Specialist registrar in cardiology St Thomas Hospital, UK .
Professor Cardiology, Divisional Lead St Thomas Hospital UK.
The number of people affected by coronary artery disease is staggering. The American Heart Association’s reports that in 2003 alone there were almost 480,000 deaths attributable to coronary disease in the United States, representing 1 in 5 of all deaths. In addition, over 13 million Americans suffer from the consequences of heart attack, which include angina and heart failure. Furthermore, cardiovascular disease is no longer regarded as being particular to developed economies: almost 80% of deaths due to heart and blood vessel dysfunction worldwide occur in emerging economies.
Therefore, it will come as no surprise that a great deal of effort has been made in developing new technologies for the injured heart. Possibly the most high profile scientific endeavour in medical science over the past 10 years has been the attempt to harness the potential of embryonic stem cells and adult progenitor cells. These cells are defined by their ability to self-renew and mature into one or more cell types. Instead of replacing the entire damaged organ therefore, this approach provides precursor cells that may replace damaged components. In theory, there are several different sources from which these cells can be harvested: foetal tissue (from terminated pregnancies), embryos, umbilical cord, bone marrow and possibly other sites such as fat tissue.
Unfortunately, progress in stem cell science has sometimes been in the spotlight for the wrong reasons. We believe this has two principal explanations.
Firstly, some countries lack clear legislative measures to bolster the ethical boundaries created by research committees. In India several reports have emerged in recent years of clinics offering miraculous cures, albeit with an eye-watering fee attached, but whose results have not fallen under the scrutiny of peer-review. Hence, accusations have arisen of the exploitation of potentially desperate people. Perhaps it is this relative paucity of regulation that has attracted foreign businesses, which are known to use Indian patients as a test bed for their stem cell research, both in private and government-funded institutions. Another widely publicised case in point is that of the eminent Korean stem cell scientist, Hwang Woo-Suk, whose reputation was called into question over the issue of whether he was aware of the donation of eggs for experimentation by one of his own researchers.
The use of embryonic or fetal stem cells is the most strictly regulated. Although these are the most powerful weapons in the regenerative therapy armamentarium, they are also the most complex from an ethical perspective. Unregulated embryo research is possibly the reason for much of the negative attention that this field has drawn, underlining the need for more exacting controls.
Secondly, despite the presence of a strict legislative and ethical framework, much of the work that has emerged from the study of stem cells in heart disease has been notable for a lack of cohesion. Although it has been less than a decade since the possibility of a cell-based repair method for the heart working with animal models arose, there have since been literally dozens of experiments conducted in humans reported in the scientific press. The rapidity of translation from the laboratory bench to the bedside is perhaps a reflection of the potential rewards to pioneers in this new era of biotechnology. Maybe because of this haste, scientific rigor has been pushed aside in favour of perceived progress. As a result, there is a confusing— some might say chaotic—variety of different approaches to the same problem. How can we separate the signal from the noise?
To date, the main categories of cells that have been investigated for their potential to repair damaged heart tissue include skeletal myoblasts (resident satellite stem cells of skeletal muscle), and multipotent stem cells, derived from bone marrow.
Skeletal myoblasts were the first cells to be used in a clinical trial. Cells were injected in the scarred portions of heart muscle damaged by heart attack. Importantly, there was a small but significant improvement in the pumping function after almost a year. However, there was a significant downside. The pilot trial failed to demonstrate that these cells from skeletal muscle could transform into heart muscle cells. Moreover, 4 of the 10 patients developed potentially life-threatening heart rhythm abnormalities. This was possibly due to a lack of integration at the electrical level between the host cells and the implanted cells. Patients in the latest phase of this trial now require prophylactic insertion of an internal defibrillator, a specialised pacemaker capable of delivering an electric “shock” to revert the rhythm to normal.
In 2001 came the first report of bone marrow cells being used in the context of a heart attack (myocardial infarction), and these are now the most commonly used type of cells. A 46 year old man received his own bone marrow derived stem cells delivered by an injection into his coronary artery. Not only was the procedure safe, but at 10 weeks the patient had significantly improved the pumping capacity of his heart. These investigators subsequently published the first trial of cell therapy in acute myocardial infarction, in which patients derived a similar degree of benefit. The profusion of trials that followed all seemed to show promise. On closer inspection, however, the benefits observed in stem cell recipients should be tempered by considering some important methodological criticisms.
Some trials, such as TOPCARE-AMI (Transplantation Of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction), were not randomised, thus opening the door to unwanted bias, and leaving the possibility that observed effects may have occurred despite the presence of stem cell infusion. Others did not include a group in whom a “sham” bone marrow harvest or infusion occurred such as BOOST-(BOne marrOw transfer to enhance ST-elevation infarct regeneration), thereby allowing for a potential confounding effect of the bone-marrow harvest procedure itself.
Furthermore, in BOOST, the relative improvement in heart function seen at 6 months was no longer evident at 18 months, suggesting that in this case, at least, the effect of cell therapy was simply to accelerate recovery.
There are numerous other areas of contention. It is not clear, for example, which subset of bone marrow stem cell is the most effective, or if a generalised “soup” of cells is preferable to a highly selected population. Other investigators have used cells harvested after prior “enrichment” with growth factors designed to expand the desired cell sub-population. However, in some experiments, patients treated in this way had an acceleration of re-narrowing of the coronary arteries which were originally opened to treat the myocardial infarction.
The timing of delivery of stem cells has varied from hours to days after the heart attack. The mode of delivery of cells also differs between experiments. Some have been given intravenously, some down the coronary arteries, and some injected directly into the heart muscle itself. Similarly, there is no consensus as to the number of cells which should be delivered, which varies by up to 3 orders of magnitude.
Another crucial factor determining the success of a study is the method by which it is measured. Most studies have determined the change in the function of the left ventricle (LV), the main pumping chamber of the heart, as the principal outcome measure. This is because LV function appears to be one of the best indicators of prognosis after myocardial infarction. The method of assessment of LV function, however, encompasses the spectrum of modalities available, including, angiography, echo, magnetic resonance imaging (MRI), and single positron emission tomography (SPECT), all of which have been used at variable time-points after infarction, and each having different sensitivities for detecting change.
Even after these differences are taken into account, the magnitude of improvement is typically not large. REPAIR-AMI (Reinfusion of Enriched Progenitor Cells And Infarct Remodelling in Acute Myocardial Infarction) is the largest double blind, placebo-controlled trial to date. This rigorously designed and well-executed study investigated 101 patients, in whom there was an improvement of LV function in the cell-treated group of 5.5% vs. 3.0% (measured by LV angiography) at 4 months, with fewer adverse clinical events in the treated group after 1 year. This result should be put into context, however. In a recent study, patients were treated for their heart attack with standard therapy, i.e. they did not receive stem cells. At 5 months, with just usual care, ejection fraction as measured by contrast-enhanced MRI (ce-MRI) had improved by 7%, with a 31% reduction in infarct size. This is a result comparable to the best of those from cell therapy studies.
Given the current state of affairs, perhaps it is time to resolve the many unanswered questions such as: Which cell to use? How many cells to deliver? Which delivery route is best? When should cells be delivered? Which endpoint is of most relevance? Offering cell therapy to patients is tempting, particularly if no other option seems to be available. But proceeding into largely uncharted territory with contradictory scientific studies as the only means of guidance, may result in a step back from, rather than in to, the future.