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Background: The full impact of the intake of citrus fruits on the risk of depression in individuals with chronic heart failure (HF) is unknown. Here, we examined the associations between the estimated habitual intakes of citrus fruits and depressive symptoms in patients with chronic HF. Methods: We enrolled 150 stable outpatients with chronic HF who had a history of worsening HF. To assess the patients' daily dietary patterns, we used a brief self-administered diet-history questionnaire to calculate the daily consumption of foods and nutrients. To assess the patients' mental state, we used a nine-item Patient Health Questionnaire (PHQ-9). Results: Twelve patients (8%) were identified as having moderate-to-severe depression (PHQ-9 score > 10). The patients with PHQ-9 > 10 had lower daily intakes of citrus fruits compared to those with no or mild depressive symptoms (PHQ-9 < 10). The daily intakes of various antioxidants, including vitamin C, beta- carotene, and beta-cryptoxanthin, all of which are abundant in citrus fruits, were reduced in the patients with PHQ-9 > 10, accompanied by higher serum levels of 8-isoprostane (an oxidative stress marker). A multivariate logistic regression analysis using forward selection showed that a lowered daily intake of citrus fruits was an independent predictor of the comorbidity of moderate-to-severe depression in patients with chronic HF, after adjustment for age, gender, and the hemoglobin value. Conclusions: A lower daily consumption of citrus fruits was associated with higher prevalence of depression in patients with chronic HF. Our findings support the hypothesis that a daily consumption of citrus fruits has a beneficial effect on the prevention and treatment of depression in chronic HF patients. (C)2021 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Background: The full impact of the intake of citrus fruits on the risk of depression in individuals with chronic heart failure (HF) is unknown. Here, we examined the associations between the estimated habitual intakes of citrus fruits and depressive symptoms in patients with chronic HF. Methods: We enrolled 150 stable outpatients with chronic HF who had a history of worsening HF. To assess the patients' daily dietary patterns, we used a brief self-administered diet-history questionnaire to calculate the daily consumption of foods and nutrients. To assess the patients' mental state, we used a nine-item Patient Health Questionnaire (PHQ-9). Results: Twelve patients (8%) were identified as having moderate-to-severe depression (PHQ-9 score > 10). The patients with PHQ-9 > 10 had lower daily intakes of citrus fruits compared to those with no or mild depressive symptoms (PHQ-9 < 10). The daily intakes of various antioxidants, including vitamin C, beta- carotene, and beta-cryptoxanthin, all of which are abundant in citrus fruits, were reduced in the patients with PHQ-9 > 10, accompanied by higher serum levels of 8-isoprostane (an oxidative stress marker). A multivariate logistic regression analysis using forward selection showed that a lowered daily intake of citrus fruits was an independent predictor of the comorbidity of moderate-to-severe depression in patients with chronic HF, after adjustment for age, gender, and the hemoglobin value. Conclusions: A lower daily consumption of citrus fruits was associated with higher prevalence of depression in patients with chronic HF. Our findings support the hypothesis that a daily consumption of citrus fruits has a beneficial effect on the prevention and treatment of depression in chronic HF patients. (C)2021 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Background: The full impact of the intake of citrus fruits on the risk of depression in individuals with chronic heart failure (HF) is unknown. Here, we examined the associations between the estimated habitual intakes of citrus fruits and depressive symptoms in patients with chronic HF. Methods: We enrolled 150 stable outpatients with chronic HF who had a history of worsening HF. To assess the patients' daily dietary patterns, we used a brief self-administered diet-history questionnaire to calculate the daily consumption of foods and nutrients. To assess the patients' mental state, we used a nine-item Patient Health Questionnaire (PHQ-9). Results: Twelve patients (8%) were identified as having moderate-to-severe depression (PHQ-9 score > 10). The patients with PHQ-9 > 10 had lower daily intakes of citrus fruits compared to those with no or mild depressive symptoms (PHQ-9 < 10). The daily intakes of various antioxidants, including vitamin C, beta- carotene, and beta-cryptoxanthin, all of which are abundant in citrus fruits, were reduced in the patients with PHQ-9 > 10, accompanied by higher serum levels of 8-isoprostane (an oxidative stress marker). A multivariate logistic regression analysis using forward selection showed that a lowered daily intake of citrus fruits was an independent predictor of the comorbidity of moderate-to-severe depression in patients with chronic HF, after adjustment for age, gender, and the hemoglobin value. Conclusions: A lower daily consumption of citrus fruits was associated with higher prevalence of depression in patients with chronic HF. Our findings support the hypothesis that a daily consumption of citrus fruits has a beneficial effect on the prevention and treatment of depression in chronic HF patients. (C)2021 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Oxidative stress plays a role in the progression of chronic heart failure (CHF). We investigated whether systemic oxidative stress is linked to exercise intolerance and skeletal muscle abnormalities in patients with CHF. We recruited 30 males: 17 CHF patients, 13 healthy controls. All participants underwent blood testing, cardiopulmonary exercise testing, and magnetic resonance spectroscopy (MRS). The serum thiobarbituric acid reactive substances (TBARS; lipid peroxides) were significantly higher (5.1 +/- 1.1 vs. 3.4 +/- 0.7 mu mol/L, p<0.01) and the serum activities of superoxide dismutase (SOD), an antioxidant, were significantly lower (9.27.1 vs. 29.4 +/- 9.7 units/L, p<0.01) in the CHF cohort versus the controls. The oxygen uptake (VO2) at both peak exercise and anaerobic threshold was significantly depressed in the CHF patients; the parameters of aerobic capacity were inversely correlated with serum TBARS and positively correlated with serum SOD activity. The phosphocreatine loss during plantar-flexion exercise and intramyocellular lipid content in the participants' leg muscle measured by (31)phosphorus- and (1)proton-MRS, respectively, were significantly elevated in the CHF patients, indicating abnormal intramuscular energy metabolism. Notably, the skeletal muscle abnormalities were related to the enhanced systemic oxidative stress. Our analyses revealed that systemic oxidative stress is related to lowered whole-body aerobic capacity and skeletal muscle dysfunction in CHF patients.

Oxidative stress plays a role in the progression of chronic heart failure (CHF). We investigated whether systemic oxidative stress is linked to exercise intolerance and skeletal muscle abnormalities in patients with CHF. We recruited 30 males: 17 CHF patients, 13 healthy controls. All participants underwent blood testing, cardiopulmonary exercise testing, and magnetic resonance spectroscopy (MRS). The serum thiobarbituric acid reactive substances (TBARS; lipid peroxides) were significantly higher (5.1 +/- 1.1 vs. 3.4 +/- 0.7 mu mol/L, p<0.01) and the serum activities of superoxide dismutase (SOD), an antioxidant, were significantly lower (9.27.1 vs. 29.4 +/- 9.7 units/L, p<0.01) in the CHF cohort versus the controls. The oxygen uptake (VO2) at both peak exercise and anaerobic threshold was significantly depressed in the CHF patients; the parameters of aerobic capacity were inversely correlated with serum TBARS and positively correlated with serum SOD activity. The phosphocreatine loss during plantar-flexion exercise and intramyocellular lipid content in the participants' leg muscle measured by (31)phosphorus- and (1)proton-MRS, respectively, were significantly elevated in the CHF patients, indicating abnormal intramuscular energy metabolism. Notably, the skeletal muscle abnormalities were related to the enhanced systemic oxidative stress. Our analyses revealed that systemic oxidative stress is related to lowered whole-body aerobic capacity and skeletal muscle dysfunction in CHF patients.

Oxidative stress plays a role in the progression of chronic heart failure (CHF). We investigated whether systemic oxidative stress is linked to exercise intolerance and skeletal muscle abnormalities in patients with CHF. We recruited 30 males: 17 CHF patients, 13 healthy controls. All participants underwent blood testing, cardiopulmonary exercise testing, and magnetic resonance spectroscopy (MRS). The serum thiobarbituric acid reactive substances (TBARS; lipid peroxides) were significantly higher (5.1 +/- 1.1 vs. 3.4 +/- 0.7 mu mol/L, p<0.01) and the serum activities of superoxide dismutase (SOD), an antioxidant, were significantly lower (9.27.1 vs. 29.4 +/- 9.7 units/L, p<0.01) in the CHF cohort versus the controls. The oxygen uptake (VO2) at both peak exercise and anaerobic threshold was significantly depressed in the CHF patients; the parameters of aerobic capacity were inversely correlated with serum TBARS and positively correlated with serum SOD activity. The phosphocreatine loss during plantar-flexion exercise and intramyocellular lipid content in the participants' leg muscle measured by (31)phosphorus- and (1)proton-MRS, respectively, were significantly elevated in the CHF patients, indicating abnormal intramuscular energy metabolism. Notably, the skeletal muscle abnormalities were related to the enhanced systemic oxidative stress. Our analyses revealed that systemic oxidative stress is related to lowered whole-body aerobic capacity and skeletal muscle dysfunction in CHF patients.

Oxidative stress plays a role in the progression of chronic heart failure (CHF). We investigated whether systemic oxidative stress is linked to exercise intolerance and skeletal muscle abnormalities in patients with CHF. We recruited 30 males: 17 CHF patients, 13 healthy controls. All participants underwent blood testing, cardiopulmonary exercise testing, and magnetic resonance spectroscopy (MRS). The serum thiobarbituric acid reactive substances (TBARS; lipid peroxides) were significantly higher (5.1 +/- 1.1 vs. 3.4 +/- 0.7 mu mol/L, p<0.01) and the serum activities of superoxide dismutase (SOD), an antioxidant, were significantly lower (9.27.1 vs. 29.4 +/- 9.7 units/L, p<0.01) in the CHF cohort versus the controls. The oxygen uptake (VO2) at both peak exercise and anaerobic threshold was significantly depressed in the CHF patients; the parameters of aerobic capacity were inversely correlated with serum TBARS and positively correlated with serum SOD activity. The phosphocreatine loss during plantar-flexion exercise and intramyocellular lipid content in the participants' leg muscle measured by (31)phosphorus- and (1)proton-MRS, respectively, were significantly elevated in the CHF patients, indicating abnormal intramuscular energy metabolism. Notably, the skeletal muscle abnormalities were related to the enhanced systemic oxidative stress. Our analyses revealed that systemic oxidative stress is related to lowered whole-body aerobic capacity and skeletal muscle dysfunction in CHF patients.

New Findings What is the central question of this study? We questioned whether the disruption of invariant natural killer T (iNKT) cells exacerbates left ventricular (LV) remodelling and heart failure after transverse aortic constriction in mice. What are the main findings and their importance? Pressure overload induced by transverse aortic constriction increased the infiltration of iNKT cells in mouse hearts. The disruption of iNKT cells exacerbated LV remodelling and hastened the transition from hypertrophy to heart failure, in association with the activation of mitogen-activated protein kinase signalling. Activation of iNKT cells modulated the immunological balance in this process and played a protective role against LV remodelling and failure. Chronic inflammation is involved in the development of cardiac remodelling and heart failure (HF). Invariant natural killer T (iNKT) cells, a subset of T lymphocytes, have been shown to produce various cytokines and orchestrate tissue inflammation. The pathophysiological role of iNKT cells in HF caused by pressure overload has not been studied. In the present study, we investigated whether the disruption of iNKT cells affected this process in mice. Transverse aortic constriction (TAC) and a sham operation were performed in male C57BL/6J wild-type (WT) and iNKT cell-deficient J alpha 18 knockout (KO) mice. The infiltration of iNKT cells was increased after TAC. The disruption of iNKT cells exacerbated left ventricular (LV) remodelling and hastened the transition to HF after TAC. Histological examinations also revealed that the disruption of iNKT cells induced greater myocyte hypertrophy and a greater increase in interstitial fibrosis after TAC. The expressions of interleukin-10 and tumour necrosis factor-alpha mRNA and their ratio in the LV after TAC were decreased in the KO compared with WT mice, which might indicate that the disruption of iNKT cells leads to an imbalance between T-helper type 1 and type 2 cytokines. The p

Heart failure (HF) is associated with aberrant skeletal muscle impairments. which are closely linked to the severity of HE. A low level of brain-derived neurotrophic factor (BDNF), a myokine produced in the skeletal muscle, is known to be involved in reduced exercise capacity and poor prognosis in HF. However. little is known about the factors or conditions of skeletal muscle associated with BDNF levels. We investigated the association between serum BDNF levels and the skeletal muscle mass and function in HF patients (n = 60. 63 13 years) and age-matched controls (n = 29, 61 +/- 16 years). The serum BDNF level was significantly lower in the HF patients compared to the controls (24.9 +/- 0.9 versus 28.6 +/- 1.3, P = 0.021). In a univariate analysis, BDNF was significantly correlated with the peak oxygen uptake, estimated glomerular filtration rate, 10-m gait speed, and muscle strength, but not with the body mass index or lean mass in the HF group. A multiple linear regression analysis revealed that BDNF was independently associated with muscle strength beta-coefficient = 2.80, 95%CI: 1.89-11.8, P = 0.008). Serum BDNF levels were associated with exercise capacity and skeletal muscle function, but not with muscle mass. These novel findings may suggest that BDNF production is controlled by muscle function and activity and consequently regulates exercise capacity, highlighting the importance of adequate training regarding skeletal muscle in HF patients.

Background Transforming growth factor beta (TGF-beta)-Smad2/3 is the major signaling pathway of fibrosis, which is characterized by the excessive production and accumulation of extracellular matrix (ECM) components, including collagen. Although the ECM is an essential component of skeletal muscle, fibrosis may be harmful to muscle function. On the other hand, our previous studies have shown that levels of angiotensin II, which acts upstream of TGF-beta-Smad2/3 signaling, is increased in mice with myocardial infarction (MI). In this study, we found higher skeletal muscle fibrosis in MI mice compared with control mice, and we investigated the mechanisms involved therein. Moreover, we administered an inhibitor based on the above mechanism and investigated its preventive effects on skeletal muscle fibrosis. Methods Male C57BL/6 J mice with MI were created, and sham-operated mice were used as controls. The time course of skeletal muscle fibrosis post-MI was analyzed by picrosirius-red staining (days 1, 3, 7, and 14). Mice were then divided into 3 groups: sham + vehicle (Sham + Veh), MI + Veh, and MI + lisinopril (an angiotensin-converting enzyme [ACE] inhibitor, 20 mg/kg body weight/day in drinking water; MI + Lis). Lis or Veh was administered from immediately after the surgery to 14 days postsurgery. Results Skeletal muscle fibrosis was significantly increased in MI mice compared with sham mice from 3 to 14 days postsurgery. Although mortality was lower in the MI + Lis mice than the MI + Veh mice, there was no difference in cardiac function between the 2 groups at 14 days. Skeletal muscle fibrosis and hydroxyproline (a key marker of collagen content) were significantly increased in MI + Veh mice compared with the Sham + Veh mice. Consistent with these results, protein expression of TGF-beta and phosphorylated Smad2/3 in the skeletal muscle during the early time points after surgery (days 1-7 postsurgery) and blood angiotensin II at 14 days postsurgery was increased in M

New Findings What is the central question of this study? We questioned whether the disruption of invariant natural killer T (iNKT) cells exacerbates left ventricular (LV) remodelling and heart failure after transverse aortic constriction in mice. What are the main findings and their importance? Pressure overload induced by transverse aortic constriction increased the infiltration of iNKT cells in mouse hearts. The disruption of iNKT cells exacerbated LV remodelling and hastened the transition from hypertrophy to heart failure, in association with the activation of mitogen-activated protein kinase signalling. Activation of iNKT cells modulated the immunological balance in this process and played a protective role against LV remodelling and failure. Chronic inflammation is involved in the development of cardiac remodelling and heart failure (HF). Invariant natural killer T (iNKT) cells, a subset of T lymphocytes, have been shown to produce various cytokines and orchestrate tissue inflammation. The pathophysiological role of iNKT cells in HF caused by pressure overload has not been studied. In the present study, we investigated whether the disruption of iNKT cells affected this process in mice. Transverse aortic constriction (TAC) and a sham operation were performed in male C57BL/6J wild-type (WT) and iNKT cell-deficient J alpha 18 knockout (KO) mice. The infiltration of iNKT cells was increased after TAC. The disruption of iNKT cells exacerbated left ventricular (LV) remodelling and hastened the transition to HF after TAC. Histological examinations also revealed that the disruption of iNKT cells induced greater myocyte hypertrophy and a greater increase in interstitial fibrosis after TAC. The expressions of interleukin-10 and tumour necrosis factor-alpha mRNA and their ratio in the LV after TAC were decreased in the KO compared with WT mice, which might indicate that the disruption of iNKT cells leads to an imbalance between T-helper type 1 and type 2 cytokines. The p

Background Transforming growth factor beta (TGF-beta)-Smad2/3 is the major signaling pathway of fibrosis, which is characterized by the excessive production and accumulation of extracellular matrix (ECM) components, including collagen. Although the ECM is an essential component of skeletal muscle, fibrosis may be harmful to muscle function. On the other hand, our previous studies have shown that levels of angiotensin II, which acts upstream of TGF-beta-Smad2/3 signaling, is increased in mice with myocardial infarction (MI). In this study, we found higher skeletal muscle fibrosis in MI mice compared with control mice, and we investigated the mechanisms involved therein. Moreover, we administered an inhibitor based on the above mechanism and investigated its preventive effects on skeletal muscle fibrosis. Methods Male C57BL/6 J mice with MI were created, and sham-operated mice were used as controls. The time course of skeletal muscle fibrosis post-MI was analyzed by picrosirius-red staining (days 1, 3, 7, and 14). Mice were then divided into 3 groups: sham + vehicle (Sham + Veh), MI + Veh, and MI + lisinopril (an angiotensin-converting enzyme [ACE] inhibitor, 20 mg/kg body weight/day in drinking water; MI + Lis). Lis or Veh was administered from immediately after the surgery to 14 days postsurgery. Results Skeletal muscle fibrosis was significantly increased in MI mice compared with sham mice from 3 to 14 days postsurgery. Although mortality was lower in the MI + Lis mice than the MI + Veh mice, there was no difference in cardiac function between the 2 groups at 14 days. Skeletal muscle fibrosis and hydroxyproline (a key marker of collagen content) were significantly increased in MI + Veh mice compared with the Sham + Veh mice. Consistent with these results, protein expression of TGF-beta and phosphorylated Smad2/3 in the skeletal muscle during the early time points after surgery (days 1-7 postsurgery) and blood angiotensin II at 14 days postsurgery was increased in M

Heart failure (HF) is associated with aberrant skeletal muscle impairments. which are closely linked to the severity of HE. A low level of brain-derived neurotrophic factor (BDNF), a myokine produced in the skeletal muscle, is known to be involved in reduced exercise capacity and poor prognosis in HF. However. little is known about the factors or conditions of skeletal muscle associated with BDNF levels. We investigated the association between serum BDNF levels and the skeletal muscle mass and function in HF patients (n = 60. 63 13 years) and age-matched controls (n = 29, 61 +/- 16 years). The serum BDNF level was significantly lower in the HF patients compared to the controls (24.9 +/- 0.9 versus 28.6 +/- 1.3, P = 0.021). In a univariate analysis, BDNF was significantly correlated with the peak oxygen uptake, estimated glomerular filtration rate, 10-m gait speed, and muscle strength, but not with the body mass index or lean mass in the HF group. A multiple linear regression analysis revealed that BDNF was independently associated with muscle strength beta-coefficient = 2.80, 95%CI: 1.89-11.8, P = 0.008). Serum BDNF levels were associated with exercise capacity and skeletal muscle function, but not with muscle mass. These novel findings may suggest that BDNF production is controlled by muscle function and activity and consequently regulates exercise capacity, highlighting the importance of adequate training regarding skeletal muscle in HF patients.

Epicardial adipose tissue (EAT), a source of adipokines, is metabolically active, but the role of EAT mitochondria in coronary artery disease (CAD) has not been established. We investigated the association between EAT mitochondrial respiratory capacity, adiponectin concentration in the EAT, and coronary atherosclerosis. EAT samples were obtained from 25 patients who underwent elective cardiac surgery. Based on the coronary angiographycal findings, the patients were divided into two groups; coronary artery disease (CAD; n = 14) and non-CAD (n = 11) groups. The mitochondrial respiratory capacities including oxidative phosphorylation (OXPHOS) capacity with non-fatty acid (complex I and complex I + II-linked) substrates and fatty acids in the EAT were significantly lowered in CAD patients. The EAT mitochondrial OXPHOS capacities had a close and inverse correlation with the severity of coronary artery stenosis evaluated by the Gensini score. Intriguingly, the protein level of adiponectin, an anti-atherogenic adipokine, in the EAT was significantly reduced in CAD patients, and it was positively correlated with the mitochondrial OXPHOS capacities in the EAT and inversely correlated with the Gensini score. Our study showed that impaired mitochondrial OXPHOS capacity in the EAT was closely linked to decreased concentration of adiponectin in the EAT and severity of coronary atherosclerosis.

Systemic oxidative stress plays a key role in the development of chronic heart failure (CHF). We tested the hypothesis that mitochondrial reactive oxygen species (ROS) generation in circulating peripheral blood mononuclear cells (PBMCs) contributes to CHF progression. A total of 31 patients who had a history of hospital admission due to worsening HF were enrolled and grouped as having either mild CHF defined as NewYork Heart Association (NYHA) functional class I-II or moderate-to-severe CHF defined as NYHA functional class III. ROS levels in PBMC mitochondria were significantly increased in CHF patients with NYHA functional class III compared to those with NYHA functional class I-II, accompanied by impaired mitochondrial respiratory capacity in PBMCs. ROS generation in PBMC mitochondria was positively correlated with urinary 8-hydroxydeoxyguanosine, a systemic oxidative stress marker, in CHF patients. Importantly, mitochondrial ROS generation in PBMCs was directly correlated with plasma levels of B-type natriuretic peptide, a biomarker for severity of HF, and inversely correlated with peak oxygen uptake, a parameter of exercise capacity, in CHF patients. The study showed that ROS generation in PBMC mitochondria was higher in patients with advanced CHF, and it was associated with disease severity and exercise intolerance in CHF patients.

Epicardial adipose tissue (EAT), a source of adipokines, is metabolically active, but the role of EAT mitochondria in coronary artery disease (CAD) has not been established. We investigated the association between EAT mitochondrial respiratory capacity, adiponectin concentration in the EAT, and coronary atherosclerosis. EAT samples were obtained from 25 patients who underwent elective cardiac surgery. Based on the coronary angiographycal findings, the patients were divided into two groups; coronary artery disease (CAD; n= 14) and non-CAD (n = 11) groups. The mitochondrial respiratory capacities including oxidative phosphorylation (OXPHOS) capacity with non-fatty acid (complex I and complex I + II-linked) substrates and fatty acids in the EAT were significantly lowered in CAD patients. The EAT mitochondrial OXPHOS capacities had a close and inverse correlation with the severity of coronary artery stenosis evaluated by the Gensini score. Intriguingly, the protein level of adiponectin, an anti-atherogenic adipokine, in the EAT was significantly reduced in CAD patients, and it was positively correlated with the mitochondrial OXPHOS capacities in the EAT and inversely correlated with the Gensini score. Our study showed that impaired mitochondrial OXPHOS capacity in the EAT was closely linked to decreased concentration of adiponectin in the EAT and severity of coronary atherosclerosis.

Systemic oxidative stress plays a key role in the development of chronic heart failure (CHF). We tested the hypothesis that mitochondrial reactive oxygen species (ROS) generation in circulating peripheral blood mononuclear cells (PBMCs) contributes to CHF progression. A total of 31 patients who had a history of hospital admission due to worsening HF were enrolled and grouped as having either mild CHF defined as NewYork Heart Association (NYHA) functional class I-II or moderate-to-severe CHF defined as NYHA functional class III. ROS levels in PBMC mitochondria were significantly increased in CHF patients with NYHA functional class III compared to those with NYHA functional class I-II, accompanied by impaired mitochondrial respiratory capacity in PBMCs. ROS generation in PBMC mitochondria was positively correlated with urinary 8-hydroxydeoxyguanosine, a systemic oxidative stress marker, in CHF patients. Importantly, mitochondrial ROS generation in PBMCs was directly correlated with plasma levels of B-type natriuretic peptide, a biomarker for severity of HF, and inversely correlated with peak oxygen uptake, a parameter of exercise capacity, in CHF patients. The study showed that ROS generation in PBMC mitochondria was higher in patients with advanced CHF, and it was associated with disease severity and exercise intolerance in CHF patients.

Epicardial adipose tissue (EAT), a source of adipokines, is metabolically active, but the role of EAT mitochondria in coronary artery disease (CAD) has not been established. We investigated the association between EAT mitochondrial respiratory capacity, adiponectin concentration in the EAT, and coronary atherosclerosis. EAT samples were obtained from 25 patients who underwent elective cardiac surgery. Based on the coronary angiographycal findings, the patients were divided into two groups; coronary artery disease (CAD; n= 14) and non-CAD (n = 11) groups. The mitochondrial respiratory capacities including oxidative phosphorylation (OXPHOS) capacity with non-fatty acid (complex I and complex I + II-linked) substrates and fatty acids in the EAT were significantly lowered in CAD patients. The EAT mitochondrial OXPHOS capacities had a close and inverse correlation with the severity of coronary artery stenosis evaluated by the Gensini score. Intriguingly, the protein level of adiponectin, an anti-atherogenic adipokine, in the EAT was significantly reduced in CAD patients, and it was positively correlated with the mitochondrial OXPHOS capacities in the EAT and inversely correlated with the Gensini score. Our study showed that impaired mitochondrial OXPHOS capacity in the EAT was closely linked to decreased concentration of adiponectin in the EAT and severity of coronary atherosclerosis.

Epicardial adipose tissue (EAT), a source of adipokines, is metabolically active, but the role of EAT mitochondria in coronary artery disease (CAD) has not been established. We investigated the association between EAT mitochondrial respiratory capacity, adiponectin concentration in the EAT, and coronary atherosclerosis. EAT samples were obtained from 25 patients who underwent elective cardiac surgery. Based on the coronary angiographycal findings, the patients were divided into two groups; coronary artery disease (CAD; n= 14) and non-CAD (n = 11) groups. The mitochondrial respiratory capacities including oxidative phosphorylation (OXPHOS) capacity with non-fatty acid (complex I and complex I + II-linked) substrates and fatty acids in the EAT were significantly lowered in CAD patients. The EAT mitochondrial OXPHOS capacities had a close and inverse correlation with the severity of coronary artery stenosis evaluated by the Gensini score. Intriguingly, the protein level of adiponectin, an anti-atherogenic adipokine, in the EAT was significantly reduced in CAD patients, and it was positively correlated with the mitochondrial OXPHOS capacities in the EAT and inversely correlated with the Gensini score. Our study showed that impaired mitochondrial OXPHOS capacity in the EAT was closely linked to decreased concentration of adiponectin in the EAT and severity of coronary atherosclerosis.

Systemic oxidative stress plays a key role in the development of chronic heart failure (CHF). We tested the hypothesis that mitochondrial reactive oxygen species (ROS) generation in circulating peripheral blood mononuclear cells (PBMCs) contributes to CHF progression. A total of 31 patients who had a history of hospital admission due to worsening HF were enrolled and grouped as having either mild CHF defined as NewYork Heart Association (NYHA) functional class I-II or moderate-to-severe CHF defined as NYHA functional class III. ROS levels in PBMC mitochondria were significantly increased in CHF patients with NYHA functional class III compared to those with NYHA functional class I-II, accompanied by impaired mitochondrial respiratory capacity in PBMCs. ROS generation in PBMC mitochondria was positively correlated with urinary 8-hydroxydeoxyguanosine, a systemic oxidative stress marker, in CHF patients. Importantly, mitochondrial ROS generation in PBMCs was directly correlated with plasma levels of B-type natriuretic peptide, a biomarker for severity of HF, and inversely correlated with peak oxygen uptake, a parameter of exercise capacity, in CHF patients. The study showed that ROS generation in PBMC mitochondria was higher in patients with advanced CHF, and it was associated with disease severity and exercise intolerance in CHF patients.

Epicardial adipose tissue (EAT), a source of adipokines, is metabolically active, but the role of EAT mitochondria in coronary artery disease (CAD) has not been established. We investigated the association between EAT mitochondrial respiratory capacity, adiponectin concentration in the EAT, and coronary atherosclerosis. EAT samples were obtained from 25 patients who underwent elective cardiac surgery. Based on the coronary angiographycal findings, the patients were divided into two groups; coronary artery disease (CAD; n= 14) and non-CAD (n = 11) groups. The mitochondrial respiratory capacities including oxidative phosphorylation (OXPHOS) capacity with non-fatty acid (complex I and complex I + II-linked) substrates and fatty acids in the EAT were significantly lowered in CAD patients. The EAT mitochondrial OXPHOS capacities had a close and inverse correlation with the severity of coronary artery stenosis evaluated by the Gensini score. Intriguingly, the protein level of adiponectin, an anti-atherogenic adipokine, in the EAT was significantly reduced in CAD patients, and it was positively correlated with the mitochondrial OXPHOS capacities in the EAT and inversely correlated with the Gensini score. Our study showed that impaired mitochondrial OXPHOS capacity in the EAT was closely linked to decreased concentration of adiponectin in the EAT and severity of coronary atherosclerosis.

Systemic oxidative stress plays a key role in the development of chronic heart failure (CHF). We tested the hypothesis that mitochondrial reactive oxygen species (ROS) generation in circulating peripheral blood mononuclear cells (PBMCs) contributes to CHF progression. A total of 31 patients who had a history of hospital admission due to worsening HF were enrolled and grouped as having either mild CHF defined as NewYork Heart Association (NYHA) functional class I-II or moderate-to-severe CHF defined as NYHA functional class III. ROS levels in PBMC mitochondria were significantly increased in CHF patients with NYHA functional class III compared to those with NYHA functional class I-II, accompanied by impaired mitochondrial respiratory capacity in PBMCs. ROS generation in PBMC mitochondria was positively correlated with urinary 8-hydroxydeoxyguanosine, a systemic oxidative stress marker, in CHF patients. Importantly, mitochondrial ROS generation in PBMCs was directly correlated with plasma levels of B-type natriuretic peptide, a biomarker for severity of HF, and inversely correlated with peak oxygen uptake, a parameter of exercise capacity, in CHF patients. The study showed that ROS generation in PBMC mitochondria was higher in patients with advanced CHF, and it was associated with disease severity and exercise intolerance in CHF patients.

Systemic oxidative stress plays a key role in the development of chronic heart failure (CHF). We tested the hypothesis that mitochondrial reactive oxygen species (ROS) generation in circulating peripheral blood mononuclear cells (PBMCs) contributes to CHF progression. A total of 31 patients who had a history of hospital admission due to worsening HF were enrolled and grouped as having either mild CHF defined as NewYork Heart Association (NYHA) functional class I-II or moderate-to-severe CHF defined as NYHA functional class III. ROS levels in PBMC mitochondria were significantly increased in CHF patients with NYHA functional class III compared to those with NYHA functional class I-II, accompanied by impaired mitochondrial respiratory capacity in PBMCs. ROS generation in PBMC mitochondria was positively correlated with urinary 8-hydroxydeoxyguanosine, a systemic oxidative stress marker, in CHF patients. Importantly, mitochondrial ROS generation in PBMCs was directly correlated with plasma levels of B-type natriuretic peptide, a biomarker for severity of HF, and inversely correlated with peak oxygen uptake, a parameter of exercise capacity, in CHF patients. The study showed that ROS generation in PBMC mitochondria was higher in patients with advanced CHF, and it was associated with disease severity and exercise intolerance in CHF patients.

Epicardial adipose tissue (EAT), a source of adipokines, is metabolically active, but the role of EAT mitochondria in coronary artery disease (CAD) has not been established. We investigated the association between EAT mitochondrial respiratory capacity, adiponectin concentration in the EAT, and coronary atherosclerosis. EAT samples were obtained from 25 patients who underwent elective cardiac surgery. Based on the coronary angiographycal findings, the patients were divided into two groups; coronary artery disease (CAD; n = 14) and non-CAD (n = 11) groups. The mitochondrial respiratory capacities including oxidative phosphorylation (OXPHOS) capacity with non-fatty acid (complex I and complex I + II-linked) substrates and fatty acids in the EAT were significantly lowered in CAD patients. The EAT mitochondrial OXPHOS capacities had a close and inverse correlation with the severity of coronary artery stenosis evaluated by the Gensini score. Intriguingly, the protein level of adiponectin, an anti-atherogenic adipokine, in the EAT was significantly reduced in CAD patients, and it was positively correlated with the mitochondrial OXPHOS capacities in the EAT and inversely correlated with the Gensini score. Our study showed that impaired mitochondrial OXPHOS capacity in the EAT was closely linked to decreased concentration of adiponectin in the EAT and severity of coronary atherosclerosis.

Epicardial adipose tissue (EAT), a source of adipokines, is metabolically active, but the role of EAT mitochondria in coronary artery disease (CAD) has not been established. We investigated the association between EAT mitochondrial respiratory capacity, adiponectin concentration in the EAT, and coronary atherosclerosis. EAT samples were obtained from 25 patients who underwent elective cardiac surgery. Based on the coronary angiographycal findings, the patients were divided into two groups; coronary artery disease (CAD; n = 14) and non-CAD (n = 11) groups. The mitochondrial respiratory capacities including oxidative phosphorylation (OXPHOS) capacity with non-fatty acid (complex I and complex I + II-linked) substrates and fatty acids in the EAT were significantly lowered in CAD patients. The EAT mitochondrial OXPHOS capacities had a close and inverse correlation with the severity of coronary artery stenosis evaluated by the Gensini score. Intriguingly, the protein level of adiponectin, an anti-atherogenic adipokine, in the EAT was significantly reduced in CAD patients, and it was positively correlated with the mitochondrial OXPHOS capacities in the EAT and inversely correlated with the Gensini score. Our study showed that impaired mitochondrial OXPHOS capacity in the EAT was closely linked to decreased concentration of adiponectin in the EAT and severity of coronary atherosclerosis.

Systemic oxidative stress plays a key role in the development of chronic heart failure (CHF). We tested the hypothesis that mitochondrial reactive oxygen species (ROS) generation in circulating peripheral blood mononuclear cells (PBMCs) contributes to CHF progression. A total of 31 patients who had a history of hospital admission due to worsening HF were enrolled and grouped as having either mild CHF defined as NewYork Heart Association (NYHA) functional class I-II or moderate-to-severe CHF defined as NYHA functional class III. ROS levels in PBMC mitochondria were significantly increased in CHF patients with NYHA functional class III compared to those with NYHA functional class I-II, accompanied by impaired mitochondrial respiratory capacity in PBMCs. ROS generation in PBMC mitochondria was positively correlated with urinary 8-hydroxydeoxyguanosine, a systemic oxidative stress marker, in CHF patients. Importantly, mitochondrial ROS generation in PBMCs was directly correlated with plasma levels of B-type natriuretic peptide, a biomarker for severity of HF, and inversely correlated with peak oxygen uptake, a parameter of exercise capacity, in CHF patients. The study showed that ROS generation in PBMC mitochondria was higher in patients with advanced CHF, and it was associated with disease severity and exercise intolerance in CHF patients.

Background: Oxygen uptake (V̇O2) at peak workload and anaerobic threshold (AT) workload are often used for grading heart failure (HF) severity and predicting all-cause mortality. The clinical relevance of respiratory exchange ratio (RER) during exercise, however, is unknown.Methods and Results: We retrospectively studied 295 HF patients (57±15 years, NYHA class I–III) who underwent cardiopulmonary exercise testing. RER was measured at rest; at AT workload; and at peak workload. Peak V̇O2 had an inverse correlation with RER at AT workload (r=−0.256), but not at rest (r=−0.084) or at peak workload (r=0.090). Using median RER at AT workload, we divided the patients into high RER (≥0.97) and low RER (<0.97) groups. Patients with high RER at AT workload were characterized by older age, lower body mass index, anemia, and advanced NYHA class. After propensity score matching, peak V̇O2 tended to be lower in the high-RER than in the low-RER group (14.9±4.5 vs. 16.1±5.0 mL/kg/min, P=0.06). On Kaplan-Meier analysis, HF patients with a high RER at AT workload had significantly worse clinical outcomes, including all-cause mortality and rate of readmission due to HF worsening over 3 years (29% vs. 15%, P=0.01). Conclusions: High RER during submaximal exercise, particularly at AT workload, is associated with poor clinical outcome in HF patients.

Background Exercise intolerance is a common clinical feature and is linked to poor prognosis in patients with heart failure (HF). Skeletal muscle dysfunction, including impaired energy metabolism in the skeletal muscle, is suspected to play a central role in this intolerance, but the underlying mechanisms remain elusive. Lysine acetylation, a recently identified post-translational modification, has emerged as a major contributor to the derangement of mitochondrial metabolism. We thus investigated whether mitochondrial protein acetylation is associated with impaired skeletal muscle metabolism and lowered exercise capacity in both basic and clinical settings of HF. Methods We first conducted a global metabolomic analysis to determine whether plasma acetyl-lysine is a determinant factor for peak oxygen uptake (peak VO2) in HF patients. We then created a murine model of HF (n=11) or sham-operated (n=11) mice with or without limited exercise capacity by ligating a coronary artery, and we tested the gastrocnemius tissues by using mass spectrometry-based acetylomics. A causative relationship between acetylation and the activity of a metabolic enzyme was confirmed in in vitro studies. Results The metabolomic analysis verified that acetyl-lysine was the most relevant metabolite that was negatively correlated with peak VO2 (r = -0.81, P < 0.01). At 4 weeks post-myocardial infarction HF, a treadmill test showed lowered work (distancexbody weight) and peak VO2 in the HF mice compared with the sham-operated mice (111 vs. 23 +/- 1J, P < 0.01; 143 +/- 5 vs. 159 +/- 3mL/kg/min, P = 0.01; respectively). As noted, the protein acetylation of gastrocnemius mitochondria was 48% greater in the HF mice than the sham-operated mice (P = 0.047). Acetylproteomics identified the mitochondrial enzymes involved in fatty acid-oxidation (FAO), the tricarboxylic acid cycle, and the electron transport chain as targets of acetylation. In parallel, the FAO enzyme (beta-hydroxyacyl CoA dehydrogenase) a

Hyperuricemia is an independent predictor of mortality in patients with chronic heart failure. The aim of the study is to determine whether a urate-lowering agent febuxostat, an inhibitor of xanthine oxidase, may improve the clinical outcomes in chronic heart failure patients with hyperuricemia when compared to conventional treatment. This multicenter, prospective, randomized, open-label, blinded endpoint study with a follow-up period of 24 weeks will enroll 200 Japanese chronic heart failure patients with hyperuricemia. The eligibility criteria include a diagnosis of chronic heart failure (New York Heart Association functional class II-III with a history of hospitalization due to worsening of heart failure within the last 2 years), reduced left ventricular systolic function (left ventricular ejection fraction < 40%) and increased plasma natriuretic peptide [plasma B-type natriuretic peptide (BNP) ? 100 pg/mL or N-terminal pro BNP (NT-proBNP) ? 400 pg/mL], and hyperuricemia (serum uric acid >7.0 mg/dL and ? 10 mg/dL) at the screening visit. The primary outcome is the difference in the plasma BNP levels between the baseline and 24 weeks of treatment. The plasma BNP levels are measured in the central laboratory in a blinded manner. This study investigates the efficacy and safety of febuxostat in chronic heart failure patients with hyperuricemia.

Background: Oxygen uptake (V̇O2) at peak workload and anaerobic threshold (AT) workload are often used for grading heart failure (HF) severity and predicting all-cause mortality. The clinical relevance of respiratory exchange ratio (RER) during exercise, however, is unknown.Methods and Results: We retrospectively studied 295 HF patients (57±15 years, NYHA class I–III) who underwent cardiopulmonary exercise testing. RER was measured at rest; at AT workload; and at peak workload. Peak V̇O2 had an inverse correlation with RER at AT workload (r=−0.256), but not at rest (r=−0.084) or at peak workload (r=0.090). Using median RER at AT workload, we divided the patients into high RER (≥0.97) and low RER (<0.97) groups. Patients with high RER at AT workload were characterized by older age, lower body mass index, anemia, and advanced NYHA class. After propensity score matching, peak V̇O2 tended to be lower in the high-RER than in the low-RER group (14.9±4.5 vs. 16.1±5.0 mL/kg/min, P=0.06). On Kaplan-Meier analysis, HF patients with a high RER at AT workload had significantly worse clinical outcomes, including all-cause mortality and rate of readmission due to HF worsening over 3 years (29% vs. 15%, P=0.01). Conclusions: High RER during submaximal exercise, particularly at AT workload, is associated with poor clinical outcome in HF patients.

Background Exercise intolerance is a common clinical feature and is linked to poor prognosis in patients with heart failure (HF). Skeletal muscle dysfunction, including impaired energy metabolism in the skeletal muscle, is suspected to play a central role in this intolerance, but the underlying mechanisms remain elusive. Lysine acetylation, a recently identified post-translational modification, has emerged as a major contributor to the derangement of mitochondrial metabolism. We thus investigated whether mitochondrial protein acetylation is associated with impaired skeletal muscle metabolism and lowered exercise capacity in both basic and clinical settings of HF. Methods We first conducted a global metabolomic analysis to determine whether plasma acetyl-lysine is a determinant factor for peak oxygen uptake (peak VO2) in HF patients. We then created a murine model of HF (n=11) or sham-operated (n=11) mice with or without limited exercise capacity by ligating a coronary artery, and we tested the gastrocnemius tissues by using mass spectrometry-based acetylomics. A causative relationship between acetylation and the activity of a metabolic enzyme was confirmed in in vitro studies. Results The metabolomic analysis verified that acetyl-lysine was the most relevant metabolite that was negatively correlated with peak VO2 (r = -0.81, P < 0.01). At 4 weeks post-myocardial infarction HF, a treadmill test showed lowered work (distancexbody weight) and peak VO2 in the HF mice compared with the sham-operated mice (111 vs. 23 +/- 1J, P < 0.01; 143 +/- 5 vs. 159 +/- 3mL/kg/min, P = 0.01; respectively). As noted, the protein acetylation of gastrocnemius mitochondria was 48% greater in the HF mice than the sham-operated mice (P = 0.047). Acetylproteomics identified the mitochondrial enzymes involved in fatty acid-oxidation (FAO), the tricarboxylic acid cycle, and the electron transport chain as targets of acetylation. In parallel, the FAO enzyme (beta-hydroxyacyl CoA dehydrogenase) a

Hyperuricemia is an independent predictor of mortality in patients with chronic heart failure. The aim of the study is to determine whether a urate-lowering agent febuxostat, an inhibitor of xanthine oxidase, may improve the clinical outcomes in chronic heart failure patients with hyperuricemia when compared to conventional treatment. This multicenter, prospective, randomized, open-label, blinded endpoint study with a follow-up period of 24 weeks will enroll 200 Japanese chronic heart failure patients with hyperuricemia. The eligibility criteria include a diagnosis of chronic heart failure (New York Heart Association functional class II-III with a history of hospitalization due to worsening of heart failure within the last 2 years), reduced left ventricular systolic function (left ventricular ejection fraction < 40%) and increased plasma natriuretic peptide [plasma B-type natriuretic peptide (BNP) ? 100 pg/mL or N-terminal pro BNP (NT-proBNP) ? 400 pg/mL], and hyperuricemia (serum uric acid >7.0 mg/dL and ? 10 mg/dL) at the screening visit. The primary outcome is the difference in the plasma BNP levels between the baseline and 24 weeks of treatment. The plasma BNP levels are measured in the central laboratory in a blinded manner. This study investigates the efficacy and safety of febuxostat in chronic heart failure patients with hyperuricemia.

Hyperuricemia is an independent predictor of mortality in patients with chronic heart failure. The aim of the study is to determine whether a urate-lowering agent febuxostat, an inhibitor of xanthine oxidase, may improve the clinical outcomes in chronic heart failure patients with hyperuricemia when compared to conventional treatment. This multicenter, prospective, randomized, open-label, blinded endpoint study with a follow-up period of 24 weeks will enroll 200 Japanese chronic heart failure patients with hyperuricemia. The eligibility criteria include a diagnosis of chronic heart failure (New York Heart Association functional class II-III with a history of hospitalization due to worsening of heart failure within the last 2 years), reduced left ventricular systolic function (left ventricular ejection fraction < 40%) and increased plasma natriuretic peptide [plasma B-type natriuretic peptide (BNP) ? 100 pg/mL or N-terminal pro BNP (NT-proBNP) ? 400 pg/mL], and hyperuricemia (serum uric acid >7.0 mg/dL and ? 10 mg/dL) at the screening visit. The primary outcome is the difference in the plasma BNP levels between the baseline and 24 weeks of treatment. The plasma BNP levels are measured in the central laboratory in a blinded manner. This study investigates the efficacy and safety of febuxostat in chronic heart failure patients with hyperuricemia.

Skeletal muscle atrophy is induced by an imbalance between protein synthesis and degradation. Our previous studies reported that angiotensin II (AII) directly induced muscle atrophy in mice. This study investigated the role of NAD(P)H oxidase 2 (Nox2) activation by AII in the induction of skeletal muscle atrophy. For 4 weeks, either saline (vehicle: V) or AII (1000 ng kg(-1) min(-1)) was infused into male wild-type (WT) and Nox2 knockout (KO) mice via osmotic minipumps. Experiments were performed in the following 4 groups: WT + V, KO + V, WT + AII, and KO + AII. Body weight, muscle weight, and myocyte cross-sectional area were significantly decreased in WT + AII compared to WT + V mice, and these changes were not observed in KO + AII mice. Akt phosphorylation of Ser473 and p70S6K of Thr389 was decreased, gene expression levels of MuRF-1 and atrogin-1 were increased in WT + AII compared to WT + V, and these changes were significantly attenuated in KO + AII mice. The deletion of Nox2 prevented AII-induced skeletal muscle atrophy via improving the balance between protein synthesis and degradation. Therefore, Nox2 may be a therapeutic target for AII-induced skeletal muscle atrophy.

Background Exercise intolerance is a common clinical feature and is linked to poor prognosis in patients with heart failure (HF). Skeletal muscle dysfunction, including impaired energy metabolism in the skeletal muscle, is suspected to play a central role in this intolerance, but the underlying mechanisms remain elusive. Lysine acetylation, a recently identified post-translational modification, has emerged as a major contributor to the derangement of mitochondrial metabolism. We thus investigated whether mitochondrial protein acetylation is associated with impaired skeletal muscle metabolism and lowered exercise capacity in both basic and clinical settings of HF. Methods We first conducted a global metabolomic analysis to determine whether plasma acetyl-lysine is a determinant factor for peak oxygen uptake (peak VO2) in HF patients. We then created a murine model of HF (n=11) or sham-operated (n=11) mice with or without limited exercise capacity by ligating a coronary artery, and we tested the gastrocnemius tissues by using mass spectrometry-based acetylomics. A causative relationship between acetylation and the activity of a metabolic enzyme was confirmed in in vitro studies. Results The metabolomic analysis verified that acetyl-lysine was the most relevant metabolite that was negatively correlated with peak VO2 (r = -0.81, P < 0.01). At 4 weeks post-myocardial infarction HF, a treadmill test showed lowered work (distancexbody weight) and peak VO2 in the HF mice compared with the sham-operated mice (111 vs. 23 +/- 1J, P < 0.01; 143 +/- 5 vs. 159 +/- 3mL/kg/min, P = 0.01; respectively). As noted, the protein acetylation of gastrocnemius mitochondria was 48% greater in the HF mice than the sham-operated mice (P = 0.047). Acetylproteomics identified the mitochondrial enzymes involved in fatty acid-oxidation (FAO), the tricarboxylic acid cycle, and the electron transport chain as targets of acetylation. In parallel, the FAO enzyme (beta-hydroxyacyl CoA dehydrogen

Skeletal muscle atrophy is induced by an imbalance between protein synthesis and degradation. Our previous studies reported that angiotensin II (AII) directly induced muscle atrophy in mice. This study investigated the role of NAD(P)H oxidase 2 (Nox2) activation by AII in the induction of skeletal muscle atrophy. For 4 weeks, either saline (vehicle: V) or AII (1000 ng kg(-1) min(-1)) was infused into male wild-type (WT) and Nox2 knockout (KO) mice via osmotic minipumps. Experiments were performed in the following 4 groups: WT + V, KO + V, WT + AII, and KO + AII. Body weight, muscle weight, and myocyte cross-sectional area were significantly decreased in WT + AII compared to WT + V mice, and these changes were not observed in KO + AII mice. Akt phosphorylation of Ser473 and p70S6K of Thr389 was decreased, gene expression levels of MuRF-1 and atrogin-1 were increased in WT + AII compared to WT + V, and these changes were significantly attenuated in KO + AII mice. The deletion of Nox2 prevented AII-induced skeletal muscle atrophy via improving the balance between protein synthesis and degradation. Therefore, Nox2 may be a therapeutic target for AII-induced skeletal muscle atrophy.

Background Exercise intolerance is a common clinical feature and is linked to poor prognosis in patients with heart failure (HF). Skeletal muscle dysfunction, including impaired energy metabolism in the skeletal muscle, is suspected to play a central role in this intolerance, but the underlying mechanisms remain elusive. Lysine acetylation, a recently identified post-translational modification, has emerged as a major contributor to the derangement of mitochondrial metabolism. We thus investigated whether mitochondrial protein acetylation is associated with impaired skeletal muscle metabolism and lowered exercise capacity in both basic and clinical settings of HF. Methods We first conducted a global metabolomic analysis to determine whether plasma acetyl-lysine is a determinant factor for peak oxygen uptake (peak VO2) in HF patients. We then created a murine model of HF (n=11) or sham-operated (n=11) mice with or without limited exercise capacity by ligating a coronary artery, and we tested the gastrocnemius tissues by using mass spectrometry-based acetylomics. A causative relationship between acetylation and the activity of a metabolic enzyme was confirmed in in vitro studies. Results The metabolomic analysis verified that acetyl-lysine was the most relevant metabolite that was negatively correlated with peak VO2 (r = -0.81, P < 0.01). At 4 weeks post-myocardial infarction HF, a treadmill test showed lowered work (distancexbody weight) and peak VO2 in the HF mice compared with the sham-operated mice (111 vs. 23 +/- 1J, P < 0.01; 143 +/- 5 vs. 159 +/- 3mL/kg/min, P = 0.01; respectively). As noted, the protein acetylation of gastrocnemius mitochondria was 48% greater in the HF mice than the sham-operated mice (P = 0.047). Acetylproteomics identified the mitochondrial enzymes involved in fatty acid-oxidation (FAO), the tricarboxylic acid cycle, and the electron transport chain as targets of acetylation. In parallel, the FAO enzyme (beta-hydroxyacyl CoA dehydrogenase) a

Hyperuricemia is an independent predictor of mortality in patients with chronic heart failure. The aim of the study is to determine whether a urate-lowering agent febuxostat, an inhibitor of xanthine oxidase, may improve the clinical outcomes in chronic heart failure patients with hyperuricemia when compared to conventional treatment. This multicenter, prospective, randomized, open-label, blinded endpoint study with a follow-up period of 24 weeks will enroll 200 Japanese chronic heart failure patients with hyperuricemia. The eligibility criteria include a diagnosis of chronic heart failure (New York Heart Association functional class II-III with a history of hospitalization due to worsening of heart failure within the last 2 years), reduced left ventricular systolic function (left ventricular ejection fraction < 40%) and increased plasma natriuretic peptide [plasma B-type natriuretic peptide (BNP) ? 100 pg/mL or N-terminal pro BNP (NT-proBNP) ? 400 pg/mL], and hyperuricemia (serum uric acid >7.0 mg/dL and ? 10 mg/dL) at the screening visit. The primary outcome is the difference in the plasma BNP levels between the baseline and 24 weeks of treatment. The plasma BNP levels are measured in the central laboratory in a blinded manner. This study investigates the efficacy and safety of febuxostat in chronic heart failure patients with hyperuricemia.

Background: Oxygen uptake (V̇O2) at peak workload and anaerobic threshold (AT) workload are often used for grading heart failure (HF) severity and predicting all-cause mortality. The clinical relevance of respiratory exchange ratio (RER) during exercise, however, is unknown.Methods and Results: We retrospectively studied 295 HF patients (57±15 years, NYHA class I–III) who underwent cardiopulmonary exercise testing. RER was measured at rest; at AT workload; and at peak workload. Peak V̇O2 had an inverse correlation with RER at AT workload (r=−0.256), but not at rest (r=−0.084) or at peak workload (r=0.090). Using median RER at AT workload, we divided the patients into high RER (≥0.97) and low RER (<0.97) groups. Patients with high RER at AT workload were characterized by older age, lower body mass index, anemia, and advanced NYHA class. After propensity score matching, peak V̇O2 tended to be lower in the high-RER than in the low-RER group (14.9±4.5 vs. 16.1±5.0 mL/kg/min, P=0.06). On Kaplan-Meier analysis, HF patients with a high RER at AT workload had significantly worse clinical outcomes, including all-cause mortality and rate of readmission due to HF worsening over 3 years (29% vs. 15%, P=0.01). Conclusions: High RER during submaximal exercise, particularly at AT workload, is associated with poor clinical outcome in HF patients.

Aims/Introduction: Low aerobic capacity is a strong and independent predictor of all-cause mortality in patients with metabolic syndrome (MetS). Here, we investigated the effects of pioglitazone treatment on whole-body aerobic capacity and skeletal muscle energy metabolism in MetS patients. Materials and Methods: A total of 14 male patients with MetS received oral pioglitazone 15 mg/day for 4 months. To assess whole-body aerobic capacity, exercise testing with a bicycle ergometer was carried out before and after pioglitazone treatment. To assess skeletal muscle energy metabolism, intramyocellular lipid in the resting leg and high-energy phosphates in the calf muscle during plantar-flexion exercise were measured using 1proton- and 31phosphorus magnetic resonance spectroscopy, respectively. Results: Pioglitazone significantly increased peak oxygen uptake (25.1 ± 4.9 mL/kg/min pretreatment vs 27.2 ± 3.9 mL/kg/min post- treatment, P < 0.05) and anaerobic threshold (12.7 ± 1.9 mL/kg/min pretreatment vs 13.6 ± 1.6 mL/kg/min post-treatment, P < 0.05), although daily physical activity was comparable before and after the treatment. Intramyocellular lipid content was significantly reduced after pioglitazone treatment by 26%, indicating improved skeletal muscle fatty acid metabolism. Pioglitazone also significantly decreased the muscle phosphocreatine loss during exercise by 13%, indicating improved skeletal muscle high-energy phosphate metabolism. Notably, the increase in anaerobic threshold; that is, submaximal aerobic capacity, closely correlated with the decrease in intramyocellular lipid content after pioglitazone treatment. Conclusions: Pioglitazone significantly improved the MetS patients' whole-body aerobic capacity and skeletal muscle energy metabolism. The beneficial effect of pioglitazone on whole-body aerobic capacity might be at least in part through improved fatty acid metabolism in the skeletal muscle.

Aims/Introduction: Low aerobic capacity is a strong and independent predictor of all-cause mortality in patients with metabolic syndrome (MetS). Here, we investigated the effects of pioglitazone treatment on whole-body aerobic capacity and skeletal muscle energy metabolism in MetS patients. Materials and Methods: A total of 14 male patients with MetS received oral pioglitazone 15 mg/day for 4 months. To assess whole-body aerobic capacity, exercise testing with a bicycle ergometer was carried out before and after pioglitazone treatment. To assess skeletal muscle energy metabolism, intramyocellular lipid in the resting leg and high-energy phosphates in the calf muscle during plantar-flexion exercise were measured using 1proton- and 31phosphorus magnetic resonance spectroscopy, respectively. Results: Pioglitazone significantly increased peak oxygen uptake (25.1 ± 4.9 mL/kg/min pretreatment vs 27.2 ± 3.9 mL/kg/min post- treatment, P < 0.05) and anaerobic threshold (12.7 ± 1.9 mL/kg/min pretreatment vs 13.6 ± 1.6 mL/kg/min post-treatment, P < 0.05), although daily physical activity was comparable before and after the treatment. Intramyocellular lipid content was significantly reduced after pioglitazone treatment by 26%, indicating improved skeletal muscle fatty acid metabolism. Pioglitazone also significantly decreased the muscle phosphocreatine loss during exercise by 13%, indicating improved skeletal muscle high-energy phosphate metabolism. Notably, the increase in anaerobic threshold; that is, submaximal aerobic capacity, closely correlated with the decrease in intramyocellular lipid content after pioglitazone treatment. Conclusions: Pioglitazone significantly improved the MetS patients' whole-body aerobic capacity and skeletal muscle energy metabolism. The beneficial effect of pioglitazone on whole-body aerobic capacity might be at least in part through improved fatty acid metabolism in the skeletal muscle.

Background: It has been reported that skeletal muscle mass and strength are decreased in patients with heart failure (HF), and HF is associated with both reduced exercise capacity and adverse clinical outcomes. Myostatin has been known as a negative regulator of muscle growth, follistatin as the myostatin antagonist, maintaining tissue homeostasis. We thus determined serum myostatin levels in HF patients and whether they are associated with skeletal muscle wasting. Methods and results: Forty one consecutive HF patients (58 +/- 15 years old, New York Heart Association class I-III) and 30 age-matched healthy subjects as controls (53 +/- 8 years old) were studied. Serum myostatin levels were significantly lower in HF patients than controls (18.7 +/- 7.4 vs. 23.6 +/- 5.2 ng/mL, P < 0.001). Circumference of the thickest part of the right thigh was significantly small (468 +/- 72 vs. 559 +/- 37 mm, P = 0.001) and lower extremity muscular strength was lower in patients with HF (129 +/- 55 vs. 219 +/- 52 N × m, P < 0.001). Fourteen HF patients (34%) had muscle wasting. By univariate analysis, higher age, higher serum follistatin, and lower serum myostatin were significantly associated with the presence of muscle wasting. By multivariate analysis, serum myostatin levels were independently associated with muscle wasting (OR = 0.77, 95% CI [0.58, 0.93], P = 0.02). Conclusion: Serum myostatin levels were significantly decreased in HF patients and associated with lower extremity muscle wasting, suggesting that myostatin may be an important factor for maintaining skeletal muscle mass and strength in HF.

Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6 J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10 mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress.

Background: Transverse aortic constriction (TAC) operation is used as an experimental model of left ventricular (LV) hypertrophy and LV failure in mice. The severity of LV remodeling or failure may depend on the degree of TAC, but is variable among operated animals. Therefore,we tried to identify the optimal diameter of TAC to create this model with ease and high reproducibility. Methods and results: To produce TAC in C57BL/6J mice (7-9 weeks, body weight 19-26 g, n = 109), a 7-0 nylon suture ligature was tightly tied around the transverse aorta against needles with 3 different diameters (mm); 0.40, 0.385 and 0.375. LVwall thickness, end-diastolic dimension, fractional shorteningweremeasured by echocardiography. At 4 weeks after TAC, no mouse with the 0.400 mm gauge progressed in LV failure. The 0.385 mm pin gauge mouse kept a more survival rate compared with the 0.375 mm (59% vs 48%), representing same efficient in LV failure.With the 0.385mmpin gauge, hearts of mice remained LV hypertrophy at 1 week after TAC, followed by LV failure at 4 weeks. Conclusion: TACwith the diameter of 0.385mmcan effectively induce the transition from LV hypertrophy to failure in mice with relatively preserved survival.

Background: Transverse aortic constriction (TAC) operation is used as an experimental model of left ventricular (LV) hypertrophy and LV failure in mice. The severity of LV remodeling or failure may depend on the degree of TAC, but is variable among operated animals. Therefore,we tried to identify the optimal diameter of TAC to create this model with ease and high reproducibility. Methods and results: To produce TAC in C57BL/6J mice (7-9 weeks, body weight 19-26 g, n = 109), a 7-0 nylon suture ligature was tightly tied around the transverse aorta against needles with 3 different diameters (mm); 0.40, 0.385 and 0.375. LVwall thickness, end-diastolic dimension, fractional shorteningweremeasured by echocardiography. At 4 weeks after TAC, no mouse with the 0.400 mm gauge progressed in LV failure. The 0.385 mm pin gauge mouse kept a more survival rate compared with the 0.375 mm (59% vs 48%), representing same efficient in LV failure.With the 0.385mmpin gauge, hearts of mice remained LV hypertrophy at 1 week after TAC, followed by LV failure at 4 weeks. Conclusion: TACwith the diameter of 0.385mmcan effectively induce the transition from LV hypertrophy to failure in mice with relatively preserved survival.

Background: It has been reported that skeletal muscle mass and strength are decreased in patients with heart failure (HF), and HF is associated with both reduced exercise capacity and adverse clinical outcomes. Myostatin has been known as a negative regulator of muscle growth, follistatin as the myostatin antagonist, maintaining tissue homeostasis. We thus determined serum myostatin levels in HF patients and whether they are associated with skeletal muscle wasting. Methods and results: Forty one consecutive HF patients (58 +/- 15 years old, New York Heart Association class I-III) and 30 age-matched healthy subjects as controls (53 +/- 8 years old) were studied. Serum myostatin levels were significantly lower in HF patients than controls (18.7 +/- 7.4 vs. 23.6 +/- 5.2 ng/mL, P < 0.001). Circumference of the thickest part of the right thigh was significantly small (468 +/- 72 vs. 559 +/- 37 mm, P = 0.001) and lower extremity muscular strength was lower in patients with HF (129 +/- 55 vs. 219 +/- 52 N × m, P < 0.001). Fourteen HF patients (34%) had muscle wasting. By univariate analysis, higher age, higher serum follistatin, and lower serum myostatin were significantly associated with the presence of muscle wasting. By multivariate analysis, serum myostatin levels were independently associated with muscle wasting (OR = 0.77, 95% CI [0.58, 0.93], P = 0.02). Conclusion: Serum myostatin levels were significantly decreased in HF patients and associated with lower extremity muscle wasting, suggesting that myostatin may be an important factor for maintaining skeletal muscle mass and strength in HF.

Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6 J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10 mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress.

Background: It has been reported that skeletal muscle mass and strength are decreased in patients with heart failure (HF), and HF is associated with both reduced exercise capacity and adverse clinical outcomes. Myostatin has been known as a negative regulator of muscle growth, follistatin as the myostatin antagonist, maintaining tissue homeostasis. We thus determined serum myostatin levels in HF patients and whether they are associated with skeletal muscle wasting. Methods and results: Forty one consecutive HF patients (58 +/- 15 years old, New York Heart Association class I-III) and 30 age-matched healthy subjects as controls (53 +/- 8 years old) were studied. Serum myostatin levels were significantly lower in HF patients than controls (18.7 +/- 7.4 vs. 23.6 +/- 5.2 ng/mL, P < 0.001). Circumference of the thickest part of the right thigh was significantly small (468 +/- 72 vs. 559 +/- 37 mm, P = 0.001) and lower extremity muscular strength was lower in patients with HF (129 +/- 55 vs. 219 +/- 52 N × m, P < 0.001). Fourteen HF patients (34%) had muscle wasting. By univariate analysis, higher age, higher serum follistatin, and lower serum myostatin were significantly associated with the presence of muscle wasting. By multivariate analysis, serum myostatin levels were independently associated with muscle wasting (OR = 0.77, 95% CI [0.58, 0.93], P = 0.02). Conclusion: Serum myostatin levels were significantly decreased in HF patients and associated with lower extremity muscle wasting, suggesting that myostatin may be an important factor for maintaining skeletal muscle mass and strength in HF.

Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6 J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10 mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress.