Rationale and study design of the GOREISAN for heart failure (GOREISAN-HF) trial: A randomized clinical trial.

BACKGROUND: The decongestion strategy using loop diuretics is essential for improving signs and symptoms of heart failure (HF). However, chronic use of loop diuretics in HF has been linked to worsening renal function and adverse clinical outcomes in a dose-dependent manner. Goreisan, a traditional Japanese herbal medicine, has a long history of use in Japan for regulating body fluid homeostasis and has been recognized as causing less adverse outcomes such as dehydration in contrast to loop diuretics in clinical practice. Therefore, we designed the GOREISAN-HF trial to evaluate the long-term effects of a new decongestion strategy adding Goreisan to usual care in patients with HF and volume overload. METHODS: The GOREISAN-HF trial is an investigator-initiated, multicenter, pragmatic, randomized, comparative effectiveness trial in which we will enroll 2,192 patients hospitalized for HF at 68 hospitals in Japan. All study participants will be randomly assigned to either a decongestion strategy that adds Goreisan at a dose of 7.5 g daily on top of usual care or usual care alone. Investigators have the flexibility to change the existing diuretic regimen in both groups. The primary end point is the improvement rate of cardiac edema at 12-month follow-up, and the co-primary end point is a composite of all-cause death or hospitalization up to the end of the planned follow-up period. Secondary end points include longitudinal changes in patient-reported outcomes, loop diuretics dose, and renal function. CONCLUSIONS: The GOREISAN-HF is the first large-scale randomized pragmatic trial to assess the efficacy and safety of a new congestion control strategy adding Goreisan to usual care in patients with HF and volume overload. REGISTRATION NUMBER: NCT04691700.

The fasting 13C-glucose breath test is a more sensitive evaluation method for diagnosing hepatic insulin resistance as a cardiovascular risk factor than HOMA-IR.

BACKGROUND: Although we previously reported the fasting 13C-glucose breath test (FGBT) was useful for the diagnosis of hepatic insulin resistance (IR), there has been no report in an actual clinical setting. We therefore performed the FGBT in patients with heart disease to assess the difference in the diagnostic ability of HIR between the FGBT and HOMA-IR; we also assessed the relationship between the FGBT and known cardiovascular risk factors. METHODS: Two hundred patients (100 with ischemic heart disease [IHD], 50 with non-ischemic heart disease [NIHD], and 50 with non-cardiac lifestyle-related disease [NCD]) participated in this study. The data of 40 healthy volunteers [HV] was obtained in our previous study. We evaluated the 13C excretion rate at 120 min (C120) as the indicator of hepatic IR in the FGBT. RESULTS: The value of C120 in each disease group was significantly lower than in HV, but the HOMA-IR in the IHD and NCD groups was not significantly different from that in HV. The value of C120 significantly correlated with known cardiovascular risk factors. CONCLUSIONS: These results indicated the FGBT is more sensitive than HOMA-IR for evaluating hepatic IR as a cardiovascular risk factor and is likely useful for managing patients to prevent cardiovascular disease.

Effects of Mokuboito, a Japanese Kampo medicine, on symptoms in patients hospitalized for acute decompensated heart failure - A prospective randomized pilot study.

BACKGROUND: Although standard treatment for heart failure (HF) has been established, it remains difficult to relieve HF-associated symptoms in some patients. Kampo medicines have been used to treat various diseases; however, it remains unclear whether they are effective in HF patients. We therefore performed a prospective, randomized, controlled trial to investigate whether Mokuboito, a Kampo medicine, affected symptoms and other parameters in hospitalized patients with acute decompensated HF (ADHF), as compared to standard therapy alone. METHODS: Forty patients were allocated randomly to Group S (standard therapy alone) or Group M (oral administration of Mokuboito plus standard therapy). The primary outcome was changes in global clinical status based on a visual analog scale (VAS) from baseline at day 10 or discharge if earlier. RESULTS: The decrease in VAS score was significantly greater in Group M than Group S (p=0.001). Although there were no differences between the groups in changes in the secondary endpoints of body weight, peripheral edema, biochemical and echocardiographic parameters, left ventricular end-diastolic diameter, and serum total bilirubin levels were significantly reduced in Group M (p=0.038; 0.002, respectively) but not in Group S, implying that Mokuboito might attenuate organ congestion and cardiac preload. CONCLUSIONS: Oral administration of Mokuboito significantly improved ADHF-related symptoms. Our observations might provide the basis for a novel therapeutic strategy in hospitalized patients with ADHF.

The retinoic acid receptor-related orphan receptor α positively regulates tight junction protein claudin domain-containing 1 mRNA expression in human brain endothelial cells.

Members of the claudin family play important roles in the formation of tight junctions (TJs) in several tissues. Claudin domain containing 1 (CLDND1) is homologous to this family and localizes to TJs and the cytoplasm when exogenously expressed in cultured epithelial cell lines. Furthermore, serum antibody levels of CLDND1-derived peptides are elevated in patients with cerebral infection, cardiovascular disease or diabetes mellitus as compared to healthy controls. However, CLDND1 transcriptional regulation remains poorly analyzed and most regional transcription factor binding sites remain to be defined. Notably, the CLDND1 promoter contains a putative response element for retinoic acid receptor-related orphan receptor α (RORα), which is involved in the above-mentioned disorders. In this study, we found that Cldnd1 and Rora mRNA levels are correlated in rat tissues and that RORα overexpression in human brain endothelial cells enhanced CLDND1 transcript expression. In addition, siRNA-mediated knockdown of RORα significantly decreased CLDND1 transcription. An electrophoresis mobility shift assay indicated that RORα binds to the identified response element in a sequence-specific manner. Furthermore, luciferase reporter assays confirmed that RORα interacts with the CLDND1 promoter to enhance transcription. Taken together, our findings strongly suggest that CLDND1 is a direct RORα target.

Effects of Oral L-Citrulline Supplementation on Lipoprotein Oxidation and Endothelial Dysfunction in Humans with Vasospastic Angina.

BACKGROUND: Decreased nitric oxide (NO) bioavailability and increased lipid oxidation are associated with progressive endothelial dysfunction. L-Citrulline, the effective precursor of L-arginine which is essential as a substrate for endothelial NO synthase (eNOS), is effective in enhancing NO-dependent signaling. However, little is known about the efficacy of L-citrulline supplementation on lipoprotein oxidation and endothelial dysfunction. METHODS: Twenty-two patients (aged 41 - 64 years old) diagnosed with vasospastic angina with flow-mediated dilation (FMD) of the brachial artery (< 5.5 %) received 800 mg/day of L-citrulline for 8 weeks. FMD (%), blood NOx, asymmetric dimethylarginine (ADMA), small dense LDL, oxidized lipids, amino acids concentrations were measured before and after supplementation. RESULTS: Compared with baseline values, FMD (%) was significantly improved at 4 and 8 weeks as well as at 4 weeks after the end of intake. L-Citrulline supplementation caused a significant lowering of plasma ADMA levels. Plasma L-arginine/ADMA ratio and NOx levels rose markedly throughout the study period. Moreover, significant reductions of serum oxidized LDL and lectin-like oxidized LDL receptor 1 (LOX-1) ligand containing ApoB (LAB), an indicator of the biological activity of oxidized lipoprotein binding to LOX-1, were observed after L-citrulline intake. CONCLUSIONS: L-Citrulline supplementation improves endothelial dysfunction, probably due to potentiating NO-dependent reactions and decreasing the state of lipoprotein oxidation in humans.