Causative mutations and premature cardiovascular disease in patients with heterozygous familial hypercholesterolaemia

Background Familial Hypercholesterolemia (FH) is a common autosomal dominant disease, caused by mutations leading to elevated LDL cholesterol and, if untreated to premature cardiovascular disease (CVD). Methods Patients (young adults with family history of hypercholesterolemia or premature CVD) with an LDL cholesterol concentration > 4.9 mmol/L, after excluding Familial Combined Hyperlipidemia, were evaluated for causative mutations, MedPed and WHO score calculation and non-invasive ultrasound examination of carotid arteries. Results Among the 263 patients, 210 were heterozygotes for LDL receptor (LDLR) mutations, 4 had apo B gene mutations, 1 PCSK9 gene mutation, while 48 had no evidence of mutations. Among 194 unrelated index cases 149 heterozygotes had mutations (77 %). Among patients with LDLR mutations (n= 145), we found 9 compound heterozygotes, 75 patients with radical mutations and 65 with missense mutations. We performed follow-up and treatment ( statin + ezetimibe ) of 178 patients: a mean reduction of 49 % was achieved, with 21 % of patients reaching the LDL target of 2.6 mmol/L. In a multivariate analysis, carotid plaques, at ultrasound examination, were associated with the presence of mutation (p = 0.014), LDL cholesterol (p< 0.001), MedPed and WHO score (p< 0.001), independently of age, gender, smoking habits , blood pressure. LDL cholesterol (p< 0.003), MedPed and WHO score (p < 0.001) and Carotid plaque (p= 0.017). were independently associated with premature CVD. Conclusions We identified patients with causative mutations in 82 % of cases under study. In addition to LDL Cholesterol and MEDPed and WHO score, carotid plaques at ultrasound evaluation provides direct evidence of premature vascular disease and high risk for cardiovascular events.