Why don't statins significantly lower Lp(a) levels?

Statins primarily work by upregulating LDL receptors, which effectively clear LDL particles. However, Lp(a) clearance is less dependent on LDL receptors, and the additional apolipoprotein(a) may interfere with binding, thus statins have minimal effect on Lp(a) particle count.

What are the best ways to measure Lp(a) concentration?

While Lp(a) mass is often measured, it can be a weak metric due to variations in particle composition. A more accurate measure is the Lp(a) particle count, which can be determined through methods like agarose gel electrophoresis combined with immunostaining for apolipoprotein B.

Are there any drugs in development to specifically lower Lp(a)?

Yes, an antisense oligonucleotide targeting the synthesis of apolipoprotein(a) is under investigation and in Phase 3 trials. This drug aims to directly inhibit the production of the apolipoprotein component of Lp(a).

What are the roles of ADMA and SDMA as biomarkers?

ADMA (asymmetric dimethylarginine) and SDMA (symmetric dimethylarginine) are biomarkers that can inhibit nitric oxide synthesis, reflecting impaired endothelial function. Elevated levels are associated with increased cardiovascular risk and can be indirectly linked to high homocysteine.

How can we assess oxidative stress and inflammation related to cardiovascular health?

While oxLDL can be measured, markers like myeloperoxidase (MPO) and f2-isoprostanes (via urine test) are considered better indicators of a pro-oxidative state. Inflammation can be assessed with C-reactive protein and fibrinogen.

What is the significance of VLDL remnants in metabolism?

VLDL remnants are triglyceride-rich lipoproteins that have lost triglycerides. They are markers of insulin resistance and can contribute to atherosclerosis. Their identification is complex, and therapies targeting them often involve addressing insulin resistance and carbohydrate restriction.

What is the role of Apolipoprotein C3 in cardiovascular health?

Apolipoprotein C3 is a protein that retards the clearance of triglyceride-rich lipoproteins. Elevated levels of ApoC3-enriched LDL particles have been linked to a lack of benefit from statins in some high-triglyceride populations and are associated with longevity. An antisense molecule targeting ApoC3 production is under development.

What are the latest findings on Omega-3 fatty acids (EPA and DHA) for heart health?

New data suggests that prescription-strength EPA, particularly when used adjunctively with statins, may lead to additional ApoB lowering and potentially improve cardiovascular outcomes. DHA is also noted for its role in lowering ApoC3 and brain health.

Why are red blood cells generally not considered a direct cause of atherosclerosis?

While red blood cells carry more cholesterol molecules than lipoproteins, they do not readily penetrate the arterial wall or undergo oxidation in the same way as atherogenic particles like LDL. Atherosclerosis is primarily driven by the accumulation and oxidation of lipoproteins within the arterial wall.

What lessons can be learned from the personal story shared about Earl?

The story of Earl, who died young from a myocardial infarction due to a lack of proactive cardiovascular care, emphasizes the tragedy of preventable disease and the critical importance of regular health screenings and accurate biomarker assessment.

How has the field of lipidology evolved, and what is Tom Dayspring's approach to learning?

The field is infinitely more complex than previously imagined. Tom Dayspring emphasizes continuous learning from experts, rigorous scientific literature, and a first-principles approach validated by clinical data, rather than relying on unproven theories.

Key Moments

#24 – Tom Dayspring, M.D., FACP, FNLA – Part V of V: Lp(a), inflammation, oxLDL, remnants, and more

Peter Attia MD

People & Blogs3 min read90 min video

Jan 1, 2020|8,112 views|153|10

Lp(a)inflammation oxLDL remnants

Save to Pod

Key Moments

TL;DR

Experts discuss Lp(a), inflammation, oxLDL, and biomarkers for cardiovascular health.

Key Insights

Lp(a) is a distinct and potentially pathogenic LDL particle requiring specific measurement beyond mass.

Statin therapy does not effectively lower Lp(a) particle count, unlike PCSK9 inhibitors which show some effect.

Inflammation, targeted by drugs like IL-1 inhibitors, plays a role in cardiovascular disease, but with potential side effects.

Biomarkers like oxidized LDL, myeloperoxidase (MPO), and F2-isoprostanes can indicate a pro-oxidative state.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) has shown poor predictive value for cardiovascular risk in large trials.

Asymmetric and symmetric dimethylarginine (ADMA/SDMA) are key biomarkers for endothelial dysfunction and kidney health.

UNDERSTANDING LIPOPROTEIN(A) AND ITS CHALLENGES

The discussion begins by clarifying Lipoprotein(a) [Lp(a)], distinguishing it from HDL and emphasizing correct terminology. Lp(a) is an LDL-like particle with an added apolipoprotein (a). Standard Lp(a) mass measurements can be misleading due to the variable weight of apolipoprotein (a). A more accurate assessment involves quantifying Lp(a) particle number, which can be determined through specialized electrophoretic methods, not NMR. Current treatments like niacin offer only modest Lp(a) reduction, while PCSK9 inhibitors may have individual effects. The focus is shifting towards developing therapies that inhibit the synthesis of apolipoprotein (a), the root cause of elevated Lp(a).

THE ROLE OF INFLAMMATION AND CARDIOVASCULAR HEALTH

Inflammation is a critical component of atherosclerosis. Trials involving IL-1 inhibitors have shown positive outcomes by reducing inflammation, although these drugs are expensive and carry risks like increased cancer incidence due to immune system suppression. Low-dose methotrexate is also being investigated for its anti-inflammatory effects in cardiovascular disease. The concept is that reducing systemic inflammation can positively impact vascular health, potentially independent of lipid levels, highlighting the multifactorial nature of cardiovascular risk.

BIOMARKERS FOR OXIDATIVE STRESS AND ENDOTHELIAL DYSFUNCTION

Accurate assessment of oxidative stress and endothelial dysfunction can refine cardiovascular risk prediction. Biomarkers such as oxidized LDL (Ox-LDL), myeloperoxidase (MPO), and F2-isoprostanes are discussed. While Ox-LDL indicates a pro-oxidative state, it's important to understand that plasma LDL isn't truly oxidized; rather, assays often detect minimally oxidized forms or aldehydes on apoB. MPO is a pro-oxidative enzyme, and F2-isoprostanes are byproducts of fatty acid oxidation. These markers can guide nutritional interventions aimed at combating oxidative stress.

EVALUATING LIPASED LIPASE A2 AND ARGININE METABOLITES

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is presented as a less reliable cardiovascular risk biomarker. Large clinical trials using Lp-PLA2 inhibitors failed to show outcome improvements, questioning its utility. The enzyme is involved in oxidizing phospholipids within the arterial wall. In contrast, arginine metabolites like ADMA and SDMA are significant indicators of endothelial dysfunction. Elevated levels suggest impaired nitric oxide production, crucial for vascular health. These biomarkers can be particularly useful in primary prevention to guide aggressive lifestyle modifications.

UNDERSTANDING VLDL REMNANTS AND APO-C3 CONTENT

The concept of VLDL remnants is clarified; they are smaller, triglyceride-depleted particles derived from VLDL. While elevated triglycerides can be an indicator, the presence of apolipoprotein C3 (apo-C3) on LDL particles significantly impacts their clearance and atherogenicity. High apo-C3 enrichment in LDL is linked to higher cardiovascular risk and reduced efficacy of statin therapy in individuals with high triglycerides. Emerging therapies aim to inhibit apo-C3 production, and specific omega-3 fatty acids like DHA are noted for their ability to lower apo-C3.

THE EMERGING ROLE OF OMEGA-3 FATTY ACIDS AND CLINICAL TRIALS

Omega-3 fatty acids, specifically EPA and DHA, are gaining attention beyond general supplementation. Prescription-strength EPA is showing promise in cardiovascular outcome trials, potentially offering additional LDL particle lowering. The vehicle of delivery (esterified vs. free fatty acids) and the emphasis on measuring red blood cell omega-3 levels (omega-3 index) over plasma levels are crucial for assessing efficacy. The upcoming results from major trials are expected to shift the mainstream perspective on omega-3s, particularly for cardiovascular risk reduction.

PERSISTENT CHALLENGES IN LIPID MANAGEMENT AND PERSONALIZATION

Despite advancements, challenges remain in lipid management, particularly for Lp(a). The conversation underscores the need for personalized medicine, where biomarkers guide treatment decisions rather than a one-size-fits-all approach. The complexity of lipid metabolism and the multifactorial nature of cardiovascular disease necessitate a thorough understanding of various pathways and their interplay. This pursuit of knowledge, grounded in scientific evidence and expert consultation, is vital for improving patient outcomes and preventing premature, needless deaths.

Mentioned in This Episode

●Supplements

●Software & Apps

●Companies

●Organizations

●Drugs & Medications

●Concepts

●People Referenced

Common Questions

Lp(a) is an LDL-like particle with an added apolipoprotein(a). It's a concern because it is independently associated with an increased risk of cardiovascular events, and traditional lipid-lowering therapies have limited impact on its levels.

Topics

Health & Longevity Neuroscience & the Brain Oxidative Stress Endothelial Function Medicine & Clinical Lipoprotein Metabolism Cardiovascular Risk Factors Biomarker Analysis

Mentioned in this video

Concepts

vascular endothelial growth factor

Although mentioned in the context of inflammation trials and an IL-1 agonist, it was not substantively discussed.

C-reactive protein

A biomarker for inflammation, mentioned as a factor in stratifying patients for personalized interventions.

Nitric Oxide

A powerful regulatory molecule for vascular reactivity, whose synthesis is dependent on arginine and can be impaired by ADMA and SDMA.

Oxidized LDL

A measure of LDL particles that have undergone oxidation, particularly in the arterial wall, which can be an indicator of a pro-oxidative state.

Apolipoprotein C3

A protein content of LDL particles that retards their clearance and is linked to longevity; its inhibition is being investigated.

Familial hypercholesterolemia

A genetic disorder characterized by high cholesterol levels, which was discussed in the context of undertreated patients leading to tragic outcomes.

Interleukin-1

A target for an anti-inflammatory drug trial, showing positive outcomes but with downsides like increased cancer risk and high cost.

Cystatin C

A biomarker used in conjunction with creatinine to provide a more accurate assessment of kidney function (eGFR).

Fibrinogen

A biomarker mentioned alongside C-reactive protein for assessing inflammation, relevant for patient stratification.

Apolipoprotein B

The main apolipoprotein on LDL particles, which is also measured in Lp(a) mass assays and is a target for statin therapy.

Homocysteine

An amino acid whose elevated levels are associated with greater disease risk, linked to ADMA/SDMA through impaired clearance and nitric oxide production.

Drugs & Medications

PCSK9 Inhibitors

Drugs that increase LDL receptor availability and can potentially lower Lp(a) levels, though not their primary indication.

Statins

A class of drugs that lower LDL cholesterol but do not significantly lower Lp(a) particle count.

Methotrexate

A low-dose anti-inflammatory drug used for conditions like rheumatoid arthritis, with ongoing trials for vascular health.

Software & Apps

Agarose gel electrophoresis

A technique used to separate lipoproteins based on surface charge, allowing for the identification and quantification of Lp(a) particles.

Symmetric dimethylarginine

Another isoform of ADMA that can inhibit nitric oxide production, reflecting endothelial dysfunction and often linked to renal disease.

Myeloperoxidase

A pro-oxidative enzyme secreted by granulocytes, measurable in blood as a signal of a pro-oxidative state.

Lipoprotein phospholipase A2

An enzyme analyzed for its mass or activity, which can oxidize phospholipids on LDL particles; considered a poor biomarker for risk by some.

Asymmetric dimethylarginine

A biomarker that inhibits nitric oxide synthesis and reflects endothelial dysfunction, implicated in cardiovascular disease.

F2-isoprostanes

A biomarker for pro-oxidative states, measurable via a urine test, considered a better marker than oxLDL or MPO.

eGFR

A measure of kidney function, the importance of which can be overlooked in early stages of impairment despite being a major vascular risk factor.

Albumin

A protein measured to assess kidney function, indicating potential membrane issues in glomeruli or blood vessels.

Organizations

NIH

National Institutes of Health, where Peter Atia's mentor shared a story about switching from physics to biology.

American Heart Association

The venue where significant new trial data on EPA is expected to be presented in November.

Companies

Amgen

A company that developed an EPA product (Vascepa/Vazita) and took the FDA to court to allow doctors to share data, leading to increased sales.

True Health Diagnostics

A lab that Tom Dayspring worked with, which absorbed the development of the Lp(a)-ApoB assay.

AstraZeneca

The company that owns Repatha, and was hoping for a combo product with their EPA formulation.

Supplements

Methylated B Vitamins

Used to lower homocysteine levels, particularly in patients with MTHFR mutations, though outcome data is controversial.

DHA

An omega-3 fatty acid that lowers ApoC3 levels and is important for brain health; compared to EPA in trials.

EPA

An omega-3 fatty acid that can lower ApoB and inflammatory markers, with prescription-strength forms showing promise in outcome trials.

Niacin

A vitamin that can lower Lp(a) to a lesser extent than other methods, though its efficacy is debated in this context.

People

Eric Rimm

Mentioned as an advocate of EPA, whose work might be influenced by new findings on omega-3s.

Allen Molin

Director of NHLBI, co-authored a chapter on lipids and apolipoproteins with Tom Dayspring.

Mike Davison

Referred to as calling Tom Dayspring a 'self-taught lipidologist'.

Bill Harris

Developer of the red blood cell phospholipid fatty acid assay, an expert on omega-3 fatty acids.

Locations

Madison Square Garden

The venue where Tom Dayspring attended his first ice hockey game, an experience that significantly impacted him and his son.

Paterson, New Jersey

The city where Tom Dayspring and his friend Earl grew up and went to high school.

Found this useful? Build your knowledge library

Get AI-powered summaries of any YouTube video, podcast, or article in seconds. Save them to your personal pods and access them anytime.

Try Summify free