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Significant reduction in infarct propagation is observed when mechanical unloading is coupled with reperfusion, but little is known of the effect this reduction in wall stress and extracellular matrix with LVADs has on the heart's regenerative capacity. This study investigates the effect coronary reperfusion coupled with mechanical unloading has on myocardial fibrosis, and the impact of these changes in extracellular matrix on the heart's regenerative potential. MI was induced by coronary artery ligation in Lewis rats. Hearts underwent permanent coronary ligation (AMI) or were reperfused after 90\u00a0min (AMI\/R). In each group, hearts were either loaded (AMI-L or AMI\/R-L) or unloaded (AMI-U or AMI\/R-U). In the unloaded subgroup, the infarcted hearts were explanted after 90\u00a0min and transplanted into the abdomen of healthy recipients via heterotopic abdominal heart\u2013lung transplantation. The recipient\u2019s heart acted as control. Hearts were analysed on day 7. 30 hearts were studied. In the permanent ligation group, fibrosis increased in both the loaded and unloaded hearts with no significant rise in cardiomyocyte proliferation. After coronary reperfusion, no increase in fibrosis was observed with mechanical unloading but cardiomyocyte proliferation rose significantly (AMI\/R-L vs AMI\/R-U\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0001). Cardiomyocyte proliferative rate in the loaded and unloaded hearts was 0.6% and 3.7%, respectively, after permanent ligation, and 0.5% and 10.4%, respectively, after coronary reperfusion. These data show that coronary reperfusion coupled with mechanical unloading reduces myocardial fibrosis and upregulates cardiomyocyte proliferation after myocardial infarction.\n                  <\/jats:p>","DOI":"10.1007\/s00395-025-01147-4","type":"journal-article","created":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T02:27:35Z","timestamp":1763778455000},"page":"43-57","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mechanical unloading coupled with coronary reperfusion stimulates cardiomyocyte proliferation and prevents unloading-induced fibrosis after myocardial infarction"],"prefix":"10.1007","volume":"121","author":[{"given":"Sean O.","family":"Bello","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charanjit","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Perbellini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prakash P.","family":"Punjabi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2761-0696","authenticated-orcid":false,"given":"Cesare M.","family":"Terracciano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,22]]},"reference":[{"key":"1147_CR1","doi-asserted-by":"publisher","first-page":"2680","DOI":"10.1016\/j.jacc.2021.01.059","volume":"77","author":"C Andersson","year":"2021","unstructured":"Andersson C, Nayor M, Tsao CW, Levy D, Vasan RS (2021) Framingham Heart Study. 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