Elevated lipoprotein(a) and progression of aortic stenosis measured by Doppler echocardiography: A population-based cohort study

Abstract

Elevated lipoprotein(a) (Lp(a)) is a dyslipoproteinaemia that causes atherosclerotic cardiovascular disease and calcified aortic valve stenosis (AS) [1, 2]. AS develops over decades and can lead to valve obstruction requiring an aortic valve procedure. Both genetic variations in the LPA gene and an elevated plasma Lp(a) level are associated with an increased incidence of AS [3, 4]. Measurement of peak aortic jet velocity (V_max; m/s) with Doppler echocardiography is used to assess and monitor AS in clinical routine. In the ASTRONOMER trial, a limited number of participants (n = 220) with mild-to-moderate AS (initial V_max ≥ 2.5 m/s) who underwent repeated echocardiography exhibited faster V_max progression with elevated Lp(a) [5-7]. Similar faster haemodynamic progression at higher Lp(a) levels was reported in 129 subjects with AS (initial V_max ≥ 2.0 m/s) from the SATIRE trial and Ring of Fire study [8]. However, the impact of Lp(a) on AS progression in an unselected population has remained unexplored. The aim of the present study was to determine the effect of elevated plasma Lp(a) on AS progression measured as V_max by repeated Doppler echocardiography in a large cohort with and without AS at any stage.

We performed an observational retrospective cohort study by linking two databases of individuals who had had their plasma Lp(a) level measured 2003–2017 (n = 23,398) and who had ≥2 Doppler echocardiography V_max measurements with ≥6 months of interval 2003–2018 (n = 9889) in the clinical routine in Region Stockholm, Sweden (Fig. S1). Lp(a) was analysed using accredited laboratory methods, reporting values in nmol/L or mg/dL as previously described [9]. Participants were subdivided into three Lp(a) strata defined as low (<70 nmol/L or <30 mg/dL), intermediate (70–169 nmol/L or 30–69 mg/dL) and high (≥170 nmol/L or ≥70 mg/dL). Transthoracic Doppler echocardiography was performed at Karolinska University Hospital using standard equipment. The current European Society of Cardiology guidelines recommendation on AS management in relation to AS progression is based on the change in V_max, measured in m/s/year, which was calculated in the present study as the difference between the first and the last Doppler measurement divided by the time interval. Individuals who underwent aortic valve replacement (AVR) were excluded if the procedure was performed before the first echocardiography and censored if undergoing AVR during the observational period. The individuals’ cardiovascular status was specified by the International Classification of Diseases diagnoses. Differences between individuals in Lp(a) strata were compared using the Kruskal–Wallis test, Dunn's post hoc test and unbalanced adjusted analysis of covariance with ranked transformed data. The study was approved by the Ethical Review Authority.

A total of 694 subjects (average 3.5 Doppler measurements/subject) met the study criteria and were allocated to the low (n = 434), intermediate (n = 125) and high (n = 135) Lp(a) subgroups (Table S1). The mean age in the groups was 51, 50 and 58 years, and the proportion of women was 37%, 43% and 39%, respectively, at the timepoint of the first Doppler measurement. The initial median V_max and the median follow-up time of V_max progression were similar between subgroups with 1.42 m/s and 3.7 years (low), 1.44 m/s and 2.9 years (intermediate), and 1.42 m/s and 3.0 years (high) (p = 0.82 and 0.35). The median (25th–75th percentile) progression rates were 0.01 (−0.04 to 0.07), 0.02 (−0.03 to 0.14) and 0.03 (−0.02 to 0.12) m/s/year, respectively (p = 0.013) (Fig. 1). The difference in V_max progression between Lp(a) strata remained significant after adjustment for age, sex and baseline V_max (p = 0.027). The V_max progression was significantly higher in the intermediate (p = 0.039) and high (p = 0.003) compared with the reference low Lp(a) subgroups. When including only individuals with an initial V_max of >1.5 m/s, the median rates increased in the high Lp(a) group to 0.05 (−0.04 to 0.20) m/s/year compared to neutral median rates of 0.00 (−0.10 to 0.11) m/s/year in the corresponding low Lp(a) group and 0.00 (−0.04 to 0.13) m/s/year in the intermediate Lp(a) group (p = 0.058). As a reference, individuals with ≥2 Doppler measurements but without a Lp(a) measurement (n = 9195) had no change in annual median V_max (0.00 [−0.07 to 0.08] m/s/year) during a median follow-up of 3.0 years (Fig. 1).

This is the first report associating high plasma Lp(a) with a 3-fold faster V_max progression compared to low Lp(a) in the general population regardless of the presence or absence of AS at any stage at baseline. Although the V_max progression was low compared to individuals with mild-to-moderate AS [5, 8], the V_max progression rates are not linear with time. An early small increase in V_max progression will shorten the time to stages of accelerated V_max progression towards AS. The present study highlights the long-term effects of Lp(a) exposure for AS development and identifies Lp(a) as a potential biomarker of AS progression in the general population. These results identify high Lp(a) as a possible indicator of the need for echocardiographic surveillance of AS development. The clinical implications are, however, limited by the fact that, at present, no therapy exists to slow down AS progression [10].

Jonas Brinck, Karin Littmann and Magnus Bäck: Conceptualization; visualization; investigation; writing; editing and reviewing. Jonas Brinck and Magnus Bäck: Project administration and funding acquisition. Linnea Widman: Methodology/Statistics; reviewing. Daniel Eriksson Hogling, Kenneth Caidahl, Maria Eriksson and Karolina Szummer: Reviewing; editing. All authors approve the final version for publication and agree to be accountable for all aspects of the work.

JB reports institutional grants from Amgen, Novartis and Ionis outside the submitted work, and honoraria from Amgen, Novartis, Sanofi and Ultragenyx. DEH has received institutional honoraria from Amgen. KL reports research grant funding from Amgen and Stockholm Innovation Fund outside the submitted work and honoraria from Amgen and Sanofi. MBs’ institution has received speaker and consultant fees from Amarin, Amgen, Heel, Novartis and Fresenius Kabi. The remaining authors have nothing to disclose in relation to this work.

MB is supported by the Swedish Research Council, Grant Number: 2023-02652; Heart-Lung Foundation, Grant Number: 20240697.

The study was approved by the Ethical Review Authority.