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Sudden cardiac death has cellular cause, say Stanford researchers

Stanford cardiovascular researcher Joseph Wu, MD, PhD, and colleagues have used the power of patient-specific stem cells (also called induced pluripotent stem cells, or iPS cells) to create heart muscle cells from 10 members of a family with an inherited heart condition called hypertrophic cardiomyopathy, or HCM. The research was published today in Cell Stem Cell.

The word "hypertrophic" indicates that the heart of affected people is enlarged. People with the disease can have symptoms of arrhythmia and chest pain upon exercise, but there can also be no symptoms at all. HCM is the most common cause of sudden cardiac death in young athletes.

As I wrote in our release:

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.


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.

Further study showed that the cells with the mutation beat more sporadically than those without, and responded differently to the waves of calcium that control cardiac activity. It's the first time that the disorder has been shown at the single-cell level; until now it was unclear whether the patient's enlarged heart was a symptom or a cause of the condition. Said Wu, who co-directs the Stanford Cardiovascular Institute, in our release:

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.

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. In this study, for example, the researchers went on to show that those drugs that affect calcium channel function were able to block many of the abnormal reactions that developed in the mutant cells. The research suggests that it may be worthwhile to explore the idea of starting drug therapy for those with HCM before any clinical symptoms develop.

Previously: New leaders in heart medicine at Stanford and Lab-made heart cells mimic common cardiac disease in Stanford study
Video courtesy of the Joseph Wu lab

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