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There has been longstanding scientific, engineering, and medical interest in creating mathematical models of the heart that capture, explain, and predict these fluid\u2013structure interactions (FSIs). However, existing computational models that account for interactions among the blood, the actively contracting myocardium, and the valves are limited in their abilities to predict valve performance, capture fine-scale flow features, or use realistic descriptions of tissue biomechanics. Here we introduce and benchmark a comprehensive mathematical model of cardiac FSI in the human heart. A unique feature of our model is that it incorporates biomechanically detailed descriptions of all major cardiac structures that are calibrated using tensile tests of human tissue specimens to reflect the heart\u2019s microstructure. Further, it is the first FSI model of the heart that provides anatomically and physiologically detailed representations of all four cardiac valves. We demonstrate that this integrative model generates physiologic dynamics, including realistic pressure\u2013volume loops that automatically capture isovolumetric contraction and relaxation, and that its responses to changes in loading conditions are consistent with the Frank\u2013Starling mechanism. These complex relationships emerge intrinsically from interactions within our comprehensive description of cardiac physiology. Such models can serve as tools for predicting the impacts of medical interventions. They also can provide platforms for mechanistic studies of cardiac pathophysiology and dysfunction, including congenital defects, cardiomyopathies, and heart failure, that are difficult or impossible to perform in patients.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgae392","type":"journal-article","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T14:01:23Z","timestamp":1725976883000},"source":"Crossref","is-referenced-by-count":31,"title":["Simulating cardiac fluid dynamics in the human heart"],"prefix":"10.1093","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3909-9664","authenticated-orcid":false,"given":"Marshall","family":"Davey","sequence":"first","affiliation":[{"name":"Curriculum in Bioinformatics and Computational Biology, University of North Carolina , Chapel Hill, NC 27599 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1258-8433","authenticated-orcid":false,"given":"Charles","family":"Puelz","sequence":"additional","affiliation":[{"name":"Department of Pediatrics-Cardiology, Baylor College of Medicine and Texas Children\u2019s Hospital , Houston, TX 77030 ,","place":["USA"]},{"name":"Department of Mathematics, University of Houston , Houston, TX 77204 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Mathematics, University North Carolina , Chapel Hill, NC 27599 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1480-5714","authenticated-orcid":false,"given":"Margaret Anne","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Mathematics, University North Carolina , Chapel Hill, NC 27599 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8325-9186","authenticated-orcid":false,"given":"David R","family":"Wells","sequence":"additional","affiliation":[{"name":"Department of Mathematics, University North Carolina , Chapel Hill, NC 27599 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory M","family":"Sturgeon","sequence":"additional","affiliation":[{"name":"Department of Radiology, Duke University Medical Center , Durham, NC 27705 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3687-5733","authenticated-orcid":false,"given":"W Paul","family":"Segars","sequence":"additional","affiliation":[{"name":"Department of Radiology, Duke University Medical Center , Durham, NC 27705 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P","family":"Vavalle","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of North Carolina School of Medicine , Chapel Hill, NC 27599 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3749-9864","authenticated-orcid":false,"given":"Charles S","family":"Peskin","sequence":"additional","affiliation":[{"name":"Courant Institute of Mathematical Sciences, New York University , New York, NY 10012 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9800-7504","authenticated-orcid":false,"given":"Boyce E","family":"Griffith","sequence":"additional","affiliation":[{"name":"Department of Mathematics, University North Carolina , Chapel Hill, NC 27599 ,","place":["USA"]},{"name":"Department of Biomedical Engineering, University of North Carolina , Chapel Hill, NC 27599 ,","place":["USA"]},{"name":"Carolina Center for Interdisciplinary Applied Mathematics, University of North Carolina , Chapel Hill, NC 27599 ,","place":["USA"]},{"name":"Computational Medicine Program, University of North Carolina School of Medicine , Chapel Hill, NC 27599 ,","place":["USA"]},{"name":"McAllister Heart Institute, University of North Carolina School of Medicine , Chapel Hill, NC 27599 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,9,10]]},"reference":[{"issue":"7394","key":"2024103012142609200_pgae392-B1","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/484314a","article-title":"Medicine: Leonardo\u2019s anatomy years","volume":"484","author":"Clayton","year":"2012","journal-title":"Nature"},{"issue":"52","key":"2024103012142609200_pgae392-B2","doi-asserted-by":"crossref","first-page":"18129","DOI":"10.1073\/pnas.0407817101","article-title":"Functional assembly of engineered myocardium by electrical stimulation of cardiac 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