Endogenous and exogenous erythropoietin in left ventricular dysfunction

Dit proefschrift heeft zich gericht op onderzoek naar erytropoietine (Epo). Ten eerste is het effect bestudeerd van gesynthetiseerd Epo op de pompfunctie wanneer dit werd toegediend aan patiënten met een acuut myocardinfarct (HEBE III studie). Ten tweede werd bij hartfalenpatiënten het lichaamseigen Epo en de oorzaken van anemie onderzocht. In het eerste deel van dit proefschrift worden de opzet en de resultaten van de HEBE III studie beschreven. De HEBE III studie is een gerandomiseerde, multicenter studie waaraan in totaal 529 patiënten hebben deelgenomen. Patiënten werden behandeld met een eenmalige hoge dosering Epo na een succesvolle dotterbehandeling voor een eerste myocardinfarct. De pompfunctie werd 6 weken na het infarct bepaald met behulp van een MUGA scan. De resultaten van deze studie worden gepubliceerd in dit proefschrift. Het tweede deel omvat onderzoek naar het lichaamseigen Epo-gehalte en de oorzaken van anemie in hartfalenpatiënten. Verhoogde ontstekingsfactoren in hartfalenpatiënten blijken voorspellend te zijn voor de aanwezigheid van anemie en zijn geassocieerd met een slechtere prognose. Een andere studie toonde aan dat de samenhang tussen Epo en hemoglobine verdwijnt, wanneer hartfalen ontstaat. Een derde studie liet zien dat patiënten met persisterend verhoogde Epo-spiegels gedurende follow-up én patiënten die Epo-resistent lijken (hogere Epo spiegel dan verwacht obv het hemoglobine gehalte), een slechtere prognose hebben. Samenvattend kan worden geconcludeerd dat bij patiënten met hartfalen sprake is van verhoogde Epo-spiegels in het bloed hetgeen samenhangt met een ongunstige prognose. De hoogte van het Epo-gehalte lijkt niet zozeer te worden bepaald door het Hb-niveau, maar eerder door verhoogde ontstekingsfactoren.

Non-communicable diseases in Indian slums: re-framing the Social Determinants of Health

Background: The epidemic of non-communicable diseases (NCDs) in slums has pushed its residents to heightened vulnerability. The Social Determinants of Health (SDH) framework has been used to understand the social dynamics and impact of NCDs, especially in poorly resourced communities. Whilst the SDH has helped to discredit the characterisation of NCDs as diseases of affluence, its impact on policy has been less definite. Given the multitude of factors that interact in the presentation of NCDs, operationalising the SDH for policies and programmes that account for the contextual complexity of slums has stalled. Objective: To organise the complex networks of relations between SDH in slums so as to identify options for Indian municipal policy that are feasible to implement in the short term. Methods: The study reviews the literature describing SDH in Indian slums, specifically those that establish causal relations between SDH and NCDs. Root cause analysis was then used to organise the identified relations of SDH and NCDs. Results: Although poverty remains the largest structural determinant of health in slums, the multi-dimensional relations between SDH and NCDs are structured around four themes that describe the dynamics of slums, namely scarce clean water, low education, physical (in)activity and transportation. From the reviewed literature, four logic trees visualising the relations between SDH in slums and NCDs were constructed. The logic trees separate symptomatic problems from their more distal causes, and recommendations were formulated based on features of these relationships that are amenable to policy intervention. Conclusion: Root cause analysis provides a means to focus the lens of examination of SDH, as evidenced here for Indian slums. It provides a guide for the development of policies that are grounded in the actual health concerns of people in slums, and takes account of the complex pathways through which diseases are socially constituted

Endogenous Erythropoietin and Outcome in Heart Failure

Background-Endogenous erythropoietin is increased in patients with heart failure (HF). Previous small-scale data suggest that these erythropoietin levels are related to prognosis. This study aims to analyze the clinical and prognostic value of erythropoietin levels in relation to hemoglobin in a large cohort of HF patients. Methods and Results-In patients hospitalized for HF, endogenous erythropoietin levels were measured at discharge and after 6 months. In anemic patients, the relation between erythropoietin and hemoglobin levels was determined by calculating the observed/predicted ratio of erythropoietin levels. We studied data from 605 patients with HF. Mean age was 71 +/- 11 years; 62% were male; and mean left ventricular ejection fraction was 0.33 +/- 0.14. Median erythropoietin levels were 9.6 U/L at baseline and 10.5 U/L at 6 months. Higher erythropoietin levels at baseline were independently related to an increased mortality at 18 months (hazard ratio, 2.06; 95% confidence interval, 1.40 to 3.04; P <0.01). In addition, persistently elevated erythropoietin levels (higher than median at baseline and at 6 months) were related to an increased mortality risk (hazard ratio, 2.24; 95% confidence interval, 1.02 to 4.90; P = 0.044). The observed/predicted ratio was determined in a subset of anemic patients, 79% of whom had erythropoietin levels lower than expected and 9% had levels higher than expected on the basis of their hemoglobin. Multivariate Cox regression analysis revealed that a higher observed/predicted ratio was related to an increased mortality risk (hazard ratio, 3.52; 95% confidence interval, 1.53 to 8.12; P = 0.003). Conclusions-Erythropoietin levels predict mortality in HF patients, and persistently elevated levels have an independent prognostic value. In anemic HF patients, the majority had a low observed/predicted ratio. However, a higher observed/predicted ratio may be related to an independent increased mortality risk. (Circulation. 2010; 121: 245-251.

Erythropoietin levels in heart failure after an acute myocardial infarction: Determinants, prognostic value, and the effects of captopril versus losartan

Background In patients with chronic heart failure, erythropoietin (Epo) levels are increased and related to a poor prognosis. Furthermore, Epo levels in these patients show a weak correlation with hemoglobin levels. Methods This is a retrospective analysis of a subgroup of the OPTIMAAL (Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan) trial in which serum Epo levels were measured at baseline, at 1 month, and at 1 and 2 years in 224 patients with an acute myocardial infarction complicated by signs or symptoms of heart failure. We investigated the determinants and the prognostic role of elevated Epo levels in these patients, and we studied the change in Epo levels by either captopril or losartan. Results The correlation between Epo and hemoglobin at baseline (r* = 0.348, P <.001) and after 1 month (r = 0.272, P <.001) disappeared after 1 year of follow up (r = 0.129, P = .102). At 1 year, C-reactive protein was the only factor associated with Epo levels. Higher Epo levels at baseline were independently related to a higher mortality during 2 years of follow-up (hazard ratio 2.84, P = .014). In the captopril group, IogEpo levels decreased from 1.19 (+/- 0.26) to 0.95 (+/- 0.20) mIU/mL, and in the losartan group. from 1.19 (+/- 0.27) to 1.01 (+/- 0.17) mIU/mL (P = .036 between groups). Conclusion In this substudy of the OPTIMAAL trial, the correlation between Epo and hemoglobin disappeared in early post-acute myocardial infarction heart failure patients. Furthermore, elevated Epo levels at baseline predicted increased mortality. (Am Heart J 2009;157:91-6.

Effects of erythropoietin after an acute myocardial infarction:Rationale and study design of a prospective, randomized, clinical trial (HEBE III)

Background Preclinical studies have consistently shown that erythropoietin (EPO), administered after an acute myocardial infarction (AMI), reduces infarct size and improves left ventricular function. Furthermore, EPO promotes endothelial progenitor cell growth, which increases angiogenesis. A recent pilot study in patients with AMI suggested that a single bolus of EPO was safe and well tolerated. Methods The HEBE III is a multicenter, prospective, randomized, open-label trial with blinded evaluation of the primary end point. The primary objective is to study the effect on left ventricular ejection fraction (LVEF) of a single bolus of EPO, administered directly after a primary percutaneous coronary intervention (PCI) for a first AMI. A total of 466 patients with thrombolysis in myocardial infarction 0/1 flow before the PCI procedure and 2/3 flow after a successful PCI are randomly assigned to either receive standard medical care or a single bolus with 60,000 IU of EPO on top of standard medical care within 3 hours of the PCI procedure. Primary end point of the study is LVEF after 6 weeks, assessed by planar radionuclide ventriculography. Implications If an improvement of LVEF with a single bolus of EPO is demonstrated, this simple approach might further improve clinical outcome of patients with AMI

Erythropoietin stimulates normal endothelial progenitor cell-mediated endothelial turnover, but attributes to neovascularization only in the presence of local ischemia

Purpose We aimed to evaluate whether ischemia is required for erythropoietin (EPO) induced stimulation of endothelial progenitor cells (EPCs) and their related effects on endothelial and cardiac function. Methods Bone marrow of rats was replaced by transgenic cells to allow tracking of EPCs. Ischemic heart failure was induced by left coronary artery ligation to induce myocardial infarction (MI) and control rats received a sham procedure. Three weeks after surgery, rats were randomized to receive EPO (darbepoetin alfa 40 mu g/kg per 3 weeks) or vehicle and were sacrificed 9 weeks after surgery. Results In all treated groups, EPO significantly increased circulating EPCs and their incorporation into the endothelium of the ischemic and non-ischemic hearts as well as in the control organs; kidney and liver. This was associated with significantly improved endothelial function, which was strongly correlated with circulating EPCs (R=0.7, p Conclusions In general, EPO stimulates normal endothelial progenitor cell-mediated endothelial turnover, but improves cardiac microvascularization and function only in the presence of ischemia

Inflammation and anaemia in a broad spectrum of patients with heart failure.

Aims Anaemia in heart failure (HF) is associated with a poor prognosis. Although inflammation is assumed to be an important cause of anaemia, the association between anaemia and inflammatory markers in patients with HF has not been well established. Methods Data from a multicentre randomised clinical trial, in which patients were eligible if they were >18 years of age and admitted for HF (New York Heart Association II-IV), were used. In a subset of 326 patients, haemoglobin (Hb), haematocrit, high sensitivity C-reactive protein (hsCRP), interleukin-(IL) 6, soluble tumour necrosis factor receptor (sTNFR)-1 and erythropoietin (Epo) were measured at discharge and the primary endpoint was all-cause mortality. Follow-up was 18 months. Results Anaemia (Hb Conclusion Anaemia is present in 40% of patients hospitalised for HF and is independently associated with inflammation