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Grenkowitz T.,Charité - Medical University of Berlin | Kassner U.,Charité - Medical University of Berlin | Wuhle-Demuth M.,Charité - Medical University of Berlin | Salewsky B.,Charité - Medical University of Berlin | And 17 more authors.
Atherosclerosis | Year: 2016

Background and aims Autosomal-dominant familial hypercholesterolemia (FH) is characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and a dramatically increased risk to develop cardiovascular disease (CVD). Mutations in three major genes have been associated with FH: the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB), and the proprotein convertase subtilisin/kexin 9 gene (PCSK9). Here we investigated the frequency and the spectrum of FH causing mutations in Germany. Methods We screened 206 hypercholesterolemic patients, of whom 192 were apparently unrelated, for mutations in the coding region of the genes LDLR, PCSK9 and the APOB [c.10580G > A (p.Arg3527Gln)]. We also categorized the patients according to the Dutch Lipid Clinic Network Criteria (DLCNC) in order to allow a comparison between the mutations identified and the clinical phenotypes observed. Including data from previous studies on German FH patients enabled us to analyse data from 479 individuals. Results Ninety-eight FH causing variants were found in 92 patients (nine in related patients and 6 patients with two variants and likely two affected alleles), of which 90 were located in the LDLR gene and eight mutations were identified in the APOB gene (c.10580G > A). No mutation was found in the PCSK9 gene. While 48 of the LDLR mutations were previously described as disease causing, we found 9 new LDLR variants which were rated as “pathogenic” or “likely pathogenic” based on the predicted effect on the corresponding protein. The proportions of different types of LDLR mutations and their localization within the gene was similar in the group of patients screened for mutations here and in the combined analysis of 479 patients (current study/cases from the literature) and also to other studies on the LDLR mutation spectrum, with about half of the variants being of the missense type and clustering of mutations in exons 4, 5 and 9. The mutation detection rate in the 35 definite and 45 probable FH patients (according to DLCNC) was 77.1% and 68.9%, respectively. The data show a similar discriminatory power between the DLCNC score (AUC = 0.789 (95% CI 0.721–0,857)) and baseline LDL-C levels (AUC = 0.799 (95% CI = 0.732–0.866)). Conclusions This study further substantiates the mutation spectrum for FH in German patients and confirms the clinical and genetic heterogeneity of the disease. © 2016


Heigl F.,Medical Care Center Kempten Allgaeu | Hettich R.,Medical Care Center Kempten Allgaeu | Lotz N.,Medical Care Center Kempten Allgaeu | Reeg H.,Medical Care Center Kempten Allgaeu | And 4 more authors.
Clinical Research in Cardiology Supplements | Year: 2015

Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) are established causal risk factors for cardiovascular disease (CVD). Efficacy, safety, and tolerability of lipoprotein apheresis (LA) were investigated in 118 patients with CVD covering a period with 36,745 LA treatments in a retrospective, monocentric study. Indications for LA were severe hypercholesterolemia (n = 83) or isolated Lp(a) hyperlipoproteinemia (Lp(a)-HLP) (n = 35). In patients with hypercholesterolemia, initial pre-LA LDL-C was 176.4 ± 67.0 mg/dL. In patients with isolated Lp(a)-HLP, initial pre-LA Lp(a) was 127.2 ± 67.3 mg/dL. Mean reduction rates of LA were 67 % for both LDL-C and Lp(a). During chronic LA, the average annual rate of major adverse cardiac events of all patients declined by 79.7 % (p < 0.0001). Subgroup analysis showed decline by 73.7 % (p < 0.0001) in patients with severe hypercholesterolemia, and by 90.4 % (p < 0.0001) in patients with isolated Lp(a)-HLP. Adverse events occurred in 1.1 % of treatments. LA treatment of patients with a high risk for CVD due to hypercholesterolemia and/or Lp(a)-HLP demonstrated clinical benefit and was safe and well tolerated. © 2015, The Author(s).


Heigl F.,Medical Care Center Kempten Allgaeu | Hettich R.,Medical Care Center Kempten Allgaeu | Lotz N.,Medical Care Center Kempten Allgaeu | Reeg H.,Medical Care Center Kempten Allgaeu | And 4 more authors.
Atherosclerosis Supplements | Year: 2015

LDL cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) are main risk factors for cardiovascular disease (CVD).Efficacy, safety, and tolerability of lipoprotein apheresis (LA) were investigated in 36,745 LA treatments of 118 patients with CVD in a retrospective, monocentric study. Indications were severe hypercholesterolemia (n=83) or isolated Lp(a) hyperlipoproteinemia (n=35). Average age of patients at start of LA treatment was 58.1 years for males and 62.5 years for females. Medium interval between the first cardiovascular event and LA treatment was 6.4±5.6 years and the average LA treatment period was 6.8±4.9 years. On average treatments were performed once a week, via peripheral venous access in 79.3% of non-hemodialysis patients. In patients with hypercholesterolemia initial pre-LA LDL-C was lowered from 176.4±67.0mg/dL by 66.7±10.8% per session, achieving a long-term interval mean value of 119.8±34.7mg/dL, i.e. reduction by 32.1±19.6% (p<0.0001). In patients with isolated elevated Lp(a) initial pre-LA Lp(a) was lowered from 127.2±67.3mg/dL by 66.8±5.8% per session, achieving a long-term interval mean value of 60.0±19.5mg/dL, i.e. reduction by 52.8±23.0% (p<0.0001). After start of LA the average annual rate of major adverse coronary events (MACE) of all patients declined by 79.7% (p<0.0001). Subgroup analysis showed decline by 73.7% (p<0.0001) in patients with severe hypercholesterolemia, and by 90.4% (p<0.0001) in patients with isolated elevated Lp(a). Adverse events (AE) occurred in 1.1% of treatments. LA treatment of patients with high risk for CVD due to LDL and/or Lp(a) hyperlipoproteinemia was effective, safe, and well tolerated. The number of cardiovascular events, at least during a six-year period, declined by 80%. © 2015 Elsevier Ireland Ltd.


PubMed | Medical Care Center Kempten Allgaeu
Type: | Journal: Clinical research in cardiology supplements | Year: 2015

Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) are established causal risk factors for cardiovascular disease (CVD). Efficacy, safety, and tolerability of lipoprotein apheresis (LA) were investigated in 118 patients with CVD covering a period with 36,745 LA treatments in a retrospective, monocentric study. Indications for LA were severe hypercholesterolemia (n=83) or isolated Lp(a) hyperlipoproteinemia (Lp(a)-HLP) (n=35). In patients with hypercholesterolemia, initial pre-LA LDL-C was 176.467.0mg/dL. In patients with isolated Lp(a)-HLP, initial pre-LA Lp(a) was 127.267.3mg/dL. Mean reduction rates of LA were 67% for both LDL-C and Lp(a). During chronic LA, the average annual rate of major adverse cardiac events of all patients declined by 79.7% (p<0.0001). Subgroup analysis showed decline by 73.7% (p<0.0001) in patients with severe hypercholesterolemia, and by 90.4% (p<0.0001) in patients with isolated Lp(a)-HLP. Adverse events occurred in 1.1% of treatments. LA treatment of patients with a high risk for CVD due to hypercholesterolemia and/or Lp(a)-HLP demonstrated clinical benefit and was safe and well tolerated.

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