Barriers and shortcomings in access to cardiovascular management and prevention for familial hypercholesterolemia during the COVID‐19 pandemic

Abstract Familial hypercholesterolemia (FH) is a hereditary condition caused by mutations in the lipid pathway. The goal in managing FH is to reduce circulating low‐density lipoprotein cholesterol and, therefore, reduce the risk of developing atherosclerotic cardiovascular disease (ASCVD). Because FH patients were considered high risk groups due to an increased susceptible for contracting COVID‐19 infection, we hypothesized whether the effects of the pandemic hindered access to cardiovascular care. In this review, we conducted a literature search in databases Pubmed/Medline and ScienceDirect. We included a comprehensive analysis of findings from articles in English related and summarized the effects of the pandemic on cardiovascular care through direct and indirect effects. During the COVID‐19 pandemic, FH patients presented with worse outcomes and prognosis, especially those that have suffered from early ASCVD. This caused avoidance in seeking care due to fear of transmission. The pandemic severely impacted consultations with lipidologists and cardiologists, causing a decline in lipid profile evaluations. Low socioeconomic communities and ethnic minorities were hit the hardest with job displacements and lacked healthcare coverage respectively, leading to treatment nonadherence. Lock‐down restrictions promoted sedentary lifestyles and intake of fatty meals, but it is unclear whether these factors attenuated cardiovascular risk in FH. To prevent early atherogenesis in FH patients, universal screening programs, telemedicine, and lifestyle interventions are important recommendations that could improve outcomes in FH patients. However, the need to research in depth on the disproportionate impact within different subgroups should be the forefront of FH research.


| INTRODUCTION
Hereditary familial hypercholesterolemia (FH), a rare hereditary condition that causes early atherosclerosis, is characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) in the bloodstream. 1 In order for FH patients to survive, aggressive LDL-C reduction is essential to slow the development of atherosclerosis to minimize the incidence of major cardiovascular (CV) events. 2 Homozygous FH, a more severe form, affects approximately one out of every million individuals, while heterozygous FH is estimated to affect one in 300−500 people 3 ; these statistics suggest that about 10 million people across the globe have FH. 4 The phenotype of FH can vary across ancestries as a result of variable penetrance and expression of genetic mutations causing low-density lipoprotein receptor (LDL-R) defects; for example, FH could potentially occur as a result of pathogenic somatic mutations in the liver or through vertical transmission due to germinal mosaicism. 5,6 The founder effect phenomenon has been used to explain how different populations could have different causes of FH. Africans, Canadians, Lebanese, and Finns have high rates of specific mutations that make FH particularly common in these groups, with high prevalence in the United States. De Ferranti et al. reported prevalence to be between age 60−69 with obese patients more vulnerable to adverse coronary outcomes. 7 As a result, the goal of preventative management is to reduce plasma LDL levels below 5 mmol/L. 8 One of the main concerns regarding patients suffering from FH to contract COVID-19, is that FH was shown to predispose the vascular lining to infectious and immune attacks, thus largely increasing the possibility to develop atherosclerotic cardiovascular disease (ASCVD). 9 This inevitably increases the need to employ continuous and long-term pharmacological intervention, with frequent follow-ups and screening for ASCVD risk. However, this paradigm became obsolete during the COVID-19 pandemic due to its direct and indirect effects on FH care. 10,11 The COVID-19 pandemic has generated significant burdens in health management worldwide, with systems struggling to meet the needs of most individuals with comorbidities. 12 The long-term effects of COVID-19 symptoms and its detrimental impact on CV care pose a major burden in healthcare systems worldwide. The impact of the COVID-19 pandemic has been discussed in multiple conditions needing continuous long-term management, ranging from bariatric surgery patients to individuals with acute myocardial infarction, arrhythmias, and cardiac arrest. [13][14][15] Nevertheless, it is paramount to disseminate the impact of the pandemic on CV prevention in FH patients to improve future risk-stratification protocols and raise awareness amongst clinicians. With the emerging public health concern of FH patients, this review aims to highlight the direct and indirect impact of the COVID-19 pandemic on CV outcomes in FH.
By identifying information gaps in the literature, possible recommendations can be formulated for better intervention and access to CV care.

| THE GENETICS OF FAMILIAL HYPERCHOLESTEROLEMIA
Inherited genetic mutations on chromosome 9 and subsequent enzymatic defects can explain the pathophysiology and causative mechanisms of FH in the LDL-R, such as proprotein convertase subtilisin/Kexin type 9 (PCSK9) and apolipoprotein B 8 (Figure 1).
Clinical studies have accounted for over 1600 genetic defects and mutations of the LDL-R in 90% of patients diagnosed with FH. 1 When such genes are defeated by the uptake of LDL particles, cholesterol levels are also increased, leading to FH. The mechanism of action that leads to FH involves the impairment of the LDL-R synthesis, defects in transport from endoplasmic reticulum to Golgi bodies, binding with LDL, LDL internalization, recycling of LDL-R, defect in the apoB-100 ligand on the LDL and gain-of-function mutations causing increased activity of PCSK9. 16,17 These lead to increased degradation of the LDL-R which reduces LDL clearance from plasma, thereby causing an elevated level of LDL in the serum. 17 Cellular enzymes/inhibitors for example PCSK9 secreted by the liver is vital for degrading LDL-R and inhibiting LDL-R recycling to the cell membrane by binding to it extracellularly to reduce cholesterol levels 18 (Figure 1). Patients with one copy of the defective gene will experience moderate accumulation of plasma LDL while two copies of the defective gene or coexisting mutations will be more extensive due to the lack of LDL removal from plasma. 19 As a result, this could accelerate the onset of CVD, given patients are likely to experience atherosclerotic heart disease at an early age. On the contrary, it is also important to note that mutations that inactivate PCSK9 can cause lower plasma LDL levels and can reduce coronary heart disease (CHD). 20,21 Morbidity following FH begins from a young age after defective genes have been inherited. If early diagnosis and treatment is not implemented, this condition will progress to coronary episodes and can occur between 42 and 64 years or earlier in heterozygous FH patients. 22 33 Evidence toward the use of WES/WGS is still controversial, as there are a lack of novel causative genes that have been strongly identified, with exception to novel mutations in the aforementioned genes. [34][35][36] Although the novel finding of STAP1 involvement in FH is promising, its clinical significance and utility in FH yet to be established. 37

| PREEXISTING CV COMORBIDITIES IN FH INCREASE THE RISK OF COVID-19 INFECTION AND HOSPITALIZATION
Patients who already have ASCVD seem to be more likely to contract COVID-19 and have more severe disease with poorer clinical outcomes. 38 Therefore, there may be a markedly increased risk for and severity of COVID-19 infection in people with FH, particularly those with HoFH, as well as a tendency to develop ASCVD episodes. 39 The entry of the SARS-CoV-2 virus into the host cell via the ACE2 receptor may also be increased in the presence of elevated cholesterol levels, as cholesterol-rich regions of the viral membrane were hypothesized to accelerate spike-mediated cell−cell fusion. 40 Therefore, if they contracted COVID-19, individuals with HoFH may be much more at risk of adverse events than individuals with HeFH. The prognosis of these participants could be morbid, as available studies suggest that a cytokine storm perpetuated by the COVID-19 infection could destabilize atherosclerotic plaque, increasing the risk of suffering a myocardial infarction. 41 Despite long-term cholesterol-lowering medication, HoFH is likewise characterized by a systemic inflammatory phenotype, and the much higher Lp(a) levels reported in HoFH participants (as in HeFH) may increase their risk for atherothrombotic events following viral infection. 42 In the acute phase of the infection, FH patients with  appear to be at a high risk for COVID-19 consequences, and over the long term, they are likely to experience accelerated atherogenesis 39 ( Figure 2). Both HeFH and, in particular, HoFH individuals are expected to have hypercholesterolemia-induced endothelial dysfunction from birth because increased levels of LDL-C are already present prenatally and the degree of dysfunction correlates with serum LDL-C level. 40 Additionally, many FH patients have increased serum Lp(a), an endothelium-damaging lipoprotein variant that poses a significant risk factor for the development of atherosclerosis. Whilst acute coronary syndromes in people with severe COVID-19 seem to be caused by thrombus formation in the epicardial coronary arteries during the acute stage of the disease, dysfunction of the myocardial microvascular endothelium, the coronary microcirculation, and seems to progress during the convalescent and chronic stages of the illness. 43,44 Inflammation and thrombosis from COVID-19 infection can both interact to drive CV risk, which often occur through the surge of pro-coagulation and proinflammatory activity 39 (Figure 2). In addition to this, COVID-19 may cause a continuous acceleration of atherosclerosis overtime. Because FH patients previously carry elevations of LDL-C from birth, a "two-hit" mechanism may explain why the risk of an acute sequelae of COVID-19 infection is attenuated in these patient demographics. 45  substitutions, and postponement of active LDL-C measurements, diagnosed FH cases were poorly managed and also a culprit of increased CVD risk. 55 The fear of COVID-19 infection was an important topic of discussion within the medical community, as the decline in consultations may also be attributed due to fear of patients contracting COVID-19 infection. 56  worsening the already reduced work productivity in those with FH and losing a source of income essential for consistent management.
Moreover, people with low-income status were mostly affected by this displacement from work as their jobs were often not possible for remote services hence reducing their capability to afford necessary medications, diet plans and increased the chances of morbidity. 69 Researchers have hypothesized that the indirect impacts of the COVID-19 pandemic in low-socioeconomic families is due to the inability to recoup lost wages from unemployment, as lower SES were more likely to be impacted by layoffs and the potential loss of employer-provided health insurance. 70,71 Ultimately, the lack of general coverage prevails in low-income households and will only worsen the care of FH due to the inability to meet the financial demands of management during the insecurities perpetuated by the pandemic. 72

| Racial and ethnic minorities disproportionately affected by COVID-19
Over 90% of those affected by FH remain undiagnosed in underrepresented demographics and experience higher frequency of FH due to the founder effect. 73

| Community-wide impacts of social-distancing and lockdown measures on healthcare systems
As with other uncommon diseases, HoFH and HeFH patients require consistent medical care even in the midst of pandemics. As a result of the current COVID-19 crisis, which included social isolation and nation-wide lockdowns, physical activity levels have decreased significantly. 85 Patients with FH are classified as a high-risk patient group during the pandemic, which warranted the government to issue pandemic-related statements to isolate and maintain social distancing. 10  LDL-C reduction was not achieved or due to adverse allergic reactions against these agents. As a result, a further treatment option for FH patients includes PCSK9 inhibitors, which have been proven to be superior compared to other lipid-lowering agents such as resins and ezetimibe. 108 These act to reduce possible CVD events by lowering atherosclerotic plaques. Interestingly, it was shown that PCSK9 inhibitors also have an anti-inflammatory action, also leading to lowered cytokines levels, and clinically with reduced intubation needs and mortality in affected patients. 109 Life-style changes are also considered to improve long-term ASCVD management in FH and are included in various clinical practice guidelines. For instance, the American Heart Association recommends the incorporation of a healthy diet alongside pharmacological management, which includes a higher intake of vegetables and fruit, low fat poultry and dairy products, as well as limited red meats and sweets. 110  processes and a lack of research disseminating its outcomes. 119 The resurgence of ASCVD and hereditary dyslipidemia post-pandemic could potentially overwhelm healthcare resources and the abovementioned limitations, posing as a major public health concern in FH care. 120 As a result, primary care, including preventive measures, and screening must be strengthened.

| FUTURE RECOMMENDATIONS IN THE POST-COVID 19 ERA
There is a continued concern for the financial burden amongst other aspects of the healthcare system to address post-COVID-19 lockdown health-related issues and unmet healthcare needs of patients.
Worse still, the existing healthcare gaps in socioeconomic and