Study Claims Heart Disease In Elderly May Be Prevented By Anti-Inflammatory Therapies

The findings of a new study from researchers at Columbia University Vagelos College of Physicians and Surgeons suggest that anti-inflammatory therapies may be an effective way to prevent heart disease in people with a common age-related blood condition.

Therapies that soothe inflammation could be an effective way to prevent heart disease in people with a common age-related blood condition, according to a new study from researchers at Columbia University Vagelos College of Physicians and Surgeons.

Their study was published in the journal Nature.

The researchers identified how the blood condition, called clonal hematopoiesis, worsens atherosclerosis, and their findings suggest that an anti-inflammatory drug previously tested in a wider population of people with cardiovascular disease may have potential if used only in those with clonal hematopoiesis.

"The main message from our research is that anti-inflammatory therapies for atherosclerotic heart disease may be particularly effective in patients with clonal hematopoiesis," said Alan Tall, MD, the Tilden Weger Bieler Professor of Medicine, the study's co-senior author with Nan Wang, MD, associate professor of medical sciences (in medicine).

Although great strides have been made in reducing atherosclerotic heart disease with therapies such as statins that reduce cholesterol, many people still have increased disease despite these current treatments.

"Over the years, researchers have learned that the ageing process itself is a major contributor to cardiovascular disease," says Trevor P. Fidler, PhD, an associate research scientist in medicine, the study's first author. "But how ageing itself can lead to heart disease--and how it could be prevented--is not well understood."

In the new study, the researchers took a close look at a common blood condition, called clonal hematopoiesis, that is associated with ageing.

Clonal hematopoiesis is thought to occur in roughly 10% of people over age 70, and most people have no symptoms. But researchers recently realized that the condition--for unknown reasons--raises the risk of heart disease by 40%.

Clonal hematopoiesis occurs when hematopoietic (blood) stem cells acquire mutations. As people age, each hematopoietic stem cell acquires genetic mutations, though most of these mutations have no impact. But in clonal hematopoiesis, some mutations supercharge the stem cell so that it produces a greater number of blood cells compared with other stem cells.

Clonal hematopoiesis usually arises when one of four specific genes is mutated. The Columbia team looked specifically at JAK2, which imparts the strongest risk of premature coronary artery disease.

In atherosclerosis, white blood cells called macrophages accumulate in plaques and proliferate as the plaque grows.

In studies of mice, the researchers found that the JAK2 mutations led to a number of changes in macrophages that increased macrophage proliferation, increased inflammation in the atherosclerotic plaques, and enhanced the plaque's necrotic core.

"We know in humans that such regions are associated with unstable plaques, which can rupture, causing heart attacks or strokes," Fidler says.

The researchers also traced the molecular mechanisms that led to these changes, including increased activation of the AIM2 inflammasome, a complex of proteins that induces inflammation.

Inhibiting various components of the inflammasome improved the stability of the plaques, as did inhibition of IL-1ss, a product of the inflammasome.

Though an IL-1ss inhibitor called canakinumab reduced cardiovascular events in a clinical trial, the drug was associated with a small risk of infection and has not been marketed to reduce cardiovascular disease.

"If instead, we take a precision medicine approach and only use canakinumab to treat patients with JAK-driven clonal hematopoiesis," Fidler says, "we may increase the cardiovascular benefit. Even if infection risk remains unchanged, we may provide an overall benefit to this specific population."

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