{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T18:09:16Z","timestamp":1788804556456,"version":"build-2803163510"},"reference-count":49,"publisher":"American Society for Clinical Investigation","issue":"17","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":54,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institute of Health Research","doi-asserted-by":"crossref","award":["496671"],"award-info":[{"award-number":["496671"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,8]]},"abstract":"<jats:p>The pericardium plays an important homeostatic role for the neighboring heart, providing both lubrication and structural support. In vivo models have further identified a protective role for the pericardium in modulating cardiac remodeling following myocardial infarction, possibly through the actions of tissue-resident pericardial macrophages. Using patient-derived pericardial samples, we establish that human pericardial immune cells directly inhibit cardiac fibroblast fibrotic activity, and this action is dampened following myocardial infarction. Using single-cell RNA sequencing of patient pericardial fluid cells, we identify two pericardial macrophage subsets that are uniquely altered in response to myocardial infarction, which contributes to a shift in their effector molecule expression profiles. We confirm that fibronectin-expressing human pericardial macrophages are the primary driver of the pericardial antifibrotic actions through the release of cystatin C. Finally, we establish cystatin C as a myeloid cell\u2013derived cardioprotective effector molecule in an in vivo model of myocardial infarction. 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