Letter by Ly Regarding Article, “Direct Intramyocardial but Not Intracoronary Injection of Bone Marrow Cells Induces Ventricular Arrhythmias in a Rat Chronic Ischemic Heart Failure Model”
To the Editor:
We read with great interest the article by Fukushima et al1 on arrhythmia induction after bone marrow cell–based therapy in a rat model of postinfarction heart failure. We congratulate the authors on a provocative study. Although their conclusion that intramyocardially injected bone marrow–derived cell clusters induce proarrhythmia effects is insightful, there remain issues raised by the authors that we feel merit further attention.
First, further mechanistic insight might have been provided if intramyocardial injection had been explored differently. The difference between injecting directly into the scarred myocardium and into the border zone has only begun to be scrutinized in translational models of infarction.2 This key technical aspect is pivotal, as electromechanical mapping represents a safe and readily usable delivery strategy for cells too large to be injected via an intracoronary route (such as skeletal myoblasts). Moreover, the importance of the precise target site deserves further deciphering, as it can impact clinical decision making.
Second, current data from clinical trials3 contradict the assumptions on the part of Fukushima et al1 that the retrograde coronary venous route might be more suitable than the antegrade route. We agree with the authors that cell retention remains a pivotal challenge in the field of cardiac cell-based therapy, but would add that this problem plagues most, if not all, available routes of cell delivery. Although antegrade intracoronary injection remains an imperfect solution, as previously reported,4 it is still arguably the most practical means of cell delivery, and it provides a method to obtain widespread cell distribution into the vascular territory of the infarct-related artery. Further intense research is required to determine whether cell type selection (selected versus unselected mononuclear bone marrow cells, mesenchymal stem cells, or endothelial progenitor cells) or ex vivo cell manipulation (by gene transfer, by cytokines/growth factor preconditioning, or in combination with biopolymers) will lead to enhanced cell engraftment and improve the retention potential of injected cells.
Lastly, the contrasting findings of low myocardial cell retention and positive cardiac effects highlight the increasingly recognized contribution of cellular paracrine effects and signal-ing factors. It would have been interesting to correlate myocardial inflammation (histological changes and elicited cytokines) after both types of injection methods with documented arrhythmic side effects and to investigate whether intramyocardial delivery of cell clusters, as compared with a more diffuse intramyocardial distribution after intracoronary injection, resulted in different levels of key signaling factors, such as vascular endothelial growth factor or stromal derived factor-1.5
Fukushima S, Varela-Carver A, Coppen SR, Yamahara K, Felkin LE, Lee J, Barton PJ, Terracciano CM, Yacoub MH, Suzuki K. Direct intramyocardial but not intracoronary injection of bone marrow cells induces ventricular arrhythmias in a rat chronic ischemic heart failure model. Circulation. 2007; 115: 2254–2261.
Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Suselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM. Intracoronary bone marrow–derived progenitor cells in acute myocardial infarction. N Engl J Med. 2006; 355: 1210–1221.
Hofmann M, Wollert KC, Meyer GP, Menke A, Arseniev L, Hertenstein B, Ganser A, Knapp WH, Drexler H. Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation. 2005; 111: 2198–2202.