Dose-dependent decrease in anti-oxidant capacity of whole blood after irradiation: A novel potential marker for biodosimetry

Many reports have demonstrated that radiation stimulates reactive oxygen species (ROS) production by mitochondria for a few hours to a few days after irradiation. However, these studies were performed using cell lines, and there is a lack of information about redox homeostasis in irradiated animals and humans. Blood redox homeostasis reflects the body condition well and can be used as a diagnostic marker. However, most redox homeostasis studies have focused on plasma or serum, and the anti-oxidant capacity of whole blood has scarcely been investigated. Here, we report changes in the anti-oxidant capacity of whole blood after X-ray irradiation using C57BL/6 J mice. Whole-blood anti-oxidant capacity was measured by electron spin resonance (ESR) spin trapping using a novel spin-trapping agent, 2-diphenylphosphinoyl-2-methyl-3,4-dihydro-2H-pyrrole N-oxide (DPhPMPO). We found that whole-blood anti-oxidant capacity decreased in a dose-dependent manner (correlation factor, r > 0.9; P < 0.05) from 2 to 24 days after irradiation with 0.5–3 Gy. We further found that the red blood cell (RBC) glutathione level decreased and lipid peroxidation level increased in a dose-dependent manner from 2 to 6 days after irradiation. These findings suggest that blood redox state may be a useful biomarker for estimating exposure doses during nuclear and/or radiation accidents

A comparison between hospital follow‐up and collaborative follow‐up in patients with acute heart failure

AIMS: There are no previous studies focusing on collaborative follow-ups between hospitals and clinics for patients discharged after acute heart failure (AHF) in Japan. The purpose of this study was to determine the status of collaboration between hospitals and clinics for patients with AHF in Japan and to compare patient characteristics and clinical outcomes using a large Japanese observational database. METHODS AND RESULTS: Of 4056 consecutive patients hospitalized for AHF in the Kyoto Congestive Heart Failure registry, we analysed 2862 patients discharged to go home, who were divided into 1674 patients (58.5%) followed up at hospitals with index hospitalization (hospital follow-up group) and 1188 (41.5%) followed up in a collaborative fashion with clinics or other general hospitals (collaborative follow-up group). The primary outcome was a composite of all-cause death or heart failure (HF) hospitalization within 1 year after discharge. Previous hospitalization for HF and length of hospital stay longer than 15 days were associated with hospital follow-up. Conversely, ≥80 years of age, hypertension, and cognitive dysfunction were associated with collaborative follow-up. The cumulative 1-year incidence of the primary outcome, all cause death, and cardiovascular death were similar between the hospital and collaborative follow-up groups (31.6% vs. 29.6%, P = 0.51, 13.1% vs, 13.9%, P = 0.35, 8.4% vs. 8.2%, P = 0.96). Even after adjusting for confounders, the difference in risk for patients in the hospital follow-up group relative to those in the collaborative follow-up group remained insignificant for the primary outcome, all-cause death, and cardiovascular death (HR: 1.11, 95% CI: 0.97-1.27, P = 0.14, HR: 1.10, 95% CI: 0.91-1.33, P = 0.33, HR: 0.96, 95% CI: 0.87-1.05, P = 0.33). The cumulative 1-year incidence of HF hospitalization was higher in the hospital follow-up group than in the collaborative follow-up group (25.5% vs. 21.3%, P = 0.02). The risk of HF hospitalization was higher in the hospital follow-up group than in the collaborative follow-up group (HR: 1.19, 95% CI: 1.01-1.39, P = 0.04). CONCLUSIONS: In patients hospitalized for AHF, 41.5% received collaborative follow-up after discharge. The risk of HF hospitalization was higher in the hospital follow-up group than in the collaborative follow-up, although risk of the primary outcome, all-cause death, and cardiovascular death were similar between groups

Metabolic analysis of radioresistant medulloblastoma stem-like clones and potential therapeutic targets

Medulloblastoma is a fatal brain tumor in children, primarily due to the presence of treatment-resistant medulloblastoma stem cells. The energy metabolic pathway is a potential target of cancer therapy because it is often different between cancer cells and normal cells. However, the metabolic properties of medulloblastoma stem cells, and whether specific metabolic pathways are essential for sustaining their stem cell-like phenotype and radioresistance, remain unclear. We have established radioresistant medulloblastoma stem-like clones (rMSLCs) by irradiation of the human medulloblastoma cell line ONS-76. Here, we assessed reactive oxygen species (ROS) production, mitochondria function, oxygen consumption rate (OCR), energy state, and metabolites of glycolysis and tricarboxylic acid cycle in rMSLCs and parental cells. rMSLCs showed higher lactate production and lower oxygen consumption rate than parental cells. Additionally, rMSLCs had low mitochondria mass, low endogenous ROS production, and existed in a low-energy state. Treatment with the metabolic modifier dichloroacetate (DCA) resulted in mitochondria dysfunction, glycolysis inhibition, elongated mitochondria morphology, and increased ROS production. DCA also increased radiosensitivity by suppression of the DNA repair capacity through nuclear oxidization and accelerated the generation of acetyl CoA to compensate for the lack of ATP. Moreover, treatment with DCA decreased cancer stem cell-like characters (e.g., CD133 positivity and sphere-forming ability) in rMSLCs. Together, our findings provide insights into the specific metabolism of rMSLCs and illuminate potential metabolic targets that might be exploited for therapeutic benefit in medulloblastoma

Left atrial reverse remodeling improves risk stratification in patients with heart failure with recovered ejection fraction

We aimed to investigate the relationship between left atrial (LA) reverse remodeling and prognosis of heart failure (HF) with recovered ejection fraction (EF) (HFrecEF). Among 1, 246 patients with acute heart failure enrolled in the prospective longitudinal follow-up study, 397 patients with HF with mildly-reduced EF and with reduced EF at discharge were analyzed. Echocardiography was performed during the index hospitalization and at the 6-month follow-up after discharge. They were divided into non-HFrecEF (n = 227) and HFrecEF (n = 170) groups. The primary outcome measure was a composite of all-cause death or hospitalization for HF. The cumulative 180-day incidence of the primary outcome measure after follow-up echocardiography was significantly lower in the HFrecEF group than in the non-HFrecEF group (8.9% versus 23.4%, log-rank P = 0.0002). LA reverse remodeling was associated with a lower cumulative 6-month incidence of the primary outcome measure in the HFrecEF group (4.7% versus 18.0%; HR: 0.27, 95%CI: 0.09-0.79, P = 0.01), but not in the non-HFrecEF group (24.4% versus 22.6%; HR: 1.13, 95%CI: 0.65-1.96, P = 0.28) with a significant LA reverse remodeling-by-HFrecEF interaction (P for interaction = 0.02). Combination of left ventricular and atrial reverse remodeling may help in improving HF risk stratification

Risk Factors and Clinical Outcomes of Nonhome Discharge in Patients With Acute Decompensated Heart Failure: An Observational Study

Background: No clinical studies have focused on the factors associated with discharge destination in patients with acute decompensated heart failure. Methods and Results: Of 4056 consecutive patients hospitalized for acute decompensated heart failure in the KCHF (Kyoto Congestive Heart Failure) registry, we analyzed 3460 patients hospitalized from their homes and discharged alive. There were 3009 and 451 patients who were discharged to home and nonhome, respectively. We investigated the factors associated with nonhome discharge and compared the outcomes between home discharge and nonhome discharge. Factors independently and positively associated with nonhome discharge were age ≥80 years (odds ratio [OR], 1.76; 95% CI, 1.28–2.42), body mass index ≤22 kg/m2 (OR, 1.49; 95% CI, 1.12–1.97), poor medication adherence (OR, 2.08; 95% CI, 1.49–2.88), worsening heart failure (OR, 2.02; 95% CI, 1.46–2.82), stroke during hospitalization (OR, 3.74; 95% CI, 1.75–8.00), functional decline (OR, 12.24; 95% CI, 8.74–17.14), and length of hospital stay >16 days (OR, 4.14; 95% CI, 3.01–5.69), while those negatively associated were diabetes mellitus (OR, 0.69; 95% CI, 0.51–0.94), cohabitants (OR, 0.62; 95% CI, 0.46–0.85), and ambulatory state before admission (OR, 0.25; 95% CI, 0.18–0.36). The cumulative 1‐year incidence of all‐cause death was significantly higher in the nonhome discharge group than in the home discharge group. The nonhome discharge group compared with the nonhome discharge group was associated with a higher adjusted risk for all‐cause death (hazard ratio, 1.66; P<0.001). Conclusions: The discharge destination of patients with acute decompensated heart failure is influenced by factors such as prehospital social background, age, body mass index, low self‐care ability, events during hospitalization (worsening heart failure, stroke, etc), functional decline, and length of hospital stay; moreover, the prognosis of nonhome discharge patients is worse than that of home discharge patients. Registration Information: clinicaltrials.gov. Identifier: NCT02334891

Prognostic value of reduction in left atrial size during a follow-up of heart failure: an observational study

OBJECTIVE: The association between sequential changes in left atrial diameter (LAD) and prognosis in heart failure (HF) remains to be elucidated. The present study aimed to investigate the link between reduction in LAD and clinical outcomes in patients with HF. DESIGN: A multicentre prospective cohort study. SETTING: This study was nested from the Kyoto Congestive Heart Failure registry including consecutive patients admitted for acute decompensated heart failure (ADHF) in 19 hospitals throughout Japan. PARTICIPANTS: The current study population included 673 patients with HF who underwent both baseline and 6-month follow-up echocardiography with available paired LAD data. We divided them into two groups: the reduction in the LAD group (change <0 mm) (n=398) and the no-reduction in the LAD group (change ≥0 mm) (n=275). PRIMARY AND SECONDARY OUTCOMES: The primary outcome measure was a composite of all-cause death or hospitalisation for HF during 180 days after 6-month follow-up echocardiography. The secondary outcome measures were defined as the individual components of the primary composite outcome measure and a composite of cardiovascular death or hospitalisation for HF. RESULTS: The cumulative 180-day incidence of the primary outcome measure was significantly lower in the reduction in the LAD group than in the no-reduction in the LAD group (13.3% vs 22.2%, p=0.002). Even after adjusting 15 confounders, the lower risk of reduction in LAD relative to no-reduction in LAD for the primary outcome measure remained significant (HR 0.59, 95% CI 0.36 to 0.97 p=0.04). CONCLUSION: Patients with reduction in LAD during follow-up after ADHF hospitalisation had a lower risk for a composite endpoint of all-cause death or HF hospitalisation, suggesting that the change of LAD might be a simple and useful echocardiographic marker during follow-up

Improved and new-onset anemia during follow-up in patients with acute decompensated heart failure

There was no previous report on the prognostic impact of new-onset or improved anemia after discharge from acute decompensated heart failure (ADHF).We analyzed 771 patients with ADHF and who were followed in multicenters in Japan was divided into 4 groups based on the hemoglobin values at discharge and 6-month index visit: 373 patients (48.4%) with persistent anemia, 87 patients (11.3%) with new-onset anemia, 91 patients (11.8%) with improved anemia, and 220 patients (28.5%) without anemia.The primary outcome measure was a composite of all-cause death or HF hospitalization after index visit. The cumulative 6-month incidences of the primary outcome measure were 25.2% for persistent anemia, 18.5% for new onset anemia, 9.0% for improved anemia, and 9.2% for no anemia (log-rank P < .001). Compared with the no anemia group, the excess risk for the primary outcome measure remained significant in the persistent anemia group [hazard ratio (HR) 2.70, 95% confidence interval (95% CI), 1.45-5.44, P = .001] and in the new-onset anemia group (HR 2.73, 95% CI 1.19-6.25, P = .02), while it was not significant in the improved anemia group (HR 1.69, 95% CI 0.68-4.03, P = .25).Persistent and new-onset anemia at 6-month visit were associated with a subsequent higher risk for all-cause death or HF hospitalization in patients with ADHF, suggesting the importance of detecting anemia during follow-up

Lower In-Hospital Mortality With Beta-Blocker Use at Admission in Patients With Acute Decompensated Heart Failure

[Background] It remains unclear whether beta‐blocker use at hospital admission is associated with better in‐hospital outcomes in patients with acute decompensated heart failure. [Methods and Results] We evaluated the factors independently associated with beta‐blocker use at admission, and the effect of beta‐blocker use at admission on in‐hospital mortality in 3817 patients with acute decompensated heart failure enrolled in the Kyoto Congestive Heart Failure registry. There were 1512 patients (39.7%) receiving, and 2305 patients (60.3%) not receiving beta‐blockers at admission for the index acute decompensated heart failure hospitalization. Factors independently associated with beta‐blocker use at admission were previous heart failure hospitalization, history of myocardial infarction, atrial fibrillation, cardiomyopathy, and estimated glomerular filtration rate <30 mL/min per 1.73 m2. Factors independently associated with no beta‐blocker use were asthma, chronic obstructive pulmonary disease, lower body mass index, dementia, older age, and left ventricular ejection fraction <40%. Patients on beta‐blockers had significantly lower in‐hospital mortality rates (4.4% versus 7.6%, P<0.001). Even after adjusting for confounders, beta‐blocker use at admission remained significantly associated with lower in‐hospital mortality risk (odds ratio, 0.41; 95% CI, 0.27–0.60, P<0.001). Furthermore, beta‐blocker use at admission was significantly associated with both lower cardiovascular mortality risk and lower noncardiovascular mortality risk. The association of beta‐blocker use with lower in‐hospital mortality risk was relatively more prominent in patients receiving high dose beta‐blockers. The magnitude of the effect of beta‐blocker use was greater in patients with previous heart failure hospitalization than in patients without (P for interaction 0.04). [Conclusions] Beta‐blocker use at admission was associated with lower in‐hospital mortality in patients with acute decompensated heart failure

Weight loss during follow-up in patients with acute heart failure: From the KCHF registry

[Backgrounds] The prognostic implication of weight loss after discharge from acute heart failure (AHF) remains unclear. We sought to investigate the association of weight loss between discharge and 6-month visit with subsequent clinical outcomes in patients with AHF. [Methods] We analyzed 686 patients with AHF in the prospective longitudinal follow-up study derived from the Kyoto Congestive Heart Failure registry, and divided them into 2 groups based on the weight loss at 6-month index visit. We defined the weight loss as ≥ 5% decrease in body weight from discharge to 6-month index visit. [Results] There were 90 patients (13.1%) with a weight loss at 6-month visit. Patients in the weight loss group compared with those in the no weight loss group had higher body weight at discharge and lower body weight at 6-mont visit. Patients in the weight loss group had a lower systolic blood pressure, higher brain-type natriuretic peptide, lower serum albumin, lower hemoglobin, higher prevalence of heart failure with reduced ejection fraction at 6-month visit, and a lower prescription rate of inhibitors of renin-angiotensin system than those in the no weight loss group. The cumulative 6-month incidence of all-cause death was significantly higher in the weight loss group than in the no weight loss group (14.2% and 4.3%, log-rank P<0.001). The excess adjusted risk of the weight loss group relative to the no weight loss group remained significant for all-cause death (HR 2.39, 95%CI 1.01–5.65, P = 0.048). [Conclusion] Body weight loss of ≥5% at 6-month visit after discharge was associated with subsequent all-cause death in patients with AHF

Serum cholinesterase as a prognostic biomarker for acute heart failure

[Aims]The association between serum cholinesterase and prognosis in acute heart failure (AHF) remains to be elucidated. We investigated the serum cholinesterase level at discharge from hospitalization for AHF and its association with clinical outcomes in patients with AHF. [Methods and results]Among 4056 patients enrolled in the Kyoto Congestive Heart Failure multicentre registry, we analysed 2228 patients with available serum cholinesterase data. The study population was classified into three groups according to serum cholinesterase level at discharge: low tertile (<180 U/L, N = 733), middle tertile (≥180 U/L and <240 U/L, N = 746), and high tertile (≥240 U/L, N = 749). Patients in the low tertile had higher tricuspid pressure gradient, greater inferior vena cava diameter, and higher brain natriuretic peptide (BNP) levels than those in the high tertile. The cumulative 1-year incidence of the primary outcome measure (a composite endpoint of all-cause death and hospitalization for HF) was higher in the low and middle tertiles than in the high tertile [46.5% (low tertile) and 31.4% (middle tertile) vs. 22.1% (high tertile), P < 0.0001]. After adjustment for 26 variables, the excess risk of the low tertile relative to the high tertile for the primary outcome measure remained significant (hazard ratio 1.37, 95% confidence interval 1.10–1.70, P = 0.006). Restricted cubic spline models below the median of cholinesterase demonstrated incrementally higher hazards at low cholinesterase levels. [Conclusions]Low serum cholinesterase levels are associated with congestive findings on echocardiography, higher BNP, and higher risks for a composite of all-cause death and HF hospitalization in patients with AHF