Prevention of endothelial dysfunction and thrombotic events in COVID-19 patients with familial hypercholesterolemia.

The importance of dyslipidemia medications in patients with coronavirus disease 2019 (COVID-19) is currently not sufficiently recognized in the prevention of thrombotic events. This is especially true for COVID-19 patients with familial hypercholesterolemia (FH), a genetically determined form of hypercholesterolemia.

FH is the most common genetic cause of cardiovascular disease, with an estimated worldwide prevalence of 1 in 250. The lifelong highly elevated serum LDL cholesterol (LDL-C) concentration leads to a strongly increased risk of a premature atherosclerotic cardiovascular disease (ASCVD) event. The persistent high level of LDL-C also causes endothelial dysfunction already in young children, and there is a positive correlation between serum LDL-C and severity of endothelial dysfunction in children with FH. , Moreover, Charakida et al. found that plasminogen activator inhibitor 1 levels were higher in children with FH and were associated with the concentrations of both total cholesterol and lipoprotein(a) [Lp(a)], the latter of which, besides carrying cholesterol into atherosclerotic lesions, also possesses direct proinflammatory and atherothrombotic features. Thus, in patients with FH, throughout their lives, the vascular endothelium is exposed to metabolic abnormalities, notably high plasma LDL-C and Lp(a) levels, which are associated with endothelial dysfunction.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects humans via angiotensin-converting enzyme 2 receptors, which are expressed primarily in endothelial cells. Analysis of in-hospital deaths among COVID-19 patients has confirmed that previous ASCVD associates with increased mortality. Of note, SARS-CoV-2 causes endotheliitis (ie, inflammation particularly of the microvascular endothelium), which may be related to systemic impairment of microcirculatory function and lead to activation of the coagulation cascade. Indeed, COVID-19 patients suffer from the formation of microthrombi, which is potentially even more prevalent in FH patients with pre-existing endothelial dysfunction caused by the lifelong elevated serum LDL-C and Lp(a) levels.

FH patients with diagnosed ASCVD usually need a combination of a statin and a PCSK9 inhibitor to achieve very low LDL-C target levels. Regarding FH patients with COVID-19, it is noteworthy that statins decrease serum D-dimer levels by about 15%, and PCSK9 inhibitors decrease the level of the atherothrombogenic Lp(a) by about 30%. , Accordingly, statin-PCSK9 inhibitor dual therapy has the potential to decrease two factors underlying the increased risk of thrombotic complications in COVID-19, and FH patients suffering from COVID-19 should receive maximal cholesterol-lowering therapy also for this reason. In particular, the unique feature of statins as mild anticoagulants and the demonstrated favorable prognosis in hospitalized COVID-19 patients on statin therapy favor such conclusion.