When a young athlete dies unexpectedly on the basketball court or the football field, it's both shocking and tragic. Now Stanford University School of Medicine researchers have, for the first time, identified the molecular basis for a condition called hypertrophic cardiomyopathy that is the most common cause for this type of sudden cardiac death.
To do so, the Stanford scientists created induced pluripotent stem cells, or iPS cells, from the skin cells of 10 members of a family with a genetic mutation that causes the condition. The researchers then coaxed the cells to become heart muscle cells so they could closely study the cells' behavior and responsiveness to the chemical and electrical signals that keep a heart beating normally. They also used these bioengineered heart cells to quickly pinpoint the drugs most likely to be effective in human patients and to study their potential as preventive medications.
"For obvious reasons, it's difficult to get primary human heart tissue from living patients for study," said cardiologist and stem cell researcher Joseph Wu, MD, PhD. "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."
The research highlights what many experts consider to be some of the main advantages of iPS cells - the ability to quickly create patient-specific cells of nearly any tissue type for study, as well as to allow rapid and safe drug screening.
Wu, an associate professor of medicine and the co-director of the Stanford Cardiovascular Institute, is the senior author of the research, which will be published Jan. 3 in Cell Stem Cell. Postdoctoral scholars Feng Lan, PhD, and Ping Liang, PhD, and graduate student Andrew Lee are co-first authors of the work.
Hypertrophic cardiomyopathy, which affects about 0.2 to 0.5 percent of the population, is a condition in which the muscle of the heart is abnormally thickened without any obvious physiological cause. It is also a leading cause of sudden cardiac death in young, seemingly healthy athletes. Clinical symptoms, including arrhythmia and chest pain when exercising, typically emerge in late teenage years or young adulthood, but can occur at nearly any age.
Although clinicians have known for some time that the disorder can be caused by any one of several genetic mutations, until now it has not been clear how these mutations cause the thickening and eventual failure of the heart muscle.
The Stanford team compared cells from family members of a newly diagnosed 53-year-old woman with a mutation in the MYH7 gene, which partially encodes for a protein in the heart called beta myosin. Mutations in this gene have previously been associated with hypertrophic cardiomyopathy. Four of the woman's eight children had inherited the mutant copy of the gene from their mother; the other four carried two healthy copies of the gene.
The father of the children did not have the mutation.
The two oldest affected children, aged 21 and 18, displayed slightly enlarged hearts; the youngest affected children, aged 14 and 10, displayed a slight increase in blood volume (another symptom of the condition).
Wu and his colleagues collected skin samples from all 10 family members and used them to create iPS cells in the laboratory. They then compared iPS-generated heart muscle cells, or cardiomyocytes, from the family members who have the mutation to those without it. They found that although all the cardiomyocytes appeared normal at first (e.g., beating rhythmically in a laboratory dish), the cells with the mutation began to change after about 30 to 40 days in culture.
"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," said Lan, one of the co-first authors. "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."
Under normal conditions, waves of calcium entering heart muscle cells cause the muscle to contract to pump blood throughout the body. Efficient contraction depends on a tightly managed system that controls when, how and where calcium is admitted into the cell. Perturbations in this system can cause abnormal rhythms, but until now there was no way to prove the calcium processing is the culprit in patients with hypertrophic cardiomyopathy.