Repeat Measures of Lipoprotein(a) Molar Concentration and Cardiovascular Risk

Abstract

Background: When indicated, guidelines recommend measurement of lipoprotein(a) for cardiovascular risk assessment. However, temporal variability in lipoprotein(a) is not well understood, and it is unclear if repeat testing may help refine risk prediction of coronary artery disease (CAD).

Objectives: The authors examined the stability of repeat lipoprotein(a) measurements and the association between instability in lipoprotein(a) molar concentration with incident CAD.

Methods: The authors assessed the correlation between baseline and first follow-up measurements of lipoprotein(a) in the UK Biobank (n = 16,017 unrelated individuals). The association between change in lipoprotein(a) molar concentration and incident CAD was assessed among 15,432 participants using Cox proportional hazards models.

Results: Baseline and follow-up lipoprotein(a) molar concentration were significantly correlated over a median of 4.42 years (IQR: 3.69-4.93 years; Spearman rho = 0.96; P < 0.0001). The correlation between baseline and follow-up lipoprotein(a) molar concentration were stable across time between measurements of <3 (rho = 0.96), 3-4 (rho = 0.97), 4-5 (rho = 0.96), and >5 years (rho = 0.96). Although there were negligible-to-modest associations between statin use and changes in lipoprotein(a) molar concentration, statin usage was associated with a significant increase in lipoprotein(a) among individuals with baseline levels ≥70 nmol/L. Follow-up lipoprotein(a) molar concentration was significantly associated with risk of incident CAD (HR per 120 nmol/L: 1.32 [95% CI: 1.16-1.50]; P = 0.0002). However, the delta between follow-up and baseline lipoprotein(a) molar concentration was not significantly associated with incident CAD independent of follow-up lipoprotein(a) (P = 0.98).

Conclusions: These findings suggest that, in the absence of therapies substantially altering lipoprotein(a), a single accurate measurement of lipoprotein(a) molar concentration is an efficient method to inform CAD risk.

Keywords: Lp(a); coronary artery disease; lipoprotein(a); longitudinal; repeat testing.

Figure 1.. Flow diagram of how the study cohort was used for analyses.

Unrelated participants from the UK Biobank with baseline and follow-up measurements of lipoprotein(a) were included in this study to assess the stability of repeat lipoprotein(a) measurements. The majority of these participants without prevalent coronary artery disease, were studied to assess the association between lipoprotein(a) instability and risk of incident coronary artery disease. Coronary artery disease (CAD), lipoprotein(a) (Lp[a]).

Figure 2.. Repeat measurements of lipoprotein(a) molar concentration are relatively stable.

(A) The correlation between baseline and follow-up lipoprotein(a) molar concentration is depicted for UK Biobank participants. Waterfall plots show: (B) the absolute delta of lipoprotein(a) molar concentration for each UK Biobank participant (follow-up – baseline) and (C) the mean percent change in lipoprotein(a) molar concentration. Red dotted lines depict difference in lipoprotein(a) molar concentration ≥ 120 nmol/L or mean percent changes greater than 25%. (D) The percentage of UK Biobank participants versus the size of delta lipoprotein(a) levels is shown. Lipoprotein(a) [Lp(a)].

Figure 3.. Association between statin use and changes in lipoprotein(a) molar concentration.

(A) Boxplots depict the median and interquartile range of the mean percent change in lipoprotein(a) molar concentration associated with statin medication use by UK Biobank participants. For individuals naïve to stain medication at baseline, boxplots depict the median and interquartile range in the mean percent change of lipoprotein(a) molar concentration for UK Biobank participants (B) newly starting specific statin treatments prior to follow-up biomarker measurement and (C) lipoprotein(a) molar concentration based on thresholds of baseline lipoprotein(a) (only 7/16,017 [0.04%] of individuals had a mean percent change greater than 2,000). The line within the boxplots represents the median. The upper and lower edges of the boxplots represent the 1^st and 3^rd quartile, respectively. The whiskers represent the 1^st quantile – 1.5 x interquartile range or 3^rd quartile + 1.5 x interquartile range, while individual points represent outliers that are extreme values to these ranges. Numeric values above the boxplots depict the n per group. The dotted black lines depict a mean percent change of 0 (no change). Lipoprotein(a) [Lp(a)].

Figure 4.. Association of lipoprotein(a) instability with risk of incident coronary artery disease.

Forest plots show the adjusted hazard ratios for incident coronary artery disease for UK Biobank participants with decreased, stable, or increased follow-up lipoprotein(a) molar concentration based on the thresholds of <70, 70-150, and >=150 nmol/L. Follow-up lipoprotein(a) molar concentrations that were >10% different from baseline measurements were considered unstable. Hazard ratios were adjusted for age, age squared, sex, and the first 4 principal components of ancestry. Lipoprotein(a) [Lp(a)].

Central Illustration.. Repeat measurements of lipoprotein(a) molar concentration and incident coronary artery disease.

This study assessed the relationship between repeat lipoprotein(a) measurements and coronary artery disease in up to 16,017 unrelated UK Biobank participants. This work suggests that modest changes in repeat lipoprotein(a) measurements are common, but do not associate with incident coronary artery disease. Coronary artery disease (CAD).