Atherogenic Triad

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 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 (see “See No Evil, Hear No Evil, Speak No Evil” - Obesity).  

It’s not clear however, that inflammatory markers would’ve been helpful (“The Itch that Rashes” - Inflammation). 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.