Kozue Murata,1,3 Akiko Makino,2 Keizo Tomonaga,2,* and Hidetoshi Masumoto1,3,4,*

Patients with chronic cardiomyopathy may have persistent viral infections in their hearts, particularly with SARS-CoV-2, which targets the ACE2 receptor highly expressed in human hearts. This raises concerns about a potential global heart failure pandemic stemming from COVID-19, an SARS-CoV-2 pandemic in near future. Although faced with this healthcare caveat, there is limited research on persistent viral heart infections, and no models have been established. In this study, we created an SARS-CoV-2 persistent infection model using human iPS cell -derived cardiac microtissues (CMTs). Mild infections sustained viral presence without significant dysfunction for a month, indicating persistent infection. However, when exposed to hypoxic conditions mimicking ischemic heart diseases, cardiac function deteriorated alongside intracellular SARS-CoV-2 reactivation in cardiomyocytes and disrupted vascular network formation. This study demonstrates that SARSCoV-2 persistently infects the heart opportunistically causing cardiac dysfunction triggered by detrimental stimuli such as ischemia, potentially predicting a post COVID-19 era heart failure pandemic.