ETD

• animal model
• atherosclerosis
• Cardiovascular disease
• Golden Syrian Hamster
• SARS-CoV-2 Infection

The COVID-19 pandemic has revealed an important link between SARS-CoV-2 infection and the cardiovascular system. It is now clear that the virus can directly affect not only the respiratory tract but also the cardiovascular system, increasing the risk of diseases such as myocardial infarction and stroke for up to one year after infection. Patients with pre-existing cardiovascular conditions, such as atherosclerosis, are known to have a worse prognosis and a higher rate of complications during COVID-19. Autopsy studies from patients who died from COVID-19 have shown the direct presence of the virus in coronary arteries, mainly in atheromatous regions rich in macrophages. These findings suggest that SARS-CoV-2 can infect the vascular wall, enhancing inflammation and contributing to plaque progression. However, the lack of an animal model that can reproduce both atherosclerosis and SARS-CoV-2–related cardiovascular infection has so far limited the study of the molecular mechanisms behind these effects.
The aim of this work was to develop and validate an experimental animal model able to study, at the same time, the effects of SARS-CoV-2 infection and atherosclerosis. For this purpose, two animal models were tested: the transgenic hACE2 GREAT-GEMM mouse and the Golden Syrian hamster. Both were fed a Western diet and received an intraperitoneal injection of AAV8-hPCSK9 to induce hypercholesterolemia and atherosclerotic lesions. Then, animals were infected intranasally with the SARS-CoV-2 USA-WA1/2020 strain and analyzed at different time points after infection.
In the mouse model, although a strong hypercholesterolemia was successfully induced, the infection remained limited to the lungs, with no evidence of cardiovascular involvement. For this reason, this model was considered unsuitable for the purpose of the study. On the other hand, the Golden Syrian hamster proved to be naturally susceptible to infection, without the need for genetic modification, and developed clinical and pathological changes similar to those seen in humans. The virus was found not only in the lungs and heart but also in vascular tissues, with active viral replication detected in the aorta at three days post-infection and viral clearance at ten and thirty days. From a metabolic point of view, hamsters with atherosclerosis showed significantly higher cholesterol levels compared to controls, as well as a higher lung viral load in the acute phase. Histological analysis revealed an increased lipid content in the plaques of infected hamsters, with a peak at ten days post-infection, when the virus was already cleared from the tissues. This suggests that infection can have delayed and indirect effects on plaque composition, possibly due to persistent inflammation or virus-induced lipid metabolism changes. In contrast, collagen content did not show significant differences, in line with the early-stage nature of the lesions in this model, which are mainly characterized by “fatty streaks.”
Overall, the Golden Syrian hamster represents the first validated animal model able to reproduce both atherosclerosis and SARS-CoV-2–related cardiovascular infection. This model offers several advantages: it is naturally susceptible to the virus, shows sex differences similar to humans, develops atherosclerosis in a reproducible way, and allows the study of both acute infection and long-term cardiovascular effects.
In conclusion, this study provides a new experimental tool to explore the cardiovascular complications of COVID-19. The Golden Syrian hamster model can help to better understand how viral infection interacts with atherosclerosis, to test possible therapeutic strategies, and to clarify the role of SARS-CoV-2 as a long-term cardiovascular risk factor in the general population.