Macrophages Found to be Key Contributor to HFpEF
Key findings
- Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of human heart failure cases, yet has no effective treatment
- Researchers observed in mouse models, a rise in neutrophils in the myocardium and a density of macrophages in the left ventricle, and elevated levels of a human cytokine synthesis inhibitory factor called IL-10
- Human studies confirmed the elevated level of macrophages and found increased levels of monocytes
- In a mouse model with deleted IL-10 in cardiac macrophages, the upregulation of macrophages was prevented and the number and activation of cardiac fibroblasts were reduced
- The study reveals that reducing the production of IL-10 in could be a potential drug target for HFpEF treatment
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Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of human heart failure cases, yet has no effective treatment. HFpEF has become more common as its risk factors including advanced age, obesity, diabetes and hypertension have become more pervasive. The 5-year survival of HFpEF is 35%, which is worse than most cancers.
In diseased or inflamed hearts, high numbers of macrophages are activated to heal tissue and are accompanied by fibroblasts, which generate connective tissue and collagen to repair and remodel cardiac tissue. However, an overabundance of fibroblasts can cause the tissue to stiffen and lessen its ability to relax. Consequently, fibroblasts are believed to be a major contributor to the development of HFpEF.
A team led by Maarten Hulsmans, PhD, research fellow in the Center for Systems Biology at Massassachusetts General Hospital, discovered that macrophage activity is a key player in the development of HFpEF. The results were published in the Journal of Experimental Medicine.
The Mass General team, which includes senior author Matthias Nahrendorf, MD, PhD, investigator in the Center for Systems Biology, conducted a series of experiments to evaluate cardiac macrophages in two mouse models of diastolic dysfunction that characterize HFpEF. These results were evaluated against studies conducted on tissue and blood from HFpEF patients.
The researchers conducted mice experiments using two validated methods of assessing cardiac macrophages to examine cardiac dysfunction of the left ventricle: one with induced hypertension via exposure to salty drinking water, unilateral nephrectomy and chronic exposure to aldosterone (SAUNA), and the other physiologically aged. Researchers observed, in both SAUNA and aged models, a rise in neutrophils in the myocardium and a density of macrophages in the left ventricle. They also found elevated levels of factor IL-10, which contributes to fibroblast activation and stimulates an overproduction of collagen.
Human studies confirmed the elevated level of macrophages and found increased levels of monocytes.
In a mouse model with deleted IL-10 in cardiac macrophages and where hypertension is induced, the upregulation of macrophages was prevented and the number and activation of cardiac fibroblasts were reduced.
The Mass General study contributes to an understanding of how macrophages play a role in HFpEF pathophysiology, and reveals that reducing the production of IL-10 in macrophages and subsequently reducing the activation of fibroblasts could be a potential drug target for HFpEF treatment.
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