#240 ‒ The confusion around HDL and its link to cardiovascular disease | Dan Rader, M.D.
Dr. Dan Rader, Professor at UPenn, delves into the complex biology of high-density lipoproteins (HDL). He clarifies why high HDL-C levels don't directly equate to low cardiovascular disease risk and explores its metabolism, function, and association with neurodegenerative diseases, hinting at future therapeutic interventions.
Deep Dive Analysis
16 Topic Outline
Introduction to Lipoproteins and HDL Biology
Clarifying ApoA and LP(a) Nomenclature
Genesis and Maturation of High-Density Lipoproteins (HDL)
HDL Metabolism Differences in Humans vs. Other Mammals
HDL Particle Subclasses and Clinical Relevance
Role of Lipases and CETP in HDL Metabolism
CETP Inhibitors and the 'Good Cholesterol' Hypothesis
Importance of Hard Outcome Trials in Cardiovascular Medicine
SR-B1 Receptor and HDL Clearance
High HDL and Atherosclerosis Risk: Clinical Implications
Niacin's Effect on HDL and Cardiovascular Outcomes
HDL, Triglycerides, and Insulin Resistance
Reverse Cholesterol Transport and Cholesterol Efflux Capacity
Measuring HDL Functionality and Future Clinical Assays
HDL and Neurodegenerative Diseases: The Role of ApoE
Other Potential HDL Functions and Future Frontiers
8 Key Concepts
Lipoproteins
Lipoproteins are complex particles evolved to transport lipids, like oil, within the water-based environment of the blood. They consist of a lipid core and proteins on the surface, enabling sophisticated metabolism and binding to receptors.
ApoA1
ApoA1 (Apolipoprotein A1) is the primary protein characterizing High-Density Lipoproteins (HDL). Unlike ApoB, multiple ApoA1 molecules can be on an HDL particle, and ApoA1 can exchange between particles, making HDL metabolism highly dynamic.
ABCA1
ABCA1 (ATP-binding cassette transporter A1) is a key transport protein responsible for exporting lipids, including cholesterol and phospholipids, from cells to newly secreted ApoA1. This interaction is crucial for the initial formation of nascent HDL particles.
LCAT
LCAT (Lecithin-cholesterol acyltransferase) is an enzyme that rides on nascent HDL particles. It transfers a fatty acid from a phospholipid to free cholesterol, creating a cholesterol ester, which then forms the core of a mature HDL particle.
CETP
CETP (Cholesterol Ester Transfer Protein) is a protein that transfers cholesterol esters between ApoB-containing lipoproteins and HDL. Its activity significantly modifies HDL particle size and composition, and its inhibition leads to elevated HDL cholesterol levels.
SR-B1
SR-B1 (Scavenger Receptor B1) is a major HDL receptor, primarily found on liver cells. It binds to HDL particles and selectively removes cholesterol esters from them, releasing the cholesterol-depleted HDL back into circulation for reuse.
Reverse Cholesterol Transport (RCT)
Reverse Cholesterol Transport is a physiological process where cholesterol is picked up from peripheral tissues, like artery walls, by ApoA1 and HDL, and then transported back to the liver for excretion. This process is thought to be protective against atherosclerosis.
Cholesterol Efflux Capacity
Cholesterol efflux capacity measures the effectiveness of HDL in removing cholesterol from cells, particularly macrophages. This functional measurement of HDL is considered a better predictor of atherosclerotic cardiovascular disease risk than static HDL cholesterol levels.
8 Questions Answered
Lipoproteins are large complexes that transport lipids, which are insoluble in water, through the bloodstream. They are essential for moving fats and cholesterol throughout the body for energy and other functions.
ApoA (specifically ApoA1, with a capital 'A') is the main protein of HDL, while LP(a) (lipoprotein little a, with a lowercase 'a') is a distinct lipoprotein particle that is a subset of LDL and a significant risk factor for cardiovascular disease.
HDL formation begins with ApoA1 secreted by the intestine and liver, which then acquires lipids (phospholipids and free cholesterol) from cells via ABCA1. This nascent HDL is then matured by LCAT, which converts free cholesterol into cholesterol esters, forming the core of the mature HDL particle.
While historically considered 'good cholesterol,' studies on CETP inhibitors and genetic conditions like SR-B1 deficiency show that simply raising HDL cholesterol levels does not directly translate to reduced cardiovascular risk. The *functionality* of HDL, rather than just its quantity, is more important.
Insulin resistance is strongly associated with lower HDL cholesterol. HDL cholesterol acts as an inverse barometer of triglyceride metabolism efficiency, reflecting chronic triglyceride excursions and other metabolic effects of insulin resistance over time.
RCT is the process by which HDL picks up excess cholesterol from peripheral cells, including macrophages in artery walls, and transports it back to the liver for excretion. This process is believed to protect against the initiation and progression of atherosclerotic plaque.
Yes, 'cholesterol efflux capacity,' which measures HDL's ability to remove cholesterol from cells, has been shown to be a better predictor of cardiovascular disease risk than HDL cholesterol levels. Efforts are underway to develop a clinically available assay for this function.
Observational data suggest that ApoA1 in the brain and CSF may be protective against neurodegenerative diseases, particularly Alzheimer's. This is an active area of research, with a focus on how ApoA1 crosses the blood-brain barrier and interacts with lipid transport in the brain, especially in relation to ApoE isoforms.
8 Actionable Insights
1. Do Not Rely on High HDL-C
Understand that HDL cholesterol itself is not directly and causally protective against atherosclerotic cardiovascular disease, as demonstrated by genetic studies and failed drug trials. Therefore, do not use a high HDL cholesterol level as a reason to forgo necessary preventive therapies like statins if other risk factors warrant treatment.
2. Interpret Low HDL-C as Metabolic Risk
View a low HDL cholesterol level as an integrator of information related to insulin resistance, triglycerides, and inflammation, signaling increased cardiovascular risk even if not directly causal. In cases where treatment decisions are borderline, a low HDL can contribute to tilting towards more aggressive preventive therapy.
3. Understand HDL-C & Triglyceride Link
Recognize that HDL cholesterol levels reflect 24-hour triglyceride metabolism and postprandial triglyceride excursions more comprehensively than a single overnight fasting triglyceride measurement. Higher chronic triglyceride levels lead to lower HDL cholesterol.
4. Aim for Lower ApoB
Consider that humans are less efficient at clearing ApoB-containing lipoproteins compared to other mammals, leading to higher ApoB concentrations and increased risk of atherosclerotic cardiovascular disease. Aiming for lower ApoB levels, potentially around 20 mg/dL, could significantly reduce lifetime ASCVD risk.
5. Avoid HDL Fractionation
Do not rely on HDL fractionation metrics (e.g., HDL1, HDL2, HDL3, or various NMR sizes) for clinically valuable information or to predict cardiovascular risk, as current evidence does not support their utility for this purpose.
6. Exercise Caution with Clomid
If using clomiphene (Clomid) for testosterone replacement, be aware that it can significantly increase desmosterol levels, which may be associated with adverse cardiovascular outcomes, similar to the historical drug triparanol. Monitor desmosterol levels and consider long-term risks, especially with prolonged use.
7. Advocate for HDL Functional Assays
Be aware that cholesterol efflux capacity, a measure of HDL function, is a better predictor of cardiovascular risk than simply measuring HDL cholesterol. As these assays become more widely available clinically in the next 2-3 years, consider using them for a more sophisticated assessment of risk.
8. Consider HDL Particle Number
If available, HDL particle number (HDLP) may offer a slightly better prediction of cardiovascular risk compared to HDL cholesterol, though it remains a static measure.
5 Key Quotes
HDL cholesterol itself is not directly and causally protective against atherosclerotic cardiovascular disease.
Dan Rader
Lipoproteins are these big complexes that really are evolved to transport lipids within the blood. You know, lipids are like oil. They don't mix well with water.
Dan Rader
High HDL is never a reason not to treat someone who would have otherwise merited treatment.
Dan Rader
HDL as a molecule, as a lipoprotein, I think of as a platform. It's a platform for all sorts of proteins and lipids that get transported by HDL in the blood and then transfer off HDL to other things, to ApoB-containing lipoproteins.
Dan Rader
HDL cholesterol, while not causally related to disease, is sort of like an HbA1c for cardiovascular risk factors. It's an integrator of information related to insulin resistance, related to triglycerides, related to inflammation, that in one number, in most people, when it's low, it's telling you something about cardiovascular risk, even though itself, it isn't directly impacting on risk.
Dan Rader