Lp(a) as a causal risk factor for cardiovascular outcomes -- ESA consensus statement strengthens evidence

The recent statement, published in the European Heart Journal updates the evidence for the Lp(a) role in aortic valve stenosis and atherosclerotic cardiovascular disease (ASCVD). It provides clinical guidance for testing and treating the increased levels of Lp(a), and considers its inclusion in global risk estimation.

Since the 2015 EAS consensus statement, the following new points have been added:

• Strong evidence for a causal association between Lp(a) concentration and cardiovascular outcomes in different ethnicities. This association is continuous even at low levels of low-density lipoprotein cholesterol.
• Lp(a) is a new risk factor for aortic valve stenosis.
• Lifelong very low Lp(a) concentrations may associate with diabetes mellitus.
• does not support Lp(a) as a risk factor for venous thromboembolism and impaired fibrinolysis.
• Lp(a) should be measured at least once in adults.
• Specific effective Lp(a)-lowering therapies are in Phase II/III clinical trials.
• A high Lp(a) concentration should be interpreted in the context of other risk factors and absolute global cardiovascular risk, and addressed through intensified lifestyle and risk factor management.

To cover these new additions, the authors released the following consensus:

Influence of genetics and ethnicity on Lp(a)

• Lp(a) concentration is predominantly determined by genetics (>90%), more than any other lipoprotein.
• Several frequent and rare functional SNPs profoundly modify the inverse correlation of isoform size and Lp(a) concentration.
• The K-IV repeat polymorphism explains most of the variability in Lp(a) concentration.
• Lp(a) level varies with ethnicity (in increasing order: Chinese, White, South Asian, and Black individuals).

Lp(a) and clinical outcomes

• Observational and genetic evidence convincingly demonstrates that high Lp(a) concentration is causal for ASCVD, AVS, and cardiovascular and all-cause mortality in men and women and across ethnic groups.
• The risk of ischaemic stroke and heart failure increases at higher Lp(a) levels than those associated with the risk of myocardial infarction and AVS.
• The relation between Lp(a) concentration and these outcomes is continuous; elevated Lp(a) is a risk factor even at very low LDL-C concentrations.
• Lp(a) is not a risk factor for venous thromboembolism.
• In children, an Lp(a) >30 mg/dL (>75 nmol/L) is associated with increased risk of (recurrent) arterial ischaemic stroke.

Proposed mechanisms for the pathogenicity of Lp(a) in ASCVD and AVS

• Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the OxPLs carried by Lp(a).
• High Lp(a) induces the expression of inflammatory and calcification genes in vascular and valvular cells and associates with increased incidence and progression of AVS.
• A potential role for Lp(a) in pro-thrombotic and anti-fibrinolytic activity in vivo remains unproven.

Consensus panel recommendations for testing of Lp(a)

• Lp(a) should be measured at least once in adults to identify those with high cardiovascular risk.
• Cascade testing for high Lp(a) is recommended in the settings of FH, family history of (very) high Lp(a), and personal or family history of ASCVD.
• Screening is also recommended in youth with a history of ischaemic stroke or a family history of premature ASCVD or high Lp(a) and no other identifiable risk factors.

Consensus panel recommendations for the measurement of Lp(a)

• Laboratories should use an Lp(a) assay that is insensitive to apo(a) isoform and traceable to official reference materials.
• Rather than absolute values, clinical guidelines should consider using risk thresholds with 'grey' zones (e.g., 30–50 mg/dL or 75–125 nmol/L) to either rule-in (≥50 mg/dL; 125 nmol/L) or rule-out (<30 mg/dL; 75 nmol/L) cardiovascular risk.
• Measurement of Lp(a) should be in molar units if available. If not, the units in which the assay is calibrated should be used for reporting.

Consensus panel recommendations for the management of high Lp(a) concentration

• Among patients with high Lp(a), all cardiovascular risk factors should be comprehensively addressed as per guideline recommendations.
• In the absence of specific Lp(a)-lowering therapies, early risk factor management is recommended for individuals with elevated Lp(a), taking into account their absolute global cardiovascular risk and Lp(a) level.
• Niacin is not recommended for Lp(a) lowering.
• Lipoprotein apheresis can be considered in patients with very high Lp(a) and progressive cardiovascular disease despite optimal management of risk factors.

The researchers wrote in their conclusion, "this statement reinforces the evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are crucial for confirming clinical benefit for aortic valve stenosis and cardiovascular disease." 

Reference:

Florian Kronenberg, Samia Mora, Erik S G Stroes, Brian A Ference, Benoit J Arsenault, Lars Berglund, Marc R Dweck, Marlys Koschinsky, Gilles Lambert, François Mach, Catherine J McNeal, Patrick M Moriarty, Pradeep Natarajan, Børge G Nordestgaard, Klaus G Parhofer, Salim S Virani, Arnold von Eckardstein, Gerald F Watts, Jane K Stock, Kausik K Ray, Lale S Tokgözoğlu, Alberico L Catapano, Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement, European Heart Journal, 2022;, ehac361, https://doi.org/10.1093/eurheartj/ehac361