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Background Functional mitral regurgitation (FMR) is not uncommon in atrial fibrillation (AF) patients. Left atrial (LA) substrate remodeling and corresponding mitral valve annulus dilation has been reported as the most possible cause of FMR. Percutaneous catheter ablation (CA) is an effective treatment for AF. Although significant FMR could be improved by sinus restoration, patients with mitral regurgitation were more likely to experience recurrent AF post ablation, especially those with significant mitral regurgitation. There is no information available on the efficacy of CA for persistent AF in patients with FMR. Purpose The purpose of this study is to investigate the predictors of FMR improvement by CA and to determine the efficacy of substrate and trigger CA for persistent AF in patients with FMR. Methods We prospectively studied 512 consecutive patients admitted for persistent AF ablation from the EARNEST-PVI (Prospective Multicenter Randomized Study of Effect of Extensive Ablation on Recurrence in Patients with Persistent Atrial Fibrillation Treated with Pulmonary Vein Isolation) trial. On admission, enrolled patients were randomly assigned in a 1:1 ratio to pulmonary vein isolation (PVI) or PVI-plus additional ablation (linear ablation or/and CFAE ablation). Of the 512 patients, we studied 94 patients with preoperative echocardiography showing moderate or greater baseline FMR. FMR grades were classified into 5 grades (0/1/2/3/4). The FMR improvement group (FMRI(+)) was defined as a case in which the FMR was improved by two or more grades compared the preoperative echocardiography and the one year follow-up examination. Results Of the 94 patients, 42 were in the PVI group and 52 were in the PVI-plus additional ablation group. There were 30 cases in the FMRI(+) group and 64 cases in the FMRI(−) group. There were no significant baseline differences in age, sinus rhythm maintenance, plasma B-type natriuretic peptide (BNP) level, left ventricular diastolic dimension, or left atrium dimension between the FMRI(+) and FMRI(−) groups. AF duration was significantly shorter in the FMRI(+) group than FMRI(−) groups (5.8±9.4 months vs 12.4±15.4 months, p Conclusions Catheter ablation is a valid option for the treatment of AF in patients with functional MR and additional substrate and trigger ablation were the only independent predictor of FMR improvement. Funding Acknowledgement Type of funding sources: None.

Background Systemic inflammation plays a critical role in the outcomes of heart failure. Malnutrition is also associated with poor outcome in heart failure patients. It has been recently reported that advanced lung cancer inflammation index (ALI), which is calculated as body mass index × serum albumin / neutrophil to lymphocyte ratio (NLR), is an independent prognostic marker in several types of cancer. However, there is no information available on the prognostic impact of ALI in patients admitted with acute decompensated heart failure (ADHF), especially in comparison with malnutrition. Methods and results We studied 263 ADHF patients discharged with survival. At the discharge, we measured ALI. Malnutrition was assessed by prognostic nutritional index (PNI) and controlling nutritional status score (CONUT). During a follow up period of 5.1±4.3 yrs, 67 patients had cardiovascular death (CVD). ALI was significantly smaller in patients with than without CVD (32.5±18.2 vs 52.2±30.2, p53.6: HR 5.80 [2.60–12.94]) (48% vs 21% vs 9%, p Conclusion ALI, a systemic inflammation-nutrition index, is more useful prognostic marker than malnutrition in patients admitted with ADHF. Funding Acknowledgement Type of funding sources: None.

Background Sarcopenia and malnutrition are associated with poor clinical outcome in patients with chronic heart failure. However, there is little information available on the prognostic significance of the combination of sarcopenia and malnutrition in patients with acute decompensated heart failure (ADHF), relating to reduced or preserved left ventricular ejection fraction (HFrEF or HFpEF). Methods We prospectively studied 543 consecutive ADHF patients who survived to discharge (HFrEF [LVEF Results During a follow-up period of 2.8±1.4 years, 161 patients had all-cause death. Multivariate Cox analysis showed that both FFMI and GNRI were independently associated with all-cause death in both HFrEF (p=0.0064 and p Conclusions Sarcopenia or malnutrition at discharge was associated with all-cause death even in ADHF patients, irrespective of reduced or preserved LVEF. The combination of sarcopenia and malnutrition could provide prognostic information in ADHF patients with reduced LVEF. Funding Acknowledgement Type of funding sources: None. Figure 1

PurposePublications are an important information source for clinicians, researchers, and patients. Key methodological elements must be reported for maximum transparency. We identified key methodological elements necessary for fully understanding pharmacoepidemiological research in pregnancy and quantified the proportion of studies that report these elements in a sample of publications.MethodsKey methodological elements were identified from guidelines from regulatory agencies, literature, and subject-matter knowledge: source of information to determine pregnancy start; mother- or father-infant linkages (process, success rate); unit of analysis; and whether non-live births and fetuses with various anomalies were included in the study population.We conducted a literature review for recent observational studies on medical product utilization or safety during pregnancy and estimated the prevalence of reporting these elements.ResultsData were extracted from a random sample of 100 publications; 8% were published in epidemiology/pharmacoepidemiology journals; 85% were medical product–safety studies.Of included publications, 43% reported the source for determining pregnancy start; 57% reported whether the study population included multifetal pregnancies; 39%, whether it included more than 1 pregnancy per woman; 27%, whether it included fetuses with chromosomal abnormalities; 60%, fetuses with major congenital malformations; and 93%, non-live births. Of the 20 studies with mother-infant linkage, 35% described the process; 21% reported the linkage success rate. Among studies with more than one pregnancy/offspring per woman, 22% reported methods addressing sibling correlation.ConclusionsIn this sample of pregnancy-related pharmacoepidemiology publications, completeness of reporting can be improved. A pregnancy-specific checklist would help to increase transparency in the dissemination of study results.Key points▪Publications on the utilization or safety of medical products in pregnancy (pregnancy pharmacoepidemiology) are fully understandable when all key methodological elements are presented to the reader.▪We identified 17 methodological elements from guidelines, literature, and subject-matter knowledge that we felt were crucial for understanding publications on pregnancy pharmacoepidemiology.▪In a random sample of 100 publications, completeness of reporting varied across elements, with almost perfect reporting on whether non-live births were included in the study population to a 21% completeness on mother-infant linkage success rate.▪A pregnancy-specific checklist would help to increase transparency in the dissemination of study results.

Background Comorbidities are strongly associated with poor clinical outcome in heart failure patients (pts). The Age-adjusted Charlson comorbidity index (ACCI), which is well-known widely used comorbidity index, recently has been used as a robust prognostic model in heart failure pts. On the other hand, AHEAD risk score has been recently reported as a useful long-term risk stratification score in acute decompensated heart failure (ADHF) pts. Recently, a new group of heart failure pts with mid-range ejection fraction (HFmrEF) has been defined, separated from reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). We sought to compare the prognostic value of ACCI and AHEAD score in ADHF pts, relating to HFrEF, HFmrEF and HFpEF. Methods We prospectively studied 410 consecutive ADHF pts (HFrEF [n=143], HFmrEF [n=99] and HFpEF [n=168]) with survival discharge. ACCI contains 19 issues which was weighted according to their potential influence on mortality. AHEAD risk score is a simple index, which is range 0–5; atrial fibrillation, hemoglobin 70 years, creatinine >130 μmol/L, and diabetes mellitus. The endpoint of this study was all cause death (ACD). Results During a follow-up period of 2.4±1.4 years, 119 pts had ACD (42, 29 and 48 pts in HFrEF, HFmrEF and HFpEF, respectively). At univariate Cox analysis, ACCI and AHEAD risk score were significantly associated with ACD in each subgroup. At multivariate Cox analysis, in HFrEF pts, ACCI, but not AHEAD risk score, showed the significant and independent association with ACD. In HFmrEF, both ACCI and AHEAD risk score was significantly and independently associated with ACD and ROC analysis showed AUC of ACCI was greater than that of AHEAD risk score (0.778 [0.683–0.855] vs 0.637 [0.572–0.764], p=0.07). On the other hand, in HFpEF pts, AHEAD risk score, but not ACCI, showed the significant and independent association ACD. Conclusion ACCI provides more prognostic value in HFrEF pts, and AHEAD risk score has more prognostic value in HFpEF pts. In HFmrEF pts, both ACCI and AHEAD score might have prognostic values, although ACCI tends to be more associated with ACD than AHEAD score. Funding Acknowledgement Type of funding source: None

Background The transtubular potassium concentration gradient (TTKG) has been reported to be a marker of renal aldosterone bioactivity, and has been shown to be a surrogate of arterial underfilling in patients with acute decompensated heart failure (ADHF). Moreover, high TTKG at discharge has been shown to be associated with poor prognosis in ADHF patients. Empagliflozin, one of the sodium glucose cotransporter 2 inhibitors, has been shown to reduce the risk of cardiovascular mortality in patients with type 2 diabetes mellitus (T2D) and cardiovascular disease. However, little is known about the effect of empagliflozin as add-on therapy on TTKG in T2D patients with ADHF. Purpose We sought to elucidate the effect of empagliflozin as add-on therapy on TTKG in T2D patients with ADHF. Methods We enrolled 58 consecutive T2D patients admitted for ADHF. On admission, enrolled patients were randomly assigned in a 1:1 ratio to either empagliflozin add-on therapy (EMPA(+)) or conventional glucose-lowering therapy (EMPA(−)). All patients in EMPA(+) group received empagliflozin (10 mg/day) throughout the study period. Left ventricular ejection fraction (LVEF) was measured at baseline using echocardiography. Body weight and vital signs, such as blood pressure and heart rate, were measured, and blood and urine samples were collected at baseline and 1, 2, 3 and 7 days after randomization. The TTKG was measured using the first morning urine samples collected on each day. TTKG was calculated according to the following equation: TTKG = (Ku/Ks)×(plasma osmolality/urine osmolality), where Ku is urine potassium concentration and Ks is serum potassium concentration, as previously reported. Results Thirty patients were assigned to the EMPA(+) group, and 28 patients were assigned to the EMPA(−) group. There were no significant baseline differences in LVEF, plasma B-type natriuretic peptide (BNP) level, body mass index, or serum creatinine level between the EMPA(+) and EMPA(−) groups. TTKG did not significantly differ between the two groups at baseline. However, seven days after randomization, plasma BNP level was significantly lower in the EMPA(+) group than in the EMPA(−) group (median 227 [IQR 114–381] pg/mL vs 362 [227–554] pg/mL, p=0.0294). Furthermore, TTKG of the EMPA(+) group was significantly lower at 2, 3 and 7 days after randomization (Figure). Conclusions This study demonstrated that empagliflozin as add-on therapy can lower TTKG in T2D patients with ADHF. Figure 1 Funding Acknowledgement Type of funding source: None

Background Malnutrition is one of the most important comorbidities among heart failure (HF) patients, and serum cholinesterase (CHE) has been reported to be a prognostic factor in HF patients. On the other hand, atrial fibrillation (AF) is frequently observed in patients with HF with preserved ejection fraction (HFpEF). However, there is little information available on the prognostic value of nutritional status in HFpEF patients, with and without AF. We sought to clarify the prognostic value of CHE in HFpEF with and without AF and compare it with that of other nutrition indices such as gastric nutritional risk index (GNRI), controlling nutritional status (CONUT), and the prognostic nutritional index (PNI). Methods and results Patients data were extracted from The Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with Preserved Ejection Fraction (PURSUIT HFpEF) study, which is a prospective multicenter observational registry for acute decompensated heart failure patients with left ventricular ejection fraction ≥50% in Osaka. We analyzed 380 patients (median age: 80 [75–87] years, male: 46%) after exclusion of patients with in-hospital death, missing follow-up data, or missing data to calculate nutritional indices. On admission, 155 patients had AF. Laboratory data were obtained at discharge. During a mean follow up period of 1.1±0.6 years, 131 patients had a composite endpoint (CE) of all-cause death and hospitalization for worsening heart failure or cerebrovascular disorder. In multivariate Cox analysis, in patients with AF, CHE was significantly associated with CE independently of age, gender and body mass index after the adjustment with serum albumin, total cholesterol levels and total lymphocyte count, while it was not significantly associated with CE in patients without AF. C-index of CHE (0.708) was higher than that of GNRI (0.555, p=0.0028), CONUT (0.651, p=0.208) and PNI (0.635, p=0.208) in AF patients, while there were no significant differences in those nutritional indices in patients without AF. Kaplan-Meier curve analysis revealed that AF patients with lower CHE ( Conclusions Prognostic value of CHE would be stronger than other nutritional indices in HFpEF patients with AF, while it would be weak in HFpEF patients without AF. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Roche Diagnostics K.K.; Fuji Film Toyama Chemical Co. Ltd.

Background The novel nutrition index; triglyceride (TG) × total cholesterol (TG) × body weight (BW) index (TCBI) has been reported to be an easy and useful predictor for patients with coronary artery disease. However, there is no information available on the prognostic value of TCBI in patients with heart failure with preserved LVEF (HFpEF) who admitted with acute decompensated heart failure (ADHF). Methods and results Data were extracted from The Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with Preserved Ejection Fraction (PURSUIT HFpEF) study. PURSUIT-HFpEF study is a prospective multicenter observational study in which collaborating hospitals recorded clinical, echocardiographic, and outcome data of ADHF pts with HFpEF. We enrolled consecutive 757 HFpEF patients who admitted with ADHF from June 2016 to June 2019. TCBI was calculated by the formula; TG × TC × BW / 1000 at the discharge. After we excluded patients with in-hospital death or without sufficient data, we analyzed 419 patients. The primary endpoint was all-cause mortality. During a median follow up period of 1.1 (0.9–1.9) years, 59 patients died. ROC analysis revealed that TCBI at discharge was a fair discriminator for predicting all-cause mortality (AUC 0.676, sensitivity 53%, specificity 78%). Multivariate Cox proportional analysis showed that TCBI (p=0.002) was an independent predictor for all cause death after adjustment with major confounders such as age, gender, NT-proBNP, hemoglobin and serum creatinine level. We divided patients into 4 groups according to quartiles of TCBI. Kaplan-Meier analysis showed a significantly higher risk of all-cause death in relation to the decrease in TCBI. Conclusion TCBI, a simple and novel nutrition index, is a useful and strong long-term prognostic indicator in ADHF patients with HFpEF. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Roche Diagnositics K.K.; Fuji Film Toyoma Chemical Co. Ltd.

Introduction Cather ablation (CA) has been identified as an effective and safe treatment option for patients with atrial fibrillation (AF). One of the serious complications associated AF is cerebral infarction (CI). Recent studies reported that CA was associated with lower incidence of ischemic stroke in patients with AF. However, CA for AF itself has a potential risk of CI. Several previous studies showed that the incidence of silent CI (SCI) assessed by magnetic resonance imaging (MRI) of the brain occurred 5 to 18% during CA for AF. Recently, CA for AF made a remarkable progress in technology. However, there are few information available that the impact of 3-dimensional electroanatomical mapping system on the incidence of SCI. This study aimed to clarify the prevalence and predictors of SCI during CA for AF. Methods We enrolled 893 consecutive patients (male 534, age 71±10 years), who underwent CA for AF and MRI of brain 1 day after the procedure. We collected patients data such as physical examinations, blood sampling, echo cardiography, and CA data. A brain MRI was performed the next day following the procedure to identify any CIs. One-hundred and forty-six of patients used the Rhythmia® mapping system catheter, and the other mapping system such as CARTO or EnSite system used in the remaining 747 patients. Results The MRI depicted acute micro-CIs in 144 (16%) patients, but neither symptoms nor abnormal neurological findings were present in these patients. Patients with SCI had significantly higher prevalence of persistent AF (60 vs 43%, p=0.0002), CHADS2 Score (2 (1–3) vs 1 (1–2), p=0.0001), higher prevalence of previous stroke (19 vs 12%, p=0.02), larger left atrial (LA) diameter (43.2±6.4 vs 41.7±6.5mm, p=0.01), lower left ventricular ejection fraction (LVEF) (59.0±13.2 vs 64.2±11.3%, p≤0.0001), higher B-type natriuretic peptide level (221±236 vs 163±225 pg/dl, p≤0.0001), more Rhythmia® mapping system use (30 vs 8%, p Conclusion Acute SCI occurred about 16% after CA for AF. Rhythmia® mapping system use exhibited a higher incidence of acute SCI after catheter ablation for AF than the other mapping system use. Rhythmia® mapping system use, LVEF, CHADS2 score, and procedure time are associated with SCI relating CA for AF. Funding Acknowledgement Type of funding source: None

Background Diuretics has been reported to have a potential for an activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system, leading to a possibility of poor clinical outcome in patients with cardiovascular disease. However, few data are available on clinical impact of diuretics on long-term outcome in patients with acute myocardial infarction (AMI) based on plasma volume status. Methods To address the issue, a total of 3,416 survived patients with AMI who were registered to a large database of the Osaka Acute Coronary Insufficiency Study (OACIS) were studied. Plasma volume status was assessed with the estimated plasma volume status (ePVS) that was calculated at discharge as follows: actual PV = (1 − hematocrit) × [a + (b × body weight)] (a=1530 in males and a=864 in females, b=41.0 in males and b=47.9 in females); ideal PV = c × body weight (c=39 in males and c=40 in females), and ePVS = [(actual PV − ideal PV)/ideal PV] × 100 (%). Multivariable Cox regression analysis and propensity score matching were performed to account for imbalances in covariates. The endpoint was all-cause of death (ACD) within 5 years. Results During a median follow-up period of 855±656 days, 193 patients had ACD. In whole population, there was no significant difference in long-term mortality risk between patients with and without diuretics in both multivariate cox regression model and propensity score matching population. When patients were divided into 2 groups according to ePVS with a median value of 4.2%, 46 and 147 patients had ACD in groups with low ePVS and high ePVS, respectively. Multivariate Cox analysis showed that use of diuretics was independently associated with an increased risk of ACD in low ePVS group, (HR: 2.63, 95% confidence interval [CI]: 1.22–5.63, p=0.01), but not in high ePVS group (HR: 0.70, 95% CI: 0.44–1.10, p=0.12). These observations were consistent in the propensity-score matched cohorts; the 5-year mortality rate was significantly higher in patients with diuretics than those without among low ePVS group (4.7% vs 1.7%, p=0.041), but not among high ePVS group (8.0% vs 10.3%, p=0.247). Conclusion Prescription of diuretics at discharge was associated with increased risk of 5-year mortality in patients with AMI without PV expansion, but not with PV expansion. The role of diuretics on long-term mortality may differ in plasma volume status. Therefore, prescription of diuretics after AMI may be considered based on plasma volume status. Funding Acknowledgement Type of funding source: None

Background Concomitant presence of pulmonary hypertension in heart failure (HF) is associated with increased adverse events and may be related to interventricular uncoupling and impaired cardiac efficiency. An increased mean pulmonary artery pressure to mean systemic arterial pressure ratio (MPS ratio), a marker of interventricular coupling and efficiency, is reported to be associated with worse clinical outcomes in patients with advanced HF. On the other hand, cardiohepatic interactions have been a focus of attention in HF, and liver dysfunction in HF patients is caused by liver congestion, which is related to liver stiffness. It has been recently shown that liver stiffness assessed by non-invasive fibrosis marker such as Fibrosis-4 (FIB4) index predicts the mortality in HF patients. However, there is no information available on the prognostic value of the combination of MPS ratio and FIB4 index in patients with acute decompensated heart failure (ADHF). Methods and results We studied 238 patients admitted for ADHF, who underwent right heart catheterization at the admission and were discharged with survival. MPS ratio was obtained at the admission. FIB4 index was calculated by the formula: age (yrs) × AST [U/L] / (platelets [103/μL] × √(ALT[U/L])). FIB4 index >2.67 was defined as abnormal, as previously reported. During a follow up period of 5.2±4.4 yrs, 93 patients died. At multivariate Cox analysis, MPS ratio (p=0.01) and FIB4 index (p=0.01) were significantly associated with the total mortality, independently of creatinine level and prior heart failure hospitalization, after the adjustment with hemoglobin, albumin levels and body mass index. The patients with both MPS ratio ≥0.388 (determined by ROC analysis; AUC 0.613 [0.541–0.687]) and abnormal FIB4 index had a significantly increased risk of the total mortality than those with either greater MPS or abnormal FIB4 index and none of them (52% vs 40% vs 28%, p=0.0068, respectively). Conclusion The combination of MPS ratio and FIB4 index might be useful for stratifying ADHF patients at higher risk for the total mortality. Funding Acknowledgement Type of funding source: None

Background Comorbidities are strongly associated with poor clinical outcome in heart failure patients. The Age-adjusted Charlson comorbidity index (ACCI), which is well-known widely used comorbidity index, recently has been used as a robust prognostic model in heart failure patients. On the other hand, Cystatin C, as a novel and important biomarker of renal function, has been recently reported as a useful long-term risk stratification score in heart failure patients. However, there is no information available on the impact of comorbidities on the prognostic value of cystatin-C in patients admitted for acute decompensated heart failure (ADHF). Methods We prospectively studied 458 consecutive ADHF patients with survival discharge. Patients with hemodialysis were excluded. Echocardiography and venous blood sampling were performed just before discharge and serum cystatin-C level was measured. Comorbidity was measured with the Age-adjusted Charlson comorbidity index (ACCI). ACCI was commonly used for the evaluation of the comorbid condition which is weighted and scored, with additional points added for age. The endpoint was all-cause death (ACD). Results During a follow-up period of 2.8±1.5 years, 132 patients had ACD. At multivariate Cox analysis, ACCI (p=0.0015) and cystatin-C level (p=0.0145) were significantly and independently associated with ACD. Patients with high ACCI (≥6: determined by ROC analysis) had a significantly greater risk of ACD (37.2% vs 17.8%, p Conclusions The prognostic value of cystatin-C is not affected by comorbidities and cystatin-C provide prognostic information even in patients admitted for ADHF, irrespective of comorbid burden. All-cause death-free rate in ADHF pts Funding Acknowledgement Type of funding source: None

Background It is widely known that even new-generation drug-eluting stent (DES) induce coronary vasomotion abnormality. On the other hand, recent studies reported that drug-coated balloon (DCB) for native coronary artery was non-inferior to DES in medium term outcomes. However, there is no available information about vasomotion after treatment with DCB. Purpose The aim of this study was to prospectively compare coronary vasomotion in patients treated with DCB versus new-generation DES. Methods Twenty-seven patients were randomly treated with angioplasty with DCB (n=12) versus implantation of bioabsorbable polymer everolimus-eluting stent (BP-EES, n=15) after successful predilation. At 8 months after treatment, endothelium-dependent and -independent vasomotion were evaluated by intracoronary infusion of incremental doses of acetylcholine (for right coronary artery: low-dose 5μg, high-dose 50μg and for left coronary artery: low-dose 10μg, high-dose 100μg) and nitroglycerine (200μg). Mean luminal diameter of the distal segments, beginning 5 mm and ending 15 mm distal to the edge of the treated segment was quantitatively measured by angiography. Results Clinical and procedural characteristics were not different between two groups. Vasoconstriction after acetylcholine infusion was less pronounced in the DCB group than the BP-EES group (low-dose: 4±13% vs −4±14%, p=0.158, high-dose: −2±14% vs −28±30%, p=0.013). The response to nitroglycerin was not different between two groups (17±13% vs 18±24%, p=0.838). Conclusion Vasoconstriction after acetylcholine infusion in the peri-treated region was more pronounced in the BP-EES group than in the DCB group, which suggests that endothelial function of coronary vessel treated by DCB can be more preserved than new-generation DES. Figure 1 Funding Acknowledgement Type of funding source: None

Background Cardiac sympathetic nerve dysfunction, which is assessed by I-123 metaiodobenzylguanidine (MIBG) imaging, is associated with the poor outcomes in patients with chronic heart failure (CHF). Serial evaluation of cardiac MIBG imaging was shown to be useful for predicting adverse outcome in CHF. However, there was no information available on long-term serial changes of cardiac sympathetic nerve dysfunction after discharge of acute decompensated heart failure (ADHF) hospitalization. Purpose We aimed to clarify the serial change of cardiac MIBG imaging parameter in long-term after discharge of heart failure hospitalization, especially relating to HFrEF (LVEF Methods We studied 112 patients (HFrEF; n=44, HFmrEF; n=23 and HFpEF; n=45) who were admitted for ADHF, discharged with survival and without heart failure hospitalization during follow-up period. All patients underwent cardiac MIBG imaging at the timing of discharge, in 6–12 months and in 18–24 months after discharge. The cardiac MIBG heart to mediastinum ratio (H/M) was calculated on the early image and the delayed image (late H/M). The cardiac MIBG washout rate (WR) was calculated from the early and delayed planar images after taking radioactive decay of I-123 into consideration. Results In HFrEF patients, late H/M was significantly improved from discharge to 6–12 months data (1.60±0.24 vs 1.75±0.31, p Conclusion The improvement in cardiac sympathetic nerve dysfunction was observed in patients with HFrEF and HFmrEF, not in HFpEF, after the discharge of acute heart failure hospitalization. Funding Acknowledgement Type of funding source: None

Background Cardiac sympathetic nerve dysfunction, which is assessed by I-123 metaiodobenzylguanidine (MIBG) imaging, is associated with the poor outcomes in patients with heart failure (HF). Most of the literature on the use of 123I-MIBG imaging is based on planar images in patients with chronic HF and reduced left ventricular ejection fraction (HFrEF), because It is technically challenging to conduct precise 123I-MIBG SPECT analysis in globally denervated heart, which is frequently observed in HFrEF patients. There was no information available on cardiac sympathetic nerve dysfunction evaluated by cardiac MIBG SPECT imaging in acute decompensated HF (ADHF) patients with preserved left ventricular ejection fraction (HFpEF). Purpose We aimed to clarify the prognostic significance of 123I-MIBG SPECT myocardial imaging in ADHF patients with HFpEF. Methods We enrolled 183 patients who were admitted for ADHF with HFpEF, discharged with survival. All patients underwent cardiac MIBG imaging at the timing of discharge. The cardiac MIBG heart to mediastinum ratio (H/M) was calculated on the early image and the delayed image (late H/M). We studied 156 patients after excluding 27 patients whose MIBG SPECT reconstruction was difficult due to too low MIBG uptake or extracardiac accumulation interference. SPECT analysis on the delayed image was conducted by using CardioBull, a fully automated software for the quantification of I-123 MIBG SPECT. All of 17 regional tracer uptake were compared with normal control database. A scoring algorithm for the evaluation of low uptake employs a 5-point scoring system as 0–4 for normal, mildly abnormal, moderately abnormal, severe abnormal, and perfusion defect, respectively. The summed severity (SSS) scores were obtained by summing the score for all segments. SSS could range from 0 to 68. The endpoint of this study is cardiac events defined as the composite of unplanned heart failure hospitalization and cardiac death. Results During a mean follow up period of 2.4±1.6 years, 60 patients reached cardiac events. SSS was significantly high in patients with than without cardiac events (20 [10–27] vs 7 [4–16], p10, defined by median) had significantly greater risk of cardiac event (56% vs 21%, Hazard ratio: 3.56 (2.00–6.33, p Conclusion Cardiac MIBG SPECT imaging was useful for risk stratification in ADHF patients with HFpEF. Funding Acknowledgement Type of funding source: None

Background Malnutrition is associated with increased mortality risk in patients (pts) with acute decompensated heart failure (ADHF). On the other hand, concomitant presence of pulmonary hypertension in heart failure is associated with increased adverse events and may be related to interventricular uncoupling and impaired cardiac efficiency. It has recently been shown that an increased mean pulmonary artery pressure to mean systemic arterial pressure ratio (MPS ratio), a marker of interventricular coupling and efficiency, is associated with worse clinical outcomes in patients with advanced heart failure. However, there is no information available on the long-term prognostic value of the combination of malnutrition and MPS ratio in pts admitted for ADHF. Methods and results We studied 248 pts admitted for ADHF, who underwent right heart catheterization at the admission and were discharged with survival. Malnutrition was assessed by geriatric nutritional risk index (GNRI), prognostic nutritional index (PNI) and controlling nutritional status score (CONUT). During a mean follow-up period of 5.2±4.4 yrs, 62 pts had cardiovascular death (CVD). MPS ratio was significantly greater in pts with than without CVD (0.408±0.114 vs 0.347±0.102, p=0.0001). GNRI and PNI were significantly lower, CONUT was significantly greater in pts with than without CVD. At multivariate Cox regression analysis, GNRI and MPS ratio were significantly associated with CVD, independently of prior heart failure hospitalization, eGFR, and serum sodium level and anemia, although PNI and CONUT showed the association with CVD at unvariate analysis. Pts with malnutrition (GNRI≤median value=96.5) and greater MPS ratio (≥median value=0.346) had a significantly higher CVD risk than those with either and none of them (51% vs 20% vs 12%, p Conclusions The combination of malnutrition and MPS ratio might be useful for stratifying pts at risk for CVD in patients with ADHF. Funding Acknowledgement Type of funding source: None

Acral melanoma (AM) is an epidemiologically and molecularly distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. We aimed to analyze the efficacy of anti-programmed cell death 1 (anti-PD-1) antibodies in advanced AM.We retrospectively evaluated unresectable stage III or stage IV AM patients treated with an anti-PD-1 antibody in any line at 21 Japanese institutions between 2014 and 2018. The clinicobiologic characteristics, objective response rate (ORR, RECIST), survival estimated using Kaplan-Meier analysis, and toxicity (Common Terminology Criteria for Adverse Events 4.0.) were analyzed to estimate the efficacy of the anti-PD-1 antibodies.In total, 193 patients (nail apparatus, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 patients (74.1%). Baseline lactate dehydrogenase (LDH) was within the normal concentration in 102 patients (52.8%). The ORR of all patients was 16.6% (complete response, 3.1%; partial response, 13.5%), and the median overall survival (OS) was 18.1 months. Normal LDH concentrations showed a significantly stronger association with better OS than abnormal concentrations (median OS 24.9 versus 10.7 months; P0.001). Although baseline characteristics were similar between the nail apparatus and the palm and sole groups, ORR was significantly lower in the nail apparatus group [6/70 patients (8.6%) versus 26/123 patients (21.1%); P = 0.026]. Moreover, the median OS in this group was significantly poorer (12.8 versus 22.3 months; P = 0.03).Anti-PD-1 antibodies have limited efficacy in AM patients. Notably, patients with nail apparatus melanoma had poorer response and survival, making nail apparatus melanoma a strong candidate for further research on the efficacy of novel combination therapies with immune checkpoint inhibitors.

Background Overdose of insulin often causes long-lasting severe hypoglycaemia. Insulin degludec has the longest duration of action among the available insulin products; thus, an overdose of insulin degludec can lead to long-lasting hypoglycaemia. In the present paper, we report the case of a woman with long-lasting hypoglycaemia attributable to insulin degludec overdose and markedly prolonged insulin degludec half-life. Case report A 64-year-old woman with Type 2 diabetes receiving insulin therapy was taken to an emergency department because of disturbed consciousness 21 h after self-injection of 300 units of insulin degludec (4.34 units/kg). Her plasma glucose level was 2.3 mmol/l. She received repeated intravenous boluses of dextrose for 43 h with continuous intravenous dextrose infusion, but no improvement in long-lasting hypoglycaemia or consciousness was observed. Considering the possibility of adrenal insufficiency, intravenous dexamethasone was administered, and her plasma glucose levels subsequently remained above 5.5 mmol/l without intravenous dextrose boluses. She gradually regained consciousness. A total of 34 h after the overdose, her plasma immunoreactive insulin levels were markedly increased and then gradually declined over ~400 h. The insulin degludec half-life was 40.76 h. Conclusion Although the reported half-life of insulin degludec in the body is ~25 h when administered in standard doses (0.4-0.8 units/kg), no study has investigated its half-life after overdose. In the present case, the half-life of insulin degludec was ~1.6 times longer than that observed with standard doses, probably leading to long-lasting hypoglycaemia. Physicians should be aware of the possibility of unexpected long-lasting severe hypoglycaemia resulting from insulin degludec overdose.

Purpose Cardiac allograft tolerance in non-human primates (NHPs) has been achieved by our group using a mixed chimerism model with allogeneic bone marrow transplant after non-myeloablative conditioning but not without kidney co-transplantation. B cell lymphoma 2 (Bcl2) inhibition has allowed for durable mixed chimerism with reduced conditioning in the murine skin transplant model. We investigated whether the Bcl2 inhibitor ABT199 could enhance mixed chimerism and induce cardiac allograft tolerance in the absence of kidney cotransplantation. Methods Fifteen cynomolgus recipients underwent mixed chimerism conditioning (ATGAM, total body and thymic irradiation) then organ and bone marrow transplantation. Group 1 recipients received heart alone (n=5), Group 2 recipients received heart and kidney cotransplants (n=7), and in Group 3, heart recipients received ABT199 in lieu of kidney cotransplants (n=3).Group 1 and 2 received 3Gy total body irradiation (TBI) while Group 3 received 1.5Gy TBI. All recipients underwent a 28-day course of immunosuppression with a calcineurin inhibitor and anti-CD154 mAb after which all immunosuppression was stopped. Results All five Group 1 recipients demonstrated cellular rejection (ISHLT 3R) by 96 days post bone marrow transplant (pBMTx). In contrast, no Group 2 recipients showed early rejection and 6/7 survived >400 days pBMTx. The first two Group 3 recipients developed GvHD and succumbed by days 59 and 68 pBMTx without evidence of rejection. However, after reducing the size of the donor BMT, the third recipient is now 76 days pBMTx with excellent allograft contractility and no evidence of GVHD. Mean peak lymphoid chimerism was 10% on day 26 pBMTx for Group 1, 26% on day 33 pBMTx for Group 2, and 57% on day 54 pBMTx for Group 3. (Figure 1) Conclusion After further refinement of the conditioning regimen, ABT199 may allow for the induction of heart allograft tolerance without the need for kidney co-transplantation and with a reduction in TBI thereby improving safety.

We developed L band frequency 1.275 GHz circularly polarized synthetic aperture radar circularly polarized SAR on-board unmanned aerial vehicle UAV. This paper explains the configuration of system, antenna, and car-based experiment of circularly polarized SAR. The comparison of circularly polarized SAR and linearly polarized SAR by full polarimetric scattering experiment in anechoic chamber was done and discussed. The result shows circular polarization has less effect of orientation angle of target and could avoid the misalignment of transmitter and receiver antenna during UAV operation. Axial ratio and ellipticity images are also derived and introduced as novel classification technique in microwave remote sensing field using circularly polarized SAR or ellipticity characteristic of scattering wave.

Background Recent studies showed that both worsening renal function (WRF) and improved renal function (IRF) during hospitalization are associated with poor prognosis in patients with acute decompensate heart failure (ADHF). On the other hand, plasma volume (PV) expansion plays an essential role in ADHF. However, there is little information about the difference of prognostic impact of WRF and IRF in ADHF patients, relating to PV status (PVS). Methods We prospectively studied 348 patients admitted for ADHF. PVS was defined as follows: actual PV = (1 - hematocrit) × [a + (b × body weight)] (a=1530 in males and a=864 in females, b=41.0 in males and b=47.9 in females); ideal PV = c × body weight (c=39 in males and c=40 in females); and PVS = [(actual PV - ideal PV)/ideal PV] × 100 (%). WRF and IRF were defined as an increase and a decrease in serum creatinine of ≥0.3 mg/dl from admission to discharge, respectively. The endpoint was readmission for worsening heart failure (WHF) within 1 year. Result Median PVS was 6.7% (IQR: −4.1%–16.7%). 43 and 21 patients had WHF in groups with high PVS (PVS ≥ median) and low PVS (PVS > median), respectively. In high PVS group, multivariate Cox analysis showed that IRF was independently and significantly associated with WHF (p=0.016, HR: 2.4 [1.2–4.8]), but WRF was not (p=0.55, HR: 0.7 [0.3–2.1]). On the other hand, in low PVS group, WRF was independently associated with WHF (p=0.035, HR: 3.0 [1.1–8.1]), but IRF was not (p=0.27, HR: 2.1 [0.6–8.0]). Kaplan-Meier analysis revealed that only patients with IRF had a significantly higher risk of WHF than those with stable renal function (SRF) in high PVS group, while patients with WRF had a significantly higher risk of WHF than those with SRF in low PVS group. Worsening heart failure-free rate curves Conclusion In ADHF patients with PV expansion, IRF during hospitalization could predict poor outcomes, but WRF could not. On the other hand, in ADHF patients without PV expansion, not IRF but WRF could predict poor outcomes. PVS guided-therapy may be considered in secondary prevention for WHF.

Background Liver dysfunction in patients with heart failure (HF) is caused by liver congestion, which is related to liver stiffness. It was reported that liver stiffness assessed by non-invasive fibrosis marker such as Fibrosis-4 (FIB4) index (based on age, aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels, and platelet counts) predicts mortality in HF pts. Acute kidney injury (AKI) during HF treatment is associated with poor outcome in pts admitted for acute decompensated heart failure (ADHF). However, there is no information available on the long-term prognostic significance of the combination of FIB4 index and AKI in ADHF pts. Methods and results We studied 299 ADHF pts with survival discharge. FIB4 index was calculated by the formula: age (yrs) × AST[U/L]/(platelets [103/μL] × (ALT[U/L])1/2). AKI during ADHF treatment was defined according to AKI Network criteria (stage 1: mild, stage 2: moderate, stage 3: severe). During a follow-up period of 4.3±3.3 yrs, 94 pts died. At multivariate Cox analysis, FIB4 index and stage2/3 AKI, but not stage1 AKI, significantly associated with total mortality, independently of prior HF hospitalization and serum sodium and blood urea nitrogen levels after adjustment with BMI, systolic blood pressure, hemoglobin, serum creatinine and albumin levels, left ventricular end-diastolic and left atrial dimension indexes. Pts with both greater FIB4 index (>2.674: median) and stage 2/3 AKI had a significantly higher risk of total mortality than those with none of them. Adjusted hazard ratio in pts with both greater FIB4 index and stage 2/3 AKI was 3.5 (95% CI 1.6–7.7), which was two-fold of that in pts with either of them (1.7 [95% CI 1.1–2.7]). Conclusion The combination of FIB4 index and moderate to severe AKI might identify higher risk subset for total mortality in ADHF pts.

Background Catheter ablation (CA) for atrial fibrillation (AF) is a curable treatment option. However, AF recurrence after CA remains an important problem. Although the success rate has been improved after catheter ablation (CA) in patients with paroxysmal AF (PAF), outcome data after CA for persistent AF (PeAF) are highly variable. Previous studies showed the PeAF is one of independent predictors for AF recurrence in comparison to PAF. However, there are little information available on the prognostic significance of AF duration after CA for AF. The aim of this study is to evaluate the impact of AF duration on long-term outcomes of AF ablation in patients with PeAF compared with PAF. Methods We enrolled 778 consecutive patients, who were referred our institution between August 2015 and December 2017 for undergoing the first time CA for AF. We divided 5 groups (Group 1; PAF (n=442), Group 2; PeAF duration ≤6 months (n=198), Group 3; PeAF duration of 6 months to 2 years (n=87), Group 4; PeAF duration of 2–5 years (n=30) and Group 5; PeAF duration ≥5 years (n=21)). All patients followed up for at least 1 year. Outcome data on recurrence of AF after ablation were collected. Results There were no significant differences in baseline clinical characteristics before CA among 5 groups, except for the prevalence of congestive heart failure, left atrial diameter and left ventricular ejection fraction. During a mean follow-up period of 511±298 days, 217 patients had AF recurrence. Kaplan-Meier analysis revealed that AF recurrence was significantly higher in group 2 compared to group 1 (31% vs 20%, p=0.002) and in group 4 compared to group 3 (83% vs 30%, p AF Free Survival Curve Conclusion Although patients with PeAF within 2 years had significantly higher AF recurrence compared to PAF, AF ablation might still be a good contributor as the first line approach to improve outcomes in patient with PeAF within 2 years.

Background Plasma volume status (PVS) has been shown to be a well-validated prognostic indicator which relate to morbidity and mortality in heart failure. However, it remains unclear whether PVS would have the prognostic significance in patients with acute myocardial infarction (AMI). Global Registry of Acute Coronary Events (GRACE) risk score is a powerful predictor of prognosis after acute coronary event, but there is no information available on the additional prognostic value of PVS to GRACE in AMI patients. Methods We retrospectively studied 3930 AMI patients. GRACE score and PVS was obtained on the admission. PVS was calculated as follows: actual PV = (1 - hematocrit) × [a + (b × body weight)] (a=1530 in males and a=864 in females, b=41.0 in males and b=47.9 in females); ideal PV = c × body weight (c=39 in males and c=40 in females); and PVS = [(actual PV - ideal PV)/ideal PV] × 100 (%). The endpoint was All cause of death (ACD) within 5 years. Results During a mean follow-up period of 2.4±1.9 years, 406 patients had ACD. PVS was significantly greater in patients with ACD than without ACD (8.1±14.9% vs −1.7±13.3%, p0%) were significantly higher risk of ACD than those without PV expansion in patients both with high risk in GRACE score (>140) (28% (225/803) vs 19% (78/412), p=0.01, HR: 7.5) and with low risk in GRACE score (≤140) (6% (52/894) vs 3% (51/1821), p=0.009, HR: 6.2). Survival rate curves Conclusion PVS, which represents intravascular compartment and congestion, could identify poor prognosis in patients with AMI. In addition, PVS would provide additional prognostic information to GRACE score.

Background It has been reported that the objective nutritional indices such as the Controlling Nutritional Status (CONUT) score, Geriatric Nutritional Risk Index (GNRI) and Prognostic Nutritional Index (PNI) are useful for the prediction of prognosis in patients with heart failure. However, there is no information available on the prognostic value of the combination of these objective nutritional indices in patients with acute decompensated heart failure (ADHF). Purpose We sought to assess the usefulness of the Combined Objective Nutritional Score for the prediction of post-discharge clinical outcome in ADHF patients. Methods We studied 361 consecutive patients who were admitted for ADHF and survived to discharge. Venous blood sampling, echocardiography, and measurement of body weight were performed just before discharge. CONUT score, GNRI and PNI were calculated as previously reported. We determined the Combined Objective Nutritional Score by assigning 1 point each for high CONUT score (2–12), low GNRI (≤98) or low PNI (≤38). Patients were followed-up for up to 5 years. The study endpoint was all-cause death. Results During a follow-up period of 2.4±1.3 years, 106 patients had all-cause death. Multivariate Cox analysis showed that the Combined Objective Nutritional Score was independently associated with all-cause death after adjustment for age, gender, history of coronary artery disease, left ventricular ejection fraction, brain natriuretic peptide level and estimate glomerular filtration rate (p Figure 1 Conclusion This study showed that the Combined Objective Nutritional Score is a useful tool to risk stratify the patients hospitalized with ADHF.

Background The mainstay of treatment of acute decompensated heart failure (ADHF) is decongestion by diuretic therapy. Empagliflozin has been shown to reduce the risk of hospitalization for heart failure in patients (pts) with type 2 diabetes mellitus (T2D) and cardiovascular disease. This may be explained by natriuresis and osmotic diuresis caused by empagliflozin, leading to plasma volume (PV) contraction and decongestion. However, little is known about the therapeutic effect of empagliflozin on decongestion and its association with renal function in T2D pts with ADHF. Purpose We sought to elucidate the effect of empagliflozin as add-on therapy on plasma B-type natriuretic peptide (BNP) level, hemoconcentration, PV contraction and renal function in T2D pts with ADHF. Methods We enrolled 38 consecutive T2D pts admitted for ADHF. On admission, enrolled pts were randomly assigned in a 1:1 ratio to either empagliflozin add-on therapy (EMPA(+)) or conventional glucose-lowering therapy (EMPA(−)). All pts in EMPA(+) group received empagliflozin (10mg/day) throughout the study period. Left ventricular ejection fraction (LVEF) was measured at baseline using echocardiography. Body weight and vital signs, such as blood pressure and heart rate, were measured, and blood and urine samples were collected at baseline and 1, 2, 3 and 7 days after randomization. Hemoconcentration was defined as a ≥3% absolute increase in hematocrit (Hct). Percent change in PV between admission and subsequent timepoints (%ΔPV) was calculated using the Strauss formula as follows: %ΔPV = ([(Hb1/Hb2) × ((100 − Hct2)/(100 − Hct1))] − 1) × 100 (%), where 1 = baseline values and 2 = subsequent values. Worsening renal function (WRF) was defined as an increase in serum creatinine ≥0.3 mg/dL above baseline within 7 days of randomization. Results Twenty pts were assigned to the EMPA(+) group, and 18 pts were assigned to the EMPA(−) group. There were no significant baseline differences in LVEF, plasma BNP level, Hct or serum creatinine level between the EMPA(+) and EMPA(−) groups. Seven days after randomization, plasma BNP level was significantly lower in the EMPA(+) group than in the EMPA(−) group (median 213 [IQR 116–360] pg/mL vs 362 [226–776] pg/mL, p=0.0437) and hemoconcentration was more frequently observed in the EMPA(+) group than in the EMPA(−) group (53% vs 12%, p=0.0105). The decrease in %ΔPV was larger in the EMPA(+) group than in the EMPA(−) group 2 days (−8.74±9.92% vs 1.14±14.71%, p=0.0228), 3 days (−11.28±10.65% vs −0.02±14.70%, p=0.0121) and 7 days after randomization (−10.62±14.89% vs 0.97±13.72%, p=0.0211). The incidence of WRF did not significantly differ between the EMPA(+) and EMPA(−) groups (15% vs 22%). Conclusions This study demonstrated that empagliflozin as add-on therapy can achieve effective decongestion without an increased risk of WRF in T2D pts with ADHF.

Background Elevated serum uric acid (UA) level has been shown to be associated with reduced survival among patients (pts) with heart failure. Sodium glucose cotransporter 2 (SGLT2) inhibitors have been reported to lower serum uric acid level in pts with type 2 diabetes mellitus (T2D). Empagliflozin, one of the SGLT2 inhibitors, has been shown to reduce the risk of cardiovascular mortality in T2D pts with cardiovascular disease, and involvement of UA lowering effect by empagliflozin in the reduction of cardiovascular mortality has been suggested. However, little is known about the effect of empagliflozin as add-on therapy on serum UA level in T2D pts with acute decompensated heart failure (ADHF). Purpose We sought to elucidate the effect of empagliflozin as add-on therapy on serum UA level in T2D pts with ADHF. Methods We enrolled 38 consecutive T2D pts admitted for ADHF. On admission, enrolled pts were randomly assigned in a 1:1 ratio to either empagliflozin add-on therapy (EMPA(+)) or conventional glucose-lowering therapy (EMPA(−)). All pts in EMPA(+) group received empagliflozin (10 mg/day) throughout the study period. Left ventricular ejection fraction (LVEF) was measured at baseline using echocardiography. Body weight and vital signs, such as blood pressure and heart rate, were measured, and blood and urine samples were collected at baseline and 1, 2, 3 and 7 days after randomization. Renal handling of UA was evaluated by fractional excretion of UA (FEUA). Results Twenty pts were assigned to the EMPA(+) group, and 18 pts were assigned to the EMPA(−) group. There were no significant baseline differences in LVEF, plasma brain natriuretic peptide level, body mass index, or serum creatinine level between the EMPA(+) and EMPA(−) groups. In addition, prevalence rate of hyperuricemia, serum UA level, and FEUA did not significantly differ between the two groups at baseline. However, there was significant difference in the change in serum UA level from baseline at 2, 3 and 7 days after randomization between the two groups (Figure A). As a result, serum UA level was significantly lower in the EMPA(+) group than in the EMPA(−) group at 7 days after randomization (6.2±1.8 mg/dL vs 7.8±1.8 mg/dL, p=0.0127). Moreover, FEUN of the EMPA(+) group was significantly higher at 1, 2 and 7 days after randomization (Figure B), which suggested that serum UA level was lowered in the EMPA(+) group by increased urinary excretion of UA. Figure 1 Conclusions This study demonstrated that empagliflozin as add-on therapy can lower serum UA level in T2D pts with ADHF through the effect on the urinary excretion rate of UA.

Background The reduced diuretic response (DR) has been shown to be associated with poor clinical outcome in patients with acute decompensated heart failure (ADHF). In addition, hypoalbuminemia, which is related to DR, has been also reported to predict poor prognosis in ADHF patients. However, there is no information available on the impact of albumin level on the prognostic value of DR in patients with ADHF. Methods We prospectively studied 296 consecutive patients who were admitted for ADHF and survived to discharge. The patients were divided into 2 groups according to the presence or absence of hypoalbuminemia at the admission, defined as the serum level of albumin at admission Results There were 144 patients with hypoalbuminemia and 152 patients without hypoalbuminemia. During a mean follow-up period of 2.2±1.5 years, 88 patients with hypoalbuminemia and 53 patients without hypoalbuminemia reached the endpoint. In group with hypoalbuminemia, DR was significantly smaller in patients with than without the endpoint (0.85 [0.50–1.50] vs 1.60 [0.76–2.70] kg/40mg furosemide, p=0.003), while there was no significant difference in DR between them in group without hypoalbuminemia (1.17 [0.59–1.66] vs 1.07 [0.75–1.88] kg/40mg furosemide, p=0.381). At multivariate Cox analysis, in group with hypoalbuminemia, DR was significantly associated with the endpoint, independently of age, left ventricular ejection fraction, and serum creatinine and plasma BNP levels. On the other hand, in group without hypoalbuminemia, DR showed no significant association with the endpoint at univariate Cox analysis. Kaplan-Meier analysis showed that patients with poor DR (≤1.08 kg/40mg furosemide: median value) had a significantly higher risk of the endpoint in group with hypoalbuminemia, but not in group without hypoalbuminemia (Figure). Figure 1 Conclusion Our results suggested that prognostic value of DR in ADHF patients is affected by the presence or absence of hypoalbuminemia.

Background Plasma volume (PV) expansion plays an essential role in heart failure and PV status provides prognostic information in patients (pts) with acute decompensated heart failure (ADHF). On the other hand, concomitant presence of pulmonary hypertension in heart failure is associated with increased adverse events and may be related to interventricular uncoupling and impaired cardiac efficiency. It has recently been shown that an increased mean pulmonary artery pressure to mean systemic arterial pressure ratio (MPS ratio), a marker of interventricular coupling and efficiency, is associated with worse clinical outcomes in patients with advanced heart failure. However, there is no information available on the long-term prognostic value of the combination of PV status and MPS ratio in pts admitted for ADHF. Methods We studied 248 pts admitted for ADHF, who underwent right heart catheterization at the admission and were discharged with survival. PV status and MPS ratio were obtained at the admission. PV status was calculated as the following: Actual PV = (1 − hematocrit) x [a + (b x body weight)] (a=1530 in males and a=864 in females, b=41 in males and b=47.9 in females), Ideal PV = c x body weight (c=39 in males and c=40 in females), and PV status = [(actual PV − ideal PV)/ideal PV] x 100(%). The study endpoint was cardiovascular death (CVD). Results During a mean follow-up period of 5.2±4.4 yrs, 62 pts had CVD. PV status (10.0±16.2 vs 5.0±15.3%, p=0.03) and MPS ratio (0.408±0.114 vs 0.347±0.102, p=0.0001) were significantly greater in patients with than without CVD. At multivariate Cox regression analysis, PV status and MPS ratio were significantly associated with CVD, independently of prior heart failure hospitalization, eGFR, and serum sodium level and anemia. Patients with greater PV status (> median value = 4.6%) and MPS ratio (> median value = 0.346) had a significantly higher CVD risk than those with either and none of them (44% vs 22% vs 14%, p Conclusions The combination of PV status and MPS ratio might be useful for stratifying patients at risk for CVD in patients with ADHF.

Background Comorbidities are associated with poor clinical outcome in heart failure patients (pts). AHEAD (A: atrial fibrillation; H: hemoglobin; E: elderly; A: abnormal renal parameters; D: diabetes mellitus) score has been related to clinical outcomes in acute decompensated heart failure (ADHF) pts. On the other hand, heart failure is one of a number of disorders associated with the development of wasting syndrome. Previous studies have reported reduced mortality rates in heart failure patients with increased body mass index (BMI), so-called, obesity paradox. We sought to investigate the prognostic value of the combination of AHEAD score and the cachectic state in ADHF pts, relating to reduced or preserved LVEF (HFrEF or HFpEF). Methods and results We studied 303 pts admitted for ADHF and discharged with survival (HFrEF (LVEF 70 years, creatinine >130 μmol/L, and diabetes mellitus) and wasting syndrome was defined as BMI Conclusion The combination of AHEAD score and wasting syndrome would be useful for stratifying patients at risk for the mortality in ADHF pts, regardless of HFrEF or HFpEF.

Background Comorbidities are associated with poor clinical outcome in patients with chronic heart failure, and acute kidney injury (AKI) also provides prognostic information in patients with heart failure. However, there is no information available on the impact of comorbidities on the prognostic value of AKI in patients admitted for acute decompensated heart failure (ADHF). Methods We prospectively studied 357 consecutive ADHF patients with survival discharge. Patients with hemodialysis were excluded. Comorbidity was measured with the Age-adjusted Charlson comorbidity index (ACCI) which is commonly used for the evaluation of the comorbid condition which is weighted and scored, with additional points added for age. AKI was defined as an absolute increase in serum creatinine of 0.3mg/dl or more during hospitalization. The endpoint was all-cause death (ACD). Results During a follow-up period of 2.2±1.4 years, 97 patients had ACD. At multivariate Cox analysis, ACCI (p Conclusions The presence of AKI was associated with the increased risk of mortality in ADHF patients with higher comorbidity burden but not in those without them.

Background The Get with The Guidelines (GWTG) heart failure (HF) risk score was developed in the GWTG inpatient HF registry to predict in-hospital mortality and also reported to be associated with post-discharge long-term outcomes. Plasma volume (PV) expansion plays an essential role in HF. Recently, it has been reported that PV is estimated by a simple formula based on hematocrit and body weight, not using radioisotope assays, and PV status provides prognostic information in patients (pts) with acute decompensated heart failure (ADHF). However, there is no information available on the long-term prognostic value of the combination of PV status and GWTG-HF risk score in pts admitted for ADHF. Methods and results We studied 301 ADHF pts discharged with survival. Variables required for the GWTG-HF risk score were race, age, systolic blood pressure, heart rate, serum levels of blood urea nitrogen and sodium, and the presence of chronic obstructive pulmonary disease. PV status was calculated as the following: Actual PV = (1 − hematocrit) x [a + (b x body weight)] (a=1530 in males and a=864 in females, b=41 in males and b=47.9 in females), Ideal PV = c x body weight (c=39 in males and c=40 in females), and PV status = [(actual PV − ideal PV)/ideal PV] x 100(%). During a follow-up period of 4.3±3.2 yrs, 95 pts had all-cause death (ACD). At multivariate Cox analysis, GWTG-HF risk score and PV status were significantly associated with the total mortality, independently of eGFR and the prior history of heart failure hospitalization, after the adjustment with serum albumin level and anemia. Pts with both high GWTG-HF risk score (≥39 by ROC analysis; AUC 0.655 [0.586–0.724]) and greater PV status (≥8.1% by ROC analysis; AUC 0.624 [0.566–0.692]) had a significantly higher risk of ACD than those with either or none of them (58% vs 30% vs 21%, p Conclusion PV status would provide the additional long-term prognostic information to GWTG-HF risk score in ADHF pts.

Background Concomitant presence of pulmonary hypertension in heart failure is associated with increased adverse events and may be related to interventricular uncoupling and impaired cardiac efficiency. It has recently been shown that an increased mean pulmonary artery pressure to mean systemic arterial pressure ratio (MPS ratio), a marker of interventricular coupling and efficiency, is associated with worse clinical outcomes in patients with advanced heart failure. However, there is little information available on the long-term prognostic value of MPS ratio in patients with acute decompensated heart failure (ADHF), relating to reduced or preserved left ventricular ejection fraction (HFrEF or HFpEF). Methods and results We studied 240 patients admitted for ADHF, who underwent right heart catheterization and were discharged with survival (HFrEF (LVEF≤40%); n=110, HFpEF (LVEF>40%); n=130). MPS ratio was obtained at the admission. During a mean follow-up period of 5.2±4.4 yrs, 59 patients had cardiovascular death (CVD). In both groups with HFrEF and HFpEF, MPS ratio was significantly greater in patients with than without CVD (HFrEF; 0.453±0.101 vs 0.382±0.116, p=0.0035, HFpEF; 0.374±0.118 vs 0.323±0.083, p=0.0091). At multivariate Cox regression analysis, MPS ratio was significantly associated with CVD, independently of eGFR and serum sodium level in HFrEF and HFpEF groups. Patients with high MPS ratio (>0.386 in HFrEF and >0.415 in HFpEF determined by ROC curve analysis) had a significantly increased risk of CVD than those with low MPS ratio in both groups. Conclusions MPS ratio could provide the long-term prognostic information in patients admitted for ADHF, regardless of reduced or preserved LVEF.

Purpose Induction of tolerance in combined heart/kidney transplantation in non-human primates is possible by applying a mixed chimerism-based conditioning protocol which induces indefinite tolerance. However, donor brain death negatively impacts tolerance induction, leading to a higher incidence of humoral as well as cellular rejection. Here, we investigated whether delaying conditioning and donor bone marrow transplantation (DBMT) until four months after organ transplantation would diminish the detrimental effects of donor brain death and permit tolerance induction despite donor brain death. Methods Nine cynomolgus monkeys underwent combined heart/kidney transplantation using organs from donors rendered brain-dead 4 hours prior to organ procurement. Six recipients underwent nonmyeloablative conditioning that included total body irradiation, thymic irradiation, horse anti-thymocyte globulin, anti-CD154 mAb, CyA and DBMT on the day of solid organ transplantation, three animals were kept on triple immunosuppression for four months after combined heart/kidney transplantation before undergoing the identical conditioning protocol prior to DBMT. All drugs were stopped 29 days after DBMT. Results Three brain-dead donor animals rejected their allografts on day 127, 131 and 383, respectively. Two brain dead donor animals were euthanized without signs of rejection on day 30 and day 114 after transplantation due to sepsis and PTLD, respectively. One brain dead donor animal underwent elective euthanasia on day 400 after transplantation without signs of rejection. One animal in the delayed conditioning group developed no detectable donor chimerism and rejected its allografts on day 135, another delayed animal was euthanized for sepsis without signs of graft rejection on day 59 after DBMT. A third animal in the same group is still ongoing without histological signs of cellular or humoral allograft rejection on day 420 after DBMT. Conclusion Donor brain death negatively impacts tolerance induction after mixed chimerism conditioning leading to a higher incidence of allograft rejection. Delaying recipient conditioning and DBMT might eliminate the detrimental effects of donor brain death and its associated pro-inflammatory side-effects, thus increasing the chance of long-term tolerance.