Is Atherosclerosis an LDL-Cholesterol or Immune Disease? The Answer May Be Both

Experts at the annual EAS meeting tasked with arguing these two theories ultimately agreed that the answer is not black and white.

Is Atherosclerosis an LDL-Cholesterol or Immune Disease? The Answer May Be Both

PRAGUE, Czech Republic—The origin of atherosclerosis remains the holy grail of lipidology, but experts do not necessarily agree that causality lies solely with LDL cholesterol. Others maintain that inflammation plays a direct role despite a lack of hard evidence.

Arguing on behalf of those two positions during the opening plenary session of the 2017 European Atherosclerosis Society (EAS) meeting, speakers instead appeared to accept the possibility that atherosclerosis has multiple causes.

It is “healthy” to want to debate, “but at the end of the day I think there's a contribution of LDL, that's for sure, but also probably a contribution of inflammation,” said Benoit Arsenault, PhD (Québec City, Canada), who attended the session. “It's all a matter of interaction. Cardiovascular disease is a complex disease, and there is more than one root cause,” he told TCTMD, adding that there is a “synergy” between both factors in that “low-grade inflammation actually contributes to heart disease in conjunction with LDL particles making unstable plaques where LDL can also accumulate and deliver cholesterol.”

What’s interesting, Arsenault added, is that “this inflammation actually very, very often originates from the adiposity and the visceral fat, so that's why it's important to measure not only LDL but consider other risk factors as well such as waist circumference, triglyceride levels, and insulin resistance.”

The Case for LDL

Arguing on the side of LDL cholesterol as the main cause of atherosclerosis, Chris Packard, PhD (University of Glasgow, Scotland), began by saying that it was “very strange” to be asked to speak on this subject at the 85th meeting of the EAS, implying that this debate should have been put to rest long ago. “But here we are,” he said. “The context, of course, is that it seems that the better that we get at controlling cholesterol for individuals and in populations, the more there is pushback from some sections of the media, government, and payers to restrict our ability to lower cholesterol in individuals with risk, partly because they think the evidence is too weak and also because there is an economic aspect to that.”

Referencing the EAS consensus document published yesterday regarding LDL cholesterol’s causal role in atherosclerosis, Packard, who served on the writing committee, said that it is a “a useful tool to talk to individuals who would want to push back on cholesterol lowering as the primary means of controlling the epidemic of [coronary heart disease (CHD)].”

In his presentation, which he structured as if he were “a prosecuting attorney in an American court room,” Packard reviewed evidence from genetics, pathology, epidemiology, and intervention trials of the last several decades including FOURIER, IMPROVE-IT, GLAGOV, and WOSCOPS. The big trials, he argued, “importantly [show that] LDL and its contained cholesterol is the smoking gun of the crime of atherosclerosis” and that lowering LDL cholesterol is effective in improving outcomes in both primary and secondary prevention patients.

LDL and its contained cholesterol is the smoking gun of the crime of atherosclerosis. Chris Packard

“So we have very strong evidence that LDL is causal. Without LDL you do not get atherosclerosis,” Packard said. “My analogy is: think about putting your foot on a rusty nail. If you stand on one, you’ll get an inflammatory response and you'll have a sore foot. [But] you can walk all day and you might have sore feet but not an inflammatory response. So LDL cholesterol is . . . the rusty nail that drives the whole process forward.”

It is up to the field’s researchers to understand this, he continued, in order to “model the impact of LDL lowering and actually achieve a strategic framework for CHD prevention that delivers the results that we want.

Awaiting Evidence for Inflammation

Starting his presentation, longtime “inflammation hypothesis” proponent Peter Libby, MD (Brigham and Women’s Hospital, Boston, MD), said that “it’s no mystery to anyone in this world that inflammation is part and parcel of the atherosclerotic process.” Specifically, inflammation is present from the beginning, drives the “long silent, stable phase of progression,” and then persists throughout the “thrombotic complications that bring the patient to our attention as clinicians most dramatically,” he added.

It’s no mystery to anyone in this world that inflammation is part and parcel of the atherosclerotic process. Peter Libby

Referring to a presentation he gave at this same meeting more than a decade ago, Libby explained his concept of the “cardiovascular continuum,” explaining how factors throughout the body, including in the spleen, brain, and sympathetic nervous system, are linked to cardiovascular health.

Prior studies, some led by Libby, have supported the link between inflammation and atherosclerosis. Notably in the 1990s, C-reactive protein (CRP), a marker of inflammation, was observed to rise after acute MI, and now it is routinely measured. In 2008, researchers including Libby showed that giving rosuvastatin to healthy adults without hyperlipidemia—pretreatment LDL levels were less than 130 mg/dL—but with elevated CRP levels could reduce the risk of major cardiovascular events.

And the appetite to continue to study whether modulating inflammatory response to prevent cardiovascular events remains strong, Libby argued.

Studies looking at cytokines and other potential pathways are ongoing. The placebo-controlled, randomized CANTOS study of more than 10,000 MI patients with elevated high-sensitivity CRP—which tested the safety and efficacy of the novel agent canakinumab (Novartis), a drug that inhibits the cytokine interleukin (IL)-1β, in preventing recurrent events—is scheduled to be presented at the European Society of Cardiology Congress in Barcelona, Spain, later this year. Additionally, the ongoing CIRT trial is looking at the ability of low-dose methotrexate to significantly decrease plaque inflammation for secondary prevention. Methotrexate reduces IL-6 and CRP levels, and observational studies have suggested lower rates of vascular events among rheumatoid arthritis patients treated with the drug.

“If CANTOS is positive, I’ll light the fireworks,” Libby said.

Indeed, CANTOS “will be very informative because while we have some evidence of a causal association, [no study has] hit the last nail of the coffin” to ultimately confirm causality, Arsenault commented.

Regardless, Libby was willing to compromise on the fact that there really is no contest over whether LDL cholesterol or an immune response causes atherosclerosis. “That is a false dichotomy,” he said. “Inflammation does not supplant or demote any of the traditional risk factors that each of us have an interest in, but it provides a single mechanism that links them to altered arterial wall function that we think gives expression to the disease and its complications.”

Packard agreed that both he and Libby could be right. “If we take away the insult, particularly early in life, then inflammation is not a problem,” he told TCTMD. “But if you actually are a pro-inflammatory person who then has a high LDL, then you've doubled the jeopardy.”

CANTOS will show, “in people who have disease, whether the inflammation root is actually going to give us added benefit outside of LDL lowering,” Packard added. “So we'll wait and see.”

  • Packard CJ. The case for cholesterol: lowering LDL-C for cardiovascular disease. Presented at: EAS 2017. April 24, 2017. Prague, Czech Republic.

  • Libby P. The case for immune cells: an expanded cardiovascular continuum. Presented at: EAS 2017. April 24, 2017. Prague, Czech Republic.

  • Packard reports receiving grants from MSD; receiving honoraria from MSD, Roche, Sanofi, Regeneron, Amgen, Pfizer, and Daiichi-Sankyo; and serving as a consultant to Pfizer, Sanofi, and Regeneron.
  • Libby reports receiving grant/research support from Novartis; serving as an unpaid consultant to Amgen, AstraZeneca, Esperion, GlaxoSmithKline, Kowa, Merck, Novartis, Pfizer, and Sanofi-Aventis-Regeneron; and serving on the scientific advisory board of Interleukin Genetics, Athera, Medimmune, DalCor, Amgen, Novartis, Cordidia, and Olatec.
  • Arsenault reports serving as a consultant to and receiving research grants from Pfizer and INS Pharmaceuticals.

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George Henderson

4 months ago
It seems bizarre that the debate is between LDL, which is only one lipid marker associated with ASCVD and not the strongest, and inflammation, which is a poorly defined concept. The risks of hyperinsulinaemia, for example, are metabolic and translational and may not be proximally mediated by the immune system. For example, HMG-CoA reductase activity is induced by insulin and inhibited by glucagon. The fasting TG/HDL ratio is a sensitive proxy of the 2-hour insulin response and is more strongly associated with CVD in heterozygous FH than is the LDL level. The atherogenicity of the LDL particles themselves is influenced by the insulin response to carbohydrate (via increases in small, dense LDL and oxidised LDL fractions), which is why the risk increases with a type 2 diabetes diagnosis, even though diabetic dyslipidemia is not usually a high LDL state. Inflammation will be present, measured by CRP, but is not necessary or sufficient to explain any of this. Tsimane indians of Bolivia have high CRP but very low CAC scores; they have both low insulin and low LDL levels. It is odd to use FOURIER as proof of LDL involvement for 3 reasons - 1) reduction in events was lower than predicted from LDL modelling. 2) there was no reduction in CVD or all-cause mortality, indeed a non-significant increase, only a reduction in mostly unblinded event outcomes (outcomes for which LDL level is one of the diagnostic criteria) 3) there was no reduction in events in the largest contributing region, Europe. In this region lowering of LDL was not associated with benefit.