Why Do Some People With Very High Lipoprotein(a) Have Clean Arteries?

Lipoprotein(a), or Lp(a), has been a major focus in cardiovascular research for years. Elevated levels are strongly linked to increased risks of heart attacks, strokes, and atherosclerosis (plaque buildup in arteries). Yet, a paradox exists—some individuals with very high Lp(a) levels have clean coronary arteries and show no signs of cardiovascular disease (CVD).

This raises an important question: Why do some people with high Lp(a) remain free from cardiovascular complications?

While the full answer is still unknown, researchers have identified several possible explanations. Let’s explore the key factors behind this medical mystery.

1. Genetic Variability: Not All Lp(a) Is Created Equal

The LPA gene controls both Lp(a) levels and structure, but its influence is more complex than a simple “high or low” measurement. Genetic differences impact how harmful Lp(a) is.

• Kringle IV-2 Repeats: The apolipoprotein(a) component of Lp(a) varies in size based on the number of kringle IV-2 repeats. Fewer repeats result in smaller, denser, and more atherogenic particles. More repeats may produce a less harmful form, even when Lp(a) levels are high.
• Single Nucleotide Polymorphisms (SNPs): Specific variations in the LPA gene influence how pro-inflammatory or pro-thrombotic Lp(a) is. Some SNPs may reduce the molecule’s tendency to promote atherosclerosis.
• ApoB Context: Lp(a) contains apolipoprotein B (ApoB), a key protein in atherogenic lipoproteins. However, some individuals may have Lp(a) variants that interact differently with LDL receptors, reducing their impact on plaque buildup.

These genetic differences mean that two people with the same Lp(a) level could have vastly different risks for cardiovascular disease.

2. Oxidized Phospholipids (OxPL): The Real Culprit?

One of the key ways Lp(a) promotes cardiovascular disease is through oxidized phospholipids (OxPL), highly inflammatory molecules that trigger immune responses and drive plaque formation.

• Some individuals with high Lp(a) have lower OxPL content, reducing inflammation and limiting arterial damage.
• Studies suggest that OxPL may be a better predictor of cardiovascular risk than Lp(a) itself. Measuring OxPL levels alongside Lp(a) could provide a clearer risk assessment.

This variation in OxPL content could explain why some people with very high Lp(a) remain free from cardiovascular disease despite their lab results.

3. Protective Factors: The Body’s Built-In Defense System

While high Lp(a) is a risk factor, other protective mechanisms can counterbalance its effects. Some individuals benefit from a combination of biological and lifestyle-related defenses.

• Low Traditional Risk Factors: If someone has low LDL cholesterol, avoids smoking, maintains a healthy weight, and has normal blood pressure, their overall cardiovascular risk remains low despite high Lp(a).
• Favorable Clotting Profiles: Lp(a) contributes to cardiovascular risk by promoting blood clots. However, differences in fibrinolysis (the body’s ability to break down clots) may make some individuals less susceptible to clot formation.
• Anti-Inflammatory Resilience: Some individuals naturally have lower systemic inflammation, which may reduce the damaging effects of Lp(a)-related oxidative stress.

These protective factors highlight why cardiovascular risk isn’t determined by Lp(a) alone—it’s part of a broader, interconnected risk profile.

4. Heterogeneity in Lipoprotein(a)’s Function

While Lp(a) is often considered harmful, some researchers believe it may serve important physiological roles, depending on the individual.

• Wound Healing and Vascular Repair: Some evidence suggests Lp(a) contributes to tissue repair and endothelial healing. In certain cases, these beneficial functions may overshadow its atherogenic properties.
• Variability in Biological Activity: Just as not all LDL cholesterol is equally harmful, different Lp(a) subtypes may vary in their biological activity. Some forms may be more inert, making them less likely to cause damage.
• Hormonal and Metabolic Influences: Factors like insulin sensitivity, thyroid function, and sex hormones can modify how Lp(a) behaves. Some individuals may have metabolic conditions that reduce Lp(a)-related harm.

These variations mean Lp(a) is not a one-size-fits-all risk factor—context matters.

5. The Role of Lifestyle and Environment

Lifestyle plays a critical role in determining whether high Lp(a) translates into actual cardiovascular disease. While Lp(a) levels are largely genetic, lifestyle choices influence how much damage it causes.

• Regular Exercise: Physical activity improves endothelial function, reduces inflammation, and enhances blood vessel elasticity. These benefits may counteract some of Lp(a)’s harmful effects.
• Anti-Inflammatory Diet: Diets rich in omega-3 fatty acids, antioxidants, and polyphenols (found in nuts, seeds, fruits, and vegetables) may help neutralize oxidative stress and lower cardiovascular risk.
• Metabolic Health: Managing insulin resistance, reducing visceral fat, and maintaining healthy blood sugar levels all contribute to a lower overall cardiovascular burden.

Although lifestyle changes don’t lower Lp(a) directly, they dramatically reduce the overall risk of cardiovascular disease.

What Does This Mean for Patients With High Lipoprotein(a)?

If you have elevated Lp(a), remember that cardiovascular risk is multi-factorial. A high Lp(a) level alone doesn’t determine your fate. Here are key steps to take:

• Assess Your Full Risk Profile: Work with a lipidologist to evaluate LDL cholesterol, blood pressure, diabetes status, inflammation markers, and family history.
• Focus on Modifiable Risks: While you can’t change your genetics or directly lower Lp(a) with lifestyle, you can manage diet, exercise, smoking, weight, and other risk factors.
• Monitor New Therapies: Treatments targeting Lp(a), such as antisense oligonucleotides (e.g., pelacarsen), are in clinical trials. These therapies may offer future solutions for lowering elevated Lp(a) levels.
• Consider Additional Testing: Measuring oxidized phospholipids (OxPL), LDL particle count, and inflammatory markers may provide a clearer picture of your actual cardiovascular risk.

Summary

The mystery of why some people with high Lp(a) avoid cardiovascular disease highlights the complexity of human biology. Genetic variability, OxPL content, protective mechanisms, and lifestyle all shape individual outcomes.

As research uncovers more about this enigmatic lipoprotein, we gain new tools to predict and prevent cardiovascular disease. If you have high Lp(a), focus on what you can control while staying optimistic about future advancements.

This blog aims to shed light on this fascinating topic while empowering readers with practical knowledge. If you’d like to explore Lp(a) further or have questions about cardiovascular health, feel free to reach out!

References

1. Kamstrup, P. R., & Nordestgaard, B. G. (2021). Lp(a) concentrations and incident atherosclerotic cardiovascular disease (ASCVD). Arteriosclerosis, Thrombosis, and Vascular Biology. Available at: AHA Journals.
2. Tsimikas, S., & Moriarty, P. M. (2024). Genetics and pathophysiological mechanisms of lipoprotein(a). Journal of the American Heart Association. Available at: AHA Journals.
3. Wilson, D. P., et al. (2022). Lipoprotein(a): A genetically determined, causal, and prevalent risk factor for cardiovascular diseases. Arteriosclerosis, Thrombosis, and Vascular Biology. Available at: AHA Journals.
4. Clarke, R., et al. (2022). Elevated lipoprotein(a) and genetic polymorphisms in the LPA gene predict cardiovascular events. Scientific Reports. Available at: Nature.
5. Virani, S., et al. (2024). Lipoprotein(a) and long-term cardiovascular risk in a multi-ethnic cohort study. Journal of the American College of Cardiology. Available at: JACC.
6. Kostner, K., et al. (2012). Lipoprotein(a) as a cardiovascular risk factor: Current status and future perspectives. PubMed Central (PMC). Available at: PMC.
7. StatPearls Publishing LLC (2024). Lipoprotein A – Overview of cardiovascular risk factors associated with Lp(a). NCBI Bookshelf. Available at: NCBI.
8. Thanassoulis, G., et al. (2022). Ancestry, lipoprotein(a), and cardiovascular risk thresholds: A review of genetic differences and clinical implications. Journal of the American College of Cardiology. Available at: JACC.

Dr. Tashko