Erythropoietin Induces Neovascularization and Improves Cardiac Function in Rats With Heart Failure After Myocardial Infarction

Meer, Peter van der; Lipšic, Erik; Henning, Robert H.; Boddeus, Kristien M.; Velden, Jolanda van der; Voors, Adriaan A.; Veldhuisen, Dirk J. van; Gilst, Wiek H. van; Schoemaker, Regien G.

doi:10.1016/j.jacc.2005.03.044

Cited by 229 publications

(184 citation statements)

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“…Therefore, we investigated the effects of a nonerythropoietic EPO dose to avoid elevation of haematocrit, and consequently the changes in rheology and oxygen-binding capacity of the blood. We compared these effects to a high EPO dose, with previously established effects on cardiac function in post-MI heart failure [10]. Moreover, similar to the high-dose treatment, low-dose treatment resulted in noticeably improved cardiac function, as reflected by a significantly enhanced developed LVP, together with improved contractility and relaxation indices of the LV.…”

Section: Discussionmentioning

confidence: 90%

“…Although cardiomyocyte proliferation after ischaemic injury seems limited, the formation of new vessels in the noninfarcted part of the ventricle could lead to an improvement of function and attenuation of ventricular remodelling [27,28]. Evidence is accumulating to suggest that EPO exerts potent pleiotropic effects on the myocardium in the setting of acute myocardial infarction and chronic heart failure as well [2,[5][6][7][8][9][10]29]. Therefore, in addition to its acute protective effects, EPO might evolve as a standard "cardioregenerative" therapy in the setting of chronic myocardial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…Control (MI) and SHAM rats received corresponding injections of saline. The high-dose of darbepoetin was based on our previous study [10], demonstrating increased neovascularisation in this model, together with significant elevation of haematocrit levels. To avoid the effect of EPO treatment on haematocrit we included a low-dose EPO group, with 100-times lower darbepoetin dosage (0.4 μg/kg/ 3 weeks), which in a pilot experiment did not cause elevation of haematocrit (data not shown).…”

Section: Design Of the Studymentioning

confidence: 99%

“…In addition, EPO improves cardiac function in experimental models of chronic myocardial dysfunction, which is consistently associated with improved microvascularisation of the myocardium [5][6][7][8][9][10]. The neovascularisation by EPO is associated with marked mobilisation and vascular incorporation of endothelial progenitor cells (EPC) [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

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Low‐dose erythropoietin improves cardiac function in experimental heart failure without increasing haematocrit

Lipšic

Westenbrink

Meer

et al. 2008

European J of Heart Fail

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Background: Erythropoietin (EPO) may improve cardiac function and induce neovascularisation in experimental models of chronic heart failure (CHF). However, the increased haematocrit associated with EPO treatment might exert concomitant deleterious effects. Aim: To investigate the haematocrit independent effects of EPO on cardiac function. Methods and results: Rats underwent permanent coronary artery ligation to induce myocardial infarction (MI) or sham surgery. Three weeks after MI, rats were randomly allocated to treatment with vehicle (MI) or the long-acting EPO analogue darbepoetin alfa administered in a high (40 μg/kg/3 weeks, MI-EPO-high) or a low-dose (0.4 μg/kg/3 weeks, MI-EPO-low). After 9 weeks, haemodynamic parameters, myocardial histology and Myosin Heavy Chain (MHC) isoforms were determined. High-dose EPO resulted in a significant increase in haematocrit (p b 0.01) while low-dose EPO had no effect on haematocrit levels. EPO significantly improved cardiac function in both EPO groups, reflected by increased left ventricular (LV)-developed pressure and improved contractility (dP/dt max ) and relaxation (dP/dt min ) indices of the LV at 9-weeks (all p b 0.05 compared to MI). The improved cardiac function was associated with increased capillary growth (38% in MI-EPO-high (p b 0.01) and 27% in MI-EPO-low (p b 0.05)) and an attenuated switch to slow β-MHC isoforms in both EPO groups. Conclusions: EPO improves cardiac function and induces neovascularisation at a dose that does not increase haematocrit, thereby circumventing the possible deleterious effects of increased erythropoiesis.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Design Of the Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Low‐dose erythropoietin improves cardiac function in experimental heart failure without increasing haematocrit

Lipšic

Westenbrink

Meer

et al. 2008

European J of Heart Fail

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“…Furthermore it has been discovered, that inhibition of the prolyl hydroxylase stimulates erythropoietin production [21,22]. Hence erythropoietin [23,24] is known to be supportive in chronic heart failure possibly by induction of VGEF and NOS this might be another possible mechanism behind the beneficial effects of FG 2216. Different P4-HIs seem to target different subunits of the enzymes [16] resulting in stabilizing HIF and thereby inducing NOS, VEGF and EPO or in modulation of the collagen matrix.…”

Section: Discussionmentioning

confidence: 99%

Induction of Hypoxia Inducible Factor Rather than Modulation of Collagen Metabolism Improves Cardiac Function and Reduces Left Ventricular Hypertrophy after Aortocaval Shunt in Rats

Philipp¹

2012

J Clin Exp Cardiolog

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Introduction: Matrix reorganization and collagen formation have been suggested to be responsible for cardiac remodeling. Recently, Hypoxia Inducible Factors (HIF) has been shown to be also involved. To differentiate the pathogenesis of cardiac remodeling we used two different prolyl 4-hydroxylase (P4H) inhibitors, FG 0041 known for its potential in reducing collagen formation, FG 2216 for its capability to induce HIF. This study was performed to analyze whether the beneficial effects of P4-HI are mediated by induction of HIF or by effects on collagen metabolism.Methods: 8-week-old Wistar rats either had sham operations (n=14) or received Aortocaval Shunt (ACS). From day 2 rats received P4-HI (n=10 for each P4-HI) or vehicle (n=15) by oral gavage. Echocardiography was performed 28 days after ACS; hemodynamic measurements were done after 30 days. Activity of the metalloproteinase 2 and its inhibitor (TIMP), mRNA levels of CTGF, TGFß1, ITGß1 and Collagen I and III protein were measured.Results: After 30 days both HIF was induced in ACS. Treatment with FG 2216 led to an increase of HIF after 30 days compared to FG 0041 and vehicle. Only FG 2216 prevented left ventricular end-diastolic (7.9 mm vs. 9.8 mm; p<0.001) and end-systolic (4.1 vs. 6.0 mm, p<0.001) dilatation and improved left ventricular ejection fraction (85% vs. 74%, p<0.05). Heart weight (1416 ± 71 vs. 1871 ± 51 mg, p<0.001) and lung weight, as a marker for heart failure, (1958 ± 102 mg vs. 2276 ± 105 mg, p<0.05) were lower in the group receiving FG 2216. Collagen protein and metalloproteinase activity accompanying ACS were significantly decreased by FG 0041, but not by FG 2216. Conclusion:Induction of HIF improves cardiac function and reduces cardiac hypertrophy independent of changes in mRNA, collagen protein or metalloproteinase activity in this model of hypertrophy. Thus FG 2216 affects remodeling by directly targeting cardiomyocytes and has negligible effect on collagen production or extracellular matrix composition.

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Evaluation of Agents to Reduce Infarct Size

Bhatt¹

2011

JAMA

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Erythropoietin Induces Neovascularization and Improves Cardiac Function in Rats With Heart Failure After Myocardial Infarction

Abstract: In addition to its effect on infarct size reduction, EPO treatment improves cardiac function in a rat model of post-MI heart failure. This observation may be explained by neovascularization, associated with an increased alpha-MHC expression.

Cited by 229 publications

References 45 publications

Low‐dose erythropoietin improves cardiac function in experimental heart failure without increasing haematocrit

Low‐dose erythropoietin improves cardiac function in experimental heart failure without increasing haematocrit

Induction of Hypoxia Inducible Factor Rather than Modulation of Collagen Metabolism Improves Cardiac Function and Reduces Left Ventricular Hypertrophy after Aortocaval Shunt in Rats

Evaluation of Agents to Reduce Infarct Size

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