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.
Read the original article.

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.
Read the original article.

 

To Err Is Human, To Study Errors Is Science

The family of cholesterol lowering drugs known as ‘statins’ are among the most widely prescribed medications for patients with cardiovascular disease. Large-scale clinical studies have repeatedly shown that statins can significantly lower cholesterol levels and the risk of future heart attacks, especially in patients who have already been diagnosed with cardiovascular disease. A more contentious issue is the use of statins in individuals who have no history of heart attacks, strokes or blockages in their blood vessels. Instead of waiting for the first major manifestation of cardiovascular disease, should one start statin therapy early on to prevent cardiovascular disease?

If statins were free of charge and had no side effects whatsoever, the answer would be rather straightforward: Go ahead and use them as soon as possible. However, like all medications, statins come at a price. There is the financial cost to the patient or their insurance to pay for the medications, and there is a health cost to the patients who experience potential side effects. The Guideline Panel of the American College of Cardiology (ACC) and the American Heart Association (AHA) therefore recently recommended that the preventive use of statins in individuals without known cardiovascular disease should be based on personalized risk calculations. If the risk of developing disease within the next 10 years is greater than 7.5%, then the benefits of statin therapy outweigh its risks and the treatment should be initiated. The panel also indicated that if the 10-year risk of cardiovascular disease is greater than 5%, then physicians should consider prescribing statins, but should bear in mind that the scientific evidence for this recommendation was not as strong as that for higher-risk individuals.

 

Oops button – via Shutterstock

Using statins in low risk patients

The recommendation that individuals with comparatively low risk of developing future cardiovascular disease (10-year risk lower than 10%) would benefit from statins was met skepticism by some medical experts. In October 2013, the British Medical Journal (BMJ) published a paper by John Abramson, a lecturer at Harvard Medical School, and his colleagues which re-evaluated the data from a prior study on statin benefits in patients with less than 10% cardiovascular disease risk over 10 years. Abramson and colleagues concluded that the statin benefits were over-stated and that statin therapy should not be expanded to include this group of individuals. To further bolster their case, Abramson and colleagues also cited a 2013 study by Huabing Zhang and colleagues in the Annals of Internal Medicine which (according to Abramson et al.) had reported that 18 % of patients discontinued statins due to side effects. Abramson even highlighted the finding from the Zhang study by including it as one of four bullet points summarizing the key take-home messages of his article.

The problem with this characterization of the Zhang study is that it ignored all the caveats that Zhang and colleagues had mentioned when discussing their findings. The Zhang study was based on the retrospective review of patient charts and did not establish a true cause-and-effect relationship between the discontinuation of the statins and actual side effects of statins. Patients may stop taking medications for many reasons, but this does not necessarily mean that it is due to side effects from the medication. According to the Zhang paper, 17.4% of patients in their observational retrospective study had reported a “statin related incident” and of those only 59% had stopped the medication. The fraction of patients discontinuing statins due to suspected side effects was at most 9-10% instead of the 18% cited by Abramson. But as Zhang pointed out, their study did not include a placebo control group. Trials with placebo groups document similar rates of “side effects” in patients taking statins and those taking placebos, suggesting that only a small minority of perceived side effects are truly caused by the chemical compounds in statin drugs.

 

Admitting errors is only the first step

Whether 18%, 9% or a far smaller proportion of patients experience significant medication side effects is no small matter because the analysis could affect millions of patients currently being treated with statins. A gross overestimation of statin side effects could prompt physicians to prematurely discontinue medications that have been shown to significantly reduce the risk of heart attacks in a wide range of patients. On the other hand, severely underestimating statin side effects could result in the discounting of important symptoms and the suffering of patients. Abramson’s misinterpretation of statin side effect data was pointed out by readers of the BMJ soon after the article published, and it prompted an inquiry by the journal. After re-evaluating the data and discussing the issue with Abramson and colleagues, the journal issued a correction in which it clarified the misrepresentation of the Zhang paper.

Fiona Godlee, the editor-in-chief of the BMJ also wrote an editorial explaining the decision to issue a correction regarding the question of side effects and that there was not sufficient cause to retract the whole paper since the other points made by Abramson and colleagues – the lack of benefit in low risk patients – might still hold true. Instead, Godlee recognized the inherent bias of a journal’s editor when it comes to deciding on whether or not to retract a paper. Every retraction of a peer reviewed scholarly paper is somewhat of an embarrassment to the authors of the paper as well as the journal because it suggests that the peer review process failed to identify one or more major flaws. In a commendable move, the journal appointed a multidisciplinary review panel which includes leading cardiovascular epidemiologists. This panel will review the Abramson paper as well as another BMJ paper which had also cited the inaccurately high frequency of statin side effects, investigate the peer review process that failed to identify the erroneous claims and provide recommendations regarding the ultimate fate of the papers.

 

Reviewing peer review

Why didn’t the peer reviewers who evaluated Abramson’s article catch the error prior to its publication? We can only speculate as to why such a major error was not identified by the peer reviewers. One has to bear in mind that “peer review” for academic research journals is just that – a review. In most cases, peer reviewers do not have access to the original data and cannot check the veracity or replicability of analyses and experiments. For most journals, peer review is conducted on a voluntary (unpaid) basis by two to four expert reviewers who routinely spend multiple hours analyzing the appropriateness of the experimental design, methods, presentation of results and conclusions of a submitted manuscript. The reviewers operate under the assumption that the authors of the manuscript are professional and honest in terms of how they present the data and describe their scientific methodology.

In the case of Abramson and colleagues, the correction issued by the BMJ refers not to Abramson’s own analysis but to the misreading of another group’s research. Biomedical research papers often cite 30 or 40 studies, and it is unrealistic to expect that peer reviewers read all the cited papers and ensure that they are being properly cited and interpreted. If this were the expectation, few peer reviewers would agree to serve as volunteer reviewers since they would have hardly any time left to conduct their own research. However, in this particular case, most peer reviewers familiar with statins and the controversies surrounding their side effects should have expressed concerns regarding the extraordinarily high figure of 18% cited by Abramson and colleagues. Hopefully, the review panel will identify the reasons for the failure of BMJ’s peer review system and point out ways to improve it.

 

To err is human, to study errors is science

All researchers make mistakes, simply because they are human. It is impossible to eliminate all errors in any endeavor that involves humans, but we can construct safeguards that help us reduce the occurrence and magnitude of our errors. Overt fraud and misconduct are rare causes of errors in research, but their effects on any given research field can be devastating. One of the most notorious occurrences of research fraud is the case of the Dutch psychologist Diederik Stapel who published numerous papers based on blatant fabrication of data – showing ‘results’ of experiments on non-existent study subjects. The field of cell therapy in cardiovascular disease recently experienced a major setback when a university review of studies headed by the German cardiologist Bodo Strauer found evidence of scientific misconduct. The significant discrepancies and irregularities in Strauer’s studies have now lead to wide-ranging skepticism about the efficacy of using bone marrow cell infusions to treat heart disease.

 

It is difficult to obtain precise numbers to quantify the actual extent of severe research misconduct and fraud since it may go undetected. Even when such cases are brought to the attention of the academic leadership, the involved committees and administrators may decide to keep their findings confidential and not disclose them to the public. However, most researchers working in academic research environments would probably agree that these are rare occurrences. A far more likely source of errors in research is the cognitive bias of the researchers. Researchers who believe in certain hypotheses and ideas are prone to interpreting data in a manner most likely to support their preconceived notions. For example, it is likely that a researcher opposed to statin usage will interpret data on side effects of statins differently than a researcher who supports statin usage. While Abramson may have been biased in the interpretation of the data generated by Zhang and colleagues, the field of cardiovascular regeneration is currently grappling in what appears to be a case of biased interpretation of one’s own data. An institutional review by Harvard Medical School and Brigham and Women’s Hospital recently determined that the work of Piero Anversa, one of the world’s most widely cited stem cell researchers, was significantly compromised and warranted a retraction. His group had reported that the adult human heart exhibited an amazing regenerative potential, suggesting that roughly every 8 to 9 years the adult human heart replaces its entire collective of beating heart cells (a 7% – 19% yearly turnover of beating heart cells). These findings were in sharp contrast to a prior study which had found only a minimal turnover of beating heart cells (1% or less per year) in adult humans. Anversa’s finding was also at odds with the observations of clinical cardiologists who rarely observe a near-miraculous recovery of heart function in patients with severe heart disease. One possible explanation for the huge discrepancy between the prior research and Anversa’s studies was that Anversa and his colleagues had not taken into account the possibility of contaminations that could have falsely elevated the cell regeneration counts.

 

Improving the quality of research: peer review and more

Despite the fact that researchers are prone to make errors due to inherent biases does not mean we should simply throw our hands up in the air, say “Mistakes happen!” and let matters rest. High quality science is characterized by its willingness to correct itself, and this includes improving methods to detect and correct scientific errors early on so that we can limit their detrimental impact. The realization that lack of reproducibility of peer-reviewed scientific papers is becoming a major problem for many areas of research such as psychology, stem cell research and cancer biology has prompted calls for better ways to track reproducibility and errors in science.

One important new paradigm that is being discussed to improve the quality of scholar papers is the role of post-publication peer evaluation. Instead of viewing the publication of a peer-reviewed research paper as an endpoint, post publication peer evaluation invites fellow scientists to continue commenting on the quality and accuracy of the published research even after its publication and to engage the authors in this process. Traditional peer review relies on just a handful of reviewers who decide about the fate of a manuscript, but post publication peer evaluation opens up the debate to hundreds or even thousands of readers which may be able to detect errors that could not be identified by the small number of traditional peer reviewers prior to publication. It is also becoming apparent that science journalists and science writers can play an important role in the post-publication evaluation of published research papers by investigating and communicating research flaws identified in research papers. In addition to helping dismantle the Science Mystique, critical science journalism can help ensure that corrections, retractions or other major concerns about the validity of scientific findings are communicated to a broad non-specialist audience.

In addition to these ongoing efforts to reduce errors in science by improving the evaluation of scientific papers, it may also be useful to consider new pro-active initiatives which focus on how researchers perform and design experiments. As the head of a research group at an American university, I have to take mandatory courses (in some cases on an annual basis) informing me about laboratory hazards, ethics of animal experimentation or the ethics of how to conduct human studies. However, there are no mandatory courses helping us identify our own research biases or how to minimize their impact on the interpretation of our data. There is an underlying assumption that if you are no longer a trainee, you probably know how to perform and interpret scientific experiments. I would argue that it does not hurt to remind scientists regularly – no matter how junior or senior- that they can become victims of their biases. We have to learn to continuously re-evaluate how we conduct science and to be humble enough to listen to our colleagues, especially when they disagree with us.

 

Note: A shorter version of this article was first published at The Conversation with excellent editorial input provided by Jo Adetunji.

 

Abramson, J., Rosenberg, H., Jewell, N., & Wright, J. (2013). Should people at low risk of cardiovascular disease take a statin? BMJ, 347 (oct22 3) DOI: 10.1136/bmj.f6123

Does Human Fat Contain Stem Cells?

Aeon Magazine recently published my longform essay on our research with human liposuction samples and our attempts to use fat for regenerative and therapeutic purposes. Many research groups, including our own group, have been able to isolate stem cells from human fat. However, when it came to using this cells for treating cardiovascular disease, the cells behaved in a manner that we had not anticipated.

Undifferentiated mesenchymal stem cells (left) and their fat neighbors (right) – From our PLOS One paper

We were unable to convert them into heart muscle cells or blood vessel endothelial cells, but we found that they could help build large networks of blood vessels by releasing important growth factors. Within a few years of our initial publication, clinical trials with patients with blocked arteries or legs were already being planned, and are currently underway.

We decided to call the cells “adipose stromal cells” because we wanted to emphasize that they were acting as a “stroma” (i.e. supportive environment for blood vessels) and not necessarily as stem cells (i.e. cells that convert from an undifferentiated state into mature cell types). In other contexts, these same cells were indeed able to act like “stem cells”, because they could be converted into bone-forming or cartilage-forming cells, thus showing the enormous versatility and value of the cells that reside within our fat tissues.

The answer to the question “Does Human Fat Contain Stem Cells?” is Yes, but these cells cannot be converted into all desired tissues. Instead, they have important supportive functions that can be used to engineer new blood vessels, which is a critical step in organ engineering.

In addition to describing our scientific work, the essay also mentions the vagaries of research, the frustrations I had as a postdoctoral fellow when my results were not turning out as I had expected, and how some predatory private clinics are already marketing “fat-derived stem cell therapies” to paying customers, even though the clinical results are still rather preliminary.

 

For the readers who want to dig a bit deeper, here are some references and links:

 

1. The original paper by Patricia Zuk and colleagues which described the presence of stem cells in human liposuction fat:

Zuk, P et al (2001) “Multilineage Cells from Human Adipose Tissue: Implications for Cell-Based Therapies”

 

2. Our work on how the cells can help grow blood vessels by releasing proteins:

Rehman, J et al (2004) “Secretion of Angiogenic and Antiapoptotic Factors by Human Adipose Stromal Cells”

 

3. Preliminary findings from ongoing clinical studies in which heart attack patients receive infusions of fat derived cells into their hearts to improve heart function and blood flow to the heart:

Houtgraf, J et al (2012) “First Experience in Humans Using Adipose Tissue–Derived Regenerative Cells in the Treatment of Patients With ST-Segment Elevation Myocardial Infarction”

 

4. Preliminary results from an ongoing trial using the fat-derived cells in patients with severe blockages of leg arteries:

Bura, A et al (2014) “Phase I trial: the use of autologous cultured adipose-derived stroma/stem cells to treat patients with non-revascularizable critical limb ischemia”

 

5. Example of how “cell therapies” (in this case bone marrow cells) are sometimes marketed as “stem cells” but hardly contain any stem cells:

The Largest Cell Therapy Trial in Heart Attack Patients Uses Hardly Any Stem Cells

 

6. The major scientific society devoted to studying the science of fat and its cells as novel therapies is called International Federation for Adipose Therapeutics and Science (IFATS).

I am not kidding, it is I-FATS!

Explore their website if you want to learn about all the exciting new research with fat derived cells.

 

7. Some of our newer work on how bone marrow mesenchymal stem cells turn into fat cells and what role their metabolism plays during this process:

Zhang, Y et al (2013) “Mitochondrial Respiration Regulates Adipogenic Differentiation of Human Mesenchymal Stem Cells”

 

Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, & Hedrick MH (2001). Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue engineering, 7 (2), 211-28 PMID: 11304456

 

 

 

Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, Pell CL, Johnstone BH, Considine RV, & March KL (2004). Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation, 109 (10), 1292-8 PMID: 14993122

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.
Read the original article.

 

 

 

 

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

Replicability of High-Impact Papers in Stem Cell Research

I recently used the Web of Science database to generate a list of the most highly cited papers in stem cell research. As of July 2013, the search for original research articles which use the key word “stem cells” resulted in the following list of the ten most widely cited papers to date:

Human ES cell colony – Nuclei labeled in blue, Mitochondria labeled in green- Rehman lab.1. Pittenger M et al. (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143-147

Citations: 8,157

2.  Thomson JA et al. (1998) Embryonic stem cell lines derived from human blastocysts. Science 282(5391):1145-1147

Citations: 5,565

3. Takahashi K and Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4): 663-676

Citations: 5,034

4. Takahashi K et al. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861-872

Citations: 4,061

5. Donehower LA et al  (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356(6366): 215-221

Citations: 3,279

6. Al-Hajj M et al (2003) Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences 100(7): 3983-3988

Citations: 3,183

 7. Yu J et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858): 1917-1920

Citations: 3,086

 8. Jiang YH et al (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418(6893):41-49

Citations: 2,983

9. Orlic D et al (2001) Bone marrow cells regenerate infarcted myocardium. Nature 410 (6829):701-705

Citations: 2,961

10. Lu J et al (2005) MicroRNA expression profiles classify human cancers. Nature 435(7043): 834-838

Citations: 2,917

 

Three of the articles (Donehower et al, Al-Hajj et al and Lu et al) in this “top ten list” do not focus on stem cells but are actually cancer research papers. They were probably identified by the search because the authors may have made comparisons to stem cells or used stem cells as tools.The remaining seven articles are indeed widely known in the stem cell field.

The Science paper by Pittenger and colleagues in 1999 provided a very comprehensive description of mesenchymal stem cells (MSCs), a type of adult stem cell which is found in the bone marrow alongside hematopoietic stem cells (HSCs). Despite the fact that MSCs and HSCs are both adult stem cells in the bone marrow, they have very different functions. HSCs give rise to circulating blood cells, whereas MSCs primarily form bone, fat and cartilage as was nicely demonstrated by Pittenger and colleagues.

The article by Thomson and colleagues was published in 1998 in the journal Science described the derivation of human embryonic stem cells (ESCs) and revolutionized the field of stem cell research. While adult stem cells have a very limited capacity in terms of lineages they can turn into, ESCs are derived from the early blastocyst stage of embryonic development (within the first 1-2 weeks following fertilization) and thus retain the capacity to turn into a very wide range of tissues, such as neurons, heart cells, blood vessel cells or liver cells. This paper not only identified the methods for isolating human ESCs, but also how to keep them in culture and expand them as undifferentiated stem cells.

The Cell paper by Takahashi and Yamanaka in 2006 represented another major advancement in the field of stem cell biology, because it showed for the first time that a mouse adult skin cell (fibroblast) could be reprogrammed and converted into a truly pluripotent stem cell (an induced pluripotent stem cell or iPSC) which exhibited all the major characteristics of an embryonic stem cell (ESC). It was as if the adult skin cell was traveling back in time, erasing its identity of having been a skin cell and returning to primordial, embryonic-like stem cell. Only one year later, Dr. Yamanaka’s group was able to demonstrate the same phenomena for adult human skin cells in the 2007 Cell paper (Takahashi et al), and in the same year a different group independently confirmed that adult human cells could be reprogrammed to the iPSC state (Science paper by Yu et al in 2007). The generation of iPSCs described in these three papers is probably the most remarkable discovery in stem cell biology during the past decade. It is no wonder that each of these three papers have been cited several thousand times even though they were published only six or seven years ago, and that Dr. Yamanaka was awarded the 2012 Nobel prize for this pioneering work.

All five of the above-mentioned stem cell papers have one thing in common: the results have been repeated and confirmed by numerous independent laboratories all over the world. However, this does not necessarily hold true for the other two highly cited stem cell papers on this list.

The 2002 Nature paper by Jiang and colleagues from Dr. Verfaillie’s laboratory at the University of Minnesota proposed that the bone marrow contained a rather special subset of adult MSCs which had a much broader differentiation potential than had been previously recognized. While adult MSCs were thought to primarily turn into bone, cartilage or fat when given the appropriate cues, this rare new cell type – referred to as MAPCs (multipotent adult progenitor cells) – appeared to differentiate into a much broader range of tissues. The paper even showed data from an experiment in which these adult mouse bone marrow stem cells were combined with embryonic cells and gave rise to a chimeric mouse. i.e. a mouse in which the tissues were in part derived from standard embryonic cells and in part from the newly discovered adult MAPCs. Such chimerism suggested that the MAPCs were embryonic-like, contributing to the formation of all the tissues in the mice. At the time of its publication, this paper was met with great enthusiasm because it proved that the adult body contained embryonic-like cells, hidden away in the bone marrow, and that these MAPCs could be used to regenerate ailing organs and tissues without having to use ethically problematic human embryonic stem cells.

There was just one major catch. Many laboratories around the world tried to replicate the results and were unable to identify the MAPCs, and even when they found cells that were MAPCs, they were unable to confirm the embryonic-like nature of the cells. In a remarkable example of investigative journalism, the science journalists Peter Aldhous and Eugenie Reich identified multiple irregularities in the publications involving MAPCs and documented the inability of researchers to replicate the findings by publishing the results of their investigation in the New Scientist (PDF).

The second high profile stem cell paper which was also plagued by an inability to replicate the results was the 2001 Nature paper by Orlic and colleagues. In this paper from Dr. Anversa’s laboratory, the authors suggested that adult hematopoietic (blood-forming) stem cells from the bone marrow could regenerate an infarcted heart by becoming heart cells (cardiomyocytes). It was a rather bold claim, because simply injecting these blood-forming stem cells into the heart seemed to be sufficient to redirect their fate. Instead of giving rise to red and white blood cells, these bone marrow cells were generating functional heart cells. If this were the case, then every patient could be potentially treated with their own bone marrow and grow back damaged heart tissue after a heart attack. Unfortunately, it was too good to be true. Two leading stem cell laboratories partnered up to confirm the results, but even after years of experiments, they were unable to find any evidence of adult bone marrow stem cells converting into functional heart cells. They published their findings three years later, also in the journal Nature:

Murry CE et al (2004) Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428(6983): 664-668

Citations: 1,150

Interestingly, the original paper which had made the claim that bone marrow cells can become functional heart cells has been cited nearly 3,000 times, whereas the refutation by Murry and colleagues, published in the same high-profile journal has been cited only 1,150 times. The vast majority of the nearly 3,000 citations of the 2001 paper by Orlic and colleagues occurred after it had been refuted in 2004! The 2001 Orlic et al paper has even been used to justify clinical trials in which bone marrow was obtained from heart attack patients and injected into their hearts. As expected after the refutation by Murry and colleagues, the success of these clinical trials was rather limited One of the largest bone marrow infusion trials in heart attack patients was recently published, showing no success of the therapy.

These claims of the two papers (Orlic et al and Jiang et al) were quite innovative and exciting, and they were also published in a high-profile, peer-reviewed journal, just like the other five stem cell papers. The crucial difference was the fact that their findings could not be replicated by other laboratories. Despite their lack of replicability, both papers had an enormous impact on the field of stem cell research. Senior scientists, postdocs and graduate students may have devoted a substantial amount of time and resources to developing projects that built on the findings of these two papers, only to find out that they could not be replicated. If there is a lesson to be learned, it is that we need to be rather cautious in terms of our enthusiasm for new claims in stem cell biology until they have been appropriately confirmed by other researchers. Furthermore, we need to streamline the replicability testing process so that we do not have to wait years before we find out that one of the most highly prized discoveries cannot be independently confirmed.

 

Update 7/24/2013: Peter Aldhous reminded me that the superb job of investigative journalism into the question of MAPCs was performed in partnership with the science writer Eugenie Reich, the author of a book on scientific fraud. I have updated the blog post to reflect this.

Cellular Alchemy: Converting Fibroblasts Into Heart Cells

Medieval alchemists devoted their lives to the pursuit of the infamous Philosopher’s Stone, an elusive substance that was thought to convert base metals into valuable gold. Needless to say, nobody ever discovered the Philosopher’s Stone. Well, perhaps some alchemist did get lucky but was wise enough to keep the discovery secret. Instead of publishing the discovery and receiving the Nobel Prize for Alchemy, the lucky alchemist probably just walked around in junkyards, surreptitiously collected scraps of metal and brought them to home to create a Scrooge-McDuck-style money bin.  Today, we view the Philosopher’s Stone as just a myth that occasionally resurfaces in the titles of popular fantasy novels, but cell biologists have discovered their own version of the Philosopher’s Stone: The conversion of fibroblast cells into precious heart cells (cardiomyocytes) or brain cells (neurons).

 

Fibroblasts are an abundant cell type, found in many organs such as the heart, liver and the skin. One of their main functions is to repair wounds and form scars in this process. They are fairly easy to grow or to expand, both in the body as well as in a culture dish. The easy access to large quantities of fibroblasts makes them analogous to the “base metals” of the alchemist. Adult cardiomyocytes, on the other hand, are not able to grow, which is why a heart attack which causes death of cardiomyocytes can be so devastating. There is a tiny fraction of regenerative stem-cell like cells in the heart that are activated after a heart attack and regenerate some cardiomyocytes, but most of the damaged and dying heart cells are replaced by a scar – formed by the fibroblasts in the heart. This scar keeps the heart intact so that the wall of the heart does not rupture, but it is unable to contract or beat, thus weakening the overall pump function of the heart. In a large heart attack, a substantial portion of cardiomycoytes are replaced with scar tissue, which can result in heart failure and heart failure.

A few years back, a research group at the Gladstone Institute of Cardiovascular Disease (University of California, San Francisco) headed by Deepak Srivastava pioneered a very interesting new approach to rescuing heart function after a heart attack.  In a 2010 paper published in the journal Cell, the researchers were able to show that plain-old fibroblasts from the heart or from the tail of a mouse could be converted into beating cardiomyocytes! The key to this cellular alchemy was the introduction of three genes – Gata4, Mef2C and Tbx5 also known as the GMT cocktail– into the fibroblasts. These genes encode for developmental cardiac transcription factors, i.e. proteins that regulate the expression of genes which direct the formation of heart cells. The basic idea was that by introducing these regulatory factors, they would act as switches that turn on the whole heart gene program machinery. Unlike the approach of the Nobel Prize laureate Shinya Yamanaka, who had developed a method to generate stem cells (induced pluripotent stem cells or iPSCs) from fibroblasts, Srivastava’s group bypassed the whole stem cell generation process and directly created heart cells from fibroblasts. In a follow-up paper published in the journal Nature in 2012, the Srivastava group took this research to the next level by introducing the GMT cocktail directly into the heart of mice and showing that this substantially improved heart function after a heart attack. Instead of merely forming scars, the fibroblasts in the heart were being converted into functional, beating heart cells – cellular alchemy with great promise for new cardiovascular therapies.

As exciting as these discoveries were, many researchers remained skeptical because the cardiac stem cell field has so often seen paradigm-shifting discoveries appear on the horizon, only to later on find out that they cannot be replicated by other laboratories. Fortunately, Eric Olson’s group at the University of Texas, Southwestern Medical Center also published a paper in Nature in 2012, independently confirming that cardiac fibroblasts could indeed be converted into cardiomyocytes. They added on a fourth factor to the GMT cocktail because it appeared to increase the success of conversion. Olson’s group was also able to confirm Srivastava’s finding that directly treating the mouse hearts with these genes helped convert cardiac fibroblasts into heart cells. They also noticed an interesting oddity. Their success of creating heart cells from fibroblasts in the living mouse was far better than what they would have expected from their experiments in a dish. They attributed this to the special cardiac environment and the presence of other cells in the heart that may have helped the fibroblasts convert to beating heart cells. However, another group of scientists attempted to replicate the findings of the 2010 Cell paper and found that their success rate was far lower than that of the Srivastava group. In the paper entitled “Inefficient Reprogramming of Fibroblasts into Cardiomyocytes Using Gata4, Mef2c, and Tbx5” published in the journal Circulation Research in 2012, Chen and colleagues found that very few fibroblasts could be converted into cardiomyocytes and that the electrical properties of the newly generated heart cells did not match up to those of adult heart cells. One of the key differences between this Circulation Research paper and the 2010 paper of the Srivastava group was that Chen and colleagues used fibroblasts from older mice, whereas the Srivastava group had used fibroblasts from newly born mice. Arguably, the use of older cells by Chen and colleagues might be a closer approximation to the cells one would use in patients. Most patients with heart attacks are older than 40 years and not newborns.

These studies were all performed on mouse fibroblasts being converted into heart cells, but they did not address the question whether human fibroblasts would behave the same way. A recent paper in the Proceedings of the National Academy of Sciences by Eric Olson’s laboratory (published online before print on March 4, 2013 by Nam and colleagues) has now attempted to answer this question. Their findings confirm that human fibroblasts can also be converted into beating heart cells, however the group of genes required to coax the fibroblasts into converting is slightly different and also requires the introduction of microRNAs – tiny RNA molecules that can also regulate the expression of a whole group of genes. Their paper also points out an important caveat.  The generated heart-like cells were not uniform and showed a broad range of function, with only some of the spontaneously contracting and with an electrical activity pattern that was not the same as in adult heart cells.

Where does this whole body of work leave us? One major finding seems to be fairly solid. Fibroblasts can be converted into beating heart cells. The efficiency of conversion and the quality of the generated heart cells – from mouse or human fibroblasts – still needs to be optimized. Even though the idea of cellular alchemy sounds fascinating, there are many additional obstacles that need to be overcome before such therapies could ever be tested in humans. The method to introduce these genes into the fibroblasts used viruses which permanently integrate into the DNA of the fibroblast and could cause genetic anomalies in the fibroblasts. It is unlikely that such viruses could be used in patients. The fact that the generated heart cells show heterogeneity in their electrical activity could become a major problem for patients because patches of newly generated heart cells in one portion of the heart might be beating at a different rate of rhythm than other patches. Such electrical dyssynchony can cause life threatening heart rhythm problems, which means that the electrical properties of the generated cells need to be carefully understood and standardized. We also know little about the long-term survival of these converted cells in the heart and whether the converted cells maintain their heart-cell-like activity for months or years. The idea of directly converting fibroblasts by introducing the genes into the heart instead of first obtaining the fibroblasts, then converting them in a dish and lastly implanting the converted cells back into the heart sounds very convenient. But this convenience comes at a price. It requires human gene therapy which has its own risks and it is very difficult to control the cell conversion process in an intact heart of a patient. On the other hand, if cells are converted in a dish, one can easily test and discard the suboptimal cells and only implant the most mature or functional heart cells.

This process of cellular alchemy is still in its infancy. It is one of the most exciting new areas in the field of regenerative medicine, because it shows how plastic cells are. Hopefully, as more and more labs begin to investigate the direct reprogramming of cells, we will be able to address the obstacles and challenges posed by this emerging field.

 

Image credit: Painting in 1771 by Joseph Wright of Derby – The Alchymist, In Search of the Philosopher’s Stone via Wikimedia Commons

 

Nam, Y., Song, K., Luo, X., Daniel, E., Lambeth, K., West, K., Hill, J., DiMaio, J., Baker, L., Bassel-Duby, R., & Olson, E. (2013). Reprogramming of human fibroblasts toward a cardiac fate Proceedings of the National Academy of Sciences, 110 (14), 5588-5593 DOI: 10.1073/pnas.1301019110

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.

 

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