Efficacy and safety of lomitapide in homozygous familial hypercholesterolaemia: the pan-European retrospective observational study
Abstract Aims Lomitapide is a lipid-lowering agent indicated as an adjunct therapy for adult homozygous familial hypercholesterolaemia (HoFH). This study evaluated the medium-term effectiveness and safety of lomitapide in a large cohort of HoFH patients in Europe. Methods and results In a multicentre retrospective, observational study including 75 HoFH patients treated with lomitapide in a real-world clinical setting from 9 European countries, low-density lipoprotein cholesterol (LDL-C) changes, adverse events (AEs), and major adverse cardiovascular events (MACE) were assessed. After a median 19 months (interquartile range 11–41 months) of treatment with a mean dosage of 20 mg of lomitapide…
Long-term efficacy of lipoprotein apheresis and lomitapide in the treatment of homozygous familial hypercholesterolemia (HoFH): a cross-national retrospective survey
Abstract Background Homozygous familial hypercholesterolemia (HoFH) is a rare life-threatening condition that represents a therapeutic challenge. The vast majority of HoFH patients fail to achieve LDL-C targets when treated with the standard protocol, which associates maximally tolerated dose of lipid-lowering medications with lipoprotein apheresis (LA). Lomitapide is an emerging therapy in HoFH, but its place in the treatment algorithm is disputed because a comparison of its long-term efficacy versus LA in reducing LDL-C burden is not available. We assessed changes in long-term LDL-C burden and goals achievement in two independent HoFH patients’ cohorts, one treated with lomitapide in Ita…
Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia
: Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and Results An lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause …
Expression of inflammation-related genes in human atherosclerotic plaques
Aims: Atherosclerosis is an inflammator y disease which molecular mechanisms are not been completely investigated. Our aim is to perform a wide expression study of inflammation related genes in human atherosclerotic plaques. Methods: The Human Inflammation Array (Applied Biosystems) was used to perform the mRNA quantification of 92 inflammation-related genes in 12 atherosclerotic plaques, their respective adjacent regions (with a lower grade lesion) and 7 healthy ar teries. The principle of the array is the real-time PCR amplification with a TaqMan probe specific for each gene. Data analysis was performed with SDS 2.3 software with the comparative Ct method using the gene beta-2-microglobulin as h…
Additional file 1 of Long-term efficacy of lipoprotein apheresis and lomitapide in the treatment of homozygous familial hypercholesterolemia (HoFH): a cross-national retrospective survey
Additional file 1: Table 1. Patients’ genotypes. All mutations were classified according to ACMG guidelines (Chora JR, Medeiros AM, Alves AC, Bourbon M. Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis. Genet Med. 2018;20(6):591-598). For 3 Homozygous LDLR and 1 LDLRAP1 causing mutations were not available and the diagnosis was only on clinical base. *Double Heterozygote patient for mutations in both LDLR (c.373C>T) and PCSK9 (c.60_ 65dupGCTGCT) genes.
Efficacy of Long-Term Treatment of Autosomal Recessive Hypercholesterolemia With Lomitapide: A Subanalysis of the Pan-European Lomitapide Study
Backgroundand aim: Autosomal recessive hypercholesterolemia (ARH) is a rare autosomal recessive disorder of low-density lipoprotein (LDL) metabolism caused by pathogenic variants in the LDLRAP1 gene. Like homozygous familial hypercholesterolemia, ARH is resistant to conventional LDL-lowering medications and causes a high risk of atherosclerotic cardiovascular diseases (ASCVDs) and aortic valve stenosis. Lomitapide is emerging as an efficacious therapy in classical HoFH, but few data are available for ARH.Results: This is a subanalysis carried out on nine ARH patients included in the Pan-European Lomitapide Study. The age at starting lomitapide was 46 (interquartile range (IQR), 39.0–65.5) y…
Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study
Abstract Background Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by elevated plasma levels of LDL-cholesterol that confers an increased risk of premature atherosclerotic cardiovascular disease. Early identification and treatment of FH patients can improve prognosis and reduce the burden of cardiovascular mortality. Aim of this study was to perform the mutational analysis of FH patients identified through a collaboration of 20 Lipid Clinics in Italy (LIPIGEN Study). Methods We recruited 1592 individuals with a clinical diagnosis of definite or probable FH according to the Dutch Lipid Clinic Network criteria. We performed a parallel sequencing of the major…
Altered expression of inflammation-related genes in human carotid atherosclerotic plaques.
Abstract Objective Inflammation is a pivotal process in atherosclerosis development and progression, but the underlying molecular mechanisms remain largely obscure. We have conducted an extensive expression study of atherosclerotic plaques to identify the inflammatory pathways involved in atherosclerosis. Methods We studied 11 human carotid plaques, their respective adjacent regions and 7 control arteries from different subjects. Expression of 92 genes was studied by TaqMan low-density array human inflammation panel. Human aortic endothelial and smooth muscle cells were used for in vitro experiments. Results The mRNA levels of 44/92 genes (48%) differed significantly between the tissues exa…
Familial hypercholesterolemia: The Italian Atherosclerosis Society Network (LIPIGEN)
Background and aims: Primary dyslipidemias are a heterogeneous group of disorders characterized by abnormal levels of circulating lipoproteins. Among them, familial hypercholesterolemia is the most common lipid disorder that predisposes for premature cardiovascular disease. We set up an Italian nationwide network aimed at facilitating the clinical and genetic diagnosis of genetic dyslipidemias named LIPIGEN (LIpid TransPort Disorders Italian GEnetic Network). Methods: Observational, multicenter, retrospective and prospective study involving about 40 Italian clinical centers. Genetic testing of the appropriate candidate genes at one of six molecular diagnostic laboratories serving as nationw…
Decreased Paraoxonase-2 Expression in Human Carotids During the Progression of Atherosclerosis
Objective— Many gene products involved in oxidation and inflammation are implicated in the pathogenesis of atherosclerosis. We investigated paraoxonase 2 (PON2), 5-lipoxygenase (5-LO), and 5-LO activating protein (FLAP) expression and malondialdehyde (MDA) levels in carotid lesions to assess their involvement in plaque formation. Methods and Results— We measured gene expression and MDA levels in atherosclerotic plaques from 59 patients undergoing carotid endarterectomy, and in plaque-adjacent tissue from 41/59 patients. Twenty-three fetal carotids and 6 mammary arteries were also investigated. Real-time polymerase chain reaction and immunohistochemistry revealed decreased PON2 expression i…
Additional file 2 of Long-term efficacy of lipoprotein apheresis and lomitapide in the treatment of homozygous familial hypercholesterolemia (HoFH): a cross-national retrospective survey
Additional file 2: Figure 1. LDL-C burden according to lomitapide or LA treatment. A Box plot graphs represent the median values of cumulative LDL-C burden in the Lomitapide cohort (dark grey) and in the LA cohort (light grey). For the total LDL-C burden calculation see Methods. P values are adjusted for age at follow-up, untreated LDL-C values and gender. B, C Box plot graphs represent the median values of TC and LDL-C burden at baseline and on-treatment. For baseline and on-treatment TC or LDL-C burden calculation see Methods. Δ% represents TC and LDL-c percent reduction from baseline and is reported with the respective statistical significance. B shows data form Lomitapide cohort whereas…