0.39). Multivariate logistic regression analysis revealed that off-hours presentation was not significantly associated with in-hospital mortality [odds ratio (OR) 0.94; 95% CI, 0.68-1.30, p = 0.70]. Conclusion: The clinical impact of presenting during off-hours or regular hours on AMI patients in Japan is comparable in contemporary practice. (C) 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Background: A modestly elevated circulating D-dimer level may be relevant to coronary artery disease (CAD), but its prognostic value, both independently and in combination with estimated glomerular filtration rate (eGFR), for long-term death has not been fully evaluated in stable CAD patients. Methods and Results: Baseline plasma D-dimer levels and eGFR were measured in 1,341 outpatients (mean age: 65 years) with prior myocardial infarction (MI), coronary revascularization, and/or angiographic evidence of a significant stenosis (&gt; 50%) for at least one of the major coronary arteries. Among these patients, 43% had prior MI, 47% had prior coronary revascularization, 41% had multivessel CAD, 14% had paroxysmal or persistent atrial fibrillation, 32% had diabetes, and 32% had chronic kidney disease (eGFR &lt; 60 mL/min/1.73 m2). D-dimer levels weakly correlated with eGFR (r=-0.25; P&lt; 0.0001). During a mean follow-up period of 73 months, there were 124 deaths, including 61 cardiovascular deaths. Multivariate Cox regression analysis identified D-dimer levels (P=0.001) and eGFR (P=0.006) as independent predictors of all-cause death. Adding both D-dimer and eGFR to a baseline model with established risk factors improved the net reclassification (P&lt; 0.005) and integrated discrimination improvement (P&lt; 0.05) greater than that of any single biomarker or baseline model alone. Conclusions: The combinatorial value of assessing D-dimer levels and eGFR may provide useful insight regarding stable CAD patients' long-term risk stratification.

BACKGROUND We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. METHODS In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months. RESULTS The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P&lt; 0.001; z = -4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P&lt; 0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P = 0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban- alone group. CONCLUSIONS Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events.

Background: According to troponin-based criteria of myocardial infarction (MI), patients without elevation of creatine kinase (CK), formerly classified as unstable angina (UA), are now diagnosed as non-ST-elevation MI (NSTEMI), but little is known about their outcomes. Methods and Results: Between July 2012 and March 2014, 3,283 consecutive patients with MI were enrolled. Clinical follow-up data were obtained up to 3 years. The primary endpoint was a composite of all-cause death, non-fatal MI, non-fatal stroke, cardiac failure and urgent revascularization for UA. There were 2,262 patients with ST-elevation MI (STEMI), 563 NSTEMI with CK elevation (NSTEMI+ CK) and 458 NSTEMI without CK elevation (NSTEMI-CK). From day 0, Kaplan-Meier curves for the primary endpoint began to diverge in favor of NSTEMI-CK for up to 30 days. The 30-day event rate was significantly lower in patients with NSTEMI-CK (3.3%) than in STEMI (8.6%, P&lt;0.001) and NSTEMI+ CK (9.9%, P&lt;0.001). Later, the event curves diverged in favor of STEMI. The event rate from 31 days to 3 years was significantly lower in patients with STEMI (19.8%) than in NSTEMI+ CK (33.6%, P&lt;0.001) and NSTEMI-CK (34.2%, P&lt;0.001). Kaplan-Meier curves from 31 days to 3 years were almost identical between NSTEMI+ CK and NSTEMI-CK (P=0.91). Conclusions: Despite smaller infarct size and better short-term outcomes, long-term outcomes of NSTEMI-CK after convalescence were as poor as those for NSTEMI+CK and worse than for STEMI.

Characterization of endothelial shear stress (ESS) may allow for prediction of the progression of atherosclerosis. The aim of this investigation was to develop a non-invasive approach for in vivo assessment of ESS by coronary computed tomography angiography (CTA) and to compare it with ESS derived from invasive coronary angiography (ICA). A total of 41 patients with mild or intermediate coronary stenoses who underwent both CTA and ICA were included in the analysis. Two geometrical models of the interrogated vessels were reconstructed separately from CTA and ICA images. Subsequently, computational fluid dynamics were applied to calculate the ESS, from which ESSCTA and ESSICA were derived, respectively. Comparisons between ESSCTA and ESSICA were performed on 163 segments of 57 vessels in the CTA and ICA models. ESSCTA and ESSICA were similar: mean ESS: 4.97 (4.37-5.57) Pascal versus 4.86 (4.27-5.44) Pascal, p = 0.58; minimal ESS: 0.86 (0.67-1.05) Pascal versus 0.79 (0.63-0.95) Pascal, p = 0.37; and maximal ESS: 14.50 (12.62-16.38) Pascal versus 13.76 (11.44-16.08) Pascal, p = 0.44. Good correlations between the ESSCTA and the ESSICA were observed for the mean (r = 0.75, p &lt; 0.001), minimal (r = 0.61, p &lt; 0.001), and maximal (r = 0.62, p &lt; 0.001) ESS values. In conclusion, geometrical reconstruction by CTA yields similar results to ICA in terms of segment-based ESS calculation in patients with low and intermediate stenoses. Thus, it has the potential of allowing combined local hemodynamic and plaque morphologic information for risk stratification in patients with coronary artery disease.

Background: Limited data exist regarding the association between symptom presentation of acute myocardial infarction (AMI) and in-hospital outcomes. Methods: We analyzed data of the Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET). This was a prospective and multicenter registry consisting of 3085 AMI patients with available data of symptoms, who were hospitalized within 48 h from onset during July 2012 to March 2014. We defined typical symptoms as any of chest pain or pressure due to myocardial ischemia. Results: Of this study population, 642 patients (20.8%) had atypical symptoms (atypical group) and the remaining 2443 patients (79.2%) showed typical symptoms (typical group). Compared to the typical group, the atypical group was associated with higher age, more females, hypertension, diabetes, chronic kidney disease, history of cardiovascular disease, non-ST elevation MI, and Killip class &gt;2. In the atypical group, urgent percutaneous coronary intervention was less frequently performed than in the typical group, and in STEMI patients door-to-balloon time was longer in the atypical than typical group. Atypical group had larger infarct size than typical group. Furthermore, in-hospital mortality was significantly higher in atypical than in typical group (19.5% vs. 3.3%, p &lt; 0.001). In multivariable analysis, presence of atypical symptoms was an independent predictor of in-hospital mortality (odds ratio 3.12, 95% confidence interval 2.19 to 4.47, p &lt; 0.001). Moreover, the association between atypical symptoms and mortality was consistent across each subgroup. Conclusions: Atypical symptoms of AMI were associated with less invasive therapy and poor outcome. Attention should be directed to these high-risk patients. (C) 2016 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.

Additional risk stratification may provide more aggressive and focalized preventive treatment to high-risk hypertensive patients according to the Japanese hypertension guidelines. We prospectively investigated the predictive value of high-sensitivity troponin I (hsTnI), both independently and in combination with N-terminal pro-B-type natriuretic peptide (NT-proBNP), for incident heart failure (HF) in high-risk hypertensive patients with preserved left ventricular ejection fraction (LVEF). Baseline hsTnI and NT-proBNP levels and echocardiography data were obtained for 493 Japanese hypertensive outpatients (mean age, 68.5 years) with LVEF ae&lt;yen&gt; 50%, no symptomatic HF, and at least one of the following comorbidities: stage 3-4 chronic kidney disease, diabetes mellitus, and stable coronary artery disease. During a mean follow-up period of 86.1 months, 44 HF admissions occurred, including 31 for HF with preserved ejection fraction (HFpEF) and 13 for HF with reduced ejection fraction (HFrEF; LVEF &lt; 50%). Both hsTnI (p &lt; 0.01) and NT-proBNP (p &lt; 0.005) levels were significant independent predictors of HF admission. Furthermore, when the patients were stratified into 4 groups according to increased hsTnI (ae&lt;yen&gt;highest tertile value of 10.6 pg/ml) and/or increased NT-proBNP (ae&lt;yen&gt;highest tertile value of 239.7 pg/ml), the adjusted relative risks for patients with increased levels of both biomarkers versus neither biomarker were 13.5 for HF admission (p &lt; 0.0001), 9.45 for HFpEF (p = 0.0009), and 23.2 for HFrEF (p = 0.003). Finally, the combined use of hsTnI and NT-proBNP enhanced the C-index (p &lt; 0.05), net reclassification improvement (p = 0.0001), and integrated discrimination improvement (p &lt; 0.05) to a greater extent than that of any single biomarker. The combination of hsTnI and NT-proBNP, which are individually independently predictive of HF admission, could improve predictions of incident HF in high-risk hypertensive patients but could not predict future HF phenotypes.

OBJECTIVES The NIPPON (Nobori Dual Antiplatelet Therapy as Appropriate Duration) study was a multicenter randomized investigation of the noninferiority of short-term versus long-term dual antiplatelet therapy (DAPT) in patients with implantation of the Nobori drug-eluting stent (DES) (Terumo, Tokyo, Japan), which has a biodegradable abluminal coating. BACKGROUND The optimum duration of DAPT for patients with a biodegradable polymer-coated DES is unclear. METHODS The subjects were 3,773 patients with stable or acute coronary syndromes undergoing Nobori stent implantation. They were randomized 1: 1 to receive DAPT for 6 or 18 months. The primary endpoint was net adverse clinical and cerebrovascular events (NACCE) (all-cause mortality, myocardial infarction, stroke, and major bleeding) from 6 to 18 months after stenting. Intention-to-treat analysis was performed in 3,307 patients who were followed for at least 6 months. RESULTS NACCE occurred in 34 patients (2.1%) receiving short-term DAPT and 24 patients (1.5%) receiving long-term DAPT (difference 0.6%, 95% confidence interval [CI]: 1.5 to 0.3). Because the lower limit of the 95% CI was inside the specified margin of -2%, noninferiority of short-term DAPT was confirmed. Mortality was 1.0% with short-term DAPT versus 0.4% with long-term DAPT, whereas myocardial infarction was 0.2% versus 0.1%, and major bleeding was 0.7% versus 0.7%, respectively. The estimated probability of NACCE was lower in the long-term DAPT group (hazard ratio: 1.44, 95% CI: 0.86 to 2.43). CONCLUSIONS Six months of DAPT was not inferior to 18 months of DAPT following implantation of a DES with a biodegradable abluminal coating. However, this result needs to be interpreted with caution given the open-label design and wide noninferiority margin of the present study. (Nobori Dual Antiplatelet Therapy as Appropriate Duration [NIPPON]; NCT01514227) (C) 2017 Published by Elsevier on behalf of the American College of Cardiology Foundation.

Background: Acute kidney injury (AKI) is associated with poor outcome after acute myocardial infarction (AMI), but whether hernodynamic status at presentation influences this prognostic significance is unknown. Methods and Results: A total of 2,798 AMI patients admitted within 48 h after symptom onset and who underwent urgent coronary angiography were enrolled in the present study. AKI was defined as an increase in serum creatinine &gt; 0.3mg/dL or &gt;= 50 /c, within 48 h during hospitalization. Patients were classified into 3 groups according to Killip class on admission: Killip 1. n=2,164; Killip 2-3, n=366; and Killip 4, n=268. AKI occurred more frequently with increasing Killip class (Killip 1, 2-3, and 4: 6.3%, 15.3%, and 31.3%, respectively; P&lt;0.001). AKI was associated with increased in-hospital mortality, regardless of Killip class (non-AKI and AKI patients: 1.1% vs. 6.6% in Killip 1; 5.2% vs. 35.7% in Killip 2-3, and 28.8% vs. 45.2% in Killip 4, P&lt;0.01 for all). On multivariate analysis, the adjusted OR of AKI for in-hospital mortality in Killip 1, Killip 2-3, and Killip 4 were 3.79 (95% Cl: 1.54-9.33, P=0.004), 5.35 (95% Cl: 2.67-10.7, P&lt;0.001), and 1.48 (95% CI: 0.94-2.35, P=0.093), respectively. Conclusions: In AMI patients undergoing urgent coronary angiography, AKI was significantly associated with increased in-hospital mortality in Killip 1 as well as Killip 2-3 at presentation, but not in Killip 4.

Whether trough-phase rivaroxaban concentrations provide sufficient anticoagulation needs more study. We evaluated levels of coagulation activation markers in the trough concentration phase in nonvalvular atrial fibrillation (NVAF) patients, and the correlation between these markers and rivaroxaban concentration. Fifty-five Japanese NVAF patients received 24-week rivaroxaban treatment of either 15 or 10 mg once-daily in the morning. Of these, 26 patients had no history of anticoagulant therapy (naive group) and 29 had switched from warfarin (warfarin group). D-dimer and prothrombin fragment 1 + 2 (F1 + 2) levels, and protein C activities were measured at 0 (baseline), 12 and 24 weeks of rivaroxaban treatment just before the patient's regular dosing time (trough phase). For 49 patients, D-dimer, F1 + 2, and rivaroxaban concentrations were also measured twice between 28 and 32 weeks of rivaroxaban treatment at non-trough times to achieve a range of drug concentrations for correlation analysis. For the naive group, D-dimer and F1 + 2 levels were significantly reduced (p &lt; 0.01) from baseline at 12 and 24 weeks. For the warfarin group, these values were unchanged for D-dimer but significantly increased (p &lt; 0.01) for F1 + 2. Protein C activity was unchanged in the naive group and was increased (p &lt; 0.01) in the warfarin group. Prothrombin time (r = 0.92, p &lt; 0.0001) and activated partial thromboplastin time (r = 0.54, p &lt; 0.0001) correlated with rivaroxaban concentration, but not D-dimer and F1 + 2 levels. In conclusion, rivaroxaban in the trough phase is comparable to warfarin in reducing D-dimer levels. Although trough level rivaroxaban suppresses F1 + 2 less than warfarin, the higher activities of protein C with rivaroxaban treatment compared to warfarin treatment may counterbalance this. Lack of correlation between rivaroxaban concentration and D-dimer and F1 + 2 levels suggests that trough concentrations of rivaroxaban reduce their concentrations as effectively as higher levels do.

OBJECTIVES The aim of this study was to assess the volume-outcome relationship for sPCI within the nationwide registration system in Japan. BACKGROUND The effect of site and operator case load for percutaneous coronary intervention (PCI) on outcomes has not been investigated thoroughly in non-Western regions. METHODS In the present study, PCI procedural data recorded between January 2014 and December 2015 in the Japanese PCI registry, a nationwide registration system, were analyzed. Institutions and operators were categorized into deciles based on the number of PCIs performed per year. Odds ratios (ORs) for in-hospital mortality and the composite endpoint (in-hospital death and periprocedural complications) were estimated for each decile (with the lowest volume group as a reference group). RESULTS A total of 323,322 PCIs (at 625 hospitals [median PCI cases/year: 216; quartiles: 121 to 332] by 4,211 operators [median PCI cases/year: 28; quartiles: 10 to 56]) were analyzed, of which 2,959 patients (0.9%) and 7,205 patients (2.2%) experienced in-hospital mortality and the composite endpoint after PCI, respectively. The adjusted risk for in-hospital mortality and the composite endpoint was significantly higher in hospitals included in the lowest decile (&lt;150 PCIs/year); the risk remained consistently low across the remaining deciles. Contrastingly, no significant volume-outcome relationship was observed between operator volume and outcomes. A similar trend was observed when the analysis was confined to emergency/urgent PCI cases. CONCLUSIONS In contemporary Japanese PCI practice, lower institutional volume was related inversely to in-hospital outcomes, but the association of annual operator volume with outcomes was less clear. (C) 2017 by the American College of Cardiology Foundation.

Background: Takotsubo cardiomyopathy (TC) is a myopathy triggered by severe stressful events. However, little is known about the determinants of in-hospital outcomes. We prospectively determined the effect of different triggers on the prognosis of TC. Methods and results: We enrolled patients who were admitted for suspected acute coronary syndrome (ACS) from January 2008 to December 2015. TC was diagnosed according to the Mayo Clinic diagnosis criteria. The outcome was in-hospital death. Among 1861 consecutive patients with suspected ACS, 82 (4.4%) patients were diagnosed with TC. There were 43 patients (52%) with physical triggers (Physical), 26 (31%) with emotional triggers, and 13 (17%) with no identifiable triggers. The latter two groups were combined and categorized as the Non-physical trigger group. Compared with non-physical triggered TC, patients with physical triggered TC were more likely to have a malignancy (p - 0.008), lower blood pressure (p - 0.001), lower hemoglobin (p &lt; 0.001), higher serum creatinine (p &lt; 0.001) and higher norepinephrine levels (p = 0.007). During a mean hospital stay of 16 +/- 12 days, 9 (20.9%) of the Physical and 1 (2.6%) of the Non-physical patients died in-hospital (log-rank p = 0.007). After adjusting for the age, gender, trigger, malignancy, and hemoglobin level, being male (hazard ratio 11.9, 95% confidence interval, 2.43-58.5, p = 0.002) and having a physical trigger (14.7, 1.19-166, p = 0.03) were associated with in-hospital mortality. Conclusion: There was a significant difference in in-hospital mortality depending on the trigger type in TC. Being male and having a physical trigger were independent risk factors of in-hospital mortality from TC. (C) 2017 Elsevier B.V. All rights reserved.

Although the renin-angiotensin system (RAS) is counter-balanced by a salt-sensitive mechanism in the hypertensive state, both are reported to be up-regulated in chronic kidney disease (CKD) patients. We conducted this study to evaluate the associations among the RAS, renal function, hypertension, and atherosclerosis, as well as to identify markers for salt-sensitivity. A total of 213 pre-dialysis CKD patients with preserved cardiac function (EF &gt; 50 %) were enrolled. Their renal and cardiac biochemical markers and plasma renin activity (PRA) were measured, and echocardiography and carotid artery ultrasound were performed. Their salt intake was estimated by the NaCl excretion from a 24-h collected urine sample. The PRA was higher in patients with hypertension (p = 0.018), and had a significant negative correlation with the eGFR (r = -0.23, p = 0.0067). Importantly, the PRA had a strong negative correlation with the brain natriuretic peptide (BNP) level (r = -0.28, p = 0.017) regardless of whether the patients were being treated with RAS inhibitors. The BNP level was related to the renal functions (eGFR: p = 0.001, ACR: p = 0.009). There was a significant positive correlation between the BNP level and carotid intima-media thickness (p &lt; 0.001). A multivariate analysis revealed that older age and an excess of NaCl excretion were independent predictors of BNP elevation (p = 0.02 and 0.003, respectively). Our analysis revealed details of the counterbalance between BNP and PRA, as well as identifying that excess salt intake is a predictor of BNP elevation. These results indicate that the BNP could be a possible valuable marker for salt sensitivity, and that high salt sensitivity could facilitate atherosclerosis in CKD patients.

Background: Sleep-disordered breathing, particularly central sleep apnea (CSA), is highly prevalent in heart failure (HF) and an independent prognostic marker. We assessed the hypothesis that an increased hypoxemic burden during sleep may have greater prognostic value than the frequency of apneic and hypopneic episodes. Methods and Results: We prospectively conducted overnight cardiorespiratory polygraphy on consecutive HF patients referred to our hospital from 2008 to 2011. We studied CSA defined by an apnea-hypopnea index (AHI) of &gt;= 5 events/h with &gt;75% of all events being central in origin. We determined the AHI, proportion of the sleep time with SpO(2) &lt;90% (T90%), and proportion of the recording time that 4% desaturation events occurred (4%POD). We studied 112 HF patients with either systolic or diastolic dysfunction. During a follow-up period of 37 +/- 25 months, 32 patients (29%) died. Nonsurvivors had a higher 4%POD compared with survivors (11 +/- 6.4% vs 19 +/- 13%; P=.001), but did not differ significantly from survivors regarding AHI and T90%. An adjusted logistic regression analysis revealed that the 4%POD was the best independent predictor of mortality. Conclusions: The 4%POD, a novel metric for the nocturnal hypoxemic burden, is an independent prognostic marker in HF patients affected by CSA.