Cardiac macrophages promote diastolic dysfunction

Maarten Hulsmans, Hendrik B. Sager, Jason D. Roh, María Valero-Muñoz, Nicholas E. Houstis, Yoshiko Iwamoto, Yuan Sun, Richard M. Wilson, Gregory Wojtkiewicz, Benoit Tricot, Michael T. Osborne, Judy Hung, Claudio Vinegoni, Kamila Naxerova, David E. Sosnovik, Michael R. Zile, Amy D. Bradshaw, Ronglih Liao, Ahmed Tawakol, Ralph WeisslederAnthony Rosenzweig, Filip K. Swirski, Flora Sam, Matthias Nahrendorf

Research output: Contribution to journalArticlepeer-review

331 Scopus citations

Abstract

Macrophages populate the healthy myocardium and, depending on their phenotype, may contribute to tissue homeostasis or disease. Their origin and role in diastolic dysfunction, a hallmark of cardiac aging and heart failure with preserved ejection fraction, remain unclear. Here we show that cardiac macrophages expand in humans and mice with diastolic dysfunction, which in mice was induced by either hypertension or advanced age. A higher murine myocardial macrophage density results from monocyte recruitment and increased hematopoiesis in bone marrow and spleen. In humans, we observed a parallel constellation of hematopoietic activation: circulating myeloid cells are more frequent, and splenic 18 F-FDG PET/CT imaging signal correlates with echocardiographic indices of diastolic dysfunction. While diastolic dysfunction develops, cardiac macrophages produce IL-10, activate fibroblasts, and stimulate collagen deposition, leading to impaired myocardial relaxation and increased myocardial stiffness. Deletion of IL-10 in macrophages improves diastolic function. These data imply expansion and phenotypic changes of cardiac macrophages as therapeutic targets for cardiac fibrosis leading to diastolic dysfunction.

Original languageEnglish
Pages (from-to)423-440
Number of pages18
JournalJournal of Experimental Medicine
Volume215
Issue number2
DOIs
StatePublished - 1 Feb 2018
Externally publishedYes

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