Predictors of postoperative physical functional decline at hospital discharge in elderly patients with prolonged intensive care unit stay after cardiac surgery.

BACKGROUND: A prolonged stay in the intensive care (ICU) is associated with physical function decline following cardiac surgery. To predict physical function decline after cardiac surgery, it may be important to evaluate physical function in the ICU. OBJECTIVES: This study aimed to determine that physical function examination at ICU discharge was independently associated with physical functional decline at hospital discharge in elderly patients who had undergone cardiac surgery and prolonged the ICU stay. METHODS: We assessed physical function before and after cardiac surgery in elderly patients who had spent ≥72 h in the ICU in this retrospective cohort study using the short physical performance battery (SPPB). At hospital discharge, a decrease of at least 1 point on the SPPB was considered a postoperative physical functional decline. Postoperative physical functional decline at hospital discharge was predicted using multiple logistic regression. RESULTS: We revealed postoperative physical functional deterioration in 28.0% of patients who spent ≥72 h in the ICU following cardiac surgery. The Medical Research Council sum score (MRC-SS) (OR: 0.96, 95% CI: 0.82-0.99) and mechanical ventilation days (OR: 1.27, 95% CI: 1.01-1.64) were independently associated with physical functional decline at hospital discharge. CONCLUSIONS: Physical function at ICU discharge and mechanical ventilation days were predictors of postoperative physical functional decline at hospital discharge in patients. MRC-SS was more accurate in predicting postoperative physical functional decline at hospital discharge when performed at the time of ICU discharge.

Dimethyl Fumarate Ameliorated Cardiorenal Anemia Syndrome and Improved Overall Survival in Dahl/Salt-Sensitive Rats.

Cardiovascular disease, chronic kidney disease, and anemia are known to adversely affect each other. Inflammation is commonly involved in these diseases. Cardiorenal anemia syndrome (CRAS) is the name given to this mutually harmful condition. Dimethyl fumarate (DMF) is a Food and Drug Administration-approved antioxidant and anti-inflammatory agent. The purpose of this study was to investigate the effects of DMF on Dahl/salt-sensitive (DS) rats as a CRAS model. Six-week-old DS rats were divided into three groups: the control group, the high-salt (HS) group, and the HS+DMF group. The HS and HS+DMF groups were fed a high-salt diet (8% NaCl) from 6 weeks of age. In the HS+DMF group, DMF (90 mg/kg per day) was orally administered from 6 to 15 weeks of age. Systolic blood pressure was measured every 2 weeks. The heart and renal injuries were assessed with histopathological analysis. The heart and renal expression of mRNAs was assessed by reverse-transcription polymerase chain reaction. DMF significantly improved overall survival, which was shortened by HS in DS rats. Systolic blood pressure increased in the HS group compared with the control group, and DMF tended to suppress this change. DMF ameliorated the cardiac and renal abnormalities confirmed in the HS group by histopathological analysis. Furthermore, the changes in mRNA expressions associated with disease exacerbation in the HS group were suppressed by DMF. DMF also improved anemia. This study suggests that DMF improves overall survival in DS rats through organ-protective effects and is effective against cardiorenal anemia syndrome. SIGNIFICANCE STATEMENT: Dimethyl fumarate was found to improve overall survival in Dahl/salt-sensitive rats, associated with its ability to ameliorate anemia and induce cardioprotective and renoprotective effects through anti-inflammatory and antifibrotic effects.

The differences between conventional lead, thin lead, and leadless pacemakers regarding effects on tricuspid regurgitation in the early phase.

PURPOSE: Trans-venous pacemaker leads are associated with worsening of tricuspid regurgitation (TR) after pacemaker implantation (PMI) in some cases. Recently, leadless pacemakers and thin ventricular pacemaker leads without a stylet lumen have become popular. However, the differences in the effects of these leads on TR are unclear. We investigated differences in the changes in TR in the early phase after PMI in patients with conventional leads, thin leads, and leadless pacemakers. METHODS: We enrolled 65 patients who underwent PMI (32 males, 79 ± 8 years), including 48 with trans-venous PMI (29 with conventional 6.0-Fr leads and 19 with 4.1-Fr thin leads) and 17 with leadless pacemakers. Transthoracic echocardiography was performed before and 1 month after PMI for assessment of conventional echocardiographic parameters and severity of TR by quantitative assessment. RESULTS: Atrial fibrillation was the most frequent indication for PMI in patients with leadless pacemakers (p = 0.015). In the before and 1 month after PMI comparison, left ventricular ejection fraction decreased after PMI only in the conventional lead group (p = 0.022). The TR effective regurgitant orifice area (EROA) decreased post PMI in the leadless (p = 0.002) and thin lead groups (p = 0.001), but not in the conventional lead group (p = 0.596). The change in TR EROA was greater in the leadless and thin lead groups as compared with the conventional lead group (p < 0.05). CONCLUSION: The decrease in TR EROA in the early phase after PMI differed according to the type of pacemaker lead. The thin lead might be beneficial for reduction of TR after PMI.

Clinical utility of reticulocyte hemoglobin equivalent in patients with heart failure.

Anemia and iron deficiency (ID) are common in patients with heart failure (HF) and intravenous (IV) administration of iron to patients hospitalized for decompensated HF with ID improves outcome. The diagnosis of ID in routine practice is based on serum ferritin and transferrin saturation (TSAT) but both have limitations; alternatives should be considered. Reticulocyte hemoglobin equivalent (Ret-He) reflects iron content in reticulocytes but its clinical utility in patients with HF remains uncertain. We prospectively enrolled 142 patients hospitalized for decompensated HF. Sixty five percent had ID as defined in current international guidelines. Ret-He was directly correlated with serum iron and ferritin concentrations and with TSAT. There was a poor relationship between quartile of Ret-He and HF hospitalization or death but increases or decreases in Ret-He between admission and discharge were associated with a worse outcome. The clinical utility of Ret-He for identifying ID and predicting response to IV iron and prognosis for patients with HF requires further investigation.

Successful withdrawal of catecholamine with ivabradine administration in catecholamine-dependent heart failure.

Ivabradine is a heart rate (HR)-lowering agent that blocks hyperpolarization-activated cyclic nucleotide-gated channel in the sinus node without a negative inotropic effect on cardiac function. Here we report a case of catecholamine-dependent heart failure, who was intolerant to ß blockers, and successfully withdrew catecholamine by administering ivabradine. A 39-year-old male acute decompensated heart failure (ADHF) patient with severe systolic cardiac failure, refractory to diuretic and dobutamine treatment was transferred to our hospital. In addition to titration of dobutamine support, intra-aortic balloon pump, mechanical ventilation, and continuous hemodiafiltration therapy were initiated. These mechanical supports could stabilize ADHF and were removed. Upon stabilization of ADHF, we attempted to initiate a low dose of bisoprolol and taper dobutamine, but the patient could not tolerate even a low dose of bisoprolol nor tapering of dobutamine. Since his HR was consistently above 100 beats per minute and ivabradine was reported to improve stroke volume (SV), we initiated ivabradine, and his SV remarkably increased after initiation. Consequently, the dose of dobutamine was successfully tapered. Also, additional clinical advantage of ivabradine, assessed through hemodynamic parameters, appeared to be a reduction in afterload. .

Juzentaihoto improves adenine-induced chronic renal failure in BALB/c mice via suppression of renal fibrosis and inflammation.

Renal inflammation and fibrosis are observed in underlying diseases associated with the pathological progression of chronic kidney disease (CKD). The inhibition of renal inflammation and fibrosis is one method to suppress the progression of CKD. Juzentaihoto (TJ-48), a Kampo medicine, effectively relieves chronic wasting diseases and fatigue and has been reported to decrease inflammation. In this study, we investigated whether TJ-48 has a renal protective effect and its underlying mechanism in mice with adenine-induced CKD. BALB/c mice were divided into four groups for examination: (1) control, (2) dietary restriction, (3) adenine, and (4) adenine + TJ-48. Biochemical and histological analyses, gene expression analysis, and complete blood counts were performed. TJ-48 treatment decreased tubular damage and fibrosis. TJ-48 also decreased creatinine levels exacerbated by adenine, suppressed the mRNA expression of tumor necrosis factor-α, chemokine ligand 2, transforming growth factor-ß, and kidney injury molecule-1, and decreased the neutrophil/lymphocyte ratio increased by adenine. TJ-48 exerts a renoprotective effect possibly via the suppression of fibrosis and inflammation.

Low Quality of Warfarin Therapy is Associated With Female Gender but Not With Polypharmacy in Patients With Atrial Fibrillation.

Background: We examined the impact of polypharmacy on the quality of the anticoagulation therapy in patients with atrial fibrillation. We also examined the factors that affect the stability of warfarin therapy. Methods and Results: This retrospective study was conducted using data from 157 consecutive outpatients with atrial fibrillation in a single tertiary referral hospital. Patients who were prescribed warfarin continuously and for whom PT-INR was examined at least three times in a year were included in this study. We examined the quality of warfarin therapy using time in the therapeutic INR range (TTR), percentage of PT-INR determinations in range (PINRR), and the coefficient variation (CV) of PT-INR. We found that the number of prescribed medicines was significantly associated with high BMI and low eGFR, but not with TTR, PINRR, and the coefficient variation of PT-INR in patients with atrial fibrillation. We also found that female gender was independently associated with low PINRR in this study population. Conclusion: Polypharmacy did not deteriorate the quality of warfarin therapy in patients with atrial fibrillation treated in the tertiary referral hospital. Female gender was an independent predictor of the low quality of warfarin therapy.

Reduced lifespan of erythrocytes in Dahl/Salt sensitive rats is the cause of the renal proximal tubule damage.

We studied the mechanisms of anemia and the influence of anemia on renal pathology in Dahl/Salt Sensitive (Dahl/SS) rat, a model of cardio-renal-anemia syndrome. Erythrocyte lifespan was shortened and associated with decreased hemoglobin level in the Dahl/SS rats given high-salt diet. Serum haptoglobin decreased, reticulocytes increased, and erythropoiesis in the bone marrow and extramedullary hematopoiesis in the spleen was markedly stimulated by increased serum erythropoietin in them. As a mechanism of hemolysis, we investigated the incidence of eryptosis, suicidal death of erythrocytes. Eryptosis was increased, and red blood cell-derived microparticles, small particle which are generated in hemolytic disease, were also increased in Dahl/SS rats fed with high-salt diet. Deposition of hemosiderin and mitochondrial morphologic abnormality, a sign of ferroptosis, in proximal renal tubules was associated with intravascular hemolysis. Treatment with deferasirox, an oral iron chelator, reduced the renal proximal tubular injury and the glomerular sclerosis in Dahl/SS rats fed with high-salt diet. In conclusion, reduced half-life of erythrocytes induced by hemolysis is the major cause of anemia in Dahl/SS rat. Iron accumulation induced by hemolysis causes renal proximal tubule injury and accelerates renal damage in this model.

Polypharmacy Is Associated With Accelerated Deterioration of Renal Function in Cardiovascular Outpatients.

BACKGROUND: Polypharmacy is associated with poor prognosis of patients with various diseases. However, it has not been precisely addressed how polypharmacy affects the clinical characteristics of the cardiovascular outpatients. The aim of this study is to search for the clinical characteristics related to the number of prescribed drugs in the cardiovascular outpatients. Also, we examine whether the number of the prescribed drugs affects the worsening of renal function. METHODS: This retrospective study was conducted using the data of 259 continuous cardiovascular outpatients who were examined complete blood count (CBC) and serum creatinine. RESULTS: In the univariate analysis, the number of prescribed drugs were associated with the number of cardiovascular diseases or their risk factors, age, white blood cells, platelet, body mass index, anemia, and chronic kidney disease stage 3b or higher. In the multivariable analysis, independent variables that significantly correlated with the number of prescribed drugs were the number of cardiovascular diseases or their risk factors, anemia, and chronic kidney disease stage 3b or higher. Among 259 patients, 208 patients received follow-up examination of serum creatinine. The number of prescribed drugs was the only factor that was associated with accelerated deterioration of renal function. CONCLUSIONS: Polypharmacy is associated not only with poor renal function but with accelerated deterioration of renal function. Polypharmacy may be causally related with renal dysfunction.

Neutrophil/lymphocyte ratio elevation in renal dysfunction is caused by distortion of leukocyte hematopoiesis in bone marrow.

OBJECTIVE: We investigate the mechanism of neutrophil/lymphocyte ratio (NLR) elevation, a useful prognostic marker in patients with cardiovascular diseases (CVDs). METHODS: In this clinical study, we retrospectively searched for factors associated with NLR elevation in cardiovascular outpatients. In animal experiments using mice with adenine-induced nephropathy, we further examined the hematopoietic process in bone marrow and explored the mechanism of NLR elevation. RESULT: In patients with CVDs or their risk factors, multiple regression analysis revealed that decrease in estimated glemerular filtration rate and increase in white blood cell count were significantly associated with increase in NLR. In mice with adenine-induced nephropathy, NLR and serum indoxyl sulfate (IS) levels were increased. Fluorescence-activated cell sorting revealed the increase in the number of myeloid progenitors and decrease in the number of common lymphoid progenitors, suggesting biased granulocyte side in the hematopoietic process in bone marrow. Treatment with oral charcoal adsorbent AST-120 decreased serum concentration of IS and normalized NLR and bone marrow abnormalities in mice with adenine-induced nephropathy. CONCLUSION: Renal function was a strong determinant of NLR in cardiovascular outpatients. NLR elevation due to renal impairment is caused by distortion of the hematopoietic process in bone marrow. IS plays a significant role in these processes.

Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure.

Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor, which has been widely utilized throughout the cancer research field. SAHA-induced radiosensitization in normal human fibroblasts AG1522 and lung carcinoma cells A549 were evaluated with a combination of γ-rays, proton, and carbon ion exposure. Growth delay was observed in both cell lines during SAHA treatment; 2 µM SAHA treatment decreased clonogenicity and induced cell cycle block in G1 phase but 0.2 µM SAHA treatment did not show either of them. Low LET (Linear Energy Transfer) irradiated A549 cells showed radiosensitization effects on cell killing in cycling and G1 phase with 0.2 or 2 µM SAHA pretreatment. In contrast, minimal sensitization was observed in normal human cells after low and high LET radiation exposure. The potentially lethal damage repair was not affected by SAHA treatment. SAHA treatment reduced the rate of γ-H2AX foci disappearance and suppressed RAD51 and RPA (Replication Protein A) focus formation. Suppression of DNA double strand break repair by SAHA did not result in the differences of SAHA-induced radiosensitization between human cancer cells and normal cells. In conclusion, our results suggest SAHA treatment will sensitize cancer cells to low and high LET radiation with minimum effects to normal cells.

The major DNA repair pathway after both proton and carbon-ion radiation is NHEJ, but the HR pathway is more relevant in carbon ions.

The purpose of this study was to identify the roles of non-homologous end-joining (NHEJ) or homologous recombination (HR) pathways in repairing DNA double-strand breaks (DSBs) induced by exposure to high-energy protons and carbon ions (C ions) versus gamma rays in Chinese hamster cells. Two Chinese hamster cell lines, ovary AA8 and lung fibroblast V79, as well as various mutant sublines lacking DNA-PKcs (V3), X-ray repair cross-complementing protein-4 [XRCC4 (XR1), XRCC3 (irs1SF) and XRCC2 (irs1)] were exposed to gamma rays ((137)Cs), protons (200 MeV; 2.2 keV/µm) and C ions (290 MeV; 50 keV/µm). V3 and XR1 cells lack the NHEJ pathway, whereas irs1 and irs1SF cells lack the HR pathway. After each exposure, survival was measured using a clonogenic survival assay, in situ DSB induction was evaluated by immunocytochemical analysis of histone H2AX phosphorylation at serine 139 (γ-H2AX foci) and chromosome aberrations were examined using solid staining. The findings from this study showed that clonogenic survival clearly depended on the NHEJ and HR pathway statuses, and that the DNA-PKcs(-/-) cells (V3) were the most sensitive to all radiation types. While protons and γ rays yielded almost the same biological effects, C-ion exposure greatly enhanced the sensitivity of wild-type and HR-deficient cells. However, no significant enhancement of sensitivity in cell killing was seen after C-ion irradiation of NHEJ deficient cells. Decreases in the number of γ-H2AX foci after irradiation occurred more slowly in the NHEJ deficient cells. In particular, V3 cells had the highest number of residual γ-H2AX foci at 24 h after C-ion irradiation. Chromosomal aberrations were significantly higher in both the NHEJ- and HR-deficient cell lines than in wild-type cell lines in response to all radiation types. Protons and gamma rays induced the same aberration levels in each cell line, whereas C ions introduced higher but not significantly different aberration levels. Our results suggest that the NHEJ pathway plays an important role in repairing DSBs induced by both clinical proton and C-ion beams. Furthermore, in C ions the HR pathway appears to be involved in the repair of DSBs to a greater extent compared to gamma rays and protons.

Use of proton pump inhibitors is associated with anemia in cardiovascular outpatients.

BACKGROUND: Proton pump inhibitors (PPI) are frequently prescribed in combination with aspirin for preventing peptic ulcer in patients with atherosclerotic diseases. In contrast, long-term use of PPI has been suggested to be associated with iron or vitamin B12 deficiency. The effect of PPI on hemoglobin (Hb) concentration, however, has not been clarified in cardiovascular outpatients. METHODS AND RESULTS: We retrospectively investigated the clinical characteristics of 278 continuous outpatients who received blood test including complete blood count and serum creatinine concentration (mean age, 69.9 ± 10.8 years; male, 68.7%). The frequency of anemia was 51% in patients receiving PPI and 19% in those not receiving PPI (chi-squared test, P<0.001). On multivariate analysis female sex (P<0.001), peripheral artery disease (P=0.003), PPI (P=0.003), low white blood cell count (P=0.004), old age (P=0.007), and low estimated glomerular filtration rate (P=0.010) were independently associated with low Hb. Among these patients, we investigated the change in Hb after the initiation of PPI in 36 patients for whom data on Hb level within 1 year before and within 1 year after the initiation of PPI were available. Mean decrease in Hb after the initiation of PPI was 0.38 ± 0.87 g/dl (95% confidence interval: -0.67 to -0.09 g/dl). CONCLUSIONS: Use of PPI was associated with anemia in Japanese cardiovascular outpatients.

Intravenous salt supplementation with low-dose furosemide for treatment of acute decompensated heart failure.

BACKGROUND: Theoretically, salt supplementation should promote diuresis through increasing the glomerular filtration rate (GFR) during treatment of acute decompensated heart failure (ADHF) even with low-dose furosemide; however, there is little evidence to support this idea. METHODS AND RESULTS: This was a prospective, randomized, open-label, controlled trial that compared the diuretic effectiveness of salt infusion with that of glucose infusion supplemented with low-dose furosemide in 44 consecutive patients with ADHF. Patients were randomly administered 1.7% hypertonic saline solution supplemented with 40 mg furosemide (salt infusion group) or glucose supplemented with 40 mg furosemide (glucose infusion group). Our major end points were 24-hour urinary volume and GFR. Urinary volume was greater in the salt infusion group than in the glucose infusion group (2,701 ± 920 vs 1,777 ± 797 mL; P < .001). There was no significant difference in the estimated GFR at baseline. Creatinine clearance for 24 h was greater in the salt infusion group than in the glucose infusion group (63.5 ± 52.6 vs 39.0 ± 26.3 mL min(-1) 1.73 m(-2); P = .048). CONCLUSIONS: Salt supplementation rather than salt restriction evoked favorable diuresis through increasing GFR. The findings support an efficacious novel approach of the treatment of ADHF.