Younger people who experience sudden cardiac arrest are more likely to have a genetic cause than older people who experience it, according to new research from the

“If you have a family member who suffered sudden cardiac arrest, it is important to undergo genetic testing to determine if you harbor a genetic variant that increases your risk of sudden cardiac arrest or other heart conditions,” said Evan Kransdorf, MD, PhD, assistant professor of Cardiology in the Smidt Heart Institute and first author of the study. “For people who carry a variant linked to sudden cardiac arrest, a cardiologist can prescribe medications or lifestyle changes that can decrease the chances of experiencing this dangerous event.”

Sudden cardiac arrest, an electrical malfunction that causes the heart to beat very rapidly, is fatal in 90% of cases, according to the American Heart Association. The Cedars-Sinai Health Sciences University investigators found that 10% of people 29 and younger who have sudden cardiac arrest carry genetic variants linked with the condition.

The team analyzed blood samples from more than 3,000 people who experienced sudden cardiac arrest in Portland, Oregon, and Ventura County, California. The samples came from the ongoing Oregon Sudden Unexpected Death Study and the Ventura Prediction of Sudden Death in Multi-Ethnic Communities study—both created by Sumeet Chugh, MD, director of the Center for Cardiac Arrest Prevention in the Smidt Heart Institute, to improve understanding of the condition.

Investigators performed whole genome sequencing, which maps a person’s entire genetic code. They identified 15 genes in which damaging genetic variants can occur and disrupt the gene’s function and increase risk of sudden cardiac arrest. They found the prevalence of damaging genetic variants decreased with age:

• 10% of people age 29 and younger harbored a damaging genetic variant.
• 7% of people age 30-49 harbored a damaging genetic variant.
• 4% of people age 50-69 harbored a damaging genetic variant.
• 3% of people age 70 and older harbored a damaging genetic variant.

In older people, sudden cardiac arrest is more likely to be caused by a narrowed or blocked heart blood vessel rather than a heart condition caused by a damaging genetic variant, according to the investigators.

The investigators said more research will help uncover other genes linked to sudden cardiac arrest.

“This study is more representative of the U.S. population than other studies because it includes data from two communities rather than data from people already being seen at a medical center,” said Chugh, who is also vice dean and chief artificial intelligence health research officer at Cedars-Sinai and senior author of the study.

Additional Cedars-Sinai authors include Marco Mathias, BS; Kotoka Nakamura, PhD; Harpriya Chugh, BE, MSHS; David Nguyen, BS; Paul D. Pharoah, MD, PhD; and Kyndaron Reinier, MPH, PhD.

Other authors include Jonathan Tyrer, PhD; Zeynep Akdemir, PhD; Eric Boerwinkle, PhD; and Bing Yu, PhD. 

Funding: The study was funded by The National Institute of Health, NHLBI Grants R01HL145675 and R01HL147358; NIH DHHS Contracts HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, HHSN268201700005I.

Read more from Cedars-Sinai Stories and Insights: Heart Attack, Cardiac Arrest, Heart Failure—What’s the Difference?

Cingolani, director of Cardiogenetics and Preclinical Research in the Department of Cardiology in the Smidt Heart Institute at Cedars-Sinai, is exploring new ways to help patients with ventricular tachycardia (VT), a recurring, abnormally fast and irregular heartbeat that starts in the lower chambers, or ventricles, of the heart. If VT lasts for more than a few seconds at a time, it can be life-threatening.

Current therapies for recurrent VT are not very effective and have unpleasant side effects. Cingolani is studying the effectiveness of a novel, noninvasive cell-based therapy to treat VT. His approach uses stem cell-derived exosomes—tiny fluid-filled sacs found in cells—to help regrow healthy heart muscle and prevent disruptive electrical signals. His next step is to move his promising research into a first-in-human clinical trial.

Thanks to a $6 million grant from the California Institute for Regenerative Medicine (CIRM), the state’s taxpayer-funded stem cell research initiative, Cingolani is closer to that goal.

Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute and the Mark S. Siegel Family Foundation Distinguished Professor, said the funding is the first-ever CIRM grant focused on VT as well as the first to receive clinical research funding from CIRM for the use of exosomes as a therapy.

“This grant is the most advanced offered by the California Institute for Regenerative Medicine to fund the laborious studies required to procure regulatory approval for first-in-human trials,” Marbán said. “The new approach to treating VT is based 100% on Cedars-Sinai discoveries.”

The Cedars-Sinai Newsroom recently talked with Cingolani, an associate professor of Cardiology, to learn more about his quest to find an effective new treatment for VT.

Tell us about VT and why it can be such a serious heart condition.

VT is caused by faulty electrical signaling in the heart and sometimes develops after a heart attack. Patients experience a very fast heart rate—often 150 times a minute or more. A normal resting heart rate for adults is between 60 and 100 beats a minute. The rapid heartbeat may only last for a few seconds, but during that time, the heart is beating so fast that it can’t get enough blood to the rest of the body. Patients may feel a fluttering in the chest, chest pain, shortness of breath and dizziness or lightheadedness as a result. If VT is not treated, it can lead to cardiac arrest, which is when the heart stops beating. In fact, VT is the most common cause of sudden cardiac arrest.

How is VT typically treated?

Right now, there are several treatment options, but none of them are optimal. They include medications that are not very effective and cause unpleasant side effects, an implantable cardioverter-defibrillator (or ICD) that provides an internal shock to correct the heartbeat, and a procedure called catheter ablation. This is a complex procedure that destroys the abnormal heart tissue that’s causing the rapid heartbeat. Unfortunately, ablation also destroys healthy heart tissue in the process. Another drawback is that ablation is often limited to patients who can access specialized centers that perform the procedure.

How do exosomes work to treat VT?

Exosomes are tiny vesicles, secreted by cells, that naturally heal heart scars. The idea is to infuse the exosomes into diseased heart muscle that is predisposed to VT with the goal of decreasing scar tissue and preventing VT. Current ablation procedures destroy heart tissue and tend to worsen heart function. Even when they work, VT often recurs over time. Our therapy might prevent VT without those limitations.

How does CIRM grant funding help future patients?

The grant is significant because it allows us to complete the necessary preclinical research as well as the safety and efficacy studies that are needed before the therapy moves into a clinical trial for patients. It represents a unique opportunity to advance our therapy to the next level and potentially be able to treat patients with ventricular arrhythmias in a better way, without destroying healthy heart tissue. I’m grateful to the California Institute for Regenerative Medicine for helping us advance this science.

How quickly might we see a clinical trial for patients?

We are aiming to obtain permission from the FDA [Food and Drug Administration] to perform a first-in-human study within the next two years. This would be an exciting development for research and for patients.

Read more on the Cedars-Sinai Blog: Cardiac Rhythm Disorders & Advanced Therapeutic Program for Ventricular Tachycardia

Sudden cardiac arrest occurs when the heart stops beating. It causes at least 300,000 deaths in the U.S. each year. Most people die within 10 minutes of cardiac arrest. Some people survive if they can get CPR chest compressions or shocks with a defibrillator right away.

“If a person has a family member who has suffered sudden cardiac arrest, it may be helpful to undergo genetic testing to help understand one’s own risk for experiencing this dangerous condition,” said Evan Kransdorf, MD, PhD, assistant professor of Cardiology in the Smidt Heart Institute at Cedars-Sinai and senior author of the study.

Scientists are finding that some forms of sudden cardiac arrest can be prevented with an implantable defibrillator, whereas other forms of the condition aren’t responsive to interventions like defibrillators and shocks.

The condition is rare in people under the age of 35. Sudden cardiac arrest is, however, the top cause of death among young athletes.

Previous studies have found that between 12%-30% of children and young adults who experienced sudden cardiac arrest carry certain genetic variants that may have put them at higher risk for the condition.

But Kransdorf said a true figure is difficult to determine because most studies have relied on studying blood samples collected from survivors or their family members by specialized referral clinics. These samples, he said, aren’t representative of the U.S. population.

For this study, investigators analyzed blood samples collected through two ongoing community-based studies of sudden cardiac arrest: the Oregon SUDS and Ventura PRESTO studies. These are longstanding community-based programs established by Sumeet Chugh, MD, director of the Center for Cardiac Arrest Prevention in the Smidt Heart Institute and the Pauline and Harold Price Chair in Cardiac Electrophysiology Research.

As part of these studies, first responders collect blood samples from people who experience sudden cardiac arrest in Portland, Oregon, and Ventura County, California.

Investigators performed whole-genome sequencing on blood samples collected from 52 people age 21 and under who experienced sudden cardiac arrest. They found that two of the 52 young people carried genetic variants that previous studies have found to be highly associated with the condition. Four of the young people carried variants that might play a role in increasing risk for the condition, but the significance of these variants is still unknown.  

The rate of genetic variants in this population was lower than those found in other studies.  

“Additional community-based studies are going to be important to help us understand how the genetics of a diverse population compare with what has been previously established in the medical literature through studying more referral-based populations,” said Chugh.

Kransdorf, Chugh and colleagues at the Center for Cardiac Arrest Prevention are currently analyzing data from a sample of more than 3,000 people who experienced sudden cardiac arrest. They seek to better understand the extent to which genetic variants contribute to the condition.

Other Cedars-Sinai investigators who worked on the study include Lauri Holmstrom, MD, PhD, a visiting postdoctoral scientist; Kotoka Nakamura, PhD, a project scientist and team leader with the Center for Cardiac Arrest Prevention; Harpriya Chugh, a clinical research data specialist; Audrey Uy-Evanado, MD, a project scientist and team leader with the Phenotyping Core; and Faye Norby, PhD, a research assistant professor in the Department of Cardiology.

Funding: The study was funded by the National Institutes of Health (award number R01HL145675); National Heart, Lung and Blood Institute grants (R01HL147358); the Sigrid Jusélius Foundation; the Finnish Cultural Foundation; the Instrumentarium Science Foundation; the Orion Research Foundation; and the Paavo Nurmi Foundation. 

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