Challenges in reducing atherosclerotic inflammation in patients with familial hypercholesterolemia

For several decades, hypercholesterolemia and inflammation have emerged as critical determinants of athero-genesis and athero-progression by experimental, clinical and epidemiological studies.1 In animal models of atherogenesis, targeting those variables resulted in beneficial effects in all stages of disease. Recent clinical trials targeting hypercholesterolemia2 and inflammation3 also indicated potential translation into clinical practice. Hypercholesterolemia and inflammation may be then considered as ‘two sides of the same coin’. As a consequence, optimal prevention and treatment strategies should target both processes.4,5 Nevertheless, the role of inflammation in patients with familial hypercholesterolemia (FH) – a rather frequent genetic disease characterised by increased levels of circulating atherogenic lipoproteins6 – still remains unclear. This is mainly due to the low number of clinical studies focused on those settings of patients. Even pooled analyses have only provided preliminary consideration, thus leaving room for a potential difference between human and animal models. In both heterozygous and homozygous FH forms, genetic background is supposed to determine an accelerated atherogenesis, starting in childhood and resulting in the premature development of clinically overt atherosclerotic disease. Probably triggered by hypercholesterolemia, atherosclerotic inflammation is supposed to start early in these individuals. Children with FH show monocytosis with increased pro-inflammatory monocyte subpopulations as compared to healthy controls. Also, circulating monocytes appear more activated (high integrin expression) in FH children as compared to controls. Such activation is even more pronounced when FH children show low levels of high-density lipoprotein cholesterol.7 Furthermore, epigenetic reprogramming has been recently been shown to modulate inflammatory processes in FH patients. In particular, a unique miRNA profile has been identified in those patients, determining an increased monocyte reactivity and upregulated chemokine expression in macrophages (CCR3, CCR4 and CXRR1).8,9 When surrogate markers of atherosclerosis and systemic inflammation were considered, children with heterozygous FH have increased carotid intima-media thickness (IMT), serum levels of C-reactive protein (CRP) and P-selectin, as compared to healthy controls. However, only P-selectin was demonstrated as independently associated with carotid IMT in dyslipidaemic children, thus suggesting a potential selective activation of specific inflammatory pathways in this population.10 Further investigating the endothelial dysfunction, a case–control study enrolling 38 children with FH and 41 healthy controls showed a significant increase in circulating levels of plasminogen activator inhibitor 1, intercellular cell adhesion molecule 1 and interleukin 1β in FH children.11 As only plasminogen activator inhibitor 1 is independently associated with endothelial dysfunction (assessed by strain gauge plethysmography) in children with FH, a minor role for inflammation in this initial atherosclerotic phase in this setting was suggested.11 In adult patients with FH, high circulating levels of some pro-atherosclerotic cytokines (i.e. tumor necrosis factor alpha), acute-phase protein (i.e. CRP) and matrix metalloproteinase 9 were found as compared to controls,12,,–15 without clear relationships with clinical atherosclerotic outcomes. Importantly, the potential impact of different treatments targeting FH in reducing atherosclerotic inflammation was also investigated. The use of lipid-lowering drugs (i.e. statins) still remains the cornerstone of all international guidelines for the management of dyslipidemia16,17 as a result of their well-known lipid-lowering as well as lipid-independent pleiotropic effects.18,,–21 In a placebo controlled study enrolling 207 children with heterozygous FH, treatment with pravastatin was able weakly to reduce systemic inflammatory mediators as compared to placebo without affecting serum CRP levels. The authors coherently concluded that the well-known anti-inflammatory effects of statin treatment might be less relevant in children with FH than in the adult population.22 In another study, only a prolonged treatment (for 2 years) with a high dose of atorvastatin was able to reduce CRP levels in a cohort of 325 adult patients with FH.23 Of note, the anti-inflammatory effect was associated with a beneficial reduction in athero-progression (assessed by carotid IMT),23 indicating that a reduction of atherosclerotic inflammation in FH was clinically relevant. Concerning endothelial dysfunction, a study enrolling a smaller number of adult FH patients (n = 35) showed that 6 weeks of daily treatment with a high dose of simvastatin was not able to improve circulating inflammatory markers as well as flow-mediated vasodilation of the brachial artery.24 In accordance with previously mentioned studies, treatment with statins (even if aggressive) seems less effective in reducing atherosclerotic inflammation in patients with FH as compared to the general non-dysplidaemic population.22,,,–26 Of note, promising findings on a more pronounced anti-inflammatory effect have emerged by clinical studies using proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors,27 recently approved monoclonal antibodies to further reduce low-density lipoprotein cholesterol.28,29 We believe that in the near future new ‘pleiotropic’ effects of PCSK9 inhibitors will be identified particularly in patients with FH.30 Lipoprotein apheresis (LA) is currently performed in high-risk patients with homo/heterozygous FH resistant to pharmacological treatments.31 Recent evidence suggests that this approach might also induce anti-inflammatory effects in FH patients.31 The acute reduction of the levels of circulating inflammatory mediators after LA was probably related to the ‘exchange’ effect of the apheresis. However, the effect of LA was also shown at late follow-up, indicating the potential trigger of beneficial pathways that remain unknown.32 This aspect was recently demonstrated for pentraxin 3, a circulating mediator of innate immunity.33 In conclusion, inflammation and hypercholesterolaemia activate common pathways in atherogenesis. Accordingly, optimisation of anti-atherosclerotic strategies should rely on the inhibition of both risk factors to limit the residual risk demonstrated by currently used drugs.34 In patients with FH, reduction of inflammatory risk seems to be harder to obtain than in other patients at increased cardiovascular risk, thus additional pathophysiological studies are warranted to clarify the peculiar ‘resistance’ of atherosclerotic inflammation in FH patients.35 With this point of view, FH subjects could particularly benefit from the addition of selective anti-inflammatory compounds on top of the already recommended lipid-lowering drugs to blunt atherosclerotic burden and improve cardiovascular outcome. Among others, canakinumab seems the most promising anti-inflammatory strategy and should be investigated soon in the setting of FH.