Stem Cells for the Failing Heart - Does ACE Inhibition Interfere?
Stem Cells for the Failing Heart - Does ACE Inhibition Interfere?
Heinz Rupp, Peter Alter, Bernhard Maisch, Molecular Cardiology Laboratory Philipps University of Marburg
(Klinik und Forschung 2002; 1: 10-13)
Progression of heart failure
Despite recent advances in the management of congestive heart failure, the prognosis of patients with overloaded hearts remains poor 1,2. To understand progression of decompensation of overloaded hearts, the link between underlying causes and secondary consequences needs to be addressed. In order to cope with an increased wall stress, hypertrophy of cardiomyocytes occurs which is, however, associated with an unfavourable expression of various genes. A crucial deficit of the hypertrophied cardiomyocyte arises from the failure to upregulate the expression of the SR Ca2+ pump proportionally to the cell size 3,4. The impaired performance of hypertrophied cardiomyocytes is expected to initiate neuro-endocrine activation leading to a vicious cycle (Fig. 1). In addition to cardiac growth and the associated altered gene expression, neuro-humoral response mechanisms appear to be decisive for the decompensation of the heart. After myocardial infarction, the heart function is not only depressed by a restructuring of the surviving pressure loaded myocardium but also by the loss of contractile tissue. Since angiotensin II and aldosterone are produced particularly in the border zone of the infarcted area, also the non-infarcted hypertrophied myocardium is affected by a progressive increase in extracellular matrix remodelling, involving collagen deposition leading to fibrosis 5,6.
Recent progress has been made in the treatment of patients with an impaired extracellular matrix of the heart. Angiotensin-converting enzyme (ACE) inhibitors have proven efficient in partially reversing deleterious processes due to reactive fibrosis. This type of therapy has been referred to as cardioreparation 7 pointing out that the heart is damaged when treatment starts. Current candidate drugs are targeted also at optimising the gene expression of hypertrophied cardiomyocytes involving an upregulation of SERCA2 gene expression 3,4. With respect to a deleterious loss of cardiomyocytes, it remains a long sought aim to initiate the regeneration of the myocardium. Although events characteristic of cell division such as formation of mitotic spindles, formation of contractile rings, karyokinesis, and cytokinesis have been identified in regions adjacent to a myocardial infarct 8, regeneration of myocardium does not occur to an extent which would be associated with a restored pump function. Also in contrast to organs which have retained the potential of tissue reparation 9, there is not yet any evidence that specific cardiac stem cells exist which could be recruited for myocardial reparation. This leads to the alternative approach of transplanting stem cells into a heart with lost cardiomyocytes for possibly regenerating viable myocardium.
Stem cell transplantation for regenerating myocardium?
The therapeutic target of transplanting stem cells into the myocardium evolved from the recent findings that embryonic stem cells can differentiate into cardiomyocyte-like cells. In cells derived in vitro from mouse pluripotent embryonic stem cells, ion channels and Ca2+ signalling pathways 10-12 and contractile proteins 13 have been identified which are characteristic of cardiomyocytes. Also purification procedures of ventricular-like cardiomyocytes have been established 14. It is of great interest that also human embryonic stem cell-derived cardiomyocytes display structural and functional properties of early-stage cardiomyocytes 15. It was concluded that the employed differentiation system may have significant impact on cell therapy and tissue engineering 15. The stem cell plasticity becomes apparent also from the observation that cells derived from skeletal muscle of adult mice contain a remarkable capacity for hematopoietic differentiation 16.
Stem cells could either be cultured for generating a sufficient number of cardiomyocytes to be transplanted into the heart or stem cells could be transplanted with the expectation that they differentiate into cardiomyocytes. Although the aim of culturing cardiomyocytes for tissue engineering has been pursued for a number years, a clinical treatment protocol has not yet evolved. It has, however, been shown that transplantation of cardiomyocytes into myocardial scar tissue provides a greater contractility and relaxation than that of smooth muscle cells or fibroblasts 17. In view of the inherent problems involved in culturing sufficient amounts of cardiomyocytes, the putative precursors of cardiomyocytes have become an attractive target. Until recently, it has been assumed that adult multipotent stem cells have lost the potential of developing into cardiomyocyte-like cells. Since only embryonic stem cells could be used in this case, the provision of these cells was limited due to unresolved ethical considerations 18,19. In a number of studies it has, however, been shown that bone marrow 20-24 and liver stem cells 25 can acquire a cardiomyocyte-like phenotype. It remains to be shown in detail whether they can be integrated into an existing multicellular myocardial tissue and thus contribute to force generation. A caveat relates to the possibility that stem cells can acquire the phenotype of surrounding cells and could, therefore, also become fibroblast-like cells in the border zone of an infarcted area.
The transplantation of stem cells has the potential of not only generating cardiomyocytes but also of endothelial cells thereby stimulating angiogenesis 26. It was inferred from animal experiments that bone marrow cells may constitute a strategy for achieving therapeutic angiogenesis by the natural ability of stem cells to secrete potent angiogenic ligands and cytokines as well as to be incorporated into foci of neovascularization 27. It was also hypothesised that the use of autologous human bone-marrow-derived angioblasts for revascularization of infarcted myocardium has the potential of significantly reducing morbidity and mortality associated with left ventricular remodelling 28.
It has been shown by Strauer and co-workers 29 that a selective intracoronary transplantation of human autologous bone marrow cells is possible under clinical conditions and can improve left ventricular function 29. It needs to be proven that regeneration of the myocardial scar has occurred. It would be of particular interest to combine stem cell transplantation with other routine procedures such as the transmyocardial laser revascularization technique 30. In this approach, stem cells could be transplanted directly into the surrounding area of channels produced by the laser. In contrast to the approach of using single angiogenic factors in combination with transmyocardial laser revascularization, it is expected that stem cells secrete a variety of angiogenic factors which, in a concerted manner, are required for angiogenesis and arteriogenesis.
In contrast to the intracardiac route, bone marrow and/or blood progenitor cells are routinely given peripherally in patients after chemo-radiotherapy. It has already been examined whether this form of stem cell transplantation can cause cardiovascular complications. Although arrhythmias have been described 31,32, the procedure appears to be safe 33,34. Case reports, however, also indicate that peripheral blood stem cell transplantation can result in infiltration of cytotoxic T cells, cytokine release and fatal arrhythmias 35,36. For avoiding life-threatening bradyarrhythmias, it appears important to use purified products with a very low red cell content 37. Although cancer patients with cardiac disease are usually excluded from clinical trials of high-dose chemotherapy, it has recently been shown that breast cancer patients with impaired left ventricular function do not have higher complications after chemotherapy and stem cell rescue 38. Although one could imagine that under these conditions the stem cells migrated into the damaged myocardium possibly resulting in tissue repair, no such beneficial effects have yet been reported. So far, a peripheral stem cell transplantation does not appear to have a measurable impact on a depressed heart function. The possibility should, however, not be dismissed that a particular type of chemotherapy prevented a successful transplantation of stem cells or the employed hemodynamic measurements were not sensitive enough for determining any beneficial effect. Also the time required for observing any effect might have been underestimated in previous studies.
Inhibitors of stem cell proliferation
Hematopoiesis is tightly regulated by a balance of stimulatory and inhibitory factors. A number of inhibitory molecules have been identified including cytokines like TGF beta, TNF alpha, platelet factor 4, interferons, MIP1 alpha or peptides like p-EEDCK and Ac-SDKP (seraspenide) 39. It is of particular interest that the hematopoietic stem cell proliferation is affected by ACE inhibition. Ac-SDKP is degraded by ACE and is increased 5-fold after ACE inhibition 40,41. An increase in Ac-SDKP is expected to inhibit stem cell entry into S-phase 41. Furthermore, Ac-SDKP has itself an inhibitory action on ACE, thereby reducing the formation angiotensin II. The contractile response of rat aorta to angiotensin I was reduced by Ac-SDKP arising from a lower angiotensin II formation 42. In accordance with this observation would be findings that Ac-SDKP exhibits anti-fibrotic effects. In rats with renal hypertension, Ac-SDKP did not interfere with left ventricular hypertrophy but blunted the proliferating cell nuclear antigen- and monocyte/macrophage-positive cells 43. Also the increase in interstitial collagen fraction was prevented by Ac-SDKP. In renin-independent hypertension (aldosterone-salt) Ac-SDKP markedly prevented cardiac and renal fibrosis 44. It was concluded that the cardioprotective effect of ACE inhibitors may partly be attributed to an Ac-SDKP-induced inhibition of leukocyte infiltration and fibroblast proliferation. In addition to a reduced angiotensin II formation, Ac-SDKP could have also direct effects on fibroblasts. Thus, Ac-SDKP inhibited DNA and collagen synthesis in cultured cardiac fibroblasts which might involve blocking of the mitogen-activated protein kinase activity 45.
It is widely recognised that the survival of patients with advanced, symptomatic heart failure is severely compromised. The search for pathogenetic mechanisms must therefore continue, including the identification of factors that do not only mediate cardiomyocyte and nonmyocyte growth but also induce cardiomyocyte loss. While drug interventions are in development for improving gene expression of cardiomyocytes 3,4, little is known on preventing the loss of cardiomyocytes due to necrosis or apoptosis. Despite recent progress in acute interventional procedures, it remains an unmet challenge to prevent the loss of myocardium after infarction. It is thus of great importance to search for interventions which can regenerate viable myocardium and thereby prevent neuro-endocrine activation (Fig. 1). Although an attractive approach could involve transplantation of autologous adult stem cells, further studies are required to examine whether the findings on experimental animals can indeed be extrapolated to patients. Another attractive approach involves the identification of putative cardiac specific stem cells which could be recruited for regeneration of myocardium. Whether drugs such as ACE inhibitors interfere with these processes is of great interest and is under investigation (Rupp & Maisch, unpublished).
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Heinz Rupp, Ph.D. Professor of Physiology Molecular Cardiology Laboratory Department of Internal Medicine and Cardiology Karl-von-Frisch-Strasse 1 35033 Marburg E-mail Rupp@mailer.uni-marburg.de