Saturday, 5 January 2013

iPSCs help scientists shed new light in Hypetrophic Cardiomyopathy

Researchers from the Stanford University School of Medicine announced yesterday that they managed to identify the molecular basis of the Hypertrophic cardiomyopathy condition, with the help of induced pluripotent stem cells. The condition affects about 0.2 to 0.5 % of the population and is the number one cause of cardiac death in young patients.

The scientists first took skin cells from ten members of a family with a certain genetic mutation that is known to cause the condition. They used these skin cells and created induced pluripotent stem cells from which they developed heart muscle cells.

Joseph Wu, chief author of the study said:

“For obvious reasons, it’s difficult to get primary human heart tissue from living patients for study,said cardiologist and stem cell researcher. Moreover, animal hearts are not ideal substitutes either because they contract differently and have a different composition than human hearts.” 

Wu's team compared the cells from the relatives (children and husband) of a newly diagnosed 53-year-old mother that carried an allelic variant (genetic mutation) in her MYH7 gene. This mutation is associated with approximately 40% of all Hypertrophic Cardiomyopathy cases. Four of the children had inherited the mutated gene while the other four didn't. Her husband carried the healthy version of the gene.

Of the affected children the oldest two ones (21 and 18 years of age) had slightly enlarged hearts while the two youngest ones (14 and 10 years of age) presented with a slightly increased blood volume. Both of these are a common symptom of Hypertrophic Cardiomyopathy.

Video of a Cardiac muscle cell beating.

As said before, Wu and his team first created IPSCs from skin cells and then induced them to differentiate into cardiomyocytes (the cells that comprise cardiac muscle). They then compared the cardiomyocytes derived from the members with the allelic variant to the cardiomyocytes derived from the members with the normal gene. At first, all of the cardiomyocytes presented with normal functions ( e.g.  rhythmic beating). But after about a month, the cells with the mutated gene started to dysfunction. They beated more sporadically than the healthy ones and presented with abnormal calcium levels.

 Feng Lan, one of the co-authors, explains

“When we compared samples from the whole family, we discovered that these cardiomyocytes would start to display abnormal rhythms and elevated calcium levels over time. Although it had previously been speculated that calcium processing may involved in hypertrophic cardiomyopathy, this is the first time the calcium’s role has been demonstrated conclusively in human cells. In the past, much of the focus had been on whether the abnormal growth, or fibrosis, seen in affected hearts could itself be the cause of the arrhythmia experienced by patients.”

This is actually the first study that focuses on the disease on a molecular, single-cell level and not on the symptoms of the condition:

“In our study, we demonstrate that this is actually happening at the cellular level,” said Lee, another author of the study.

The researchers don't know why lab-grown cardiomyocytes presented with symptoms so early on. After all, it takes more than a decade for hypertrophic cardiomyopathy patients to show any symptoms. They speculate  that this is due to that the affected cells didn't have any other supporting cells to compensate for emerging calcium deficiencies, unlike the environment of the heart as a whole.

During the study the researchers also tried various already approved drugs for hypetrophic cardiomyopathy. They found that the ones that modulate calcium levels of the heart can restore affected cells back to normal beating. One of them, Verapamil (brand names: Isoptin, Verelan, Verelan PM), even prevented  hypetrophy before it appeared in the cells carrying the mutated gene. As of now, people are treated only after they have presented with symptoms. The later finding suggests that it might be wise to start treatment beforehand. Wu said that they hope to one day combine DNA sequencing techniques and iPS technologies for identifying the condition before any symptoms actually present:

 “Maybe by the time a person begins to exhibit clinical symptoms, the damage could not be easily undone. Earlier intervention may soon be possible in the near future. The hope is to be able to use genetic techniques, such as DNA sequencing, coupled with iPS cell-derived cardiomyocytes to identify potential patients at risk at a much earlier stage. We may also be able to treat patients earlier with the right medications to prevent enlargement and damage of the heart muscle from taking place in the first place.”

The research team is currently studying other Hypetrophic Cardiomyopathy- associated gene mutations as well, again with the help of induced pluripotent stem cells.

Hypertrophic cardiomyopathy (abbreviated as HCM) is a disease of the myocardium, in which a portion of the myocardium is hypertrophied (enlarged) for no obvious reasons. It is the leading cause of cardiac death in young athletes. Many times HCM is asymptomatic until the occurence of cardiac death. When symptoms do present, they usually are:
  • Dyspnea (shortness of breath)
  • Chest pain (sometimes known as angina)
  • Uncomfortable awareness of the heart beat
  • Lightheartedness, fatigue
  • Fainting (called syncope)
  • Sudden card
Video about Hypetrophic Cardiomyopathy

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