Copyright © 2005, European Society of Cardiology
Arrhythmogenesis after cell transplantation post-myocardial infarction. Four burning questions–And some answers
Department of Cardiology, University of Ioannina, Greece
* Tel.: +30 265 1097227; fax: +30 265 1097053. Email address: thkolet{at}cc.uoi.gr
Received 21 November 2005; accepted 7 December 2005
See article by Fernandes et al. [5] (pages 348–358) in this issue.
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1. Introduction |
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 Top 1. Introduction 2. Is cell transplantation...3. Does arrhythmogenesis depend...4. Possible mechanisms of...5. ConclusionsReferences |
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Post-myocardial infarction heart failure remains a major public health problem [1]. Cell transplantation therapy is a promising new therapy, and several studies have shown that transplanted cells can form viable grafts within the host myocardium [2]. Similarly, in small-scale clinical trials, cultured autologous skeletal myoblasts were transplanted into the heart, with significant improvement in contractile indices [3,4]. However, enthusiasm was hampered by possible proarrhythmic effects; within weeks following cell transplantation, ventricular tachycardia or sudden cardiac death occurred in over 40% of patients [3,4].
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2. Is cell transplantation therapy arrhythmogenic? |
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Top1. Introduction2. Is cell transplantation...3. Does arrhythmogenesis depend...4. Possible mechanisms of...5. ConclusionsReferences |
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The first ‘burning’ question arises: Does the increased incidence of ventricular arrhythmias reported in clinical studies [3,4] represent a true proarrhythmic effect of myoblast transplantation therapy, or do these arrhythmias reflect the natural history of ischaemic cardiomyopathy? In this issue of Cardiovascular Research, Fernandes et al. [5] provide important answers to this question. Seven days after coronary ligation in rats, myoblasts were injected in the infarcted area. In fact, Fernandes et al. [5] break down the first question into two secondary questions: Do myoblast injections constitute a substrate for ventricular arrhythmias? They answered this question by performing programmed electrical stimulation, using standard protocols including up to three extrastimuli (although no burst pacing was utilised). They report an increased inducibility of ventricular arrhythmias in myoblast-injected rats compared to controls. This was evident two and three weeks after myoblast transplantation and declined thereafter. A supplementary question follows: Was this finding translated into an actual increase in the incidence of ventricular arrhythmias? To answer this question, Fernandes et al. [5] used a miniature implantable telemetry recording system, which represents the most accurate methodology to record ‘real-life’ arrhythmias in experimental animals for extended periods of time without the confounding effects of anaesthesia. The number of arrhythmic episodes recorded with this telemetry system did not differ between myoblast-transplanted rats and the control groups. One possible explanation for this discrepancy is the variability in the occurrence of ventricular arrhythmias in the rat model, although the authors correctly tried to overcome this limitation by several hours of recording. However, all recordings were performed during time periods with a low incidence of ventricular arrhythmias. One possible way to circumvent this limitation in future studies would be by incorporating an intervention that increases the incidence of ventricular arrhythmias: for example, subcutaneous injections of small doses of isoproterenol, as previously suggested [6]. Regardless of the above discussion, the answer to the first question, based on the study by Fernandes et al. [5], could be summarised as follows: myoblast transplantation into the infarcted myocardium forms a substrate for ventricular arrhythmias.
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3. Does arrhythmogenesis depend on the cell type? |
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Top1. Introduction2. Is cell transplantation...3. Does arrhythmogenesis depend...4. Possible mechanisms of...5. ConclusionsReferences |
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The second ‘burning’ question now arises: Is the increased substrate formation an inherent limitation of cell transplantation therapy, or does it depend on the cell type used? The ‘alarming’ clinical data come from myoblast transplantation [3,4], but one case of sudden cardiac death was also reported in a series of 14 patients who underwent transplantation of bone marrow cells [7]. Fernandes et al. [5] provide an answer to this question by adding a further control group, namely rats injected with autologous bone marrow mononuclear cells. Programmed electrical stimulation in these rats did not show an increased inducibility of ventricular arrhythmias when compared to either the control or vehicle groups. This finding suggests that (a) myoblasts exhibit a specific arrhythmogenic risk, and (b) cell injection per se is not proarrhythmic. Clearly, more studies are necessary before firm conclusions can be drawn.
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4. Possible mechanisms of arrhythmogenesis |
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Top1. Introduction2. Is cell transplantation...3. Does arrhythmogenesis depend...4. Possible mechanisms of...5. ConclusionsReferences |
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A third ‘burning’ question now seems inevitable: What is the mechanism of the increased arrhythmogenesis after myoblast transplantation? The possible mechanism(s) remain unknown and several hypotheses have been proposed. These include:
- A) Myoblasts express growth factors, such as insulin-like growth factor-1, promoting myocyte hypertrophy, with consequent alterations in the action potential duration [8]. Fernandes et al. [5] measured indices of hypertrophy and found no differences between groups, indicating that the increased inducibility of ventricular arrhythmias was not related to ventricular hypertrophy. However, this finding should be viewed with caution due to the small number of animals in each group.
- B) The transplanted myoblasts display automaticity, which may lead to ventricular arrhythmias. Furthermore, the spontaneous electrical activity of transplanted cells (at different cycle lengths compared to host cardiomyocytes) may provoke afterdepolarisations and, thereby, may induce ventricular arrhythmias by triggered activity. In addition, myoblasts differentiate into hyperexcitable myotubes, with significant differences in the action potential duration, when compared to host cardiomyocytes [9,10]. Such heterogeneities predispose to reentry, a key mechanism of ventricular arrhythmias. Thus, none of the basic mechanisms of arrhythmogenesis, (enhanced automaticity, triggered activity, reentry) can be excluded, and, moreover, more than one mechanism may be operative. This assumption may be reinforced by the findings of Fernandes et al. [5], who report not only an increased inducibility of monomorphic ventricular tachycardia in the myoblast-treated rats, but also an increased percentage of degeneration of monomorphic ventricular tachycardia into ventricular fibrillation.
- C) Cardiomyocytes normally express high levels of connexin-43, resulting in electrical coupling between cells. In contrast, differentiated myotubes lack gap junctions, and, therefore, they are not coupled to surrounding ventricular myocytes or to each other [11]. A recent in vitro study demonstrated that co-culture of skeletal myoblasts and cardiomyocytes resulted in reentrant arrhythmias that could be decreased by over-expression of connexin-43 [10]. These findings implicate the lack of gap junctions as a possible mechanism for ventricular arrhythmias, and Fernandes et al. [5] confirm these observations in vivo. These results may pave the way for arrhythmia prevention by genetic modification of myoblasts to express connexin-43.
- B) The transplanted myoblasts display automaticity, which may lead to ventricular arrhythmias. Furthermore, the spontaneous electrical activity of transplanted cells (at different cycle lengths compared to host cardiomyocytes) may provoke afterdepolarisations and, thereby, may induce ventricular arrhythmias by triggered activity. In addition, myoblasts differentiate into hyperexcitable myotubes, with significant differences in the action potential duration, when compared to host cardiomyocytes [9,10]. Such heterogeneities predispose to reentry, a key mechanism of ventricular arrhythmias. Thus, none of the basic mechanisms of arrhythmogenesis, (enhanced automaticity, triggered activity, reentry) can be excluded, and, moreover, more than one mechanism may be operative. This assumption may be reinforced by the findings of Fernandes et al. [5], who report not only an increased inducibility of monomorphic ventricular tachycardia in the myoblast-treated rats, but also an increased percentage of degeneration of monomorphic ventricular tachycardia into ventricular fibrillation.
As with any good study, new findings raise new questions. The study of Fernandes et al. [5] raises a fourth question: In their animal population, why did the increased inducibility of ventricular arrhythmias decline after the third week? Does this finding reflect poor survival rates of engrafted myoblasts, or does it implicate changes in the electrophysiologic milieu over time?
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5. Conclusions |
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Top1. Introduction2. Is cell transplantation...3. Does arrhythmogenesis depend...4. Possible mechanisms of...5. ConclusionsReferences |
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Until more answers are available, we should probably adhere to the conclusion of the study by Fernandes et al. [5]: programmed electrical stimulation in rats is a useful model for the evaluation of the substrate for ventricular arrhythmias and correlates with clinical data. Consequently, such evaluation should be required prior to clinical use to identify potential arrhythmogenic risk of cell transplantation therapy.
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References |
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Top1. Introduction2. Is cell transplantation...3. Does arrhythmogenesis depend...4. Possible mechanisms of...5. ConclusionsReferences |
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