A medical image of a heart is shown with DNA.

Genetic paths to predicting heart disease

The human genome was fully sequenced more than 20 years ago and is powering ways to predict, treat, and prevent cardiovascular disease

As researchers study the genetic underpinnings of heart and vascular disease, they are creating new ways to screen, diagnose, and treat patients for a variety of heart conditions. Some are exploring how to better identify patients at increased risk for sudden cardiac death. Others are researching how genomic insight could help patients with rare conditions by using therapies that may delay or prevent heart surgery. Still others are looking into how to stop irregular heart rhythms after surgery, which may provide insight into new ways to treat atrial fibrillation.

“This is just the beginning of a new era of using genomics and other omics to diagnose, treat, and prevent blood, heart, lung, and sleep-related diseases,” said James Luo, Ph.D., a program officer specializing in genomics, data sciences, and bioinformatics in the Advanced Technologies and Surgery Branch in NHLBI’s Division of Cardiovascular Sciences. Researchers have discovered more than one billion genetic variants through the Trans-Omics for Precision Medicine (TOPMed) program, Lou said. With further research to understand their biological function, these newly discovered variants could greatly expand the use of genomics to inform clinical practice decisions.

Here are a few examples and emerging trends to follow:

Predicting sudden cardiac death

When the heart can no longer pump blood throughout the body, often due to a chaotic rhythm replacing the normal heartbeat, a person goes into cardiac arrest, often collapsing or losing their pulse or consciousness.

Most people don’t survive – about 300,000 Americans die each year and often within an hour of when symptoms occur. This is why recognizing early signs – dizziness, shortness of breath, fatigue, or back or chest pain – and calling for emergency help is essential. With fast help, a patient may receive cardiopulmonary resuscitation or support from a defibrillator, a device used to restore cardiac rhythm. Or they may get advanced life support to strengthen their long-term chance for recovery and survival.

For most, though, this critical attention rarely comes quickly enough. This is why researchers have focused on identifying patients with a genetic risk for sudden cardiac death so doctors can monitor and ensure lifesaving tools – like defibrillators – go to those who may need them the most.

In a study published in the Journal of the American College of Cardiology (JACC), researchers sought to understand the genetic connection between coronary artery disease and sudden cardiac death by using a polygenic risk score for coronary artery disease. They found individuals with coronary artery disease and higher genetic risks had a 77% increased risk for sudden cardiac death.

“Coronary disease is a condition with polygenic inheritance where many common genetic variants of small effect interact together and may play a greater role in risk prediction than just one rare variant,” said Roopinder K. Sandhu, M.D., M.P.H., a study author and associate professor of cardiology at the Smidt Heart Institute at Cedars-Sinai Medical Center. This is why the authors used broad genetic risk assessments for the study, which uniquely predicted risk for sudden cardiac death.

“There aren’t a lot of factors that specifically predict sudden death versus other kinds of death,” said Christine Albert, M.D., M.P.H., chair of the department of cardiology at Cedars-Sinai and a senior study author. “It’s unusual and something we have been searching for.”

Having a precise prediction, Albert explained, can better match patients with timely therapies.

Future randomized trials, for example, might hone in on how many lives could be saved at the early signs of distress when a certain number of high-risk patients receive implantable defibrillators.

In the meantime, Albert and Sandhu underscore the power of prevention. This includes living a heart-healthy lifestyle and managing underlying conditions, such as high blood pressure, heart disease, and diabetes.

“You can impact genetic risk,” Albert said. “It’s not finite.”

Preempting thoracic aortic events

Researchers are also studying ways genetic insight can improve and personalize predictions for thoracic aortic disease – conditions that affect the aorta, the largest artery in the body, which carries blood away from the heart. While relatively uncommon, some people – less than 10 out of every 100,000 – experience ruptures (aortic aneurysm) or tears in the thoracic aorta, which is near the chest. However, those with genetic risks could be twice as likely to experience this type of event, which is why early risk detection is critical.

“If we know that somebody is at risk, we can follow the aneurysm growth and make a decision where we can go in to repair the aorta and prevent that dissection,” said Dianna M. Milewicz, M.D., Ph.D., chair of cardiovascular medicine and the director of the division of medical genetics at the University of Texas Health Science Center at Houston McGovern Medical School.

In research published in JACC, Milewicz and others describe how seven genetic variants linked to inherited forms of thoracic aortic disease can inform decisions about clinical imaging, surgery, and monitoring. Some variants were associated with severe tears. Others were linked to aggressive events in childhood or to less-severe outcomes in midlife. This is why it’s important to know which gene and variant is causing disease, Milewicz said.

In addition to predicting the severity and timing of thoracic aortic events, researchers are studying how this knowledge may guide treatment.

For example, researchers recently found that people with Marfan syndrome, a rare disorder caused by mutations to the FBN1 gene, may benefit from a combined therapeutic approach to slow the growth of the aortic root to potentially delay or prevent future aneurysms and tears. People with certain FBN1 variants responded especially well to the treatment, which included using one or two types of blood pressure-lowering medications that slow the heart rate.

As these types of studies publish, Milewicz is working with clinical researchers through GenTAC Alliance, a thoracic aortic research alliance funded by NHLBI, to share the findings through a database to help cardiologists make quick treatment decisions.

“So, you could put in the gene, the variant,” Milewicz said. “Based on other data, it would make recommendations as to what imaging to do, the extent of imaging, the frequency of imaging, and the timing of surgery.”

It could also inform post-surgical care. People with Marfan syndrome have lower risks for thoracic aortic complications after surgery. However, people with other genes linked to thoracic aortic disease still have high risks for dissections and aneurysms in other arteries.

“How can we get all this precision medicine into clinical practice as quickly as possible?” Milewicz said is a question researchers are eager to answer. Preventing an aneurysm from rupturing could prevent death, disability, or stroke. “You can just change the outcome of the disease completely.”

A central research repository for hereditary forms of thoracic aortic disease may even help identify people who would otherwise miss a diagnosis.

About one in five people with genetic links to thoracic aortic disease don’t have physical features associated with conditions like Marfan syndrome or Loeys-Dietz syndrome. Under-detection remains a challenge. Yet, aortic dissections are the 15th leading cause of death in the U.S.

Preventing irregular heart rhythms

Using gene therapy for heart disease is another research area that aims to change clinical outcomes – but by changing the course of disease.

For example, researchers at the University of Massachusetts are starting a four-year trial in November to assess the safety and early effectiveness of using gene therapy to prevent atrial fibrillation, an irregular heart rhythm, among adults having cardiothoracic surgery.

After transferring an altered copy of the gene KCNH2-G628S to patients, researchers will observe rates of atrial fibrillation that occur within a month after surgery.

The foundation for the study started more than 12 years ago through preclinical research. Researchers studied how expressing the altered gene KCNH2-G628S for a few weeks after cardiac surgery could safely and effectively maintain a normal heart rhythm in preclinical models. The proposed trial is the first test of this strategy in humans. The potential implications are vast. Post-surgical atrial fibrillation increases the risk for stroke, heart attack, and death.

Kevin Donahue, M.D., the study’s co-principal investigator, explained the goal is to see if this approach – which is quick and easy to apply during surgery (when the chest is open) – will safely eliminate atrial fibrillation. If so, it may provide insight into ways to prevent common forms of atrial fibrillation in adults.

The overarching goal of this research, like others, is to start by helping patients who could benefit most from offsetting risks for sudden and severe cardiovascular events.

To learn more about precision medicine research supported by NHLBI, visit https://www.nhlbi.nih.gov/science/precision-medicine-activities.

To learn more about TOPMed, visit https://topmed.nhlbi.nih.gov.


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