COVID-19 pathophysiology may be driven by a loss of inhibition of the Renin-Angiotensin-Aldosterone System

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is ongoing. SARS-CoV and SARS-CoV-2 both enter human cells using the cell surface angiotensin-converting enzyme 2 (ACE2) as a receptor. SARS-CoV downregulates ACE2, with a subsequent increase in angiotensin II (ANGII) levels, which potentially creates a disruption akin to overactivating the Renin-Angiotensin-Aldosterone System (RAAS). Studies report high ANGII levels in ICU patients with COVID-19, along with an association of poorer clinical outcome.

Current clinical management guidelines for COVID-19 are mainly centered around the assumption that SARS-CoV-2 directly results in an acute lung parenchymal disease such as acute respiratory distress syndrome (ARDS) and/or high levels of cytokines leading to a cytokine-release syndrome. Many clinical trials are ongoing, some of which include targeting components of the RAAS. We initiated this study to investigate the impact of a disturbance in RAAS on the observed pathophysiology of COVID-19.

In a retrospective cohort of RT-PCR positive COVID-19 patients (n=292) who underwent computed tomography pulmonary artery angiography (CTPA) we found signs of elevated pulmonary artery (PA) pressure in 60%. A subcohort of the patients also performed echocardiography, which revealed an increased PA pressure in all patients (n=38). Using MRI, we demonstrate severe pulmonary blood perfusion disturbances in one patient with COVID-19. Furthermore, invasive pressure measurement in another patient demonstrated an increased PA pressure. To understand more about the underlying mechanisms, we developed swine models where we either “accelerate” the RAAS by infusion of ANGII or use low-dose ANGII in combination with a ACE2-blocker to simulate a “loss of brake” or a combination of blocker and supraphysiological ANGII levels. All lead to a pathophysiological syndrome very similar to COVID-19 with regards to MRI lung perfusion, echocardiography as well as physiological, histological and biochemistry markers. Finally, we use this pathophysiological COVID-19 large animal model, without viral infection, to test treatment with an angiotensin receptor blocker and low molecular weight heparin. We demonstrate a significant reduction in pulmonary artery pressure and a significant improvement in pulmonary blood perfusion as measured by MRI.

In conclusion, in a large animal models of RAAS imbalance, we demonstrate similar findings as in COVID-19 patients. This supports our hypothesis that COVID-19 is a vascular syndrome in a hypercoagulable state. Our results are translations between large animal models and the clinical presentation of COVID-19-patients. The model with low-dose ANGII and ACE2-blocker can be used for evaluation of potential drug candidates for COVID-19.