African-Americans Receive Heart Transplants at Hospitals With Poor Performance Track Records

About five million people in the US suffer from heart failure, and approximately half of them die within five years of being diagnosed. Only about 2,500 people a year receive a heart transplant – the treatment of last resort. A new heart can be life-saving, but it is also life-changing. Even under the best conditions, the surgery is complex, and recovery carries a heavy physical and emotional burden.

And not all heart transplant recipients fare equally well after the surgery. Researchers have found that black heart transplant patients are more likely to die after surgery than white or Hispanic patients.

While many different factors contribute to the disparity, the research indicates that where patients received their heart transplants played a big role. Black patients were more likely to have their transplants performed at the worst-performing centers.

Patient with his family and physician (via Shutterstock)

 

This is merely one of many examples of health disparities faced by black Americans. But as a cardiologist, I find this finding especially troubling because many of the heart failure patients I treat are black.

So how do patients decide where to have their heart transplants performed? And wouldn’t a person who needs a heart transplant choose to go to a top center?

Quality is obviously a major factor. But there is another big consideration in deciding where to get a transplant: accessibility.

Not all transplant centers have the same results

Researchers at Ohio State University reviewed the records of heart transplants performed at 102 transplant centers in the US from 2000 to 2010. The researchers focused on the rate of death during the first year after the transplant in over 18,000 heart transplant recipients.

They found that black patients had a higher rate of dying within one year of receiving a new heart (15.3%) than either Hispanics (12.5%) or whites (12.8%).

To find out why this was happening, the researchers used a mathematical model to predict the risk of dying within a year after the transplant for every patient based on the severity of their disease and complicating risk factors such as advanced age or reduced kidney function. They then compared the calculated risk with the actually observed death rates. The difference between the prediction and reality allowed them to determine the quality of a transplant center.

Care doesn’t end when surgery does.
Heart via www.shutterstock.com

It turned out that a greater proportion of blacks received their heart transplant at centers with higher-than-expected mortality as compared with whites and Hispanics (56.4% versus 47.1% versus 48.1%, respectively).

The contrast was even starker between the top- and worst-performing centers. Blacks had the lowest rate of being transplanted at centers with excellent performance (blacks: 18.5%; whites: 25.3%; Hispanics 28.3%). They also had the highest likelihood of undergoing their transplant surgery at the worst-performing centers.

It turns out that where a person has their transplant is critical. Only 8.7% of black patients died during the first year after the transplant if they were fortunate enough to undergo surgery at a top center. But this number was more than twice as high (18.3%) for blacks at the worst-performing centers.

The study didn’t provide any definitive explanations as to why the majority of blacks underwent heart transplantation at centers with lower than expected outcomes.

Choosing a transplant center isn’t much of a choice

Patients do not “choose” a transplant center by simply looking it up in a catalog or on a website. While performance statistics for each organ transplant center in the United States are publicly available in the Scientific Registry of Transplant Recipients, those statistics are only part of the decision for where a patient will get their transplant. The “choice” is often made for the patients by the doctors who refer them to a transplant center and by the accessibility of the center.

I’m a cardiologist, and in the Chicago area, where I practice, there are five active heart transplant centers. We can show the numbers for the centers to our patients when discussing the possibility of a heart transplant and also provide some additional advice based on our prior experiences with the respective transplant teams. Because our patients are nearly all based in the Chicagoland area, most of these programs are reasonable options for them. However, patients and doctors in cities or regions that don’t have as many transplant centers, or who live in more remote areas may not have the luxury of choice.

Far from home?
Hospital bed via www.shutterstock.com

Accessibility matters because care doesn’t end with the surgery

Unless you’ve had a heart transplant, or know someone who has, it’s hard to understand just how life-changing the surgery is. I’ve noticed that many people are unprepared for the emotional and physical toll from the surgery and recovery. And it’s this toll that can makes accessibility such an important factor when choosing a transplant center.

After surgery, patients spend a couple of weeks recovering in the hospital. Even when they can go home, their health is closely monitored with frequent lab tests and check ups.

After transplant, patients will start taking medications to suppress their immune systems and keep their body from rejecting the new heart. And they have to stay on these medications for their rest of their lives. This means a lifetime of close monitoring to make sure that their heart is functioning well and that there aren’t any complications from the immune suppression.

For instance, during the first couple of months after surgery, patients have heart biopsies, where a small piece of the heart is removed to check for signs of rejection, every one to two weeks. As recovery progresses, biopsies may become monthly. The heart sample is so small that it does not damage the heart, but the biopsy is still an invasive procedure requiring hospitalization. And waiting for results can be stressful.

All of this means heart recipients spend a lot of time during the first year after their transplant seeing doctors and waiting for test results. Being close to a transplant center is important – it’s just easier to get to appointments. But accessibility isn’t just about the patient. It’s also about their support network. Imagine going through all of that alone.

On a practical level, family members and friends provide rides to the hospital, keep track of medications and doctor’s appointments and help with household chores during the recovery period. But what is most important is the emotional support that they provide.

So why do black transplant patients tend to wind up in transplant centers that don’t perform as well? Right now, we don’t know. Is it because they were referred to these centers by their cardiologists despite other feasible alternatives? What role does the health insurance of patients play in determining where they receive the heart transplant? Why are centers with a high percentage of black transplant recipients performing so poorly? And most importantly, what measures need to be taken to improve the quality of care?

These are important questions that physicians, public health officials and politicians need to ask themselves in order to address these disparities.

This article was originally published on The Conversation.
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Kilic, A., Higgins, R., Whitson, B., & Kilic, A. (2015). Racial Disparities in Outcomes of Adult Heart Transplantation Circulation, 131 (10), 882-889 DOI: 10.1161/CIRCULATIONAHA.114.011676

When can you have sex after a heart attack? Most doctors do not talk about it.

Each year in the United States about 720,000 people have heart attacks and about 124,000 people in the UK and 55,000 people in Australia will have them as well. Since the 1980s, survival rates from heart attacks have improved – a lot of people get them, but more and more people are surviving. A recent study of patients in Denmark showed that in 1984-1988 31.4% of patients died within a month of having a heart attack. From 2004-2008 this was down to 14.8%.

Once a patient has made it through a heart attack and begins to recover, they get advice from their doctors on what to do to stay healthy and get back to normal. That includes a lot of things – when to go back to work, when they can start traveling again and what to eat. But there is an important item that a lot of doctors don’t talk about: sex.

There are no universal guidelines for getting back to ‘normal’

Providing advice about lifestyle can be more challenging than prescribing standardized medications or smoking cessation because “normal” life differs widely among patients and requires individualized counseling.

For instance, scientific evidence from large-scale clinical trials isn’t always available to help the cardiologist decide the ideal time for when an individual patient should return to work. A software engineer might get different advice than a butcher or construction worker who has to lift heavy objects all day long. Physicians have to carefully estimate the patient’s capacity for physical activity as well as the physical demands of the job and be pragmatic about how long a patient can take time off from work.

Sex also requires this kind individualized counseling. New research shows that patients want to talk about sexual activity with their doctors, but that all too often that conversation never takes place.

Time for a heart-to-heart with your doctor.
Heart via Syda Productions/Shutterstock

 

Let’s talk about sex

A recent study conducted in 127 hospitals in the United States and Spain suggests that doctors are not very good at broaching the topic of sexual activity after a heart attack.

Researchers studied 2,349 women and 1,152 men who had suffered from a myocardial infarction (the medical term for a heart attack). This study focused on younger heart attack patients (ages 18-55) and asked them whether they had discussed sexual activity with their doctors. With younger patients talking about life after a heart attack is especially important. The loss of sexual activity or function is a major quality of life issue, and can affect intimate relationships, reproduction and lead to depression.

In the month following the heart attack, only 12% of women and 19% of men had some discussion with a doctor about sex. In the US, most patients reported that they initiated the discussion, whereas in Spain, most discussions were initiated by the doctor. This means that more than 85% of patients received no advice from their doctors regarding if and when they could resume sexual activity.

The study found that the vast majority of patients were sexually active in the year before their heart attacks, and they valued sexuality as an important part of life. They also felt it was appropriate for physicians to initiate the discussion about having sex again.

It is interesting that in the US, patients were more likely to bring up sex and men were given more restrictive advice, while in Spain, physicians were more likely to bring up the topic and more restrictive recommendations were given to women.

The study did not specifically study the motivations of the physicians but these differences suggest that cultural differences and gender affect the counseling in regards to sexual activity. Future research could potentially also study the physicians and help uncover how culture and gender influence the counseling process.

This lack of communication between doctors and patients was not due to the patients’ unease: 84% of women and 91% of men said that they would feel comfortable talking to their doctors about sex. What is even more concerning is that the 15% or so of patients who received counseling often got inaccurate recommendations.

Sex is exercise. But doctors don’t talk about it that way

Two-thirds of those who talked about sex with their doctors were told that they could resume sexual activity with restrictions like limiting sex, taking a “passive role” or keeping their heart rate down during sex. But here’s the thing: sex is exercise. And after a heart attack doctors routinely ask patients whether they can tolerate mild to moderate physical activity such as mowing the lawn or climbing up two flights of stairs without chest pain or other major symptoms.

The Scientific Statement of the American Heart Association (AHA) on sexual activity states that it is reasonable to resume sexual activity as early as one week after an uncomplicated heart attack. If there are complications after the heart attack such as feeling out of breath or experiencing persistent chest pain then these problems need to be addressed first. And in the AHA guidelines there is no mention of “passive roles” or keeping heart rates down during sex. These restrictions are also quite impractical. How are patients supposed to monitor their heart rates and keep them down during sex?

The kind of restrictions recommended by doctors in the study – and presumably by medical practitioners who weren’t polled – are not backed up by science and place an unnecessary burden on a patient’s personal life. Hopefully, after reading the results of this study, doctors will take a more pro-active role and address the topic of sex with their heart attack patients with proper recommendations instead of leaving patients in a state of uncertainty. If a patient can handle moderate exercise, they can probably handle sex.

This article was originally published on The Conversation.
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The Largest Cell Therapy Trial in Heart Attack Patients Uses Hardly Any Stem Cells

One of the world’s largest clinical cell therapy trials has begun to enroll 3,000 heart attack patients, some of whom will have bone marrow cells extracted with a needle from their hip and fed into their heart using a catheter in their coronary arteries.

The BAMI trial has €5.9m in funding from the European Commission and will be conducted in ten European countries. Enlisted patients will be randomly assigned into two groups: one group will receive the standard care given to heart attack patients while the other will get an added infusion of bone marrow cells.

A number of studies, including one in the New England Journal of Medicine and another in the European Heart Journal, have suggested that bone marrow cells could be beneficial to patients with heart disease. However, because these studies were too small to work out whether cell infusions affected patients’ survival, they instead focused on the extent of scar formation after a heart attack or the ability of the heart muscle to contract after cell infusion.

One commonly used surrogate measure is the cardiac ejection fraction, which measures the fraction of blood squeezed out by the heart during a contraction. A healthy rate ranges from 55% to 65%. Bone marrow cell infusion has been associated with a modest but statistically significant improvement in heart function. In 2012, a comprehensive analysis of 50 major studies with a combined total of 2,625 heart disease patients showed that cardiac ejection fraction in patients receiving these infusions was 4% higher than in control patients.

While the results were encouraging, the study was a retrospective analysis with patients who had varying treatments and endpoints. There also remain questions over 400 patients included in the analysis from trials showing benefits of bone marrow cell infusions that were conducted by controversial German cardiologist Bodo Strauer, who some scientists have accused of errors in research.

The new large-scale BAMI trial will be able to provide a more definitive answer to the efficacy of bone marrow cell infusions and address the even more important question: does this experimental treatment prolong the lives of heart attack patients?

A hard cell

Despite the impressive target of enrolling 3,000 patients, there is a problem with how the trial is being framed. The underlying premise of why bone marrow cells are thought to improve heart function is that the bone marrow contains stem cells which could potentially regenerate the heart. In media reports, the BAMI trial is portrayed as a study which will test whether stem cells can heal broken hearts, and a press release by Barts Health NHS Trust, which is leading on the trial, described the study as “the largest ever adult stem cell heart attack trial”. But the scientific value of the BAMI trial for stem cell research is questionable.

In 2013, a Swiss study reported the results of treating heart attack patients with bone marrow cells. Not only did the study find no significant improvement of heart function with cell therapy, the researchers also reported that only 1% of the infused cells had clearly defined stem cell characteristics. The vast majority of the infused bone marrow cells were a broad mixture of various cell types, including immune cells such as lymphocytes and monocytes.

Scientific studies have even cast doubts about whether any of the scarce stem cells in bone marrow can convert into beating heart muscle cells. A study published in 2001 suggested bone marrow cells injected into mouse hearts could differentiate into heart muscle cells, but the finding could not be replicated in a subsequent study published in 2004.

If there are so few stem cells in the bone marrow and if the stem cells do not become cardiac cells, then how does one explain the improvements observed in the smaller studies? Researchers have proposed a variety of potential explanations, including the release of growth factors or proteins by bone marrow cells that are independent of their stem cell activity.

The disease machine

The success of modern medicine lies in its ability to isolate causal mechanisms of disease and design therapies which specifically target these mechanisms using rigorous scientific methods. Instead of using nebulous “fever tinctures” or willow bark, physicians now prescribe therapies with well-defined active ingredients such as paracetamol (acetaminophen) or aspirin.

Infusing heterogeneous bone marrow cell mixtures into the hearts of patients seems like a throwback to the era of mysterious herbal extracts containing a variety of active and inactive ingredients.

Even if the BAMI trial succeeds in demonstrating that infusion of bone marrow cell mixtures can prolong lives, then the scientific value of the results will still remain doubtful. We will not know whether the tiny fraction of stem cells contained in the bone marrow was responsible for the improvement or whether this effect was due to one of the many other cell types contained in the cell mixtures.

One could argue that it is irrelevant to know the mechanism of action as long as the infusions can prolong patient survival. But for any evidence-based therapy to succeed, it is essential for physicians to know how to dose or modify the therapy according to the needs of an individual patient. This won’t be possible if we don’t even understand how the treatment works.

We should also consider the impact of a negative result. If the BAMI trial fails to show improved survival, will the lack of efficacy be interpreted as a failure of stem cell therapy for heart disease? An alternate explanation would be that a negative result was due to infusing numerous cell types, most of which were not stem cells.

The ultimate test of a treatment’s efficacy is how it fares in controlled, large-scale trials. And these trials need to be grounded in solid scientific data and provide answers that can be interpreted in the context of scientifically sound mechanisms. The BAMI trial might provide an answer to the question of whether or not bone marrow cell infusions are efficacious in heart disease, but it will not teach us much about stem cells.

Jalees Rehman has received research funding from the National Institutes of Health (NIH).

This article was originally published on The Conversation.
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Rehman, J. (2013). Bone Marrow Tinctures for Cardiovascular Disease: Lost in Translation Circulation, 127 (19), 1935-1937 DOI: 10.1161/CIRCULATIONAHA.113.002775

 

 
Surder, D., Manka, R., Lo Cicero, V., Moccetti, T., Rufibach, K., Soncin, S., Turchetto, L., Radrizzani, M., Astori, G., Schwitter, J., Erne, P., Zuber, M., Auf der Maur, C., Jamshidi, P., Gaemperli, O., Windecker, S., Moschovitis, A., Wahl, A., Buhler, I., Wyss, C., Kozerke, S., Landmesser, U., Luscher, T., & Corti, R. (2013). Intracoronary Injection of Bone Marrow-Derived Mononuclear Cells Early or Late After Acute Myocardial Infarction: Effects on Global Left Ventricular Function Circulation, 127 (19), 1968-1979 DOI: 10.1161/CIRCULATIONAHA.112.001035

Bone Marrow Cell Infusions Do NOT Improve Cardiac Function After Heart Attack

For over a decade, cardiologists have been conducting trials in patients using cells extracted from the bone marrow and infusing them into the blood vessels of the heart in patients who have suffered a heart attack. This type of a procedure is not without risks. It involves multiple invasive procedures in patients who are already quite ill, because they are experiencing a major heart attack:

1) Patients with a major heart attack (also referred to as ST-elevation Myocardial Infarction or STEMI) usually undergo an immediate angiogram of the heart to treat the blockage that is causing the heart attack by impeding the blood flow. This is the standard of care for heart attack patients in the developed world.

2) Patients enrolled in an experimental cell therapy trial are then brought back for a second procedure during which bone marrow is extracted with a needle under local anesthesia.

3) The research patients then undergo another angiogram of the heart using a catheter which allows for the infusion of bone marrow cells into the heart.

The hope is that the stem cells contained within the bone marrow are able to help regenerate the heart, either by turning into heart cells (cardiomyocytes), blood vessel cells (endothelial cells) or releasing factors that protect the heart and prevent the formation of a large scar. Unfortunately, there is very limited scientific evidence that bone marrow stem cells can actually turn into functional heart cells. The trials that have been conducted so far have yielded mixed results – some show that infusing the bone marrow cells indeed improves heart function, others show that patients who just receive the standard therapy with cell infusions do just as well. Most of the trials have been quite small – often studying only 10-50 patients.

The SWISS-AMI cell therapy trial, published online on April 17, 2013 in the world’s leading cardiovascular research journal Circulation, addressed this question in a randomized, controlled trial, which enrolled 200 patients who had suffered a major heart attack. The published paper is entitled “Intracoronary Injection of Bone Marrow Derived Mononuclear Cells, Early or Late after Acute Myocardial Infarction: Effects on Global Left Ventricular Function” and was conducted in Switzerland.

The researchers assigned the patients to three groups: a) Standard heart attack treatment, b) Standard heart attack treatment and infusion of bone marrow cells 5-7 days after the heart attack or c) Standard heart attack treatment and infusion of bone marrow cells 3-4 weeks after the heart attack. They assessed heart function four months later using cardiac magnetic resonance imaging, one of the best tools available to determine heart function. The results were rather disappointing: Neither of the two cell treatment groups showed any improvement in their cardiac function.

This trial had some important limitations: Even though this study enrolled 200 patients and was thus larger than most other cell therapy trials for heart attack patients, it is still a rather small study when compared to other cardiovascular studies, which routinely enroll thousands of patients. Furthermore, this study only assessed heart function after four months and it is possible that if they had waited longer, they might have seen some benefit of the cell therapy. Despite these limitations, the trial will dampen the general enthusiasm for injecting bone marrow cells into heart attack patients.

Is this study a set-back for cardiac stem cell treatments? Not really. As the authors reveal in their data analysis, most of the cells contained in the bone marrow preparation that they used for the infusion were plain old white blood cells and NOT stem cells. Actually, only 1% of the infused cells were hematopoietic stem cells (stem cells that give rise to blood cells) and there was an undisclosed percentage of other stem cell types (such as mesenchymal stem cells) contained in the infused bone marrow extract. As I point out in the accompanying editorial “Bone Marrow Tinctures for Cardiovascular Disease: Lost in Translation“, using such a mixture of poorly defined cells is ill-suited to promote cardiac regeneration or repair. Therefore, this important study is not a set-back for cardiac stem cell therapy, but a well-deserved setback for injections of undefined cells, most of which are not true stem cells!

Even if the majority of infused cells had been stem cells, there is no guarantee that merely infusing them into the heart would necessarily result in the formation of new heart tissue. Regenerating heart tissue from adult stem cells requires priming or directing stem cells towards becoming heart cells and ensuring that the cells can attach and integrate into the heart, not just infusing or injecting them into the heart.

It is commendable that the journal published this negative study, because too many treatments are being marketed as “stem cell therapies” without clarifying whether the injected cells are truly efficacious. Hopefully, the results of this trial will lead to more caution when rushing to perform “stem cell treatments” in patients without carefully defining the scientific characteristics and therapeutic potential of the cells that are being used.

 

Link to the original paper:  “Intracoronary Injection of Bone Marrow Derived Mononuclear Cells, Early or Late after Acute Myocardial Infarction: Effects on Global Left Ventricular Function”

Link to the editorial: “Bone Marrow Tinctures for Cardiovascular Disease: Lost in Translation”

Image credit: Surgeon extracting bone marrow from a patient (Public Domain image via Wikimedia)

Surder, D., Manka, R., Lo Cicero, V., Moccetti, T., Rufibach, K., Soncin, S., Turchetto, L., Radrizzani, M., Astori, G., Schwitter, J., Erne, P., Zuber, M., Auf der Maur, C., Jamshidi, P., Gaemperli, O., Windecker, S., Moschovitis, A., Wahl, A., Buhler, I., Wyss, C., Kozerke, S., Landmesser, U., Luscher, T., & Corti, R. (2013). Intracoronary Injection of Bone Marrow Derived Mononuclear Cells, Early or Late after Acute Myocardial Infarction: Effects on Global Left Ventricular Function Four months results of the SWISS-AMI trial Circulation DOI: 10.1161/CIRCULATIONAHA.112.001035

Rehman, J. (2013). Bone Marrow Tinctures for Cardiovascular Disease: Lost in Translation Circulation DOI: 10.1161/CIRCULATIONAHA.113.002775

Can The Heart Regenerate Itself After A Heart Attack?

Some cardiovascular researchers believe that the heart contains cardiac stem cells or progenitor cells which can become mature cardiomyocytes (beating heart cells) following an injury and regenerate the damaged heart. The paper “Mammalian heart renewal by pre-existing cardiomyocytes” published in the journal Nature by Senyo and colleagues (online publication on December 5, 2012), on the other hand, suggests that the endogenous regenerative potential of the adult heart is very limited. The researchers studied the regeneration of cardiomyocytes in mice using a genetic label that marks cardiomyocytes with a green fluorescent protein and they also used the nonradioactive stable isotope ¹⁵N (Nitrogen-15) to track the growth of cardiomyocytes. They found that the adult mouse heart has a very low rate of cardiomyocyte regeneration and projected the annual proliferation rate to be only 0.76%. This means that less than one out of a hundred cardiomyocytes in the adult heart undergoes cell division during a one year period. Even though this number is derived from studying the turnover of cardiomyocytes in mice, it correlates very well with the proposed rate of annual cardiomyocyte self-renewal (0.5% to 1%) that Bergmann and colleagues estimated for the human heart in a 2009 paper published in Science. The key novelty of the paper by Senyo and colleagues is that they identified the source of these new cardiomyocytes. They do not arise from cardiac stem cells or cardiac progenitor cells, but are primarily derived from pre-existing adult cardiomyocytes. Does this low rate of cardiomyocyte turnover increase after an injury? Senyo and colleagues found that eight weeks after a heart attack, only 3.2% of the mouse cardiomyocytes located near the injured areas had undergone cell division.

 

This low rate of self-renewal in the adult heart sounds like bad news for researchers who thought that the adult heart had the ability to heal itself after a heart attack. However, the journal Nature also published the paper “Functional screening identifies miRNAs inducing cardiac regeneration” by Eulalio and colleagues on the same day (online publication on December 5, 2012), which indicates that the low levels of cardiomyocyte growth can be increased using certain microRNAs. A microRNA is a small RNA molecule that can regulate the expression of hundreds of genes and can play an important role in controlling many cellular processes such as cell growth, cell metabolism and cell survival. Eulalio and colleagues performed a broad screen using 875 microRNA mimics in new-born rat cardiomyocytes and identified 204 microRNAs that increase the growth of the cells. They narrowed down the number of microRNAs and were able to show that two distinct microRNAs increased the growth of cardiomyocytes after heart attacks in mice. The effect was quite significant and mice treated with these microRNAs had near-normal heart function 60 days after a heart attack.

Based on these two Nature papers, it appears that the cardiomyocytes in the adult heart have a kind of “brake” that prevents them from proliferating. Addition of specific microRNAs seems to relieve the “brake” and allow the adult heart cells to regenerate the heart after a heart attack. This could lead to potential new therapies for patients who suffer from heart attacks, but some important caveats need to be considered. MicroRNAs (and many other cardiovascular therapies) that work in mice or rats do not necessarily have the same beneficial effects in humans. The mice in the study by Eulalio and colleagues also did not receive any medications that patients routinely receive after a heart attack. Patients usually show some improvement in their heart function after a heart attack, if they are treated with the appropriate medications. Since the mice were not treated with the medications, it is difficult to assess whether the microRNAs would have a benefit beyond that what is achieved by conventional post-heart attack medications. Finally, the delivery and dosing of microRNAs is comparatively easy in mice but much more challenging in a heterogeneous group of patients.

The studies represent an important step forward towards identifying the self-renewal mechanisms in the adult heart and suggest that microRNAs are major regulators of these processes, but many additional studies are necessary before their therapeutic value for patients can be assessed.

 

Image credit: Wikimedia Commons

Recent Study Raises Questions About Using Adult Stem Cells for Chronic Heart Disease

A recent clinical study (POSEIDON Randomized Trial) investigated the effects of transplanting bone marrow derived adult stem cells into patients with known heart disease. The results were presented at the 2012 American Heart Association (AHA) meeting in Los Angeles and also published in the article “Comparison of Allogeneic vs Autologous Bone Marrow–Derived Mesenchymal Stem Cells Delivered by Transendocardial Injection in Patients With Ischemic Cardiomyopathy: The POSEIDON Randomized Trial“. The article by Dr. Joshua Hare and colleagues appeared in the online edition of the Journal of the American Medical Association on November 6, 2012.

The primary goal of the study was to compare whether adult stem cells from other donors (allogeneic cells) are just as safe as the stem cells derived from the patients’ own bone marrow (autologous cells). Thirty patients with a prior heart attack and reduced cardiac function received either allogeneic or autologous cells. The injected cells were mesenchymal stem cells (MSCs), an adult stem cell type that resides within the bone marrow and primarily gives rise to bone, fat or cartilage tissue. MSCs are quite distinct from hematopoietic stem cells (HSCs) which are also present in the bone marrow but give rise to blood cells. In the POSEIDON study, patients underwent a cardiac catheterization and the MSCs were directly injected into the heart muscle. Various measurements of safety and cardiac function were performed before and up to one year after the cell injection.

The good news is that in terms of safety, there was no significant difference when either autologous or allogeneic MSCs were used. Within the first month after the cell injection, only one patient in each group was hospitalized for what may have been a major treatment related side effect. In the long-run, the number of adverse events was very similar in both groups. The implication of this finding is potentially significant. It suggests that one can use off-the-shelf adult stem cells from a healthy donor to treat a patient with heart disease. This is much more practical than having to isolate the bone marrow from a patient and wait for 4-8 weeks to expand his or her own bone marrow stem cells.

The disappointing news from this study is that one year following the stem cell injection, there was minimal improvement in the cardiac function of the patients. The ejection fraction of the heart is an indicator of how well the heart contracts and the normal range for healthy patients is roughly 55-60%. In the current study, patients who received allogeneic cells started out with an average ejection fraction of 27.9% and the value increased to 29.5% one year after the cell injection. The patients who received autologous cells had a mean ejection fraction of 26.2% prior to the cell transplantation and a mean ejection fraction of 28.5% one year after the stem cell therapy. In both groups, the improvement was minimal and not statistically significant. A different measure of the functional capacity of the heart is the assessment of the peak oxygen consumption. This measurement correlates well with the survival of a patient and is also used to help decide if a patient needs a heart transplant. There was no significant change in the peak oxygen consumption in either of the two groups of patients, one year after the treatment. Some other measures did indicate a minor improvement, such as the reduction of the heart attack scar size in both patient groups but this was apparently not enough to improve the ejection fraction or oxygen consumption.

One of the key issues in interpreting the results is the fact that there was no placebo control group. The enrollment in a research study and the cell injection procedure itself could have contributed to minor non-specific or placebo benefits that were unrelated to the stem cell treatments. One odd finding was that the patient sub-group which showed a statistically significant improvement in ejection fraction was the group which received the least stem cells. If the observed minor benefits were indeed the result of the injected cells turning into cardiac cells, one would expect that more cells would lead to greater functional improvement. The efficacy of the lowest number of cells points to non-specific effects from the cell injection or to an unknown mechanism by which the injected cells activate cardiac repair without necessarily becoming cardiac cells themselves.

The results of this study highlight some key problems with current attempts to use adult stem cells in cardiovascular patients. Many studies have shown that adult stem cells have a very limited differentiation potential and that they do not really turn into beating, functional heart cells. Especially in patients with established, long-standing heart disease, the utility of adult stem cells may be very limited. The damage that the heart of these patients has suffered is probably so severe that they need stem cells which can truly regenerate the heart. Examples of such regenerative stem cells are embryonic stem cells or induced pluripotent stem cells which have a very broad differentiation potential. Cardiac stem cells, which exist in very low numbers within the heart itself, are also able to become functional heart cells. Each of these three cell types is challenging to use in patients, which is why many current studies have resorted to using the more convenient adult bone marrow stem cells.

Human embryonic stem cells can develop into functional heart cells, but there have been numerous ethical and regulatory concerns about using them. Induced pluripotent stem cells (iPSCs) appear to have the capacity to become functional heart cells, similar to what has been observed for human embryonic stem cells. However, iPSCs were only discovered six years ago and we still have a lot to learn more about how they work. Lastly, cardiac stem cells are very promising but isolating them from the heart requires an additional biopsy procedure which can also carry some risks for the patients. Hopefully, the fact that adult bone marrow stem cells showed only minimal benefits in the POSEIDON study will encourage researchers to use these alternate stem cells (even if they are challenging to use) instead of adult bone marrow stem cells for future studies in patients with chronic heart disease.

One factor that makes it difficult to interpret the POSEIDON trial is the lack of a placebo control group. This is a major problem for many stem cell studies, because it is not easy to ethically justify a placebo group for invasive procedures such as a stem cell implantation. The placebo patients would also have to receive a cardiac catheterization and injections into the heart tissue, but instead of stem cells, the injections would just contain a cell-free liquid solution. Scientifically, such a placebo control group is necessary to determine whether the stem cells are effective, but this scientific need has to be weighed against the ethics of a “placebo” heart catheterization. Even if one were to ethically justify a “placebo” heart catheterization, it may not be easy to recruit volunteer patients for the study if they knew that they had a significant chance of receiving “empty” injections into their heart muscle.

There is one ongoing study which is very similar in design to the POSEIDON trial and it does contain a placebo group: The TAC-HFT trial. The results of this trial are not yet available, but they may have a major impact on whether or not bone marrow stem cells have a clinical future. If the TAC-HFT trial shows that the bone marrow stem cell treatment for patients with chronic heart disease has no benefits or only minor benefits when compared to the placebo group, it will become increasingly difficult to justify the use of these cells in heart patients.

In summary, the POSEIDON trial has shown that treating chronic heart disease patients with bone marrow derived stem cells is not yet ready for prime time. Bone marrow cells from strangers may be just as safe as one’s own cells, but if bone marrow stem cells are not very effective for treating chronic heart disease, than it may just be a moot point.

 

Image credit: Wikipedia