The findings, published today in the peer-reviewed Journal of the American College of Cardiology: Clinical Electrophysiology, have the potential to enhance prevention of sudden cardiac arrest — unexpected loss of heart function — based on key risk factors identified in this study.

“All sudden cardiac arrest is not the same,” explained Sumeet Chugh, MD, director of the Center for Cardiac Arrest Prevention and lead author of the study. “Until now, no prior research has distinguished between potentially treatable sudden cardiac arrest versus untreatable forms that cause death in almost all instances.”

Out-of-hospital sudden cardiac arrest claims at least 300,000 U.S. lives annually. For those affected, 90% will die within 10 minutes of cardiac arrest.

For this largely fatal condition, prevention would have a profound impact. The biggest challenge, however, lies in distinguishing between those who stand to benefit the most from an implantable cardioverter defibrillator — and those who would not benefit from the electric jolt.

“Defibrillators are expensive and unnecessary for individuals with the type of sudden cardiac arrest that will not respond to an electrical shock,” said Chugh. “However, for patients with treatable, or ‘shockable,’ forms of the disease, a defibrillator is lifesaving.”

Chugh, also a professor and the Pauline and Harold Price Chair in Cardiac Electrophysiology Research, says this new research provides a clinical risk assessment algorithm that can better identify patients at highest risk of treatable sudden cardiac arrest — and thus, a better understanding of those patients who would benefit from a defibrillator.

The risk assessment algorithm consists of 13 clinical, electrocardiogram, and echocardiographic variables that could put a patient at higher risk of treatable sudden cardiac arrest.

The risk factors include diabetes, myocardial infarction, atrial fibrillation, stroke, heart failure, chronic obstructive pulmonary disease, seizure disorders, syncope — a temporary loss of consciousness caused by a fall in blood pressure — and four separate indicators found with an electrocardiogram test, including heart rate.

“This first-of-its-kind algorithm has the potential to improve the way we currently predict sudden cardiac arrest,” said Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute and the Mark S. Siegel Family Foundation Distinguished Professor. “If validated in clinical trials, we will be able to better identify high-risk patients and therefore, save lives.”

The research study utilized data from two ongoing multiyear studies founded by Chugh. The Oregon Sudden Unexpected Death Study is a comprehensive assessment of sudden cardiac arrests among the 1 million residents of the Portland, Oregon, metropolitan area.

The Ventura Prediction of Sudden Death in Multiethnic Communities (PRESTO) study is based in Ventura, California, with approximately 850,000 residents. Both studies are unique community partnerships with area residents, as well as first responders, medical examiners and hospital systems that deliver care within the two communities.

Both led by Chugh, the projects — now ongoing in Oregon for nearly 20 years, and more recently in Ventura — provides researchers with unique, community-based information to help determine how best to predict sudden cardiac arrest.

As a next step, Chugh plans to test their risk assessment algorithm, which was funded by the National Heart, Lung, and Blood Institute (R01HL126938 and R01HL145675), in separate prospective studies, as well as randomized clinical trials.

The researchers observed unexpected, rapid “electron precipitation” from low-Earth orbit using the ELFIN mission, a pair of tiny satellites built and operated on the UCLA campus by undergraduate and graduate students guided by a small team of staff mentors.

By combining the ELFIN data with more distant observations from NASA’s THEMIS spacecraft, the scientists determined that the sudden downpour was caused by whistler waves, a type of electromagnetic wave that ripples through plasma in space and affects electrons in the Earth’s magnetosphere, causing them to “spill over” into the atmosphere.

Their findings, published March 25 in the journal Nature Communications, demonstrate that whistler waves are responsible for far more electron rain than current theories and space weather models predict.

“ELFIN is the first satellite to measure these super-fast electrons,” said Xiaojia Zhang, lead author and a researcher in UCLA’s department of Earth, planetary and space sciences. “The mission is yielding new insights due to its unique vantage point in the chain of events that produces them.”

Central to that chain of events is the near-Earth space environment, which is filled with charged particles orbiting in giant rings around the planet, called Van Allen radiation belts. Electrons in these belts travel in Slinky-like spirals that literally bounce between the Earth’s north and south poles. Under certain conditions, whistler waves are generated within the radiation belts, energizing and speeding up the electrons. This effectively stretches out the electrons’ travel path so much that they fall out of the belts and precipitate into the atmosphere, creating the electron rain.

One can imagine the Van Allen belts as a large reservoir filled with water — or, in this case, electrons, said Vassilis Angelopolous, a UCLA professor of space physics and ELFIN’s principal investigator. As the reservoir fills, water periodically spirals down into a relief drain to keep the basin from overflowing. But when large waves occur in the reservoir, the sloshing water spills over the edge, faster and in greater volume than the relief drainage. ELFIN, which is downstream of both flows, is able to properly measure the contributions from each.

The low-altitude electron rain measurements by ELFIN, combined with the THEMIS observations of whistler waves in space and sophisticated computer modeling, allowed the team to understand in detail the process by which the waves cause rapid torrents of electrons to flow into the atmosphere.

The findings are particularly important because current theories and space weather models, while accounting for other sources of electrons entering the atmosphere, do not predict this extra whistler wave-induced electron flow, which can affect Earth’s atmospheric chemistry, pose risks to spacecraft and damage low-orbiting satellites.

The researchers further showed that this type of radiation-belt electron loss to the atmosphere can increase significantly during geomagnetic storms, disturbances caused by enhanced solar activity that can affect near-Earth space and Earth’s magnetic environment.

“Although space is commonly thought to be separate from our upper atmosphere, the two are inextricably linked,” Angelopoulos said. “Understanding how they’re linked can benefit satellites and astronauts passing through the region, which are increasingly important for commerce, telecommunications and space tourism.”

Since its inception in 2013, more than 300 UCLA students have worked on ELFIN (Electron Losses and Fields investigation), which is funded by NASA and the National Science Foundation. The two microsatellites, each about the size of a loaf of bread and weighing roughly 8 pounds, were launched into orbit in 2018, and since then have been observing the activity of energetic electrons and helping scientists to better understand the effect of magnetic storms in near-Earth space. The satellites are operated from the UCLA Mission Operations Center on campus.

Senior author Matthias Nahrendorf, MD, PhD, an investigator in MGH’s Center for Systems Biology and The Richard Moerschner professor at the MGH Research Institute and Harvard Medical School, explains that the nervous system plays a role in controlling blood cell production through chemical messengers or neurotransmitters. “This is for instance important in people exposed to stress, where stress hormones — part of the ‘fight-or-flight’ response controlled by the sympathetic nervous system — may increase bone marrow activity and cardiovascular inflammation in response to the neurotransmitter noradrenaline,” he says. The sympathetic nerves have a counter player — the parasympathetic nerves, which slow down responses and bring about a state of calm to the body, mainly through the neurotransmitter acetylcholine.

Because acetylcholine can have a protective effect against inflammation and heart disease, the researchers studied this neurotransmitter in the bone marrow. “When we looked into how acetylcholine acts on the production of blood cells, we found that it does the expected — it reduces white blood cells, as opposed to noradrenaline, which increases them,” says Nahrendorf. “What was unexpected though was the source of the neurotransmitter acetylcholine.”

The team found no evidence in the bone marrow of the typical nerve fibers that are known to release acetylcholine. Instead, B cells, which are themselves a type of white blood cell (most known for making antibodies), supplied the acetylcholine in the bone marrow. “Thus, B cells counter inflammation — even in the heart and the arteries — via dampening white blood cell production in the bone marrow. Surprisingly, they use a neurotransmitter to do so,” says Nahrendorf.

Tapping into this process may help investigators develop strategies to block inflammation in cardiovascular conditions such as atherosclerosis. “Ultimately this may lead to new therapeutics that combat myocardial infarction, stroke, and heart failure,” says Nahrendorf.

Additional study authors include Maximilian J. Schloss, Maarten Hulsmans, David Rohde, I-Hsiu Lee, Nicolas Severe, Brody H. Foy, Fadi E. Pulous, Shuang Zhang, Konstantinos D. Kokkaliaris, Vanessa Frodermann, Gabriel Courties, Chongbo Yang, Yoshiko Iwamoto, Anders Steen Knudsen, Cameron S. McAlpine, Masahiro Yamazoe, Stephen P. Schmidt, Gregory R. Wojtkiewicz, Gustavo Santos Masson, Karin Gustafsson, Diane Capen, Dennis Brown, John M. Higgins, David T. Scadden, Peter Libby, Filip K. Swirski, and Kamila Naxerova.

This work was supported in part by the National Heart Lung and Blood Institute at the National Institutes of Health (grant HL142494) and the MGH Research Scholar program.

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