A salty salute: Progenitor cell therapies and no-option heart disease
Article Outline
Cardiovascular disease is all too common, and cardiovascular diagnoses are too frequently dire. In spite of advances, many patients with cardiovascular diseases remain symptomatic and at risk. The severity and frequency of these illnesses have stimulated searches for new strategies. Some of these translational projects have never really worked out (transmyocardial laser revascularization); others have been major success stories (drug-eluting stents); and some we just do not know what to think about (enhanced external counterpulsation). All have garnered widespread notoriety that, as will be argued below, follows a stereotypical pattern: technological ascent, hyperbolic promise, and rational acceptance or rejection through the ultimate processes of randomized, controlled trials.
In the current issue of the Journal, results are presented from one of the first human studies examining the consequences of intramyocardial injection of autologous bone marrow in patients with refractory angina.1 This report is notable for having been caught up in the controversies and politicization of “stem cell” therapies, and also for its significance in raising expectations about the promise of regenerative medicine for patients with refractory cardiovascular disease. This promising study therefore invites further consideration of both of these issues.
The experimental protocol in this report was designed based on similar protocols from another group in small animal models.2 This article was originally submitted for peer review and accepted for publication in the Journal in 2003, but was subsequently withdrawn at the request of the Italian Ministry of Health to allow a review of human research involving stem cells in Italy. This is an interesting set of events insofar as the cells used in this study are autologous bone marrow cells. Why injecting these cells into the myocardium should be any more controversial, than, for instance, shooting holes in the heart with lasers, is difficult to answer. Certainly, the process described here is no different ethically than autologous bone marrow transplantation, a procedure that generates little controversy. The clamor arising from these and similar studies is due to a blurred distinction between true stem cells (particularly embryonically derived stem cells), which are self-renewing multipotential cells, and progenitor cells for one or a few lineages—which, in the case of vascular cells, happen to reside in the bone marrow. The ethical controversies (particularly with respect to embryonic manipulations) reside almost exclusively with the former, whereas at the present time, cardiovascular therapeutics such as the elegant study by Briguori et al have focused on progenitor cells.
Why have the controversies surrounding human embryo–derived stem cells metastasized in this way? Surely there are a number of reasons, including a failure of dialogue between the scientific community and the lay public. However, there is another, more insidious factor that should be brought out in the open—the willingness on the part of many investigators to invoke stem cell terminology for experimental approaches that are clearly distinct, possibly because stem cell biology is considered cutting edge or “sexy” within some aspects of the biomedical community. This fuzziness in terminology has done little to enhance the quality of the science in this field, yet it has drawn some investigators into a debate in which they do not belong. In the report by Briguori et al, the authors very clearly avoid the stem cell terminology for their bone marrow–derived cells. However, they nonetheless have suffered from guilt by association through the regulatory delays that have impeded publication.
Regardless, the work is now available and we can think about whether there will be clinical utility for these methods. The idea of injection or mobilization of bone marrow cells to treat chronic ischemic diseases first came from studies in which bone marrow cells were found to transdifferentiate into cardiomyocytes, raising the possibility that myocardium could be regenerated to restore cardiac function.2 Whether new cardiomyocytes can be formed to any clinically significant degree remains a matter of controversy, as some careful studies have failed to identify a bone marrow reservoir for cardiomyocyte progenitors.3, 4 Nevertheless, improvements in cardiac function have been observed in animal models, and it has been speculated that bone marrow–derived cells may affect outcomes either through direct incorporation into blood vessels or by serving as cytokine factories that promote new blood vessel growth in ischemic myocardium. Thus, preclinical studies have suggested a potential benefit for bone marrow–derived cellular therapies, but it is important to recognize there is no clear consensus as to their underlying mechanism of action in this setting.
In the present study, the authors have adopted a protocol similar to the one used in reported animal experiments.2 Humans with no-option angina underwent aspiration of bone marrow which was reinjected into ischemic myocardium percutaneously—2 nontrivial procedures that, nonetheless, many patients with refractory angina would probably choose. Of 10 subjects that underwent this protocol, no complications were observed in the periprocedure period; one incident of acute heart failure occurred at 7 days; and no death, malignant arrhythmias, or infarctions were documented. Modest improvements were observed in anginal frequency across all patients, and improvements in perfusion imaging were documented in a subset of patients. However, it is important to keep in mind that this pilot study was neither powered nor designed to assess efficacy.
The report by Briguori et al is one among a handful of studies in which small groups of patients with refractory angina or heart failure have been treated with fractions of bone marrow aspirates injected either intramyocardially or into the coronary circulation.5, 6, 7, 8 Each of these studies has crucial differences in design, and none is adequately powered to assess efficacy. Nevertheless, they represent an accumulating (though as yet incomplete) record of safety for this type of approach. If history is a guide, the perception of the promise for these approaches will evolve over time as more data appear and as more consideration is given to the mechanisms that underlie the therapeutic effect. One thing we can say: given that there is no clear consensus on whether or how this approach works in animal models, we are not in the optimal position to guess whether these new therapies will prove beneficial in humans.
The argument for pursuing these studies in the absence of definitive animal data generally invokes the dire condition of the patients for whom this therapy is intended. This reasonable argument has been proffered before—indeed, not so long ago, in the case of vector-based therapeutic angiogenesis. The parallels between progenitor cell therapies and the therapeutic angiogenesis phenomenon are worth considering. The notion that therapeutic angiogenesis (driven by growth factors such as vascular endothelial growth factor) would be effective treatment of ischemic vascular diseases raced from animal studies to the clinic in the space of only a few years. Phase I studies of angiogenic strategies for peripheral vascular and coronary artery diseases suggested promising benefits and, in spite that these initial accounts were case reports and uncontrolled studies, attracted significant attention in the lay press. This led to a cascading effect in which many cardiology programs felt compelled to develop experimental therapeutic angiogenesis programs. It was not until several randomized trials were published, none of which identified differences in primary end points of disease, that the initial enthusiasm waned.9, 10 The consequence of the therapeutic angiogenesis “bubble” has been a depletion of interest in this approach, which is unfortunate because the principles that underlie therapeutic angiogenesis as a clinical strategy may be sound.
Progenitor cell–based regenerative strategies for cardiovascular disease have, so far, followed this same arc. Whether these approaches will fulfill their promise in human studies or suffer the same fate as vector-based therapeutic angiogenesis approaches remains to be determined—given the ominous status of patients with no-option angina and end-stage heart failure, no one can be faulted for optimism. Nevertheless, it is worthwhile to consider some of the factors that contributed to the sense of surprise in the outcomes of randomized trials testing therapeutic angiogenesis, with the hope that these circumstances might be avoided in the future. First and foremost, it is clear in retrospect that the biological activity of the growth factors used in the first studies was not well suited to achieve the desired therapeutic outcome. It is now understood that the use of a single angiogenic agent by itself is unlikely to produce mature conductance vessels that are suitable to improve oxygen delivery to ischemic tissues.11 With a better understanding of the fundamental activities of angiogenic factors, more promising clinical approaches could have been used in the first therapeutic angiogenesis trials. This point should be kept in mind as regenerative therapies are being developed, and caution should be applied in the translation of any basic observations to clinical approaches when the underlying mechanisms are incompletely understood.
Even after therapies have advanced to the clinical realm, hyperbole can damage long-term prospects for new therapies in insidious ways. In the case of therapeutic angiogenesis, prominent commentary in the lay press raised patients' expectations beyond what was reasonable, and probably also encouraged additional clinical studies that were not rigorously designed. There are indications that negative observations from both preclinical and clinical studies were overlooked early in the development of therapeutic angiogenesis strategies, creating a bias toward the appearance of success for these approaches. Finally, signs of benefit in nonrandomized studies of therapeutic angiogenesis approaches were inappropriately attributed to the therapy itself, rather than to a powerful placebo effect or to clinical regression to the mean in patients with severe symptomatic peripheral vascular disease or angina. It was not until randomized trials were performed that these trends became apparent,9, 10 which led to the surprising failure to reject the null hypothesis in these studies and a collapse of enthusiasm for this approach.
This same outcome is not at all guaranteed for progenitor cell therapies for cardiovascular disease, and careful studies such as the one reported in this issue are essential steps toward reducing this approach to clinical practice. Nonetheless, there is much to learn from our previous experiences as we try to determine how best to bring new and complex approaches to our patients with efficacy and without harm.
References
- Direct intramyocardial percutaneous delivery of autologous bone marrow in patients with refractory myocardial angina. Am Heart J. 2005;[in press]
- Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410:701–705
- Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature. 2004;428:668–673
- Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature. 2004;428:664–668
- Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet. 2003;361:47–49
- Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002;106:1913–1918
- Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation. 2003;107:2294–2302
- Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study. J Am Coll Cardiol. 2003;41:1721–1724
- Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation. 2002;105:2012–2018
- The VIVA trial: vascular endothelial growth factor in ischemia for vascular angiogenesis. Circulation. 2003;107:1359–1365
- VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation. 2000;102:898–901
Work in the author's laboratory is supported by NIH grants GM61728, HL65619, AG02482, and HL61656. CP is an established investigator of the American Heart Association and a Burroughs Wellcome Fund Clinical Scientist in Translational Research.
PII: S0002-8703(05)00504-1
doi:10.1016/j.ahj.2005.05.009
© 2006 Mosby, Inc. All rights reserved.
