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• Depression is a major contributor to heart failure (HF) progression. • Chronic HF patients with depression had a lowered citrus fruit intake. • Dietary intakes of antioxidants were also decreased in depressed HF patients. • A lowered intake of citrus fruits was associated with depression in HF patients. 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. 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). 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, β-carotene, and β-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. 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. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Skeletal muscle is quantitatively and qualitatively impaired in patients with heart failure (HF), which is closely linked to lowered exercise capacity. Ultrasonography (US) for skeletal muscle has emerged as a useful, noninvasive tool to evaluate muscle quality and quantity. Here we investigated whether muscle quality based on US-derived echo intensity (EI) is associated with exercise capacity in patients with HF.Methods and Results: Fifty-eight patients with HF (61 ± 12 years) and 28 control subjects (58 ± 14 years) were studied. The quadriceps femoris echo intensity (QEI) was significantly higher and the quadriceps femoris muscle thickness (QMT) was significantly lower in the patients with HF than the controls (88.3 ± 13.4 vs 81.1 ± 7.5, P= .010; 5.21 ± 1.10 vs 6.54 ±1.34 cm, P< .001, respectively). By univariate analysis, QEI was significantly correlated with age, peak oxygen uptake (VO2), and New York Heart Association class in the HF group. A multivariable analysis revealed that the QEI was independently associated with peak VO2 after adjustment for age, gender, body mass index, and QMT: β-coefficient = -11.80, 95%CI (-20.73, -2.86), P= .011.Conclusion: Enhanced EI in skeletal muscle was independently associated with lowered exercise capacity in HF. The measurement of EI is low-cost, easily accessible, and suitable for assessment of HF-related alterations in skeletal muscle quality. [ABSTRACT FROM AUTHOR]

Mitochondrial function is reduced in skeletal muscles of many patients with systemic diseases and it is difficult to deliver medicinal substances to mitochondria in such tissue. In this study, we report on attempts to develop liposome-based carriers for mitochondrial delivery using mouse myoblasts (C2C12) by varying the lipid composition of the carriers. We found that a liposome that contains an optimal lipid modified with the KALA peptide (a cellular uptake and mitochondrial targeting device) was the most effective nanocarrier for achieving mitochondrial delivery in C2C12 cells. We also report on successful mitochondrial transgene expression using the carriers encapsulating a mitochondrial DNA vector as we previously reported. • We succeeded in developing a nano carrier for mitochondrial delivery using myoblasts. • We also report on successful mitochondrial transgene expression using this carrier. • A KALA peptide modification to a liposome was effective for mitochondrial delivery. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Brain-derived neurotropic factor (BDNF) is involved in cardiovascular diseases as well as skeletal muscle energy metabolism and depression. We investigated whether serum BDNF level was associated with prognosis in patients with heart failure (HF). Methods and Results We measured the serum BDNF level in 58 patients with HF (59.2 ± 13.7 years old, New York Heart Association functional class I–III) at baseline, and adverse events, including all cardiac deaths and HF rehospitalizations, were recorded during the median follow-up of 20.3 months. In a univariate analysis, serum BDNF levels were significantly associated with peak oxygen capacity (β = 0.547; P = .003), anaerobic threshold (β = 0.929; P = .004), and log minute ventilation/carbon dioxide production slope (β = −10.15; P = .005), but not Patient Health Questionnaire scores (β = −0.099; P = .586). A multivariate analysis demonstrated that serum BDNF level was an independent prognostic factor of adverse events (hazard ratio 0.41, 95% confidence interval 0.20–0.84; P = .003). The receiver operating characteristic curve demonstrated that low levels of BDNF (<17.4 ng/mL) were associated with higher rates of adverse events compared with high levels of BDNF (≥17.4 ng/mL; log rank test: P < .001). Conclusions Decreased serum BDNF levels were significantly associated with adverse outcomes in HF patients, suggesting that these levels can be a useful prognostic biomarker. [ABSTRACT FROM AUTHOR]

Background The characteristics, in-hospital management, and outcomes of patients hospitalized with worsening heart failure (HF) have been described by large-scale registries performed mainly in the USA and Europe. However, little information is available in Japan. We thus clarified the characteristics and clinical status as well as in-hospital management and outcomes among patients hospitalized with worsening HF in Japan and compared them with those reported in previous studies. Methods The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) studied prospectively the characteristics and treatments in patients hospitalized with worsening HF. From the total cohort of JCARE-CARD, 1677 patients were randomly selected and their detailed data during acute phase were collected as another registry database in the present study. The characteristics, in-hospital management, and outcomes were analyzed. Results The mean age was 70.7 years and 59.4% were male. Etiology was ischemic in 34.0% and mean left ventricular ejection fraction was 42.5%. Carperitide was highly used as in-hospital management in Japan (33.5%) compared to the use of nesiritide in the USA (8–11%). The use of angiotensin-converting enzyme inhibitors was lower and angiotensin II receptor blockers (ARB) were more commonly used in this study compared to other studies in the USA and Europe. In-hospital crude mortality rate was comparable among studies (4–8%), however, length of stay was longer in Japan (15–20 versus 4–9 days). Conclusions The characteristics, clinical status, and laboratory data on admission in patients hospitalized with worsening HF were similar between the present study and previous Japanese and western studies. Management was also similar except for higher use of carperitide and ARB. The most striking difference between Japanese registries and those from the USA and Europe was the longer length of stay. [ABSTRACT FROM AUTHOR]

Background: A subset of patients with hypertrophic cardiomyopathy (HCM) has been reported to progress into dilated-HCM (D-HCM), characterized by left ventricular (LV) systolic dysfunction and cav-ity dilatation, resembling idiopathic dilated cardiomyopathy (DCM). We compared the characteristics, treatments, and outcomes in patients with heart failure (HF) due to D-HCM vs. DCM by using national registry data in Japan. Methods and results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) is a prospective observational study of patients hospitalized due to worsening HF with an average of 2.2 years of follow-up. Patients with D-HCM (n = 41) were more likely to be male, have prior stroke, atrial fibrillation, and sustained ventricular tachycardia or ventricular fibrillation compared with DCM (n = 486). Echocardiography demonstrated that D-HCM patients had smaller LV end-systolic diameter, higher ejec-tion fraction, and greater wall thickness. Treatments for HF including angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, ß-blocker, and spironolactone were similar between groups except for higher use of amiodarone, warfarin, and implantable cardioverter-defibrillator for D-HCM. Mortality was significantly higher in patients with D-HCM (29.7% vs. 14.4%; p < 0.05). Sudden death tended to be higher also in D-HCM (8.1% vs. 2.6%; p = 0.06), which, however, did not reach statistical significance. Conclusions: HF patients with D-HCM had higher mortality risk than those with DCM. Effective manage-ment strategies are critically needed to be established for D-HCM. [ABSTRACT FROM AUTHOR]

Background: The RALES trial demonstrated that spironolactone improved the prognosis of patients with heart failure (HF). However, it is unknown whether the discharge use of spironolactone is associated with better long-term outcomes among hospitalized systolic HF patients in routine clinical practice. We examined the effects of spironolactone use at discharge on mortality and rehospitalization by comparing with outcomes in patients who did not receive spironolactone. Methods: The JCARE-CARD studied prospectively the characteristics and treatments in a broad sample of patients hospitalized with worsening HF and the outcomes were followed with an average of 2.2 years of follow-up. Results: A total of 946 patients had HF with reduced left ventricular ejection fraction (LVEF) (<40%), among whom spironolactone was prescribed at discharge in 435 patients (46%), but not in 511 patients (54%). The mean age was 66.3 years and 72.2% were male. Etiology was ischemic in 39.7% and mean LVEF was 27.1%. After adjustment for covariates, discharge use of spironolactone was associated with a significant reduction in all-cause death (adjusted hazard ratio 0.612, P = .020) and cardiac death (adjusted hazard ratio 0.524, P = .013). Conclusions: Among patients with HF hospitalized for systolic dysfunction, spironolactone use at the time of discharge was associated with long-term survival benefit. These findings provide further support for the idea that spironolactone may be useful in patients hospitalized with HF and reduced LVEF. [ABSTRACT FROM AUTHOR]

Summary: Recent epidemiological studies have demonstrated that nearly half of all patients with heart failure (HF) have preserved left ventricular ejection fraction (HFPEF). Compared to those with reduced EF, patients with HFPEF are older, more likely to be women, less likely to have coronary artery disease, and more likely to have hypertension and atrial fibrillation. Patients with HFPEF receive different pharmacological as well as nonpharmacological treatments from those with reduced EF. Morbidity and mortality in patients with HFPEF are largely similar to those with reduced EF. Although much information has recently been obtained about the clinical characteristics, medications, and outcomes of HFPEF by large-scale clinical and epidemiological studies, effective management strategies need to be established for this type of HF. [Copyright &y& Elsevier]

Sarcopenia is characterized by muscle mass and strength loss and reduced physical activity. Branched-chain amino acids (BCAAs) were recently described as an activator of protein synthesis via mammalian target of rapamycin (mTOR) signaling for muscle atrophy. In cardiovascular diseases, excessive activation of the renin-angiotensin system may induce an imbalance of protein synthesis and degradation, and this plays a crucial role in muscle atrophy. We investigated the effects of BCAAs on angiotensin II (Ang II)-induced muscle atrophy in mice. We administered Ang II (1000 ng/kg/min) or vehicle to 10–12-week-old male C57BL/6J mice via subcutaneous osmotic minipumps for 4 weeks with or without BCAA supplementation (3% BCAA in tap water). The skeletal muscle weight/tibial length and cross-sectional area were smaller in the Ang II mice than the vehicle mice; these changes were induced by an imbalance of protein synthesis and degradation signaling such as Akt/mTOR and MuRF-1/Atrogin-1. Compared to the Ang II mice, the mTOR signaling was significantly activated and Ang II-induced muscle atrophy was ameliorated in the Ang II + BCAA mice, and this attenuated the reduction of exercise capacity. Notably, the decrease of muscle weight/tibial length in the fast-twitch dominant muscles (e.g., the extensor digitorum longus) was significantly ameliorated compared to that in the slow-twitch dominant muscles (e.g., soleus). Histologically, the effect of BCAA was larger in fast-twitch than slow-twitch fibers, which may be related to the difference in BCAA catabolism. BCAA supplementation could contribute to the prevention of skeletal muscle atrophy induced by Ang II. Unlabelled Image [ABSTRACT FROM AUTHOR]