Familial hypercholesterolemia and elevated lipoprotein(a): double heritable risk and new therapeutic opportunities

Vuorio, Alpo; Watts, Gerald F.; Schneider, Wolfgang J.; Tsimikas, Sotirios; Kovanen, Petri T.

doi:10.1111/joim.12981

Cited by 93 publications

(84 citation statements)

References 142 publications

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“…Clinical conditions resulting in raised CV risk are particularly stimulating, in order to improve choices for handling Lp(a) elevations. Familial hypercholesterolemia (FH) and elevated Lp(a) are a double heritable risk [ 8 ], i.e., carriers of a receptor-negative mutation in the low-density lipoprotein receptor (LDLR) gene with high Lp(a) (> 50 mg/dL) show a higher cardiovascular disease (CVD) risk compared to patients with the same mutation and Lp(a) levels < 50 mg/dL [ 9 ]. In suspected FH patients, the proportion of cases explained by biochemical evaluation of Lp(a) is between 5% and 20%.…”

Section: Introduction—an Overviewmentioning

confidence: 99%

Lipoprotein(a) Lowering—From Lipoprotein Apheresis to Antisense Oligonucleotide Approach

Greco

Sirtori

Corsini

et al. 2020

JCM

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It is well-known that elevated lipoprotein(a)—Lp(a)—levels are associated with a higher risk of cardiovascular (CV) mortality and all-cause mortality, although a standard pharmacotherapeutic approach is still undefined for patients with high CV risk dependent on hyperlipoproteinemia(a). Combined with high Lp(a) levels, familial hypercholesterolemia (FH) leads to a greater CVD risk. In suspected FH patients, the proportion of cases explained by a rise of Lp(a) levels ranges between 5% and 20%. In the absence of a specific pharmacological approach able to lower Lp(a) to the extent required to achieve CV benefits, the most effective strategy today is lipoprotein apheresis (LA). Although limited, a clear effect on Lp(a) is exerted by PCSK9 antagonists, with apparently different mechanisms when given with statins (raised catabolism) or as monotherapy (reduced production). In the era of RNA-based therapies, a new dawn is represented by the use of antisense oligonucleotides APO(a)Lrx, able to reduce Lp(a) from 35% to over 80%, with generally modest injection site reactions. The improved knowledge of Lp(a) atherogenicity and possible prevention will be of benefit for patients with residual CV risk remaining after the most effective available lipid-lowering agents.

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Section: Introduction—an Overviewmentioning

confidence: 99%

Lipoprotein(a) Lowering—From Lipoprotein Apheresis to Antisense Oligonucleotide Approach

Greco

Sirtori

Corsini

et al. 2020

JCM

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“…8 The independent CVD risk factor lipoprotein (a) is important to take into consideration when discussing treatments available in the near future and risk stratification for hypercholesterolemic patients. 9 In about 60% to 80% of the definite FH cases, a causative mutation can be found in one of the three known genes, but only in about 20% to 30% of possible FH cases. 10,11 Since the unequivocal diagnosis of FH is primarily based on molecular testing, this leaves medical scientists with a conundrum because up to 60% of the clinically diagnosed patients turn out to be nonmutation carriers, that is, with no identified pathogenic sequence variant in one of the above mentioned genes.…”

Section: Introductionmentioning

confidence: 99%

Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia

et al. 2020

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Autosomal-dominant familial hypercholesterolemia (FH) is characterized by increased plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and a substantial risk to develop cardiovascular disease. Causative mutations in three major genes are known: the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB) and the proprotein convertase subtilisin/kexin 9 gene (PCSK9). We clinically characterized 336 patients suspected to have FH and screened them for disease causing mutations in LDLR, APOB, and PCSK9. We genotyped six single nucleotide polymorphisms (SNPs) to calculate a polygenic risk score for the patients and 1985 controls. The 117 patients had a causative variant in one of the analyzed genes. Most variants were found in the LDLR gene (84.9%) with 11 novel mutations. The mean polygenic risk score was significantly higher in FH mutation negative subjects than in FH mutation positive patients (P < .05) and healthy controls (P < .001), whereas the score of the two latter groups did not differ significantly. However, the score explained only about 3% of the baseline LDL-C variance. We verified the previously described clinical and genetic variability of FH for German hypercholesterolemic patients. Evaluation of a six-SNP polygenic score recently proposed for clinical use suggests that it is not a reliable tool to classify hypercholesterolemic patients. Ursula Kassner and Ilja Demuth contributed equally to this study.

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“…An important finding is the association between cytomegalovirus antibodies and atherosclerosis, which in the Atherosclerosis Risk in Communities Study was observed in individuals with high levels of lipoprotein(a) and fibrinogen [5]. Such an association may also apply to FH patients who have, on average, higher lipoprotein(a) levels compared with the general population [6] and, therefore, may have a higher risk of an atherothrombotic event whilst suffering from COVID-19 and even after recovery. The potential synergism between viral infection and the resulting hypercoagulability related to increased lipoprotein(a) levels merits further investigation.…”

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confidence: 99%

Familial hypercholesterolaemia and COVID‐19: triggering of increased sustained cardiovascular risk

2020

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Familial hypercholesterolemia and elevated lipoprotein(a): double heritable risk and new therapeutic opportunities

Abstract: Familial hypercholesterolemia and elevated lipoprotein(a): double heritable risk and new therapeutic opportunities (Review).

Cited by 93 publications

References 142 publications

Lipoprotein(a) Lowering—From Lipoprotein Apheresis to Antisense Oligonucleotide Approach

Lipoprotein(a) Lowering—From Lipoprotein Apheresis to Antisense Oligonucleotide Approach

Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia

Familial hypercholesterolaemia and COVID‐19: triggering of increased sustained cardiovascular risk

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