The following are key points to remember from this European Atherosclerosis Society consensus statement on lipoprotein(a) [Lp(a)] in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis:

1. The 2022 European Atherosclerosis Society Lp(a) consensus statement updates evidence for the role of Lp(a) in ASCVD and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation.
2. Observational and genetic evidence strongly support the conclusion that high Lp(a) concentration is causal for ASCVD, aortic valve stenosis, and cardiovascular and all-cause mortality in men and women and across ethnic groups. Elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol (LDL-C). Levels increase until age 5 years and gradually increased to adult levels by 20 years. In children, an Lp(a) >30 mg/dL (>75 nmol/L) is associated with increased risk of (recurrent) arterial ischemic stroke. Lp(a) is not a risk factor for venous thromboembolism.
3. Lp(a) levels are reported in mass units as mg/dL and molar units as nmol/L. Whereas both units are used in clinical practice, the panel suggests a conversion factor of 2.5 [Lp(a) 2.5 nmol/L = 1 mg/dL]. Lp(a) concentration ranges between <0.1 mg/dL and >300 mg/dL (<0.2–750 nmol/L).
4. Lp(a) is predominantly (>90%) determined by genetic variability at the LPA locus. The Kringle-IV (K-IV) repeat polymorphism explains approximately 30–70% of the variability in concentration. Expression of a low number (<23) of K-IV repeats is characterized by small apolipoprotein(a) [apo(a)] isoforms and markedly higher Lp(a) concentration compared with those with only large isoforms. Measurement of Lp(a) concentration is sufficient for Lp(a)-related risk estimation without the need for genotyping, polygenic risk scores, or investigation of expressed apo(a) isoform sizes.
5. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the OxPLs carried by Lp(a). The atherogenicity or risk associated with Lp(a) on a per-particle basis may exceed that of LDL by cell signaling rather than Lp(a) accumulation in plaque. Imaging studies revealed that Lp(a) initiates inflammation in the arterial wall, and in advanced coronary artery disease, high Lp(a) levels were associated with accelerated progression of coronary calcium and the necrotic core. A potential role for Lp(a) in prothrombotic and antifibrinolytic activity in vivo remains unproven.
6. High Lp(a) induces the expression of inflammatory and calcification genes in vascular and valvular cells and both micro and macro calcification of the aortic valve, particularly in younger persons in whom risk is increased threefold at an Lp(a) >80th percentile (about 50 mg/dL) vs. lower levels (15% vs. 4%). High Lp(a) may also promote faster progression of aortic stenosis, culminating in earlier aortic valve replacement or death.
7. In the primary prevention setting, elevated Lp(a) is associated with several ASCVD outcomes, as well as aortic valve stenosis and cardiovascular and all-cause mortality. Lp(a) levels above the 75th percentile increased the risk for aortic valve stenosis and myocardial infarction, whereas higher levels (>90th percentile) were associated with increased risk for heart failure. The risk for cardiovascular mortality and ischemic stroke only increased at very high levels (>95th percentile).
8. In secondary prevention, elevated Lp(a) is associated with an increased risk of major adverse cardiovascular events. In a meta-analysis, Lp(a) levels >80th percentile were significantly predictive of recurrent events in statin-treated patients with coronary artery disease (odds ratio, 1.40), but not when baseline LDL-C was <130 mg/dL. However, in a patient-level meta-analysis, elevated Lp(a) at baseline and on-statin showed an independent approximately linear relationship with CVD risk.
9. Lifestyle interventions have minimal impact on Lp(a). Lp(a) levels can increase markedly (2-3x) by growth hormone, nephrotic syndrome, pregnancy, peritoneal dialysis, and acute and chronic inflammation. Statins have variable effects, which may be a very large increase. Levels are 5-10% higher in women than men, and median Lp(a) increases sequentially in Chinese, White, South Asian, and Black individuals. The 50th percentile in Black people is equated with the 80th percentile in White people.
10. The European Atherosclerosis Society panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Incorporating Lp(a) to risk algorithms does little for risk discrimination, but the impact may be very high. An Lp(a) level of 100 mg/dL (∼250 nmol/L) approximately doubles the risk of ASCVD irrespective of baseline absolute risk. For individuals with a higher baseline risk, the magnitude of absolute increase in ASCVD risk is greater (e.g., from 20-40% risk) than for those with lower baseline risk (from 5-10% risk).
11. Rather than assigning Lp(a) >50 mg/dL as a risk enhancer as was done previously by European and US guidelines, the panel recommended more intensive risk factor management with increasing Lp(a) concentration and increasing baseline risk to personalize cardiovascular risk management. There are data to provide estimates of LDL-C reduction needed to reduce global cardiovascular risk to a similar extent as the risk attributable to high Lp(a). The increased risk of major cardiovascular events caused by lifetime exposure to approximately 120 nmol/L (about 50 mg/dlL higher Lp(a) can be mitigated at all ages by a lifetime exposure to approximately 0.5 mmol/L (21 mg/dL) lower LDL-C.
12. Mendelian randomization studies suggest that large absolute reductions in Lp(a) concentration (>50-100 mg/dL) are needed for a clinically meaningful reduction in the risk of ASCVD events in a ‘short-term’ (<5 years) clinical trial. Lipoprotein apheresis is an option for very high Lp(a) with progressive CVD despite optimal management of risk factors. In major studies with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, the absolute cardiovascular risk reduction was higher at higher baseline Lp(a) levels. In the FOURIER trial, the absolute risk reduction was 2.41% vs. 1.41% with an Lp(a) >50 vs. <50 mg/dL, and in the ODYSSEY OUTCOMES trial, 3.7% at Lp(a) >60 mg/dL vs. 0.5% in the lowest Lp(a) quartile. However, PCSK9 inhibitors are not recommended for Lp(a) lowering. Niacin has modest lowering effects on Lp(a) but is not recommended based on data from two outcomes trials. Aspirin Is not recommended to decrease risk attributable to Lp(a). Novel antisense and small interfering RNA (siRNA) treatments that target apo(a) production in the hepatocyte lower Lp(a) concentration with mean decreases of 80% and 72%. One of the concerns is the relationship between very low levels of Lp(a) and diabetes.

Clinical Topics: Cardiovascular Care Team, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Valvular Heart Disease, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Advanced Lipid Testing, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins, Acute Heart Failure

Keywords: Antifibrinolytic Agents, Aortic Valve Stenosis, Apolipoproteins A, Atherosclerosis, Cholesterol, LDL, Coronary Artery Disease, ESC22, ESC Congress, Heart Disease Risk Factors, Heart Failure, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Inflammation, Ischemic Stroke, Life Style, Lipoprotein(a), Myocardial Infarction, PCSK9 protein, human, Peritoneal Dialysis, Primary Prevention, RNA, Small Interfering, Secondary Prevention, Venous Thromboembolism

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