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Anemia occurs commonly in patients with chronic heart failure (CHF) and has been proposed as a novel therapeutic target in this patient population. The present review will summarize the current knowledge of the prevalence, causative factors, and pathophysiological correlates of anemia in CHF. Potential risks and benefits of therapy with erythropoietic agents for the treatment of anemia in CHF will also be discussed. Prevalence of Anemia in CHF Estimates of the prevalence of anemia in patients with CHF and low ejection fraction range widely from 4% to 61% (median 18%).1–15 Variability in estimated prevalence is partly attributable to use of inconsistent definitions of anemia in individual reports. The World Health Organization definition of anemia (hemoglobin concentration 13.0 g/dL in men and 12.0 g/dL in women) takes into account known gender differences in distribution of hemoglobin values, 16 whereas the National Kidney Foundation defines anemia as hemoglobin 12 g/dL in men and postmenopausal women. 17 These standard definitions of anemia are not based on wellestablished physiological or population norms. Published reports in CHF populations have used these and other study-specific definitions of anemia (including other arbitrary or statistically defined hemoglobin and hematocrit categories and administrative diagnostic codes from hospital records). Despite these inconsistencies in the definition of anemia cases, most studies indicate that the prevalence of anemia is increased in CHF populations with comorbid kidney disease, advanced age, and more severe symptoms (range, 30% to 61%) when compared with less symptomatic ambulatory populations (range, 4% to 23%). In patients with CHF and preserved ejection fraction, the few published reports indicate that anemia is also highly prevalent in this group.18–20 Underlying Cause of Anemia in CHF Anemia occurs when there is a deficiency in new erythrocyte production relative to the rate of removal of aged erythrocytes. Erythropoietin, a 30.4-kDa glycoprotein growth factor produced primarily by kidney, is the key component of the homeostatic system for regulation of red blood cell mass and tissue oxygen delivery.21–24 Erythropoietin prevents the programmed cell death of erythrocyte progenitor cells and thereby stimulates their proliferation, maturation, and terminal differentiation. 23 Any abnormality that reduces renal secretion of or bone marrow response to erythropoietin may result in anemia. Iron deficiency is present in 30% of anemic patients with CHF, so the majority of observed anemia is normocytic, often classified as anemia of chronic disease. Clinical characteristics commonly associated with increased risk of anemia in CHF populations are listed in the Table. Although risk factors for anemia identified in cross-sectional studies do not provide evidence of a causal link, these observations suggest that several distinct mechanisms may commonly contribute to anemia in patients with CHF. Several of the most important potential causal pathways will be discussed briefly below and are summarized in Figure 1. Chronic kidney disease is a common comorbidity in patients with CHF and is a strong independent predictor of increased risk of anemia in several studies. In chronic kidney disease populations without heart failure, moderate to severe kidney disease (defined as glomerular filtration rate [GFR] 60 mL/min) is associated with diminished erythropoietin production and a progressive decrease in hemoglobin values that is linearly related to reduction in GFR.25 The estimated prevalence of at least moderate chronic kidney disease (defined as GFR 60 mL/min) in CHF populations is 20% to 40%. 4,9,26,27 Anemia is frequently associated with decreased body mass index in published reports, a finding that suggests that patients with cachexia are at greater risk for anemia. Serum levels of proinflammatory cytokines are increased in cachectic patients with CHF and may contribute to development of anemia by several mechanisms. Proinflammatory cytokines including tumor necrosis factor- (TNF-), interleukin-1, and interleukin-6 have been shown to disrupt multiple aspects of erythropoiesis, including reduction of renal erythropoietin secretion, suppression of erythropoietin activity in red blood cell precursors in the bone marrow level, and reduction of bioavailability of iron stores for hemoglobin synthesis.28–31 Proinflammatory cytokines also increase levels of the liverderived peptide hormone, hepcidin.32,33 Hepcidin interacts with ferroportin and other iron transport proteins in the enterocyte to inhibit gut iron absorption and thereby reduces iron bioavailability for hemoglobin synthesis. 32,33 In a mouse

It has been verified that losartan has beneficial effects on ventricular remodeling (VRM) after acute myocardial infarction (AMI), but the effects of carvedilol alone or in combination with losartan on this condition have not been defined. The present study used rats to compare the effects of carvedilol and losartan alone and in combination for preventing VRM after AMI. After ligation of the left coronary artery, 100 surviving female Sprague-Dawley rats were randomly assigned to 1 of 4 groups: (1) AMI control (n=25), (2) carvedilol (Car, 1 mg x kg(-1) x day(-1)) (n=25), (3) losartan (Los, 3 mg x kg(-1) x day (-1)) (n=25), and (4) Car (1 mg x kg (-1). day(-1)) + Los (3 mg x kg(-1) x day (-1)) (n=25). A sham-operated group (n=17) was also randomly selected. Drugs were administered by gastric gavage for 4 weeks. After hemodynamic studies, the hearts were fixed and analyzed pathologically. Exclusive of the rats that had died or had an infarct size 55%, complete data were obtained for 65 rats, comprising AMI control (n=13), Car (n=12), Los (n=13), combination (n=14), and sham (n=13) groups. There were no significant differences in the size of infarct among the 4 AMI groups (45.8 approximately 46.7%, all p>0.05). Compared with the sham group, left ventricular (LV) end-diastolic pressure (LVEDP), volume (LVV), weight (LVW) and septal thickness (STh) were all significantly increased (all p

Materials/Methods: cT3-4 rectal cancer patients were randomly assigned to receive either preoperative IG-IMRT (46 Gy in 23 fractions of 2 Gy) with a SIB to the rectal tumor up to a total dose of 55.2 Gy (boost-arm) or preoperative IG-IMRT (46 Gy in 23 fractions of 2 Gy) plus capecitabine (825 mg/m2 twice daily) (chemo-arm). Surgery was performed 6-8 weeks after completion of preoperative treatment. Metabolic tumor activity reduction, assessed by comparing the maximal standardized uptake value (SUVmax) on sequential 18-fluorodeoxyglucose positron emission tomography (FDG-PET), was the primary endpoint. Acute side effects were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Results: To date, 114 patients were randomly assigned to the boost-arm (n Z 55) or chemo-arm (n Z 59). Acute grade 3 toxicity occurred in 4% of the patients in the boost-arm compared to 7% in the chemo-arm (p Z 0.38). No acute grade 4 toxicities were observed. There was a trend for a lower rate of acute grade 2 enteritis in the boost-arm (25% vs 36% in the chemo-arm; p Z 0.16). The R0 resection rate was 98% for patients in the boostand chemo-arm. Pathologic complete response rate (ypCR, Dworak grade 4) was 16% in the boost-arm compared to 21% in the chemo-arm (p Z 0.33). Dworak regression grade 3-4 was 48% and 40% in the boost-arm and chemo-arm, respectively (p Z 0.27). The mean fractional change in SUVmax at 5 weeks after completion of preoperative RT as compared to baseline was 53.5% 19.4% and 50.7% 25.7% for patients in the boost-arm and chemo-arm, respectively (p Z 0.28). Conclusions: The implementation of preoperative IG-IMRT resulted in limited acute grade 3 toxicity in both arms. In terms of downstaging, impressive rates of major histomorphologic regression (Dworak grade 3-4) were recorded in both treatment arms, with no significant difference in the ypCR rate. We observed no differences in metabolic response. Mature data from this ongoing trial are awaited later this year. Author Disclosure: B. Engels: None. A. De Paoli: None. G. Cattari: None. F. Munoz: None. S. Vagge: None. D. Norkus: None. P. Gabriele: None. G. Tabaro: None. H. Versmessen: None. M. De Ridder: None.

Background Recombinant human erythropoietin (rHuEpo) reduces myocardial injury in experimental ischemia and has been proposed as a cardioprotective agent for potential use in acute coronary syndromes. Its safety profile in clinical acute ischemic settings is uncertain because rHuEpo has been reported to increase platelet reactivity and the risk of thromboembolism in some disease populations. Whether prothrombotic effects of rHuEpo mitigate the effects of antiplatelet agents used in acute coronary syndrome patients is unknown. Methods Recombinant human erythropoietin 100, 200, 400 U/kg, or placebo was given intravenously once daily for 3 consecutive days in a double-blind randomized trial in 96 healthy subjects. A single oral dose of aspirin 325 mg or clopidogrel 300 mg was given immediately after the last dose of study drug. Bleeding time and in vitro high shear stress platelet function assays (PFA)–100 were determined before; 5 hours; and 1, 5, and 7 days after aspirin or clopidogrel. Results Recombinant human erythropoietin at doses of 100 and 200 U/kg did not alter bleeding time or PFA-100 closure times at any time point when compared with placebo. Recombinant human erythropoietin at a dose of 400 U/kg significantly blunted the post-aspirin increase in bleeding time when compared with placebo ( P = .03) but did not alter post-clopidogrel bleeding times nor PFA closure times. The 400-U/kg dose did not change hematocrit but did significantly increase the platelet count at 5 days after study drug administration when compared with placebo ( P = .014). Conclusion Short-term rHuEpo at doses up to 200 U/kg did not mitigate the effects of administration of aspirin or clopidogrel on either in vivo or in vitro measures of platelet function in healthy subjects. The 400-U/kg dose attenuated the effects of aspirin on bleeding time and increased the platelet count. Studies of the effects of rHuEpo on platelet function in patients with coronary artery disease are warranted to further characterize dose/safety profile.