Sudden cardiac death in young athletes has been a problem since the year 490 B.C., when a young Greek soldier ran from Marathon to Athens and fell suddenly to his death (Source: www.ncbi.nlm.nih.gov). The sudden death of a young athlete is tragic, but for the first time researchers have identified the molecular basis for the condition that is the most common cause of sudden cardiac death, hypertrophic cardiomyopathy.
HCM affects 0.2 to 0.5 percent of the world’s population. It is a condition in which the heart muscle is abnormally thickened without an obvious physiological cause. Symptoms can include arrhythmia and chest pain while exercising.
Researchers at the University of Stanford studied induced pluripotent stem cells (iPS cells) from the skin cells of 10 family members with a genetic mutation that causes the condition. In order to study the cells’ behavior and responsiveness to the chemical and electrical signals that keep the heart beating normally, researchers had to coax them to become heart muscle cells. Then they used the bioengineered cells to target the drugs that could potentially be preventative medications.
"For obvious reasons, it's difficult to get primary human heart tissue from living patients for study. Moreover, animal hearts are not ideal substitutes either because they contract differently and have a different composition than human hearts. As a result, it has been difficult to show the specific cause of heart failure, whether it's due to enlargement of the organ or if it's caused by abnormalities at the single-cell level,” associate professor of medicine and senior study author, Joseph Wu, MD, PhD, at the Stanford University School of Medicine, was quoted as saying.
Researchers have been aware that the disorder can be caused by several genetic mutations for some time now, but now they can see how these mutations cause the thickening and failure of the heart muscle.
A 53-year-old woman’s cells with a mutation in the MYH7 gene, which has been associated with HCM, was compared to her family members cells. Four of her eight children had inherited the mutated gene.
The two oldest affected children, ages 21 and 18, had slightly enlarged hearts. The youngest affected children, ages 14 and 10, displayed a slight increase in blood volume.
Researchers collected skin samples from all 10 family members and used them to create iPS cells. They compared the iPS cells, or cardiomyocytes, from those who had the mutation to those who did not have it. Initially the cells appeared normal, then after 30 to 40 days the mutated cells began to change.
"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 be 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,” postdoctoral scholar, Feng Lan, PhD, at the Stanford University School of Medicine, was quoted as saying.
Normally, calcium entering heart muscle cells causes the muscle to contract to pump blood through the body. Efficient contraction depends on a tightly managed system that controls when, how and where calcium is admitted into the cell. Until now there was no way to prove the calcium processing is the culprit in patients with hypertrophic cardiomyopathy.
"In our study, we demonstrate that this is actually happening at the cellular level. Fortunately, this happens much more quickly in a laboratory dish than it does in an intact human organ. In a human subject, we would have to wait a decade or more to see signs of disease,” Andrew Lee, graduate student and co-author at the Stanford University School of Medicine, was quoted as saying.
The affected cardiomyoctes were treated with drugs currently approved for patients with HCM. Researchers found that the drugs that modulated the activity of channels in the cell membrane through which calcium passes could restore normal rhythms to the affected cells. Verapamil, for example, was able to prevent abnormally large affected cells. Researchers believe that the findings suggest that earlier treatment might be more beneficial than waiting on symptoms to occur.
"Our results indicate that we may need to rethink our current treatment strategy. 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,” Dr. Wu concluded.
SOURCE: Ivanhoe Newswire