Elevated Lp(a) and PCSK9 levels associated with higher CAC in FH patients
PCSK9 and lipoprotein (a) levels are two predictors of coronary artery calcification in asymptomatic patients with familial hypercholesterolemia
Alonso R, Mata P, Muniz O, et al.
Atherosclerosis 2016; published online ahead of print
BackgroundFamilial hypercholesterolaemia (FH) is a genetic disorder associated with the development of CAD early in life. In over 90% of patients, FH is due to a mutation in one allele of the LDL receptor gene that leads to elevated LDL-C levels . Other factors that affect the age at which FH patients may develop premature atherogenesis include high Lp(a) levels and PCSK9 levels [2,3].
In this study, the effects of elevated PCSK9 and Lp(a) levels on coronary artery calcification (CAC) were evaluated in 161 asymptomatic molecularly defined FH patients on stable chronic lipid-lowering therapy, who were recruited from the Spanish Familial Hypercholesterolemia Followup Study (SAFEHEART). CAC was assessed in the epicardial coronary arteries on CT scans, with calculation of a CAC score according to Agatston’s method. CAC was detected in 98 patients (61%), of whom 55 had a mild score (0.1-100), 25 had elevated CS (101-400) and 18 patients had severe CS (>400). In 63 patients no CAC was detected.
Main resultsIn patients with a positive calcium score (CS) compared with patients without CAC:
- there was a trend for higher circulating Lp(a) levels: 34 (13-69) vs. 25 (8-67) mg/dL, P = 0.0698
- PCSK9 levels were significantly more elevated: 500 (403-578) vs. 421 (340-494) ng/mL, P = 0.0028
- Both Lp(a) and PCSK9 levels were further increased in patients with the highest CAC scores
- Apo(a) levels were not significantly increased in patients with high CAC vs. those with mild CAC [102 (58-190) vs. 100 (50-180) nM] or those with no CAC [102 (58-190) vs. 93 (52-162) nM]
- There was a significant difference in Lp(a) levels between the high CAC group [36 (14-74) mg/dL] and the groups with mild CAC [29 (9-65) mg/dL] and with no CAC [25 (8-67) mg/dL], P< 0.05.
After correction for potential confounders, only PCSK9 (β = 0.179; P = 0.02), Lp(a) (β = 0.158; P = 0.03), and apo(a) (β = 0.156; P = 0.04) remained significantly predictive of positive CAC scores.
ConclusionElevated Lp(a) and PCSK9 levels were both associated with higher CAC in asymptomatic FH patients on stable chronic lipid-lowering therapy, after adjusting for other CV risk factors. It should be noted that circulating PCSK9 levels do not necessarily reflect PCSK9 function, since statin treatment increase PCSK9 levels. Higher statin doses may to some extent explain why patients with CAC have higher PCSK9 levels than those without CAC. However, other studies have shown associations between PCSK9 and the volume of necrotic core tissue in coronary atheroma lesions and with total carotid plaque area, independently of LDL-c levels and statin use. Because monoclonal antibodies targeting PCSK9 reduce LDL-c as well as Lp(a), these agents may be beneficial in these patients.
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2. Alonso R, Andres E, Mata N, et al. Lipoprotein(a) levels in Familial Hipercholesterolaemia: an important predictor for cardiovascular disease independent of the type of LDL-receptor mutation, J. Am. Coll. Cardiol. 63 (2014) 1982e1989.
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