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Background and aims. Familial hypercholesterolemia (FH) is an inherited disorder characterized by high levels of blood cholesterol from birth and premature coronary heart disease. Thus, the identification of FH patients is crucial to prevent or delay the onset of cardiovascular events, and the availability of a tool helping with the diagnosis in the setting of general medicine is essential to improve FH patient identification. Methods. This study evaluated the performance of the Dutch Lipid Clinic Network (DLCN) score in FH patients enrolled in the LIPIGEN study, an Italian integrated network aimed at improving the identification of patients with genetic dyslipidaemias, including FH. Results. The DLCN score was applied on a sample of 1377 adults (mean age 42.9±14.2 years) with genetic diagnosis of FH, resulting in 28.5% of the sample classified as probable FH and 37.9% as classified definite FH. Among these subjects, 43.4% had at least one missing data out of 8, and about 10.0% had 4 missing data or more. When analyzed based on the type of missing data, a higher percentage of subjects with at least 1 missing data in the clinical history or physical examination was classified as possible FH (DLCN score 3-5). We also found that using real or estimated pre-treatment LDL-C levels may significantly modify the DLCN score. Conclusions. Although the DLCN score is a useful tool for physicians in the diagnosis of FH, it may be limited by the complexity to retrieve all the essential information, suggesting a crucial role of the clinical judgement in the identification of FH subjects.

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Background-HDL molecules have an established role in the regression processes of atherosclerosis as well as a putative role as antiinflammatory agents. Our study investigated whether familial hypoalphalipoproteinemia, a genetic form of dyslipidemia characterized by very low HDL levels, might be associated with increased inflammation markers such as C-reactive protein. Key Words: lipoproteins Ⅲ C-reactive protein Ⅲ hypolipoproteinemia Ⅲ inflammation Ⅲ atherosclerosis T he hypothesis that elevated levels of plasma high-density lipoprotein (HDL) protect against coronary atherosclerotic disease (CAD) was initially proposed by Barr et al 1 in the 1950s and is now firmly established. 2 Conversely, equally well-established evidence shows that low plasma HDL levels lead to atherosclerosis and are also recognized to be a major independent risk factor for CAD. 2 Thus, HDL molecules can be considered the 2-faced Janus of the atherosclerotic process, which, in turn, is increasingly believed to be an inflammatory phenomenon. Atherosclerotic lesions show activation and proliferation of macrophages and T-lymphocytes, cytokine production, and oxidized lowdensity lipoprotein (LDL) accumulation. 3,4 We hypothesized that the link between low HDL levels and atherosclerosis may depend on an upregulation of inflammation mechanisms putatively induced by low HDL, which has been shown to act as a proinflammatory agent. 5,6 Therefore, we measured C-reactive protein (CRP) in a group of patients affected by familial hypoalphalipoproteinemia (Hypoalpha), an autosomal-dominant genetic trait. Hypoalpha subjects are characterized by extremely low plasma levels of HDL (Ͻ10th percentile), 7-9 together with reduced or normal LDL levels and normal or high triglyceride (TG) levels. Hypoalpha patients have greater susceptibility to early, severe coronary atherosclerosis. 10 -12 In the general population this trait has a prevalence of Ϸ0.5%, and it is 10 to 20 times more frequent in subjects with CAD who are Ͻ60 years of age.CRP is a well-established, sensitive marker of systemic inflammation and represents an independent risk factor for cardiovascular events in population studies as well as in angina patients. 13,14 Also, CRP seems to add predictive value to total cholesterol (TC) and HDL levels with regard to the risk of future myocardial infarction in subjects with hyperlipemia and elevated concentrations of CRP. 15 The hepatic synthesis of CRP is induced by cytokines such as interleukin-6 16 ; it accumulates in the arterial wall during the atheroscle- rotic process, stimulates production of the tissue factor by monocytes, 17 and induces the synthesis of adhesion molecules in endothelial cells. Hypoalpha subjects were compared with a group of healthy controls and divided according to the presence or absence of CAD, as documented by coronary angiography, to provide a model in which to photograph the inflammatory state before and after the occurrence of clinical vascular damage. Methods PatientsThe patients recruited for the study consisted of 50 c...

Sampietro T, Bigazzi F, Rossi G, Dal Pino B, Puntoni MR, Sbrana F, Chella E, Bionda A (CNR Institute of Clinical Physiology, Pisa; and University of Pisa, Pisa; Italy). Upregulation of the immune system in primary hypercholesterolaemia: effect of atorvastatin therapy. J Intern Med 2005; 257: 523-530.Objectives. High levels of plasma high sensitivity Creactive protein (CRP), sensitive to therapy with statins, have been described in hyperchole sterolaemia. In vitro evidence shows that CRP activates the complement system, which, in turn, leads to an increased expression of ICAM-1. Our objectives were to verify whether primary hypercholesterolaemia (PHC) is associated with an upregulation of the inflammatory/immune response, and whether this is sensitive to atorvastatin. Methods and results. We examined the levels of sICAM-1, C3, C4 complement fractions in 48 patients with PHC, with (CAD group) or without (No-CAD group) coronary artery disease (CAD) in comparison with a group of 48 healthy controls. The two patient groups were studied before and after atorvastatin therapy. Both hypercholesterolaemic groups showed higher mean values of sICAM-1, C3 and C4 (P < 0.0001) when compared with the controls. The two groups of patients responded differently to atorvastatin therapy. After 3 months, the C3 levels normalized in both groups of patients (P < 0.02 compared with basal values); C4 was greatly reduced only in the CAD group (P < 0.01). After 12 months of therapy, in CAD group C3 mean levels were still significantly lower than baseline values (P < 0.01); a further decrease in the C4 values (P < 0.05 with respect to levels after 3 months of therapy) and also a substantial reduction in sICAM-1 values (P < 0.001 with respect to basal values) were observed. Conclusions. High plasma values of C3 and C4 in PHC cluster with high values of sICAM-1, distinguish subjects with CAD and could be used to monitor the anti-inflammatory effect of statin therapy in these patients.

Background Familial hypercholesterolemia is the elective clinical condition that deserves the maximal personalisation in lipid-lowering therapy, especially in the presence of statin intolerance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent a promising approach to lower low-density lipoprotein (LDL) cholesterol. Methods We enrolled 18 patients (mean age 62 ± 8 years, 72% men) affected by heterozygous familial hypercholesterolemia and cardiovascular disease, with a history of statin intolerance assigned to PCSK9 inhibitors. Six patients were also on LDL apheresis. Associated Lp(a)-hyperlipoproteinemia (defined as >60 mg/dl) was observed in two out of 18 subjects. PCSK9 inhibitor injectable monoclonal antibodies were administered, every 2 weeks, on top of patient therapy for 12 ± 4 weeks (evolocumab in 15 subjects, alirocumab in three subjects). Results After 3 months (12 ± 4 weeks) of therapy, a decrease in total cholesterol (-35%), LDL cholesterol (-51%) and Lp(a) levels (-20%) was observed. Five out of 18 patients reached LDL cholesterol levels of <70 mg/dl, seven showed LDL cholesterol values between 71 and 100 mg/dl, and six out of 18 still had LDL cholesterol levels above 100 mg/dl. Among the six patients with LDL cholesterol levels >100 mg/dl, three were already on LDL apheresis before the PCSK9 inhibitor treatment, while three were referred to LDL apheresis treatment. Adverse events were reported in two out of 18 patients on evolocumab: one presented with flu-like syndrome and the other reported episodes of mild difficulty in maintaining concentration. Conclusions PCSK9 inhibitors represent a novel therapeutic tool for patients with familial hypercholesterolemia who are intolerant to statins. However, more data are needed before cleaning up the old therapeutic armamentarium, such as LDL apheresis, which is likely to preserve its valuable role also in the new lipid-lowering era.

Objective: To test the working hypothesis that inflammation underlying precocious and severe coronary atherosclerotic disease in familial hypoalphalipoproteinaemia (FH) can be mediated by up regulation of the innate immune response. Conclusions: Increased concentrations of sICAM-1, C3c, and C4 co-express with high concentrations of CRP in FH. The lack of signs and symptoms of inflammation in these patients may suggest that the immune response is up regulated as part of the pro-inflammatory mechanisms that are activated in this atherogenic condition.

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