The intricacies of Lipoprotein(a) [Lp(a)] measurements and how they relate to the risk of atherosclerosis and aortic valve complications.

Interpreting Lp(a) Levels:

Different consensus guidelines suggest varying thresholds for high-risk Lp(a) levels, with some indicating levels over 100 nanomoles per liter or 125 nanomoles per liter as high-risk.

• Elevated Lp(a) levels are considered a significant risk factor for atherosclerosis, but it's noted that not all individuals with high Lp(a) levels will manifest atherosclerosis or aortic stenosis.

Lp(a) Risk Assessment:

High Lp(a) levels, while highly heritable and a major cause of atherosclerosis, may not always directly translate to disease manifestation in every individual.

• Clinicians assessing individuals with very high Lp(a) levels should consider them at very high risk; however, advancements in additional tests may help further evaluate individual risk profiles in the future.

Lp(a) Thresholds:

Guidelines distinguish between risk thresholds based on mass concentrations (milligrams per deciliter) and molar concentrations (particle numbers).

• Normal mass concentrations are considered under 30 milligrams per deciliter, with significant risk typically observed at levels of 50-70 milligrams per deciliter.

• For particle counts, normal levels are under 15 nanomoles per liter, with thresholds for high risk around 100-125 nanomoles per liter, approaching the 80th and 90th percentiles of the population distribution.

Factors Influencing Risk:

Other risk factors such as high LDL cholesterol, non-HDL cholesterol, apoB levels, hypertension, smoking, coagulation disorders, diabetes, and familial history can exacerbate the risk associated with elevated Lp(a) levels.

• Evaluating the collective impact of these risk factors alongside high Lp(a) levels can help gauge individual risk more comprehensively.

Genetic Influence and Drug Therapy:

Individuals with exceptional genetics or those on lipid-lowering medications can achieve low levels of Apolipoprotein B (APO B) and LDL cholesterol, indicating effective lipid management.

• Despite having optimal APO B levels, there is still a need to measure Lp(a) due to its genetic abnormality and potential risk implications.

Cascade Testing and Risk Assessment:

Cascade testing can be advisable for family members to assess Lp(a) levels due to its genetic nature.

• Recent trials with PCSK9 inhibitors, such as the Fier and Odyssey trials, have shown benefits in lowering both APO B and Lp(a) levels, which can further reduce cardiovascular risk and residual events.

Residual Risk and LP(a) Reduction:

Even with APO B levels at 30 or lower, there may still be residual risk, especially related to elevated Lp(a) levels.

• Lowering Lp(a) levels significantly, possibly by 100 milligrams per deciliter, is suggested to mitigate atherosclerotic risk, beyond what current treatments can achieve.

Drug Development and Future Perspectives:

Existing treatments like statins may not effectively reduce Lp(a) levels, even when achieving LDL cholesterol goals, indicating the need for alternative therapies.

• New drugs under development that target Lp(a) directly show promise in significantly lowering Lp(a) levels, offering potential solutions to address residual cardiovascular risk associated with elevated Lp(a).