The Cardiovascular Component of COVID-19
When Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of Corona Virus disease 2019 (COVID-19), became an emerging clinical emergency the initial approach was to treat this novel pathogen as a respiratory disease typical of other coronaviruses. It became quickly apparent that the clinical manifestations of COVID-19 were not limited to the respiratory system. As we move forward today, the need to understand all clinical aspects of COVID-19 still remains. 29% of patients admitted into hospital with COVID-19 were readmitted within six months of discharge from hospital. Of those readmitted, 29.8% had a new respiratory diagnosis and 4.8% had a major adverse cardiovascular event including either heart failure, myocardial infarction, stroke or arrhythmia. Furthermore, when a group of 7,500 Covid patients were followed for up to 18 months it was found this group, compared to uninfected people, were around 40% more likely to develop cardiovascular disease and five times more likely to die during the study period. People who had experienced severe infection were at an even higher risk.
The link between COVID-19 and the cardiovascular system is not fully understood, with continued research analysing the interactions between the respiratory epithelium (the cell lining of the lungs) and endothelial cells (the innermost layer of blood vessels). In a healthy individual the vascular endothelium, provides a dynamic interface between the circulating blood and the organs and tissues of our body. Physiological functions of the endothelium include fine control of vascular tone (vasodilation and vasoconstriction of vessels), tissue haemostasis, barrier integrity, regulation of inflammation, oxidative stress and vascular permeability. A key aspect in all cardiovascular disease is endothelial dysfunction, where the endothelial cells become damaged and no longer function correctly to enable blood flow through our blood vessels. Endothelial dysfunction is generally defined as decreased amounts of the vasodilation activator nitric oxide (NO) bioavailability and an increase in vasoconstrictors. The definition has expanded to further include oxidative stress, inflammation, leukocyte adhesion, endothelial to mesenchymal transitions (EndoMt) of endothelial cells, mitochondria dysfunction, senescence and deregulated endothelial cell metabolism. Multiple biomarkers indicative of endothelial activation and dysfunction have been found in COVID-19 patients with severe disease. There have been three main theories on the disease mechanisms that result in endothelial dysfunction in COVID-19 infections.
Initially investigations focused on the role of angiotensin-converting enzyme 2 (ACE2). ACE2 is a key regulator of the renin-angiotensin-aldosterone system that regulates our blood pressure. ACE2 is also the cell surface protein through which SARS-CoV-2 enters the cells via the SPIKE protein. ACE2 was found at much higher concentrations in the lungs of patients that died from COVD-19 compared to influenza patients as healthy controls. There was also a significant and unique pattern of endothelial damage in the lung capillaries of COVID-19 patients. Endothelial cells from COVID-19 patients showed disrupted intercellular junctions, cell swelling and a loss of contact with other integral components of the blood vessels including the basement mebrane. ACE2 is likely to play a role in the initial stages of endothelial dysfunction. ACE2 is used by SARS-CoV-2 for cellular internalization, however, during cellular internalisation SARS-CoV-2 blocks ACE2 activity and reduces the enzyme expression in the membrane. It is hypothesised that this induces an imbalance in the renin–angiotensin–aldosterone system regulating our blood pressure causing an ACE/ACE2 imbalance. This ACE/ACE2 imbalance results in an increase in inappropriate vasoconstriction, narrowing of the blood vessels, triggering the initial stages of endothelial dysfunction. This vasoconstriction is also thought to have further implications for disease progression, particularly when patients progress to produce large amounts of inflammatory cytokines- a cytokine storm.
Another possibility has examined the role of inflammation triggering indirect damage to the blood vessels. Pulmonary epithelial cells infected with SARS-CoV-2 produce increased amounts of proinflammatory cytokines and chemokines that have been associated with vascular leakage during COVID-19 infections. This release of cytokines and chemokines from the pulmonary epithelium is thought to travel through the body and then act on endothelial cells triggering an upregulation of adhesion molecules and immune cell recruitment.
It is also thought that the body’s own immune cells could cause direct damage to endothelial cells. During COVID-19 infections, increased recruitment of immune cells to the endothelial cells is observed. This increased immune cell recruitment is considered to occur either directly due to viral infection of endothelial cells or via signals from other cells such as pulmonary epithelial cells. Once recruited, the immune cells initiate programmed cell death in numerous endothelial cells and trigger widespread endothelial dysfunction.
The cardiovascular implications and endothelial damage are not just part of the initial COVID-19 infection. Patients suffering from long Covid can also exhibit endothelial dysfunction and altered endothelial cell markers.
As we continue to improve clinical treatments of COVID-19, current clinical trials that address the cardiovascular component of the disease include administering the statin atorvastatin, a compound with anti-inflammatory properties, after discharge from hospital. Another trial is focused on testing ACE inhibitors, in view of addressing both direct viral infection as well as the imbalance in vasoconstriction discussed above.
Increasing our understanding on the mechanisms that trigger endothelial damage during COVID-19 infections and identifying suitable therapeutics can only help improve the outcomes for COVID-19 patients.