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Eur J Cardiothorac Surg 2006;30:107-108
© 2006 Elsevier Science NL
University Hospital Freiburg, Department of Cardiovascular Surgery, Hugstetter Street 55, 79106 Freiburg, Germany
* Corresponding author. Tel.: +49 761 270 2818; fax: +49 761 270 2550. (Email: friedhelm.beyersdorf{at}uniklinik-freiburg.de).
In this issue, Ying Liu and coworkers [1] report on the effects of slow release FGF-2 in acute myocardial infarction in dogs. The authors incorporated FGF-2 in gelatin microspheres and injected them immediately after experimental infarction into the adjacent myocardium. Functional outcome was determined using the tagged cardiac magnetic resonance imaging method at rest and under dobutamine stress. FGF-2 therapy resulted in a higher LVEF (171% and 149% of controls after 10 and 17 days, respectively) and an improved wall motility score index at rest and with dobutamine after 10 and 17 days. Congruently, a higher number of capillaries and arterioles was found (142% and 170% of controls after 10 and 17 days, respectively).
Growth factor therapy aims at restoration of regional circulation and function in ischemic myocardium and is considered a new option for patients with severe coronary disease who are currently not amenable to surgical or interventional revascularization. Various growth factors have been studied in almost multitudinous animal experiments. However, the success in clinical trials is still limited. For example, the growth factor employed in the paper, FGF-2, has been used in the FGF initiating revascularization trial (FIRST) [2] to treat severe myocardial ischemia. The patients received a single intracoronary infusion of recombinant FGF-2 in a double-blind, randomized fashion. The therapy did not improve exercise tolerance or myocardial perfusion in long-term observation.
One of the reasons for the failure of FIRST has been discussed to be the rapid degradation of the protein in circulation. Retarded FGF-2 application could improve the outcome. We found in a porcine model of chronic myocardial ischemia that growth factor gene therapy, which also results in prolonged delivery, is superior to a single protein application [3]. Sustained FGF-2 release could also reduce the problem of hypotension associated with higher doses, a frequent adverse advent in the FIRST study.
Another limitation of clinical usage of growth factor therapy is that we still not know which growth factor – or growth factor combination – is the best one. Both development of arterial vessels (arteriogenesis) and of new capillaries (angiogenesis) contribute to the revascularization of ischemic regions [4]. In a recent experiment, we investigated the combination of FGF-2 and MCP-1, an arteriogenic cytokine, with regard to myocardial function and vessel growth. We assumed a synergistic effect of angiogenesis and arteriogenesis. We found, however, development of a functional flow reserve merely in the FGF-2-only group where angiogenesis was observed. In contrast, arteriogenesis did not result in better regional contractility. These data might indicate a better recovery of myocardial function with angiogenesis as compared to arteriogenesis [5]. This is in contrast to some reports indicating the superiority of arteriogenesis as compared to angiogenesis. A potential solution to this controversy might be the combination of angio- and arteriogenesis—like in an irrigation system.
Furthermore, the optimal delivery route for growth factor therapy has not yet been determined. The introduction of a catheter-based transendocardial delivery could open new therapeutic options even for application of growth factor-loaded microspheres. Feasibility of this injection method using left ventricular electromechanical guidance to regions pre-identified by single-photon emission computed tomography perfusion imaging in humans has been demonstrated [6,7]. The advantage of this method lies in the targeted treatment of the area in need.
A factor significantly contributing to the success of Ying Liu and coworkers is probably the early start of therapy, i.e., immediately after infarction. Three different modes of action have to be considered for FGF-2. New capillaries start to develop in the first few hours after onset of ischemia [8], this is facilitated by the angiogenicity of FGF-2. In addition, the growth factor exerts immediate protective effects on cardiomyocytes against ischemia–reperfusion injury [9] and against apoptosis [10]. Here, an early onset of treatment is apparently most important to rescue cells before they are irreversibly damaged and myocardial infarction or stunning occurs. Moreover, FGF-2 is one of the players in stem cell-derived myocardial regeneration. The existence of cardiac progenitors residing in the myocardium has been discovered only recently [11]. Now, FGF-2 has been shown to contribute to the regulation of differentiation of these precursor cells to cardiomyocytes [12]. Ischemia impairs, of course, not only cardiomyocytes, endothelial cells and others, but also resident and homing bone marrow-derived cardiac stem cells. A cytoprotective effect of FGF-2 on these cells is likely.
Ying Liu and coworkers also tackle the problem of appropriate proof of their treatment and employ tagged myocardial magnet resonance imaging. This method enables localized assessment of regional wall contractility. High-frequency magnetic impulses generate a grid across the myocardium, and the deformation of single sections is analyzed in correlation to the heart cycle. The technique has been excellently described in detail in a recent issue of this journal [13] and could become a routine diagnostic procedure in the future.
In the recent years, angiogenesis induced by growth factors has advanced to a promising tool to treat ischemic diseases. Innumerable studies have demonstrated a functional benefit for ischemic myocardium, as in the study by Ying Liu and coworkers. However, the breakthrough in clinical use is still missing. Probably, it is not only necessary to revascularize the ischemic tissue, but to enable the cardiomyocytes to survive until revascularization. In addition, a therapy using a single substance does certainly not correspond to a process as complex and dynamic as vessel growth. However, investigation of the interactions of the molecules involved, and of the interference of therapeutically applied agents, is still at the beginning.
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