Background　and　objectives:　Fractional　flow　reserve　(FFR)　is　considered　to　be　the　＂gold　standard＂　for　the　clinical　diagnosis　of　functional　myocardial　ischemia.　With　the　development　of　medical　imaging　and　computational　fluid　dynamics　(CFD),　noninvasive　computation　of　FFR　has　been　developed.　The　most　representative　calculation　method　is　the　noninvasive　FFR　derived　from　coronary　CT　angiography　(FFRCT),　but　it　cannot　thoroughly　simulate　the　real　physiological　structure　of　the　cardiovascular　system.　In　this　study,　we　propose　a　noninvasive　closed-loop　FFR　derived　from　coronary　CT　angiography　(FFRCCT).　Methods:　The　closed-loop　multi-scale　model　includes　three　parts:　the　heart　module,　the　coronary　artery　module　with　microcirculation　structure　and　the　systemic　circulation　module.　The　proposed　structure　was　formed　by　coupling　a　lumped　parameter　model　(0D)　with　a　3D　model,　such　that　the　0D　model　provides　the　boundary　conditions　for　the　3D　model.　We　enrolled　100　patients　through　a　prospective　multi-center　clinical　trial　and　calculated　their　FFRCCT.　Then,　we　extracted　the　pressure　and　flow　waveforms　of　the　coronary　stenosis　vessels　through　closed-loop　geometric　multi-scale　CFD　calculations.　We　evaluated　the　accuracy　of　FFRCCT　in　diagnosing　myocardial　ischemia　using　the　clinical　measurement　of　FFR　as　the　standard.　Results:　The　results　of　FFRCCT　calculation　in　all　patients　showed　a　good　correlation　between　FFRCCT　and　FFR　(r　=　0.64,　p　＜　0.05).　The　AUC　(95%　CI)　of　FFRCCT　was　0.819　[0.72,　0.91].　The　accuracy,　specificity,　sensitivity,　positive　predictive　value　and　negative　predictive　value　of　FFRCCT　were　86%,　95%,　62%,　86%　and　83%,　respectively.　Conclusions:　The　closed-loop　multi-scale　model　proposed　in　this　study　can　simulate　the　physiological　cycle　in　a　more　realistic　way.　FFRCCT　is　a　reliable　diagnostic　index　for　myocardial　ischemia.　(C)　2021　Elsevier　B.V.　All　rights　reserved.