When Size Matters (and when it doesn't) ...
Off the bat notice: This will not be one of my usual referenced posts. It's off the top of my head but based on research and the statements of others made in the past. So if I get something wrong please let me know, if you want links and references, please ask and as soon as time permits I will get to them. I am very busy with other matters besides this blog at the moment so please be patient. Thanks!
I think it is fair to say that Dr. Dayspring is "the particle number guy". For good reason. Of the various lipoprotein biomarker predictors these days, apoB and LDL-P seem to be the leaders of the pack. But what of LDL-C? For all the caution expressed by those clinging to TWICHOO about not throwing the proverbial baby out with the bathwater, these same people seem more than willing to throw out the bathtub, fixtures and attached plumbing!
We know from familial hypercholesterolemia, that high LDL-C promotes atherosclerosis. We know this. High LDL-C = atherogenic. Forget the errors of not eating eggs or the clogged pipe analogies etc. The fact remains: High LDL-C = atherogenic. What is high? There is some debate. Surely the current cut-off may well be too low. Truth is there can never be a single value cut-off, and these ranges are all just based on percentiles and often a few studies anyway. But Dayspring puts "high LDL-C" around 200+.
To paraphrase him, if your LDL (I'm dropping the "C") is above 200, nothing else matters. Not size, not HDL, not low trigs. In those with these LDL levels, traditional lipid panels were sufficient to identify risk!
The fact that some with LDL under 100 still develop atherosclerosis and suffer heart attacks does not mitigate one iota the reality that those with LDL over 200 predictably develop atherosclerosis.
So what's this particle number thing? How to explain those with low/normal LDL that develop atherosclerosis or suffer a "cardiac event" anyway? Here is where triglycerides and particle size come into play.
- Triglycerides: Since LDL is usually calculated, it is well documented that when trigs exceed 400, the calculated LDL will be artificially low. In other words, people with high trigs and low LDL actually have higher LDL than the lab report indicates.
- Particle Size and Concentration. If you were to gently add 10g of oil to a liter of water, the "concentration" of oil would be 10 g/L. If you were to then seal the container and shake vigorously, the oil would be broken up into many tiny bubbles, but you would still have 10 g in your liter. The "concentration" of oil in the pot is the same, it is just distributed differently. LDL particles are essentially spherical, and the volume is the amount of lipid they carry. The volume of a sphere is proportional to the cube of the diameter. According to Wiki, the low end of the small LDL range is 19 nm and the upper size of the large LDL is 22 nm -- by geometric relationship of volumes, a 22 nm particle can carry 1.55X the amount as a 19 nm particle.
Many use the vehicle vs. the cargo analogy for cholesterol, etc. It's a pretty good one. Consider your blood stream an enclosed track and the various lipoproteins as different sized and types of vehicles shuttling people around. If you have a lot of people to transport from A to B, you are going to need a lot of vehicles ... big, small, doesn't matter ... it will be a lot. With that many vehicles on the track, there are bound to be a lot of collisions with the guard rails leading to lots of people stranded on the side of the road. If you have fewer people to transport, then if you transport them in minivans your track is not very crowded and there will be few brushes with the guard rails, and few people stranded. If however you transport them all in Mini Coopers, the track gets crowded and you're back to lots of banging into the guard rails and stranded passengers.
Even Jimmy Moore and his cadre of cholesterol apologists* cannot get around the retention hypothesis, they just try to excuse it away. The cholesterol must penetrate the arterial wall and stick there to cause the damage. Clearly more factors are involved than just the numbers game, but these do not mitigate this physical/mechanical part of the process. More particles, more opportunities for the apoB wrapped particle (mostly LDL) to breach the endothelial wall of your blood vessels and get stuck there.
If you have a lot of cholesterol in LDL, size is irrelevant, because you are going to have a lot of particles. Period. If you don't have a lot of cholesterol, you may still be at risk. Now, size is relevant. If you are carrying your modest cholesterol load in small LDL then there will necessarily be more of these particles. It's not as much the small size that is the problem, but that so very many more of these particles will be required to transport the load. Often, it appears, this condition of high particle number but low cholesterol occurs concurrently with elevated triglycerides. In a future post I hope to address the issue of triglycerides as this is more closely related to the basic purpose of this blog. Carb restriction has the greatest impact on triglyceride levels and this is probably instilling a false sense of security in many.
- LDL > 200, you have high particle number and you are at elevated risk
- LDL in normal range: Particle size matters because smaller particles = more particles and elevated risk.
* I am not calling every expert in Cholesterol Clarity an apologist, just the ones that are. For many years now I've been hearing low carbers describe their LDL as "large and fluffy". This type of LDL has been described as everything from benign to protective, and in this regard the term apologist applies. At best, even Dr. Ronald Krauss describes these LDL as less harmful and this seems to be the most responsible designation. Again according to Wiki, the normal gaps in the endothelium are 26 nm in diameter. At 19-20.5 vs. 20.6-22 nm, we aren't exactly comparing throwing tennis balls vs. soccer balls through a basketball hoop here, we're talking regulation women's vs. men's basketballs. If someone with LDL of 100 and 22 nm particles has an LDL-P of 1000, that same person would have an LDL-P of 1552 if their LDL is 19 nm. I've read Dr. Dayspring put the particle size cut-off for penetration quite a bit larger than 26, more like 70 nm if memory serves. Which do you think is the more important characteristic, knowing that in familial hypercholesterolemia the LDL are large and fluffy, and atherosclerosis is almost a given?
I've been taking flack again for being "obsessed" with Jimmy Moore. For those not aware of some facts, I used to be a regular participant on his discussion forum. I also have a very good memory, especially where numbers are concerned etc. It's been two years since I was kicked out, and four years since many of the conversations I had on that board. I remember to this day a lot about people, their weight, their pets, their struggles, the teams they rooted for, their families, etc. etc. I don't want to needlessly highlight some individual that has nothing to do with this blog, or I could rattle off 10 names and 10 facts about each name off of the top of my head in about 10 minutes. Seriously, that's how my mind works.
The first time I heard of how bad Jimmy's lipid profile was was in December 2009. This was also when I began to hear about large, fluffy, protective LDL and all that. Unfortunately some posts seem to have been truncated by the switch of his forum to a new platform. (I am the unregistered Low Carb Cheater.)
Total Cholesterol 351
Triglycerides 79LDL Particle Number 2130Small LDL-P 535LDL Part. Size 22.0Large HDL-P 10.9Large VLDL-P 0.4THANK YOU for your comments, Paula. However, with all due respect, my numbers are fantastic according to Dr. Westman and my small LDL-P is still pretty amazing.
My truncated comment linked to a study where it was particle number, not size, that predicted risk. And then:
Jimmy: To Paula and anyone else who sees concern with my numbers, what would you suggest I do to "improve" them? This is a sincere question for the edification of all of us.
Me: I don't think anyone knows what exactly is the one or most significant factors. Just wanted to point out that the linked study is from the much referenced Framingham study and linked to (although I can't find direct from there) from LipoScience's site.
I am concerned as well by your HDL/LDL ratio and/or the Total/HDL ratios. I've all my life had borderline to low end of high cholesterol as my HDL is high (although LDL is not low it is only slightly high). Surprisingly my docs have avoided alarmed responses of late because my ratios and HDL levels are high (69 my last test) ... and any doc who has showed alarm has been challenged by me about my good ratios. So when I see your numbers quite the opposite I am concerned as to why.
What can you do? I believe that your numbers are what they are because you have a high fat diet AND you are in a state of overnutrition. You have mentioned gaining weight since your last test and will share weight loss with numbers but curiously don't share any gains with numbers. I follow your menu blog and you lost 15 or so lbs cutting portions and over 10 lbs on 6WC but I can only guess like everyone else that those pounds have returned and you are still struggling with a 30-40 lb regain.
IMO being in a gaining mode vs. a losing mode makes a huge difference ... LC/LF/HF/HC/whatever. If you consume more fat/carb than your energy needs, circulating lipids of various sorts increase. If your Purity pizza is any indication, you eat a LOT -- In your video it looks like you put 3-4Tbs of butter on that!!!! That's 300-400 calories before anything else is added. I don't know where this "add fat to anything because low fat is evil" notion came from, but it is crazy to add tablespoons of butter to the bread used for a pizza because the bread is low fat. I would bet a decent sum that cutting your added fats would have a beneficial impact on the scale and the lipids.
Leave the butter off those pizzas. Add some hamburger to the pepperoni. Or make a tuna melt. None is low fat ... just not overly (and unnecessarily) fatty.
Just a thought!
In his usual fashion, Jimmy asks for input and then ignores or brushes it off (when he doesn't lash out at the solicited advice he doesn't like):
Excellent info guys! THANKS! For the record, I am not at all worried about my numbers. They are stellar in my book and Dr. Westman was not fazed a bit when he saw them.
Yes, Dr. Westman. "Co-author" of his book. Silly me for thinking that this sort of information may be relevant to potential buyers of that book on Amazon, eh?
Check out about the 4:35 mark if you're wondering about the Purity pizza.
How out of of touch with reality does it get? I think the only thing thinkable even more absurd would be a "healthy all butter stick snack bar", maybe filled with double cream in chambers.
There is a major inconsistency here in how 'evidence' is treated. High LDL-p is dismissed as possibly not relevant in the context of Nutrional Ketosis, because the association between high LDL-p and heart disease comes from studie where people weren't in NK.
Then this is followed by: "and I have high HDL, low Tri's, and great ratios". But the notion that those are all markers of low risk also come from studies where people were following a normal, not NK, diet. So by the same logic, you'd think they would have to admit that we don't know if high HDL, low tryglycerides, and great ratios are really predictive of low risk in the context of Nutritional Ketosis.
The National Lipid Association says:
"Studies have linked large LDL particles
to atherosclerosis in nonhuman primates, in patients with familial
hypercholesterolemia (who have an elevated concentration of
predominantly large LDL particles), in participants of the
population-based MESA study, in normolipidemic men with CHD, and among
patients after MI [heart attack] in the Cholesterol And Recurrent Events
(CARE) study... Many studies document links between small dense LDL
particles and atherosclerotic CVD. However, these statistical
associations between small, dense LDL and CV [cardiovascular] outcomes
are either signiﬁcantly attenuated or abolished when the analyses are
adjusted for the overall number of circulating LDL particles (LDL-P)
either by adjustment for Apo B levels or by adjustment for nuclear
magnetic resonance-derived LDL-P... To date, there is no evidence that
the shift in LDL subfractions directly translates into change in disease
progression or improved outcome."
22–25.5 nm is small, 25.6–26.5 nm intermediate, and 26.6–28.5 large
LDL are spherical particles, 22–29 nm in diameter, composed of a core of esterified cholesterol and triglyceride, a surface lipid coat of unesterified cholesterol and
phospholipid, an essential structural protein, apo B, and sometimes small apos, such as apo CIII and apo E that modulate LDL metabolism. Each LDL particle has one apo B molecule, which is recognized by LDL receptors that clear LDL from plasma. Thus, the
LDL apo B concentration is the plasma concentration of LDL particles. The size of an LDL particle depends on how much lipid is in the core, and the lipid content naturally determines its density. Thus, smaller LDL is denser, larger LDL is lighter, and the two qualities are largely equivalent. Early studies using analytical ultracentrifugation revealed that distinct LDL subpopulations are present in each individual (11). Seven distinct LDL subpopulations were resolved by density-gradient ultracentrifugation and polyacrylamide-gradient gel electrophoresis (1, 12, 13). All people have LDL that is in a range of sizes that correspond to specific densities (8, 14). The size of the predominant LDL particles determines the classification: 22–25.5 nm is small, 25.6–26.5 nm intermediate, and 26.6–28.5 large (13, 14). Using mathematical modeling techniques that separated LDL size tracings on gradient-gel electrophoresis into Gaussian curves,
Austin et al. (15) identified two subclass patterns: the classical category, Pattern A, is more than 25.5 nm, and Pattern B is 25.5 nm or less.
Value of Low-Density Lipoprotein Particle Number and Size as Predictors of Coronary Artery Disease in Apparently Healthy Men and WomenThe EPIC-Norfolk Prospective Population Study
In this large study of individuals with moderately elevated LDL-C, LDL-P was related to CAD on top of FRS as well as after adjusting for LDL-C. The additional value of LDL-P was comparable to non–HDL-C, and it was abolished after adjusting for triglycerides and HDL-C.
After adjustment for HDL-C and triglycerides, LDL-P was no longer more predictive than LDL-C
SO - it still comes back to LDL-C no matter how they try to spin it.
Low density lipoproteins in atherosclerosis
Several laboratories have demonstrated an association in human beings between large LDL and increased incidence of CHD. It is possible that large LDL are also present when LDL receptor function is impaired, as in familial hypercholesterolemia where some overproduction of LDL may also occur. Increased concentration of LDL would appear to be the primary
atherogenic feature in these cases, and modified LDL particle composition may be an additional factor.
22–25.5 nm is small
Total Cholesterol 351
LDL Particle Number 2130
Small LDL-P 535
LDL Part. Size 22.0
Large HDL-P 10.9
Large VLDL-P 0.4
the LDL Particle Size of 22.0 nm is indicative of the “large” fluffy kind
Jimmy Moore is delusional!
William Davis, MD, FACC
In the Framingham study, four of five people fell into a large middle
range of cholesterol levels, whether or not they developed heart
disease. Those with extremely low total cholesterol (less than 150
mg/dL) had low (though not zero) risk for heart attack; those with
extremely high cholesterol (greater than 300 mg/dL) had high risk for
heart attack (threefold higher).
LDL-P was superior in predicting CVD events, however you will see that a large portion of those with events still had low levels of either biomarker....we still don't know and have a long way to go. High numbers of any marker does NOT mean you are going to have atherosclerosis nor does it mean you won't if your numbers are correspondingly low. This alone should scream that we have a lot more to learn. We need a better biomarker and hopefully it's coming, or maybe a better understanding of the disease itself.
At baseline, the cholesterol content per LDL particle was negatively associated with triglycerides and positively associated with LDL-C. On follow-up (median 14.8 years), 265 men and 266 women experienced a CVD event. In multivariable models adjusting for nonlipid CVD risk factors, LDL-P was related more strongly to future CVD in both genders than LDL-C or non–HDL-C. Subjects with a low level of LDL-P (<25th percentile) had a lower CVD event rate (59 events per 1000 person-years) than those with an equivalently low level of LDL-C or non–HDL-C (81 and 74 events per 1000 person-years, respectively).
"In this article, we evaluate evidence on LDL subclasses in risk assessment and therapy, reaching the conclusion that LDL subclass measurement does not add independent information to that conferred generically by the LDL concentration along with the other standard risk factors."
I hope to get to look at this more at some point but following the Wiki link to this study by NMR:
"The lipoprotein subclass categories used were the following: large LDL (21.3–23 nm), intermediate LDL (19.8–21.2 nm), small LDL (18.3–19.7 nm)"
Per my calculations in the post, comparing the largest of the large, 23 nm to the smallest of the small, 18.3, there's a factor of 1.99X difference. An LDL-P of 1000 largest translates to 1985 for smallest.
I'm pretty sure this discrepancy in particle sizes is what Chris Masterjohn was referring to in one of his podcasts with Chris Kresser -- that the best way to improve your particle size is to get a different test. Jimmy Moore's were NMR so should be compared to the NMR and are midling "large" . Your paper uses gel electrophoresis giving larger particle sizes.
FWIW, comparing the largest-large by electrophoresis, 28.5, to smallest-small, 22, there's a factor of 1.9X. An LDL-P of 1000 28.5 nm translates to 1903 of 22nm.
The relationship to the endothelial gap is curious then because by NMR there's no difference, by GE the large should be too big. I tend to think the FH having large particles indicates either the GE sizes are wrong (though I would think this method more accurate for actual size?) or the size that can penetrate is larger. I'll look for Dayspring's value -- I seem to recall a 7 at the beginning of his number but so many numbers ... ;-)
The triglyceride levels the LC'ers are hanging their hats on are usually varying shades of "normal". Hope to get to that post soon.
RE HDL: Using a drug to inhibit the transfer of cholesterol from HDL cholesterol to very low density or low density lipoproteins (which raises HDL & lowers LDL) does not have the same effect as raising HDL & lowering LDL by dietary & lifestyle modification.
The factors that determine whether a lipoprotein will invadethe intimal layer are
2) Size <70 nm and endothelial integrity. Ldl particles have a diameter in the range of18-23 nm. Of those measurements (particle concentration and particle size), only particle concentration is statistically significantly related to atherosclerosis and clinical events. Particle size is important, but by itself has no statistical independency in any study (where both LDL-P and
LDL-size were both measured) to predict events. Concentration of lipoproteins is referred to as quantity and lipoprotein size as quality. No one should be making diagnoses or risk assessment or judging therapy by looking only at lipoprotein size! In realty if you have concentration data, particle size is not that important. Put another way without concentration
data, particle size cannot help you.
There have been numerous theories in the development of atherosclerotic
plaques since its discovery. The first theory was generated in 1851 by
Rokitansky, whom suggested that atherosclerosis began in the intimal
layer with deposition with thrombus and its organization by the
infiltration of fibroblasts into the intimal layer and secondary lipid
deposition. The second theory was presented by Virchow in 1856, which
proposed the idea that atherosclerosis began with lipid transudation
into the arterial wall and its interaction with cellular and
extracellular elements, resulting with intimal proliferation. The third
theory was proposed by Ross, which proposed the idea that injury to the
endothelium made it susceptible to the accumulation of lipids and the
development of thrombus.
The current theory that is accepted is the response-to-vascular injury
theory, which is similar to Ross’s theory. The effect of vascular injury
can be classified by three particular types: Type 1, 2, and 3. Type 1
injury involves changes in the endothelium with minimal structural
changes such as increased lipoprotein permeability). Type 2 injury
involves a disruption to the endothelium, but with minimal thrombosis.
Type 3 injury involves damage to the medial layer, which can instigate
severe thrombosis. Paired with various systemic risk factors such as
cigarette smoking, hyperglycemia, etc, these types of injuries may cause
local disturbances to the blood flow at bifurcations or angled sections
of the artery, which can insinuate the series of events that lead to
the development of atherosclerosis (Singh).
Neovascularization of coronary tunica intima (DIT) is the cause of coronary atherosclerosis. Lipoproteins invade coronary intima via neovascularization from adventitial vasa vasorum, but not from the arterial lumen: a hypothesis
I think you are right about some of us caring more about him than he does himself. I would add his friends because so many of them cheer him on uncritically but would not be so enthusiastic were they sporting the same metabolic profile. Christine is bitching on FB again about me and yet she doesn't seem concerned about Jimmy's health near as much. If he were my husband I'd be making sure that he saw a kidney specialist about the stuff in his urine (and he used to talk a lot about frequency and other stuff on his menus blog) rather than throwing money down the hole testing for FH when he clearly does not have it.
I spoke to Jimmy briefly after our podcast interview about his brother, expressing condolences and about losing my own. He absolutely could not get me off the phone quickly enough at that point. Did not want to hear it apparently. Could absolutely care less about me as a human being (this was November 2009) etc. That is the real Jimmy Moore. His video dedication (http://www.youtube.com/watch?v=mbVGhnmx_y4) to his brother is one of the more bizarre things I'd ever seen ... it is one of the first things I saw when I went to his blog and watched it. His brother was obese and had not had success losing the weight and he didn't follow his doctor's advice (not passing judgment on not being able to, but clearly he didn't). Also, his brother's heart condition was likely not blockage related as there was no mention of any surgery in Jimmy's various tellings (stents and/or bypass) so we don't have the full story there. But ... use it to drum up whatever in your book dedication, right?
This book is dedicated to the memory of my late brother, Kevin Lee Moore, who needlessly died from heart disease and morbid obesity at just forty-one years of age because he was given all the wrong information about cholesterol and health.
Lipid and Lipoprotein Basics
Thomas Dayspring MD, FACP, FNLA, NCMP
It is crucial to have a clear understanding of how particle size contributes to atherogenesis (it does not). All LDL particles, large or small are atherogenic (will enter the arterial wall) if present in increased numbers (elevated LDL-P). If LDL-P is low (physiologic), there is little risk whether one has large or small LDL particles. Indeed, once LD-P is known, LDL size is no longer an independent risk factor for CHD.
If LDL-P is high, CHD risk is high no matter whether the high LDL-P is driven by toomany large LDLs, too many small LDLs or both. Keep in mind that the most lethal lipid/lipoprotein disorder is familial hypercholesterolemia. Such patients typically
have very increased numbers of the larger (PatternA) particles. All of the older studies that suggested risk is related to small LDLs per se, were never adjusted for LDL-P.
Once that adjustment is made, the risk related to LDL size is no longer statistically significant.
Because the volume of a sphere or circular particle is a third power of the radius (V = 4/3π r3), there are considerable volume differences between particles that vary only slightly in diameter. Thus if a patient has an LDL-C of 100 mg/dL it will take 40 to 70%
(depending on the exact diameter) more small LDL than large LDL to carry the 100 mg of cholesterol. Therefore, even though an LDL-C may be 100 mg/dL, the LDL-P will be
40-70% higher in patients with smaller rather than large LDL. Also if one has TG-rich
and thus cholesterol-poor LDL particles, it will take increased numbers of particles to
traffic a given level of cholesterol. And it is LDL-P that primarily determines risk.
Since any apoB particle < 70 nm in diameter can penetrate the vascular endothelium, LDL size does not influence LDL particle entry into the subintimal space(the largest
LDL is 23nm. Likewise the number of cholesterol molecules per particle has no influence on LDL particle entry. The only variables that affect vascular entry are LDL-P and endothelial integrity. However, small particles carry lipoprotein-associated phospholipase A2 (LP-PLA2) are quite prone to oxidative forces and are also less readily cleared by hepatic LDL receptors, which more easily recognize and attach to the apoB conformation on larger, normal-sized LDL. Thus almost all drug naïve patients with small LDLs have a very high LDL-P.
ApoB is associated with risk at levels > 80-100 mg/dl. Ideal is less than 80mg/dL or perhaps even 60mg/dL in very high risk patients. It is more accurate to measure LDL particle concentration (LD-P) using the NMR(nuclear magnetic resonance spectroscopy)
technique (n<1000 nmol/L).
"If LDL-P is low (physiologic), there is little risk whether one has large or small LDL particles. Indeed, once LD-P is known, LDL size is no longer an independent risk factor for CHD."
"Since any apoB particle < 70 nm in diameter can penetrate the vascular endothelium, LDL size does not influence LDL particle entry into the subintimal space(the largest
LDL is 23nm. Likewise the number of cholesterol molecules per particle has no influence on LDL particle entry. The only variables that affect vascular entry are LDL-P
and endothelial integrity."
On his last blood test Jimmy Moore's ApoB was 238 S/B <100. "ApoB is associated with risk at levels > 80-100 mg/dl. Ideal is less
than 80mg/dL or perhaps even 60mg/dL in very high risk patients. It is
more accurate to measure LDL particle concentration (LD-P) using the
NMR(nuclear magnetic resonance spectroscopy) technique (n<1000 nmol/L)."
If this is what Dr William Davis recommends then how can he lend his name to Jimmy's book??
He CANNOT say Jimmy is in "good" health based on the ranges in the link
Yes those with FH have a great risk of atherosclerosis (AC) those without, but does that mean all are destined? Those with high LDL-P or LDL-C do not necessarily have an AC fate, just as those with low markers are not excused from the disease. The point is we work on risk factors; the best we can ultimately determine is that if you have X biomarker, and you are in the "mean" your risk may be elevated or decreased juxtaposed to the mean, nothing more, nothing less. The glaring point is that we have a long way to go. I'm not saying do not ignore risk factors, LDL-C or LDL-P being two such factors, (but certainly not the only factors). I'm simply saying we are still missing a piece or pieces of the puzzle, and one day we hopefully will find those pieces and stop treating people that may not need to be treated and vice versa.
" only particle concentration is statistically significantly related to atherosclerosis and clinical events"
These young people who have very high LDL (and thus very high TC) with no signs of disease *might* just want to consider there should be a *yet* at the end of the sentence ?
The people in that Framingham study didn't have symptoms at baseline.
We agree, we are still missing pieces. My point is that just because we need to find those missing pieces doesn't mean we disregard the ones we've found. Make sense?
I'm with you in regards to lipid subfractions. There is no convincing evidence it helps even a bit and it's normally not used anywhere outside the US as far as I can tell. (Definetely not in Germany.)
On the other hand I would be curious about your position in regards to calcium scans. I don't think they are of great value in secondary prevention, but they can be absolutely amazing to find those people that have excellent risk factors but need therapy nonetheless.
"I'm not saying do not ignore risk factors, LDL-C or LDL-P being two such factors, (but certainly not the only factors)."
A better understanding is coming and hopefully in my lifetime, I look forward to this puzzle being solved.
Thomas Dayspring, MD
Alan Helmbold, DO
Dr. Dayspring is Director of the North Jersey Institute of Menopausal Lipidology in Wayne, NJ, and a Diplomate of the American Board of Internal Medicine and American Board of Clinical Lipidology.
Dr. Helmbold is a Cardiology Fellow at Brooke Army Medical Center at Fort Sam Houston, Texas, and a Diplomate of the American Board of Internal Medicine and American Board of Clinical Lipidology.
How to read a lipid panel in 6 quick steps
1. Look at the triglyceride (TG) level. If
it is >500 mg/dL, treatment is indicated, and TG reduction takes precedence over all other lipid concentrations. If TG is <500 mg/dL, go to Step 2.
2. Look at the low-density lipoprotein cholesterol (LDL-C) level. If it is >190 mg/dL, drug therapy is indicated regardless of other findings. At lower levels, the need for therapy is
based on the patient’s overall risk of cardiovascular disease (CVD). Therapeutic lifestyle recommendations are always indicated.
3. Look at high-density lipoprotein cholesterol (HDL-C). Increased risk is present if it is <50 mg/dL, the threshold for women. Do not assume that high HDL-C always means low CVD risk.
4. Calculate the total cholesterol (TC)/HDL-C ratio (a surrogate of apoB/apoA-I ratio). Increased risk is present if it is >4.0.
5. Calculate the non-HDL-C level (TC minus HDL-C). If it is >130 mg/dL (or >100 mg/dL in very-high-risk women), therapy is warranted. Newer data reveal that this calculation is
always equal to, or better than, LDL-C at predicting CVD risk. Non-HDL-C is less valuable if TG is >500 mg/dL.
6. Calculate the TG/HDL-C ratio to estimate the size of LDL. If the ratio is >3.8, the likelihood of small LDL is 80%. (Small LDL usually has very high LDL-P.)
The driving forces of atherogenesis are increased numbers of apoB-containing
lipoproteins and impaired endothelial integrity. ApoB and LDL-P are the available lab assays that most accurately quantify atherogenic particle number.
The lipid-concentration surrogates that you should be using to better predict apoB and CVD risk are:
TC (unless HDL-C is very high)
Because LDL is by far the most numerous of the apoB particles present in plasma, it is the primary agent of atherogenesis. However, apoB and LDL-P do not correlate with LDL-C when LDL particles are small, are TG-rich and cholesterol-poor, or simply cholesterol-poor (seen in some patients who have low LDL-C levels).
Both NCEP ATP-III and AHA Women’s Guidelines use the TC/HDL ratio as a powerful risk predictor. However, as a goal of therapy, these guidelines recommend normalizing LDL-C and then non-HDL-C. In reality, normalization of non-HDL-C takes care of LDL-C as well. For example, say a patient has LDL-C <100 mg/dL, but non-HDL-C >130 mg/dL or TC/HDL-C ratio >4. These readings indicate residual risk and suggest that an elevated number of apoB particles is present. Therapy to normalize non-HDL-C or, better yet, apoB/LDL-P, is warranted. The clue that residual risk is present even when LDL-C is normal is the reduction of HDL-C and elevation of TG and non-HDL-C.
It is commonly believed that low-density lipoproteins (LDLs) carry cholesterol into the artery wall. In addition, some epidemiologic studies have suggested that triglyceride-rich
lipoproteins, such as very-low-density lipoproteins (VLDLs), may be much less important than LDLs in atherogenesis. To determine if VLDLs or their metabolic remnants could have a direct role in the formation of atherosclerotic plaque, we examined lipoproteins isolated from endarterectomy specimens. Atherosclerotic plaque was obtained from eight
subjects who underwent aortoiliac endarterectomy (4), aortic aneurysm repair (2), or visceral/renal endarterectomy (2). Plaques were washed extensively, minced, and incubated with a buffered saline solution. Lipoproteins were recovered from this solution via a selected-immunoaffinity column by means of a polyclonal antibody to human LDL (apolipoprotein B-100). Particle sizing from electron photomicrographs of negatively stained specimens indicated that 8% of the lipoprotein particles were the size of plasma VLDL (350 to 800 nm). Thirty-six percent were the size of plasma VLDL remnant particles (250 to 350 nm), and 56% were consistent in size with plasma LDL (175 to 250 nm). We conclude that VLDL- and VLDL remnant-sized particles appear to comprise a significant percentage of the lipoproteins found in human atherosclerotic plaque and could have a direct role in the atherosclerotic process. (J Vasc Surg 1989;4:81–8.)
So why does having an LDL-P of 2,000 nmol/L (95th percentile) increase the risk of atherosclerosis relative to, say, 1,000 nmol/L (20th percentile)? In the end, it’s a probabilistic game. The more particles – NOT cholesterol molecules within the particles - you have, the more likely the chance a LDL-P is going to ding an endothelial cell, squeeze into the sub-endothelial space, and begin the process of atherosclerosis.
LDL particles (LDL-P), not LDL cholesterol content (LDL-C), is what drives sterols into artery walls – Don’t confuse the “boats” and the “cargo.”
There are several examples of long-term studies examining the predictive power of LDL-C versus LDL-P with respect to cardiovascular disease. This study followed a Framingham offspring cohort of about 2,500 patients over a median time period of almost 15 years in each of the four possible groups (i.e., high-high, high-low, low-high, and low-low) and tracked event-free survival. In this analysis the cut-off points for LDL-P and LDL-C were the median population values of 1,414 nmol/L and131 mg/dL, respectively. So, “high” implies above these values; “low” implies below these values. Kaplan-Meier survival curves are displayed over a 16 year period – the steeper the slope of the line the worse the outcome (survival).
A smaller LDL particle is no more or less atherogenic than a large one – a particle is a particle.
Let me repeat this point: Once you account for LDL-P, the relationship of atherosclerosis to particle size is abolished (and may even trend towards moving in the “wrong” direction – i.e., bigger particles…more atherosclerosis).
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