NEW YORK, NY (March 18, 2021)--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.
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," says 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).
Their study was published online March 17 in Nature.
Aging Contributes to Heart Disease
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 aging process itself is a major contributor to cardiovascular disease," says Trevor P. Fidler, PhD, associate research scientist in medicine, the study's first author. "But how aging itself can lead to heart disease--and how it could be prevented--is not well understood."
Common Blood Condition Increases Heart Disease
In the new study, the researchers took a close look at a common blood condition, called clonal hematopoiesis, that is associated with aging.
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.
Study of Mice Reveals Source of Extra Heart Risk
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.
Targeting Inflammasome May Reduce Cardiovascular Risk
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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More Information
The study is titled "The Aim2 inflammasome exacerbates atherosclerosis in clonal hematopoiesis."
All authors: Trevor Fidler (Columbia), Chenyi Xue (Columbia), Mustafa Yalcinkaya (Columbia), Brian Hardaway (Columbia), Sandra Abramowicz (Columbia), Tong Xiao (Columbia), Wenli Liu (Columbia), David G. Thomas (Columbia), Mohammad Ali Hajebrahimi (Ludwig Maximilian University and German Center for Cardiovascular Research), Joachim Pircher (Ludwig Maximilian University and German Center for Cardiovascular Research), Carlos Silvestre-Roig (German Center for Cardiovascular Research and IPEK, Munich), Andriana G. Kotini (Icahn School of Medicine at Mount Sinai), Larry L. Luchsinger (Columbia), Ying Wei (Columbia), Marit Westerterp (Columbia and University of Groningen), Hans-Willem Snoeck (Columbia), Eirini P. Papapetrou (Icahn School of Medicine at Mount Sinai), Christian Schulz (Ludwig Maximilian University and German Center for Cardiovascular Research), Steffen Massberg (Ludwig Maximilian University and German Center for Cardiovascular Research), Oliver Soehnlein (Ludwig Maximilian University, German Center for Cardiovascular Research, and Karolinksa Institute), Benjamin Ebert (Dana-Farber Cancer Institute), Ross L. Levine (Memorial Sloan Kettering Cancer Center), Muredach P. Reilly (Columbia), Peter Libby (Harvard Medical School), Nan Wang (Columbia), and Alan R. Tall (Columbia).
The research was supported by the Leducq Foundation, the National Institutes of Health (grants HL118567, HL155431, HL148071, HL137663, CA108671, CA008748, HL080472, HL134892, R01HL137219, and R01CA225231), a Columbia Clinical and Translational Science Award, the New York State Stem Cell Board, a Scholar Award from the Leukemia and Lymphoma Society, the German Research Foundation, the German Center for Cardiovascular Research, and the German Ministry of Education and Research.
The authors' competing interests are listed in the online version of the paper.
Columbia University Irving Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the Vagelos College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Irving Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cuimc.columbia.edu or columbiadoctors.org.
Journal
Nature