Abstract RATIONALE Chronic COVID-19 affects an estimated 6.9-16.3% of the reported 423 million infected people. Translational models are being developed to further understand chronic COVID-19. Studies have exposed transgenic mice to SARS-CoV-2 live virus, but is hampered by costly logistic burdens associated with BSL3 facilities. A non-infectious model of chronic COVID-19 may facilitate research more efficiently. We investigate the cardiopulmonary and inflammatory changes after a one-time exposure of COVID-19 spike protein in K18-hACE transgenic mice to create a potential murine model of non-infectious chronic COVID-19. METHODS Male and female K18-hACE mice (N=7/group) that were at least 12-weeks old had single oropharyngeal aspiration of either COVID-19 spike protein (Raybiotech) or buffer control diluted in saline at a dose of 400µg/kg in 2mL/kg body weight. After 12 weeks, echocardiography (VisualSonics Vevo 3100; Fujifilm) was performed with a 40-MHz probe (MX 550D). B(brightness)-, M(motion)- mode, and pulse wave doppler images in parasternal long/short axis views were obtained. Mice were then tracheotomized and pulmonary function was assessed (Flexivent; Scireq). Plasma was collected by cardiac puncture, analyzed for 32 cytokine/chemokines (Millipore), and assayed on a Luminex 200. RESULTS Cardiac Function: Chronic COVID-19 mice compared to controls had significantly lower aortic ejection time (AET) mean±SD (43.33±1.00 vs 48.61±3.13), lower left ventricular internal diameter-systolic (LVID-s) (1.07±0.06 vs 1.89±0.42), higher ejection fraction (EF) (89.62±73.17 vs 73.17±4.81), p<0.05 by Kruskal-Wallis. There was no difference in mean pulmonary artery pressure or pulmonary artery velocity time integral. COVID-19-exposed mice also trended toward having LV wall thickening, p=0.063. Pulmonary Function/Plasma Biomarkers: Forced expiratory flow in 0.05s was significantly lower in COVID-19 vs control (2.83 ±2.52 vs 7.43±1.46) respectively, p=0.038. Chronic COVID-19 showed significantly higher levels of IL-13 (25.92±6.60 vs 11.51±5.60 pg/mL), p=0.029, and RANTES (7.67±3.68 vs 1.27±1.19) than control, p=0.034. CONCLUSIONS Our attempted model of chronic COVID-19 using spike protein is characterized by left ventricular wall thickening, changes in expiratory flow, and induced cytokines. Our translational model aligns with COVID patients that have reported persistent inflammation and airway hyperreactivity and obstructive disease. However, cardiac abnormalities are often characterized by right sided heart failure and decreased EF, which differs from our model. One hypothesis could be that more time is needed to develop eventual reduced EF and subsequent right-sided disease. Increasing sample size and assessing the impact of sex could reveal different phenotypes of chronic COVID-19. Future studies will also focus on histologic comparisons of cardiopulmonary disease to optimize the model.