Macrophages Found to be the Source of a Ripple Effect in the Development of a Life-Threatening Heart Condition

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A new study published in the Journal of Experimental Medicine from the Nahrendorf lab in the Center for Systems Biology at Massachusetts General Hospital shows a classic real-life example of the ripple effect.

Like a pebble thrown into a still body of water, immune cells called macrophages – white blood cells primarily known for removing cellular debris, pathogens and other unwanted materials – cause a series of responses in the heart that can eventually compromise the organ’s ability to provide enough oxygenated blood to the body.

These new findings advance understanding of macrophages’ role in the development of a type of heart condition known as heart failure with preserved ejection fraction, or HFpEF, and provide new insight into how to prevent development of this life-threatening disease.

What is HFpEF?

Heart failure is a condition in which the heart muscle is unable to pump enough blood to meet the body’s needs. The volume of blood pumped by the heart is determined by two factors:

  1. Contraction of the heart, which sends blood to the rest of the body, and
  2. Relaxation of the heart, which allows it to fill with blood

In the case of HFpEF, the heart contracts normally but is unable to relax and allow blood to flow into the left ventricle, thus reducing the amount of blood available to pump into the aorta.

The hearts of patients with HFpEF pump a limited amount of blood with each beat which can result in symptoms like decreased exercise tolerance, fatigue, and the accumulation of blood/fluid in the lungs, veins and tissues of the body. Fluid backs up into these areas because the heart is not able to process fluids effectively. The buildup of fluid in the lungs can result in shortness of breath while fluid in the legs causes swelling.

HFpEF accounts for around half of all human heart failure cases and has a high mortality rate — the 5-year survival of HFpEF is 35%, which is worse than most cancers.

Because HFpEF is difficult to treat and carries a poor prognosis once patients start showing symptoms, preventing HFpEF and limiting disease progression is critical.

Macrophages in the heart

Macrophages play an important role in normal cardiac function. Recent research from the Nahrendorf lab found that these white blood cells help heart muscle cells maintain a steady heartbeat.

Macrophages can also be found in high numbers around inflamed or diseased hearts to help heal tissue. They are given a helping hand by cells called fibroblasts, which generate connective tissue and collagen to help repair and remodel cardiac tissue.

However, too many fibroblasts can do more harm than good, at least when it comes to heart repair. An overabundance of fibroblasts can cause the tissue to stiffen and reduce the heart’s ability to relax and refill properly. For that reason, fibroblasts are considered a major contributor to the development of HFpEF.

Despite this known role for fibroblasts, it has remained unclear if and how macrophages are involved in the development of HFpEF.

Discovery of a ripple effect

In their most recent study, a research team from the Nahrendorf lab led by Maarten Hulsmans, PhD, a research fellow in the Center for Systems Biology, sought to further define macrophages’ role in the hopes of identifying a new therapeutic target to prevent HFpEF.

The team examined cardiac macrophages in two mouse models that had developed a similar impaired relaxation of the heart muscle as seen in human patients with HFpEF. They discovered a ripple effect that stemmed from an increased number of macrophages in the mice’s left ventricles.

These macrophages had elevated levels of an anti-inflammatory agent called IL-10, which was activating a surplus of fibroblasts and stimulating an overproduction of collagen, both of which led to increased stiffness and impaired heart relaxation.

Tissue biopsies from human patients with HFpEF also had increased levels of cardiac macrophages and circulating monocytes, which are precursors of macrophages, suggesting that the same ripple effect is occurring in humans as well.

The researchers discovered that removing IL-10 in macrophages in one mouse model reduced the numbers and activation of cardiac fibroblasts, and improved the heart’s ability to relax. If researchers can develop a drug that can limit the production of IL-10 in macrophages, they may be able to subsequently reduce the activation of fibroblasts and reduce the chances of patients developing HFpEF.

“These findings put macrophages on the map when it comes to HFpEF therapy and open up previously unexplored treatment options,” says Hulsmans. “Our identification of the central involvement of macrophages should give us a new focus for drug development,” added Matthias Nahrendorf, MD, PhD, Weissman Family MGH Research Scholar, investigator in the Center for Systems Biology and senior author of this study.

About the Mass General Research Institute
Massachusetts General Hospital is home to the largest hospital-based research program in the United States. Research at Mass General takes place in over 30 departments, centers and institutes and is supported by federal and state funding, foundations, industry partners and philanthropic donations. Support our research.

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