Physicians' Academy for Cardiovascular Education

High Lp(a) levels associate with mortality, through low number of Kringle-IV type 2 repeats

High lipoprotein(a) and high risk of mortality

Literature - Langsted A, Kamstrup PR, Nordestgaard BG - Eur Heart J 2019: 40(33); 2760–2770,

Introduction and methods

Observational and genetic data have shown that high lipoprotein(a) [Lp(a)] levels are associated with high risk of CV disease, including myocardial infarction and aortic valve stenosis. Thus, the search for therapeutic options to lower Lp(a) are ongoing. No randomized, double-blind evidence is, however, available demonstrating that lowering Lp(a) will reduce the risk of CV disease [1-7].

If lowering Lp(a) lowers CV disease, it is anticipated that it will also reduce CV and all-cause mortality. High Lp(a) levels may, however, also protect against bleeding events [8,9], which implies that lowering the levels could increase mortality risk. The relationship between Lp(a) and mortality is presently unclear.

This study tested the hypothesis that Lp(a) levels are associated with risk of mortality, both observationally and causally, based on human genetic data. Data of 126,936 individuals from the Danish general population [Copenhagen City Heart Study, CCHS) and Copenhagen General Population Study (CGPS)] were used, without loss to follow-up. It was also examined whether such associations are driven by low number of LPA kringle-IV type 2 (KIV-2) repeats and thus small apolipoprotein(a) isoform size. Participants filled out a questionnaire including lifestyle and medical history and underwent a physical examination (with blood sampling for lipid and lipoprotein level measurements).

Main results


In individuals of the Danish general population, high levels of Lp(a) as a consequence of low LPA KIV-2 number of repeats, were associated with high risk of mortality. Interestingly, the LPA rs10455872 genotype and KIV-2 number of repeats showed inconsistent associations with all-cause and CV mortality, which questions the view that the rs10455872 genotype is an indirect reporter of KIV-2 variation. The data suggest that the rs10455872 genotype is primarily associated with plasma Lp(a) levels, while KIV-2 number of repeats is more related with apolipoprotein(a) isoform size, as well as plasma levels.


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Find this article online at Eur Heart J

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