Familial hypercholesterolemia is a common genetic disorder with a propensity towards early onset of atherosclerotic cardiovascular disease (CVD). The main goal of therapy is to reduce the LDL cholesterol and the treatment generally consists of statin, ezetimibe and PCSK9 inhibitors. Unfortunately, lowering LDL cholesterol may be difficult for many reasons such as the variation of response to statin therapy among the population or the high cost of some therapies (i.e., PCSK9 inhibitors).
1. Introduction
Cardiovascular diseases (CVD) are still an open public health care issue of the World Health Organization (WHO) since these are the leading causes of death worldwide
[1]. CVD encompasses multiple disorders, including platelet hyperactivity, atherosclerosis, hypertension, stroke, hyperlipidemia, and heart failure
[2]. Hypercholesterolemia (especially elevated low-density lipoprotein cholesterol or LDLc) is one of the main modifiable risk factors (hypercholesterolemia, obesity, diabetes, hypertension, and smoking) which are estimated to be the cause for more than a half of CVD
[3]. The presence of high levels of LDLc predict a much higher risk of CVD such as in individuals affected by familial hypercholesterolemia (FH).
FH is one of the most common inherited metabolic diseases defined by markedly elevated plasma levels of LDLc while off treatment (≥190 mg/dL) and a history of premature atherosclerosis (if heterozygous FH patients are left untreated, it is estimated that 50% of men at the age of 50 years and 30% of women at the age of 60 years, respectively, develop CVD; if homozygous FH patients are left untreated, they develop CVD in early childhood and generally do not survive beyond 30 years)
[4] or CVD
[5]. Another high-risk cohort encompasses individuals with polygenic hypercholesterolaemia, involving single nucleotide polymorphisms (SNPs) that individually have a minor impact, but when combined can significantly increase LDLc blood levels
[6]. FH has been associated with high rates of CVD, stroke and premature death at a very young age
[7].
The susceptibility to CVD differs among patients affected by FH, even when LDLc levels are similar, suggesting that a pathogenic role for CVD may be played by other factors
[8].
2. Coronary Artery Disease and Familial Hypercholesterolemia
The initial clinical manifestation in patients affected by familial hypercholesterolemia may be the occurrence of acute coronary syndrome (ACS) (
Table 1). ACS refers to a group of disorders characterized by decreased blood flow, including ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), and unstable angina. Current literature suggests that the prevalence of FH among individuals who require in-patient care for ACS was about 10 times higher compared with the general population
[24][9]. In a cohort of 105 individuals with very-early-onset coronary artery diseases (<35 years old), the occurrence of FH pathogenic mutations (including
LDLR,
APOB,
PCSK9,
APOE,
STAP1,
LIPA,
LDLRAP1,
ABCG5/
8) was 38.1%
[25][10].
Table 1.
Association between acute coronary syndromes and Familial Hypercholesterolemia.
, meanwhile
PCSK9 may play an interesting role in the process of thrombogenesis. It was observed that
PCSK9 knockout mice have reduced platelet activity and developed less agonist-induced arterial thrombosis compared to the animal control group. Otherwise, elevated blood levels of PCSK9 in humans are associated with an increased platelet reactivity
[39][25]. The breakdown of this blood clotting factor is facilitated by LDLR
[40][26] and PCSK9 inhibitor decreased plasma levels/activity of fibrinogen and plasminogen activator inhibitor 1
[41][27]. As a result, PCSK9 raises FVII. To conclude, the coagulation factors may play a critical role in FH
[42][28]; however, their mechanisms are still unclear.
Lp(a) is a macromolecular complex made up of one LDL-particle molecule covalently bound to an apoB-100 containing polymorphic glycoprotein molecule apo(a)
[43][29]. Apo(a) is characterized by a triple loop-like structure called “Kringle”, similar to other coagulation factors such as plasminogen (PLG) or prothrombin. Lp(a) blocks the plasmin formation competing with PLG for the binding sites on endothelial cells
[44][30]. This process leads to a delay in fibrinolysis, which means an increased ratio of thrombosis
[45][31]. Despite its role in venous thromboembolism, Lp(a) is linked to an increased incidence of CVD and in particular coronary heart disease
[46,47][32][33]. Lp(a) is also an independent risk factor for premature cardiovascular events in the general population due to a pro-atherosclerotic effect of ApoB-100. Its blood concentration is significantly influenced by sex, gender, lifestyle and chronic diseases and it seems that hyperlipoproteinemia (a) enhances the occurrence of atherosclerotic cardiovascular diseases in FH
[48][34]. Alonso et al. studied a population of over than 2000 patients, which includes individuals with or without FH, and it has been shown that FH patients, especially those with history of CVD, had elevated Lp(a) plasma levels. A significant high plasma levels of Lp(a) has been related to null and defective mutations of LDLR. Indeed, the Lp(a) could be considered an independent predictor of cardiovascular disease
[49][35]. Furthermore, higher blood levels of Lp(a) in individuals affected by FH are linked to an elevated occurrence of Lp(a) variants and the risk of CVD is increased twofold when both conditions coexist
[50][36]. Hyperlipoproteinemia(a) has been proven to be a predictor of premature atherosclerotic cardiovascular disease in a cohort of patients affected by FH
[51][37]. Furthermore, the measured blood levels of LDLc consist of aggregating LDL and Lp(a) particles. The cholesterol content of Lp(a) constitutes up to 30–45%; therefore, it is necessary to correct LDLc in order to determine the proportion of Lp(a). A study including more than 500,000 individuals discovered that LDLc was no longer a risk factor for incident cardiovascular disease if the correction of LDLc was implemented
[52][38]. Additionally, high blood levels of Lp(a) lead to elevated risk of myocardial infarction
[53][39]; therefore, a routinely testing of Lp(a) may identify individuals who will develop more premature cardiovascular events
[54][40].
Table 2.
Familial hypercholesterolemia, coagulation factors and lipoprotein a.