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.

Heart failure (HF) is a leading cause of hospitalization, morbidity, and mortality in older adults and represents a significant clinical and economic burden on the health care system. However, there are many challenges in assessing and managing HF in elderly patients, who often have coexisting multimorbidity, frailty, and malnutrition. Therefore, it is often difficult to solve these problems with Western medicine alone, and a holistic approach, including Kampo medicine, can be helpful. In particular, managing volume control and frailty by adding Kampo formulas may help improve health-related quality of life and substantially impact prognosis in HF. This review article summarizes the role of Kampo medicine for older patients with HF and frailty.

DELLA proteins are negative regulators of the signaling of gibberellin (GA), a phytohormone regulating plant growth. DELLA degradation is triggered by its interaction with GID1, a soluble GA receptor, in the presence of bioactive GA. We isolated cDNA from a spliced variant of LsDELLA1 mRNA in lettuce, and named it LsDELLA1sv. It was deduced that LsDELLA1sv encodes truncated LsDELLA1, which has DELLA and VHYNP motifs at the N terminus but lacks part of the C-terminal GRAS domain. The recombinant LsDELLA1sv protein interacted with both Arabidopsis GID1 and lettuce GID1s in the presence of GA. A yeast two-hybrid assay suggested that LsDELLA1sv interacted with LsDELLA1. The ratio of LsDELLA1sv to LsDELLA1 transcripts was higher in flower samples at the late reproductive stage and seed samples (dry seeds and imbibed seeds) than in the other organ samples examined. This study suggests that LsDELLA1sv is a possible modulator of GA signaling in lettuce.

The enlargement of receptacle cells during strawberry (Fragaria × ananassa) fruit development is a critical factor determining fruit size, with the increase in cell expansion being one of the most important physiological processes regulated by the phytohormone gibberellin (GA). Here, we studied the role of GA during strawberry fruit development by analyzing the endogenous content of bioactive GAs and the expression of key components of GA signalling and metabolism. Bioactive GA(1) , GA(3) and GA(4) were monitored during fruit development, with the content of GA(4) being extremely high in the receptacle, peaking at the white stage of development. •Genes with high homology to genes encoding GA pathway components, including receptors (FaGID1(GIBBERELLIN-INSENSITIVE DWARF1)b and FaGID1c), DELLA (FaRGA(REPRESSOR OF GA) and FaGAI(GA-INSENSITIVE)), and enzymes involved in GA biosynthesis (FaGA3ox) and catabolism (FaGA2ox), were identified, and their expression in different tissues and developmental stages of strawberry fruit was studied in detail. The expression of all of these genes showed a stage-specific pattern during fruit development and was highest in the receptacle. FaGID1c bound GA in vitro, interacted with FaRGA in vitro and in vivo, and increased GA responses when ectopically expressed in Arabidopsis. This study thus reveals key elements of GA responses in strawberry and points to a critical role for GA in the development of the receptacle.

In Arabidopsis, three receptors exist for the phytohormone gibberellin. Of the three, only a double loss-of-function mutant (atgid1a atgid1c) shows a dwarf phenotype, while other double and all single mutants show no abnormality in height. In this study we show that the expression of AtGID1b-GUS mRNA, driven by the AtGID1b promoter, is low in inflorescence stems, but may be 10% of AtGID1a-GUS mRNA, driven by the AtGID1a promoter. However, AtGID1b-GUS enzymatic activity does not exist in them. This factor strongly suggests that atgid1a atgid1c lacks sufficient AtGID1b protein for normal stem growth. In the stamens of pAtGID1c::AtGID1c-GUS transformants, we detected clear AtGID1c-GUS activity, while another atgid1a atgid1b, which has short stamens in its flowers, causes the adhesion of little pollen to stigmas thus leading to its low fertility. We then evaluated the affinity of the AtGID1-DELLA interaction by a competitive yeast three-hybrid system and also by QCM apparatus. AtGID1c showed a quite lower affinity to RGL2, the major DELLA protein in floral buds, than AtGID1a or AtGID1b. The low affinity of the AtGID1c-RGL2 interaction is likely to be responsible for the failure of AtGID1c to hold RGL2, which is required for normal stamen development. Taken together with expressional information of DELLA genes, we propose that in a double loss-of-function mutant of gibberellin receptors, the emergence of any phenotype(s) depends on the abundance of the remaining receptor and its preference to DELLA proteins existing at a target site.

Gibberellic acid (GA) is both necessary and sufficient to promote fiber elongation in cultured fertilized ovules of the upland cotton variety Coker 312. This is likely due to the temporal and spatial regulation of GA biosynthesis, perception, and subsequent signal transduction that leads to alterations in gene expression and morphology. Our results indicate that the initiation of fiber elongation by the application of GA to cultured ovules corresponds with increased expression of genes that encode xyloglucan endotransglycosylase/hydrolase (XTH) and expansin (EXP) that are involved in promoting cell elongation. To gain a better understanding of the GA signaling components in cotton, that lead to such changes in gene expression, two GA receptor genes (GhGID1a and GhGID1b) and two DELLA protein genes (GhSLR1a and GhSLR1b) that are orthologous to the rice GA receptor (GID1) and the rice DELLA gene (SLR1), respectively, were characterized. Similar to the GA biosynthetic genes, expression of GhGID1a and GhGID1b is under the negative regulation by GA while GA positively regulates GhSLR1a. Recombinant GST-GhGID1s showed GA-binding activity in vitro that was augmented in the presence of GhSLR1a, GhSLR1b, or rice SLR1, indicating complex formation between the receptors and repressor proteins. This was further supported by the GA-dependent interaction of these proteins in yeast cells. Ectopic expression of the GhGID1a in the rice gid1-3 mutant plants rescued the GA-insensitive dwarf phenotype, which demonstrates that it is a functional GA receptor. Furthermore, ectopic expression of GhSLR1b in wild type Arabidopsis led to reduced growth and upregulated expression of DELLA-responsive genes.

Phytochrome regulates lettuce (Lactuca sativa L. cv. Grand Rapids) seed germination via the control of the endogenous level of bioactive gibberellin (GA). In addition to the previously identified LsGA20ox1, LsGA20ox2, LsGA3ox1, LsGA3ox2, LsGA2ox1, and LsGA2ox2, five cDNAs were isolated from lettuce seeds: LsCPS, LsKS, LsKO1, LsKO2, and LsKAO. Using an Escherichia coli expression system and functional assays, it is shown that LsCPS and LsKS encode ent-copalyl diphosphate synthase and ent-kaurene synthase, respectively. Using a Pichia pastoris system, it was found that LsKO1 and LsKO2 encode ent-kaurene oxidases and LsKAO encodes ent-kaurenoic acid oxidase. A comprehensive expression analysis of GA metabolism genes using the quantitative reverse transcription polymerase chain reaction suggested that transcripts of LsGA3ox1 and LsGA3ox2, both of which encode GA 3-oxidase for GA activation, were primarily expressed in the hypocotyl end of lettuce seeds, were expressed at much lower levels than the other genes tested, and were potently up-regulated by phytochrome. Furthermore, LsDELLA1 and LsDELLA2 cDNAs that encode DELLA proteins, which act as negative regulators in the GA signalling pathway, were isolated from lettuce seeds. The transcript levels of these two genes were little affected by light. Lettuce seeds in which de novo GA biosynthesis was suppressed responded almost identically to exogenously applied GA, irrespective of the light conditions, suggesting that GA responsiveness is not significantly affected by light in lettuce seeds. It is proposed that lettuce seed germination is regulated mainly via the control of the endogenous content of bioactive GA, rather than the control of GA responsiveness.

1. Myocardial injury has been shown to be associated with successful percutaneous transluminal coronary angioplasty (PTCA). The present study was designed to determine whether uncomplicated successful PTCA results in myocardial injury by measuring coronary sinus (CS) cardiac troponin T (cTnT). 2. We measured cTnT in the CS and the femoral vein (FV) in 16 patients with stable angina pectoris who underwent uncomplicated PTCA for stenotic lesions of the left anterior descending artery. Blood samples were drawn from both the CS and FV before and immediately after PTCA and every 4 h for the next 12 h. 3. All patients had chest pain and electrocardiographic ST segment elevation or depression during balloon inflation and higher peak elevation of cTnT in the CS than in the FV (0.054 +/- 0.059 vs 0.036 +/- 0.022 ng/mL; P < 0.05). However, all CS cTnT levels were within the normal range over the 12 h period. 4. The fact that CS cTnT measurements showed no evidence of uncomplicated PTCA-related myocardial injury led us to conclude that uncomplicated successful PTCA does not cause myocardial injury.

Atrial fibrillation with organic heart disease shows a steady value for the time constant of left ventricular isovolumetric relaxation (TC), whereas left ventricular contractility varies from beat to beat. However, there is no report on left ventricular relaxation in lone atrial fibrillation. This study assessed left ventricular relaxation in 5 patients with lone atrial fibrillation, 3 with ischemic heart disease and one with hypertrophic cardiomyopathy. Left ventricular pressure was recorded at 3 msec intervals, with a high fidelity micromanometer-tipped catheter. Maximal positive dP/dt (dP/dtmax) and TC of isovolumetric left ventricular relaxation period [P(t) = (P0-P infinity) exp (-t/TC) + P infinity] were measured as indices of left ventricular contractility and left ventricular relaxation, respectively. Correlation coefficients of dP/dtmax and TC versus the ratio of the preceding to the pre-preceding RR-interval (RR2/RR1) were calculated. A good correlation was found between dP/dtmax and RR2/RR1 in all patients (r = 0.71-0.84, p < 0.0001). No correlation between TC and RR2/RR1 was found in patients with atrial fibrillation with organic heart disease, but a good correlation was found between TC and RR2/RR1 in patients with lone atrial fibrillation (r = 0.74-0.95, p < 0.0001). The correlation between TC and RR2/RR1 is well preserved in lone atrial fibrillation. The mechanism of the variation of TC with the RR2/RR1 interval in lone atrial fibrillation may be similar to the change of TC in postextrasystolic potentiation, which is attributed to the change of intracellular Ca2+ concentration. Absence of correlation between TC and RR2/RR1 interval may indicate that left ventricular relaxation is disturbed in patients with atrial fibrillation with organic heart disease.

This study was designed to test the hypothesis that Gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA)-enhanced magnetic resonance images (MRI) reflect the severity of ischemic injury during the acute and chronic phases of myocardial infarction (MI). Twenty-nine patients with their first acute MI underwent Gd-DTPA-enhanced MRI in the first week (4.2+/-0.3 days) and at 1 month after onset. Pairs of left ventriculograms were compared with Gd-DTPA-enhanced magnetic resonance images, classified into 3 pattern groups: hyper-enhancement, with and without a central hypo-enhanced region (P1 and P2, respectively), and non-enhancement (P3). In the acute phase of MI, P1 was found in 10, P2 in 11, and P3 in 8 patients. One month later, the image pattern had changed from P1 to P2 in a single patient, from P2 to P3 in 4 patients, and had remained identical in the others. Patients with P3 showed improvement of anterior wall motion in the 1-month follow-up study, and had higher TIMI flow grades and lower peak creatine kinase values than those without recovery. Thus, Gd-DTPA-enhanced magnetic resonance images, closely reflecting the severity of myocardial injury, are useful in predicting myocardial functional recovery after MI.

We studied the mechanism underlying regional enhancement of myocardial infarction using T1-weighted MRI with gadolinium (Gd)-DTPA. Anterior myocardial infarction (MI) was produced by left anterior descending coronary artery ligation in three groups of rats as follows: 60 minutes occlusion (occlusion group, N = 6), 60 minutes occlusion plus 120 minutes reperfusion (reperfusion group, N = 8), and sham-operated (control, N = 6). In Gd-DTPA-enhanced MRI, MI was demarcated as a hypoenhanced region in the occlusion group and as a homogeneous hyperenhanced region in the reperfusion group. Both Gd-DTPA tissue concentration and tissue water content in the anterior wall were highest in the reperfusion group (P<0.05), a finding suggestive of microscopically observed interstitial edema. The data suggest that regional accumulation of Gd-DTPA in the reperfused group can be explained by increased interstitial water content, contributing to the delayed washout of the water-soluble contrast medium.

With the advent of thrombolytic therapy, hemorrhagic myocardial infarction (HMI) has been observed in experimental and human autopsy studies. However, its clinical implications remain undetermined, because of the absence of a reliable method to detect its presence in vivo. This study was designed to evaluate the clinical implications of HMI detected by magnetic resonance (MR) imaging in vivo after coronary reperfusion. Thirty-nine patients with acute myocardial infarction (AMI) were studied. Percutaneous transluminal coronary angioplasty (PTCA) was used to reopen the occluded coronary artery. Electrocardiogram (ECG)-gated T2*-weighted gradient-echo MR imaging was performed to detect intramyocardial hemorrhage, using a 1.5-T magnet within 2 weeks after coronary reperfusion (average, 5.7 days). Thirteen patients (33%) showed intramyocardial hemorrhage as a distinct hypointense zone by gradient-echo MR imaging and 26 patients showed homogeneous intensity consistent with absence of intramyocardial hemorrhage. Coronary angiograms showed lesser development of collateral flow in the patients with HMI than in those without (81% vs. 37%). Infarct size, estimated 1 month after coronary reperfusion by thallium-201 scintigraphy, was larger among patients with HMI than in those without (37 +/- 14% vs. 21 +/- 14%, respectively, p < 0.05). Left ventricular ejection fraction at 1 month follow-up showed less recovery in patients with HMI than in those without (47 +/- 9 to 51 +/- 10%; p = 0.47, vs. 53 +/- 10 to 60 +/- 9%, respectively, p < 0.05). ECG-gated T2*-weighted gradient-echo MR imaging offers a noninvasive means of detection of intramyocardial hemorrhage in patients with reperfused AMI. HMI occurred even after primary PTCA and may be a common finding associated with severely injured myocardium.

1. The present study was designed to test the hypotheses whether platelet degranulation across the coronary bed is detectable during non-ischaemic periods in patients with vasospastic angina (VSA) and whether the exogenous nitric oxide (NO) donor nitroglycerin (GTN) is able to modify platelet degranulation, reflecting an impaired endothelial production of NO. 2. We studied 13 patients with VSA and 10 controls. The time course of coronary sinus (CS) plasma 5-hydroxytryptamine (5-HT) levels was evaluated every 4 h before and after intravenous infusion of GTN over a period of 40 h. Coronary sinus plasma 5-HT levels were significantly higher at any measured time point in patients with VSA compared with control and were significantly decreased in patients with VSA following treatment with GTN, but not in controls. Femoral artery plasma 5-HT levels remained almost constant throughout the study. The ratio of CS:aorta 6-keto-prostaglandin F1 alpha was significantly and inversely correlated with the transcardiac plasma 5-HT difference only in patients with VSA (r = -0.68; P < 0.02; n = 13). 3. The time course of CS 5-HT levels confirmed significant platelet degranulation across the coronary bed supplied by the spasming artery in patients with VSA and this was modified by GTN. The present data suggest that platelet degranulation occurs during non-ischaemic periods in patients with VSA and that prostacyclin biosynthesis may be a compensatory response to an impaired endothelial release of NO, limiting the degree of the effects of platelet degranulation.

Transcardiac serotonin differences in nonischemic patients with endothelial dysfunction significantly increased in the early morning. Platelet secretion could occur without coronary stenosis.

An 83-year-old female patient with a giant thymic cyst that was successfully treated by percutaneous aspiration and ethanol injection. The patient had complained of coughing and chest discomfort for several years. A chest X-ray film revealed the shadow of a large abnormal mass in the anterior mediastinum. We diagnosed it as a thymic cyst. The patient refused surgery because of her age. We chose a less invasive therapy, namely, ethanol sclerosis of the cyst. The cyst was successfully treated without any complications, and no recurrence was found at the one-year follow-up. This therapy may be one of the best treatments for thymic cysts, especially in very elderly patients.