Traditional cholesterol tests can be misleading—understanding LDL particle size and count provides a clearer picture of cardiovascular riskLDL Particle Size
Great post, Ram. I couldn't agree more that LDL-P and ApoB should be the gold standard.
It's frustrating that this thinking is still considered "advanced" when it has such critical real-world implications. My own experience with doctors dismissing a high ApoB reading is what led me to dive deeper into this topic and write about a framework for navigating it: https://mettaquant.substack.com/p/personal-preventive-medicine-part-1
Great post. I realized like you that we need to be advocates for own health. My cardiovascular risk is high since I am a South Asian (just being a South Asian increases your CV risk profile) and I had to plead with my PCP for a Calcium CAC test
Ram-so I have been writing about this for years. I’m on the editorial board of the journal of clinical lipidology, and a board-certified cardiothoracic surgeon. I also wrote Lipoprotein and Lipoprotein disorders: Current Clinical Guidelines with Tom Dayspring and Bill Cromwell. I am happy you wrote about this, but you need to correct the part about particle size. It does not matter and that has been to fitly shown. The size of a pore in the intima is 70nm and every ApoB with the exception of the largest chylomicrons get through the intimal wall, if present in high concentrations, I’ve written extensively about this on Substack
Thank you very much for your detailed and thoughtful comment, Dr. Richman. I very much appreciate it. I believe Peter Attia also has the same view. Please allow me some time to look into and I will make the necessary corrections.
Ram-this is the presentation I gave at Georgetown University Medical alumni and at Grand Rounds at the Medical Center. Check it out when you have time https://youtu.be/RaZvWk7PZCQ?si=CYX5wacG799ijdPE
you learned something. I had trademarked that analogy but then too many people were using it in papers and presentations and just giving me credit when appropriate so I stopped trying to enforce it…too exhausting
Peter and I know each other well. He does a lot with Tom Dayspring now and like I said, Tom, Bill Cromwell and I wrote the International Guidelines for Lipoprotein and Lipid Disorders. Tom did the whole professional section on my website www.lipidcenter.com. Feel free to go there. If you really want to deep dive and learn, Bill Cromwell and Alan Sniderman are the guys who are recognized internationally as the experts on ApoB and LDL-P
Depending on the data analysis employed, conflicting data have been reported over the past 30 years regarding the relationship of LDL particle size, particle number, and quantities of small LDL or large LDL particles with various ASCVD outcomes.
The interrelationships of particle size, particle number, and particle subclasses confound the strength of each biomarker's association with CVD risk.
Analyses that adjust for the confounding interactions between these measures yield uniquely different insights versus data that do not address this.
When LDL particle size and LDL particle number are adjusted for one another, only LDL particle number remains significantly predictive of events. (1-6)
Additionally, small LDL particles have a strong inverse relationship with large LDL particles. (6, 7)
In older reports that fail to adjust for this confounder effect, small LDL size appears more strongly related to CV risk than large LDL.
Data that address confounding of small and large LDL size demonstrate both small and large LDLs are significantly associated with CVD risk independent of each other, traditional lipids, and established risk factors, with no association between LDL size and CVD risk after accounting for the concentrations of the two subclasses. (6, 7)
Thus, rather than small dense LDL (sdLDL) being differentially atherogenic, analysis designed to address confounder variable effects demonstrates that small and large LDL particles have a similar strength of association with ASCVD risk.
These relationships underscore expert panel recommendations finding insufficient evidence to advocate measuring LDL size or subclasses to assist ASCVD risk assessment or management.
1. Contois JH, et al. Clin Chem. 2009;55:407-19.
2. Brunzell JD, et al. J Am Coll Cardiol. 2008;51:1512-24.
3. Lamarche B, et al. Circulation. 1997;95:69-75.
4. Mora S, et al. Circulation. 2009;119:931-9.
5. Blake GJ, et al. Circulation. 2002;106:1930-7.
6. Otvos JD, et al. Circulation. 2006;113:1556-63.
7. Mora S, et al. Atherosclerosis. 2007;192:211-7.
Great post, Ram. I couldn't agree more that LDL-P and ApoB should be the gold standard.
It's frustrating that this thinking is still considered "advanced" when it has such critical real-world implications. My own experience with doctors dismissing a high ApoB reading is what led me to dive deeper into this topic and write about a framework for navigating it: https://mettaquant.substack.com/p/personal-preventive-medicine-part-1
Great post. I realized like you that we need to be advocates for own health. My cardiovascular risk is high since I am a South Asian (just being a South Asian increases your CV risk profile) and I had to plead with my PCP for a Calcium CAC test
Ram-so I have been writing about this for years. I’m on the editorial board of the journal of clinical lipidology, and a board-certified cardiothoracic surgeon. I also wrote Lipoprotein and Lipoprotein disorders: Current Clinical Guidelines with Tom Dayspring and Bill Cromwell. I am happy you wrote about this, but you need to correct the part about particle size. It does not matter and that has been to fitly shown. The size of a pore in the intima is 70nm and every ApoB with the exception of the largest chylomicrons get through the intimal wall, if present in high concentrations, I’ve written extensively about this on Substack
Thank you very much for your detailed and thoughtful comment, Dr. Richman. I very much appreciate it. I believe Peter Attia also has the same view. Please allow me some time to look into and I will make the necessary corrections.
Ram-this is the presentation I gave at Georgetown University Medical alumni and at Grand Rounds at the Medical Center. Check it out when you have time https://youtu.be/RaZvWk7PZCQ?si=CYX5wacG799ijdPE
Loved the presentation, Dr. Richman. I especially loved the analogy to cars/vehicles and the passenger count in the vehicles.
Glad you watched it and hope
you learned something. I had trademarked that analogy but then too many people were using it in papers and presentations and just giving me credit when appropriate so I stopped trying to enforce it…too exhausting
Thank you. Will do
Peter and I know each other well. He does a lot with Tom Dayspring now and like I said, Tom, Bill Cromwell and I wrote the International Guidelines for Lipoprotein and Lipid Disorders. Tom did the whole professional section on my website www.lipidcenter.com. Feel free to go there. If you really want to deep dive and learn, Bill Cromwell and Alan Sniderman are the guys who are recognized internationally as the experts on ApoB and LDL-P
Depending on the data analysis employed, conflicting data have been reported over the past 30 years regarding the relationship of LDL particle size, particle number, and quantities of small LDL or large LDL particles with various ASCVD outcomes.
The interrelationships of particle size, particle number, and particle subclasses confound the strength of each biomarker's association with CVD risk.
Analyses that adjust for the confounding interactions between these measures yield uniquely different insights versus data that do not address this.
When LDL particle size and LDL particle number are adjusted for one another, only LDL particle number remains significantly predictive of events. (1-6)
Additionally, small LDL particles have a strong inverse relationship with large LDL particles. (6, 7)
In older reports that fail to adjust for this confounder effect, small LDL size appears more strongly related to CV risk than large LDL.
Data that address confounding of small and large LDL size demonstrate both small and large LDLs are significantly associated with CVD risk independent of each other, traditional lipids, and established risk factors, with no association between LDL size and CVD risk after accounting for the concentrations of the two subclasses. (6, 7)
Thus, rather than small dense LDL (sdLDL) being differentially atherogenic, analysis designed to address confounder variable effects demonstrates that small and large LDL particles have a similar strength of association with ASCVD risk.
These relationships underscore expert panel recommendations finding insufficient evidence to advocate measuring LDL size or subclasses to assist ASCVD risk assessment or management.
1. Contois JH, et al. Clin Chem. 2009;55:407-19.
2. Brunzell JD, et al. J Am Coll Cardiol. 2008;51:1512-24.
3. Lamarche B, et al. Circulation. 1997;95:69-75.
4. Mora S, et al. Circulation. 2009;119:931-9.
5. Blake GJ, et al. Circulation. 2002;106:1930-7.
6. Otvos JD, et al. Circulation. 2006;113:1556-63.
7. Mora S, et al. Atherosclerosis. 2007;192:211-7.