Publications by authors named "Eva Wärdell"

11 Publications

  • Page 1 of 1

Circulating neuregulin1-β in heart failure with preserved and reduced left ventricular ejection fraction.

ESC Heart Fail 2020 04 24;7(2):445-455. Epub 2020 Jan 24.

Department of Medicine, Karolinska Institutet - Huddinge, Huddinge, Sweden.

Aims: Neuregulin1-β (NRG1-β) is released from microvascular endothelial cells in response to inflammation with compensatory cardioprotective effects. Circulating NRG1-β is elevated in heart failure (HF) with reduced ejection fraction (HFrEF) but not studied in HF with preserved EF (HFpEF).

Methods And Results: Circulating NRG1-β was quantified in 86 stable patients with HFpEF (EF ≥45% and N-terminal pro-brain natriuretic peptide >300 ng/L), in 86 patients with HFrEF prior to and after left ventricular assist device (LVAD) and/or heart transplantation (HTx) and in 21 healthy controls. Association between NRG1-β and the composite outcome of all-cause mortality/HF hospitalization in HFpEF and all-cause mortality/HTx/LVAD implantation in HFrEF with and without ischaemia assessed as macrovascular coronary artery disease was assessed. In HFpEF, median (25th-75th percentile) NRG1-β was 6.5 (2.1-11.3) ng/mL; in HFrEF, 3.6 (2.1-7.6) ng/mL (P = 0.035); after LVAD, 1.7 (0.9-3.6) ng/mL; after HTx 2.1 (1.4-3.6) ng/mL (overall P < 0.001); and in controls, 29.0 (23.1-34.3) ng/mL (P = 0.001). In HFrEF, higher NRG1-β was associated with worse outcomes (hazard ratio per log increase 1.45, 95% confidence interval 1.04-2.03, P = 0.029), regardless of ischaemia. In HFpEF, the association of NRG1-β with outcomes was modified by ischaemia (log-rank P = 0.020; P = 0.553) such that only in ischaemic patients, higher NRG1-β was related to worse outcomes. In contrast, in patients without ischaemia, higher NRG1-β trended towards better outcomes (hazard ratio 0.71, 95% confidence interval 0.48-1.05, P = 0.085).

Conclusions: Neuregulin1-β was reduced in HFpEF and further reduced in HFrEF. The opposing relationships of NRG1-β with outcomes in non-ischaemic HFpEF compared with HFrEF and ischaemic HFpEF may indicate compensatory increases of cardioprotective NRG1-β from microvascular endothelial dysfunction in the former (non-ischaemic HFpEF), but this compensatory mechanism is overwhelmed by the presence of ischaemia in the latter (HFrEF and ischaemic HFpEF).
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http://dx.doi.org/10.1002/ehf2.12615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160501PMC
April 2020

A Spatiotemporal Organ-Wide Gene Expression and Cell Atlas of the Developing Human Heart.

Cell 2019 Dec;179(7):1647-1660.e19

Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden. Electronic address:

The process of cardiac morphogenesis in humans is incompletely understood. Its full characterization requires a deep exploration of the organ-wide orchestration of gene expression with a single-cell spatial resolution. Here, we present a molecular approach that reveals the comprehensive transcriptional landscape of cell types populating the embryonic heart at three developmental stages and that maps cell-type-specific gene expression to specific anatomical domains. Spatial transcriptomics identified unique gene profiles that correspond to distinct anatomical regions in each developmental stage. Human embryonic cardiac cell types identified by single-cell RNA sequencing confirmed and enriched the spatial annotation of embryonic cardiac gene expression. In situ sequencing was then used to refine these results and create a spatial subcellular map for the three developmental phases. Finally, we generated a publicly available web resource of the human developing heart to facilitate future studies on human cardiogenesis.
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http://dx.doi.org/10.1016/j.cell.2019.11.025DOI Listing
December 2019

Wnt/β-Catenin Stimulation and Laminins Support Cardiovascular Cell Progenitor Expansion from Human Fetal Cardiac Mesenchymal Stromal Cells.

Stem Cell Reports 2016 Apr 24;6(4):607-617. Epub 2016 Mar 24.

Division of Cardiothoracic Surgery and Anesthesiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden; Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL 33314, USA. Electronic address:

The intrinsic regenerative capacity of human fetal cardiac mesenchymal stromal cells (MSCs) has not been fully characterized. Here we demonstrate that we can expand cells with characteristics of cardiovascular progenitor cells from the MSC population of human fetal hearts. Cells cultured on cardiac muscle laminin (LN)-based substrata in combination with stimulation of the canonical Wnt/β-catenin pathway showed increased gene expression of ISL1, OCT4, KDR, and NKX2.5. The majority of cells stained positive for PDGFR-α, ISL1, and NKX2.5, and subpopulations also expressed the progenitor markers TBX18, KDR, c-KIT, and SSEA-1. Upon culture of the cardiac MSCs in differentiation media and on relevant LNs, portions of the cells differentiated into spontaneously beating cardiomyocytes, and endothelial and smooth muscle-like cells. Our protocol for large-scale culture of human fetal cardiac MSCs enables future exploration of the regenerative functions of these cells in the context of myocardial injury in vitro and in vivo.
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http://dx.doi.org/10.1016/j.stemcr.2016.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834052PMC
April 2016

Estrogen receptors do not influence angiogenesis after myocardial infarction.

Scand Cardiovasc J 2011 Aug 12;45(4):215-22. Epub 2011 Apr 12.

Department of Cardiology, Karolinska Institute, Clinical Research Center, Stockholm, Sweden.

Background: There is controversy on whether estrogen receptors are present and functioning in the myocardium. Aims. To explore if after myocardial infarction (MI) estrogen receptors α (ERα) and β (ERβ) are upregulated in myocardial tissue and to explore if the presence/ absence of ERα or ERβ influences angiogenesis after MI.

Methods: MI was induced by ligation of the left anterior descending artery in knockout (KO) mice, ERαKO and ERβKO, respectively, and non-KO littermate-controls, C57Bl/6 mice. The hearts were harvested after 12 days. A part of the periinfarct tissue was collected for ERα and ERβ mRNA expression determination by real-time polymerase chain reaction. Using immunohistochemistry, ERα and ERβ protein expression and capillary and arteriolar densities were blindly determined in the periinfarct area.

Results: In myocardium disrupted mRNA was upregulated in both ERαKO and ERβKO, (p < 0.005) and did not change after MI. There was no change in mRNA expression of ERα or ERβ in wild type mice after MI. Expression of ERβ in ERαKO and of ERα in ERβKO did not change. Following MI ERα or ERβ could not be demonstrated by immunohistochemistry in either wild type or ERαKO or ERβKO. The capillary and arteriolar densities after MI did not differ between the groups in the periinfarct area.

Conclusions: Although disrupted ER mRNA is upregulated in myocardium of ER knockout mice, no change in these or native receptors occurs following MI. At least in this model ER therefore seems not to have a role in myocardial arteriogenesis and angiogenesis after MI.
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http://dx.doi.org/10.3109/14017431.2011.569941DOI Listing
August 2011

Early first trimester human embryonic cardiac Islet-1 progenitor cells and cardiomyocytes: Immunohistochemical and electrophysiological characterization.

Stem Cell Res 2010 Jan 6;4(1):69-76. Epub 2009 Nov 6.

Karolinska Institute at Clinical Research Centre, Novum, Sweden.

The aims of this study were to systematically characterize the distribution, proliferation, and differentiation of Islet-1(+)(Isl1(+)) progenitor cells in the early first trimester human embryonic heart during which period most of the organogenesis takes place. In hearts of gestational week 5 to 10 Isl1(+)cells were identified and mainly clustered in the outflow tract and to a lesser extent in the atria and in the right ventricle. Some of the clusters were also troponin T(+). Unexpectedly a only few Isl1(+)cells were Ki67(+)while in the ventricles a majority of Isl1(-)troponinT(+)cells were Ki67(+). Cultures derived from the digested embryonic heart developed into spontaneously beating cardiospheres. At harvest cells in these cardiospheres showed frequent expression of troponin T(+)and Nkx2.5(+), while Isl1 was expressed only in scattered cells. Only a minority of the cultured cells expressed Ki67. The cardiospheres could be frozen, thawed, and recultured to beating cardiospheres. In a multielectrode array system, the beating cardiospheres were responsive to adrenergic stimulation and exhibited rate-dependent action potential duration. In conclusion, the early first trimester human embryonic heart expresses clusters of Isl1(+)cells, some of which differentiate into cardiomyocytes. Unexpectedly, only a minority of the Isl1(+)cells, while a majority of ventricular cardiomyocytes, were proliferating. Spontaneously beating cardiospheres could be derived from the human embryonic heart and these cardiospheres showed functional frequency control.
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http://dx.doi.org/10.1016/j.scr.2009.10.001DOI Listing
January 2010

Modulation of ephrinB2 leads to increased angiogenesis in ischemic myocardium and endothelial cell proliferation.

Biochem Biophys Res Commun 2008 Aug 20;373(3):355-9. Epub 2008 Jun 20.

Department of Cardiology, Karolinska University Hospital, Karolinska Institute, S141 86 Stockholm, Sweden.

Eph/ephrin signaling is pivotal in prenatal angiogenesis while its potential role in postnatal angiogenesis largely remains to be explored. Therefore its putative angiogenic and therapeutic effects were explored in endothelium and in myocardial ischemia. In culture of human aortic endothelial cells the fusion protein ephrinB2-Fc induced cell proliferation (p<0.0005) and in the murine aortic ring model ephrinB2-Fc induced increased sprouting (p<0.05). Myocardial infarction was induced by ligation of the left anterior descending artery in mouse. During the following 2 weeks mRNA of the receptor/ligand pair EphB4/ephrinB2 was expressed dichotomously (p<0.05) and other Eph/ephrin pairs were expressed to a lesser degree. Twenty-four hours after intraperitoneal administration of ephrinB2-Fc it was detected in abundance throughout the myocardium along capillaries, showing signs of increased mitosis. After 4 weeks the capillary density was increased 28% in the periinfarcted area (p<0.05) to a level not different from healthy regions of the heart where no change was observed. These results implicate that EphB4/ephrinB2 is an important signaling pathway in ischemic heart disease and its modulation may induce therapeutic angiogenesis.
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http://dx.doi.org/10.1016/j.bbrc.2008.06.036DOI Listing
August 2008

Erythropoietin has an antiapoptotic effect after myocardial infarction and stimulates in vitro aortic ring sprouting.

Biochem Biophys Res Commun 2008 Jun 14;371(1):75-8. Epub 2008 Apr 14.

Department of Cardiology, M52 Karolinska University Hospital, S14186 Stockholm, Sweden.

Aims were to explore if darbepoietin-alpha in mouse can induce angiogenesis and if moderate doses after myocardial infarction stimulates periinfarct capillary and arteriolar densities, cell proliferation, and apoptosis. Myocardial infarction was induced by ligation of LAD. Mouse aortic rings (0.8mm) were cultured in matrigel and the angiogenic sprouting was studied after addition of darbepoietin-alpha with and without VEGF-165. After 12 days the hemoglobin concentration was 25% higher in the darbepoietin-alpha treated mice than in the control group. No difference in capillary densities in the periinfarct or noninfarcted areas was seen with darbepoietin-alpha. Cell proliferation was about 10 times higher in the periinfarct area than in the noninfarcted wall. Darbepoietin-alpha treatment led to a decrease of cell proliferation (BrdU, (p<0.02)) and apoptosis (TUNEL, p<0.005) with about 30% in the periinfarct area. Darbepoietin-alpha and VEGF-165 both independently induced sprouting from aortic rings. The results suggest that darbepoietin-alpha can induce angiogenesis but that moderate doses after myocardial infarction are not angiogenic but antiapoptotic.
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http://dx.doi.org/10.1016/j.bbrc.2008.04.025DOI Listing
June 2008

Angiogenic effects of sequential release of VEGF-A165 and PDGF-BB with alginate hydrogels after myocardial infarction.

Cardiovasc Res 2007 Jul 6;75(1):178-85. Epub 2007 Apr 6.

Karolinska Institute at Department of Internal Medicine, Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.

Objective: This study investigates whether local sequential delivery of vascular endothelial growth factor-A(165) (VEGF-A(165)) followed by platelet-derived growth factor-BB (PDGF-BB) with alginate hydrogels could induce an angiogenic effect and functional improvement greater than single factors after myocardial infarction.

Methods: Alginate hydrogels were prepared by combining high and low molecular weight alginate. Growth factor release rates were monitored over time in vitro with 125I-labelled VEGF-A(165) and PDGF-BB included in the gels. One week after myocardial infarction was induced in Fisher rats, gels with VEGF-A(165), PDGF-BB, or both were given intra-myocardially along the border of the myocardial infarction. Vessel density was analysed in hearts and cardiac function was determined by Tissue Doppler Echocardiography. In addition, the angiogenic effect of sequenced delivery was studied in vitro in aortic rings from C57B1/6 mice.

Results: Alginate gels were capable of delivering VEGF-A(165) and PDGF-BB in a sustainable manner, and PDGF-BB was released more slowly than VEGF-A(165). Sequential growth factor administration led to a higher density of alpha-actin positive vessels than single factors, whereas no further increment was found in capillary density. Sequential protein delivery increased the systolic velocity-time integral and displayed a superior effect than single factors. In the aortic ring model, sequential delivery led to a higher angiogenic effect than single factor administration.

Conclusions: The alginate hydrogel is an effective and promising injectable delivery system in a myocardial infarction model. Sequential growth factor delivery of VEGF-A(165) and PDGF-BB induces mature vessels and improves cardiac function more than each factor singly. This may indicate clinical utility.
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http://dx.doi.org/10.1016/j.cardiores.2007.03.028DOI Listing
July 2007

Human mesenchymal stem cells do not differentiate into cardiomyocytes in a cardiac ischemic xenomodel.

Ann Med 2006 ;38(2):144-53

Department of Cardiothoracic Surgery and Anaesthesiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.

Aim: As the capability of human mesenchymal stem cells (hMSC) to engraft, differentiate and improve myocardial function cannot be studied in humans, exploration was performed in a xenomodel.

Methods: The rats were divided into three groups depending on the type of rats used (Rowett nude (RNU) or Fischer rats +/- immunosuppression). Different groups were treated with intramyocardial injection of hMSC (1-2 million) either directly or three days after ligation of the left anterior descending artery (LAD). Myocardial function was investigated by echocardiography. The hMSC were identified with fluorescence in situ hybridization and myocardial differentiation was assessed by immunohistochemistry.

Results: When hMSC were injected directly after LAD ligation they could be identified in half (8/16) of the RNU rats (without immunosuppression) at 4 weeks. When injected 3 days after LAD ligation in immunosuppressed RNU rats they were identified in all (6/6) rats at 6 weeks. The surviving hMSC showed signs of differentiation into fibroblasts. No cardiomyocyte differentiation was observed. There was no difference in myocardial function in treated animals compared to controls.

Conclusions: The hMSC survived in this xenomodel up to 6 weeks. However, hMSC required implantation into immunoincompetent animals as well as immunosuppression to survive, indicating that these cells are otherwise rejected. Furthermore, these cells did not differentiate into cardiomyocytes nor did they improve heart function in this xenomodel.
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http://dx.doi.org/10.1080/07853890500422982DOI Listing
August 2006

Angiogenic and cardiac functional effects of dual gene transfer of VEGF-A165 and PDGF-BB after myocardial infarction.

Biochem Biophys Res Commun 2004 Sep;322(1):292-6

Department of Cardiology, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden.

Therapeutic angiogenesis is a potential treatment modality for myocardial ischemia. phVEGF-A(165), phPDGF-BB, or a combination of the two were injected into the myocardial infarct border zone in rats 7 days after ligation of the coronary left anterior descending artery. Cardiac function was measured by echocardiography. Hearts were harvested 1 and 4 weeks after plasmid injection. phVEGF-A(165) increased capillary density more than phPDGF-BB, and phPDGF-BB preferentially stimulated arteriolar growth. The combination increased both capillaries and arterioles but did not enhance angiogenesis any more than single plasmid treatments did. VEGF-A(165) and the combination of phVEGF-A(165) and phPDGF-BB counteracted left ventricular dilatation after 1 week but did not counteract further deterioration.
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http://dx.doi.org/10.1016/j.bbrc.2004.07.101DOI Listing
September 2004

Nonsurgical direct delivery of plasmid DNA into rat heart: time course, dose response, and the influence of different promoters on gene expression.

J Cardiovasc Pharmacol 2002 Feb;39(2):215-24

Department of Cardiology, Huddinge University Hospital, Stockholm, Sweden.

Transfer of genes encoding therapeutic proteins into the myocardium shows great potential for treatment of coronary artery disease. To quantitatively elucidate the behavior of plasmid DNA following cardiac gene transfer, time kinetics, dose-response relationship, systemic spread to the liver, and the influence of different promoters on plasmid DNA gene expression in rat hearts were examined using a novel nonsurgical direct delivery method that enables testing of large numbers of animals. Plasmids encoding either vascular endothelial growth factor A 165 or a fusion protein between enhanced green fluorescent protein (EGFP) luciferase were injected directly in rat hearts under echocardiographic guidance. The results show that gene expression is dose related and that the duration of gene expression is transient. These findings underscore the necessity to explore other efficient vectors or alternative methods of gene delivery to achieve increased and prolonged gene expression.
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http://dx.doi.org/10.1097/00005344-200202000-00008DOI Listing
February 2002