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EDITORIAL |
Singapore
What do myocardial restoration and hyperspace theory have in common? The usual perception of tissue engineering, the fledgling new science, is of an art in 3 dimensions aimed at the reproduction of natural tissue in terms of structure and function. However, in the case of the heart, more than 3 dimensions need to be realized: the 4th is the heart rhythm, and the 5th is the contractile action and mechanics. Any ambitious attempt to manufacture cardiac muscle will have to address some unique issues if the product is to be one of high fidelity to nature. In the following, some important aspects of myocardial restoration will be discussed.
Some 10 years ago, aspiring tissue engineers and heart surgeons such as us, stood up and stated that Homo sapiens would be producing the first bioartificial left heart chamber within the decade. Unfortunately this prediction has proven premature, if not naïve. This is for obvious reasons. First, the heart is a highly asymmetric organ. The architecture of the diverse portions of the heart differs from site to site. The left ventricle is built differently from the right, and fulfills its function on a different scale. Furthermore, the form of the heart is not that of a simple sphere. Would it be so, then the maximal possible ejection fraction would not exceed 15%. The heart comprises a helix of uniquely arranged muscular bands (Torrent-Guasp bands), overlaying each other at an angle of approximately 60°.1 During systole, the heart functions as a vortex, thereby exploiting the maximal power possible from the muscular elements. These unique properties have not even been addressed so far by tissue engineering. All constructs without exception have been built in a symmetric fashion. With the available technology, it may be possible to produce a 3-dimensional graft that is shaped with 3 overlying layers and can be excited to twist as a vortex, but the idea has not been approached systematically so far. What has been achieved in the recent past is a mixture of collagen scaffolds and cells, and some 2-dimensional mechanical training of the constructs.2
Another important aspect of heart muscle is its anisotropy. The heart’s contraction is sustained in coordination by intercalation and a complex conduction system. Moreover, the singular muscle fibers have a high fiber-to-vessel ratio, so that every single functional contractile unit is highly angiotropic, posing a significant metabolic demand on the supplying vascular system. If we now go back to examine random and blind stem cell injections and epicardial patch or sheet implantations, the approach comes under a different light, and may cause us to reconsider. Epicardial patches are frequently reported to improve ejection fraction, albeit by a suggested mechanism: ignition of the inflammatory processes and subsequent angiogenesis. Without tangible proof, all side effects of the xenogeneic tissue implant are interpreted as beneficial events in the search for a plausible explanation of the functional improvement. Later we will examine Laplace’s law of the heart, which may underlie and excuse these allegations. As for stem cell injections, these are random and distort the described architecture of the heart. Assuming that cells are injected into the area of infarction and scar, they will be exposed to a hostile collagenous environment devoid of vascularization. In fact, up to 75% of the injected cells, no matter their origin, die within 48 hours of injection.3 It should therefore be a prominent goal of cardiac scientists to enhance viability and engraftment, an issue that has attracted increased attention lately. For instance, growth factors have been added to stem cell injections to improve the surrounding vascularization and donor cell viability.4,5 In our own hands, Bcl-2 overexpressing cells survived better and longer in in-vivo maturing matrices, as evidenced by bioluminescence.6 The prominent concern with bioartificial tissue implantation is that it would not heal where an infarct has occurred, because the natural regenerative resources of heart muscle are limited, and also because the graft itself lacks any integrated healing promoter. Therefore, efforts are now focusing on seeding co-cultures of endothelial cells and cardiomyocytes into scaffolds. One thing that needs to be born in mind is that even if endothelial cells are present, they will never form functional vessels driven only by growth factors. What they form is so-called microtubules that lack pericytes and an adequate lumen. On the basis of these preliminary studies, scientists are now far more cautious and refrain from using the initial term "regeneration", and refer to the effect of tissue engineering and stem cell transfer as "inhibition of further damage". Our little contribution to solid tissue vascularization and enhancement of in-vivo survival is co-cultures in bioreactors, which feature macroscopic vessels and are perfused. These efforts have yielded 8–10 mm thick and 4 times more viable grafts, including an anastomosable vessel good enough for transmural left ventricular wall replacement. Ongoing large animal experiments will hopefully prove that such implants can provide a sustainable myocardial replacement. Again, these constructs are still symmetric and isotropic, in contrast to the heart’s structure.
As for the clinical paradigm, we would cautiously remark: "from bench to bedside ... and back". Clinicians have pushed to utilize random stem cell injection into the area of the lesion in patients with ischemic heart disease. A plethora of clinical trials have seen the light of publicity.7 The majority of studies were not double-blind nor placebo-controlled, and were performed in conjunction with a bypass procedure. All in all, the results have been highly heterogeneous and speculative, and often revised. What we would like to remark here is that there is no single study that involves a control group of cells (fibroblasts) to reveal the net effect of the injected myocytes that are claimed to differentiate and integrate. Under the current study designs, we will never find out whether fibroblasts or other types of cell would produce the same result, due to structural support only. A finding like this would not be favored by the rapidly growing stem cell industry.
Following the "hype", is there any space for hope? We think there is. It is our responsibility in the pursuit of good scientific practice to seek ways of establishing applicable models of translational research with attainable deliverables in the field. Initially, we believe we need to go back one step and address the heart’s unique structure in vitro. Nanobiology and biomaterials science will provide new impetus to this emerging field. Micro and macro-vascularization will be of paramount importance in the design of first-line therapies for the heart, with sustainable effects. Improved clinical protocols and minimally invasive routes of stem cell and tissue administration will be necessary to render myocardial restoration a true first-line therapy. One proposal by our team in Singapore is to utilize pliable and injectable matrices as vehicles to engraft the cells and tissue for myocardial restoration through small incisions. The bioartificial tissue then consolidates and supports the structure of the left ventricle, thereby preventing thinning of the ventricular wall, and alleviates circumferential wall tension, cell death, and consequent non-ischemic expansion of the infarct. Myocardial restoration is still in a nascent state, and our humble view as cardiothoracic surgeons is that structural, paracrine, and perfusion aspects of heart disease have to be addressed with the same tenacity and versatility as the relentless search for the magic stem cell.
REFERENCES
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