Lp(a) testing in an FH cascade screening program can identify individuals at high ASCVD risk

Value of Measuring Lipoprotein(a) During Cascade Testing for Familial Hypercholesterolemia

Literature - Ellis KL, Pérez de Isla L, Alonso R et al., - J Am Coll Cardiol. 2019; 73. DOI: 10.1016/j.jacc.2018.12.037

Introduction and methods

Familial hypercholesterolemia (FH) can be diagnosed based on established clinical criteria, but genetic testing is recommended [1]. The reason for this is that a pathogenic FH-causing mutation reflects a lifetime burden of high LDL-c, which implies a higher risk of developing ASCVD in a person with genetically defined FH than in somebody with the same LDL-c level who does not have a mutation [2].

Lp(a) is another established risk factor for ASCVD. Elevated Lp(a) levels are mostly genetically determined [3,4]. Lp(a) levels do not appear to be specifically elevated in FH [5-7], but it has been shown to be an important predictor of ASCVD in FH [6-9].

Cascade screening is a cost-effective approach to identify new cases of FH and to prevent ASCVD [10,11]. Similarly, testing Lp(a) levels may also be suitable for cascade screening. This study tested the hypothesis that testing for Lp(a) is effective in detecting and risk stratifying individuals participating in an FH cascade screening program. To this end, prevalence and yield of new cases of high Lp(a) in relatives of probands with FH and high Lp(a) [systematic screening] were compared with that in relatives of probands with FH and normal Lp(a) [opportunistic screening]. Elevated Lp(a) was defined as ≥50 mg/dL.

The SAFEHEART (Spanish FH Cohort Study) study [12] is an ongoing, long-term nationwide prospective cohort study of genetically defined heterozygous FH patients. Probands with a genetic diagnosis of FH are included, as well as relatives of probands older than 15 years with a genetic diagnosis of FH, and relatives older than 15 but without FH are enrolled as FH-negative controls.

Main results

  • LDL-c was only slightly higher in probands than in relatives (175.0 vs. 165.7 mg/dL, P<0.001), but more probands received statin and/or ezetimibe therapy at inclusion (94.0 vs. 58.6%, P<0.001) and for longer than cascade-screened relatives (15.2 vs. 8.6 years, P<0.001).
  • Lp(a) levels were higher in probands than in relatives (22.3 vs. 18.8 mg/dL, P<0.001).
  • 60.7% Of screened relatives had Lp(a) <30 mg/dL, 14.2% had 30-49 mg/dL, 18.5% had 50-99 mg/dL and 6.6% had Lp(a) >100 mg/dL.
  • Systematic testing in 879 relatives of 222 probands with both FH and elevated Lp(a) revealed that 32.8% had genetic FH alone, 12.5% had only elevated Lp(a), 29.6% had genetic FH plus elevated Lp(a) and 25.1% had neither disorder. Systematic screening identified 1 new case of FH for every 1.6 relatives screened and 1 new case of elevated Lp(a) per 2.4 relatives. One case of FH plus elevated Lp(a) was seen for every 3.4 relatives screened.
  • Opportunistic testing in 1919 relatives of 533 probands with FH (no elevated Lp(a)) revealed that 55.7% had genetic FH alone, 4.0% had elevated Lp(a), 13.1% had genetic FH plus elevated Lp(a) and 27.2% had neither disorder. Opportunistic screening identified 1 new case of FH for every 1.5 relatives screened, 1 new case of elevated Lp(a) per 5.8 relatives and 1 case of FH plus elevated Lp(a) for every 5.8 relatives screened.
  • Screened relatives with elevated Lp(a) showed significantly more hypertension at baseline than those with neither condition, and those with both FH and elevated Lp(a) had higher BMI. Diabetes status and smoking did not differ significantly among groups.
  • During follow-up, 3.2% of screened relatives had an ASCVD event or died from a CV cause. Adjusted analyses suggested that patients with elevated Lp(a) alone (HR: 3.17, P=0.024) and FH alone (HR: 2.47, P=0.036) had a higher risk as compared with those without the disorders. Having both conditions was associated with an >4-fold risk (HR: 4.40, P<0.001).


Testing for elevated Lp(a) in the context of an FH cascade screening program in relatives of probands with genetically defined FH is useful to identify individuals with elevated Lp(a), who have a higher risk of ASCVD, especially if they also have FH. Using a systematic screening approach had a higher yield of cases than an opportunistic approach. Opportunistic screening may, however, be a useful approach to detect probands, with subsequent systematic testing of relatives. The authors suggest that FH cascade screening programs incorporate both systematic and opportunistic testing for elevated plasma Lp(a).

Lp(a) testing in an FH cascade screening program can identify individuals at high ASCVD risk

Systematic screening in relatives of probands with FH and elevated Lp(a) yielded more new cases than opportunistic testing in relatives of those without elevated Lp(a), but both approaches may be useful.

Editorial comment

Tsimikas notes that the Lp(a) hypothesis that lowering Lp(a) will lower CV risk can be tested in the near future, as antisense therapeutics directed at Lp(a) have entered clinical development. Identification of patients with elevated Lp(a) is lacking, despite these advances. He calculates that in the current study, 27.3% of FH patients had elevated Lp(a). He adds that if a threshold of Lp(a) >30 mg/dL would be applied for elevated risk, as this is more strongly supported by epidemiological data, the percentage might be closer to 40%. Moreover, Tsimikas states that it is increasingly becoming clear that patients with FH have elevated Lp(a) levels as compared with the general population. Together, data suggest that almost half of FH patients have elevated Lp(a) at an atherogenic level. The higher risk of aortic valve stenosis that has been associated with higher Lp(a) should also be considered.

The current data suggest that parts of the metabolism of Lp(a) are not explained by LPA genetics, because presumably the relatives had genetics similar to the proband. ‘Although kringle repeats were not reported in the current study, prior data have strongly suggested that, for similar isoform size, patients with homozygous FH have 2-fold higher Lp(a) levels, and patients with heterozygous FH, 1.5-fold higher levels than unaffected siblings.’ This may mean that the LDLR and possibly the LRP1 receptors affect Lp(a) levels.

Measuring Lp(a) in FH patients allows identification of patients with the highest risk of CVD events and death. Overall, Tsimikas thinks there is a strong rationale to consider elevated Lp(a) as part of the clinical syndrome of FH, with >30 mg/dL as the pathophysiologically supported cutoff in general populations. For clinical diagnosis of FH, elevated Lp(a) should put patients in the highest risk category.

The data showed that there was room for improvement in lowering LDL-c, as patients were not treated with niacin, colesevelam or PCSK9 inhibitors, and only 3 were on apheresis. ‘In addition, it has to be acknowledged that the measure called “LDL-C” contains the content of Lp(a)-cholesterol in it, which can account for 30% to 45% of “LDL-C”, and the “LDL-C” levels of patients with elevated Lp(a) cannot be reduced to low levels if the Lp(a) remains elevated.’ This calls for specific Lp(a)-lowering therapies.

Practice pathways need to be established to screen and identify the most appropriate patients who might benefit from early diagnosis and future therapies; not only relatives of those with FH, but also of persons identified with Lp(a)-mediated CVD. ‘Because Lp(a) is transmitted in a codominant fashion, approximately 0.5 subjects will be identified for every 1 screened, making this a highly successful cascade screening to identify preclinical elevated risk.’


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Find this article online at J Am Coll Cardiol

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