Physicians' Academy for Cardiovascular Education

ANGPTL3 deficiency linked to reduced CAD risk

ANGPTL3 Deficiency and Protection Against Coronary Artery Disease

Literature - Stitziel NO, Khera AV, Wang X, et al. - JACC 2017; published online ahead of print


Angiopoietin-like protein 3 (ANGPTL3), which is secreted by the liver, is a potent inhibitor of lipoprotein lipase and endothelial lipase [1-3]. Loss-of-function (LOF) mutations causing a complete deficiency of ANGPTL3, as in the hereditary combined hypolipidaemia, leads to low triglycerides (TG), LDL-C, and HDL-C concentrations [4,5]. Hence, ANGPTL3 deficiency may reduce the risk for coronary artery disease (CAD), but this hypothesis has not been tested.

In this study, the coronary atherosclerotic plaque burden in 3 individuals with complete ANGPTL3 deficiency was compared with wild-type first-degree relatives. Moreover, the coding regions of ANGPTL3 were examined in 180,180 individuals and it was assessed whether LOF mutations are related to a lower risk of CAD. Furthermore, circulating ANGPTL3 biomarker levels were determined in patients with a first myocardial infarction and controls.

Main results


Deep phenotyping in a family, gene sequencing in the population, and biomarker analysis in case and control subjects, showed that ANGPTL3 deficiency is associated with a reduced CAD risk. Analyses showed that coronary atherosclerotic plaque is absent in individuals with complete ANGPTL3 deficiency, that heterozygous carriers of an ANGPTL3 LOF mutations have a 34% reduction of CAD risk and that ANGPTL3 concentrations were lower in healthy controls compared to those presenting with myocardial infarction. These findings support the hypothesis that pharmacological inhibition of ANGPTL3 function may be useful in the treatment or prevention of CAD.

Editorial comment

In his editorial article [6], Genest initially comments on the study of Stitziel et al with: ‘In a series of elegant studies, they provide compelling evidence that ANGPTL3 is causally related to CAD.’ He then discusses the findings in depth, and points out that the frequency of homozygosity or compound heterozygosity of the ANGPTL3 LOF mutation is rarer than homozygous familial hypercholesterolaemia. This makes the practical implications of the study results less important, since individuals with normal or low lipid levels, even if HDL-C is low as well, are not likely to undergo DNA testing for diagnostic reasons. Regarding ANGPTL3 as a therapeutic target, the author notes that a future inhibitor of the ANGPTL3 activity may not provide an additional benefit compared with existing lipid-lowering therapies, because the presence of only 1 LOF allele was related with only modest changes in the average lipoprotein phenotype. To mimic the effect of homozygous LOF on lipoprotein phenotype, a drug that completely inhibits ANGPTL3 activity will be required.

The author concludes: ‘Then, there’s the rub: We do not fully understand the physiological roles of ANGPTL3 and the mechanisms by which its inhibition lowers LDL cholesterol. The types of patients for whom such a drug would be considered are those with combined hyperlipidemia and the dyslipidemia of diabetes and metabolic syndrome. But these patients have an increased rate of production of apoB-containing particles (especially VLDL) from the liver. Increasing lipoprotein lipase activity by inhibiting ANGPTL3 could have the paradoxical effect of increasing the conversion of VLDL into LDL particles, an effect often seen with fibric acid derivatives. Therefore, it remains to be seen whether this finding will open therapeutic avenues for novel anti-ANGPTL3 therapies as an orphan drug and how might this extend to the more common dyslipidemias.’


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