Cardiac mouse model shows role white blood cells play in arrhythmia

By Nick Paul Taylor, The Science Advisory Board contributing writer

July 13, 2022 -- Feeding mice a diet lacking in potassium induces ventricular tachycardia (VT), a rapid heartbeat, enabling researchers to study how different white blood cell subclasses influence heart rhythms.

The team behind the model, which shared its findings in Nature Cardiovascular Research, used the mice to show that white blood cells called neutrophils promote VT, while another type of white blood cells called macrophages protect against the irregular heartbeat.

Based on the study, the Massachusetts General Hospital (MGH) researchers concluded that modulation of the function of white blood cells may reduce the risk of sudden cardiac death and that additional research into the roles of white blood cells in arrhythmia could lead to new targeted therapies for irregular heart rhythms.

Unless rapidly treated, VT can kill patients. The arrhythmia contributes to the 200,000 cases of sudden cardiac death that happen every year in the U.S. Defibrillation is the standard of care, but the implants are unable to prevent recurrent arrhythmias. Barriers to the development of new treatments include the fact that mice, unlike humans, do not routinely develop VT after a heart attack.

The researchers found a way around that barrier. In mice with potassium deficiency, VT was common on the first day after a heart attack, with most episodes occurring in the first eight hours. The timeline echoes the situation in humans.

"This is a major step forward because now we can study how different white blood cell subclasses influence heart rhythms. It is also clinically relevant because every fifth patient who experiences a heart attack has low blood potassium levels, and these patients are known to be particularly likely to develop heartbeat irregularities, or arrhythmia," said senior author Dr. Matthias Nahrendorf, PhD, an investigator in MGH's Center for Systems Biology, in a statement.

After developing the VT mouse model, the researchers investigated the role white blood cells play in the irregular heartbeat. Interest in the role white blood cells play in heart health has increased as studies have shown cardiac resident macrophages support normal electrical conduction and linked big changes in myocardial leukocyte numbers and phenotypes to conditions that raise the risk of arrhythmia.

The mouse model suggested that inflammatory neutrophils promote arrhythmia by compromising the electrical function of cardiomyocytes, a type of heart muscle cell. The researchers also found that macrophages, immune cells that take up debris, are protective. In the absence of macrophages, mice with low potassium levels that had a heart attack suffered electrical storms and were more likely to die.

While the role of neutrophils suggests depleting the cells may curb electrical storms, the researchers caution that a targeted approach may be needed to achieve the desired outcomes. Other studies have found subsets of neutrophils have beneficial effects after heart attacks, leading the team to highlight the neutralization of specific pro-arrhythmic neutrophil products to limit negative side effects.

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