Atherosclerotic cardiovascular diseases (ASCVDs) comprising coronary heart disease, cerebrovascular disease, peripheral artery disease and aortic disease are common diseases affecting a huge number of patients worldwide (Virani et al., 2021). Low-density lipoprotein cholesterol (LDL-C) is an important risk factor for ASCVD, and familial hypercholesterolemia (FH) is a common, inherited disease (Hu et al., 2020) characterized by high levels of LDL-C from birth. FH could be considered a model disease for studying the pathophysiological effect of LDL-C (Domanski et al., 2020). Therefore, any diseases associated with increased LDL-C levels would be expected to be overrepresented among FH patients.

A recent editorial by Khera and Hegele asked the seemingly unnecessary question—“What Is Familial Hypercholesterolemia, and Why Does It Matter?”. Different definitions of FH lead to different groups of patients being identified as having FH (Khera and Hegele, 2020).There are several clinical scoring systems aiming to diagnose FH including the MedPed Criteria (MedPedProgram, 2005), the Simon Broome Register criteria (Group, 1991) and the modified Dutch Lipid Clinic Network score (Betteridge, 2000). These scoring algorithms for FH are useful for identifying individuals at high risk of ASCVD, but it has become evident that most individuals who meet the clinical criteria for probable or definite FH diagnosis do not have a mutation causing FH (Lee et al., 2019). However, those with a pathogenic FH mutation causing high LDL-C levels align with the classical concept of FH as a monogenic autosomal genetic disease (Khera and Hegele, 2020). Trinder et al. have clearly shown that mutation-positive FH patients, have increased risk of cardiovascular disease when compared to those with polygenic hypercholesterolemia (Trinder et al., 2019). Different criteria for FH create a knowledge gap for uniform risk assessment. Our aim with this article is to describe the risks associated with patients with a confirmed genetically verified pathological FH mutation.

In this review, we aim to summarize the literature on the risk for the various forms of ASCVD in subjects with a genetically proven FH-mutation (FH+).

In the present European guidelines for management of dyslipidemias, FH individuals are categorized as individuals at high-risk of disease by default, and in primary prevention treatment goals are at least a 50% reduction from baseline in LDL-C down to <1.8 mmol/L or <1.4 mmol/L depending on the global risk burden (Mach et al., 2019). However, very few patients with FH + reach treatment target even on maximal treatment with statins and ezetimibe and the risk of ASCVD remain high in FH + compared to controls (Arnesen et al., 2020). Use of PCSK9-inhibitors in addition to statins and ezetimibe can bring LDL-C down in many FH + patients, but its use is limited by high cost (Attipoe-Dorcoo et al., 2021). Also newer treatment options have been introduced including evinacumab, a monoclonal antibody inhibiting the angiopoetin-like 3, a hormone regulating the lipoprotein lipase (Raal et al., 2020).

Then we also included our and other groups published papers on FH + on a wide range of cardiovascular and other diseases of the heart and vessels including; coronary heart disease, cerebrovascular disease, peripheral artery disease, aortic disease, ASCVD mortality, heart failure and atrial fibrillation and aortic valve stenosis.

We searched PubMed using the search string “[(familial hypercholesterolemia AND cvd AND mutation)” or “(familial hypercholesterolemia AND cvd AND genotyped)”]. No limitation for search period was used. Date of search was 1 July 2021. We identified 132 papers that were reviewed by two authors (KR and AH) to identify the inclusion criteria which were 1) a confirmed pathogenic FH mutation in more than 90% of the study population, 2) heterozygous FH only, not homozygous, 3) CVD outcomes clearly reported, 4) English language, 5) studies reporting on quantitative data, not qualitative studies, and not single case reports. Review articles and letters to the editor were also excluded. Nine articles on CVD in mutation positive FH were included and discussed below. The references of these articles were then reviewed to identify additional studies and we also performed hand searches of papers in our collections and the reference lists of extensive review articles.

Then we also included our and other groups’ published papers on FH + on a wide range of cardiovascular and other diseases of the heart and vessels including; coronary heart disease, cerebrovascular disease, peripheral artery disease, aortic disease, ASCVD mortality, heart failure and atrial fibrillation and aortic valve stenosis. Lastly, we explore the spectrum of ASCVD in mutations positive FH patients, utilizing data from the Norwegian Register of FH+. In 2021, this register reported to have identified 264 different mutations to cause FH, of which 94.0% is in the LDL-receptor gene. Two mutations in the APOB gene (5.4%) and three mutations in the PCSK9 gene (0.6%) have been found to cause FH.

(Table 1) Receptor negative FH, in which there are no detectable LDL-receptor activity, was compared to receptor defective mutations, in which there are some LDL-receptor activity, and no difference in atherosclerotic disease assessed by measurement of intima-media thickness with carotid ultrasound and coronary calcification by CT spiral scan was found (Brorholt-Petersen et al., 2002).

When FH + patients was compared to unaffected relatives, the LDL receptor mutation type only partially contributed to the risk of future CVD (Umans-Eckenhausen et al., 2002).

When genotype-phenotype interactions were studied in FH + children the CVD risk in the parents was dependent on type of mutation (b).

In FH + patients, the presence of tendon xantomas was associated with increased risk of CVD (Civeira et al., 2005).

Small, dense LDL-particles in FH + patients were more prominent in patients with CVD (Soška et al., 2012)

Patients with severe FH + defined as LDL-C >8.0 mmol/L had increased risk of CVD with an adjusted hazard rate of 1.25 (Besseling et al., 2014) compared to those with lower LDL-C.

Using genetic risk scores in FH + patients, further enhanced prediction of CVD (Paquette et al., 2017). Also, recently, the same group has documented that rs17609940 variant of the ANKS1A gene is associated with increase in CVD events in FH + patients (Fantino et al., 2021).

Very recently, data from the prospective French and Spanish FH registries were combined, and 1624 patients with both FH+ and a coronary artery calcium score were included, and they established a high risk of future ACVD if the calcium score was above 100 (Gallo et al., 2021).

In 3162 FH + patients compared to the general Norwegian population, we found that the risk of peripheral artery disease was nearly tripled in the FH group compared to controls in both women and men (Mundal et al., 2020).

Pereira et al. also demonstrated an increased risk of peripheral artery disease in FH (90% FH+) patients with a mean age of 51 years compared to normolipidemic persons, with a prevalence of peripheral artery disease assessed by ankle-brachial index of 17.3 vs 2.3% respectively, the patients were older in the FH group, and there was more diabetes in the FH group, however there was a higher prevalence of smokers in the control group (Pereira et al., 2015).

In a study investigating presence of comorbidities at time of death among 79 mainly FH + patients, 39% of the patients had peripheral artery disease (diseases of arteries, arterioles and capillaries) at time of death at mean 60 years of age (Krogh et al., 2016).

The SAFEHEART registry with 2752 FH + patients with a mean age of 44 years upon enrollment was compared to 993 unaffected relatives showed 39 cases of any peripheral artery disease in the FH group compared to two cases in the control group, and 14 cases of peripheral artery revascularization in the FH group, compared to none in the control group (Pérez de Isla et al., 2016).

Indeed, these studies suggest that the risk of peripheral artery disease is increased in FH, and accordingly, increased LDL-C burden during life should be considered a risk factor for this kind of ASCVD.

We have recently demonstrated an increased risk of aortic disease including abdominal aortic aneurisms in FH + men, but not in women (Mundal et al., 2021). LDL-C is thought to be a risk factor for aortic aneurisms, and a Mendelian randomized trial suggests that predicted LDL-C increase the risk of aortic aneurisms (Allara et al., 2019). In 79 patients mainly mutation positive FH patients, 14% of the patients had presence of aortic aneurysm at time of death at mean 60 years of age (Krogh et al., 2016).

Clinicians should be aware of the excess risk of almost all kind of ASCVD in FH+, and the neutral risk of stroke need to be studied further in FH + patients. Clinicians should suspect an FH diagnosis in patients with high levels of LDL-C (>5.0 mmol/L in adults), and a family history of premature ASCVD. Fewer FH patients have xanthoma now compared to earlier times, as many are treated with lipid lowering drugs, however without knowing of the FH diagnosis. Further, as the number of treated FH patients increases, there will be less ASCVD in the parent generation which weakens the accuracy of the clinical scoring systems for FH. In emergency rooms and coronary care units, FH patients may present with early onset coronary artery disease, and an FH diagnosis should be suspected in young patients with high LDL-C. In suspected FH, genetic counselling and testing should then be offered to establish treatment and to perform cascade testing if a mutation is demonstrated. Early detection and correct treatment are paramount in reducing the risk of ASCVD among FH + patients.