Sleep and exercise may mitigate genetic factors in heart disease

Sleeping well and going to the gym could offset the impact of certain genetic mutations that increase the risk of heart disease and stroke.

The mutations that accumulate in immune cells during life can intensify inflammation and promote cardiovascular disease, independent of traditional risk factors such as smoking, diabetes or high cholesterol. But sleep and exercise can weaken evil of certain mutations, researchers report on June 10 Nature.

This discovery illustrates a complex interaction between genetics and behavior. Even if you can quit smoking, you can’t just get rid of your genes. But you may be able to take steps to influence their activity, says Teresa Gerhardt, a doctor who studied cardiovascular disease as a postdoc at the Icahn School of Medicine at Mount Sinai in New York.

Every day, stem cells in our blood divide and replicate to generate billions of new immune cells. This process replenishes and maintains the body’s defense system, but also creates DNA problems. Many of these mutations are harmless. But variants of certain genes can accumulate disproportionately in the blood – a condition known as clonal hematopoiesis, or CH.

In the 2010s, researchers looked for genetic variants associated with CH in DNA from blood samples. They thought these mutations might be a first step on the path to cancer, similar to polyps detected during a colonoscopy, says Siddhartha Jaiswal, an immunologist at Stanford University School of Medicine who was not involved in the new study.

Previous experiments on mice revealed the “how.” Immune cells called macrophages invade clogged arteries to eat away cholesterol deposits. But they also release inflammatory signals, increasing the risk of atherosclerosis. Certain CH mutations intensify this immune response to plaques that build up in blood vessels, says Mount Sinai neuroimmunologist Cameron McAlpine.

Other research has suggested that non-genetic factors such as diet and infections may influence the degree to which these heart disease-linked CH mutations accumulate. McAlpine, Gerhardt and their colleagues therefore studied whether lifestyle changes could mitigate the risk of genetically induced cardiovascular diseases.

Evaluating the genetic data and physical activity levels of more than 91,000 British and American adults, the team found a modest effect: the proportion of individuals with certain CH mutations fell by 13% in the subset with moderate to vigorous activity.

The data were strongest in mice, where behavioral changes had a clear influence on atherosclerosis. The mice were genetically engineered to have CH mutations and fed a high-cholesterol diet. Some animals were given an exercise wheel. This has led to an increase in physical activity, with many voluntarily running 10 kilometers a day. Others were subjected to sleep disruption from a bar that moved across the floor of the cage, waking the animals every few minutes.

These lifestyle changes influenced the frequency and behavior of mutant macrophages in some mice. “If you exercise, you have smaller plaques and fewer diseases, and if you sleep poorly, you have more diseases,” says Gerhardt, who has since moved to Germany to open his own laboratory at Goethe University in Frankfurt.

However, the effect of these behaviors was not universal. The team examined variants in four different genes involved in CH.

“Adequate sleep or exercise can reverse the risk of atherosclerosis, but it is different depending on the [gene] variants — the degree to which it happens and if it happens,” says Allan Tall, a pulmonologist at Columbia University who studies the molecular mechanisms of cardiovascular disease but was not involved in the new work.

But because one of the most dangerous mutations isn’t that rare (it affects 3 to 4 percent of Europeans), the study’s findings that lifestyle factors mitigate cardiovascular risk in mice carrying this mutation “could apply to a significant segment of the population,” Tall says.