Atherogenic Triad: The Deadly Phenotype of High Triglycerides, Low HDL-C and High sdLDL-P
Case Presentation:
“Atherogenic Triad” refers to a particularly high risk lipid profile “phenotype” characterized by:
High triglycerides (TG): > 150 mg/dL
Low HDL-C: < 50 mg/dl in women; < 40 mg/dL in men
High small dense LDL-particles (LDL-P): discordant to LDL-C reported on standard lipid panel
In June 2008, at 58 years of age, Tim Russert, moderator of NBC’s “Meet The Press” and their Chief of the Washington Bureau, died suddenly of a massive heart attack in the NBC studios despite prompt resuscitation efforts (Tim Russert, 58, NBC’s Face of Politics, Dies - The New York Times). He reportedly had no warning signs. He was being treated and was on therapy for high blood pressure (hypertension) and high cholesterol (hyperlipidemia). He was known to be overweight and prediabetic. He had passed a stress test 6 weeks prior to his heart attack, though he had known asymptomatic coronary artery disease by way of a Coronary Artery Calcium Score (CAC) of 210 in 1998 at the age of 48 (96th percentile rank by today’s standards, according to the MESA Calcium Calculator). His lipids were noted to be “acceptable” with LDL-C 68 mg/dL, HDL-C 37 mg/dL, up from the 20’s (Media Mulls Russert's Death as Cardiologists Weigh In). His internist reported he had an “enlarged heart and significant coronary artery disease.” Autopsy confirmed plaque rupture in the LAD and V-Fib arrest (Watch The Widowmaker | Prime Video).
It likely would have been prevented had we had better awareness, education and focused treatment for this dangerous lipid phenotype. See What's Your ApoB? A Practical Approach to Lipid Biomarkers.
See Deep Dive for more information on this tragic event.
Flying Under The Radar
The problem:
These patients are frequently (invariably) overlooked. Healthcare providers are prone to underestimating risk for ASCVD events such as heart attack, stroke.
Why?:
Many providers lack the education to interpret the lipid panel appropriately
Most labs are incapable of alerting the provider to the fallacy of an inferior biomarker (LDL-C) in this particular situation
Reliance on an inferior biomarker (LDL-C) due to its legacy in doing a “pretty good job” for most of us will leave many in the dust.
The particular inaccuracy of LDL-C in these patients unfortunately is in the wrong direction. These very high risk patients (in large part due to other contributing comorbidities (associated diseases) suffer from an underestimation of LDL particle count due to measurement of cholesterol in cholesterol depleted LDL particles.
The more severe the atherogenic triad (the higher the TGs and lower the HDL-C), the worse the LDL-C performs
Who is at risk for this?
In general, those with excess visceral adiposity, or sometimes called “belly fat”.
This typically includes patients with the following conditions:
Obesity (increased abdominal waist circumference)
Diabetes
Prediabetes
Metabolic Syndrome (any 3 of either hypertension, increased abdominal waist circumference, high triglycerides, low HDL-C)
Fatty liver disease
Polycystic ovarian syndrome (PCOS)
Chronic kidney disease
CardioAdvocate Checklist
See What's Your ApoB? A Practical Approach to Lipid Biomarkers
Blood tests (biomarkers):
Check ApoB
May be used as the preferred biomarker for all patients with high TG, diabetes, obesity, metabolic syndrome or “very low LDL-C” for screening, diagnosis, risk management (Ia ESC/EAS)
No fasting required. Let’s repeat that again – No fasting required
Check Lipid panel
Non-HDL-C (Total Cholesterol minus HDL-C): as good or better than LDL-C
Recommended over LDL-C when TG high (> 150 mg/dL)
Despite this ancient guideline recommendation (ca. 2001), it is seldom followed in clinical practice
Reflects LDL-C + other atherogenic cholesterol, mainly VLDL-C
Despite recommendations, many labs don’t list Non-HDL-C in report
If not listed, can be manually calculated (TC - HDL-C), but nobody likes to do math in a busy clinic
If your lab doesn’t list Non-HDL-C, request that they do - it’s not hard
Comes “free” in standard Lipid panel - but this isn’t helpful if the lab doesn’t list it, or the provider doesn’t calculate it or know what it means
No fasting required. Let’s repeat that again – No fasting required
So why do we continue to use LDL-C? Great question. Mostly because it’s cheap, available, standardized (?), and let’s face it - would probably cause mass hysteria if we replaced it overnight. It works pretty good. But we do have better tools. Only YOU can advocate for better.
LDL-C: primary biomarker for initial routine lipid screening due to availability, familiarity and legacy. Calculated metric. Usually not directly measured.
A surrogate for LDL particles
Friedewald equation no longer the preferred way to calculate LDL-C but remains most common
Hopkins-Martin or NIH are the preferred equations
If LDL-C not being calculated using above, ask your lab to change
Less accurate if TGs > 150 mg/dL
The higher the TGs, the worse LDL-C performs (discordance)
The more LDL-C is lowered (< 70 mg/dL), the less accurately it reflects LDL particles and ApoB
HDL-C: Never has been a target or goal of therapy in any cholesterol guideline
HDL-C tells us nothing about the functionality of HDL particles. For example:
High HDL-C can be seen with dysfunctional HDL, where HDL cannot offload cholesterol and hence the concentration (mg/dL) goes up
Conversely, low HDL-C has been seen with highly efficient HDL, where HDL is so efficient at offloading cholesterol that the concentration is low.
Apo A-1 Milano. Founder effect genetic variant with very low HDL-C and associated with higher lifespan
Until an HDL functional assay is developed, HDL-C or HDL-P will not be particularly helpful in lipid management
Stop saying “good cholesterol.” It’s dumb. And dangerous.
Years (decades) of poor public health messaging on this topic has set us back. We’re trying to undo this.
Giving out “points” for high HDL-C may underestimate risk
Women typically have high HDL-C than men - another example of missing the mark in assessing CV risk in women
*Caveat: There may be value in seeing a low HDL-C on a lipid panel - it may alert the clinician to a problem - particularly the “atherogenic triad.” But only if they are trained to look at TG and then observe or calculate the non-HDL-C discrepancy to LDL-C
Triglycerides (TGs): Not themselves known to be directly causal to atherosclerosis, though this continues to be investigated
If > 500 mg/dL (severe) the primary objective is to treat the TGs to avoid the risk of pancreatitis
Pancreatitis is much more likely with TG > 1000 mg/dL, but since TGs fluctuate considerably, a fasting level > 500 mg/dL is severe and warrants urgent attention
If 150-499 mg/dL, look for and address associated comorbidities (DM and dysglycemia, obesity and visceral adiposity, metabolic syndrome, fatty liver disease)
“Atherogenic triad”: High TG’s, low HDL-C, high sdLDL-P
Should alert you to the high likelihood of elevated ApoB and discordance to LDL-C (lower LDL-C may be misleading)
Underestimates risk
TC/HDL-C Ratios: Let’s just get rid of ratios, ok?
Focus on LDL-C, nonHDL-C and ApoB. That’s all you really need
In fact, if you just focused on ApoB, you’d be doing great
LDL-P: Should reflect and be concordant with ApoB.
In general, can be used in place on ApoB to account for discordance or inaccuracies with LDL-C (residual risk)
In our experience, LDL-P is not as well standardized as ApoB. We have observed not too infrequent cases of discordance between ApoB and LDL-P.
ApoB is preferred over LDL-P
ApoB/LDL-P discordance is a much more advanced and nuanced discussion with many gaps in knowledge. Use clinical judgment.
If ApoB > LDL-P, treat ApoB
If LDL-P > ApoB
Look for other cardiometabolic comorbidities (DM and dysglycemia, high TG, fatty liver, obesity) and treat
It may be prudent to consider more aggressive treatment of LDL-P
If no other cardiometabolic features present, consider LDL-P a false positive
Small dense LDL-P vs Large buoyant LDL-P (Hint: they’re all bad)
“Size Doesn’t Matter” - when it comes to LDL particles. They are all atherogenic.
No convincing data exists demonstrating increased atherogenicity to small dense LDL-P, once total LDL-particle number is accounted for
Measuring sub-particle fractions does not appear to provide additional clinical value apart from measuring ApoB, or total LDL-particle count
*Caveat - there may be some value in measuring advanced lipid subfractions in the individual with insulin resistance who has the “Pattern B” (old nomenclature for sdLDL-P) phenotype and is transitioning to a “Pattern A” (large buoyant LDL-P) through optimal treatment pathways and therefore providing some bit of “proof” of progress.
Specific Atherogenic Triad Checklist:
Review your lipid panel. Do they reflect the above characteristics? Has your TG level exceeded 150 mg/dL? HDL-C < 50 mg/dL?
Has your provider informed you of this? Consider referral to a cardiometabolic specialist (Lipidologist or preventive cardiologist)
Request an Apolipoprotein B (ApoB) blood test
This is the most accurate biomarker reflecting all “atherogenic particles.”
Every atherogenic (plaque-causing) lipoprotein contains exactly one ApoB, therefore measuring ApoB reflects your circulating atherogenic particle count.
LDL-P can be measured with advanced lipid panels but are not as validated and reproducible as ApoB
ApoB is validated across the country and inexpensive.
Treatment:
Treatment is aimed at treating all associated comorbidities based upon individual risk and goals, using lifestyle interventions and pharmacotherapy as appropriate.
Below is more specific information regarding the treatment of hypertriglyceridemia, which is a component of the “atherogenic triad.”
As this becomes updated we will link to relevant sections as they become available, such as What's Your ApoB? A Practical Approach to Lipid Biomarkers.
Severe hypertriglyceridemia: > 500 mg/dL
The objective here is to prevent pancreatitis, which has the potential to cause one of the more serious illnesses one may ever see in an ICU. Can be absolutely devastating.
Low fat diet
Nearly 0 fat for 1st week
Then begin to incorporate unsaturated fats
Then reduce simple carbohydrates
Statins + fibrates or EPA or EPA/DHA formulations of PUFA
Icosapent Ethyl (Vascepa): 2 grams twice daily
We prefer this agent in those with DM or ASCVD given the established CV benefits
Lovaza (EPA/DHA)
Niacin - here is where some guidelines mention that Niacin may be used if TG remain > 500 mg/dL despite above measures
Warning: Nobody uses Niacin anymore - it’s byproducts are linked to vascular inflammation
Pioglitazone, insulin if still > 500 mg/dL
Referral to lipid specialist
consider genetic conditions
Familial Chylomicronemia Syndrome (FCS)
Multifactorial Chylomicronemia Syndrome (MCS)
Hypertriglyceridemia (135-499 mg/dL)
Weight loss
Calorie restriction
Reduce simple carbohydrates significantly
Exercise
Cardio
Pumping Iron - increase lean muscle mass
Reduce alcohol intake
Eliminate drugs known to rase TGs
HCTZ
Drug Therapy
Statins are preferred first line for TG > 200 mg/dL (Ia ESC/EAS)
EPA/DHA formulations of PUFA
Icosapent Ethyl (Vascepa): 2 grams twice daily
Indicated and recommended for cardiovascular risk reduction for high risk patients with DM or ASCVD when TG remain > 135 mg/dL despite statins
Lovaza (EPA/DHA)
Deep Dive:
Searching for Answers but Ignoring Non-HDL-C
Tim Russert was an iconic American journalist. The shock of his death prompted a A Search for Answers in Russert’s Death - The New York Times with a follow up article in the New York Times interviewing his internist and then Heartwire from Medscape interviewing the nation’s top experts: Media Mulls Russert's Death as Cardiologists Weigh In. They all tended to focus on non-lipid risk factors and seemed to ignore clues suggesting a classic misunderstanding of lipid biomarkers and the tremendous gap in education and awareness we continue to face in preventive cardiology.
“‘If there’s one number that’s a predictor of mortality, it’s waist circumference,' said Dr. Michael A. Newman, Mr. Russert’s internist.” The article continues “But, Dr. Newman added, most people would rather focus on their LDL cholesterol, instead of taking measures to reduce their waist size. He was doing nearly all he could to lower his risk…and still it was not enough…if there is any lesson in his death, his doctors said, it is a reminder that heart disease can be silent, and that people, especially those with known risk factors, should pay attention to diet, blood pressure, weight and exercise even if they are feeling fine.”
The description of his lipids in the article represents an all too familiar misinterpretation of lipid biomarkers:
“Mr. Russert’s cholesterol was not high, and medicine controlled his high blood pressure pretty well, Dr. Newman said. But, he added, Mr. Russert was ‘significantly overweight.’ He also had a dangerous combination of other risk factors: high triglycerides, a type of fat in the blood, and a low level of HDL, the “good cholesterol” that can help the body get rid of the bad cholesterol that can damage arteries.
Adiposopathy
Heartwire (Media Mulls Russert's Death as Cardiologists Weigh In) interviewed perhaps our Nation’s most accomplished cardiologist, Dr. Eric Topol:
“Much has been made of Russert's abdominal obesity as a risk factor, something Topol does not discount. But he points out: ‘There are a lot of people walking around with obesity, but only a fraction have plaque-rupture events that are fatal, so we need to pick out that tiny fraction who are at increased risk and we need better means to do that.’
A stress test, Topol points out, is of no value for identifying arteries at risk of causing sudden cardiac death. ‘The cardiology community still doesn't get it, that stress testing isn't the way to pick up plaque ruptures.’
Dr. Topol goes on to suggest that inflammatory markers such as CRP and other genomic markers may have helped. He makes many important points, to include the limited role of stress testing, which is only helpful in detecting flow-limiting stenosis or blockages > 70% - enough to see a drop in blood flow when one exerts themself, but not at all helpful in detecting “vulnerable plaque.” Finding and treating the “vulnerable plaque” before it inevitably ruptures, remains an elusive goal and in many ways the “Holy Grail” of preventive cardiology. Exciting technology may be on the horizon with companies such as Cleerly, using Cardiac CT Angiography and AI to assess plaque composition. Clinical trials await.
Obesity is very heterogeneous, complex and warrants further investigation and designation as a true metabolic disease. The term “obesity paradox” is often used to explain the seemingly contradictory findings of “clean coronaries” in many obese patients who are taken to the cath lab, but obviously fails to adequately explain or account for the different “phenotypes” of obesity.
It’s not clear however, that inflammatory markers would’ve been helpful. The predictive value of CRP seems to fall apart when accounting for visceral adiposity or “adiposopathy,” meaning, once conditions such as “visceral obesity” or “metabolic syndrome” are accounted for, CRP is not very helpful. Or to say it differently, the information obtained from CRP can be acquired by other means readily available. Tim Russert had metabolic syndrome. In fact, he had all 5 criteria. The more criteria of the metabolic syndrome one has, the higher the likelihood of having an elevated CRP. Having 5 of 5 criteria all but guarantees an elevated CRP. So, whether Tim Russert had an elevated CRP or not, is a moot point. We have all of the information needed to conclude that his risk was elevated more than the sum of his “risk factor” parts and likely underestimated. Unfortunately, despite our best efforts at prevention, sudden cardiac death continues to happen. Whether all was done in his case to prevent his outcome is tough to know.
Primordial Prevention
6 years after his death, questions continued to arise about what could’ve been done, prompting yet another review by the LA Times: Tim Russert: the details about what caused his death - Los Angeles Times. In the article his CAC score of 210 was characterized as “‘moderate’ coronary disease”. Though this did not account for high percentile rank, which is considered “high risk” and is consistent with premature CAD.
Dr. Prediman Shah was interviewed and accurately opined: ”We obviously need, in addition to screening, widespread attention to cardiac health through lifestyle modification and probably much earlier detection of the disease at a stage where you can actually arrest its progress," Shah said. "If you detect disease in a 58-year-old, it's a different ballgame than if you detect it in the 30s or 40s. The later you detect it, the less effect therapy will have in halting the progression."
Tim Russert’s disease was detected in his 40’s. His CAC was performed when he was 48, not 58. Who knows what it was at the time of his death? We cannot apply today’s knowledge to something that happened several years ago, but we can learn from it. There are now CAC guidelines: The National Lipid Association scientific statement on coronary artery calcium scoring to guide preventive strategies for ASCVD risk reduction - Journal of Clinical Lipidology, which provide some insight in not only how aggressively to treat such patients, but also in how often to reassess their risk. In general, CAC is expected to increase by 20-30% following treatment with aggressive lipid lowering therapy (statins) due to the notion that such plaque is becoming more dense (and hopefully more stable) which increases the CAC score (area + density score). See A Picture is Worth a Thousand Words - Coronary Artery Calcium Scores
Residual Risk, Discordance and Non-Adherence to Guidelines
What is apparent in this conversation around the search for answers, is that non-HDL-C was not mentioned. Tim Russert’s non-HDL-C value would’ve undoubtedly been helpful to know and a discussion about the “residual risk” as it pertains to “discordance” with lipid biomarkers, would’ve been educational, informative and most likely preventative. The numerous articles published in an effort to search for answers is obviously so that we can all learn, adopt and prevent similar tragedies.
Why do clinicians fail to implement guidelines? The NCEP ATP III Report on High Blood Cholesterol guidelines, with an update published in 2003, clearly recommended non-HDL-C as the preferred biomarker in the setting if elevated TG’s, for exactly this reason - you underestimate risk by focusing on LDL-C when triglycerides are elevated. By stating his “cholesterol” was not high, while at the same time describing high triglycerides and low HDL-C suggests that the non-HDL-C was neither considered, nor optimized.
Despite the most popular cholesterol guideline recommendations of that era being widely disseminated, we know that medicine moves slowly. New evidence takes on average, up to 17 years, to infiltrate mainstream clinical practice (Implementation of clinical practice guidelines in the healthcare setting: A Concept Analysis - PMC). That is way too long. We can and should do better.
Understanding the Atherogenic Triad
In this dangerous lipid “phenotype”, when reviewing the lipid panel we observe that the “calculated” LDL-C may be slightly “elevated,” “normal” or even “low” (we use quotes here because what defines normal is a matter of debate). LDL-C is a “calculated” metric and represents the mass concentration of cholesterol contained within LDL particles. It therefore represents a “surrogate” for LDL particles.
LDL particles are what are being deposited in the endothelium (inner lining) of the blood vessel wall and are the main driver of atherosclerosis. All that is required for atherosclerosis to take place is cumulative exposure to LDL particles.
Therefore, having an accurate biomarker which serves to identify one's likely cumulative exposure to LDL particles is paramount to accurately assessing atherothrombotic (potential for plaque rupture or plaque complication) risk .
While LDL-C is the most commonly used and easily obtainable biomarker, it is by no means the most accurate.
Whenever two biomarkers which are meant to represent the same disease risk diverge in opposite directions, we call this “discordance”. Such is the case here.
When TGs are high and HDL-C is low, the LDL particles are often much higher than what the LDL-C would suggest. In this situation, LDL-C goes down, while LDL-P goes UP! This is discordance. And the higher the TG’s go up and the lower the HDL-C goes down, the worse the situation gets, meaning, the worse LDL-C performs.
We can also see a situation where LDL-C overestimates LDL particle count. This occurs in those with LDL particles that are chalked full of cholesterol, so-called, large buoyant, or “fluffy” particles.
Reporting LDL-C serves most of the population well in approximating LDL-P and therefore ASCVD risk, however in those with the “atherogenic triad,”reporting the LDL-C may miss the mark badly and underestimate ASCVD risk considerably. Unfortunately, the typical scenario plays out like this:
The lab fails to “flag” the LDL-C (since it’s not out of range)
Sadly, most providers do not possess the education, nor the time while scanning the labs, to pick up on the clues of “high TG’s” and “low HDL-C” which may alert them to this discordance.
The patient is often congratulated on their remarkably low or optimal LDL-C and given a pat on the back.
The patient leaves the visit with nobody the wiser that there is anything amiss with their lipid panel and ASCVD risk.
Naturally, these extremely high risk patients are inevitably undertreated.
So How Do We Stop Missing the Atherogenic Triad?
Answers:
Use the correct biomarkers
Advocate for change
If you’re a clinician, lead by example and educate your colleagues, staff and patients
If you’re a patient, you may have to advocate for yourself, find the right specialist or even help to educate your provider
Advocate the lab to include non-HDL-C
Advocate the lab to include appropriate ranges of biomarkers
Non-HDL-C
Non-HDL-C comes “free” with the lipid panel but may require you to do some math if not reported in the lab report. If it isn’t reported, ask your lab to do so.
ApoB
ApoB is the optimal biomarker in terms of accuracy when measuring particles. Non-HDL-C is still prone to discordance. The more deranged the TG to HDL axis, the better ApoB performs, relative to both LDL-C and non-HDL-C.
LDL-P
This is measured using NMR spectroscopy or gel electrophoresis. LDL-P can be used in place of ApoB and in general should be concordant. However, anecdotally, we have seen issues of discordance with ApoB and LDL-P, which can get complicated and confusing. ApoB appears to be more accurate, reproducible and validated. LDL-P assays are not as well standardized. In cases of discordance of ApoB and LDL-P, ApoB should account better for all atherogenic particles, including Lp(a). However, experts recommend evaluating each case individually. In the scenario of an otherwise healthy patient (not the atherogenic triad), ApoB is likely the more accurate biomarker when LDL-P is discordant. However, if the patient has the classic “atherogenic triad” and other features of metabolic syndrome, it may be possible that LDL-P, particularly when higher than suggested by ApoB, reflects additional residual risk. This is debated among experts. Caution is advised.
