Familial hypercholesterolaemia and COVID-19: A two-hit scenario for endothelial dysfunction amenable to treatment

Abstract

Patients with familial hypercholesterolemia (FH) are likely at increased risk for COVID-19 complications in the acute phase of the infection, and for a long time thereafter. Because in FH patients the level of low density lipoprotein cholesterol (LDL-C) is elevated from birth and it correlates with the degree of systemic endothelial dysfunction, both heterozygous FH (HeFH) patients and, in particular, homozygous FH (HoFH) patients have a dysfunctional endothelium prone to further damage by the direct viral attack and the hyper-inflammatory reaction typical of severe COVID-19. Evidence to date shows the benefit of statin use in patients with COVID-19. In FH patients, the focus should therefore be on the effective lowering of LDL-C levels, the root cause of the expected excess vulnerability to COVID-19 infection in these patients. Moreover, the ongoing use of statins and other lipid-lowering therapies should be encouraged during the COVID pandemic to mitigate the risk of cardiovascular complications from COVID-19. For the reduction of the excess risk in FH patients with COVID-19, we advocate stringent adherence to the guideline determined LDL-C levels for FH patients, or maybe even to lower levels. Unfortunately, epidemiologic data are lacking on the severity of COVID-19 infections, as well as the number of acute cardiac events that have occurred in FH subjects during the COVID-19 pandemic. Such data need to be urgently gathered to learn how much the risk for, and the severity of COVID-19 in FH are increased.

Keywords: COVID-19; Endothelial dysfunction; Familial hypercholesterolemia; PCSK9 inhibitors; Statins.

Fig. 1

The diagram shows a two-hit scenario for the development of clinical cardiovascular disease in patients with familial hypercholesterolemia (FH) and COVID-19. Among the aggravating factors are two chronic effectors associated with FH and two acute effectors associated with the SARS-CoV-2 infection. Jointly, these factors induce strong endothelial dysfunction, vascular inflammation, and a procoagulant state, which tend to trigger thrombus formation both at the microvascular level and the macrovascular arterial level (endothelial erosion or plaque rupture). In patients with FH and COVID-19, thrombosis in intramyocardial microvessels or atherosclerotic epicardial coronary arteries would lead to myocardial damage, as already documented in COVID-19 patients with other cardiovascular/cardiometabolic comorbidities. When a thrombus evolves at a critical site of an atherosclerotic extracranial or intracranial cerebral artery, an athero-embolic brain infarction may ensue. In all mentioned patient categories, the endothelial cells are not only among the primary cellular targets of the shown aggravating factors but also among the primary targets for preventive measures. Among such preventive/therapeutic strategies is lowering of the levels of LDL-cholesterol and lipoprotein (a) by hypolipidemic drugs which can act as adjunctive disease-mitigating pharmacotherapies at all stages of COVID-19 in FH patients.