From the Literature

New research indicates that cardiac macrophages play an important role in diastolic dysfunction, when the ventricles become stiff and cannot fill with blood properly, often contributing to heart failure with preserved ejection fraction (HFpEF). Studies have shown that the number of cardiac macrophages increases after a cardiac injury, but this Journal of Experimental Medicine study is the first to examine how cardiac macrophages contribute to the pathogenesis of HFpEF. “In mice and humans that suffer from HFpEF, we observed an increase of inflammatory macrophages that inhabit the myocardium, but not only the number increases. Also, the macrophage phenotypes and actions differ from the normal heart,” said senior author Matthias Nahrendorf, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, in Boston. “We found that these macrophages participate in the remodeling of the heart tissue—specifically, they instigate increased extracellular matrix production, which counters diastolic relaxation.” The research team examined 2 murine models of HFpEF, and people with the syndrome, as well. Experiments revealed that higher myocardial macrophage densities arise from monocyte recruitment and activation of hematopoiesis in bone marrow and spleen. Also, while diastolic dysfunction develops, cardiac macrophages produce interleukin-10, activate fibroblasts, and stimulate collagen deposition, leading to impaired myocardial relaxation and increased myocardial stiffness. When interleukin-10 was deleted in the macrophages of mice, diastolic function improved. The findings may have important clinical implications for HFpEF, a lifethreatening health problem with an increasing incidence and a paucity of treatments. “This work puts macrophages on the map when it comes to HFpEF therapy,” said Dr Nahrendorf. “Usually, when thinking about drug development for this condition, people consider cardiomyocytes and fibroblasts as the main protagonists. Here we show that macrophages, by talking to fibroblasts, are centrally involved.” Dr Nahrendorf envisions a new and promising focus for drug development: the delivery of therapeutics to macrophages. “There is more good news: it is actually fairly easy to reach macrophages therapeutically, for instance with nanoparticle-facilitated drug delivery.”