02274nas a2200349   4500000000100000008004100001260001500042100002000057700002000077700001400097700001900111700002200130700001000152700001400162700001600176700001800192700002000210700001400230700001400244700001700258700002200275700001300297700002000310700002100330700002600351700001900377245013800396856005500534300001300589490000700602520131500609       2024                            d  c2024-03-271 aRick Xing Ze Lu1 aNaimeh Rafatian1 aYimu Zhao1 aKarl T. Wagner1 aErika L. Beroncal1 aBo Li1 aCarol Lee1 aJingan Chen1 aEryn Churcher1 aDaniel Vosoughi1 aChuan Liu1 aYing Wang1 aAndrew Baker1 aUriel Trahtemberg1 aBowen Li1 aAgostino Pierro1 aAna C. Andreazza1 aClaudia C. dos Santos1 aMilica Radisic00aCardiac tissue model of immune-induced dysfunction reveals the role of free mitochondrial DNA and the therapeutic effects of exosomes  uhttps://www.science.org/doi/10.1126/sciadv.adk0164  aeadk01640 v103 aDespite tremendous progress in the development of mature heart-on-a-chip models, human cell–based models of myocardial inflammation are lacking. Here, we bioengineered a vascularized heart-on-a-chip with circulating immune cells to model severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced acute myocarditis. We observed hallmarks of coronavirus disease (COVID-19)–induced myocardial inflammation, as the presence of immune cells augmented the secretion of proinflammatory cytokines, triggered progressive impairment of contractile function, and altered intracellular calcium transients. An elevation of circulating cell-free mitochondrial DNA (ccf-mtDNA) was measured first in the heart-on-a-chip and then validated in COVID-19 patients with low left ventricular ejection fraction, demonstrating that mitochondrial damage is an important pathophysiological hallmark of inflammation-induced cardiac dysfunction. Leveraging this platform in the context of SARS-CoV-2–induced myocardial inflammation, we established that administration of endothelial cell–derived exosomes effectively rescued the contractile deficit, normalized calcium handling, elevated the contraction force, and reduced the ccf-mtDNA and cytokine release via Toll-like receptor–nuclear factor κB signaling axis.