Wednesday, February 28, 2018

LDL Cholesterol Particle Size and Number What Gives ?

LDL Particle Size and Particle Number, What Gives?
Ron is a 72 year old retired engineer, and has a total cholesterol of 174 which hasn’t changed over the seven years we have been following him. This is quite low. Yet, Ron is concerned because his LDL particle number and LDL particle size are “outside of the lab range”.  He is very worried about this and is concerned about his risk for future heart attack.  I explained to Ron the lab range doesn’t apply to him.  Ron’s Calcium Score is low, and his total cholesterol is 174, and he does not have metabolic syndrome or diabetes, so he doesn’t need to worry about the LDL particle size or particle number.
What does the mainstream cardiology say about the value of LDL particle size and number?
The Quebec Study – Small Dense LDL Associated with Increased Mortality from Coronary Artery Disease
Small Dense LDL associated with Increased Risk St Pierre QuebecYou might say “wait just a minute here”, the Quebec study followed 2072 males over 13 years and found that small dense LDL was associated with increased mortality from cardiovascular disease above chart).(6)  The above chart is very convincing, and the three lines for small dense LDL are nicely separated. (6) However, as pretty as the above chart looks, Correlation is not necessarily causation.  If increased small dense LDL particle number causes coronary artery disease, then an intervention that reduces small dense LDL particles should be preventive.  However we know that it is not. Above image courtesy of Medscape.
Houston, We Have a Problem,  New Drug Reduces Small LDL,
However, No Benefit in Preventing Heart Disease
Treatment with the new cholesterol lowering drug, Evacetrapib, resulted in significant decreases in “total LDL particle number (LDL-P) (up to -54%), and small LDL particle (sLDL) (up to -95%) concentrations”.(5) Yet, according to Dr Lincoff in NEJM 2017,
“treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease.”(4)
As a matter of fact, Eli Lilly abandoned drug development after this failed study.(4)  So we see that reducing total LDL particle number, or increasing LDL particle size had no benefit for preventing death from heart disease.  The benefit was same as a placebo.
Dr Allaire  agrees that LDL particle size is not very useful.  Dr Allaire writes in 2017 Current Opinion in Lipidology:(1)
“LDL particle size….has not been independently associated with CVD risk after adjustment for other risk factors such as LDL cholesterol, triglycerides, and HDL-C and that routine use of information pertaining to particle size to determine and manage patients’ risk is not yet justified.”(1)
In other words, according to Dr Allaire,  the LDL particle size is not a good predictor of cardiovascular risk.(1)
Predicting Risk: LDL Subfraction Vs. Calcium Score
The next question you might ask: “If LDL cholesterol is not helpful, then what other test is useful for predicting risk of cardiovascular disease?” 
The answer is the Calcium Score which is an inexpensive test which uses a CAT scan to measure the amount of calcium in the coronary arteries.  Studies show that the higher the number the greater the risk, the lower the number the smaller the risk.  None of the cholesterol subfractions can provide this type of information, and in my opinion should be relegated to the medial museum, as a relic from the past.
Conclusion: When it comes down to a contest between LDL Cholesterol Subfractions and Calcium Score, there is no contest.  The Calcium Score wins every time.
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie Florida 33314
954 792-4663
Articles with Related Interest
Links and References
Header Image LDL particle courtesy of Drs Wolfson
1) Curr Opin Lipidol. 2017 Jun;28(3):261-266. LDL particle number and size and cardiovascular risk: anything new under the sun? Allaire J1, Vors C, Couture P, Lamarche B.
LDL particle size, on the other hand, has not been independently associated with CVD risk after adjustment for other risk factors such as LDL cholesterol, triglycerides, and HDL-C and that routine use of information pertaining to particle size to determine and manage patients’ risk is not yet justified.
We provide here an up-to-date perspective on the potential use of LDL particle number and size as complementary risk factors to predict and manage cardiovascular disease (CVD) risk in the clinical realm.
RECENT FINDINGS:  Studies show that a significant proportion of the population has discordant LDL particle number and cholesterol indices [non-HDL cholesterol (HDL-C)]. Data also show that risk prediction may be improved when using information on LDL particle number in patients with discordant particle number and cholesterol data. Yet, most of the current CVD guidelines conclude that LDL particle number is not superior to cholesterol indices, including non-HDL-C concentrations, in predicting CVD risk. LDL particle size, on the other hand, has not been independently associated with CVD risk after adjustment for other risk factors such as LDL cholesterol, triglycerides, and HDL-C and that routine use of information pertaining to particle size to determine and manage patients’ risk is not yet justified.
SUMMARY:  Additional studies are required to settle the debate on which of cholesterol indices and LDL particle number is the best predictor of CVD risk, and if such measures should be integrated in clinical practice.
Women with discordant high particle concentration were more likely to have metabolic syndrome (MetS) and diabetes
2) Clin Chem. 2017 Apr;63(4):870-879. doi: 10.1373/clinchem.2016.264515. Epub 2017 Feb 7.  Discordance between Circulating Atherogenic Cholesterol Mass and Lipoprotein Particle Concentration in Relation to Future Coronary Events in Women.
Lawler PR1,2,3,4, Akinkuolie AO1,3, Ridker PM2,3, Sniderman AD5, Buring JE3,4, Glynn RJ3,4, Chasman DI3, Mora S6,2,3.
It is uncertain whether measurement of circulating total atherogenic lipoprotein particle cholesterol mass [non-HDL cholesterol (nonHDLc)] or particle concentration [apolipoprotein B (apo B) and LDL particle concentration (LDLp)] more accurately reflects risk of incident coronary heart disease (CHD). We evaluated CHD risk among women in whom these markers where discordant.
METHODS:Among 27533 initially healthy women in the Women’s Health Study (NCT00000479), using residuals from linear regression models, we compared risk among women with higher or lower observed particle concentration relative to nonHDLc (highest and lowest residual quartiles, respectively) to individuals with agreement between markers (middle quartiles) using Cox proportional hazards models.
RESULTS:Although all 3 biomarkers were correlated (r ≥ 0.77), discordance occurred in up to 20.2% of women. Women with discordant high particle concentration were more likely to have metabolic syndrome (MetS) and diabetes (both P < 0.001). Over a median follow-up of 20.4 years, 1246 CHD events occurred (514725 person-years). Women with high particle concentration relative to nonHDLc had increased CHD risk: age-adjusted hazard ratio (95% CI) = 1.77 (1.56-2.00) for apo B and 1.70 (1.50-1.92) for LDLp. After adjustment for clinical risk factors including MetS, these risks attenuated to 1.22 (1.07-1.39) for apo B and 1.13 (0.99-1.29) for LDLp. Discordant low apo B or LDLp relative to nonHDLc was not associated with lower risk.
CONCLUSIONS:Discordance between atherogenic particle cholesterol mass and particle concentration occurs in a sizeable proportion of apparently healthy women and should be suspected clinically among women with cardiometabolic traits. In such women, direct measurement of lipoprotein particle concentration might better inform CHD risk assessment.
3)   Curr Opin Endocrinol Diabetes Obes. 2018 Jan 10. Discordance between lipoprotein particle number and cholesterol content: an update.
Cantey EP1, Wilkins JT2.
The cholesterol content within atherogenic apolipoprotein-B (apoB) containing lipid particles is the center of consensus guidelines and clinicians’ focus whenever evaluating a patient’s risk for atherosclerotic cardiovascular disease. The pathobiology of atherosclerosis requires the retention of lipoprotein particles within the vascular intima over time followed by maladaptive inflammation resulting in plaque formation and rupture in some. The cholesterol content is widely variable within each particle creating either cholesterol-deplete or cholesterol-enriched particles. This variance in particle cholesterol content varies within and between individuals. Discordance analysis exploits this difference in cholesterol content of particles to demonstrate the differential significance of LDL-cholesterol (LDL-C) and non-HDL-C from measures of lipoprotein particle number in terms of assessing atherosclerotic cardiovascular disease risks.
RECENT FINDINGS:Three studies have added to the growing body of literature of discordance analysis. Despite wide variability of discordance cutoffs, baseline risk of atherosclerotic disease, and populations sampled, the conclusion remains the same: risk of atherosclerotic disease follows apoB lipid particle concentration rather than cholesterol content of lipid particles.
SUMMARY:In addition to traditional lipid fractions, assessments of atherogenic particle number should be strongly considered whenever assessing CVD risk in nontreated and treated individuals. There is a need for clinical trials that focus not only on the reduction in LDL-C but apoB, as well.
4)  Lincoff, A. Michael, et al. “Evacetrapib and cardiovascular outcomes in high-risk vascular disease.” New England Journal of Medicine 376.20 (2017): 1933-1942.
Although treatment with evacetrapib has resulted in reductions of 60 to 70% in the levels of small dense LDL particles,29 effects on the total number of LDL particles and on apolipoprotein B levels (reductions of 22% and 20%, respectively) are considerably less pronounced.
CONCLUSIONS:Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease.
Potent CETP inhibitors reduce plasma concentrations of atherogenic lipoprotein biomarkers of cardiovascular risk.
OBJECTIVES:To evaluate the effects of the cholesteryl ester transfer protein (CETP) inhibitor evacetrapib, as monotherapy or with statins, on atherogenic apolipoprotein B (apoB)-containing lipoproteins in mildly hypercholesterolemic patients.
METHODS:VLDL and LDL particle concentrations and sizes (using nuclear magnetic resonance spectroscopy) and lipoprotein(a) concentration (using nephelometry) were measured at baseline and week 12 in a placebo-controlled trial of 393 patients treated with evacetrapib as monotherapy (30 mg/d, 100 mg/d, or 500 mg/d) or in combination with statins (100 mg plus simvastatin 40 mg/d, atorvastatin 20 mg/d, or rosuvastatin 10 mg/d; Clinicaltrials.gov Identifier: NCT01105975).
RESULTS:Evacetrapib monotherapy resulted in significant placebo-adjusted dose-dependent decreases from baseline in Lp(a) (up to -40% with evacetrapib 500 mg), total LDL particle (LDL-P) (up to -54%), and small LDL particle (sLDL) (up to -95%) concentrations. Compared to statin alone, coadministration of evacetrapib and statins also resulted in significant reduction from baseline in Lp(a) (-31%), LDL-P (-22%), and sLDL (-60%) concentrations. The percentage of patients with concentrations above optimal concentrations for LDL-P (>1000 nmol/L) and sLDL (>600 nmol/L) decreased from 88% and 55% at baseline, respectively, to 20% and 12% at week 12, for patients treated with evacetrapib plus statins. Evacetrapib, alone or with statins, significantly increased LDL-P size.
CONCLUSIONS:Evacetrapib, as monotherapy or with statins, significantly reduces the concentrations of atherogenic apoB-containing lipoproteins, including Lp(a), LDL-P, and sLDL.
6) St-Pierre, Annie C., et al. “Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men: 13-year follow-up data from the Quebec Cardiovascular Study.” Arteriosclerosis, thrombosis, and vascular biology 25.3 (2005): 553-559.Low density lipoprotein Risk of ischemic heart disease Quebec St Pierre Annie Arterio thrombo vasc bio 2005
The objective of the present study was to investigate the association between large and small low-density lipoprotein (LDL) and long-term ischemic heart disease (IHD) risk in men of the Quebec Cardiovascular Study.
METHODS AND RESULTS:Cholesterol levels in the large and small LDL subfractions (termed LDL-C> or =260A and LDL-C<255a 13="" 2072="" 262="" a="" all="" and="" angina="" at="" baseline="" cardiovascular="" cohort="" coronary="" death="" during="" electrophoresis="" estimated="" events="" examination="" first="" followed-up="" for="" free="" from="" gel="" gradient="" ihd="" in="" infarction="" men="" myocardial="" nbsp="" nonfatal="" of="" pectoris="" period="" plasma="" polyacrylamide="" population-based="" quebec="" recorded.="" respectively="" strong="" study.="" style="border: 0px; font-family: inherit; font-style: inherit; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;" the="" unstable="" were="" which="" whole="" years="">Our study confirmed the strong and independent association between LDL-C<255a a="" and="" as="" dense="" ihd="" in="" ldl="" levels="" men="" of="" phenotype="" proxy="" risk="" small="" strong="" the="">, particularly over the first 7 years of follow-up. However, elevated LDL-C> or =260A levels (third versus first tertile) were not associated with an increased risk of IHD over the 13-year follow-up (RR=0.76; P=0.07).
CONCLUSIONS:These results indicated that estimated cholesterol levels in the large LDL subfraction were not associated with an increased risk of IHD in men and that the cardiovascular risk attributable to variations in the LDL size phenotype was largely related to markers of a preferential accumulation of small dense LDL particles.
Read the complete article here.

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