Familial hypercholesterolaemia and COVID-19: triggering of increased sustained cardiovascular risk.

Abstract

Early data from Wuhan, China, show that patients with COVID-19 are typically male, aged 40 to 60 years, and about one-third have comorbidities. Moreover, of 138 COVID-19 patients hospitalized in Wuhan and treated in an intensive care unit (ICU), 25% had cardiovascular disease and 58% hypertension; the respective figures for non-ICU-treated COVID-19 patients were10% and 22% [1]. Based on these early data, a predisposition to acute cardiac complications related to underlying atherosclerotic cardiovascular disease (ASCVD) may significantly increase the severity of COVID-19 in susceptible individuals. Familial hypercholesterolaemia (FH) is an inherited disease with an estimated prevalence of 1 in 250. It is characterized by a lifelong two- to threefold elevation of plasma LDL cholesterol concentration, which if untreated induces premature ASCVD and a markedly increased risk of an acute coronary event in middle-aged FH patients. These epidemiological data suggest that, compared with non-FH patients, FH patients with COVID-19 may be at higher risk of cardiac complications, particularly if the underlying genetic disease has remained undetected. Concern is justified because a high proportion of critically ill COVID-19 patients are under the age of 50. Below this age, clinicians typically overlook the possibility of an increased risk of premature coronary artery disease, even amongst patients with FH in whom subclinical stenosing coronary artery disease may already start to develop during their early 30s. In patients with FH, it is possible that LDL-receptor variants exist which modulate the long-term immune response to COVID-19, as has been shown for hepatitis C infection [2]. Overall, there is increasing awareness of the involvement of host genetic factors in infectious diseases. Coronavirus infections may induce long-term abnormalities in lipid and glucose metabolism, with clear adverse implications for FH patients, and, additionally, chronic Chlamydia pneumoniae infection is associated with an increased risk of coronary artery disease in patients with FH [3, 4]. An important finding is the association between cytomegalovirus antibodies and atherosclerosis, which in the Atherosclerosis Risk in Communities Study was observed in individuals with high levels of lipoprotein(a) and fibrinogen [5]. Such an association may also apply to FH patients who have, on average, higher lipoprotein(a) levels compared with the general population [6] and, therefore, may have a higher risk of an atherothrombotic event whilst suffering from COVID-19 and even after recovery. The potential synergism between viral infection and the resulting hypercoagulability related to increased lipoprotein(a) levels merits further investigation. There are several important considerations when treating an FH patient with COVID-19, including the need to intensify cholesterol-lowering treatment because of potential coronary endothelial dysfunction caused by the viral infection [7]. Statin treatment, the primary LDL cholesterol-lowering pharmacotherapy for patients with FH, may protect against endothelial dysfunction and an acute coronary event and, therefore, should not be discontinued in patients undergoing intensive care, especially those with established coronary artery disease. Because PCSK9 inhibitors effectively lower LDL cholesterol and prevent acute coronary events in FH, their use should also be continued. PCSK9 inhibitors have a good safety profile; however, experience of their use in severely ill COVID-19 patients is limited and worthy of evaluation [8]. Thus, it appears that an FH patient may be more prone to acute complications of COVID-19 than a healthy person of a similar age. In agreement with this notion, the cholesterol charity HEART UK (https://www.heartuk.org.uk/news/coronavirus), in the very recent patient information about COVID-19, has stated that patients with FH and diagnosed heart disease are considered to be at high risk and that elderly FH patients and FH patients with comorbidities such as hypertension, chronic kidney disease or diabetes may also be at high risk. Similar concerns have been raised by the FH Foundation (https://thefhfoundation.org/letter-to-the-fh-community-about-covid-19). Finally, patients with FH are likely to be at increased long-term risk of an atherothrombotic event following COVID-19, as previously observed in FH patients with Chlamydiapneumoniae infection [4] as well as in the general population with influenza or cytomegalovirus infection [5, 7]. Thus, pharmacotherapy for severe hypercholesterolaemia in an FH patient with COVID-19 should not be discontinued during infection and, due to possible excess risk of ASCVD, could even be intensified following recovery from COVID-19. Of importance, however, the potential advantages of intensifying lipid-lowering therapy for FH patients after the first COVID-19 epidemic, and the potential disadvantages of a lack of intensification, need to be explored in future epidemiological investigations. GFW has received research grants and honoraria for lectures and advisory boards from Amgen, Sanofi, Regeneron, Gemphire, Kowa and Arrowhead. PTK has received consultancy fees, lecture honoraria and/or travel fees from Amgen, Novartis, Raisio Group and Sanofi. ALpo Vuorio: Writing-original draft (equal); Writing-review & editing (equal). Gerald Watts: Writing-review & editing (equal). Petri T Kovanen: Writing-review & editing (equal).