Study: Anti-Inflammatory Therapies Could Reduce Heart Disease Risk in Elderly Patients With Clonal Hematopoiesis

Anti-inflammatory therapies could be effective at preventing heart disease in patients with clonal hematopoiesis, a common age-related blood condition, according to a new study published in Nature. The researchers identified how clonal hematopoiesis worsens atherosclerosis, and their findings suggest that an anti-inflammatory drug previously tested in a broader population of patients with cardiovascular disease may have potential for patients with atherosclerotic heart disease and clonal hematopoiesis.

Thought to occur in roughly 10% of people over 70 years of age, clonal hematopoiesis occurs when hematopoietic stem cells (HSCs) acquire mutations. As people age, each HSC acquires genetic mutations, though most mutations have no impact, according to the study.

Clonal hematopoiesis occurs when HSC mutations lead to the stem cell producing a greater number of blood cells. Although most with the condition have no symptoms, researchers discovered that the condition raises the risk of heart disease by 40%. In this study, the team focused specifically on JAK2, 1 of 4 specific genes that leads to clonal hematopoiesis, and the one that imparts the strongest risk of premature coronary artery disease

Atherosclerosis occurs when 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,” said Trevor P. Fidler, PhD, associate research scientist in medicine and the study's first author, in a press release.

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-1Beta, a product of the inflammasome.

An IL-1Beta inhibitor called canakinumab was previously found to reduce cardiovascular events in a clinical trial, but 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, we may increase the cardiovascular benefit,” Fidler said. “Even if infection risk remains unchanged, we may provide an overall benefit to this specific population.”

REFERENCE

Anti-inflammatory therapies have potential to prevent heart disease in the elderly [news release]. EurekAlert; March 18, 2021. Accessed March 24, 2021. https://www.eurekalert.org/pub_releases/2021-03/cuim-ath031821.php