Scientists turn patients' skin cells into heart muscle cells to repair their damaged hearts

For the first time scientists have succeeded in taking skin cells from heart failure patients and reprogramming them to transform into healthy, new heart muscle cells that are capable of integrating with existing heart tissue. The research, which is published online May 22 in the European Heart Journal, opens up the prospect of treating heart failure patients with their own, human-induced pluripotent stem cells (hiPSCs) to repair their damaged hearts. As the reprogrammed cells would be derived from the patients themselves, this could avoid the problem of the patients' immune systems rejecting the cells as "foreign." However, the researchers warn that there are a number of obstacles to overcome before it would be possible to use hiPSCs in humans in this way, and it could take at least five to ten years before clinical trials could start.

Recent advances in stem cell biology and tissue engineering have enabled researchers to consider ways of restoring and repairing damaged heart muscle with new cells, but a major problem has been the lack of good sources of human heart muscle cells and the problem of rejection by the immune system. Recent studies have shown that it is possible to derive hiPSCs from young and healthy people and that these are capable of transforming into heart cells. However, it has not been shown that hiPSCs could be obtained from elderly and diseased patients. In addition, until now researchers have not been able to show that heart cells created from hiPSCs could integrate with existing heart tissue.

Professor Lior Gepstein, Professor of Medicine (Cardiology) and Physiology at the Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Technion-Israel Institute of Technology and Rambam Medical Center in Haifa, Israel, who led the research, said: "What is new and exciting about our research is that we have shown that it's possible to take skin cells from an elderly patient with advanced heart failure and end up with his own beating cells in a laboratory dish that are healthy and young -- the equivalent to the stage of his heart cells when he was just born."

Ms Limor Zwi-Dantsis, who is a PhD student in the Sohnis Research Laboratory, Prof Gepstein and their colleagues took skin cells from two male heart failure patients (aged 51 and 61) and reprogrammed them by delivering three genes or "transcription factors" (Sox2, Klf4 and Oct4), followed by a small molecule called valproic acid, to the cell nucleus. Crucially, this reprogramming cocktail did not include a transcription factor called c-Myc, which has been used for creating stem cells but which is a known cancer-causing gene.

"One of the obstacles to using hiPSCs clinically in humans is the potential for the cells to develop out of control and become tumours," explained Prof Gepstein. "This potential risk may stem from several reasons, including the oncogenic factor c-Myc, and the random integration into the cell's DNA of the virus that is used to carry the transcription factors -- a process known as insertional oncogenesis."

The researchers also used an alternative strategy that involved a virus that delivered reprogramming information to the cell nucleus but which was capable of being removed afterwards so as to avoid insertional oncogenesis.

The resulting hiPSCs were able to differentiate to become heart muscle cells (cardiomyocytes) just as effectively as hiPSCs that had been developed from healthy, young volunteers who acted as controls for this study. Then the researchers were able to make the cardiomyocytes develop into heart muscle tissue, which they cultured together with pre-existing cardiac tissue. Within 24-48 hours the tissues were beating together. "The tissue was behaving like a tiny microscopic cardiac tissue composed of approximately 1000 cells in each beating area," said Prof Gepstein.

Finally, the new tissue was transplanted into healthy rat hearts and the researchers found that the grafted tissue started to establish connections with the cells in the host tissue.

"In this study we have shown for the first time that it's possible to establish hiPSCs from heart failure patients -- who represent the target patient population for future cell therapy strategies using these cells -- and coax them to differentiate into heart muscle cells that can integrate with host cardiac tissue," said Prof Gepstein.

"We hope that hiPSCs derived cardiomyocytes will not be rejected following transplantation into the same patients from which they were derived. Whether this will be the case or not is the focus of active investigation. One of the obstacles in dealing with this issue is that, at this stage, we can only transplant human cells into animal models and so we have to treat the animals with immunosuppressive drugs so the cells won't be rejected."

Much research has to be conducted before these results could be translated into treatment for heart failure patients in the clinic. "There are several obstacles to clinical translation," said Prof Gepstein. "These include: scaling up to derive a clinically relevant number of cells; developing transplantation strategies that will increase cell graft survival, maturation, integration and regenerative potential; developing safe procedures to eliminate the risks for causing cancer or problems with the heart's normal rhythm; further tests in animals; and large industry funding since it is likely to be a very expensive endeavour. I assume it will take at least five to ten years to clinical trials if one can overcome these problems."

Prof Gepstein and his colleagues will be carrying out further research into some of these areas, including evaluating using hiPSCs in cell therapy and tissue engineering strategies for repairing damaged hearts in various animal models, investigating inherited cardiac disorders, and drug development and testing.

**Source: European Society of Cardiology (ESC)

Short people are more likely to develop heart disease than tall people

Short people are at greater risk of developing heart disease than tall people, according to the first systematic review and meta-analysis of all the available evidence, which is published online today (Wednesday 9 June) in the European Heart Journal.
The systematic review and meta-analysis, carried out by Finnish researchers, looked at evidence from 52 studies of over three million people and found that short adults were approximately 1.5 times more likely to develop cardiovascular heart disease and die from it than were tall people. This appeared to be true for both men and women.
Dr Tuula Paajanen, a researcher at the Department of Forensic Medicine, University of Tampere, Tampere, Finland, said that over the years there had been a number of studies that had provided conflicting evidence on whether shortness was associated with heart disease.
“The first report on the inverse association between coronary heart disease (CHD) and height was published in 1951 and, since then, the association between short stature and cardiovascular diseases has been investigated in more than 1,900 papers. However, until now, no systematic review and meta-analysis has been done on this topic. We hope that with this meta-analysis, the association is recognised to be true and in future more effort is targeted to finding out the possible pathophysiological, environmental and genetic mechanisms behind the association, with eyes and minds open to different hypotheses,” she said.
Due to the many different ways that previous studies have investigated the association between height and heart disease, Dr Paajanen and her colleagues decided to compare the shortest group to the tallest group instead of using a fixed height limit.

From the total of 1,900 papers, the researchers selected 52 that fulfilled all their criteria for inclusion in their study. These included a total of 3,012,747 patients. On average short people were below 160.5 cms high and tall people were over 173.9 cms. When men and women were considered separately, on average short men were below 165.4 cms and short women below 153 cms, while tall men were over 177.5 cms and tall women over 166.4 cms.
Dr Paajanen and her colleagues found that compared to those in the tallest group, the people in the shortest group were nearly 1.5 times more likely to die from cardiovascular disease (CVD) or coronary heart disease (CHD), or to live with the symptoms of CVD or CHD, or to suffer a heart attack, compared with the tallest people.
Looking at men and women separately, short men were 37% more likely to die from any cause compared with tall men, and short women were 55% more likely to die from any cause compared with their taller counterparts.
“Due to the heterogeneity of studies, we cannot reliably answer the question on the critical absolute height,” write the authors in their study. “The height cut-off points did not only differ between the articles but also between men and women and between ethnic groups. This is why we used the shortest-vs.-tallest group setting.”
The findings have clinical implications. Dr Paajanen said: “The results of this systematic review and meta-analysis suggest that height may be considered as a possible independent factor to be used in calculating people’s risk of heart disease. Height is used to calculate body mass index, which is a widely used to quantify risk of coronary heart disease.”
It is not known why short stature should be associated with increased risk of heart disease. Dr Paajanen said: “The reasons remain open to hypotheses. We hypothesize that shorter people have smaller coronary arteries and smaller coronary arteries may be occluded earlier in life due to factors that increase risk, such as a poorer socioeconomic background with poor nutrition and infections that result in poor foetal or early life growth. Smaller coronary arteries also might be more affected by changes and disturbances in blood flow. However, recent findings on the genetic background of body height suggest that inherited factors, rather than speculative early-life poor nutrition or birth weight, may explain the association between small stature and an increased risk of heart disease in later life. We are carrying out further research to investigate these hypotheses.”
Dr Paajanen said that it was important that short people should not be worried by her findings. “Height is only one factor that may contribute to heart disease risk, and whereas people have no control over their height, they can control their weight, lifestyle habits such as smoking, drinking and exercise and all of these together affect their heart disease risk. In addition, because the average height of populations is constantly increasing, this may have beneficial effect of deaths and illness from cardiovascular disease.”
In an editorial on the research published at the same time [2], Jaakko Tuomilehto, Professor of Public Health at the University of Helsinki, Helsinki, Finland, welcomed the study, writing: “The systematic review and meta-analysis on this topic . . . is well justified 60 years after the first observation and the hundreds of other papers which have been published since then on this topic. The results are unequivocal: short stature is associated with increased risk of coronary heart disease. This meta-analysis provides solid proof for this, but, as the authors conclude ‘The possible pathophysiological, environmental, and genetic background of this peculiar association is not known’.”
He suspects that environmental events affecting growth before and after birth may be involved. “Socio-economic adversity in childhood is . . . associated with delayed early growth and shorter adult stature. The so-called catch-up growth during the first years of life among children who are born small has negative health effects in adulthood; much of the early growth is due to greater fat accumulation. Thus, it is most likely that short stature is the link to coronary heart disease, and that tallness is not a primary factor in preventing the disease, although it indicates healthy growth. Short stature seems to be a marker for risk.”
While more work is needed to understand the exact nature of the mechanisms at work, he writes that information on height can be used now for the prevention of heart disease and other chronic diseases linked to shortness. “Full term babies who are born small are likely to be short as adults. They should receive preventive attention early on. The primordial prevention of chronic diseases should start during foetal life, and health promotion should be targeted to all pregnant women with the aim of health development of the foetus. Low birth weight and some other birth characteristics can reveal potential problems during this period of life. After that, in babies with low birth weight, it is important to avoid excessive catch-up growth, i.e. early-life fatness.”
In adult life it becomes more difficult to discover best practices, but Prof Tuomilehto, thinks it is likely short adults would benefit from more aggressive risk factor reduction.
He concludes: “Most of us know approximately our own height ranking, and, if we are at the low end, we should take coronary risk factor control more seriously. On the other hand, tall people are not protected against coronary heart disease, and they also need to pay attention to the same risk factors as shorter people.”