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Background The spleen is an important organ that stores blood, releases erythrocytes or monocytes, and destroys no-longer-needed platelets. It can reserve 20–30% of the total blood volume, and its size is reduced in hypovolemic shock. However, the clinical significance of the spleen size in patients with heart failure (HF) remains unclear. Purpose The purpose of this study was to investigate the relationship between spleen size, hemodynamic parameters, and prognosis in patients with HF. Methods A total of 219 patients with clinically stable HF were enrolled. All patients underwent right heart catheterisation and computed tomography. The spleen size was measured using computed tomography volumetry. In addition, spleen volume was assessed using the spleen volume index (SVI), corrected for body surface area. Cardiac events were composite endpoints of cardiac death, hospitalisation for worsening HF, fatal arrhythmias, implantation of cardiac devices, implantation of left ventricular assist devices, and unexpected percutaneous coronary intervention or cardiac surgery. Spearman's rank correlation coefficient was used to examine the relationship between spleen volume and hemodynamic parameters. Multivariate Cox hazard regression models were used to investigate whether SVI was an independent determinant of cardiac events. Results Of the 219 patients (median age, 54 [interquartile range] 46–64 years), 145 (66%) were males. The median (interquartile range) spleen volume and SVI was 118.0 (91.5–156.0) mL and 67.8 (54.9–87.2) mL/m2, respectively. SVI was positively correlated with cardiac output (r=0.269, P Conclusion The spleen size may affect the prognosis in patients with HF, reflecting haemodynamics, including systemic circulating blood volume status and sympathetic nerve activity. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Background Left ventricular reverse remodeling (LVRR) is an important predictor for a good prognosis in patients with dilated cardiomyopathy (DCM). Previous reports indicated the pulmonary artery diameter (PAD) to ascending aortic diameter (AoD) ratio as a predictor of adverse outcomes in heart failure patients. However, the impact of the PAD/AoD ratio for predicting LVRR in patients with DCM is unknown. Aim The aim of this study is to investigate the association between PAD/AoD ratio and LVRR in patients with DCM. Methods From a prospective study, clinically stable DCM patients who were investigated the LVRR on echocardiography and underwent CT at baseline were enrolled. LVRR is defined as left ventricular (LV) ejection fraction increase of 10% and a decrease in indexed LV end-diastolic diameter of 10% compared to those at baseline. PAD and AoD data was collected with nonenhanced computed tomography images at baseline. Results In sixty-nine patients (mean age 50.0±13.3 years), the mean LV ejection fraction was 29.8%, and mean LV end-diastolic dimension was 64.5mm, and both of which data was no significant difference between patients with or without LVRR. LVRR was observed in 23 (33.3%) patients. The PAD/AoD ratio was significantly lower in patients with LVRR than without LVRR (81.4% vs. 92.4%, p=0.003). By ROC analysis, the best cut-off for the detection of LVRR was found for a PAD/AoD ratio of 0.9. From multivariate analyses, PAD/AoD ratio was identified as a significant predictor of LVRR. After a median follow-up duration of 2.5 years, the DCM patients with PAD/AoD≥0.9 revealed a significant higher cardiac event than those with PAD/AoD Conclusions The PAD/AoD ratio is useful for predicting LVRR in patients with DCM. The DCM patients with high PAD/AoD ratio had a poor long-term outcome. Funding Acknowledgement Type of funding sources: None. ROC curve for LVRR predictionKaplan-Meier survival curves

Background Autotaxin (ATX) has been reported to promote myocardial inflammation and subsequent cardiac remodeling through lysophosphatidic acid (LPA) production. However, the prognostic impact of ATX has not been clarified in dilated cardiomyopathy (DCM). Purpose We aimed to investigate the prognostic impact of ATX in patients with DCM. Methods We enrolled 104 DCM patients (49.8 years, 76 males). The subjects underwent blood sampling, echocardiography, cardiac catheterization, and endomyocardial biopsy. Gender differences in serum ATX levels have been reported, thus we divided the subjects into two groups using median serum ATX levels for men and women: High-ATX group and Low-ATX group. All patients were followed up by expert cardiologists. The cardiac event was defined as a composite of cardiac death and hospitalization for worsening heart failure. Results Eighty-nine percent of the subjects were classified as New York Heart Association functional class I or II. Female patients had higher serum ATX levels than male patients, with median values of 257.0 ng/mL and 203.5 ng/mL, respectively (Figure A). The average left ventricular ejection fraction and brain natriuretic peptide levels were 30.6% and 122.5 pg/mL. In survival analysis, cumulative event-free probability was significantly lower in High ATX group (p=0.007, Figure B). In Cox proportional hazards analysis, High-ATX was one of the independent predictors of composite cardiac events (Hazards Ratio, 2.575; p=0.043). On the other hand, high sensitive C-reactive protein and collagen volume fraction in myocardial samples were not significant predictors. Conclusion High serum ATX level was associated with poor prognosis in patients with DCM. Funding Acknowledgement Type of funding sources: None. Gender difference in autotaxin levelsSurvival analysis of cardiac events

The utility of abdominal aortic calcification (AAC) for prediction of cardiovascular events (CVEs) in patients with acute coronary syndrome (ACS) remains to be determined. The aim of this prospective study was to determine the predictive value of the abdominal aortic calcification index (ACI), a semi-quantitative measure of AAC, for CVEs in patients with ACS. We evaluated 314 patients with ACS. All patients underwent successful percutaneous coronary intervention to the culprit coronary vessel without in-hospital adverse events. ACI was calculated on non-contrast computed tomography images. CVEs were defined as a composite of cardiovascular death, ACS recurrence, and stroke. During a median follow-up period of 19.1 months, CVEs occurred in 29 patients (9.2%). Multivariable regression analysis after adjustment for age and gender showed a significantly higher baseline ACI in patients with CVEs than in those without [median (interquartile ranges), 42.1 (25.9–60.2) vs. 20.8 (8.8–38.6) %; P = 0.021]. The cutoff value of ACI for prediction of CVEs, estimated by receiver-operating characteristic analysis, was 29.2%, with sensitivity of 76% and specificity of 64% (area under the curve, 0.69). After adjustment for conventional cardiovascular risk factors, Cox analysis showed high ACI (≥29.2%) to be significantly associated with increased risk of CVEs (P = 0.011; hazard ratio, 1.82). Multivariate analysis identified high ACI as an independent predictor of CVEs (P = 0.012; hazard ratio, 1.80). Stepwise forward selection procedure also showed that high ACI was a significant independent determinant of CVEs (P = 0.004; R2, 0.089). Both net reclassification improvement (0.64; P = 0.001) and integrated discrimination improvement (0.04; P

Background and purpose Fluorine-18-flurodeoxyglucose positron emission tomography (18FDG-PET) is a useful examination assessing active inflammatory myocardium noninvasively in patients with cardiac sarcoidosis (CS). Though immunosuppression like prednisolone (PSL) and Methotrexate (MTX) as alternative therapy is used to suppress the inflammation, little is known about the rate of response and efficacy of MTX for intolerance to PSL therapy. Methods From Aug 2016, we prospectively enrolled CS with positively accumulated of FDG in the heart. The initial dose of PSL was 30mg/day, wherefrom the dose was tapered down 5mg/month until 6 months. After 6 months, follow-up 18FDG-PET was performed. Using 18FDG-PET images, we calculated total lesion glycolysis (TLG; SUVmeam x metabolic volume) and calculated the reduction rate of TLG. In order to estimate the response rate to PSL therapy, responder group (R-group) was defined as TLG reduction rate ≥70% and poor-responder group (PR-group) was defined as TLG reduction rate Results In 64 CS patients, 55 patients had serial 18FDG-PET before and 6 months after PSL therapy. 18FDG-PET images were acquired following 7 day's carbohydrate limitation and after at least 18-h fasting (mean free fatty acid level right before 18FDG-PET acquisition was 1.05 mEq/L). The mean age was 63.4 years old and 42 (76.4%) patients were female. Because of 6 months PSL therapy, even though there were no significant difference in BNP (from 59.9 (26.2–137.6) to 60.4 (18.5–122.0) (P=0.593), LV-Dd (from 50.9 (44.5–59.5) to 49.7 (45.5–61.3) (P=0.666) and LV-EF (from 49.5 (34.4–62.5) to 49.9 (38.0–62.0) (P=0.792) at pre and post therapy, respectively, TLG were detected significant reduction from 216.4 (74.2–411.6) to 0.8 (0.0–8.2), (p Conclusions 1) By immunosuppression therapy using PSL for CS, about 86% patients showed significant reduction of myocardial FDG accumulation. 2) When detected intolerance for PSL therapy, MTX might be effective for reduction of inflammation of sarcoidosis in the heart, which might be effective as an alternate therapy in CS. The TLG level after randomization Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Grant-in-aid for scientific research

Background The spleen has been recognized as an important organ with several functions such as a reservoir of blood volume, and an involvement in iron metabolism by processing of aged red blood cells and recycling iron. During exercise, spleen contracts, and red blood cells pooled in the spleen are recruited into the systemic circulation. So far, we reported that spleen size changed in advanced heart failure (HF) with left ventricular assist device (LVAD). In addition, spleen volume was related to pulmonary capillary wedge pressure (PCWP) or right atrial pressure (RAP) as parameters of cardiac preload. However, it remains unclear about the relationship between spleen volume and exercise capacity in advanced HF with LVAD. Purpose The purpose of this study was to investigate the associations between spleen volume and exercise capacity in advanced HF patients with LVAD. Methods We enrolled 27 HF patients (21 males, 45±12 years) with LVAD (HeartMate II™; Abbott, Chicago, IL, USA) for use as a bridge to heart transplantation. All patients underwent blood test, echocardiography, right heart catheterization, computed tomography (CT) and cardiopulmonary exercise testing (CPET). Spleen size was measured by CT volumetry. We excluded patients with splenic infarction or aortic valve closure surgery. Results At baseline, body mass index, blood brain natriuretic peptide levels, hemoglobin levels, left ventricular ejection fraction were 21.4±3.1 kg/m2, 73.8 (51.9–165.8) pg/mL, 12.1 (10.6–13.4) g/dL, 24.8±14.7%, respectively. Total cardiac output (CO), the sum of pump flow and CO of native heart was 4.6±0.9 L/min, and spleen volume was 184.9±48.8 mL. As for parameters of CPET, peak heart rate (HR), peak VO2, and peak O2 pulse were 128±25 beats/min, 14.2±3.3 mL/kg/min, and 6.6±1.9 mL/beat. At rest, there were significant correlations between spleen volume and PCWP (r=0.382, p=0.049), RAP (r=0.406, p=0.035) or pulsatility index (r=0.384, p=0.047), despite no correlations with total CO or pump flow. During exercise, there were significant interrelations of spleen volume with peak VO2 (r=0.451, p=0.018) and peak O2 pulse (r=0.427, p=0.026). Furthermore, peak VO2 was interrelated with peak HR (r=0.481, p=0.011) or hemoglobin levels (r=0.649, p Conclusion Spleen volume could be a useful predictor of exercise capacity in advanced HF patients with LVAD, reflecting splenic function to modulate cardiac preload and blood hemoglobin levels. Spleen volume and exercise parameters Funding Acknowledgement Type of funding source: None

Background Dilated cardiomyopathy (DCM) is characterized by a reduction in left and/or right ventricular myocardial contraction, dilatation of biventricular cavity and major cause of heart failure with high morbidity and mortality rates. Right ventricular dysfunction (RVD) recently have been received attention because of 34% of DCM had RVD and considered as a powerful predictor of impaired prognosis in DCM. Pulmonary Artery Pulsatility index (PAPi) is a novel hemodynamic index shown to predict RVD in advanced heart failure, however, it is unknown that even at early phase, PAPi can reflects latent right myocardial damage and predict long-term prognosis in stable DCM patients. Methods From April 2000 to March 2018, we enrolled 566 consecutive patients with cardiomyopathy. All patients underwent laboratory measurement, echocardiography, and cardiac catheterization to evaluate their general conditions. After excluded secondary cardiomyopathy, ischemic cardiomyopathy, and valvular heart disease, finally 162 DCM patients were enrolled. All enrolled patients had NYHA I/II/III and NYHA I/II were 150 patients (92.6%). PAPi was calculated as (systolic pulmonary artery pressure – diastolic pulmonary artery pressure (Pulmonary artery pulse pressure: PAPP)) / right atrial pressure. Median followed up for 4.85 years. In this study 149 patients were performed endomyocardial biopsy in order to exclude secondary cardiomyopathies and 95 patients were assessed using Sirius red staining. Myocardial fibrosis in biopsy specimen was assessed using Sirius red staining, and the positive region was quantified as the collagen volume fraction (CVF). Results The mean age and LV ejection fraction (EF) was 50.9±12.6 years and 30.5±8.3%, respectively. When divided into two groups by median PAPi value [PAPi Conclusion In the calculation of PAPi, PAPP reflects both RV contractility and left atrial filling pressure and this index considered as RV adaptive response to afterload. The denominator of the PAPP is defined by RA pressure, which serves as a marker of RV preload. Thus, PAPi reflect both preload and afterload of RV at the same time and even though estimated patients at early phase, RVD exists in DCM patients without severe myocardial fibrosis, and PAPi may help stratify DCM and predict cardiac events. Kaplan-Meier analysis Funding Acknowledgement Type of funding source: None

Background Sepsis is a systemic condition of profoundly impaired health in which an infection leads to a dysregulated host response, and consecutively causes organ dysfunction, shock, and even death. Septic cardiomyopathy (SCM) is one of the multiple organ dysfunctions. SCM is typically defined as left ventricular (LV) dysfunction, presented by decreased LV ejection fraction (LVEF). However, it remains unclear about the detailed mechanism of cardiac dysfunction. In addition, the prognostic impact of right heart dysfunction in SCM patients has not been fully investigated. Purpose The purpose of this study was to investigate the prognostic impact of right heart dysfunction in patients with SCM. Methods We used the MIMIC-III (Medical Information Mart for Intensive Care III) critical care database, which is a large, freely-available database comprising deidentified health-related data associated with over forty thousand patients who stayed in critical care units of the Beth Israel Deaconess Medical Center between 2001 and 2012. We retrospectively analyzed data of patients with septic shock on admission to intensive care unit (ICU). Septic shock was defined as the presence of any suspected infections, the need for vasopressors, and the lactate level exceeding 2 mmol/L, based on the Sepsis-3 criteria. Patients were performed portable transthoracic echocardiography (TTE) during hospitalization. LVEF and right ventricular (RV) function were determined predominately by visual estimation in the parasternal long-axis view. SCM was defined as having a minimum LVEF of 50% or less during hospitalization. Patients with hyperdynamic motion of LVEF >70% were excluded. Results In total, there were 2254 patients with septic shock. Of these, 604 patients who underwent TTE were enrolled, and 314 patients were diagnosed with SCM. At baseline, age, gender, Sequential Organ Failure Assessment (SOFA) score, maximum lactate levels, and maximum norepinephrine dosage were 70 [59–79] years, 194 males, 13 [11–15], 4.0 [2.7–6.2] mmol/L, and 0.20 [0.10–0.31] mcg/kg/min, respectively. All patients were treated with vasopressors. In Kaplan-Meier survival analysis, patients with SCM had increased 28-day mortality compared with those without SCM (log-rank, p=0.09). In addition, we divided SCM patients into two groups; SCM with and without RV dysfunction. SCM patients with RV dysfunction had significant increased 28-day mortality compared with those without RV dysfunction (log-rank, p=0.01) (Figure). In Cox proportional hazard regression analysis adjusted for age, male sex, SOFA score, and maximum lactate levels, RV dysfunction was an independent determinant of 28-day mortality (hazard ratio, 1.59; 95% confidence interval, 1.03–2.46; p=0.03). Conclusions The presence of RV dysfunction increased 28-day mortality in patients with SCM. It might be useful for predicting the prognosis of SCM to evaluate not only left heart function but also right heart function. Kaplan-Meier survival curves Funding Acknowledgement Type of funding source: None

Accumulated evidence shows that some antidiabetic agents attenuate the progression of carotid atherosclerosis assessed as intima-media thickness (IMT). Although some studies have demonstrated an inhibitory effect of dipeptidyl peptidase-4 inhibitors on carotid IMT progression, in the PROLOGUE study sitagliptin failed to slow progression relative to conventional therapy for 24 months. We hypothesized that differences in the concomitant antidiabetic agents between the groups have influenced the progression of carotid IMT. We performed a post hoc analysis of the PROLOGUE study using subgroups stratified by concomitant antidiabetic agents. Although no subgroup with any combination of agents in the overall patients showed a significant difference between sitagliptin group and conventional therapy group in the changes from baseline in mean common carotid artery (CCA)-IMT at 24 months, a significant attenuation of mean CCA-IMT progression was observed in the sitagliptin group relative to conventional therapy group only in three combination subgroups aged

The aim of this study was to evaluate the association of functional mitral regurgitation (FMR), preserved or reduced ejection fraction (EF), and ischemic or nonischemic origin with outcomes in patients discharged alive after hospitalization for acute decompensated heart failure (HF). Of the 4,842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 3,357 patients were evaluated to assess the association of FMR, preserved or reduced EF, and ischemic or nonischemic origin with the primary end point (all-cause death and readmission for HF after discharge). At the time of discharge, FMR was assessed semiquantitatively (classified as none, mild, or moderate to severe) by color Doppler analysis of the regurgitant jet area. According to multivariable analysis, in the ischemic group, either mild or moderate to severe FMR in patients with a preserved EF had a significantly higher risk of the primary end point than patients without FMR (hazard ratio [HR] 1.60; 95% confidence interval [CI] 1.12 to 2.29; p = 0.010 and HR 1.98; 95% CI 1.30 to 3.01; p = 0.001, respectively). In patients with reduced EF with an ischemic origin, only moderate to severe FMR was associated with a significantly higher risk of the primary end point (HR 1.67; 95% CI 1.11 to 2.50; p = 0.014). In the nonischemic group, there was no significant association between FMR and the primary end point in patients with either a preserved or reduced EF. In conclusion, among patients with acute decompensated HF with a preserved or reduced EF, the association of FMR with adverse outcomes may differ between patients who had an ischemic or nonischemic origin of HF.

Background The spleen has been recognized as an important organ to reserve 20–30% of the total blood volume. Generally, splenomegaly has been thought to be related to congestion. However, in the setting of hypovolemic shock or hypoxemia, it has been reported that spleen contracted and splenic volume decreased. On the other hand, in advanced heart failure (HF), the hemodynamics is characterized by both low cardiac output (LO) and systemic congestion, and patients sometimes need support of left ventricular assist device (LVAD). However, it remains unclear about the association between spleen size and hemodynamic parameters in patients with LO who need LVAD support. Purpose The purpose of this study was to investigate the relationship between spleen size and hemodynamic parameters in advanced HF before and after LVAD implantation. Methods We enrolled 12 advanced HF patients with LVAD (11 males, 45±10 years). All patients underwent blood test, echocardiography, right heart catheterization, and computed tomography (CT) before and after LVAD implantation. Spleen size was measured by CT volumetry. We excluded patients with splenic infarction, or any infections, or mean right atrial pressure (RAP) Results At pre- and post-LVAD implantation, cardiac output, cardiac index (CI), mean RAP, and mean pulmonary capillary wedge pressure were 3.1±0.6 vs. 4.9±0.9L/min, p=0.002; 1.7±0.3 vs. 2.8±0.3L/min/m2, p=0.002; 14±5 vs. 9±3mmHg, p=0.059; and 30±7 vs. 10±3mmHg, p=0.002, respectively. The serum brain natriuretic peptide level had significantly decreased (1101 [517–1446] vs 74 [35–216] pg/mL, p=0.002). In all patients, CI had increased to over 2.2L/min/m2. The splenic volume significantly increased from pre- to post-LVAD implantation (172±48 vs. 233±78mL, p=0.002) (Figure). Furthermore, all patients were divided into two groups; elevated RAP group (n=4) and non-elevated RAP group (n=8) after LVAD support. In elevated RAP group, there were no significant changes in the spleen size between pre- and post-LVAD implantation (167±45 vs. 223±111mL, p=0.068). On the other hand, in non-elevated RAP group, the spleen volume had significantly increased from pre- to post-LVAD support (172±53 vs. 231±62mL, p=0.011). In addition, there was one patient whose hemodynamic state had changed to LO again because of LVAD failure due to pump thrombosis. In this case, the splenic volume was 212mL before LVAD implantation with LO, and increased to 418mL after LVAD implantation with non-LO, although decreased to 227mL after LVAD pump failure with LO again. Splenic volume changes Conclusions The spleen may change its size in order to keep cardiac output by regulating cardiac preload depending on the systemic perfusion in advanced HF with LVAD. Acknowledgement/Funding None

Background In patients with hypertensive acute decompensated heart failure (ADHF), intravenous vasodilators are commonly used. However, little is known about optimal use in blood pressure (BP) management to avoid acute kidney injury (AKI). Purpose To investigate the association between systolic BP (SBP) changes in first 6 h and incidence of AKI within 48 h in patients with hypertensive ADHF. Methods Post-hoc analysis was performed on a prospectively enrolled cohort. We investigated 245 patients with ADHF and SBP >140 mmHg on arrival (mean age, 76 years; 40% female). We defined “SBP-fall” as maximum percent reduction in SBP 6h after intravenous treatment. AKI was defined as serum creatinine (SCr) ≥0.3 mg/dL, or urine output Results Mean SBP, SBP-fall and SCr level at arrival were 180 mmHg, 29.4%, and 1.21 mg/dL, respectively. Sixty-six patients experienced AKI. There were no significant differences in age, NYHA functional class, SBP and SCr at admission between AKI and Non-AKI group. AKI group had the greater SBP-fall compared with Non-AKI (36.7%versus 27.2%, p≤0.0001). Logistic regression analyses revealed that SBP-fall had an independent predictor of AKI (Table). In addition, SBP-fall had positive association with the number of concomitant used intravenous vasodilators in first 6 h (Figure). Logistic regression analyses for AKI Univariate Multivariate AUC OR 95% CI P OR 95% CI P Ages, years, per 10 years 1.04 0.82–1.33 0.17 0.75 SBP at arrival, per 10 mmHg 1.01 0.93–1.11 0.77 SBP-fall, per 10% 1.49 1.22–1.81 SBP-fall odds ration for AKI Conclusion In the first 6h of management for hypertensive ADHF patients, aggressive SBP reduction by the combination use of vasodilator agents predicted the incidence of AKI.

Background Given that early-onset type 2 diabetes mellitus (T2DM), metabolic syndrome, and hyperuricemia have been shown to have strong genetic components, statistical power of a genetic association study may be increased by focusing on early-onset subjects with these conditions. Although genome-wide association studies have identified various genes and loci significantly associated with T2DM, metabolic syndrome, and hyperuricemia, genetic variants that contribute to predisposition to these conditions in Japanese individuals remain to be identified definitively. Purpose The purpose of the study was to identify genetic variants that confer susceptibility to early-onset T2DM, metabolic syndrome, or hyperuricemia in Japanese. We have now performed exome-wide association studies (EWASs) for early-onset subjects with T2DM, metabolic syndrome, or hyperuricemia and corresponding controls. Methods A total of 8102 individuals aged ≤65 years was enrolled in the study. The EWAS for T2DM was performed with 7407 subjects (1696 cases, 5711 controls), that for metabolic syndrome with 4215 subjects (2296 cases, 1919 controls), and that for hyperuricemia with 7919 subjects (1365 cases, 6554 controls). Single nucleotide polymorphisms (SNPs) were genotyped with Illumina Human Exome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The relation of allele frequencies for 31,210, 31,521, or 31,142 SNPs that passed quality control to T2DM, metabolic syndrome, or hyperuricemia, respectively, was examined with Fisher's exact test. To compensate for multiple comparisons of genotypes with T2DM, metabolic syndrome, or hyperuricemia, we applied Bonferroni's correction for statistical significance of association. Results The EWAS of allele frequencies revealed that four, six, or nine SNPs were significantly associated with T2DM (P Conclusion Given that OR4F6 was significantly associated with both T2DM and metabolic syndrome, we thus newly identified four genes (ZNF860, OR4F6, OR52E4, HERPUD2) that confer susceptibility to early-onset T2DM, metabolic syndrome, or hyperuricemia. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for T2DM, metabolic syndrome, or hyperuricemia in Japanese.

Background and purpose Fluorine-18-flurodeoxyglucose positron emission computed tomography (18FDG-PET CT) is the sole but time-consuming and expensive examination assessing active inflammatory myocardium noninvasively in patients with cardiac sarcoidosis (CS). Though immunosuppression is used to treat CS, little is known about the cardiac biomarkers for determining therapeutic effect to immunosuppression therapy other than 18FDG-PET. Methods From Aug 2016, we prospectively enrolled 50 sarcoidosis patients with positively accumulated of FDG in the heart. The initial dose of prednisolone was 30mg/day, wherefrom the dose was tapered down 5mg/month until 6 months. After 6 months, follow-up 18FDG-PET was performed. Using 18FDG-PET images, we calculated total lesion glycolysis (TLG; SUVmeam x metabolic volume) and compared it to various cardiac markers. Non-responder was defined as TLG reduction rate Results In 50 CS patients, 41 patients had serial 18FDG-PET before and 6 months after immunosuppression therapy. 18FDG-PET images were acquired following 7 day's carbohydrate limitation and after at least 18-h fasting (mean free fatty acid level right before 18FDG-PET acquisition was 1.03 mEq/L). The mean age and plasma brain natriuretic peptide (BNP) level were 61.9 years old, 184 pg/mL at baseline, respectively. Because of immunosuppression therapy, TLG was significantly reduced from 195.3 (38.6–339.6) to 1.1 (0.01–7.37), p Figure 1 Conclusions 1) By immunosuppression therapy using prednisolone for CS, about 85% patients showed significant reduction of increased myocardial FDG accumulation. 2) The sustained high level of serum TnT at post 6 months therapy indicates persistent inflammation of sarcoidosis in the heart, which could be an expedient marker for determining therapeutic effect.

Background Given that substantial genetic components have been shown in ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), a heritability may be higher in early-onset than late-onset individuals with these conditions. Although genome-wide association studies have identified various genes and loci significantly associated with ischemic stroke, ICH, or intracranial aneurysm mainly in European ancestry populations, genetic variants that contribute to susceptibility to these disorders in Japanese individuals remain to be identified definitively. Purpose The purpose of the study was to identify genetic variants that confer susceptibility to ischemic stroke, ICH, or SAH in Japanese. We have now performed exome-wide association studies (EWASs) in early-onset subjects with these conditions and corresponding controls. Methods A total of 6649 individuals aged ≤65 years were examined. For the EWAS of ischemic or hemorrhagic stroke, 6224 individuals (450 subjects with ischemic stroke, 5774 controls) or 6179 individuals (261 subjects with ICH, 176 subjects with SAH, 5742 controls), respectively, were examined. EWASs were performed with the use of Illumina Human Exome-12 v1.2 DNA Analysis BeadChip or Infinium Exome-24 v1.0 BeadChip. To compensate for multiple comparisons of allele frequencies with ischemic stroke, ICH, or SAH, we applied a false discovery rate (FDR) of Results The relation of allele frequencies of 31,245 single nucleotide polymorphisms (SNPs) that passed quality control to ischemic stroke was examined with Fisher's exact test, and 31 SNPs were significantly (FDR Conclusion We have thus newly identified nine genes that confer susceptibility to early-onset ischemic stroke, ICH, or SAH. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for ischemic stroke, ICH, or SAH in Japanese.

Background Myofibroblasts, which are activated fibroblasts, play an important role in interstitial fibrosis in non-ischemic dilated cardiomyopathy (NIDCM). Recently, human epididymal body protein 4 (HE4) has attracted attention as a marker specific to myofibroblasts. However, the prognostic impact of HE-4 on cardiovascular events in NIDCM patients has not been reported. Purposes The purpose of this study was to investigate the impact of circulating serum HE4 on the prognosis in patients with NIDCM. Methods Forty-four NIDCM patients underwent echocardiography, laboratory measurements, cardiac catheterization, and endomyocardial biopsy within one week under stable heart failure condition. Patients with cancer were excluded from this study. We collected blood samples from peripheral vain, ascending aorta, and coronary sinus during cardiac catheterization and measured serum HE4 level. They were divided into two groups at the median of HE4 level: High-HE4 group (HE4 >69 pmol/L); n=22, Low-HE4 group (HE4 Results The mean age, left ventricular ejection fraction (LVEF), and plasma brain natriuretic peptide level were 56 years, 32%, and 205 pg/mL. Between two groups, there were no significant differences in age, gender, LVEF, left ventricular end-diastolic diameter, cardiac index, and pulmonary capillary wedge pressure. However, estimated glomerular filtration rate was significantly lower in the High-HE4 group (p=0.025). Kaplan-Meier survival analysis revealed that the High-HE group had a higher rate of cardiac composite event (p=0.011, see Figure). However, as for the pathological analysis, not only the peripheral HE4 level but also HE4 value subtracting coronary sinus from ascending aorta did not significantly correlate with collagen volume fraction in biopsy samples. Circulating HE4 level and prognosis Conclusion Elevated circulating HE4 is associcated with poor prognosis in ambulatory patients with NIDCM.

Background Although veno-arterial extracorporeal oxygenation (VA-ECMO) is widely used as mechanical circulatory support, it reduces native left ventricular (LV) stroke volume through the cardiac preload decrease and afterload increase. Therefore some patients with severe cardiac dysfunction present persistently closed aortic valve (AV). The closed AV is considered to increase the risk of pulmonary edema or intracardiac thrombosis. However, little is known about the variables that contribute to persistently closed AV under the management of VA-ECMO. Purpose We investigated the factors that could predict persistently closed AV at the time of VA-ECMO initiation. Methods This was a retrospective chart review. We investigated the patients who received the management of VA-ECMO due to cardiogenic shock from April 2011 to December 2018, and analyzed 18 patients (43±16 years, 50% female) who presented closed AV immediately after the introduction of VA-ECMO. We obtained the hemodynamic data at the time of VA-ECMO initiation (baseline) and 24h after. The patients who presented persistently closed AV during 24h were defined as Close-group (n=8). The patients whose AV was opened within 24h were defined as Open-group (n=10). The status of AV was investigated by the echocardiogram. Results All patients were managed by concomitant use of intra-aortic balloon pumping. The etiologies were myocarditis (56%), cardiomyopathy (33%), and acute myocardial infarction (11%). Nine patients experienced in-hospital death (6 were Close-group and 3 were Open-group, p=0.15). At baseline, there were no significant differences between mean arterial blood pressure (mABP) (p=0.07), central venous pressure (CVP) (p=0.71), and left ventricular ejection fraction (p=0.44). However, Close-group had significantly lower mean pulmonary artery pressure (MPAP) and pulmonary artery pulse pressure (PAPP) than Open-group (Close-group versus Open-group; MPAP, 15±6 mmHg versus 27±11 mmHg, p=0.01; PAPP, 3±2 mmHg versus 8±3 mmHg, p=0.01). Logistic regression analyses revealed the lower MPAP and PAPP had the predictive value of closed AV within 24-h after VA-ECMO initiation [MPAP: odds ratio (OR) 0.78, 95% confidence interval (95% CI) 0.62–0.99, P=0.003; PAPP: OR 0.18, 95% CI 0.02–1.13, P Conclusion At the time of VA-ECMO initiation, lower MPAP and PAPP had the predictive value for persistently closed AV. LV preload derived from right heart function would have major impact on AV status.

Background Fulminant myocarditis is one of the fatal diseases for which effective management has not yet been established. Immunosuppressive therapy (IST) using corticosteroid has been actively applied to giant cell or eosinophilic myocarditis, there is no consensus on the efficacy of lymphocytic myocarditis, which is suspected of involving viral infection. Actually, IST for lymphocytic myocarditis is not recommended in the European Society of Cardiology guidelines, but in the Japanese Circulation Society guidelines, it is approved for use in refractory cases in the absence of curative therapy for myocarditis established. Purpose The purpose of this study was to explore the potential efficacy of immunosuppressive therapy on acute phase in fulminant lymphocytic myocarditis (FLM) requiring veno-arterial extracorporeal membranous oxygenation (VA-ECMO) support. Method We conducted CHANGE-PUMP study that was retrospectively enrolled 99 patients with fulminant myocarditis required VA-ECMO support in the Tokai area (central part of Japan) for the past 20 years. Lymphocytic myocarditis was defined by pathological category. Patients were divided into two groups depending on whether IST using corticosteroid was performed in the clinical course. Results: Sixty-six patients were pathologically diagnosed as fulminant myocarditis by endomyocardial biopsy, of which only 49 patients were FLM. IST were indicated in 8 (16%) out of 49 patients of FLM (IST group; n=8, non-IST group; n=41). Kaplan-Meier survival analysis showed a lower survival rate in the IST group than in the non-IST group (p=0.073). However, in all cases, based on our guidelines, IST was initiated after becoming refractory to MCS treatment. Immunosupressive therapy and prognosis Conclusion In the retrospective analysis, biopsy-proven FLM patients with IST required VA-ECMO support had low survival rates. However, the timing of IST introduction was late and concerned. In the present era when advanced mechanical support appears and the survival rate of fulminant myocarditis is expected to improve, a multicenter prospective study is needed to establish an indication of IST in the acute phase of fulminant myocarditis.

Left ventricular (LV) systolic dysfunction independently predicts mortality in patients with ST-elevation myocardial infarction (STEMI). However, deterioration of LV diastolic function in STEMI patients has not been well studied. Furthermore, long-term follow-up in patients with LV diastolic

A 35-year-old woman was admitted to our hospital because of a sudden cardiac arrest caused by an acute anterior myocardial infarction. Emergency coronary angiography showed total occlusion of the proximal left anterior descending artery (LAD). We performed an intravascular ultrasound (IVUS) to detect the LAD orifice and successfully inserted the guidewire to the occluded LAD. An IVUS revealed coronary dissection and no atheromatous plaque from the orifice to the mid-portion of the LAD and the guidewire was in the true lumen. Two bare metal stents were implanted in the proximal and mid portion of the LAD. After stenting to the LAD, coronary dissection retrogradely extended to the left circumflex artery (LCx). Therefore, we performed additional stent implantation from the left main trunk (LMT) to the proximal LCx and the just proximal LAD. An IVUS guided percutaneous coronary intervention (PCI) enabled complete revascularization to spontaneous coronary artery dissection.

Chlorophenols including monochlorophenol, dichlorophenol, trichlorophenol, tetrachlorophenol, and pentachlorophenol in water were extracted into dialkylated cationic surfactant-silica gel admicelles. The dialkylated cationic surfactants such as didecyldimethylammonium bromide (DC10) and didodedyldimethylammonium bromide (DC12) sorbed on silica gel surfaces to form admicelles at pH 9. Approximately 200mg of DC10 was quantitatively sorbed on 1g of silica gel. The sorption further increased by further addition of DC10. This is in contrast to the fact that the maximum sorption of mono-alkylated cetyltrimethyammonium chloride (CTAC) was only ca. 100mg. Based on the fluorescent spectra of a molecular probe, N-phenyl-1-naphthylamine, DC10- and DC12-silica gel admicelles were more hydrophobic than CTAC-silica gel admicelles. The extents of the extraction of chlorophenols into DC10-silica gel admicelles were greater than those into CTAC-silica gel admicelles. However, the extractions to DC12-silica gel admicelles were insufficient due to leakage of DC12 vesicles. Consequently, DC10-silica gel admicelles were the most adequate for concentrating chlorophenols in water. An admicelle column was prepared by passing aqueous buffer solution of DC10 through a Bond Elut Jr. silica gel solid-phase extraction cartridge. It was successfully applied to the 500-fold concentration of chlorophenols including hydrophilic mono-substituted chlorophenol in water samples prior to their HPLC analysis.

Isolation of bacteria from wet skin lesions was attempted using Naruto Research Institute Otsuka Atrichia (NOA) mice, which develop such lesions spontaneously at a high rate. As a result, Staphylococcus aureus was demonstrated to have colonized the wet skin lesions at high density. In addition, the isolated S. aureus was found to be similar to the strain of S. aureus thought to colonize the eczematous lesions seen in humans with atopic dermatitis. Furthermore, a survey of the S. aureus colonization status of NOA mice with no wet skin lesions confirmed colonization at higher density than in HR-1 mice as control, indicating that the skin of the NOA mouse has the novel characteristic of increased susceptibility to S. aureus colonization. Thus, by using changes in S. aureus counts as an index, the NOA mouse can be expected to serve as a useful animal model for evaluating the effects of topical antiseptics. The antiseptic effects of an ointment and a lotion containing chlorhexidine gluconate were confirmed using this animal model.

The effects of housing on the onset time and prevalence of wet skin lesions were investigated in NOA mice, which spontaneously develop these lesions at a high rate. Wet skin lesions developed earliest in mice that were housed individually. For mice that were housed in groups, the lesions developed earlier in mice with non-littermate group housing than in mice with littermate group housing. The prevalence of lesions was in the following order: individual housing > non-littermate group housing > littermate group housing. These results suggest that socio-psychological factors are involved in the etiology of wet skin lesions in the NOA mouse. Under individual housing conditions, two other novel characters of the NOA mouse were also observed, specifically, development of dry skin and wet skin lesions at the tail root. These characteristics developed early and with high prevalence and were easily observed on external examination. Therefore, these novel characteristics observed in NOA mice are potential markers of the psychological state of the animals.

Several studies have shown that mechanisms for lumen enlargement following conventional balloon angioplasty (BA) consist of plaque reduction and vessel expansion. To assess the mechanisms of lumen enlargement after Cutting Balloon (CB) angioplasty, intravascular ultrasound images were analyzed in 180 lesions (89 CB and 91 BA). External elastic membrane (EEM) cross-sectional area (CSA), lumen CSA, and plaque plus media (P+M) CSA were measured before and after angioplasty. In the CB group, lower balloon pressure was utilized (P < 0.0001). DeltaP+M CSA was significantly larger (P = 0.02) and deltalumen CSA showed a trend toward being larger (P = 0.07) compared to BA group. For noncalcified lesions, CB resulted in a larger deltaP+M CSA (P < 0.05) and a smaller deltaEEM CSA (P = 0.10) than BA. For calcified lesions, deltalumen CSA was significantly larger in the CB group (P < 0.05) without significant differences in deltaEEM CSA and deltaP+M CSA. Dissections complicated with calcified lesions were associated with larger deltalumen CSA for the CB group. In conclusion, for noncalcified lesions, CB achieves similar luminal dimensions with larger plaque reduction and less vessel expansion compared to BA. On the other hand, for calcified lesions, the CB achieves larger lumen gain, especially in lesions with evidence of dissections.

Cetyltrimethylammonium chloride was sorbed on silica gels and formed stable admicelles at pH 9. The extractabilities of chlorophenols were greater than those to sodium dodecyl sulfate–γ-alumina adm...

BACKGROUND The purpose of the present study was to compare the 5-year clinical outcomes after implantation of drug-eluting stent (DES) and bare-metal stent (BMS) in Japanese patients with acute myocardial infarction (AMI). METHODS AND RESULTS This study was a subgroup analysis of the Nagoya Acute Myocardial Infarction Study (NAMIS). It included 658 AMI patients, of which 280 were treated with a DES and 378 with a BMS. The major adverse cardiac event (MACE)-free rates during the 5-year follow-up period were similar between the 2 groups (95.7% vs. 96.8%, P=0.482). A significant difference was seen, however, in the target lesion revascularization (TLR) rates (7.9% vs. 17.7%, P

The mi locus of mice encodes a member of the basic-helix-loop-helix- leucine zipper (bHLH-Zip) protein family of transcription factors (hereafter called MITF). Cultured mast cells of mi/mi genotype (mi/mi CMCs) did not normally respond to stem cell factor (SCF), a ligand for the c-kit receptor tyrosine kinase. The poor response of mi/mi CMCs to SCF was attributed to the deficient expression of c-kit both the mRNA and protein levels. The purpose of the present study is to investigate the effect of MITF on the transcription of the c-kit gene. First, we introduced cDNA encoding normal (+) MITF or mutant (mi) MITF into mi/mi CMCs using the retroviral vector. Overexpression of (+)-MITF but not mi- MITF normalized the expression of the c-kit and the poor response of mi/mi CMCs to SCF, indicating the involvement of (+)-MITF in the c-kit gene transactivation. Second, we analyzed the promoter of the c-kit gene. Three CANNTG motifs recognized by bHLH-Zip-type transcription factors were conserved between the mouse and human c-kit promoters. Among these three CANNTG motifs, only the CACCTG motif (nt -356 to - 351) was specifically bound by (+)-MITF. When the luciferase gene under the control of the c-kit promoter was contransfected into NIH/3T3 fibroblasts with cDNA encoding (+)-MITF or mi-MITF, the luciferase activity significantly increased only when (+)-MITF cDNA was cotransfected. The deletion of the promoter region containing the CACCTG motif or the mutation of the CACCTG to CTCCAG abolished the transactivation effect of (+)-MITF, indicating that (+)-MITF transactivated the c-kit gene through the CACCTG motif. When the luciferase gene under the control of the c-kit promoter was introduced into the FMA3 mastocytoma and FEC-P1 myeloid cell lines, remarkable luciferase activity was observed only in FMA3 cells. Thus, the involvement of (+)-MITF in the c-kit transactivation appeared to be specific to the mast cell lineage.

Adherence to antipsychotic treatment is particularly important in the long-term management of schizophrenia and other related psychotic disorders since poor adherence to medication is associated with poor health outcomes. Although the patients' subjective satisfaction with the medication is crucial for adherence to medication, few studies have examined the relationship between subjective satisfaction with antipsychotics and adherence. In this study, we investigated subjective satisfaction with antipsychotics in patients with schizophrenia by using the Treatment Satisfaction Questionnaire for Medication (TSQM), a self-reporting instrument to assess the major dimensions of patients' satisfaction with their medication. The subjects included 121 clinically stabilized outpatients who met the following criteria: 1) patients between 20 and 65 years of age, diagnosed with schizophrenia or other psychotic disorders as defined by DSM-IV, 2) patients undergoing oral antipsychotic monotherapy or taking only an antiparkinsonian agent as an adjuvant remedy, and 3) patients who had received a stable dose of an antipsychotic for more than four weeks. Patients were asked to answer the TSQM questions, and their clinical symptoms were also evaluated by the Brief Psychiatric Rating Scale (BPRS). Satisfaction with regard to side-effects (p=0.015) and global satisfaction (p=0.035) were significantly higher in patients taking second-generation antipsychotics (SGAs, n=111) than those taking first-generation antipsychotics (FGAs, n=10), whereas no significant difference was found between the two groups in clinical symptoms according to BPRS (p=0.637) or the Drug-induced Extrapyramidal Symptoms Scale (DIEPSS, p=0.209). In addition, correlations were not significant between the subjective satisfactions and clinician-rated objective measures of the symptoms. These findings suggest that SGAs have more favorable subjective satisfaction profiles than FGAs in the treatment of schizophrenia. Since it is often difficult to detect the difference by a traditional objective assessment of the patients, it is desirable that physicians pay attention to the patients' subjective satisfaction in conjunction with their own objective clinical assessment.

Restenosis after successful balloon angioplasty remains problematic. Early elastic response after angioplasty is significant when considering the possible development of restenosis. The purpose of this study was to compare early elastic recoil within 10 minutes after successful percutaneous transluminal coronary angioplasty and early lumen loss at 24 hours after angioplasty in a cutting balloon group and a conventional balloon group.Extent of early elastic recoil was quantitatively measured as the difference of mean balloon diameter at maximal inflation pressure and minimal luminal diameter after angioplasty in 82 cutting balloon-treated lesions and 51 conventional balloon-treated lesions.Reference diameter and balloon/artery ratio were similar between the cutting balloon and conventional balloon groups (2.89 0.47 mm vs. 2.88 0.60 mm; 1.19 0.11 vs. 1.19 0.13, respectively). Early elastic recoil after angioplasty was significantly smaller in the cutting balloon than the conventional balloon group (0.96 0.40 mm vs. 1.12 0.37 mm, respectively; p = 0.04). Also, the mean amount of lumen loss from 10 minutes after angioplasty to 24 hours after was significantly smaller in the cutting balloon than the conventional balloon group (0.08 0.28 mm vs. 0.20 0.33 mm, respectively; p = 0.02).There is significantly less early elastic recoil in the cutting balloon angioplasty than in the conventional balloon angioplasty group. The efficacy of cutting balloon continues 24 hours after angioplasty.

Background: At the initial stages of percutaneous transluminal coronary angioplasty (PTCA), several studies reported on the feasibility of coronary artery incision and dilatation leading to the extension of the PTCA technique. Hypothesis: This study was designed to determine the immediate and chronic results of cutting balloon (CB) angioplasty. Methods: This procedure was performed on 127 lesions in 110 patients (male 83%, age 61.8 ± 9.3 years). Results: The overall procedural success rates for the CB were 93.7% (119 lesions) and 92.7% (102 patients), while solitary CB without pre- and/or postdilatation was 76.4% (91 lesions). There was one major in-hospital complication (Q-wave myocardial infarction, 0.9%), but there were no deaths or emergency coronary artery bypass graftings. Significant angiographic dissections (≥ grade C) occurred in four patients, and coronary perforation occurred in one. The successfully treated CB group (95 lesions) was matched with the successful conventional angioplasty group (PTCA group) for chronic result assessment in regard to reference vessel size and lesion characteristics. In the CB group, postprocedural minimal luminal diameters were significantly larger and the percentage of stenosis at the stenotic site was significantly lower compared with the PTCA group. Restenosis occurred in 22 lesions (23.1%). This showed a significantly lower restenosis rate compared with the PTCA group (42.1%). In addition, the restenosis rate of the CB without inclusion of the pre- and/or postdilatation-treated lesions was 19.7%. Conclusions: (1) Cutting balloon angioplasty procedures can be performed with high success rates with few major in-hospital events. (2) The restenosis rate in the CB group was significantly lower compared with the PTCA group.

Background and purpose: The maximal exercise capacity is generally reduced in heart failure (HF) patients. In addition, renal insufficiency was reported to be prevalent in patients with HF. However, the influence of renal dysfunction on exercise capacity, such as peak oxygen consumption (VO2), has not fully established. Therefore, the aim of this study was to investigate the relationship between cardiopulmonary exercise testing (CPX) parameters and renal function in HF patients. Methods: Four hundred and thirty patients with HF underwent echocardiography, laboratory measurements, and CPX. They were divided into two groups according to estimated glomerular filtration rate (eGFR)