Europace Advance Access originally published online on October 19, 2007
Europace 2007 9(12):1222-1223; doi:10.1093/europace/eum190
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EXPERIMENTAL STUDIES
Ventricular arrhythmias following intracoronary bone marrow stem cell transplantation
1 Instituto de Ciencias del Corazón (ICICOR), Hospital Clínico Universitario of Valladolid, Valladolid, Spain; 2 Servicio de Cardiología, Hospital General Universitario Gregorio Marañón, Madrid, Spain
Manuscript submitted 15 April 2007. Accepted after revision 8 August 2007.
* Corresponding author: Servicio de Cardiología, Hospital General Universitario Gregorio Marañón, C/o Dr Esquerdo 46, 28007 Madrid, Spain. Tel: +34 914265882; fax: +34 915868276. E-mail address: faviles{at}secardiologia.es
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We describe the appearance of delayed episodes of ventricular arrhythmias in 4 patients out of 72 undergoing intracoronary transplantation of autologous bone marrow mononuclear cells (BMMC) following ST elevated myocardial infarction (STEMI). Two cases with severely depressed systolic function presented electrical storms with monomorphic sustained ventricular tachycardia (SVT) within 2 to 3 days following cell transplantation, even though there were no periprocedural complications. Both patients were implanted with an internal defibrillator (ICD) after ruling out coronary re-occlusion. The remaining 2 patients presented several asymptomatic episodes of non-sustained ventricular tachycardia within one month following cell transfer. Only one of the latter presented syncopal SVT through programmed ventricular stimulation, undergoing ICD implantation afterwards. Neither new arrhythmic episodes nor ICD interventions have occurred during later follow-up of the three ICD patients (639±59 days). Information from large multicenter databases and our historical cohort of STEMI patients indicates that the rate of VT occurring within the first weeks after the initial 48 hours of infarction is significantly lower than that observed in our cell-therapy experience. The lack of information regarding the appearance of malignant arrhythmias in patients with severe systolic dysfunction following this type of therapy after STEMI requires us to be extremely cautious. However, any claim of a mechanism related to cell transfer would be completely speculative with the available data. Therefore, our only aim when reporting our findings is to recommend a short but longer stay (2-3 days) following cell transplantation, particularly in patients with a natural tendency to develop arrhythmic events.
Key Words: ventricular tachycardia, stem cells, bone marrow, acute myocardial infarction
In this case report, we describe the appearance of delayed episodes of ventricular arrhythmias in 4 patients out of 72 who received intracoronary transplantation of 92 ± 54 x 106 autologous bone marrow mononuclear cells (BMMCs) 10 ± 4 days after ST-elevated myocardial infarction. The study protocol included 24 h Holter recordings before discharge, at 1 month, and 9 months later. Two cases with severe left ventricular systolic dysfunction (Patients 1 and 2, Table 1) presented electrical storms with repeated monomorphic sustained ventricular tachycardia (SVT) within 2–3 days following cell transplantation, even though there were no periprocedural complications, arrhythmias on ECG monitoring, or rise in myocardial injury markers on serial determinations during the 24 h immediately thereafter. Both episodes were controlled with infusion of amiodarone, and patients were subsequently implanted with an internal defibrillator (ICD) after ruling out coronary re-occlusion. The remaining two patients, with mild and moderate baseline systolic dysfunction, respectively (Table 1), presented several asymptomatic episodes of non-SVT on ECG–Holter recordings within 1 month following cell transfer. One of them (Patient 3) received ICD implantation 6 months after infarction, as syncopal SVT was reproducible through programmed ventricular stimulation, whereas the other one (Patient 4) failed to show inducible arrhythmias at the electrophysiological study. Neither new arrhythmic episodes (SVT or ventricular fibrillation) nor ICD interventions have occurred during later follow-up of the three patients who underwent device implantation (639 ± 59 days), and only one of them continued to receive oral therapy with amiodarone following the arrhythmic event.
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Ventricular arrhythmias following stem cell therapy for cardiac repair have only been reported thus far in clinical trials using myoblasts in the context of chronic ischaemic heart disease. The unexpected high rate of symptomatic ventricular arrhythmias found within the first weeks after myoblasts injection raised concern as to whether such events were due to the intervention or the natural history of the underlying condition. In contrast to such experiences within the chronic setting, randomized controlled trials assessing the use of BMMCs in the context of acute myocardial infarction published so far (Figure 1) have failed to detect any pro-arrhythmic effect of stem cell therapy. However, information from large multicentre databases (GISSI-3 trial) as well as from our historical cohort of patients with reperfused ST-elevated AMI indicates that the rate of ventricular tachycardia occurring within the first weeks after the initial 48 h of myocardial infarction is significantly lower than that observed in our cell therapy experience (Figure 1).
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Historical cohort of patients with successfully reperfused acute myocardial infarction; sudden cardiac death and sustained ventricular tachycardia included. 
Sustained ventricular tachycardia.The lack of information regarding the appearance of malignant arrhythmias in patients with severely depressed ventricular function following this type of therapy after acute myocardial infarction requires us to be extremely cautious. Indeed, mean left ventricular ejection fraction at baseline in the aforementioned randomized cell therapy-controlled trials ranged from 48 to 55%. However, although some reasons may argue in favour of an acute arrhythmogenic effect of intracoronary bone marrow cell transplantation in Patients 1 and 2 (short time from cell transfer to SVT, absence of triggering factors such as myocardial ischaemia, ionic disorders or pro-arrhythmic drugs, absence of recurrent arrhythmic episodes throughout almost 2 years of follow-up), any claim of a mechanism related to cell transfer would be completely speculative with the available data. Therefore, our only aim when reporting our findings is to recommend a short but longer stay (2 or 3 days) following the cell transplantation procedure particularly in patients with a natural tendency to develop arrhythmic events. Future randomized studies focused on patients at risk should definitely prove the safety of this approach.
Potential conflict of interest: This work is supported in part by the Junta de Castilla y Leon (Regional Government) and the Instituto de Salud Carlos III (Red Cardiovascular y Red de Terapia Celular) from the National Health Service of Spain.
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  F. Cao, D. Sun, C. Li, K. Narsinh, L. Zhao, X. Li, X. Feng, J. Zhang, Y. Duan, J. Wang, et al. Long-term myocardial functional improvement after autologous bone marrow mononuclear cells transplantation in patients with ST-segment elevation myocardial infarction: 4 years follow-up Eur. Heart J., August 2, 2009; 30(16): 1986 - 1994. [Abstract] [Full Text] [PDF]
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