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Cardiothoracic Surgery/Cardiac Surgical Research, The Rayne Institute (King's College London), Guy's and St Thomas’ NHS Foundation Trust, St Thomas’ Campus, London SE1 7EH, UK
Received 7 January 2008; received in revised form 7 January 2008; accepted 8 January 2008.
* Corresponding author. (Email: david.chambers{at}kcl.ac.uk).
Angiogenesis is a generalised term that can be used to summarise the extremely complex process of new vessel growth that can occur via three different mechanisms: vasculogenesis, angiogenesis or arteriogenesis [1,2]. Vasculogenesis refers to the formation of new vessels from endothelial precursors during embryogenesis; angiogenesis is a process by which thin-walled structures lined with endothelium (but lacking in smooth muscle) are formed (such as capillaries in wound healing), whereas arteriogenesis refers to the formation of new vessels complete with smooth muscle wall (such as occurs with collateral development). Experimental studies in angiogenesis with various growth factors (such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) have shown promising results in alleviating myocardial ischaemic injury in various animal models, and these have been summarised in a number of recent and comprehensive reviews [2–4]. Despite the promising results in these animal model studies, therapeutic angiogenesis remains an experimental treatment that targets ‘final option’ patients, in whom potential treatment modalities (such as pharmacological means of reducing myocardial demand and increasing coronary vasodilatation, or improving myocardial revascularisation by percutaneous coronary interventions or coronary bypass surgery) have been exhausted. The reviews summarise some of the large number of studies conducted in this area over the past few years and highlight the hype that has occurred with regard to the possibilities of angiogenic therapy. Most importantly, they detail the essential factors that have emerged from this wealth of information required for further study of this topic. These essential factors are that: (i) the use of young healthy hearts in angiogenic studies is not relevant to the condition under investigation. It is important to induce an element of myocardial dysfunction which will usually also involve vascular dysfunction, (ii) the mode of treatment delivery is crucial with local delivery over a prolonged period of time being vitally important, (iii) the recognition that angiogenesis is an extremely complex process that is unlikely to be induced by a single growth factor.
The study by Boodhwani and colleagues [5] is important in that it emphasises some of the reasons why previous experimental studies may not have been reproduced clinically, and it addresses two of the three essential factors described above. Myocardial dysfunction was addressed by feeding the treatment group animals a high cholesterol diet for a sustained period of time (20 weeks). This regime was demonstrated to induce a hypercholesterolaemic vascular dysfunction in terms of both the ability for microvessels of branches of the LAD to relax and associated levels of perfusion flow to the ischaemic territory. In addition, during the final 7 weeks of the diet, an ameroid constrictor was used to induce a chronic ischaemic injury to the myocardial territory perfused by the proximal left circumflex artery. Growth factor treatment was started three weeks after the placement of the constrictor, and this suggests that the injury induced before treatment starts is unlikely to be sufficiently severe to be of the ‘final option’ variety that is thought to be the ‘optimal’ for this type of treatment. Consequently, it is tempting to wonder how effective this treatment regime might be in the face of a more severe ischaemic injury; however, it is possible that, once the therapy has been optimised, it could be a viable option for less severe ischaemic injury, and so the regime outlined in this study is interesting from a clinical viewpoint.
The mode of treatment delivery over a prolonged period has also been addressed in this study. The individual growth factors were provided locally at the site of the ischaemic myocardium, either by direct infusion of a solution containing VEGF into the ischaemic area via microcatheter, or by implantation in the ischaemic myocardium of sustained release beads containing FGF-2. Interestingly, the placebo hypercholesterolaemic group had implantation of sustained release beads without any growth factor (FGF-2), but there was no specific placebo group for the VEGF infusion! This raises two questions; firstly, are the lesser effects of VEGF treatment a result of the different delivery procedures and, secondly, is VEGF actually having any effect or could the changes observed be a result of the direct infusion of small volumes of a heparin-based solution over a sustained period? To their credit, the authors do acknowledge that the different delivery regimes of the growth factors do represent a limitation to the study, and it is explained that the sustained release beads were not available for VEGF. One wonders whether the positive effects observed with FGF-2 would have been similar if provided by direct infusion? Indeed, these authors previously demonstrated [6] that alternative delivery modes of FGF-2 (via transendocardial or transepicardial myocardium) were more effective at providing higher myocardial deposition and retention and lower systemic recirculation of growth factors than an intracoronary, intrapericardial or intravenous mode of delivery. It is, however, somewhat unclear as to the exact delivery mode of VEGF, as it is stated that it is delivered by microcatheter implanted in the ischaemic territory. Nevertheless, the different delivery modes, and the absence of a placebo group for VEGF delivery, are a slight concern for an effective comparison of the efficacy of these growth factors.
The third factor identified as crucial for effective angiogenesis was, disappointingly, not addressed in this study. It has become clear from the wealth of previous studies that the process of angiogenesis is extremely complex and all the reviews [2–4] mention the multifactorial interactions involving activation and inhibition of various mediators (including the review by authors of this study [3]). It is, therefore, surprising that this factor was not addressed, and it would have been extremely interesting to have included an additional group of combined growth factor administration to determine whether there was enhanced efficacy compared to individual effects. Obviously, however, this would make for a considerably more complicated study and it is likely that this may be planned for the future.
Finally, it is worth considering whether angiogenesis is an appropriate target for therapeutic study, in comparison to arteriogenesis. As indicated above and in recent reviews [2–4,7], angiogenesis is defined as a process by which thin-walled structures lined with endothelium (but lacking in smooth muscle) are formed, whereas arteriogenesis is the formation of new vessels complete with smooth muscle walls. Should arteriogenesis be the main target for therapeutic revascularisation studies or are the two processes so intricately entwined that one is a manifestation of the other and the terminology only a function of definition?
The study by Boodhwani and colleagues [5] goes someway into defining why many experimental studies have failed to be efficacious in the clinical arena, and is an important addition to studies of the efficacy of growth factors in ameliorating ischaemic heart disease. However, the many limitations inherent in this and the myriad of other studies on this subject show the need for continued, considered and focused research effort in this fascinating area.
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