Associations of ANGPTL3/4/8 proteins and complexes with heart failure and heart failure mortality

Angiopoietin-like 3/4/8 (ANGPTL3/4/8) proteins play critical roles in modulating lipid metabolism through calorically sensitive and tissue-specific regulation of lipoprotein lipase (LPL) activity via formation of ANGPTL3/8 and ANGPTL4/8 complexes. ANGPTL3/4/8 proteins are also associated with cardiovascular risk. Circulating levels of ANGPTL3, ANGPTL4/8, and C-terminal domain-containing ANGPTL4 (CD-ANGPTL4) have been associated with overall cardiovascular mortality. In this study, we investigated the associations of ANGPTL3/4/8 proteins and complexes with heart failure (HF) and HF death. We studied 2,394 participants of the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study, a cohort of patients referred for coronary angiography. HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) were diagnosed at baseline. There was a follow-up period with a median (interquartile range) duration of 9.80 (8.75–10.40) years. ANGPTL3/4/8 proteins and complexes were measured at baseline using dedicated immunoassays, and their serum concentrations were compared to HF data. There was an inverse association of ANGPTL3/8 with the N-terminal prohormone of B-type natriuretic peptide (NT-proBNP). ANGPTL3 was positively associated with NT-proBNP, HFpEF, and the New York Heart Association (NYHA) functional class. ANGPTL4/8 was positively associated with HFrEF, HFpEF, and NT-proBNP and was inversely associated with the left ventricular ejection fraction (LVEF). CD-ANGPTL4 was positively associated with the NYHA functional class, HFrEF, HFpEF, and NT-proBNP and was inversely associated with LVEF. A total of 101 participants died from HF. ANGPTL3/8 and ANGPTL4/8 were not associated with HF mortality. In contrast, ANGPTL3 and especially CD-ANGPTL4 were positively associated with HF death. We found positive associations of ANGPTL3 and CD-ANGPTL4 with HF and HF mortality. Of particular interest, serum levels of CD-ANGPTL4 demonstrated positive associations with HFrEF, HFpEF, NT-proBNP, and NYHA functional class and an inverse association with LVEF. CD-ANGPTL4 also demonstrated the strongest positive association with HF mortality. The explanation for these associations is not currently apparent. Further investigation will be required to understand more fully the possible biochemical mechanisms that may be responsible for these associations.