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      Effects of autologous bone marrow stem cell transplantation on beta-adrenoceptor density and electrical activation pattern in a rabbit model of non-ischemic heart failure

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          Abstract

          Background

          Since only little is known on stem cell therapy in non-ischemic heart failure we wanted to know whether a long-term improvement of cardiac function in non-ischemic heart failure can be achieved by stem cell transplantation.

          Methods

          White male New Zealand rabbits were treated with doxorubicine (3 mg/kg/week; 6 weeks) to induce dilative non-ischemic cardiomyopathy. Thereafter, we obtained autologous bone marrow stem cells (BMSC) and injected 1.5–2.0 Mio cells in 1 ml medium by infiltrating the myocardium via a left anterolateral thoracotomy in comparison to sham-operated rabbits. 4 weeks later intracardiac contractility was determined in-vivo using a Millar catheter. Thereafter, the heart was excised and processed for radioligand binding assays to detect β 1- and β 2-adrenoceptor density. In addition, catecholamine plasma levels were determined via HPLC. In a subgroup we investigated cardiac electrophysiology by use of 256 channel mapping.

          Results

          In doxorubicine-treated animals β-adrenoceptor density was significantly down-regulated in left ventricle and septum, but not in right ventricle, thereby indicating a typical left ventricular heart failure. Sham-operated rabbits exhibited the same down-regulation. In contrast, BMSC transplantation led to significantly less β-adrenoceptor down-regulation in septum and left ventricle. Cardiac contractility was significantly decreased in heart failure and sham-operated rabbits, but was significantly higher in BMSC-transplanted hearts. Norepinephrine and epinephrine plasma levels were enhanced in heart failure and sham-operated animals, while these were not different from normal in BMSC-transplanted animals. Electrophysiological mapping revealed unaltered electrophysiology and did not show signs of arrhythmogeneity.

          Conclusion

          BMSC transplantation improves sympathoadrenal dysregualtion in non-ischemic heart failure.

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          Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells.

          K. A. Jackson, S Majka, H. Wang … (2001)
          Myocyte loss in the ischemically injured mammalian heart often leads to irreversible deficits in cardiac function. To identify a source of stem cells capable of restoring damaged cardiac tissue, we transplanted highly enriched hematopoietic stem cells, the so-called side population (SP) cells, into lethally irradiated mice subsequently rendered ischemic by coronary artery occlusion for 60 minutes followed by reperfusion. The engrafted SP cells (CD34(-)/low, c-Kit(+), Sca-1(+)) or their progeny migrated into ischemic cardiac muscle and blood vessels, differentiated to cardiomyocytes and endothelial cells, and contributed to the formation of functional tissue. SP cells were purified from Rosa26 transgenic mice, which express lacZ widely. Donor-derived cardiomyocytes were found primarily in the peri-infarct region at a prevalence of around 0.02% and were identified by expression of lacZ and alpha-actinin, and lack of expression of CD45. Donor-derived endothelial cells were identified by expression of lacZ and Flt-1, an endothelial marker shown to be absent on SP cells. Endothelial engraftment was found at a prevalence of around 3.3%, primarily in small vessels adjacent to the infarct. Our results demonstrate the cardiomyogenic potential of hematopoietic stem cells and suggest a therapeutic strategy that eventually could benefit patients with myocardial infarction.
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            Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts.

            Liane R Ginsburg, R Cubicciotti, W S Sageman … (1982)
            To identify the role of the myocardial beta-adrenergic pathway in congestive heart failure, we examined beta-adrenergic-receptor density, adenylate cyclase and creatine kinase activities, muscle contraction in vitro, and myocardial contractile protein levels in the left ventricles of failing and normally functioning hearts from cardiac-transplant recipients or prospective donors. Eleven failing left ventricles had a 50 to 56 per cent reduction in beta-receptor density, a 45 per cent reduction in maximal isoproterenol-mediated adenylate cyclase stimulation, and a 54 to 73 per cent reduction in maximal isoproterenol-stimulated muscle contraction, as compared with six normally functioning ventricles (P less than 0.05 for each comparison). In contrast, cytoplasmic creatine kinase activity, adenylate cyclase activities stimulated by fluoride ion and by histamine, histamine-stimulated muscle contraction, and levels of contractile protein were not different in the two groups (P less than 0.05). We conclude that in failing human hearts a decrease in beta-receptor density leads to subsensitivity of the beta-adrenergic pathway and decreased beta-agonist-stimulated muscle contraction. Regulation of beta-adrenergic receptors may be an important variable in cardiac failure.
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              What is the role of beta-adrenergic signaling in heart failure?

              Martin J. Lohse, Stefan Engelhardt, Thomas Eschenhagen (2003)
              This review addresses open questions about the role of beta-adrenergic receptors in cardiac function and failure. Cardiomyocytes express all three beta-adrenergic receptor subtypes-beta1, beta2, and, at least in some species, beta3. The beta1 subtype is the most prominent one and is mainly responsible for positive chronotropic and inotropic effects of catecholamines. The beta2 subtype also increases cardiac function, but its ability to activate nonclassical signaling pathways suggests a function distinct from the beta1 subtype. In heart failure, the sympathetic system is activated, cardiac beta-receptor number and function are decreased, and downstream mechanisms are altered. However, in spite of a wealth of data, we still do not know whether and to what extent these alterations are adaptive/protective or detrimental, or both. Clinically, beta-adrenergic antagonists represent the most important advance in heart failure therapy, but it is still debated whether they act by blocking or by resensitizing the beta-adrenergic receptor system. Newer experimental therapeutic strategies aim at the receptor desensitization machinery and at downstream signaling steps.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Cardiothorac Surg
                Title: Journal of Cardiothoracic Surgery
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1749-8090
                Publication date Collection: 2006
                Publication date (Electronic): 26 June 2006
                Volume: 1
                Page: 17
                Affiliations
                [1 ]Clinic for Cardiac Surgery, Heart Centre Leipzig, University of Leipzig, Germany
                [2 ]Institute for Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, Germany
                [3 ]Institute of Veterinary Pathology, University of Leipzig, Faculty of Veterinary Medicine, Germany
                Article
                Publisher ID: 1749-8090-1-17
                DOI: 10.1186/1749-8090-1-17
                PMC ID: 1533828
                PubMed ID: 16800896
                SO-VID: 37d7134e-9150-4854-be0c-730b2a50231e
                Copyright © Copyright © 2006 Dhein et al; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 11 April 2006
                Date accepted : 26 June 2006
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Surgery
                Data availability:
                ScienceOpen disciplines: Surgery

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