March 22-28 2021
How do we prevent heart disease linked to COVID-19?
Infection by SARS-CoV-2 causes heart damage or abnormalities in 20 to 30% of hospitalized patients and increases the risk of death in those with a history of heart disease. Unfortunately, we do not know enough about how this comes about. Amongst possible explanations, we know that some pro-inflammatory cytokines such as the TNF (Tumor Necrosis Factor), of which levels are extremely high following the hyper-inflammation that occurs in severe cases of COVID-19, can cause heart disease. Hyper-inflammation may also cause septic shock due to the presence of bacteria in the blood, which is known to lead to cardiac dysfunction.
Researchers in Australia at the Berghofer Medical Research Institute have recently identified those components that regulate cardiac function specifically targeted by COVID-19-related hyperinflammation.
They used an organoid model (3D cell culture mimicking physiological cell organization) created from cardiac stem cells, endothelial cells (located inside blood vessels) and pericytes (located below the endothelium). By comparing blood samples from COVID-19 patients, they tested combinations of cytokines that best reproduce cytokine storm conditions occurring during hyperinflammation. In order to evaluate the effects, they carried out so-called “high-throughput” analyses of phosphorylated proteins (phosphoproteomics) and sequencing of expressed genes (single nuclei RNA-seq).
The results show that the “CS” mixture [cytokine storm, IFNg+IL-1+poly(I :C)] causes changes in the diastolic function: when the heart relaxes between two contractions and fills up with blood, the relaxation time increases from between 20 to 50%. The TNF induces systolic dysfunction, that is, during the heart’s contraction. This correlates with clinical observations and validates the model’s pertinence. At the molecular level, the CS causes strong upregulation of STAT1 and the epigenetic regulator BRD4 (bromodomain 4). Serpin1, which blocks blood clot dissolution, is overexpressed 2.8-fold in the heart, similar to the cardiac micro-thrombosis seen in nearly one-third of patients who have died from COVID-19.
So what are the therapeutic perspectives? After having evaluated the effects of several components, the researchers showed that Bromodomain Extra-Terminal (BETi) inhibitors are effective in blocking all the effects resulting from the CS. The BETi reduce the expression of ACE2 (the SARS-CoV-2 receptor) and consequently the infection of cardiac cells. In mouse-based models, the INCB054329 inhibitor (the most effective) blocks those cardiac dysfunctions induced by SARS-CoV-2. This effect can also be observed using the blood samples of COVID-19 patients (containing elevated doses of pro-inflammatory cytokines) or with lipopolysaccharides (LPS, bacterial components causing severe inflammation).
However, certain BETi have secondary effects, but others such as Apabetalone, which proved effective in this study, have an already established clinical safety profile and are currently in development. These molecules are promising for the treatment of cardiac problems that are linked to COVID-19, as well as to other illnesses involving chronic inflammation such as diabetes and obesity.