Haemoglobin levels as a predictor for the occurrence of future cardiovascular events in adults-Sex-dependent results from the EPIC trial.

BACKGROUND: The impact of hemoglobin levels on the occurrence of future health events remains equivocal. Due to its integral role in human hemostasis, both, high and low hemoglobin levels may play a significant role in the development of future cardiovascular (CV) events in otherwise healthy adults. METHODS: Data from the European Prospective Investigation into Cancer (EPIC)-InterAct cohort was analyzed. In 13.648 individuals, physical activity, body mass index, family history of cardiovascular events, kidney function, smoking status, blood pressure and LDL levels were modelled to concomitant hemoglobin levels and correlated to the occurrence of clinically-overt cardiovascular events and death over a 21-year period. (Sex specific) cox regression analysis were used to develop hazard ratios (HRs) for CV events and all-cause mortality. RESULTS: Anemia (hemoglobin (HGB) levels < 13.0 g/dl in men and < 12.0 g/dl in non-pregnant women) were associated with an increased all-cause mortality in men but not in women (HR anemia in men 1.4 (1.2; 1.6)) p=<0.0001).This was particularly visible with increasing age. Various sex specific Cox regression models, accounting for several CV risk factors confirmed these results. The incidence of future CV events and myocardial infarction was significantly influenced by underlying HGB levels in men with increasing age but not in women. CONCLUSION: The influence of HGB levels on future cardiovascular events is sex-dependent. In men, presenting with anemia at baseline, the overall survival probability was impaired with increasing age. After adjusting for several CV risk factors, abnormal hemoglobin levels could be identified as a risk factor for the development of clinically-apparent future CV events in men. None of these effects were observed in women.

Chronic anemia is associated with systemic endothelial dysfunction.

Background: In acute myocardial infarction and heart failure, anemia is associated with adverse clinical outcomes. Endothelial dysfunction (ED) is characterized by attenuated nitric oxide (NO)-mediated relaxation responses which is poorly studied in chronic anemia (CA). We hypothesized that CA is associated with ED due to increased oxidative stress in the endothelium. Methods: CA was induced by repeated blood withdrawal in male C57BL/6J mice. Flow-Mediated Dilation (FMD) responses were assessed in CA mice using ultrasound-guided femoral transient ischemia model. Tissue organ bath was used to assess vascular responsiveness of aortic rings from CA mice, and in aortic rings incubated with red blood cells (RBCs) from anemic patients. In the aortic rings from anemic mice, the role of arginases was assessed using either an arginase inhibitor (Nor-NOHA) or genetic ablation of arginase 1 in the endothelium. Inflammatory changes in plasma of CA mice were examined by ELISA. Expression of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), myeloperoxidase (MPO), 3-Nitrotyrosine levels, and 4-Hydroxynonenal (4-HNE) were assessed either by Western blotting or immunohistochemistry. The role of reactive oxygen species (ROS) in ED was assessed in the anemic mice either supplemented with N-Acetyl cysteine (NAC) or by in vitro pharmacological inhibition of MPO. Results: The FMD responses were diminished with a correlation to the duration of anemia. Aortic rings from CA mice showed reduced NO-dependent relaxation compared to non-anemic mice. RBCs from anemic patients attenuated NO-dependent relaxation responses in murine aortic rings compared to non-anemic controls. CA results in increased plasma VCAM-1, ICAM-1 levels, and an increased iNOS expression in aortic vascular smooth muscle cells. Arginases inhibition or arginase1 deletion did not improve ED in anemic mice. Increased expression of MPO and 4-HNE observed in endothelial cells of aortic sections from CA mice. NAC supplementation or inhibition of MPO improved relaxation responses in CA mice. Conclusion: Chronic anemia is associated with progressive endothelial dysfunction evidenced by activation of the endothelium mediated by systemic inflammation, increased iNOS activity, and ROS production in the arterial wall. ROS scavenger (NAC) supplementation or MPO inhibition are potential therapeutic options to reverse the devastating endothelial dysfunction in chronic anemia.

SYSTEMI - systemic organ communication in STEMI: design and rationale of a cohort study of patients with ST-segment elevation myocardial infarction.

BACKGROUND: ST-segment elevation myocardial infarction (STEMI) still causes significant mortality and morbidity despite best-practice revascularization and adjunct medical strategies. Within the STEMI population, there is a spectrum of higher and lower risk patients with respect to major adverse cardiovascular and cerebral events (MACCE) or re-hospitalization due to heart failure. Myocardial and systemic metabolic disorders modulate patient risk in STEMI. Systematic cardiocirculatory and metabolic phenotyping to assess the bidirectional interaction of cardiac and systemic metabolism in myocardial ischemia is lacking. METHODS: Systemic organ communication in STEMI (SYSTEMI) is an all-comer open-end prospective study in STEMI patients > 18 years of age to assess the interaction of cardiac and systemic metabolism in STEMI by systematically collecting data on a regional and systemic level. Primary endpoint will be myocardial function, left ventricular remodelling, myocardial texture and coronary patency at 6 month after STEMI. Secondary endpoint will be all-cause death, MACCE, and re-hospitalisation due to heart failure or revascularisation assessed 12 month after STEMI. The objective of SYSTEMI is to identify metabolic systemic and myocardial master switches that determine primary and secondary endpoints. In SYSTEMI 150-200 patients are expected to be recruited per year. Patient data will be collected at the index event, within 24 h, 5 days as well as 6 and 12 months after STEMI. Data acquisition will be performed in multilayer approaches. Myocardial function will be assessed by using serial cardiac imaging with cineventriculography, echocardiography and cardiovascular magnetic resonance. Myocardial metabolism will be analysed by multi-nuclei magnetic resonance spectroscopy. Systemic metabolism will be approached by serial liquid biopsies and analysed with respect to glucose and lipid metabolism as well as oxygen transport. In summary, SYSTEMI enables a comprehensive data analysis on the levels of organ structure and function alongside hemodynamic, genomic and transcriptomic information to assess cardiac and systemic metabolism. DISCUSSION: SYSTEMI aims to identify novel metabolic patterns and master-switches in the interaction of cardiac and systemic metabolism to improve diagnostic and therapeutic algorithms in myocardial ischemia for patient-risk assessment and tailored therapy. TRIAL REGISTRATION: Trial Registration Number: NCT03539133.

Consistency of left ventricular ejection fraction measurements in the early time course of STEMI.

BACKGROUND: Early after ST-segment elevation myocardial infarction (STEMI), initial LV reshaping and hypokinesia may affect analysis of LV function. Concomitant microvascular dysfunction may affect LV function as well. OBJECTIVE: To perform a comparative evaluation of left ventricular ejection fraction (LVEF) and stroke volume (SV) by different imaging modalities to assess LV function early after STEMI. METHODS: LVEF and SV were assessed using serial imaging within 24 h and 5 days after STEMI using cineventriculography (CVG), 2-dimensional echocardiography (2DE), 2D/3D cardiovascular magnetic resonance (CMR) (2D/3D) in 82 patients. RESULTS: 2D analyses of LVEF using CVG, 2DE and 2D CMR yielded uniform results within 24 h and 5 days of STEMI. SV assessment between CVG and 2DE was comparable, whereas values for SV were higher using 2D CMR (p < 0.01 all). This was due to higher LVEDV measurements. LVEF by 2D versus 3D CMR was comparable, 3D CMR yielded higher volumetric values. This was not influenced by infarct location or infarct size. CONCLUSIONS: 2D analysis of LVEF yielded robust results across all imaging techniques implying that CVG, 2DE, and 2D CMR can be used interchangeably early after STEMI. SV measurements differed substantially between imaging techniques due to higher intermodality-differences of absolute volumetric measurements.

The role of anemia on admission in acute coronary syndrome - An umbrella review of systematic reviews and meta-analyses.

INTRODUCTION: The role of erythrocytes in the acute coronary syndrome (ACS) is complex. The aim of this review in terms of PICO (P: patients; I: intervention; C: comparison; O: outcome) was to summarize systematic reviews in patients (P) with acute coronary syndrome, evaluating the effects of (I) 1) iron deficiency, 2) administration of an erythropoiesis-stimulating agent (ESA), 3) anemia on admission, 4) red blood cell transfusion, 5) a restrictive transfusion strategy in comparison (C) to 1) no iron deficiency, 2) no ESA 3) no anemia on admission, 4) no red blood cell transfusion, 5) a liberal transfusion strategy on mortality (O). METHODS: We used AMSTAR2 to assess the methodological quality of systematic reviews and grade the available research. The primary endpoint was all-cause mortality. RESULTS: Using the data from 2,787,005 patients, the following conditions were associated with worse outcome in patients with ACS: anemia on admission (RR 2.08 95%CI 1.70-2.55) and transfusion (1.93 95%CI 1.12-3.34) of red blood cells. A liberal transfusion (RR 0.86 95%CI 0.70-1-05), administration of ESA (RR 0.55 95%CI 0.22-1.33) and iron deficiency (OR 1.24 95%CI 0.12-13.13) were not associated with altered all-cause mortality. CONCLUSION: Patients suffering from ACS and anemia on admission are at particular risk for adverse outcome. There is evidence of associations between adverse outcomes and receiving red blood cell transfusions.

Relevance of pre-existing anaemia for patients admitted for acute coronary syndrome to an intensive care unit: a retrospective cohort analysis of 7418 patients.

Aims: Patients with acute coronary syndrome (ACS) frequently suffer from anaemia, but its role in patients admitted to an intensive care unit (ICU) is unclear. This analysis evaluates the prognostic relevance of different degrees of anaemia and their specific impact on disease severity and the outcome in critically ill ACS patients. Methods and results: and results The multi-centre electronic Intensive Care Unit Collaborative Research Database was used, and all patients admitted with ACS were included in a retrospective analysis. Anaemia and its degrees were defined according to the criteria by the World Health Organization. A multi-level logistic regression analysis was used to fit three sequential regression models for the binary primary outcome of hospital mortality. A total of 7418 patients were included; 3437 patients (46%) had anaemia on admission. Patients with anaemia were significantly older [61 (53-70) vs. 70 (61-78) years, P < 0.001], more often female (P < 0.001), and required an increased rate of vasopressor use (P < 0.001) and mechanical ventilation (P < 0.001). With the higher Sequential organ failure assessment score (1 vs. 2; P < 0.001) and Acute Physiology And Chronic Health Evaluation (35 vs. 47; P < 0.001) scores, a higher degree of anaemia was associated with prolonged ICU stay (2 vs. 5 days, P < 0.001). Even patients with mild anaemia needed significantly from more intensive treatment and suffered worse outcome. Intensive care unit and hospital mortality were inversely associated with haemoglobin levels. Conclusion: Nearly half of critically ill patients with ACS suffer from anaemia, which is associated with increased illness severity, complex ICU procedures, and mortality-even in mild anaemia. Haemoglobin on admission is an independent factor for adverse outcome.

Safety and efficacy of iron supplementation after myocardial infarction in mice with moderate blood loss anaemia.

AIMS: Iron deficiency is frequently observed in patients with acute coronary syndrome and associates with poor prognosis after acute myocardial infarction (AMI). Anaemia is linked to dysregulation of iron metabolism, red blood cell dysfunction, and increased reactive oxygen species generation. Iron supplementation in chronic heart failure is safe and improves cardiac exercise capacity. Increases in iron during ischaemia or immediately after reperfusion are associated with detrimental effects on left ventricular (LV) function. The safety and applicability of iron during or immediately after reperfusion of AMI in anaemia are not known. We aimed to study the safety and efficacy of iron supplementation within 1 h or deferred to 24 h after reperfusion of AMI by analysing LV function and infarct size. METHODS AND RESULTS: In a mouse model of moderate blood loss anaemia (n = 6-8 mice/group), the effects of iron supplementation (20 mg iron as ferric carboxymaltose per kg body weight) within 1 h and deferred to 24 h after ischaemia/reperfusion were assessed. Cardiac function was analysed in vivo by echocardiography at baseline (Day 3) with and without anaemia, after AMI (24 h), and after administration of intravenous iron. Anaemia was characterized by iron deficiency and a trend towards increased haemolysis, which was supported by increased plasma free-haemoglobin [sham vs. anaemia (n = 8/group): P < 0.05]. Anaemia increased heart rate, LV end-diastolic volume, stroke volume, and cardiac output, while LV end-systolic volume remained unchanged at baseline. Superimposition of AMI deteriorated global LV function, whereas infarct sizes remained unaffected [sham vs. anaemia (n = 6/group): P = 0.9]. Deferred iron supplementation 24 h after ischaemia/reperfusion resulted in reversal of end-systolic volume increase and reduced infarct size [% of area at risk: sham vs. anaemia + iron after 24 h; (n = 6/group); 48 ± 7 vs. 38 ± 7; P < 0.05], whereas administration within 1 h after reperfusion was neutral [sham vs. anaemia + iron; (n = 6/group); 48 ± 7 vs. 42 ± 8; P = 0.56]. Moreover, iron application after reperfused AMI showed unaltered mortality compared with sham. CONCLUSIONS: Iron supplementation 24 h after reperfusion of AMI is safe and reversed enlargement of end-systolic volume after AMI resulting in increased stroke volume and cardiac output. This highlights its potential as adjunctive treatment in anaemia with ID after reperfused AMI. Time point of iron application after reperfusion appears critical.

Anaemia is associated with severe RBC dysfunction and a reduced circulating NO pool: vascular and cardiac eNOS are crucial for the adaptation to anaemia.

Anaemia is frequently present in patients with acute myocardial infarction (AMI) and contributes to an adverse prognosis. We hypothesised that, besides reduced oxygen carrying capacity, anaemia is associated with (1) red blood cell (RBC) dysfunction and a reduced circulating nitric oxide (NO) pool, (2) compensatory enhancement of vascular and cardiac endothelial nitric oxide synthase (eNOS) activity, and (3) contribution of both, RBC dysfunction and reduced circulatory NO pool to left ventricular (LV) dysfunction and fatal outcome in AMI. In mouse models of subacute and chronic anaemia from repeated mild blood loss the circulating NO pool, RBC, cardiac and vascular function were analysed at baseline and in reperfused AMI. In anaemia, RBC function resulted in profound changes in membrane properties, enhanced turnover, haemolysis, dysregulation of intra-erythrocytotic redox state, and RBC-eNOS. RBC from anaemic mice and from anaemic patients with acute coronary syndrome impaired the recovery of contractile function of isolated mouse hearts following ischaemia/reperfusion. In anaemia, the circulating NO pool was reduced. The cardiac and vascular adaptation to anaemia was characterised by increased arterial eNOS expression and activity and an eNOS-dependent increase of end-diastolic left ventricular volume. Endothelial dysfunction induced through genetic or pharmacologic reduction of eNOS-activity abrogated the anaemia-induced cardio-circulatory compensation. Superimposed AMI was associated with decreased survival. In summary, moderate blood loss anaemia is associated with severe RBC dysfunction and reduced circulating NO pool. Vascular and cardiac eNOS are crucial for the cardio-circulatory adaptation to anaemia. RBC dysfunction together with eNOS dysfunction may contribute to adverse outcomes in AMI.

Rehabilitation in Patients With Coronary Heart Disease: Participation and Its Effect on Prognosis.

BACKGROUND: In Germany, rehabilitation is considered to be indicated after an acute hospital stay for the treatment of a severe cardiac condition. In comparative studies, at least 51% of German hospital patients with coronary heart disease (CHD) who were entitled to rehabilitative measures actually took part n rehabilitation. METHODS: We examined data on 1910 patients with CHD who took part in two prospective cohort studies at the University Hospital of Halle (Saale) in the years 2007-2011. We contacted these patients again with a questionnaire to determine which ones had undergone rehabilitation. For patients who died before we could contact them, the attempt was made to obtain the dates and causes of death from the local authorities. The primary endpoint of was overall mortality. RESULTS: The median duration of follow-up was 136 ± 71 weeks. 727 patients (38.1%) had applied for rehabilitation during their acute hospitalization, but only 552 patients (28.9%) actually underwent it. Patients who did not undergo rehabilitation were older than those who did (68.6 ± 10.3 vs. 64.9 ± 10.5 years) and suffered more commonly from diabetes (41.3% vs. 33.7%; p = 0.002), arterial hypertension (89.2% vs. 85.3%; p = 0.017), and peripheral arterial occlusive disease (15.3% vs. 9.8%; p = 0.002). There were more smokers in the rehabilitation group. Kaplan-Meier analysis and multivariate Cox regression analysis both showed that the patients who underwent rehabilitation had lower mortality (hazard ratio 0.067, 95% confidence interval 0.025-0.180, p < 0.001). CONCLUSION: Rehabilitation for cardiac patients was associated with lower mortality. Fewer patients underwent rehabilitation in this study than in other, comparable studies. Those who did not were older and had a greater burden of accompanying disease.