CARDIOVASCULAR COMPLICATIONS OF BETA-CORONAVIRUS INFECTION: INTEGRATING MOLECULAR MECHANISMS AND IN VIVO OUTCOMES

In beta-coronavirus infections the occurrence of cardiovascular complications is associated with poor disease outcomes, high mortality rates, and long COVID. At this conference, we will present data from our group on lethal and long COVID. Our research focused on studying the molecular mechanisms underlying cardiovascular dysfunction and the associated in vivo cardiovascular complications of the disease. The beta-coronavirus MHV-3 and SARS-CoV-2 were used as models for the lethal disease and the beta-coronavirus MHV-59 was used to induce long COVID. In wild-type C57BL/6 mice, MHV-3 given nasally infected the vascular endothelium and reduced aorta and vena cava contractility, cardiac output, arterial blood pressure and blood flow, resulting in death. Resistance mesenteric arteries showed increased contractility. In the aorta, contractility was normalized by removal of the endothelium, inhibition of iNOS, genetic deletion of iNOS, or scavenging of NO. Additionally, iNOS and phospho-NF-kB p65 subunit expressions were enhanced, along with an increase in basal NO production. TNF production was augmented in plasma and vascular tissues. Genetic deletion of TNFR1 prevented aorta and vena cava contractile changes, and death. Basal NO production and iNOS expression were also increased by SARS-CoV-2 infection in K18-hACE2 transgenic mice expressing human ACE2. On the other hand, MHV-59 given nasally to C57BL/6 mice was not lethal. However, after the pulmonary disease and clinical symptoms had been resolved, the animals developed a time-dependent and long-lasting endothelium-dependent increase in vascular contractility and hypertension. In conclusion, this study showed that in two animal models that reproduce lethal COVID-19, beta-coronavirus infection causes severe contractile dysfunction in macro- and micro-arteries, and veins, associated with circulatory failure, decrease in cardiac output, hypotension, poor blood supply to organs and death via a TNF/NF-κB/iNOS/NO-dependent pathway. The present findings emphasize the crucial role played by the vascular system in beta-coronavirus lethality and the potential role of TNF in clinical applications. Long COVID, on the other side, was associated with increased vascular contractility and hypertension. Since cardiovascular diseases represent the largest cause of morbidity and mortality worldwide, long COVID has the potential to become a serious public health problem in the near future.