#210 - Lp(a) and its impact on heart disease | Benoît Arsenault, Ph.D.
Benoît Arsenault, a research scientist, discusses Lp(a), the most significant genetically inherited trait for cardiovascular disease risk. The episode covers Lp(a)'s biology, measurement, and its role in ASCVD and aortic stenosis, alongside current and future therapies like statins, PCSK9 inhibitors, and antisense oligonucleotides.
Deep Dive Analysis
17 Topic Outline
Benoit Arsenault's Introduction to Lp(a) Research
Epidemiology and Historical Challenges of Lp(a) Measurement
Genetic Insights into Lp(a) and Cardiovascular Risk
Lp(a) Biology, Production, and Measurement Methods
Statin Effects on Lp(a) and its Unique Atherogenicity
Apolipoprotein(a) Structure and Plasminogen Homology
Lp(a)'s Role in Aortic Valve Stenosis
Lp(a) Isoform Size vs. Particle Number for Risk
Inheritance and Clinical Testing of Lp(a) Levels
Physician Awareness and Holistic Management of High Lp(a)
Variability in Disease Expression with High Lp(a)
Lp(a) Association with Other Cardiovascular Diseases
Niacin's Ineffectiveness in Lowering Lp(a) and Improving Outcomes
PCSK9 Protein Biology and its Impact on LDL Receptors
PCSK9 Inhibitors: Effects on Lp(a) and Residual Risk
Future Therapies: Antisense Oligonucleotides and siRNA for Lp(a)
Horizon Trial and the Future of Lp(a) Treatment
7 Key Concepts
Lp(a) (Lipoprotein(a))
A supercharged low-density lipoprotein (LDL) particle that is particularly nefarious due to an additional apolipoprotein(a) (Apo(a)) covalently bound to the ApoB-100 of an LDL particle. It is a significant genetically inherited risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis.
Apolipoprotein(a) (Apo(a))
A glycoprotein that binds to an LDL particle, forming Lp(a). Its structure includes Kringle repeats, particularly Kringle 4 type 2 (which dictates isoform size variability) and Kringle 4 type 9 (responsible for covalent binding to ApoB). Apo(a) shares sequence homology with plasminogen, influencing thrombosis.
Mendelian Randomization
A research method that uses genetic variants as instrumental variables to infer causal relationships between a modifiable risk factor (like Lp(a) levels) and a disease outcome. It leverages the random assortment of genes at conception to mimic a randomized controlled trial, helping to overcome confounding in observational studies.
Oxidized Phospholipids (OxPLs)
These are much higher on Lp(a) particles compared to LDL particles. OxPLs on Lp(a) send signals that drive pro-inflammatory, pro-thrombotic, and pro-calcifying processes in cells like endothelial cells, smooth muscle cells, macrophages, and valvular interstitial cells, making Lp(a) more atherogenic.
Aortic Valve Stenosis
A disease characterized by the calcification and narrowing of the aortic valve, significantly associated with high Lp(a) levels. Lp(a) is believed to initiate and accelerate this process by promoting osteoblastic changes in valvular interstitial cells and contributing to inflammation and calcification.
PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9)
A protein that regulates the LDL receptor. PCSK9 can bind to the LDL receptor inside cells, leading to its degradation in the lysosome, or extracellularly, preventing the LDL receptor from binding LDL particles and hindering its recycling, thereby reducing LDL clearance from the blood.
Antisense Oligonucleotides (ASOs) / siRNA
A new class of therapeutic agents designed to lower Lp(a) levels. ASOs are single-stranded synthetic nucleic acids that bind to specific mRNA sequences, preventing the production of the target protein (Apo(a)). siRNA (small interfering RNA) are double-stranded RNA molecules that silence gene expression by degrading specific mRNA. Both aim to reduce Apo(a) production in the liver.
11 Questions Answered
Lp(a) is a lipoprotein particle similar to LDL but with an additional apolipoprotein(a) attached, making it highly atherogenic. It is the single most important genetically inherited trait for atherosclerotic cardiovascular disease (ASCVD) risk, affecting about 15-20% of the population.
Early studies on Lp(a) often yielded negative results due to unreliable assays that couldn't accurately measure its complex structure. Interest was revived around 2009-2011 by genetic association studies (GWAS) and Mendelian randomization, which convincingly linked genetic variants associated with high Lp(a) levels to cardiovascular events, bypassing assay limitations.
Lp(a) is measured using immunoturbidometric assays. The preferred measurement is in nanomoles per liter (nmol/L) as it provides a better sense of the number of Lp(a) particles, which is the most important factor for risk assessment, rather than milligrams per deciliter (mg/dL) which can be influenced by isoform size.
Lp(a) is more atherogenic than standard LDL particles on a per-particle basis, primarily due to carrying a higher number of oxidized phospholipids. These oxidized phospholipids drive pro-inflammatory, pro-thrombotic, and pro-calcifying signals, contributing to plaque formation, progression, and aortic valve stenosis.
Statins primarily lower LDL by upregulating LDL receptors on liver cells, which clear ApoB-containing lipoproteins. However, statins do not effectively lower Lp(a) and may even cause a small increase, because Lp(a) is not catabolized by the LDL receptor in the same way as LDL.
No, genetic studies have shown unequivocally that Lp(a) isoform size itself is not directly associated with the risk of heart attacks and strokes. Instead, the isoform size matters because it is associated with different levels (number) of Lp(a) particles, and it is the number of Lp(a) particles that truly dictates risk.
Lp(a) follows an autosomal dominant pattern of inheritance, meaning you typically need only one genetic variant from a parent to have high Lp(a). However, due to the complexity of many variants, you cannot reliably predict offspring's Lp(a) levels from parents' levels; direct measurement is required. The Lp(a) gene is fully expressed by age two, and levels are relatively stable through adulthood, so testing can be done early.
Physician awareness is low partly because guidelines for Lp(a) measurement are relatively new and take time to be widely adopted. Additionally, some physicians are reluctant to measure it due to the historical lack of specific treatments, fearing it might cause anxiety without offering solutions. Increased education and the emergence of new therapies are crucial to improve awareness.
Niacin can reduce Lp(a) levels by about 20-30% by inhibiting its production. However, large cardiovascular outcome trials (AIM-HI, HPS2-THRIVE) have shown no cardiovascular benefits from niacin treatment, despite its effects on lipids, and it carries significant side effects like flushing. Therefore, niacin is generally not recommended for Lp(a) lowering.
PCSK9 inhibitors reduce Lp(a) levels by approximately 25-30% on average, primarily by reducing the production rate of apolipoprotein(a) in the liver. The variability in reduction can be significant, and while beneficial for LDL, this reduction in Lp(a) may not be sufficient to fully ameliorate Lp(a)-specific residual risk.
Antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) are highly promising. These therapies target the LPA gene to reduce the production of apolipoprotein(a) in the liver, leading to substantial (e.g., 80% or more) reductions in Lp(a) levels. Clinical trials, such as the Horizon trial for an ASO, are currently underway to assess their impact on cardiovascular outcomes.
10 Actionable Insights
1. Demand LP(a) Test
Demand your physician checks your LP(a) level, as there’s a significant chance it’s elevated (10-20% of the population) and many doctors don’t routinely test it. A milligram per deciliter mass measurement is likely sufficient if nanomoles/L is not available, as both methods will identify high-risk levels.
2. Aggressively Manage All CV Risk Factors
If you have high LP(a), aggressively manage all other cardiovascular risk factors (smoking, diet, physical activity, body weight, LDL cholesterol, diabetes, blood pressure) to significantly reduce your overall risk of events by up to two-thirds.
3. Aggressive ApoB Lowering & PCSK9
For patients with elevated LP(a), aggressively lower ApoB to a physiological level (30-40 mg/dL) and liberally use PCSK9 inhibitors, which can reduce LP(a) by approximately 30% on average, as part of a comprehensive lipid management strategy.
4. Screen Aortic Valve for Stenosis
If you have elevated LP(a), get a baseline echocardiogram or cardiac MRI to check for early signs of aortic stenosis, as early identification and intervention lead to better outcomes.
5. Measure LP(a) in Children
Measure LP(a) levels in children by age two to five, especially if there’s a family history of early heart attack or stroke, as the gene is fully expressed by age two and levels are stable from age five into adulthood.
6. Avoid Niacin for LP(a) Lowering
Do not use niacin to lower LP(a) levels, despite its ability to reduce LP(a) by 20-30%, because large cardiovascular outcome trials have shown no cardiovascular benefits and significant side effects.
7. Do Not Avoid Statins for High LP(a)
Do not avoid prescribing or taking statins if you have high LP(a), as statin treatment is beneficial in patients with high LP(a) levels, potentially even more so than in those with low LP(a), despite a small potential increase in LP(a) levels.
8. Prefer Nanomole/Liter LP(a) Measurement
When measuring LP(a), ideally seek a lab that provides results in nanomoles per liter, as this gives a more accurate sense of the number of LP(a) particles, which is the most important risk factor.
9. LP(a) Measurement Once in Lifetime
Measure LP(a) once in a lifetime, as its levels are remarkably stable over time and do not require repeated testing for risk assessment.
10. Advocate for Physician Education on LP(a)
Advocate for increased physician education and awareness regarding LP(a) measurement and management, as it is a highly prevalent and important driver of cardiovascular disease often overlooked.
7 Key Quotes
Lp(a) was actually the strongest of them that was predicting residual cardiovascular risk.
Benoit Arsenault
Lp(a) is the single highest genetically inherited trait that confers high risk of ASCVD.
Peter Attia
On a per-particle basis, Lp(a) is much more atherogenic than an equivalent LDL particles.
Benoit Arsenault
It's really the Lp(a) number that matters.
Benoit Arsenault
You cannot predict the phenotype of the offspring from the phenotype of the parents.
Peter Attia
Even though there's no specific therapy for high Lp(a), it doesn't mean you can't do anything.
Benoit Arsenault
If you can hit a 15% relative risk reduction, which ultimately turned into a bigger risk reduction in 2.2 years on a group of patients who show up on the maximum dose of a statin, whose LDL is already at the 10th percentile, you've changed the field of cardiovascular medicine.
Peter Attia
2 Protocols
General Management of High Lp(a) Risk Factors
Benoit Arsenault- Measure Lp(a) levels at least once in a lifetime.
- Target and manage other cardiovascular risk factors including smoking, diet, physical activity, body weight, LDL cholesterol, diabetes, and blood pressure.
- Consider statin therapy to lower LDL cholesterol aggressively, as statins have shown benefits in patients with high Lp(a) by reducing overall cardiovascular risk.
Peter Attia's Clinical Approach to Managing Patients with Elevated Lp(a)
Peter Attia- Aggressively eradicate ApoB by targeting an ApoB level of approximately 30-40 mg/dL (a physiologic level).
- Liberally use PCSK9 inhibitors, as they can reduce Lp(a) by about 30% on average, in addition to their potent ApoB-lowering effect.
- Insist on at least one baseline echocardiogram to check for even the earliest signs of aortic stenosis, as early intervention improves outcomes.