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Abstract Aims Elevated plasma branched‐chain amino acids (BCAAs) are tightly linked to incident diabetes and its complications, while lower BCAAs are associated with adverse outcomes in the elderly and heart failure (HF) patients. The interplay between body compositions and plasma BCAAs, especially under the influence of co‐morbid diabetes in HF patients, is not well understood. Here, we examined the impact of diabetes on the prognostic value of plasma BCAA and its association with body compositions in HF patients. Methods and results We retrospectively examined 301 HF patients (70 ± 15 years old; 59% male), among which 36% had diabetes. Blood samples for plasma BCAA measurements were collected in a fasting state after stabilization of HF and analysed using ultraperformance liquid chromatography. A dual‐energy X‐ray absorptiometry scan assessed regional body compositions, and muscle wasting was defined as appendicular skeletal muscle mass index (ASMI)

Abstract Aims Iron deficiency (ID) is common in patients with heart failure (HF) and is reportedly associated with exercise intolerance and impaired quality of life. Iron supplementation therapy in HF patients with ID improves exercise capacity. Conversely, protective roles of iron depletion in the development of diabetes mellitus (DM) and its complications have been proposed. This study aimed to determine the impact of ID on physical function in HF patients with and without DM. Methods and results We enrolled consecutive patients who were admitted to our institute for HF diagnosis and management. The short physical performance battery (SPPB) was used to evaluate physical function, and low physical function was defined as an SPPB score of

Abstract Aims The mechanism by which a sodium-glucose cotransporter inhibitor (SGLT2i) induces favorable effects on diabetes and cardiovascular diseases including heart failure (HF) remains poorly understood. Metabolomics including amino acid profiling enables detection of alterations in whole body metabolism. The aim of this study was to determine whether plasma amino acid profiles are modulated by SGLT2i use in HF patients with type 2 diabetes mellitus (T2DM). Methods We retrospectively examined 81 HF patients with T2DM (68 ± 11 years old; 78% male). Plasma amino acid concentrations in a fasting state after stabilization of HF were determined using ultraperformance liquid chromatography. To minimize potential selection bias in the retrospective analyses, the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an inverse probability of treatment weighting (IPTW)-adjusted analysis. Results Of amino acids measurable in the present assay, plasma β -aminoisobutyric acid (BAIBA), an exercise-induced myokine-like molecule also known as 3-aminoisobutyric acid or 3-amino-2-methyproponic acid, was detected in 77% of all patients and the proportion of patients in whom plasma BAIBA was detected was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (93% vs. 67%, p = 0.01). Analyses in patients in whom plasma BAIBA was detected showed that plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (6.76 ± 4.72 vs. 4.56 ± 2.93 nmol/ml, p = 0.03). In multivariate logistic regression analyses that were adjusted for age and sex, SGLT2i use was independently associated with BAIBA detection. The independent association between BAIBA and SGLT2i use remained after inclusion of body mass index, HF with reduced ejection fraction, ischemic etiology, renal function, NT-proBNP, albumin, hemoglobin, and HbA1c into the Cox proportional hazards model. When the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an IPTW-adjusted analysis, least squares mean of plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i. Conclusion SGLT2i use is closely associated with increased circulating BAIBA concentration in HF patients with T2DM.

Abstract Aims The role of necroptosis in dilated cardiomyopathy (DCM) remains unclear. Here, we examined whether phosphorylation of mixed lineage kinase domain‐like protein (MLKL), an indispensable event for execution of necroptosis, is associated with the progression of DCM. Methods and results Patients with DCM (n = 56, 56 ± 15 years of age; 68% male) were enrolled for immunohistochemical analyses of biopsies. Adverse events were defined as a composite of death or admission for heart failure or ventricular arrhythmia. Compared with the normal myocardium, increased signals of MLKL phosphorylation were detected in the nuclei, cytoplasm, and intercalated discs of cardiomyocytes in biopsy samples from DCM patients. The phosphorylated MLKL (p‐MLKL) signal was increased in enlarged nuclei or nuclei with bizarre shapes in hypertrophied cardiomyocytes. Nuclear p‐MLKL level was correlated negatively with septal peak myocardial velocity during early diastole (r = −0.327, P = 0.019) and was correlated positively with tricuspid regurgitation pressure gradient (r = 0.339, P = 0.023), while p‐MLKL level in intercalated discs was negatively correlated with mean left ventricular wall thickness (r = −0.360, P = 0.014). During a median follow‐up period of 3.5 years, 10 patients (18%) had adverse events. To examine the difference in event rates according to p‐MLKL expression levels, patients were divided into two groups by using the median value of nuclear p‐MLKL or intercalated disc p‐MLKL. A group with high nuclear p‐MLKL level (H‐nucMLKL group) had a higher adverse event rate than did a group with low nuclear p‐MLKL level (L‐nucMLKL group) (32% vs. 4%, P = 0.012), and Kaplan–Meier survival curves showed that the adverse event‐free survival rate was lower in the H‐nucMLKL group than in the L‐nucMLKL group (P = 0.019 by the log‐rank test). Such differences were not detected between groups divided by a median value of intercalated disc p‐MLKL. In δ‐sarcoglycan‐deficient (Sgcd−/−) mice, a model of DCM, total p‐MLKL and nuclear p‐MLKL levels were higher than in wild‐type mice. Conclusion The results suggest that increased localization of nuclear p‐MLKL in cardiomyocytes is associated with left ventricular diastolic dysfunction and future adverse events in DCM.

Mitochondrial disease, most cases of which are caused by mitochondrial DNA (mtDNA) mutation, is present with multiple phenotypes including diabetes mellitus, sensorineural hearing loss, cardiomyopathy, muscle weakness, renal dysfunction, and encephalopathy, depending on the degree of heteroplasmy. While mitochondria play an important role in intracellular glucose and lactate metabolism in insulin-sensitive tissues such as muscles, appropriate strategies for glycemic control have not yet been established in a patient with mitochondrial disease, which is often complicated by myopathy. Here, we describe the history of a 40-year-old man with mtDNA 3243A > G who had sensorineural hearing loss, cardiomyopathy, muscle wasting, and diabetes mellitus with stage 3 chronic kidney disease. He developed mild diabetic ketoacidosis (DKA) in the process of treatment for poor glycemic control with severe latent hypoglycemia. According to the standard therapy for DKA, he was treated with continuous intravenous insulin infusion therapy, which unexpectedly resulted in an abrupt and transient elevation in blood lactate levels without exacerbation of heart failure and kidney function. Since blood lactate levels are determined by the balance between lactate production and consumption, an abrupt and transient lactate elevation following intravenous insulin injection therapy may reflect not only enhanced glycolysis in insulin-sensitive tissues with mitochondrial dysfunction but also decreased lactate consumption in the sarcopenic skeletal muscle and failing heart. Intravenous insulin infusion therapy in patients with mitochondrial disease may unmask derangements of intracellular glucose metabolism in response to insulin signaling.

Abstract Aims The clinical outcome of heart failure (HF) is complicated by the presence of multiple comorbidities including malnutrition and cachexia, and prediction of the outcome is still difficult in each patient. Metabolomics including amino acid profiling enables detection of alterations in whole body metabolism. The aim of this study was to determine whether plasma amino acid profiling improves prediction of clinical outcomes in patients with HF. Methods and results We retrospectively examined 301 HF patients (70 ± 15 years old; 59% male). Blood samples for measurements of amino acid concentrations were collected in a fasting state after stabilization of HF. Plasma amino acid concentrations were measured using ultraperformance liquid chromatography. Clinical endpoint of this study was adverse event defined as all‐cause death and unscheduled readmission due to worsening HF or lethal arrhythmia. During a mean follow‐up period of 380 ± 214 days, 40 patients (13%) had adverse events. Results of analyses of variable importance in projection score, a measure of a variable's importance in partial least squares–discriminant analysis (PLS‐DA) showed that the top five amino acids being associated with adverse events were 3‐methylhistidine (3‐Me‐His), β‐alanine, valine, hydroxyproline, and tryptophan. Multivariate Cox‐proportional hazard analyses indicated that a high 3‐Me‐His concentration and low β‐alanine and valine concentrations were independently associated with adverse events. When HF patients were divided according to the cut‐off values of amino acids calculated from receiver operating characteristic curves, Kaplan–Meier survival curves showed that event‐free survival rates were lower in HF patients with high 3‐Me‐His than in HF patients with low 3‐Me‐His (68% vs. 91%, P

Abstract Background There are a lot of reports of the renal failure and heart failure due to coarctation of the aorta. However, there are no case reports in which revascularization dramatically improved left ventricular function in patients with progressive decline in left ventricular function. Herein, we present a rare case in which the left ventricular function was dramatically improved by surgical treatment for progressive left ventricular dysfunction due to atypical coarctation of the aorta. Case presentation A 58-year-old man underwent left axillary artery-bilateral femoral artery bypass at another hospital for atypical coarctation of the aorta due to Takayasu’s arteritis. Approximately 10 years later, he was re-hospitalized for heart failure, and the left ventricular ejection fraction gradually decreased to 28%. Computed tomography showed severe calcification and stenosis at the same site from the peripheral thoracic descending aorta to the lower abdominal aorta of the renal artery, and aortography showed delayed bilateral renal artery blood flow. An increase in plasma renin activity was also observed. Despite the administration of multiple antihypertensive drugs, blood pressure control was insufficient. We decided to perform surgical treatment to improve progressive cardiac dysfunction due to increased afterload and activated plasma renin activity. Descending thoracic aorta-abdominal aorta bypass and revascularization of the bilateral renal arteries via the great saphenous vein grafts were performed. Postoperative blood pressure control was improved, and the dose of antihypertensive drugs could be reduced. Plasma renin activity decreased, and transthoracic echocardiography 1.5 years later showed an improvement in contractility with a left ventricular ejection fraction of 58%. Conclusion In atypical coarctation of the aorta in patients with decreased bilateral renal blood flow, heart failure due to renal hypertension, and progressive decrease in left ventricular contractility, descending thoracic aorta-abdominal aortic bypass and bilateral renal artery recirculation can be extremely effective.

Abstract Multiple factors regulate glucagon-like peptide-1 (GLP-1) secretion, but a group of apparently healthy subjects showed blunted responses of GLP-1 secretion in our previous study. In this study, we examined whether the reduction in GLP-1 secretory capacity is associated with increased extent of coronary artery stenosis in non-diabetic patients. Non-diabetic patients who were admitted for coronary angiography without a history of coronary interventions were enrolled. Coronary artery stenosis was quantified by Gensini score (GS), and GS ≥ 10 was used as an outcome variable based on its predictive value for cardiovascular events. The patients (mean age, 66.5 ± 8.8 years; 71% males, n = 173) underwent oral 75 g-glucose tolerant tests for determination of glucose, insulin and active GLP-1 levels. The area under the curve of plasma active GLP-1 (AUC-GLP-1) was determined as an index of GLP-1 secretory capacity. AUC-GLP-1 was not correlated with fasting glucose, AUC-glucose, serum lipids or indices of insulin sensitivity. In multivariate logistic regression analysis for GS ≥ 10, AUC-GLP-1

Abstract Background Although high body mass index (BMI) is a risk factor of heart failure (HF), HF patients with a higher BMI had a lower mortality rate than that in HF patients with normal or lower BMI, a phenomenon that has been termed the “obesity paradox”. However, the relationship between body composition, i.e., fat or muscle mass, and clinical outcome in HF remains unclear. Methods We retrospectively analyzed data for 198 consecutive HF patients (76 years of age; males, 49%). Patients who were admitted to our institute for diagnosis and management of HF and received a dual-energy X-ray absorptiometry scan were included regardless of left ventricular ejection fraction (LVEF) categories. Muscle wasting was defined as appendicular skeletal muscle mass index 25% in males and > 30% in females. Results The median age of the patients was 76 years (interquartile range [IQR], 67–82 years) and 49% of them were male. The median LVEF was 47% (IQR, 33–63%) and 33% of the patients had heart failure with reduced ejection fraction. Increased FM and muscle wasting were observed in 58 and 67% of the enrolled patients, respectively. During a 180-day follow-up period, 32 patients (16%) had cardiac events defined as cardiac death or readmission by worsening HF or arrhythmia. Kaplan-Meier survival curves showed that patients with increased FM had a lower cardiac event rate than did patients without increased FM (11.4% vs. 22.6%, p = 0.03). Kaplan-Meier curves of cardiac event rates did not differ between patients with and those without muscle wasting (16.5% vs. 15.4%, p = 0.93). In multivariate Cox regression analyses, increased FM was independently associated with lower cardiac event rates (hazard ratio: 0.45, 95% confidence interval: 0.22–0.93) after adjustment for age, sex, diabetes, muscle wasting, and renal function. Conclusions High percent body fat mass is associated with lower risk of short-term cardiac events in HF patients.

Abstract Aims A high prevalence of muscle wasting, that is, reduction in muscle mass, in patients with peripheral artery disease (PAD) and heart failure (HF) has been reported. However, whether the association between PAD and muscle wasting is independent of shared risk factors such as diabetes mellitus has not been examined. Methods and results We retrospectively enrolled 440 HF patients (mean age, 74 years; inter‐quartile range, 64–82 years; 52% male). Muscle wasting was defined as an appendicular skeletal muscle mass index (ASMI) of

Abstract Background Gasping during cardiac arrest is associated with favourable neurological outcomes for out-of-hospital cardiac arrest. Moreover, while extracorporeal cardiopulmonary resuscitation (ECPR) performed for refractory cardiac arrest can improve outcomes, factors for favourable neurological outcomes remain unknown. This study aimed to examine whether gasping during cardiac arrest resuscitation during transport by emergency medical services (EMS) was independently associated with a favourable neurological outcome for patients who underwent ECPR. This retrospective study was based on medical records of all adult patients who underwent ECPR due to refractory cardiac arrest. The primary endpoint was neurologically intact survival at discharge. The study was undertaken at Sapporo Medical University Hospital, a tertiary care centre approved by the Ministry of Health, Labour and Welfare, located in the city of Sapporo, Japan, between January 2012 and December 2018. Results Overall, 166 patients who underwent ECPR were included. During transportation by EMS, 38 patients exhibited gasping, and 128 patients did not. Twenty patients who exhibited gasping during EMS transportation achieved a favourable neurological outcome (20/38; 52.6%); 14 patients who did not exhibit gasping achieved a favourable neurological outcome (14/128; 10.9%). Gasping during transportation by EMS was independently associated with favourable neurological outcome irrespective of the type of analysis performed (multiple logistic regression analysis, odds ratio [OR] 9.52; inverse probability of treatment weighting using propensity score, OR 9.14). Conclusions The presence of gasping during transportation by EMS was independently associated with a favourable neurological outcome in patients who underwent ECPR. The association of gasping with a favourable neurological outcome in patients with refractory cardiac arrest suggests that ECPR may be considered in such patients.

Abstract Takayasu arteritis (TA) is a large vessel vasculitis of unknown aetiology characterized by chronic inflammatory changes of the aorta and its major branches. We report the active TA case who had severe heart failure due to acute myocardial infarction and aortic regurgitation. Bentall procedure was successfully performed, but he had severely depressed left ventricular function and muscle wasting together with vascular inflammation. The treatment with tocilizumab, an interleukin‐6 receptor monoclonal antibody, in addition to prednisolone and standard heart failure therapy led to prompt remission of TA activity and improvement of left ventricular function and muscle wasting. Taken together with possible involvement of interleukin‐6 in the pathogenesis of heart failure and muscle wasting, inhibition of interleukin‐6 receptor signalling by tocilizumab may be a safe and reasonable approach in the treatment of active TA with heart failure and muscle wasting.

BackgroundThe histological diagnosis of cardiac sarcoidosis (CS) is based on the presence of myocardial granulomas; however, the sensitivity of endomyocardial biopsy is relatively low. We investigated whether immunocompetent cells including dendritic cells (DC) and macrophages in nongranuloma sections of endomyocardial biopsy samples could be histopathological surrogates for CS diagnosis. Methods and ResultsThe numbers of DC and macrophages were investigated in 95 consecutive CS patients and 50 patients with nonischemic cardiomyopathy as controls. All patients underwent endomyocardial biopsy, and immunohistochemical staining was performed on all samples. We examined these immunocompetent cells in nongranuloma sections in CS patients diagnosed by the presence of myocardial granulomas (n=26) and in CS patients without myocardial granulomas diagnosed by the Japanese Ministry of Health Welfare 2007 criteria (n=65) or the Heart Rhythm Society 2014 criteria (n=26). In CS patients with and without myocardial granulomas, CD209+ DC and CD68+ macrophages were more frequently observed (P