June 27, 2016

Metabolic disease

When does heart disease begin (and what this tells us about prevention)?

by Peter Attia

Read Time 16 minutes

Before I get into this post I want to lay a few things out.

  1. This post is written mostly for doctors, but also for patients who really want to understand this topic, if for no other reason than to help them choose the right doctors. I don’t go out of my way to simplify the terminology and I assume the reader is familiar with the topics covered in the cholesterol series I wrote. If you encounter a term you don’t understand, Google is a pretty good place to find the definition.
  2. I will not use this post to in any way get into prescriptive strategies, which involve modifications of nutrition, hormones, and yes, lots of drugs across four or five classes (i.e., much more than just statins) depending on the specific situation at hand and the risk appetite of the patient and physician, as well as the other comorbidities that must be co-managed. Even if I wanted to write out all of my prescriptive leanings I could not do it briefly.
  3. Please do not email your lab results or ask me to weigh in on your case. You know the disclaimer: I can’t practice medicine on a blog or over email.

There was a day when the only thing I argued about was who the greatest boxer of all time was. (I’m fighting all urges to turn this post into a manifesto of 1965-67 Muhammad Ali vs. 1938-41 Joe Louis vs. 1940’s Sugar Ray Robinson vs. 1937-42 Henry Armstrong.)

Today, however, I find myself arguing about so many things—some of them actually important—from why symptomatic women should receive hormone replacement therapy after menopause (and, by extension, why the Women’s Health Initiative tells us so, if you know how to read it) to why monotherapy with T4 for hypothyroidism is a recipe for disaster for most patients. But there is nothing I find myself debating more than the misconceptions most doctors have about heart disease. This is especially troubling since heart disease kills more Americans than any other disease. To put this in perspective, a woman in the United States is 7 to 8 times more likely to die from heart disease than she is from breast cancer.

Here are the typical arguments put forth, almost always by doctors, which invariably result in my need/desire to counter:

  1. Heart disease is caused by too much “bad” cholesterol (LDL-C).
  2. LDL-C is the only target of therapy you need to worry about.
  3. Calcium scores and CT angiograms (CTA) are great ways to further risk-stratify (the corollary: when these tests are negative, there is no need to treat the patient).
  4. Atherosclerosis is a “pipe narrowing” disease (ok, nobody uses these words, but they imply this by saying it’s a luminal narrowing disease).
  5. There is no role for preventatively treating young people, except in very rare cases like familial hypercholesterolemia.

Briefly, here are my counters:

  1. Atherosclerosis is caused by an inflammatory response to sterols in artery walls. Sterol delivery is lipoprotein-mediated, and therefore much better predicted by the number of lipoprotein particles (LDL-P) than by the cholesterol they carry (LDL-C) [Bonus point: always measure Lp(a)-P in your patients—but we’ll have to save Lp(a) for another day; it certainly owns its own blog post].
  2. Ditto point #1. And don’t ever bring up LDL-C again.
  3. Calcium scores and CT angiograms of exceptional quality (the operative word being exceptional—most are not) are helpful in a few settings, but this assertion is patently false, and I will leave this discussion for another blog post as the topic is too rich in nuance for a few lines.
  4. We’ll discuss this today.
  5. By necessity, we’ll be forced to confront this today, also.

Before diving into this topic it’s really important for me to acknowledge the person who has taught me almost everything I know about this disease, beginning back in 2011 when I first became aware that I basically had no idea what atherosclerosis was. For many years Dr. Tom Dayspring’s generosity has been remarkable and I’m humbled to be his most sponge-like student. Tom has not only given me an on-the-side lipidology fellowship, but he has also introduced me to the finest lipidologists and cardiologists in the country who have, in turn, been incredibly generous with their time and knowledge. I’m not the only one to benefit from Tom’s wisdom and generosity. I had dinner with Tom’s son and his wife once and I described Tom to them as a national treasure. That’s really how I feel about him. He is a nationally-recognized educator and his writing and presentations are devoured by fanatics like me across the globe. With Tom’s permission, I’ve deconstructed a video he put together into a series of figures which I’ll use to begin this discussion of how atherosclerosis actually takes place.

The physics of luminal narrowing

Traditionally, the atherosclerotic process was believed to involve plaque accumulation that prompted the gradual narrowing of the lumen, with the eventual development of stenosis. Stenosis then caused impaired control of flow (stable angina) and plaque rupture and thrombosis (unstable angina and MI). Consequently, prevailing opinion held that coronary angiography would be able to gauge the atherosclerotic process at all stages of disease.

However, in 1987, Glagov and colleagues proposed an alternative model of atherosclerosis development. After performing histological analyses of coronary artery sections, Glagov et al. reported that early atherosclerosis was characterized by plaque accumulation in the vessel wall and enlargement of the external elastic membrane (EEM) without a change in lumen size.

As atherosclerosis progressed, they found that plaque continued to accumulate in the vessel wall until the lesion occupied approximately 40% of the area within the EEM. At this point, the lumen area began to narrow. These findings have since been confirmed by intravascular ultrasound (IVUS). Due to the complex remodeling that occurs in the earlier stages of atherosclerosis, coronary angiography, which only visualizes the lumen, tends to underestimate the degree of atherosclerosis. In other words, atherosclerosis is well under way long before angiography is able to identify it.

I was reminded of the words of my Pathology professor back in the first year of medical school, “The only doctors who actually understand atherosclerosis are pathologists.” I would add lipidologists to that list, but I saw his point.

Most people, doctors included, think atherosclerosis is a luminal-narrowing condition—a so-called “pipe narrowing” condition. It’s true that eventually the lumen of a diseased vessel does narrow, but this is sort of like saying the defining feature of a subprime collateralized debt obligation (CDO) is the inevitable default on its underlying assets. By the time that happens, eleven other pathologic things have already happened and you’ve missed the opportunity for the most impactful intervention to prevent the cascade of events from occurring at all.

To reiterate: atherosclerosis development begins with plaque accumulation in the vessel wall, which is accompanied by expansion of the outer vessel wall without a change in the size of the lumen. Only in advanced disease, and after significant plaque accumulation, does the lumen narrow.

Michael Rothberg wrote a fantastic article on the misconception of the “clogged pipe” model of atherosclerosis. He opens with the following story:

A recent advertisement on the back cover of a special health issue of the New York Times Magazine section read “Ironic that a plumber came to us to help him remove a clog.” The ad referred to doctors in the cardiac catheterization laboratory as “one kind of pipe specialist,” and noted that the patient in the ad returned to work “just 2 days after having his own pipes cleaned out.” Although the image of coronary arteries as kitchen pipes clogged with fat is simple, familiar, and evocative, it is also wrong [emphasis mine].

Dr. Rothberg goes on to explain that for patients with stable disease, local interventions can only relieve symptoms; they do not prevent future myocardial infarctions. To be clear, at least 12 randomized trials conducted between 1987 and 2007, involving more than 5,000 patients, have found no reduction in myocardial infarction attributable to angioplasty in any of its forms. And yet, despite this overwhelming evidence, the plumbing model, complete with blockages that can be fixed, continues to be used to explain stable coronary disease to patients, who understandably assume that angioplasty or stents will prevent heart attacks—which they patently do not.

The root of the problem, in my view at least, is that we as doctors—and by extension, our patients and media—spend too much time looking at images like this (angiograms of coronary arteries complete with “clogged pipes”):



Image by Todt et al., 2012 is licensed under CC by 2.0

And not enough time looking at images like these (the histological, i.e., pathology, sections of coronary arteries):


Image by Nichols et al., 2015 is licensed under CC by 4.0

But who can blame us, I mean, angiograms are cool! But, alas, it’s time to get serious about understanding this disease if we want to prevent/delay it.

Atherosclerosis, for the cognoscenti

Ok, so now let’s get rigorous about the pathology that kills more Americans than any other disease. To understand this, as Frederic Bastiat wrote long ago, we must resort to “long and arid dissertations.” Buckle up.

The following figures were constructed from a video Tom Dayspring produced in one of his stellar lectures on the development of atherosclerosis. I’ve broken the video down into 20 or so steps which show the transition from a completely normal endothelium (i.e., at birth) through myocardial infarction. Each figure is preceded by a brief explanation of its content.

The endothelium is a protective one cell layer lining the surface of the artery lumen. Endothelial cells perform many complex functions and are capable of modulating vascular tone, as well as inflammatory and thrombotic processes. Their function depends on many circulating and local factors.

Low density lipoprotein (“LDL”) is a lipid (the bulk of which is cholesterol) transport particle. Please re-read this sentence. It is not “bad cholesterol,” a term that has no meaning. LDL—the particle—allows lipids (cholesterol, but also triglyceride, phospholipid) to be delivered through the aqueous medium of the blood, since lipids are hydrophobic (i.e., repel water) and a “carrier” is needed to transport them in blood (which is mostly water).

If LDL particles are present in physiologic (i.e., normal) concentrations, they effectively deliver cholesterol to those tissues that require it (recall: all tissues make cholesterol but some don’t make enough for their own needs and therefore cholesterol needs to be trafficked around the body).

The term LDL particle, LDL-P, and apoB are used interchangeably (the latter, because LDL particles are defined by the wrapping of a lipoprotein called apolipoprotein B-100).

When LDL particle concentration is elevated, the lipoprotein penetrates into the subendothelial space. Once in the intimal layer, they are securely attached to intimal proteoglycan molecules. The first step in atherogenesis is surface phospholipid (PL) exposure to reactive oxygen species and oxidation of the PL. LDL particles that are not oxidized are not atherogenic.  To be clear, it’s not the “getting in there” part that is the problem (HDL particles do this all the time and so do LDL particles, for that matter), it’s the “getting stuck and oxidized in there” part, formally known as retention and oxidation.

Once retained in the subendothelial space, the LDL particle may be modified, or oxidized (the clusters of yellow circles in the subendothelial space, below).

Oxidized LDL particles are toxic to the endothelium.  Now-dysfunctional endothelial cells express selectins and vascular cell adhesion molecules (VCAMS) which mark the injured areas of the vascular wall. It is worth pausing here for a moment. This step is kind of the turning point in the story. It’s also a perfectly “normal” thing for the epithelium to do. They sense a problem and like any law-abiding tissue, they ask for help from law enforcement. Think of the selectins and VCAMS as 911-calls. The police, who show up shortly, are the monocytes.

Selectins and VCAMS increase monocyte adherence to the endothelium.

The endothelial cells also express messenger cytokines such as interlukin-6 (IL-6) and tumor necrosis factor (TNF) which circulate to the liver and induce the production of C-reactive protein (CRP).

Monocytes penetrate the subendothelial space…

…and when they do, the monocytes differentiate into (i.e., “become”) macrophages (a more specific type of immune cell). Macrophages phagocytize (basically “ingest”) the modified or oxidized LDL particles.

The phagocytosis of oxidized LDL particles (oxLDL) and accumulation of lipid in the macrophage creates something called a foam cell.

Multiple foam cells coalesce to form the characteristic fatty streak, the hallmark of an early atherosclerotic plaque. Keep this in mind. Later in this post we’ll come back to “fatty streaks” and I want you to remember how much has taken place to get us to this stage. I will posit that no one reading this post does not have fatty streaks unless there are some brilliant 5-year-olds reading this during recess..

Nascent Apo A-I containing particles (also known as prebeta-HDL particles) accumulate free or unesterified cholesterol from the macrophages using ATP Binding Cassette Transporters A1.

As the HDL particle lipidates itself by delipidating the macrophage (i.e., takes lipid out of the foam cell), the HDL particle, utilizing an enzyme called LCAT, esterifies the free cholesterol forming cholesteryl ester (CE). As a result, the HDL particle enlarges and is free to be delipidated at a variety of tissues. HDL delipidation occurs through multiple mechanisms using Cholesteryl Ester Transfer Protein (CETP), aqueous free diffusion, SRB1 receptors in endocrine glands or gonads (e.g., to make hormones), adipocytes (a major cholesterol storage organ) or the liver (e.g., to package for biliary delivery). HDLs can also be internalized as entire particles by surface liver receptors.

A brief, but important, digression: the complexity, above, is probably the reason why every trial that has tried to increase the concentration of cholesterol in HDL particles (i.e., raise HDL-C) has failed, and failed epically, to reduce events. The value in HDL particles (the so-called “good cholesterol”—my god I hate that term as much as I hate the term “bad cholesterol” when referring to LDL) is almost assuredly in its functional capacity—what it is doing that might be cardioprotective (very hard to measure) rather than its cholesterol content (HDL-C), which is relatively easy to measure, but probably offers zero insight other than its positive epidemiological associations. In other words, measuring HDL cholesterol content tells you little about its cholesterol efflux capacity or any other of the numerous HDL functional properties.

Macrophages that become engorged with oxLDL remain full-fledged foam cells. Foam cells produce Angiotensin II, metalloproteinases, collagenases, elastases, and other proteins, which undermine the integrity of the arterial wall, causing more endothelial dysfunction. This is where the process goes to hell. Now you’ve got a damaged barrier and the looting begins. Oh, by the way, the process to date goes unnoticed by the calcium scan and CTA.

Chemotactic factors (i.e., chemical signals) trigger migration of smooth muscle cells to the area of injury in an attempt to repair the damage and pervert further disruption. Again, all of this is taking place in good faith on the part of the immune system. The smooth muscle cells are transformed into secretory cells that lay down a matrix to heal the injured wall. This matrix becomes the fibrous cap of the atherosclerotic plaque. Only now is the arterial lumen becoming encroached.

Metalloproteinases and collagenases are upregulated and they start to dissolve or weaken the plaque cap, typically at the shoulder regions where the diseased endothelial cells meet healthy endothelial cells. Some have used the term “vulnerable” to describe such plaques, which may be a correct term, but it also gives a false sense of confidence that we can treat atherosclerosis on a lesion-by-lesion basis. History has taught us that such hubris is unwarranted. Until proven otherwise, atherosclerosis should be viewed as a systemic condition of the arterial system. To see one of the best (and my favorite) papers on this topic, look no further than to this paper by Armin Arbab-Zedeh and the venerable Valentin Fuster, aptly titled “The Myth of the Vulnerable Plaque.”

The plaque can become obstructive—i.e., it can obstruct the lumen—over time. Lipid rich plaques are unstable, and can rupture. Platelets adhere to the ruptured surface of the plaque through electrostatic factors and through binding to specific ligands.

The platelets then serve as a cradle for the coagulation cascade to produce a net of fibrin (the white “net” in the figure), leading to a red clot, as red blood cells are caught in the net. A non-obstructive plaque can lead to a clinical event after the superimposition of red and white thrombus, which can occur quickly and without warning. The degree of stenosis (luminal narrowing) does not predict when this will happen.

Why all of this matters

So back to this impetus for this post—Allan’s editorial. When I first met Dr. Allan Sniderman, we immediately hit it off. Like Tom, Allan has been a remarkable mentor and teacher. In fact, one of the gifts Allan gave me a while back was his personal copy of Herbert Stary’s legendary pathology textbook on atherosclerosis, Atlas of Atherosclerosis Progression and Regression. I devoured this textbook and have since purchased additional copies to always have one on hand. Ask my patients…most of them have had to sit through viewings of it like it was a vacation photo album.

Allan and I were having dinner and discussing our favorite topic. Allan asked me to guess what fraction of cardiac events (“event” is a pretty common word in the vernacular of cardiovascular disease and basically refers to a Q-wave MI, the need for re-vascularization, or cardiac death) take place in North America in those younger than 65. I knew it was a loaded question, so I rounded my guess up to 25%. I was wrong. How wrong I wouldn’t find out until Allan and his colleagues completed their analysis which formed the basis for their editorial recently published in JAMA Cardiology. Add it to your weekly reading list.

You don’t have to be a lipidologist or a pathologist to understand this paper, but it helps to understand the basics of math—big denominators can drown out even modest numerators. The aggregate figure from this paper is one of the most elegant representations of a dot product. The subfigure on the left is how most doctors (myself included until the 2nd decade of the 21st century) and authorities think of coronary heart disease (CHD)—it’s virtually silent until the 7th or 8th decade of life. What folks who think this way miss is the middle figure—the population base (the “denominator”) is shrinking while the incidence (the “numerator”) is rising. In a situation like this, the only way to really see what’s happening is to do what Sniderman et al. did—calculate the absolute event rate, as shown on the right.

Image credit: Sniderman et al., 2016

Yes, you’re reading this graph correctly. A little over half of all events in men (24% + 28%) and a little less than a third of events in women (13% + 19%) take place below the age of 65.

Tying these two insights together

Insight #1: Atherosclerosis takes a long time to evolve, and involves many steps.

Insight #2: Many cardiovascular events—half in men and one-third in women—take place in young people (i.e., those 64 or younger)

How do we reconcile these findings? Enter the pathologists. As I mentioned above, my first year pathology professor in med school insisted that pathologists were the only doctors who really understood heart disease, because they actually did the autopsies and examined the coronary arteries under microscopes.

And this brings me to my point. The only way Insight #1 and Insight #2 can be correct is if atherosclerosis takes a long time to develop. Any guesses as to what the greatest single risk factor is for heart disease? Smoking? Nope. High blood pressure? Nope. The wickedly deadly particle I have yet to write the most deserving post on, Lp(a)? Nope. LDL-P or apoB? Nope. LDL-C? I thought I told you to never say that again. CRP? Nope. None of these things. It’s age. Age trumps everything. In this sense, atherosclerosis is an “integral” disease (in the calculus sense of the word)—meaning it’s a disease of compounding injuries, as I painstakingly went through above. Age = persistent exposure to LDL-P/apoB.

Just like wealth is compounded in a highly non-linear way, so too is illness and no disease to my knowledge does so more clearly than atherosclerosis. So the jugular question is when do we need to start treating patients? That is a question I can’t answer for you. Not because I don’t have a point of view, which I most certainly do, but because it comes down to risk tolerance. I can no more impart my world view of this problem on you (though the answer seems painfully obvious to me) as I can my world view of how to raise kids or combat ISIS. But I do hope to leave you with a clear picture, at least of the disease process.

Perhaps the greatest insights into the pathogenesis of atherosclerosis, especially as they pertain to age, comes via autopsies of two variants: those of people known to die of some cause other than heart disease and those known or suspected of cardiac death. The table, below, taken from this paper, summarizes the six stages of atherosclerosis. Stary’s stages are identical, except that he further divides the sixth of these stages into three stages, for a total of eight stages, but the points remain the same. The points being, of course:

  1. In the first decade of life fatty streaks are being formed. That’s right, before the age of 10.
  2. Atheromas are present by the time most people are in their 20’s.
  3. By the time you are in your 30’s you are quite likely to have fibroatheroma formation.
  4. The vast majority of atherosclerosis-initiating sterols get into the artery as “passengers” in apoB-containing particles most of which (90%) are LDL particles.
Image credit: Stary et al., 1995

I’ll close with another interesting study, published in Circulation in 2001. The title of the study—High Prevalence of Coronary Atherosclerosis in Asymptomatic Teenagers and Young Adults—pretty much tells you what they found. The authors performed intravascular ultrasound (IVUS) on 262 heart transplant recipients about a month following their transplant. Before going any further, it’s worth pointing out that IVUS is not as sensitive as pathologic sectioning so this study is likely underestimating the degree of disease present in the hearts (but obviously one can’t section the coronary arteries of donor hearts). By doing the IVUS on the recipients so soon after they received their transplant the authors were able to study the hearts of the donors, many of whom were quite young.

The figures below, both taken from the paper, show the frequency distribution and prevalence of intimal thickening for each age cohort of donors. Consistent with the pathology studies, which actually cut open the arteries and examined them histologically, the IVUS study found a similar trend. Namely, atherosclerosis is starting much sooner than previously recognized. In this series of 262 heart donors, one out of six hearts donated by a teenager was found to have clinically measurable atherosclerosis. The authors conclude: “These findings suggest the need for intensive efforts at coronary disease prevention in young adults.”

Image credit: Tuzcu et al., 2001
Image credit: Tuzcu et al., 2001

Final thoughts

I was 35 years old, the year my daughter was born, when I first confronted my own inevitable demise which, based on my family history, was likely to be a cardiovascular one. I’m sure I’d be better off if I had that epiphany when I was 25 or possibly 15, but I’m glad it happened when it did. Today, I manage all modifiable risk factors to the level of my risk appetite and interpretation of the most nuanced scientific literature on cardiovascular disease. Does this mean I won’t succumb to heart disease? Of course not. But this is a stochastic game and the objective of the game is to increase the odds in your favor while delaying the onset of bad outcomes. It’s up to each person, and his or her doctor if necessary, to determine how aggressively he or she wants to confront the inevitable—we all have atherosclerosis at some level.


Let me add another thought that may address some concerns.

Clearly there are factors here we (at least I) do not understand. Why do some people just stop with fatty streaks and stay that way for decades, while others progress to clinically significant heart disease? I’m sure if one normalizes for LDL-P, Lp(a)-P, and even particle size, the answer will still elude us (me). I think what people are missing here is that there is a difference between what we can infer from population-based (i.e., heterogeneous) statistics–clinical trials with drugs, epidemiology, ecology, hundreds of autopsies–and what happens at the individual level. Furthermore, the only probabilities that matter when it comes to an individual are “0” and “1”–in other words we go from the most heterogeneous to the most homogeneous.

I’m reminded of an analogy Allan Sniderman shared with me: If you’re a parent, with kids in your home, and want to know the probability that your child (or any child in your home) will die from an accidental gun shot wound, you can look at the stats, which are readily available. They will say the risk is actually pretty low–which it is on average. But what if we now adjust the information (in the Bayesian sense of the word) and note that you have a loaded .45 under your pillow (you know, for home protection). Now what happens to the risk? Of course it goes up dramatically. Why? Not just because we have “more” information–we actually have very specific “new” information. We have information about the causative agent, the gun. LDL-P and Lp(a)-P are the causative agents, and while other forces matter (e.g., inflammatory response), there is no getting around the fact that high LDL-P and Lp(a)-P are stacking the odds against you. The gun won’t pull the trigger on its own, but it’s still the causative agent. People are too quick to confuse “necessary and sufficient” with “necessary but not sufficient”–in both cases reducing the “necessary” component helps.

While I do not doubt that some people with high LDL-P and Lp(a)-P may be immune to the typical “rules” of atherosclerosis, we don’t have good enough tools to predict this, especially non-invasively. Ergo, the risk of doing something to lower these modifiable risks, even if that means taking drugs, must be weighed against the risk of doing nothing. This last point is often dismissed.

Most kids in homes with loaded guns will not die from those guns, but to ignore the loaded gun in that setting is crazy, in my opinion.

I’m going to remove the gun and put the odds back in my favor.

Image credit: Dr. Edwin P. Ewing, Jr. Gross pathology of atherosclerosis, aorta. Autopsy specimen of aorta has been opened lengthwise to reveal luminal surface studded with lesions of atherosclerosis.

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  • Mark Cafiero

    How do you suggest we find good doctors? From my experience, there are zero in Colorado who subscribe to modern medicine.

    • It’s tough but I guess it’s like finding a good anything: work of mouth; knowing what you’re looking for; interviewing them; etc.

    • Lexi

      Try a search on functionalmedicine.org to find IFM-certified (or affiliated) practitioners in your area.

    • Heather Wood

      Mark, don’t write your local doctors off without talking to them. I am a psychiatrist in New Mexico obsessed with patient-controlled ways to influence mental health, and I know from experience how discouraging it is to keep offering this information to people who only want medical (usually controlled) substances. My unwillingness to prescribe them under most circumstances keeps my practice exclusive ????. But when people call me and express some interest in being self-efficacious, or at least willingness to consider it, I am overjoyed. Your area docs may know more about it than they usually get a chance to express.

    • Peter G

      Mark. For Colorado there’s @JeffryGerberMD.

    • Neil B Cooper

      Dr. Attia,

      Please tell me how a New Yorker might become one of your patients.

      We have been in touch before, and I am interested in pursuing the relationship.

      My best,

      Neil B. Coooper

    • Neil Cooper

      I asked in August about your NYC practice and am just seeing your reply which asks me to contact you directly. How do I go about that?

      Neil Cooper

    • Matthew Sylvester

      Do you know of any good doctors in MA?

  • Nigella Pressland

    Dear Dr Attia, thank you for your surprisingly easy to understand post about the process of heart disease. Are there cultures who have later & slower developments of atherosclerosis? If there are, do you know why this is the case? I was also wondering if the damage can be reversed or slowed down & if so how? I’m a huge fan of Dr Malcolm Kendrick, who writes eloquently in the UK about the heart disease & refutes the use of statins & says that cholesterol is not the cause of heart disease. His blog is here: https://drmalcolmkendrick.org/

    I was equally heartened to read that you believe that T4 monotherapy is far from ideal. I sincerely hope you might elaborate on that belief in a future post. As a hypothyroid person, self-medicating with natural dessicated thyroid (because it is almost impossible to get a British GP to prescribe NDT), I would warmly welcome your views on the inadequacy of T4 monotherapy.

    • I will definitely expand on the T4 stuff at some point.

  • Jason Luchtefeld


    Thanks again for an excellent post.

    I don’t have an opinion on the best boxer but with the summer olympics approaching I will throw out Jesse Owens as the best track & field athlete in history.


    • Tough to argue that.

    • slrzpk

      Emil Zatopek 🙂

      • Given the differences in distance between them, I think we can make room for both Jesse and Emil on that list!

    • Joseph R. Fleming

      You might consider Jim Thorpe.

  • Naren

    Arid dissertations indeed. Great post, Peter. Thank you for taking the time. As a 35 year old, I’m highly interested in the how of “increasing the odds in your favor” and “delaying the onset of bad outcomes”, which you’ve covered to some extent in your recent podcast appearances.

    Can’t wait for the book.

    P.S. – very excited about Paul’s new PapaAlpha blog, highly relevant to my circumstances and aspirations.

    • Thank you, Naren. Glad you like Paul’s blog. Pretty different from mine, huh?

    • Isaac

      Could you direct me to some of these podcasts? I would like to learn how to improve my odds.

  • Carol

    Another fine article. do I correctly understand that high LDL contributes to the pathogenic process by increasing the likelihood that some particles will oxidize? Everything else being equal, double the particle count means double the oxidation? If so, how to control the particle number? This seems to be a difficult factor to control by diet.

    • I don’t think it’s quite linear in math, but do not discount the ability of diet to control this process.

  • Dan Walker

    Reaching waaaay back to senior immunology here but, I thought that macrophages were supposed to return to the spleen, or something, for disposal once they had phagocytized (and presented in the case of a true pathogen). Is there a particular reason why they get stuck and cannot return to circulation in this case?

    • I’m guessing they are too large to exit, but may be some forced retention, too.

  • Dan Walker

    Whoops, sorry about that, I glossed right over the upregulation of the vascular cell adhesion molecules. I wonder if there are any (or many) genetic polymorphisms in VCAM structural genes or maybe even possibly in VCAM expression control that could make a difference at that juncture?

  • Hank S

    Another great post. Your ability to break the science down into digestible pieces is awesome — I’m still digesting this one!

    Question: do you still prefer the NMR lipid profile for patients, or has anything better or more widely available come along since you recommended it? This article is a bit old, but questions the accuracy of the different profiles, including NMR – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735461/

    Looking forward to your next post!

    • Yes, NMR is still the only test I use to measure lipoproteins, including Lp(a)-P (vs. mass or cholesterol).

  • Conrad

    Brilliant. Could you please point me to a blog post or article on the modifiable risk factors? Thank you

  • Steve Brecher

    I’m so far not persuaded that excessive LDL particles should not be considered causative and that, rather, it’s just age. Mightn’t it be some function of cumulative LDL particle exposure and therefore of both LDL-P level and age?

    Do the data showing that CVD is progressive from youth come from Americans and Europeans who eat like … Americans and Europeans? Surely you’re aware of populations, e.g., those of mid-20th C. Okinawa and Japanese, whose incidence of CVD (symptoms or disability or mortality) was rare?

    • Look at both the MESA data and Framingham date, Steve. The survival curves are telling.

  • Lexi

    Fascinating. I would love to hear you write more about Lp(a).
    At the end of the post, you have two figures, both are “Figure 3” and I think you mean to have two different ones from the Circulation paper.
    Thank you for the explanations.

  • Vanessa

    Hi Dr. Attia,
    I don’t mean to hijack this post into something other than the intended subject matter, but do you have any references that I can read to understand the following comment you made or can you elaborate further? I’ve been reading a lot about thyroid disorders lately as I feel I might suffer from one, so this comment was intriguing to me.

    “why monotherapy with T4 for hypothyroidism is a recipe for disaster for most patients”


    • Another time. Just can’t address complex topics in a few lines.

  • Jason


    Thanks. Very well described. How did you make the jump from astronautics to medicine? I’ve been working at NASA for more than a decade, but this sort of information is so fascinating to me that I can’t stop reading. I guess I ended up in the wrong profession! A bit too late to change now, sadly, with me now mid-career and with two children.

    So many questions, and so few answers…not that you have the answers, or time to respond! What happens to foam cells when someone fasts for a period of time (days, not hours)? Is there any known thing that can actually reverse atherosclerosis? It doesn’t look like there’s even an easy way to test for methods, since there doesn’t seem to be a noninvasive way to measure foam cells. Guess I’ll have to go back and re-read your series on cholesterol, and do what I can to keep total cholesterol numbers down.

    Fascinating. Thanks again.


  • Thanks for the information, super valuable… I been struggling with many years to find answers from many different family physicians.. Even thought in 2015 had a heart attack.. I am still educating myself daily, and been on Ketogenic diet for more than few month… and hoping at least this would give me a kick to get me started properly.


  • JB

    Hi Peter,

    Thanks so much for your continuing work on this. The why’s and how’s of that first step still stop me. Why do some LDL particles get retained and others not? I understand the idea that it’s a concentration thing that starts retention, but many particles still do not get retained while others do. Is that related to the number or characteristics of the intimal proteoglycan molecules (maybe in the way a receptor molecule works)? Or some characteristic of the particles that do get retained? Can a particle only get oxidized once it’s retained, or can it start to get oxidized before retention, thereby making it more likely to get retained?

    Further along in the process, if the HDL could completely delipidate the foam cells, might there not be such a large or destructive immune response? Does the macrophage compete somehow with the HDL for foam cell dominance?
    That step is such a hot mess on the immune system side.

    Yes I know, if all of us asked you 30 questions, you’d never see your family again. This is mostly a rhetorical rumbling of my brain, but if you have any insights of course they’re very appreciated.

    As a female (although on BHRT), I had a significant wide-eyed moment when looking at that Sniderman chart. Thanks for including it and the paper.

    I only wish I had read it all *after* I carried that heavy air conditioner unit up three flights of stairs, not before. 🙁

    C’mon, you know it’s really LDL-C….

  • Owen

    First !!
    I didnt think the wording was very difficult. Not as much as i thought anyways. Well above my head on some stuff. Thank you for the post.

  • bill

    Do you believe the endothelium is only one layer thick:


    …and that lipoproteins get by it from the lumen?

  • Darlene

    Thank You.

  • jf

    Amazing article as usual, thank you for this great synthesis of other articles and adding your knowledge to them . I believe there are two typos:
    1] IS …covered ‘in’ the cholesterol series…
    WAS …covered the cholesterol series…
    2] IS … especially ‘as’ they pertain to age…
    WAS …especially at they pertain to age…

  • ProudDaddy

    Could you take a moment to explain to me why theses processes don’t, to my knowledge, occur in veins?

    • Probably because they lack the same wall structure as arteries. Perhaps pressure has something to do with it also.

    • Stipetic

      Veins do develop atherosclerosis in CABG.

      • That’s a good point. I have not seen the histologic features of diseased SVs, though. Curious as to sequence and pattern.

    • Nicolas

      Wouldn’t the lack of oxygen (and therefore, the lack of oxidation) in the blood passing through the veins—as compared to the oxygenated blood of the arteries—explain, at least in part, why these processes don’t occur in veins?

    • Gwyn

      I see a lot of calcified veins on mammograms. Especially in diabetics.

  • Patrick Snook


    Have you seen this recent description of the mechanics of atherosclerosis? It’s quite different from the version you describe. What do you make of it?



    • Yes I have seen this and don’t find it as compelling as this model.

  • Brad

    “Today, I manage all modifiable risk factors to the level of my risk appetite and interpretation of the most nuanced scientific literature on cardiovascular disease. ”

    Can you point to a summary of this somewhere either from yourself or a source you trust? Or is your approach totally custom and not something you would be willing to share? Obviously, I’m not looking for medical advice here simply guidance through the swamp of untrustworthy sources on the internet 🙂 Like what are the risk factors that matter and the theoretical best methods for managing them? If one listens to conventional “wisdom” then they’ll be eating a super low-fat diet lol

    Thank you very much for the article as well, I’m sure I will not be the only one it is eye opening for. I had no idea these problems all start in the walls instead of the artery itself!

    • Maybe I’l get to at some point. Likely in book.

  • T. Black

    Very happy you exceeded your one post limit.

    • Possible there will be another in 2016… HRT is brewing…

  • Jane

    Peter, thank you. This is very interesting.
    Apparently we are all going to die.

    I still need to know what to tell my adult children.

    So, may I conclude that we should suggest to our children that they avoid high insulin levels; eat not too much and only nutrient dense foods? And exercise regularly of course: move around a lot more often, using their muscles?
    Or, since this is the eating academy, can you say more?
    I understand that you will remain silent about specific comments about statins.
    But what do you think about those medical doctors who “think they should be added to our water supply”?

    I cannot paste links that would take you directly to the scientific sources. The links are on the blog at thefatemperor.com

    You might find interesting two papers on this subject, which were pointed last week out by Ivor Cummins on his blog thefatemperor.com

    • Jane

      Hmm, I guess I cannot revise my writing here,

      D you have any thoughts about the papers that Cummins brought to our attention?

      In terms of health-promoting behavior, to keep the fat out of our blood vessels, is it as simple as “do not become less thin”?

      Thank you so much for your new post!!!

  • Joan Mercantini

    This explains so much . Thanks for all you do . Disappointed as I was expecting some mention of inflammatory o-6 oils, combined with a high carb diet. However, I am still going to stick with my LCHF diet.

  • Hi Peter

    Have you read Vladimir Subbotin’s latest paper? It seems all is not well with the orthodox view of atherosclerosis development (including the leaky ‘single-cell’ endothelium…) Vladimir certainly takes a pathologist’s view of the phenomenon…and then some 🙂 http://www.thefatemperor.com/blog/2016/6/25/atherosclerosis-vladimir-subbotin-is-back-must-read-for-athero-afficionados

    • Yes, familiar with his work. I don’t agree, obviously, but not quick response so this will have to wait.

  • Lindsey

    Why is “getting stuck and oxidizing” a function of LDL particle concentration? Is it simply a numbers game — if more particles are present over time, there are more particles to get stuck/oxidize and lead to damage? My take away from that would be a focus on lifestyle modifications to reduce LDL particle number.

    • More particles increases odds of more getting in increases odds of more getting retained (and oxidized).

  • Steve

    Wow, thank you Dr. Attia..time to go deep

  • Antonio

    “The endothelium is a protective one cell layer lining the surface of the artery lumen”

    Dr Attia, so what´s your opinion about the obligatory development of DIT (diffuse intimal thickening) in human epicardial arteries? (and the work of Nakashima et al. among others)


  • Gregg

    Ok, getting older is the predominant factor. Can the process of atherosclerosis be reversed? Or, is it game over once the lumen narrows and stenosis develops?

    • It can probably be reversed and definitely slowed. But you to be rigorous when you define “reversed.”

  • This was an exceptional post. Thank you for the information. Couple of questions:

    1. LDC-C at low levels seems to correlate from studies i have read with plaque regression, so looking at LDL-C may not be so bad after all?
    2. I am aware of statins and drugs that block absorption of cholesterol, ie Zetia. What other drugs might you have reference too that fill out the 4/5 classes if these are two?
    3. You can have low CRP and CVD?
    4. Does a highly allergic person with an overreactive immune system face a higher risk of CVD?
    Thanks again,

    • LDL-C is a fine marker, as long as it agrees with LDL-P (concordance), but then again, so is eye color.
      Other drugs include fenofibrate, bile acid sequestrants, PCSK9i, etc.
      Not sure.

    • Tom Jeanne

      Re #4, look up Kounis syndrome (allergic angina and allergic myocardial infarction). This may shed some light. : http://www.medscape.com/viewarticle/864654 (The original article is Am J Epidemiol. 2016;183(7):613-621. if you can’t view that).

  • John U

    Very very interesting and persuasive from a science standpoint. I wonder, however, whether the evidence gathered from examinations of the arteries during autopsies may be showing trends which are recent and not representative of populations which were not eating the SAD (standard American Diet). This diet would have been heavily carb loaded with lots of PUFA’s to boot since about the 40’s or 50’s. The effect of both of these nutrients together would contribute to the oxidation of pufa’s and hence their contribution of harm to the arteries. It would be interesting to know if other tribes or populations which did not eat the SAD, such as the inuit, would exhibit similar fatty streaks at such an early age.

    • A very good point, I wish we had those data.

    • Steve Brecher

      Can’t help with early fatty streaks in the Inuit, but as to the incidence of CVD…

      “It is a common notion that coronary heart disease (CHD) is rare among the Inuit … The overall prevalence of CHD (AP+self-reported MI+ECG defined MI) was 10.8% in men and 10.2% in women. The highest prevalence was observed in the least westernized areas in Greenland.”

      High prevalence of markers of coronary heart disease among Greenland Inuit.
      Atherosclerosis. 2008 Feb;196(2):772-8. Epub 2007 Feb 15.


      “The notion that the incidence of ischemic heart disease (IHD) is low among the Inuit subsisting on a traditional marine diet has attained axiomatic status. The scientific evidence for this is weak and rests on early clinical evidence and uncertain mortality statistics. … The mortality from all cardiovascular diseases combined is not lower among the Inuit than in white comparison populations. If the mortality from IHD is low, it seems not to be associated with a low prevalence of general atherosclerosis.”

      Low incidence of cardiovascular disease among the Inuit–what is the evidence?
      Atherosclerosis. 2003 Feb;166(2):351-7.

      • I’m going to add this point as an addendum to the post:

        Clearly there are factors here we (at least I) do not understand. Why do some people just stop with fatty streaks and stay that way for decades, while others progress to clinically significant heart disease? I’m sure if one normalizes for LDL-P, Lp(a)-P, and even particle size, the answer will still allude us (me). I think what people are missing here is that there is a difference between what we can infer from population-based (i.e., heterogeneous) statistics–clinical trials with drugs, epidemiology, ecology, autopsies–and what happens at the individual level. Furthermore, the only probabilities that matter when it comes to an individual are “0” and “1”–in other words we go from the most heterogeneous to the most homogeneous.

        I’m reminded of an analogy Allan Sniderman shared with me a few years ago: If you’re a parent, with kids in your home, and want to know the probability that your child (or any child in your home) will die from an accidental gun shot wound, you can look at the stats, which are readily available. They will say the risk is actually pretty low–which it is on average. But what if we now adjust the information (in the Bayesian sense of the word) and note that you have a loaded .45 under your pillow (you know, for home protection). Now what happens to the risk? Of course it goes up dramatically. Why? Not just because we have “more” information–we actually have very specific “new” information. We have information about the causative agent, the gun. LDL-P and Lp(a)-P are the causative agents, and while other forces matter (e.g., inflammatory response), there is no getting around the fact that high LDL-P and Lp(a)-P are stacking the odds against you. The gun won’t pull the trigger on its own, but it’s still the causative agent. People are too quick to confuse “necessary and sufficient” with “necessary but not sufficient”–in both cases reducing the “necessary” component helps.
        So while I do not doubt that some people with high LDL-P and Lp(a)-P may be immune to the typical “rules” of atherosclerosis, we don’t have good enough tools to predict this, especially non-invasively. Ergo, the risk of doing something to lower these modifiable risks, even if that means taking drugs, must be weighed against the risk of doing nothing. This last point is often dismissed.

        Most kids in homes with loaded guns will not die from those guns, but to ignore the loaded gun in that setting is crazy, in my opinion.
        I’m going to remove the gun and put the odds back in my favor.

  • gerry

    A very outstanding post!

    Emphasizes a lot of information that simply is not being discussed by doctors when they see patients.
    It reminded me of the many people I know. In terms of CV events, I see them as walking land mines–
    nobody knows when they will go off.

    There are many risk factors for CVD, many of which can be controlled. Thanks to the internet, I see many
    people getting better educated about what they can do to ” increase the odds in your favor” and reduce risk.

    Keep up the great work Peter, I hope to see the Lp(a) piece very soon.

  • Don Bonner

    Peter, great article as usual. My question is what non-invasive test to you believe is the best for early detection of endothelial dysfunction, and when do you think they should be performed?
    Thanks, Don

    • No single test, though some in pipeline could be compelling.

    • patricia

      re endothelial dysfunction prediction: ? for women – preeclampsia? earlier in life

  • Ibraheem

    What’s the role of sodium intake in this process
    I wonder if atherosclerosis is accelerating now because of excessive salt intake

    • I see no reason to believe (despite what CDC might say) this is a driver.

  • Pat Smith

    Everything I have learned (mostly from you) has lead me to believe that high insulin levels in the blood damage the vessel walls and make them susceptible. I watched the following video and read Dr Joseph Kraft (pathologist) book, Diabetic epidemic &You. The timing of increasing insulin level and the slow evolution of cardiovascular disease seems well synchronized and Dr Kraft clearly believes this is not just serendipity. What are your thoughts?


    • I agree that hyperinsulinemia is a problem.

  • Yolanda

    Excuse me for contacting you. You don’t know me I just googled to find someone who was prepared to ask the big question ‘What if modern medicine has got it wrong’and wasn’t from a family of doctors and the more I read about you the more you seemed to fit my criteria eg someone who appeared to be a very logical thinker but a ‘family man’ who could trace genetic patterns. The more I read about you the more your experiences seemed to fit my theory (which incidentally has nothing to do with alien abductions or religion). i know you must be contacted by many people but would you be kind enough to listen to my theory of why modern medicine is founded on a false premise and medication is harming rather than healing us. If it seems crazy you can tell me and I won’t bother you again.

    • Ray Jennings

      Yolanda, They do not have it all wrong, but their template needs major updating. And yes a lot of “not so honest” money being made. I hope Peter replies to your post, but in so many words, he had posted 3 or 4 years ago, that what he learned in school was not really answering the problems of obesity, Diabetes, Diet, and yes heart disease which alone account for the vast majority of all health problems.

  • Anthony Llabres

    Great read for sure. Thank you. Any actionable advice based on this? You clearly are making diet and lifestyle changes to address you personal scenario. I would like to hear what we can do out here to reduce CVD.

    Be well…


  • Tuck

    There is a root cause. It’s not age, as atherosclerosis is not strictly age-related.

    It’s a chemical called 4-HNE, and related oxidized linoleic acid metabolites (OXLAMs).

    This is *always* found in atherosclerotic plaques, in humans and in animals, it causes endothelial wall damage. OXLAMs are causative in fatty-liver disease (I know you were looking into that at one point), and a diet structured to reduce OXLAMs in people with fatty-liver disease had a 100% cure rate in the one small study designed to test the theory.

    They are causative in age-related macular degeneration, and they (along with LA) are causative in mitochondrial dysfunction, which is found in every aspect of the metabolic syndrome.

    High levels of 4-HNE in the brain are symptomatic of Alzheimer’s, and high levels of 4-HNE in the blood is symptomatic after a stroke. High levels of 4-HNE are also symptomatic of traumatic brain injury.

    As 4-HNE and OXLAMs have a single source, and cannot be produced endogenously without that single exogenous source, and diets structured to reduce it (in animals and humans) have been shown to reduce the effects of the metabolic syndrome, we’re looking at a pretty strong candidate for a single cause for the entire packet of diseases—all of which are highly correlated, of course. And, in some cases, worsened by consumption w/ carbohydrates, which increase ROS production and increase the creation of OXLAMs. OXLAMs cause an order of magnitude more oxidative damage than ROS, and, unlike ROS, can spread though cell walls.

    This is a pretty good place to start:

    “Effects of 4-hydroxynonenal on vascular endothelial and smooth muscle cell redox signaling and function in health and disease”

    “…Depending on its relative concentration, HNE can induce a range of hormetic effects in vascular endothelial and smooth muscle cells, including kinase activation, proliferation, induction of phase II enzymes and in high doses inactivation of enzymatic processes and apoptosis. HNE also plays an important role in the pathogenesis of vascular diseases such as atherosclerosis, diabetes, neurodegenerative disorders and in utero diseases such as pre-eclampsia. This review examines the known production, metabolism and consequences of HNE synthesis within vascular endothelial and smooth muscle cells, highlighting alterations in mitochondrial and endoplasmic reticulum function and their association with various vascular pathologies….”

    We can get into how they cause DNA damage and break down cartilage—the ACL tear, for instance, did not exist as a condition until after polyunsaturated fat consumption spiked in the 1960s. Another comment, maybe.

    • Tuck

      BTW, atherosclerosis appears to be age-related because 4-HNE production and LA concentration in tissues are age-related.

    • David

      Tuck, aren’t there other AGE/ALE resulting from autoxidation of common foods? Rather, shouldn’t we zoom-out from HNE and address eating patterns increasing our exposure to all oxidative compounds? Thanks for the note, though!


    • Tuck

      “Tuck, aren’t there other AGE/ALE resulting from autoxidation of common foods? Rather, shouldn’t we zoom-out from HNE and address eating patterns increasing our exposure to all oxidative compounds?”

      Actually, if you zoom *in* to the process that produces HNE, you’ll find even more compelling evidence that this is the root cause. Cellular apoptosis though oxidative damage is *caused* by the precurser to HNE, through making mitochondria susceptible to oxidative damage, directly and by overwhelming the repair mechanisms. Cardiolipin, which is composed mostly of the precurser to HNE, when oxidized travels to the mitochondrial wall and triggers mitosis and apoptosis, releasing HNE and other chemicals which are an order of magnitude more damaging than simple reactive oxidation species. This can cause a cascade of damage. As mitochondrial dysfunction and oxidative damage are the hallmarks of every aspect of the metabolic syndrome, and the couple of studies that have attempted to treat metsym by reducing these causes of oxidative damage have high success rates (100% for fatty liver disease, on a *high-carb diet*, I think we can safely say that carbs are a co-factor, but not causative.

      LDL-P may well be another symptom. But consider that tests looking for oxidized LDL look for HNE and the related chemical MDA, both produced from the same precurser in the mitochondria.


      At some point, it’s simple logic to say, hey, if these chemicals are always at the scene of the crime, and they’re not produced in the body except when introduced by an exogenous source, maybe that exogenous source is the cause?

    • Great add, thank you! I’d love to read more if you could please direct me? I have full access to about every journal, though most of the vocab I’ve yet to learn, as this area is simply a hobby to me. I thought I remember reading, though, that some Malondialdehyde was made in vivo… probably getting my acronyms mixed.

      Just to clarify–if I want to encourage health (in this respect) I can’t just tell the average person to “stop eating so much 4-HNE”. So, you think it’s more effective to make dietary recommendations based on reducing oxidized fats? In my experience, the level of familiarity required to “get it” in those terms is more approachable to the average person. You can tell someone to avoid cooking with corn and soybean oil, for example.

    • rick

      “As 4-HNE and OXLAMs have a single source, and cannot be produced endogenously without that single exogenous source”

      what are you implying that single source is Tuck ?


    • Paula

      ALDH2 protects against stroke by clearing 4-HNE.


  • Jim Bush

    “…and what this tells us about prevention”

    I must have missed this part! Unless, it is don’t age.

    • I wish. Start with keeping LDL-P as low as possible.

  • Blaire

    Wow. Thank you. How do you personally “manage all modifiable risk factors”?

    Btw, I am not a diabetic but I bought a cgm after your last post as a self experiment and I am amazed. It has completely changed what/when/how I eat, sleep, exercise, etc. Even motivates my temperament. Amazing.

    I am your age, and like you, realize just how beautiful life is and how much longer I want to be around. Thank you so much for all your work.

    • CGM is remarkable, indeed. I’m convinced everyone would learning something from it!

  • Guy

    Great article. As a 41 year old a had a pain got a stress test then angiogram and found 3 blockages and they st
    ented me. Good BP and cholesterol, always exercised a lot and Never smoked. Now they just want me to take drugs to lower the BP when it was not high and drugs for cholesterol as well. I am struggling to find a doctor/cardiologist who does not recommend this. Is there and article or book that I can read on recommended treatments other that just the old fashion drugs? I live in Australia. Thanks Guy

  • Andrew


    Love your blog. As an engineer, I appreciate your scientific approach to medicine (which is seemingly rare). Just a thought – make a flow chart for people to follow. I generally read your stuff then have to create a flowchart for myself so I don’t have re-read it (in two years when I need to reference it again). I think this would be really helpful for people to get to the bottom line of the action they should take based on lab results they get. Just thought I would mention it.

    • Brian E. Brumwell

      He’s got a degree in engineering too.

  • tim d

    Dr Dayspring IS a national treasure, and so are you Dr Attia … brother. Thanks!

    This; “And don’t ever bring up LDL-C again”
    Cue the LL Cool J

    Love to ya Dr Attia

  • Max

    Thanks Peter, very interesting. Given the fact, that the development starts so early and over 3-4 decades – what would you consider “best practice” in protecting young adults from the majority of the risk of speeding up the development. Clearly ones appear to be things like avoid obesity, high blood pressure or diabetis – so exercise and a somewhat “healthy” diet ( I won’t get into that one), sleep. But what else would you consider for the general population – not knowing individual risk factors of that person/patient? How “drastic” do you thing a diet would need to be designed to make a real difference? Is preventing obesity and ensuring enough exercise “enough”? Best from Berlin. Max

    • By 30-35 in men and probably 40-45 in women (this excludes FH, Lp(a), and other virulent hereditary factors), people need to have LDL-P under control, even it it means pharmacology.

    • Yossi Mandel

      Or, at the very least, understand well the risks in not doing so.

  • Rambo
  • Ginger Sladky

    Very Interesting and I have to also recommend Scottish Dr. Malcom Kendrick’s Heart Disease series (which one of your commenters already recommended). He is now on his 17th installment. https://drmalcolmkendrick.org/2016/06/19/what-causes-heart-disease-part-xvii/

  • Maryna

    Awesome idea to illustrate every step of desease development with a beautiful schematic picture!
    I’ve been able to understand your articles without pictures, however it took some decent effort and rereading at times, given no medical background. So, pictures are so helpful.
    What could be your reader’s dream, Peter, is an instruction-type article, like do these 5 things and here’s why. Or, at least, a roadmap to the order of reading on the blog and broader around. I’ve read all of it in the last few months and am following recommendations that I can draw from you but I am far from having a clear schema in my mind what is most critical and what I may be missing.

  • Super Nate

    Great article Doc, pretty elated you didn’t mention Tyson. Surprised you wouldn’t include Jack Johnson on your list though.

    • Johnson was great, and Tyson had the potential, but not the category of boxers I mentioned here. Top 5 heavyweights IMO (in chrono order): Johnson, Dempsey, Louis, Marciano, Ali. A case can be made to add Holmes and Lewis to this list, but who would you displace to add either of them? My list of all time greats is, of course, pound for pound.

  • Marion vdWillik

    Trying to make sense of how my body works, to prevent disease, overcome personal health challenges naturally, and to live a long, healthy life of vitality, is the reason I’m naturally curious.

    During my search for answers, I discovered you in an interview with Swedish Dr Andreas Eenfeldt, MD. I have followed your scientific research and work ever since.

    I appreciate and encourage critical thinking in contrast to blind acceptance of the status quo of conventional wisdom.

    Without you asking questions, and more of the right ones, that encourage investigation of ideas, the world will not be as rich in wealth of knowledge.

    Because of your insights with regard to cardiovascular health, diabetes, metabolic syndrome, approach to obesity, nutrition and fitness, my health and vitality has improved incredibly.

    I want to encourage you to continue, while I follow with great interest the ideas you present, as an invaluable contribution to society and the medical community of the world.

  • Russ C

    Excellent post – very clear. Seems like potentially much behind this statement…

    “When LDL particle concentration is elevated, the lipoprotein penetrates into the subendothelial space.”

    Do you think it is a) the elevated particle concentration that causes initial penetration of any kind (e.g. past some threshold), or b) just that the elevated concentration statistically causes more penetration that differentially accumulates faster with age (leading to accelerated threshold event state), or c) the rate of penetration exceeds some threshold/balance of repair functions, or d) there is some other property of the lipid particle associated with the elevated P-count that increases attraction/penetration, or e)…?

    …or f) just a topic for further research?

    • Good question and I think it has to do with many factors, but primarily the concentration and the health of the endotheleium. I am not sure if this is linear or not.

  • Cillian Hurley

    Hi Peter,

    Great article. Haven’t seen diagrams like that since I left school and always enjoyed their ability to explain. By any chance is Tom’s video available online?

    • Probably on LecturePad, but not sure. It’s been a while since he made this.

  • steve

    1. What do you consider a physiological normal level of LDL-P
    2.Will this level allow for plaque regression or stabilization or do you have to have a lower level
    3. You recommend a high/higher fat diet, but would you still if it raises CRP even slightly where CRP is already low?
    4. If on meds, and LDL-P results are within a physiological normal range, does it matter if on lo or higher fat diet?
    5. What role does HDL-P play in all this, particularly with regard to regression?

    Thank you!

    • 1. 50th percentile is about 1,200 nmol/L so probably around there
      2. Not sure, but that’s an important question
      3. Can’t make a blanket statement in isolation
      4. Yes, especially as diet pertains to inflammation and hyperinsulinemia
      5. Probably meaningful, but we need know than # of HDL (almost assuredly better than HDL-C)–need to know function, which we can’t really measure yet.

    • steve

      From what i have read and heard, plaque regression appears to take place at an LDL-C of 50, so i would guess that 500-600 LDLP would be concordant with that level. Does this seem to be what you have seen in the data?

      • Yes, but it might also depend how that reduction in LDL-P is achieved. My patient-specific targets are based on several factors.

    • steve

      I have not come across many who can achieve an LDL-P of 500-600 without drugs. Perhaps some, but for most a statin seems to be required, perhaps with an absorption blocker. In which case, maybe the anti-inflammatory benefit of the statin combined with a diet that raises LDL-P( higher fat for most to achieve this too). Have you seen many get to these low levels of LDL-P and high levels of HDL-P( assume their functional) with only diet?

      Seems to be lots of controversy over what an anti-inflammatory diet is and in part this may be based on individual metabolism( ex, high sugar intake). Would IR/IS status in addition to CRP level give a hint at the individual level? At population level i think it is a lower carb level, say under 200 grams per day.
      Thank you.

  • Gerald Davies MD

    The fact of inevitability of atherosclerosis with aging, (like grey hair and cataracts) prompts us to understand the cause in order to age with minimal suffering. The LDL (even p) theory fails to explain the focal nature of plaques. They occur and junctions, bends, low flow and areas of turbulence: all areas associated with high endothelial turnover. Laminar flow, like gravity for astronauts, is a requirement for normal endothelial function. Endothelial apoptosis and phagocytic scavenging is a normal physiological function which is greatly accelerated in areas prone to plaque. Furthermore, cholesterol (present in all cell membrane) has no enzyme degradation pathway and accumulates in other situations of high cell turnover, infection and inflammation; for example cholesteatomas.
    How do you explain the very poor correlation of LDL with ‘events’, and the order of magnitude higher risk of events associated with hyperglycemica and hyperinsulinemia, just for starters. Red herrings are not innocuous if the real killer goes undetected to continue killing.

    • Gerald, I don’t disagree at all that flow characteristics matter (I used to be a mechanical engineer and fluid dynamics was my passion), but I’m still waiting for a better idea to reduce the risk of CHD/CVD than reducing LDL-P/Lp(a)-P and improving the metabolic milieu (e.g., reducing hyperinsulinemia and hyerglycemia). Why does it have to be one or the other? This post focuses on the former. God knows I’ve written plenty about the latter.

  • Fred Miller

    What’s your take on nanobacteria calcification in atherosclerosis?

  • caroline

    Thank you Dr. for your easy-to-follow description of the progression of atherosclerosis. I first learned about the stages of this pathology during my graduate studies: fellow lab associates were studying this very process. My particular area of study was using autologous stem cells to ameliorate/mitigate coronary desease progression. Anyway, my question is a simple one but I am sure there’s no clear, simple answer. Here is it anyway: You state that the pathology begins from an overloading of LDLs in the blood stream which then migrate across that epithelial layer and become oxidized. How is it that these levels increase in the first place? I’m afraid that I lack a great deal of knowledge in diet and yet this is exactly what my Dr. emphasizes for me… eat less fatty foods, eat less salt, increase fruit and vegetable consumption Yet, I am now reading studies where increasing fat with a drastic reduction in sugar consumption is far more healthy and beneficial (Ketogenic diet). For three years previous to this discovery of the Ketogenic diet, I used to drink a fruit infused protein shake every morning, eat giant kale salads loaded with “super food” fruit and veggies at lunch (low fat dressing) and dinner was usually more veggies paired with a lean protein. I rarely lost a single pound and was always hungry. Starting this keto diet two months ago, I have so far lost 28 lbs., feel far more satisfied and have more energy. But now my worry is, am I overloading my blood concentration of these LDLs by increasing fats? I have been reading that SUGAR is the actual culprit in initial atherosclerotic formation as it causes system-wide inflammation which then promotes the start of these plaque formations. What are your thoughts? How do you manage or mitigate your likelihood of adding to this age-associated pathology?

    • Caroline, if you’re asking how do LDL-P levels increase the answer is complex and we know some things and don’t know others. Things that increase LDL-P (on average) include: more sterol synthesis, which can be heavily diet-driven; more TG, poor LDL-receptor clearance, genetic variants, and more.
      Sugar probably contributes to heart disease by not only increasing LDL-P, but also amplifying the particle response (retention, oxidation, etc.).

    • Yossi Mandel

      Thank you for giving us a hint of what will come in your recommendations for prevention and healing…

  • Daniel Zbarski

    Doc, what would U consider “optimal” apoB? No LDL-P NMR for Europeans i’m afraid…

  • Luke Banchy

    Great post! Heard you on Tim’s podcast and, forgive the corniness, my life has been changed for the better. I’m a 22 year old pre-med student at Madison. I’m so happy I discovered your work as early as I did in life. Please know that these posts are far reaching and very impactful. Thank you for taking the time to write these.

  • Jeremy Fox

    Are there any commonly prescribed drug interventions to lower LDL-P and Lp(a) that you are not in favor of?

    • Wrong question. I’m not in favor of any tool being used incorrectly.

  • Ivor Cummins


    Thanks for your last reply. Would be super if you could give just one or two top-level bullets on where Subbotin’s hypothesis falls down (Kepner Tragoe style). Not to worry though – another quick question, this time on the Lp(a) front. I seem to find much data that suggest Lp(a) is only a risk factor in the context of certain scenarios. In the absence of these scenarios, do you still perceive it as something to be lowered regardless i.e. an independent deleterious agent?
    Or rather is it a highly dependent form of ’cause’, that has little meaning without a disadvantageous milieu being active. In which case the latter milieu is more appropriate to be deemed as the true ’cause’ of poor outcomes. In otherwords Lp(a) would be a classic interacting variable, which perforce must be scrutinised carefully in the context of other (more important) ones. This may read badly, but it’s late in Ireland and I’m heading to bed shortly… 🙂 Below link will elucidate my thoughts, in my usual rant format:




    • It’s clear to me, even in my clinical practice, which is small by most standards, that not all Lp(a) are created equal. I’ve seen families with modest elevations–say, 150 nmol/L–which are ravaged by CHD (e.g., MI’s in 40’s and 50’s), and I’ve seen families with off the charts values–say, 400 nmol/L or more–with relative “normal” patterns of CHD. I will try to address this when I post on Lp(a), which I will do at some point. I suspect the Kringle folds play a role in virulence. I also do not know how much overlap exists between different variants of pathology–for example, CHD vs. aortic stenosis.

  • Tuck

    “Gerald, I don’t disagree at all that flow characteristics matter (I used to be a mechanical engineer and fluid dynamics was my passion), but I’m still waiting for a better idea to reduce the risk of CHD/CVD than reducing LDL-P/Lp(a)-P and improving the metabolic milieu (e.g., reducing hyperinsulinemia and hyerglycemia). Why does it have to be one or the other? This post focuses on the former. God knows I’ve written plenty about the latter.”

    I’d be interested to hear your take on how you reconcile those two viewpoints with this old post from Stephan Guyenet looking at the difference between CVD rates in populations differing in geography and environment, but not genetics:


    It’s pretty clearly an environmental cause. If it was due to the shape of our circulatory system or carbs, you wouldn’t see this dramatic a divergence (note the huge difference in CVD rates between Japanese living in Japan and those in the US).

    • Gerald Davies MD

      Thanks for the personal reply, like you I have many more questions than answers and anyone who tries to keep up with the enormous literature regarding age related diseases knows that anyone claiming truth is a fraudster as “our knowledge only leads to deeper levels of confusion”.

      Just a little about me; 66 yr old retired anesthetist/intensivist, read Yudkin in 1967 and have avoided sugar ever since. Bought into the fat hypothesis and also the fiber hypothesis after attending a Denis Burkett lecture in 1971. Always athletic BMI between 20 and 22 and still biking and jogging now. Adopted a typical non focused healthy eating strategy for best part of 30 years and BMI edged up to 24. Read Taubes’ titanic work in 2007 and became much more focused on avoiding all the high glycemic carbs and dropped 20 lbs in 6 weeks: 6 ft and 174 lbs for the last 9 years on a low carb high fiber diet otherwise unrestricted, no calorie counting. Age 64 suddenly developed what I suspected might be stable angina, continued to exercise for 2 years with no change in onset of symptoms. FInally age 65 stress test positive; angiogram isolated CTO right coronary distal to CMFLX and after a complex retrograde canulation of the RCA via the LCA got a couple of stents and am totally angina free and back to HIIT on my favorite hill in the park at The Quarry, Shrewsbury, UK. The figures you show of the near universal finding of some degree of atherosclerosis at age

      So I have a personal interest in seeking the ‘truth’ of these matters. An immediate question is the relevance of atorvastatin. In my case I took 40 mg for 11 months and I am 3 weeks into a personal trial stopping the statin and have a feeling?? that exercise recovery muscle aches have improved.
      What is the evidence that LDL particles penetrate the endothelium of arteries and are the all important cause of plaque. LDL may penetrate endothelium to deliver its energy substrate to cells as a normal physiological function?.
      Foam cells are phagocytes engorged with fat that fail to depart the intima and become necrotic leading to fatty streaks and the beginning of plaque formation,
      This only happens in certain arterial locations where there is increased endothelial apoptosis. These apoptotic cells are cleared and recycled in a normal fashion by immune cell phagocytosis.
      Any situation that may lead to excessive apoptosis and/or less than optimal clearance by the immune cells could conceivably overload the system where necrotic immune cells (foam cells) would start plaque formation process. For instance cholesterol build up in chronic otitis media (cholesteatoma) is residue from insufficiently cleared necrotic immune cells.
      Interestingly, with diabetes plaque formation is much more diffuse rather than localized.
      Endothelial cells and immune cells have insulin receptors. Macrophage activation and endothelial function are influenced by insulin and disturbed with hyperinsulinemia and regular postprandial hyperglycemia.
      Autophagy is necessary for phagocytosis is suppressed by insulin through mTOR activation.
      Lipoprotein B (LDL) synthesis by the liver is stimulated by insulin, the weak association of LDL with CAD events may be, even more likely confounding than causative. JUPITER study suggests that the protective effect of statins was more likely due to their anti-inflammatory side effects as it was not related to LDL levels. In fact the benefits of statins were only seen in patients with raised CRP.
      Clearly CAD is complex and my main point in all of this is to expose a red herring for the damage it can do and it’s looking more and more like LDL is a red herring, meanwhile huge resources of money and attention are being diverted to controlling it.
      Interesting historical studies on Japanese in Tokyo and California, maybe the difference was caused by the greater accessibility to rice in those living the good life in California?
      Much appreciate the chance to do some thinking here, hope to follow your blogs from now on, Cheers

      • Gerry, see a more recent analysis of JUPITER (Circulation. 2015;132:2220-2229). Lots of good questions, but it’s all I can do to write the posts.

    • Tuck

      To provide an answer to some of Gerald’s questions, I posted this as a comment at Hyperlipid’s site earlier. To be clear, I eat low-carb myself, but I don’t think that’s the root cause of our issues with the metabolic syndrome any more.

      To your comment about endothelial apoptosis, the cause of that is pretty well-determined, you just need to find the right term to search for. oxLDL is a better guide to CVD than other things, and it’s pretty clear what oxidizes LDL, it’s the same thing that causes oxidative damage throughout the rest of the body. And it’s not glucose. That term is below.

      “Whilst relatively low doses of HNE can orchestrate cell signaling events, higher concentrations of HNE appear to modify a further set of target proteins, inhibiting or dysregulating previously functional cellular processes and organelle functions. In particular, endothelial cells, which form the primary vascular interface for potentially oxidized circulating components, appear to be highly susceptible to HNE induced damage [10,85]. HNE can exert a range of pathophysiological effects, including interfering with the synthesis and release of vasoactive mediators, breakdown of the endothelial barrier function and inducing a pro-inflammatory phenotype within the vessel wall.”

      It also impairs NO, but that’s not all!

      “Elevated plasma levels of HNE also damage endothelial barrier function [10,87] due to impaired cell–cell communication and inhibition of membrane associated enzymes [85].”

      There’s also this:

      “Cholesterol consumption reportedly increases HNE synthesis [11], with HNE inducing low-density lipoprotein oxidation and increased uptake by macrophages [12], and HNE accumulation within atherosclerotic plaques [13].

      “Effects of 4-hydroxynonenal on vascular endothelial and smooth muscle cell redox signaling and function in health and disease”


      Another paper sums it up thus:

      “Both HNE and oxysterols then appear to be candidates for a primary role in the progression of the atherosclerotic process.”

      “4-Hydroxynonenal and cholesterol oxidation products in atherosclerosis”


      But even that’s not all!

      “Among the factors known to accumulate with aging, advanced lipid peroxidation end products (ALEs) are a hallmark of oxidative stress-associated diseases such as atherosclerosis. Aldehydes generated from the peroxidation of polyunsaturated fatty acids (PUFA), (4-hydroxynonenal, malondialdehyde, acrolein), form adducts on cellular proteins, leading to a progressive protein dysfunction with consequences in the pathophysiology of vascular aging. The contribution of these aldehydes to ECM modification is not known. This study was carried out to investigate whether aldehyde-adducts are detected in the intima and media in human aorta, whether their level is increased in vascular aging, and whether elastin fibers are a target of aldehyde-adduct formation. Immunohistological and confocal immunofluorescence studies indicate that 4-HNE-histidine-adducts accumulate in an age-related manner in the intima, media and adventitia layers of human aortas, and are mainly expressed in smooth muscle cells….”

      “The accumulation of 4-HNE-adducts is very high in the intimal aorta, mainly in older patients with high atherosclerosis grade. These data were expected since oxidized LDL and lipids accumulate in the intima in the early lesions and in the lipid core of advanced atherosclerotic lesions [23,24]. These data confirm that 4-HNE is a main marker of oxidative stress and LDL oxidation which could contribute to the evolution of the lesions via its ability to modify proteins and generate cell dysfunction. 4-HNE expression was also increased in the adventitia of the elderly, probably associated with the vasa vasorum, which are involved in the supplying of nutrients and oxygen to atherosclerotic lesions, and the development of angiogenesis in the atherosclerotic plaque [32,42]. The recently reported angiogenic effect of 4-HNE suggests a role for this aldehyde in the development of vasa vasorum and microcapillaries in atherosclerotic plaque [35,43].”

      “Elastin aging and lipid oxidation products in human aorta”


  • Andre

    Hi Peter,
    When thinking of endothelial cell damage I always think of hyperhomocysteinemia. Why no mentiona, studies still too ambiguous?

    If reversal was possible, what could the mechanism theoretically be and what would impact it most? Here some wild guesses: VLCD (to become fat adapted), endurance (higher avg blood flow) or interval taining daily (blood pressure variation), hyperbaric oxygen treatment (to increase ROS and destroy those foams), extended fasts (like 10-14d) … any guesses?

    • It probably contributes, but I omitted many things that damage the endothelium (smoking, HTN) much more than homocysteine.

  • Carol

    Your contributions are priceless in helping people take charge of their health. “Start with keeping LDL-P as low as possible.” I hope you will address how to do this. Since adopting LCHF all of my cardiac bio markers have improved (as well as several chronic health conditions that have disappeared) with the exception of small LDLp, which is close to 2000. The standard advice to opt for plant oils in lieu of animal fats will rob Peter to pay Paul. I am not a candidate for statins due to risk of heart failure, which killed my mother, and their benefit is dubious. Will increasing vitamin D sulphate via sun exposure improve LDLp? What else is there?

    • I am not sure if vit D will reduce LDL-P, but if it does I would expect the effect to be very small.

  • Al

    Thanks for another brilliant post that’s also easy-to-understand by non-medical people…

    I just want to know, maybe based on your own observation, that a low LDL-C or VLDL-C can also mean low LDL-P? or to put it in another perspective, would it be possible to have high LDL-P though LDL-C is low?

    Also, correct me if I am wrong, I still remember in one of your articles about apoB/cholesterol that the consumption of sugar is directly concordant with apoB or LDL-C. My own experience on a LCHF for almost 4 years showed that my LDL-C decreases – would this be safe to assume that my LDL-P is also low?

    I don’t have access to NMR testing for LDL-P at the moment, it’s not available in my country that’s why seeing my LDL-C low maybe a good sign (or not based on your own thoughts).

    Thanks again and more power!

  • Eric Best

    I’m not sure whether or not you have already read/heard of Uffe Ravnskov’s theory of atherosclerosis; but I think that you might find it interesting.

  • Chris Marr

    Great article Dr Attia! Even though this blog might not be the forum, I’d love to see your thoughts on the p4p king of all time! Unless, of course, you choose someone other than Ray Robinson, because then you’re just flat out wrong… Seriously though, I’d love reading that!

    • There are two separate issues: who is the P4P king and which fight was the greatest performance of all time. I can make a case for all of these guys being the greatest of all time (and keep in mind, we we robbed of Ali’s best 3 years), but I lean to Ali vs. Williams in Nov ’66 as the greatest performance of all time. Jim Jacobs noted on the film that Ali’s hand and foot speed–on that night at least–exceeded that of Robinson.

  • Mark B McColl,MD

    Another great article. Thanks for this post. I’ve followed your blog and Dr. Dayspring’s work for years and have benefited personally and professionally. Keep up the good work. As to HDL-C’s role in the disease process, I’d love to be able to measure HDL-TG. That might show some of the function of HDL particles. Those particles overloaded by TG from excessive carbohydrate intake and hyperinsulinemic states probably can’t lipidate as well thereby leaving the macrophages engorged. The increased oxidation and inflammation driven by the hyperinsulinemia only worsens the disease process.

    Thanks again,

    • Mark, these assays are being worked at this moment. In fact, LDL-TG and HDL-TG may prove to be great functional tests, as you note (certainly better than cholesterol content and probably accretively with particle size and number).

  • Daniel Zbarski

    Any known effects on apoB/Lp(a)-P/LDL-P by CETP inhibitors? I’d be pretty telling….

    • CETP inhibitors were thought to improve outcomes by raising HDL-C (when it was believed such a thing was helpful). I believe their first trial was in combination with atorvastatin.

  • Andre

    Trying to summarize your article: no oxLDL, no problem –> reduce oxidation + reduce LDL. That simple? Take statins and Anti-Oxidant? (with Vitamin E at least that failed at least due to some specific effects of Vit E)

    Quick check on new oxLDL studies and learning that it is a gradual oxidation process from mildly (=no immune response) to heavily oxidized, some suggest it is still controversial, for example:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612790/table/tbl01/ (pathogenic, neutral, protective results)

    Disappointing really, has been studied for 20-30 years and still we lack detailed level understanding…

    • Part of the trouble, Andre, is that (to my counting) there are still 3 assays out there to measure oxLDL in some capacity or another. So this tool is still in its infancy.

    • Andre

      Agree on the oxLDL, too many sites on the LDL that can be oxidized with different effects contribute to the problem.

      What is your view on PAI, TG, C-Peptide and HDL vs ApoB and Insulin?

      • This makes me want to write another post to clarify all the confusion around biomarkers. Folks need to understand that all cardiac biomarkers need to be evaluated in a 2×2 matrix: X-axis is causal vs. not causal (e.g., LDL-P is causal; CRP is not); Y-axis is treatable vs. not treatable (e.g., LDL-P is treatable; Lp(a)-P is not*). There is so much mindless rambling about this biomarker versus that one, but folks are missing the big picture. I’m a framework guy, frankly, because it forces a modicum of discipline. Perhaps I’ll get to this in the next year. I certainly have a lot to say! (* Lp(a)-P has historically not been treatable, but PCSK9i are lowering by as much as 30% and I’ve seen >50% in one patient, and soon anti-sense drugs will, hopefully, render Lp(a) obsolete).

    • Bill

      “LDL-P is causal”

      As I know you know, apart from extreme cases establishing causation in biology is no easy task. The history of biology and medicine is littered with causal claims that turned out to be either false or vastly oversimplified.

      Perhaps I’m missing something, but I’ve yet to see anything like evidence that truly establishes causality for LDL-P in CVD. Significant associations with possible direct causal links, yes, but it takes so much more than that. At some point it would be instructive to hear why you are convinced enough about LDL-P to use non-benign pharmaceuticals to lower it.

      And even beyond that (If I understand correctly) to screen seemingly healthy people for LDL-P and treat at least some of those who test positive. Even beyond the steep challenge of really knowing a “risk factor” is causal, the history of screening apparently healthy populations is not very encouraging. The more great sounding ideas such as screening PSA tests and mammography are carefully studied the less enticing their benefit/risk ratio appears.

      PS: In the case of illnesses that will be very rare in the screened population, as we know Bayes’s Theorem requires almost 100% specific tests to avoid harms exceeding benefits. We don’t generally have tests like that, one of the fundamental problems with screening. I recognize that if you believe CVD is *not* rare in the screened population Bayes’s Theorem is more forgiving of imperfect tests. But it’s still a steep challenge, to me at least, to have confidence that benefits will outweigh harms. Of course you could say the same thing about not screening, but under conditions of extreme uncertainty I prefer the razor of nonintervention. I realize that sometimes that will be a mistake.

      • I think the best case for LDL-P being causal is made from a few combined observations:

        1. Heterozygous FH patients
        2. The folks with nonsense PCSK9 mutations. This was described 10 years ago in NEJM (see Fig 1): http://www.nejm.org/doi/full/10.1056/NEJMoa054013#t=article
        3. The K-M curves for MESA and Framingham comparing LDL-P vs. LDL-C
        4. LDL-C genes like HMGCoA and others are linked with atherosclerosis causality in Mendelian randomization trials. This is as close to causality as you get without doing an experiment which, obviously, can’t be done in this case.

        Furthermore, the only sine qua non for atherosclerosis is sterols in the artery wall. They do not come from de novo synthesis but rather LDL particle trafficking through the endothelium or vasa vasorum.

        Bill, I’m not here to convince anyone to do anything, including my own patients, let alone a bunch of complete strangers reading my blog.
        But I hope people concerned with the risks of taking drugs when necessary to lower LDL-P (or Lp(a)-P) also consider the risk of NOT doing so.

    • Andre

      Before writing anything, please also have a look at Rhonda interviewing Dr. Satchin Panda on Time-Restricted Feeding and Its Effects on Obesity, Muscle Mass & Heart Heal 😉

      conforims the benefits of intermittent fasting (12-16h), Mitochondria optimization, different clocks we have and which need to be in synch (liver/food, light, activity)

    • Bill

      Peter, thanks for taking the time to answer this.

      “I’m not here to convince anyone to do anything, including my own patients, let alone a bunch of complete strangers reading my blog.”

      Understood. I only wanted to appreciate your thinking on this better. I’ve always found that smart people with different views can be my best teachers :-).

  • Daniel Zbarski

    evacetrapib — Participants taking the drug saw their LDL levels fall to an average of 55 milligrams per deciliter from 84. Their HDL levels rose to an average of 104 milligram per deciliter from 46. Stopped Stage 3 trial. No benefit.

  • Mauricio Trambaioli

    Dear Peter Attia
    Great post.
    Just wondering, instead of apoB INTERHEART found apoB/apoA a more solid indicator for MI
    Regardless of the absotule apoB level ?
    Any thoughts ? Or studies.
    Best Mauricio Trambaioli

    • I’m not really sure what to make of that, but if I recall apoB/apoA1 was even higher HR than smoking vs. not, which seems odd to me. Smoking is generally a higher risk than apoB.

  • Anon

    Your ldl-p / gun analogy is interesting. Not to be too literal, but it got me thinking- a loaded gun under your pillow in a war zone without any children around could be smart. Understanding the ldl-p link with heart disease (using poor overall societal health status including SAD diet, inactivity, stress, etc) is there any physiological benefit of elevated ldl-p you are aware of, particularly in the absence of obvious known risk factors? For it to be purely negative seems a strange biological program-?

    • Probably benefits to high cholesterol, though not sure there are benefits to high LDL-P. If high HDL-P can do most of the trafficking, then a great state of life might be modest-to-high cholesterol with lots of apoA and few apoB.

    • Yossi Mandel

      Dr. Dayspring blew my mind when he tweeted that there is no need for LDL at all – the body is fine at 0! I got the feeling he doesn’t think there are any benefits…

      • Well, some of the people with nonsnese PCSK9 mutations have LDL-C levels of 10-20 mg/dL (!!!) and seem to do just fine in addition to being seemingly immune to atherosclerosis.

  • K.Mohan.S

    Dr Peter,
    A great article ..further to your series on Cholesterol.

    But, to put everything squarely on ” AGE ” …..To quote you..

    “Smoking? Nope. High blood pressure? Nope. The wickedly deadly particle I have yet to write the most deserving post on, Lp(a)? Nope. LDL-P or apoB? Nope. LDL-C? I thought I told you to never say that again. CRP? Nope. None of these things. ” None of this may be, is the greatest single risk factor.. You may be right there….

    But is it not true that ……CVD is the result of a cumulative effect of multiple risk factors,.
    ……the body is a drum with multiple abuse inputs leading to overflow (VHD/CVD, Cancer).
    What about the importance of food and lifestyle in ” trying to remove the gun and put the odds back in our favor.”
    My sincere respects to you for a great article.

    • You missed my point, but I’m too lazy to write it out more clearly. Hopefully someone else does so for me. You’re confusing the greatest absolute risk (which happens to NOT be modifiable) with all forms of modifiable risk.

  • Peter

    Hi, dr.Peter 😉
    In my case I had a heart stroke at 37 (stent in my left coronary).. The diagnosis was a hypercholesterolemia..
    I had a stroke when practice spearfishing (apnea).
    After stent implantation they prescribed me to take 20mg statin drug. My total cholesterol level is 8 mmol/l.. with statins this went down to 4.3 but I had several pain in my legs and chest so I leaved them.. I also tryed with LCHF food.. with LCHF my tryglicerides went down from 1,3 to 0,6 mmol/l , LDL went from 4 to 6 and HDL from 1 – 1.5 mmol/l.. (I don’t know if this if good aproach)..
    After one years I went to my doctor (cardio) and he prescribed me a new medicine “Repatha”.. It’s now second week I’am using it (without any side effect for now)..
    I’am little confused because some say that LCHF is danger for atherosclerosis some say that isn’t…
    I practice sport 3-4 times a week (running, cardio trennings, spearfishing), I don’t dink and I never smoked..
    I’am 181 cm height and weight 82 kg… (same weight last 20 years)..

    Here is my complete cholesterol levels from 2014 til now…

    What do you think about hypercholesterolemia? (I have also a doughter 8 years old with high level of cholesterol) (also my father and mother)..

    thank you for any info.

    • Peter you likely have a genetic condition and should see a lipid specialist to confirm this. If you do have a genetic condition, it will important for your kids to be checked also.

  • Gerald Davies MD

    Checked the reanalysis of JUPITER Circulation. 2015;132:2220-2229.
    In placebo-allocated participants, baseline LDL-C was not associated with CVD (adjusted hazard ratio [HR] per SD, 1.03; 95% confidence interval [CI], 0.88–1.21). In contrast, associations with CVD events were observed for baseline non–high-density lipoprotein (HDL) cholesterol (HR, 1.18; 95% CI, 1.01–1.38), apolipoprotein B (HR, 1.28; 95% CI, 1.11–1.48), and ion mobility–measured non-HDL particles (HR, 1.19; 95% CI, 1.05–1.35) and LDL particles (HR, 1.21; 95% CI, 1.07–1.37).

    Worst Hazard Ratio was for Apo B=1.28 while LDLp = 1.21. While the association my be statistically significant it is so marginal to be hardly relevant to actual cause and much more likely to be peripheral or downstream effect of other causes. For instance HgbA1C between 6.5-7% in EPIC-Norfolk was associated with HR 3.0 while higher HgbA1C HR 7.0. Little old LDL comes in 1.3 at best and 1.03 (NS) in 2 the above placebo arm. HR of smoking and lung cancer is 13-20, and that’s the sort of power you need to establish cause. Are we guilty of sleeping at the watch while the safe is being burgled?

    • I don’t think the HRs here establish cause. Agree that HR below 5-10 is not helpful for that reason. The reason (in my opinion) HRs are lousy for diseases like heart disease is that the condition is so prevalent. And, as pointed out, apoB is only necessary, but not sufficient to initiate the disease.

    • Ivor Cummins

      Hi Peter !

      Thanks for your reply on Lp(a) – agreed there’s a lot more going on here – with Lp(a) kinda carried along for the ride perhaps. 🙂 Multi-factor fun I guess.

      Anyway, on to more serious matters. I thought a little at the weekend while preparing slides for an upcoming talk I’m giving (to big group of Paramedics). I drifted down the ApoB hole whilst doing a simplified Root Cause Diagram (to help them understand the basics of CHD driving mechanisms).
      My thoughts on ApoB as an independent driver surfaced as I drafted. There are lots of comments already on this post (unfortunately they are chronologically ordered from the bottom one up – Squarespace, eh?). Anyway, would be interested in your thoughts – although I will understand if you are too busy to run through the content…


      Thanks as always for your assessments



  • Moussa

    Great article.. what do you think of the predictive value of calcium scoring?

    • Probably adds some value in young patients (i.e., ID those at high risk), but if anything, folks on statins probably have better outcomes and calcification increases (plaque stabilization).

  • Ben

    Thank you for the article, Peter!

    I was recently researching autophagy, it seems autophagy (or rather lack of it) is involved in atherosclerosis too. Relevant studies:
    – mTOR Enhances Foam Cell Formation by Suppressing the Autophagy Pathway
    – Nicotinate-Curcumin Impedes Foam Cell Formation from THP-1 Cells through Restoring Autophagy Flux
    – Regulation of Lipid Droplet Cholesterol Efflux From Macrophage Foam Cells

    Research on autophagy seems relatively new, but logically it makes sense. High levels of insulin from the modern diet & constant snacking (no fasting) reduce autophagy, which likely contributes to atherosclerosis

    • No doubt mTOR–which is probably the central cellular regulator of autophagy–plays a role in all disease. CHD is no exception.

  • Richard S.


    Another great post. Thank you.

    I look forward to your post about Lp(a). In that post, it would help me (and perhaps others) if you addressed the implications of Chasman’s findings (Atherosclerosis, April 2009) about the effects of low-dose aspirin on some people with particular polymorphisms of the Lp(a) gene.

    I am intrigued by the finding that aspirin seemed to eliminate the increased risk that some people have from high Lp(a) levels. Of course, I wonder what that finding means for others with high Lp(a), when we don’t know other details about our generic make-up.

    Thanks again,


    • Yes, this would be a great post, Richard. Of course, what makes Lp(a) so “bad” is not only its particle properties, but also its thrombotic properties. Not sure if LpPLA2 helps stratify risk.

  • Chris MacSweyn

    Hey Peter,

    Just wanted to reach out and say thanks for writing this post. Also thanks for appearing on Tim Ferriss podcast where I was first introduced to you. The 2 awesome youtube videos; “Readdressing Dietary Guidelines”, and “An Advantaged Metabolic Stage.” have been a huge help to me and my personal improvement journey. Keep fighting the good fight. 🙂


    • Thank you, Chris. Glad you find them helpful.

  • Roger Butler


    Your contenders for greatest boxers of all time seems rather American, and still missing Joe Gans! I would want to nominate Bob Fitzsimmons and Jim Driscoll, in the latter case emphasising ‘boxer’ rather than ‘puncher’. Obviously this is a futile discussion, but fun!

    As someone with next to no understanding of biology or chemistry I should perhaps have given this post a miss but having now read it three times I think I may have caught the gist of it.

    I think it is worth pointing out that if you are right about the efficacy of medication in increasing one’s chances of prolonging life that does require the caveat that the longer life may come at the cost of impaired physical and mental functioning. I was on statins for about 10 years and the arthritis and increasingly foggy brain function I had were blamed by my doctor on inevitable consequences of getting old. When I decided, about 5 years ago, to stop taking statins my physical health and brain function returned over time to a remarkable degree. In the case of physical health this is to some extent an objective judgement, not only have the pains diminished significantly but I am stronger than I was 10 years ago (I have gym records to prove it) and my maximum heart rate has increased from the low 160s to 180 last week (I am close to 67 years old). You must also be aware that there are blogs where people who seem to know what they are writing about assert that statistically, in old age, high cholesterol appears to be protective when it comes to heart disease.

    It’s all very confusing! But many thanks for taking the time to let us share your research and expertise, it is much appreciated.

  • Leung Hon Yew

    Dear Dr. Peter,

    Thanks for your wonderful post.
    I am heartened by your reply to Carol on how to control LDL-P particle number: “… do not discount the ability of diet to control this process.” I sincerely hope you will go deeper into the dietary aspects of LDL-P control in future posts.

    I have been doing great on LCHF for several years – also lost significant weight. But a recent lipid test (unfortunately can’t get NMR test in Singapore) showed that my conventional numbers are through the roof. Even though I do not know what my LDL-P number is, I am assuming that my LDL-C is concordant with it, and have stopped eating SFA as much as possible, use MUFA whenever I can, and reintroduce reasonable amount of carbs back to my diet. Hope to do a conventional lipid test again in 2 months to see how the numbers are trending, before exploring other options – I guess including pharmacology.

    You have posted previously that dietary cholesterol have very very little to do with serum cholesterol. Are there individuals that respond differently? Do you think it makes sense for someone with high LDL-P after LCHF to experiment by cutting out eggs from their diet, for example?

    Once again, thanks for your wonderful blog.

    • I alluded to this very briefly in a previous post, but I don’t recall which one. Definitely in the past 3 or 4 posts. I think some time in 2015.

    • Naren


      If you find the post that Peter is referring to, would you mind sharing a link as a follow-up comment here?

      I too am interested in the answer to that question.

      Thank you!

    • Leung Hon Yew

      Hi Naren,

      I could not find specific comments about eggs, but I did find one concerning tolerance to dairy. The question was whether there is a lab test to prove dairy tolerance.

      Dr. Attia’s reply:
      “Not that I know of, and even if there was a way, I wouldn’t trust it. The gold standard is elimination. Knock it completely out for a month and see what happens.”

      I guess we need to do the same if we want to know if eggs can affect our LDL-P, eliminate and see what happens?

      (Dr. Attia, is this the post you meant? Thanks)

      The question was asked by Aubrey under “Random find (plus pi)”, about half way down the comments section.

    • Naren

      Thank you for digging this up, Leung.

  • Gerald Davies MD

    LDL particles pass through endothelial pores in all tissues including arteries, they are ever present and a low level risk factor for atherosclerosis. How they become oxidized along with foam cell function and integrity is a far more worthwhile field of study regarding early CVD events: http://link.springer.com/article/10.1007%2Fs00109-016-1385-4
    Liver cell production LDL is promoted by insulin and would explain a marginal association between LDL and atherosclerotic events. Insulin also inhibits autophagy and promotes foam cell apoptosis and type 1 macrophage transformation. Dramatic reductions in insulin levels is possible by avoiding carbs, ketogenic diets and fasting and will reduce LDL levels as well as obesity, diabetes, inflammation, cancer risk, etc.

    • Tuck

      “LDL particles pass through endothelial pores in all tissues including arteries, they are ever present and a low level risk factor for atherosclerosis. How they become oxidized along with foam cell function and integrity is a far more worthwhile field of study regarding early CVD events”

      That’s been done.

      “One of the characteristics of oxidized LDL is the production of such reactive aldehydes as MDA and HNE by
      the decomposition of lipid hydroperoxides (5, 9, 10). That both MDA and HNE become incorporated into the oxidized (ox-) LDL particle by covalently coupling to amino acid residues on apoB-100 is suggested by the result that monoclonal antibodies directed at LDL modified with MDA or with HNE cross-react with oxidized LDL (11). That one of the adducts formed between apoB-100 and HNE in ox-LDL is a Schiff-base is suggested from the similarity in fluorescence at 360 ex/430 em between HNE-modified LDL and Cu2+-ox-LDL (8, 10, 12). Thus, it is conceivable that LDL modified with both HNE and MDA might mimic ox-LDL in several structural and functional properties. Recently, we and others have shown that an LDL-sized fraction isolated from human atherosclerotic lesions demonstrates several characteristics of ox-LDL, primary of which are the reactivities with anti-MDA-LDL (13, 14), anti-HNE-LDL (14), and fluorescence properties characteristic of HNE-modified LDL (10). Thus, lesion-derived LDL appears to be modified by both HNE and MDA.”

      “Structural and functional changes in LDL after modification with both 4-hydroxynonenal and malondialdehyde”


      Remember, the precursor to both HNE and MDA has risen dramatically in the last 100 years, and is not a normal part of the human diet in the high doses currently consumed…

  • Michael

    Hi Peter –

    Thanks for starting to post more regularly. I’m a big fan of Dr. Dayspring’s and always feel like reading you is having someone who can communicate to mortals help us through the wilds of biochemistry.

    Always love your take on things – I’m Lowish Carb but very mindful of all clinical markers- including good ol’ LDL-P.


    Am I reading the above article correctly that fasting could reverse atherosclerosis? Do you think there are some potential benefits to CVD risk from fasting?

    Keep up the excellent work – looking forward to it.


    • If you buy that your fasting regimen (fasting a pretty broad term) induces enough autophagy to reverse the process I describe.

  • Ryan

    Hi Peter! Great article!

    I’m curious to learn more about the interplay between carbohydrate consumption and changes in LDL-P, as insulin and glucose relate to particle clearance, inflammation, and the potential for oxidized & glycated lipoproteins, which drive atherosclerosis.

    I’ve read that brief periods of hyper-caloric starch intakes in the post-workout window increase insulin production to raise leptin / thyroid hormones which in turn promote increases in LDL particle clearance, lean body mass, muscle growth, energy production, fat burning, and quality of sleep.

    I’m curious if it would be wise to remain in uninterrupted HFLC territory, or if it might be wise to have a post-workout “high-carb re-feed day” a couple times a week or some other strategic injection of carbohydrates for the purposes of increasing lean mass / balancing hormones. Or, if moderation is the key, somewhere in that consistent ~50-100g carb per meal low-carb diet. Which eating strategy do you tend to lean more toward with health+fitness in mind? (Or, is there a better, more nuanced approach?)

  • Leung Hon Yew

    Dear Dr. Attia,

    Oops. Will go back to re-read your 2015 posts again. Thanks

    I came across a recent talk by Dr. Sarah Hallberg where she hypothesized that very low insulin level from LCHF could be a possible reason for raised LDL-P:

    (from about 14:50)

    Can I get your views on the possible mechanisms she described?

    Thanks again,

    Hon Yew

  • Dr. Craig

    Hi, Peter, your posts are always a treat. Here’s a summary I (and the rest of the medical world) received today, which will certainly cause much new controversary:

    Study Cites the Fats That Could Shorten Your Life

    TUESDAY July 5, 2016, 2016 — Hold the butter, margarine and high-fat dairy: A new study supports the notion that these “saturated” fats are bad for you.

    The study, which followed more than 126,000 people for three decades, found that people who ate higher amounts of saturated fats and trans fats died earlier than those who stuck to healthier unsaturated fats.

    Unsaturated fats include plant-based, unprocessed fats such as those found in olive, canola or soybean oil, the study authors explained.

    “These findings support current dietary recommendations to replace saturated fat and trans fat with unsaturated fats,” concluded a team of researchers led by Dr. Frank Hu of Harvard School of Public Health in Boston.

    Source: The study was published online July 5 in JAMA Internal Medicine.

    • We should probably stop using the word “study” to describe epidemiological exercises with low hazard ratios.

    • Matt

      The majority of people in these large cohort studies would be eating grain-fed meat which has a different and more inflammatory composition of saturated fatty acids compared to grass-fed. I’d like to see a study following people that only eat animals that are fed their natural diets, I bet the slight risk would disappear.

  • Rick

    Hi Dr. Attia,

    Can CT scan Coronary Calcium scoring detect or distinguish from Mönckeberg’s arteriosclerosis and the type of atherosclerosis you are discussing?

    Thanks for the blog..it is a great resource.

    • You’d have to ask a radiologist, which I’m not, but my guess it that a CAC probably would NOT but with a CTA you would have a better shot at differentiating.

  • Tuck

    An excellent overview of the gory details of LDL oxidation and damage that is intimately involved, if not causative, of atherogenesis. I’d wager high LDL-P count is the result of LDL that is so damaged the body can’t clear it. Remove the cause, remove the problem?

    “Oxidized LDL: Diversity, Patterns of Recognition, and Pathophysiology”

    Remember, both HNE and MDA have the same precursor. Peter, perhaps you can pass this along to Dr. Dayspring?

  • Lillian

    Hi Peter, Dr. Attia,

    I am a 35 y/o Taiwanese American woman, based in Los Angeles (went to school down in San Diego), who was diagnosed with Type II Diabetes a few years ago, out of the blue. I have always been careful (aka wary) of diabetes since my mother has been a diabetic all my life (and is one of the most disciplined diabetics I’ve known), and has always been a nazi about “preventative measures” with her kids. My glucose levels were in the 70-90 range all my life, so I was never worried, but a few summers ago it suddenly jumped from one summer of 70-90 range, to the 150-180 range. And hence, my journey with battling Diabetes II began.

    The doctor I was working with then had suggested that the sudden increase may be due to my anxious personality, and workaholic lifestyle and after procrastinating for a year, I quit my executive corporate position 3 years ago, and took a very long, needed sabbatical. Experimenting with different things, as the case with many diabetics, I have been through highs and lows, and am now happy to say that I am hopefully on the road of managed, type II diabetes.

    I came across your TedMed Talk about your research, and am so so so so SO (you get the idea) moved, and touched by your talk, as well as the work you do, the passion you convey, that I had to essentially google-stalk you (sorry) in hopes to just see where you are at as of this year. I am so impressed by the incredible impact of your obvious genius and yet simultaneous humility, and clearly, the topics you speak of hit close to home.

    Seeing that I go to San Diego all the time and that you mention you have a practice there, I was wondering if there is any way I can work with you (as a patient, as a marketing professional pro bono simply because I believe in what you do, as a friend), or at least follow your work so that I can work on trying to make those changes in my life too. Doctors tell me all the time how “young” I still am, and have to really get on things, and I know it’s an impending doom if I don’t “get with the program.”

    Hope I haven’t completely creeped you out with my comment here, and sorry it is so personal and yet so public– I also find it SO AWESOME, that you personally respond to comments here.

    Thanks, and hope to connect with you,

  • Joanie

    Question: why do some macrophages get de-lipidated whilst others go on to become foam cells? Do all foam cells end up as fatty streaks? Any of this process able to be halted or reversed? Thanks

  • Michael

    Peter – What about the issue that LDL-P only contributes partially to the CV risk burden ? I have several 8th decade patients with extremely high LDL-P yet no major CV event has occured. Surely they have a fairly high AUC for overall CV risk . Yet no events . Perhaps their early life was very active and their early nutrition was whole food oriented . That would have delayed the progression of CV risk and reduced the AUC ( especially if there is some sort of critical “window ” effect on developing lesions ) I am speculating here but I do worry much about spending resources on tests that make little substantive difference.

    Did you ever run across this article?

    From Dr Samia Mora – it argues against too much use of LDL-P over nonHDLC .

    Thanks for your blog . Appreciate the thought provoking nature it exudes.

    • Everything only contributes partially, including smoking and hypertension. The HRs are all individually quite small.

  • Rik G

    I wonder if anyone has thought about the following: smaller LDL particles have a fundamentally harder surface than larger LDL particles, and are more likely to penetrate deeper into sub-endothelial spaces. Why do I imagine this: oil and water do not mix; oil has a cohesive energy that decreases when it meets water. So it forms a sphere to maintain cohesion. That sphere has a surface tension. I rarely see this mentioned in the literature around atherogenesis. The outer layer of any lipid sphere in water is like a drum skin. The larger the particle size – the looser the drum skin. The smaller the particle size the tighter the drum skin – i.e. the more desperately the small particle is trying to maintain cohesion. The small particle will have a ‘drum skin’ so tight it will actually be overpressurized relative to the water around it. So what’s more likely to penetrate past the endothelium – a large, floppy, liquid-like sphere or tiny hard pellet? Once in the subendothelial space this collection of small spheres has a very high surface area-to-volume ratio for oxidation reactions. The rate at which the lipid within oxidizes should be faster than for a larger sphere. Having high blood pressure only makes “all of the above” worse because it forces lipid spheres to be smaller (and therefore harder) as a response to high-arterial pressure.

  • Hi Peter !

    Thanks for your reply on Lp(a) – agreed there’s a lot more going on here – with Lp(a) kinda carried along for the ride perhaps. ???? Multi-factor fun I guess.

    Anyway, on to more serious matters. I thought a little at the weekend while preparing slides for an upcoming talk I’m giving (to big group of Paramedics). I drifted down the ApoB hole whilst doing a simplified Root Cause Diagram (to help them understand the basics of CHD driving mechanisms).
    My thoughts on ApoB as an independent driver surfaced as I drafted. There are lots of comments already on this post (unfortunately they are chronologically ordered from the bottom one up – Squarespace, eh?). Anyway, would be interested in your thoughts – although I will understand if you are too busy to run through the content…


    Thanks as always for your assessments



  • Ivor Cummins

    Ooops nearly forgot – I have some contrasting views on CAC too, which would be cathartic to air and have assessed. Angiograms are questionable I think – they look at narrowing, an aspect of the disease by all means. But can be misleading in terms of plaque rupture likelihood (i.e. most MI’s). But CAC looks at the disease process itself. Far more satisfying to an engineer (in my case anyway). I only show snippits of the myriad studies here – but all tend to agree. I’m not sure what I’m missing – honestly. And cardiology giants Brundage, Rumberger, Hecht, Budoff, Agatston, Davis and others all agree. Also the extraordinary physicist Doug Boyd, whose genius created the method, has been very clear on the fundamentals.


    My recent interview with Bruce Brundage is here. From 20mins onwards, he hits on some fundamentals. I would be interested in why CAC comes up in a very negative light in this post – I’m not sure you mentioned it before?




  • Feras Maidaa

    Hi Dr.Attia,
    I want to congratulate you on your success via the eating academy and the other project you are excelling in.
    I have learned a lot about you through a podcast with Tim Ferris and other videos.
    I am originally from Syria and I am planning a Fundraiser cycling ride, and I have a couple questions about endurance training and how to hack my body to perform better during this ride.
    please email me at fmaidaa@housing.ucsb.edu
    your help is much appreciated.

  • Palak Kundu

    Dr. Attia, this post reminded me of my own M1 path lecture on atherosclerosis found in young soldiers who had died in Vietnam. Seems like we’ve known about this for a while, but I unfortunately recall the takeaway being that we can’t do much aside from not smoke and avoid dietary “bad” cholesterol. On a side note, while teaching-hospital based residencies are great to appreciate acute pathophysiology after shit hits the fan, do you think physicians are being adequately trained on chronic disease prevention and management with respect to understanding causative factors?

  • Eric R

    Dr. Attia. What strategy do you take for APOE4 patients with elevated cholesterol, in particular, LDL-P elevations? Some arguments have been made that APOE4 patients need more cholesterol to overcome the transport defects in the brain associated with the APOE4 allel. Others say lower ldl-p at all costs. Some say statins should be used especially if desmosterol is high while others say that high desmosterol is a good thing. Even as a physician I find this all so confusing! I’m feeling especially clueless when my patients are now coming to me with their 23andMe results in hand. Any tidbits you could share would be helpful.

    • Too complicated for a trite response, unfortunately.

  • Priscilla Koo Wilkens

    I have to say I’m a fan of your blog and so well written posts.
    As a brazilian engineer and mother of two little girls I was gratefully surprised to know you are Senna’s fan!
    Can’t wait for the book.
    If only there were more doctors like you out there…
    Congratulations on your approach on health!

  • Jerry Salazar

    Dr. Attia,

    I really appreciate the time and knowledge you give everyone on your blog. Just curios, but I’ve read that calculating non-HDL (Total Cholesterol – HDL cholesterol=Non-HDL Cholesterol) is simple way to determine highly atherogenic lipoproteins. Is this formula too simplistic to have any validity?

    With best regards,


  • Mad Max

    Hi Peter

    Hope you’re well. I’ve learnt a lot from your previous blog posts, though I think this one is a bit technical for lay persons. I know you won’t be likely blogging for a year, but I just wanted to put a couple of things out there in terms of weight loss/your clinical practice as a GP, which might be interesting topics for you to blog on eventually. Not just in terms of the ‘state of the art’, but what relevance you see to them in terms of your day to day work.

    I’ve struggled with weight loss, being obese since 7 myself, going down to a ‘normal weight’ in my twenties but developing an eating disorder to do so (exercise bulimia) and gone up and down in weight many times. I would think there would be a lot of overweight/obese people in your practice who fit that pattern.

    However one of the good things/hopeful things that is occurring more recently is that (i think) scientists and doctors (endocrinologists in particular) seem to be becoming more accurate at working out the physiological factors relating to weight loss. These include some things other than strict low carb/high fat (though the advances seem to be in line with LCHF mechanisms for explaining obesity).

    The things I was hoping you might address (in terms of day to day practice) are:
    – What effect you consider vitamin d deficiency to have on insulin sensitivity/weight loss.
    – Whether you counsel patients to have larger breakfasts (with a significant amount of protein) and to not eat at night.
    – Whether, further to the above question, you see intermittent fasting as helpful for weight loss/control (I think I’ve read previously that you consider hunger might be generally counterproductive).
    – Whether you counsel the use of low volume HIT exercise that can be done without ‘formal exercising’ e.g. sprinting up the stairs every day while going to work etc.
    – The importance of the micro biome in weight loss e.g. in avoiding artificial sweeteners which tend to induce insulin resistance through their effects on the micro biome.
    – The use of DNA testing to try to ascertain the particular metabolic strengths and vulnerabilities of individual patients.

    I guess I am interested to see what an MD very interested and well read in weight loss thinks about the above. These seem to be some of the latest and greatest attempts by other doctors/scientists to help with weight loss.

    Take Care

    Mad Max

  • Conan

    This was a very depressing blog. No remedies, no hypothesis for reversal. Inevitable blockages for all.
    1. Is aspirin helpful preventing blockages ? Dave Asprey says there is no evidence of usefulness, and it just destroys your gut
    2.what is your thoughts on vitamin k2 as a preventative? Anecdotally I’ve read that it helps keeps the aorta from calcifying.

    The Best

    • There are many remedies, but it’s pretty hard to practice medicine on a blog. There is no disease that should generate more optimism among the “big 3” than CHD. Buck up, man!

  • Ivor Cummins

    Hey Peter

    Just got sent this link – think it may help in the assessment of Vladimir Subbotin’s hypotheses (mentioned earlier in thread…). Amazingly, the full pdf is free to download – like all papers should be of course 🙂




  • Pingback: ” Spoiling” your child with food. | lchf4health()

  • Ivor Cummins

    Hello again Peter

    Here’s another good one on role of vasa vasorum in atherosclerosis (just sent to me). Would be great to get your latest thoughts on the balance of probabilities between the competing hypotheses (i.e. simple lipid infiltration from lumen, versus the compound mechanisms in the VV hypothesis…)




  • Matt

    Hi Peter,

    Studies have shown elevated levels of LDL-P in patients with LPS endotoxins in their bloodstream (eg. SIBO patients), due to LDL circulating with LPS-binding proteins.
    Do you think intestinal permeability could be a major contributing factor to CVD?


  • Martin


    thank you very much for your many well written and interesting posts. This is my first time writing here, since it is hard for me to stop worrying ever since you wrote “monotherapy with T4 for hypothyroidism is a recipe for disaster for most patients” at the beginning of this post. Being on (pretty high and steadily rising dosed) monotherapy I tried to google information on your statement but was not successful. I found one paper that says substituting about 50 units of T4 with about 20 units of T3. Other papers claim that T4 alone is perfectly safe.

    May I ask what made you say that? Also do you have any suggestions on how one should proceed when on monotherapy?

  • Ray Jennings

    Peter…..I’m wanting to know what role Carbs play in heart disease. Is a low carb high fat diet a logical conclussion to decreasing risk?

  • Mike

    Peter, In your video with IHMC on how to live better I believe you mentioned the exceptional class of ketogenic attempters who fail due to rising lipids. I think the following comments from Rhonda Patrick I got from running my 23andme results through her tool may be of interest pay particular attention to the 2nd to last paragraph: (As an aside I wonder what the impact of apoe4 might have on this snp and what the common incidence is between the two.)

    “PPAR alpha rs1800206(C;G) abnormal fat metabolism
    This gene is called proliferator-activated receptor alpha (PPAR-?) gene, is a master regulator of lipid metabolism, carbohydrate metabolism, and amino acid metabolism and is activated by polyunsaturated fatty acids. PPAR-? is highly found in brown adipose tissue, the liver, and, to a lesser extent, in the kidney, skeletal muscle, heart, and small and large intestines.

    PPAR-alpha also plays a very important role in the process of ketogenesis (ketone bodies that are produced from the oxidation of fat which normally occurs during carbohydrate restriction or fasting).

    Activation of PPAR-alpha promotes uptake, utilization, and catabolism of fatty acids by activating genes involved in fatty acid transport, fatty binding and activation, and fatty acid oxidation. PPAR-alpha is primarily activated through binding of polyunsaturated fatty acids.

    This genotype has been associated with lower PPAR-alpha activity and a 2-fold higher risk of type 2 diabetes, increased levels of triglycerides, total cholesterol, LDL cholesterol, and small-dense LDL particles when saturated fat intake is higher than polyunsaturated fat intake. Polyunsaturated fats are found in foods like fatty fish such as salmon, herring and polyunsaturated fat is also found in nuts. Saturated fat is found in fatty beef, pork, butter, cheese, and other dairy products.

    Since this gene is activated by PUFAs and plays a major role in lipid metabolism including fat oxidation, a ketogenic diet that is high in saturated fat and low in polyunsaturated fats may be detrimental to health. It may be best to make sure that the majority of dietary fat intake has a higher polyunsaturated fats to saturated fat ratio.

    Pterostilbene is a plant compound present in blueberries, cranberries, and almonds have been shown to activate PPAR-alpha and lower triglycerides, and blood glucose levels.”

  • Elena

    Hi Peter-

    New to your site. My husband is a type 1 diabetic and partakes in a very low carb diet, works out daily, and is on the pump. He also has CVD. If you saw him on the street you would have no clue that he has these issues. He looks like a specimen of health, extremely lean and fit. He had a cortisone shot for a bad elbow and then had his blood work drawn for his diabetic check up apx one week later. His LDL-P went from 614 in February to 1167 on 7/22/16. After reading your cholesterol posts I’m extremely concerned. Is it possible that the cortisone shot is affecting those numbers? If not, what other things do you suggest to lower LDL-P? Again, he eats an extremely low carb diet as it is. Any suggestions or insight would be greatly appreciated.


  • Ian Beveridge

    Great post – as usual. I was just a little surprised at the abrupt conclusion – stating that to control LDL drugs should not be excluded. It appears to be the case that overall cholesterol levels (I assume this means all particles) in older people (at least) confers protection from “all causes” of death and those taking statins die off sooner – as do those with lower cholesterol. This appears to contradict your conclusion at least in a limited way. This also applies specifically to statin use for all age groups as far as I know.

    I would have thought however that regardless of anything else it would be wiser – to mention the benefits of simple nutritional aids – such a nicotinic acid (vitamin B3) – before endorsing in any way the use of toxic medication and the killing of cells producing cholesterol in the liver. Perhaps you were just in a rush to conclude a long article?

    • If CHD/CVD death goes down, all cause tends to go up–that’s the math of it. You have to die somehow. The purpose of this article as not at all to get into treatment strategies.

  • Sharon

    Hi Peter,

    I love your blogs, but you had me freaked out… I’m a 54 y o female, BMI 22.0, exercising regularly, eating a Paleo diet and had the True Health Diagnostics test done:

    Total cholesterol: 164
    Triglycerides: 95
    Apo B: 82
    LDL P: 1273
    Apo B/Apo A-1 ratio: .55

    From the best I can make out, the median LDL-P and Apo B are 1300 and 116. In fact, Apo B 25%ile is 90 for my age and sex. Yet, the test flagged my Apo B as high risk and LDL-P as intermediate risk.

    Are these flags just a ploy to sell statins? Or should I be really concerned? I sure was when I read your blogs and comments on Apo B and LDL-P being the biggest predictors of cardiac risk.

    Thank you!

  • It makes sense to see a lipidologist now if there is any family history of heart disease.

  • Travis

    PLEASE WRITE A BOOK AS SOON AS POSSIBLE. I will bulldog every single person I know into reading it. Your stuff is so good. Thanks, Dr. Attia!

  • Marcel Crok

    “monotherapy with T4 for hypothyroidism is a recipe for disaster for most patients”

    I am not a doctor myself but I think that making such a claim and then not explaining it is not very careful.
    Maybe you should either remove it or – better – explain what’s your idea behind the claim.

    Thanks btw for a very interesting blog post again

    • Thanks for the advice, Marcel.

    • Bob Niland

      re: …making such a claim and then not explaining it is not very careful.

      There are ample web resources that detail the festering problem of thyroid mis-testing, mis-diagnosis and mis-treatment under the Standard of Care, such as: http://www.stopthethyroidmadness.com/

      (I’m not associated with that site.)

    • Hal

      I would appreciate having you write a blog post on the problems with T4 monotherapy. I had 1/2 of my thyroid removed in 1986, and have been on 0.1 mg Levothyroxine since then. I have raised the issues of supplementation with a combination of T3/T4 with my doctor, but I get the standard answer that T4 is enough. And we only need to look at TSH to assess thyroid condition.

  • David

    Dr. Attia, I read that cancer growth occurs anaerobic even in the presence of sufficient oxygen. If this is true, do you think a lower basal respiratory quotient an individual is the lower the risk of cancer development?

    • Probably not due the RQ, but due to the metabolic milieu necessary to have a low RQ.

  • Stephen

    Sad news to report on Quest Bars. If you look at the ingredients, you will notice that they do not include isomalto-ogliosaccharides anymore.
    They made a public statement on their website that they were changing the composition of their bars to make them more cost effective. This amounts to increasing the amount of sugar alcohols they use in all of their bars.
    This has resulted in the bars, IMHO, having that sickly, sugar alcohol taste so common to all the other protein bars that are LCHF.
    Just as bad, sugar alcohols are not easily absorbed by our digestive systems, and we can only tolerate fifteen grams of sugar alcohols before those well-known digestive symptoms start occurring.
    The only alternatives left are purchasing IMO Syrup separately, and making your own protein bars using LCHF protein powder, or buying Raw Revolution’s GLO bars, the only protein bar RR makes that uses IMO syrup (isomalto-ogliosacchiarides) in their composition.
    If you make your own bars, you at least reduce the amount of preservatives you use, depending on the type of protein powder you choose.

  • Jody

    Thank you so much for this post! I am a nutrition student with no science background (except for my first year of nutrition), and I think I was able to understand everything pretty clearly.

    I just have a question about statins and LDL-P. How does a doctor make a proper determination of whether or not to prescribe statins without knowing what LDL-P is? If LDL P is low, then there is no need to lower LDL levels? Is that wrong?

    I personally know an individual whose TOTAL cholesterol is not over 80. He is diabetic and his doctor prescribed a statin. That just seems crazy to me. Is it possible that his LDL-P is high with a total cholesterol that low???

    I think people are worried about taking statins unnecessarily, because of the side effects. And there seems to be growing belief that (which you validate with this post) that the entire picture isn’t being taken into account when considering the need to administer this drug.

    I hope I don’t sound stupid, but also hoping you won’t mind answering my question. 🙂
    Thanks again!!

    • A very good, but complicated, question. Many docs actually incorrectly prescribe statins. Three most common mistakes are targeting LDL-C, not LDL-P; not using cholesterol synthesis markers (e.g., desmosterol) to guide therapy; and not understanding “residual risk” and therefore not knowing how to customize the LDL-P target.

  • Trevor

    Hi Peter Attia

    I have read your “The Straight Dope On Cholesterol” from 1 through 9 & while a lot of the material was above my pay scale I did learn a lot & thank you for your time & knowledge. I am assuming that #10 has not been invented on paper yet but if it gets done I will be a reader.

    I know this is way off topic but early in this blog you stated “monotherapy with T4 for hypothyroidism is a recipe for disaster for most patients” & reading it hit me like a hammer because I have hypothyroidism & am being treated with monotherapy T4. Could you please direct me to some literature that leads you to make this comment? I have done a google search on the subject but did not find any articles with such a strong opinion. Thanks

  • Jason

    Hey Peter,

    I tried searching for the office numbers in NY/San Diego – but had no luck finding it. I wanted to forward your information to someone who is having thyroid issues. Any guidance would help.

    Thank you

  • Diana

    Please forgive if this question was asked and answered. Admittedly, I did not read these studies that you are referencing. So my question is were the subjects all modern people? Did the subjects only consume a “western” diet? I would be curious to know if indigenous people who only ate an ancestral diet also experience the “narrowing” progression that you have described in the same time frames. Isn’t coronary artery disease a modern disease? Couldn’t we infer that ultimately the culprit is our modern western diet? Thanks in advance for your response. And yes, as everyone else has said, thank you so much for you time. 🙂

    • It’s certainly a disease that is made worse in the modern environment, but there is evidence it was present before. The point of this post isn’t which elements of modern life make it worse, it’s to understand one of the mechanistic drivers.

  • Frances Katrishen

    Since elevated LDL-P is the most important antecedent to atherosclerosis it seems that anyone, with LDL-P above 1000 would benefit from trying to reduce their LDL-P. From looking at your various blogs and lectures, it seems that there is some evidence replacing some saturated fat with MUFA may reduce LDL-P for those already following a low carb diet, lot of exercise, sleep and low stress.

    • It seems to in some people, but it’s not clear why.

  • Steven

    Great post.

    I will refer this to anyone that says a Ketogenic Diet and butter will give me a heart attack…… this is actually everyone I tell I am LCHF!!!!

    I have been keto since Jan’16 and training for a marathon since April, and I am loving the lifestyle.


  • Frances Katrishen

    Thanks, There is some evidence of that in s case study by Dayspring’s in the article “Lipidaholics Anonymous Case 291: Can losing weight worsen lipids?” on Lectured.org. The article gives an excellent explanation why some people LDL-P increases on a LCHF diet. Then how switching to MUFA & PUFA from SFA can lower LDL-P for those people. Unfortunately for dedicated low careers, some have to either increase their carbs or go on statins.

  • John


    I have dived headfirst into a more knowledgeable and research-driven approach to wellbeing thanks to you, so I just wanted to thank you for that.

    I have, however, found considerable trouble in knowing where to get reliable tests that you recommend, such as the OGTT and NMR, even after requesting from my physician and calling local endocrinologists. (I have found OGTT in many places that measures glucose, but have yet to find one that measures insulin, even after consulting my doctor.) I am in Texas.

    I have dug through your comments and checked out True Health Diagnostics, which pointed me to Any Lab Test Now, but it was unclear from their site whether they used the proper LipoScience technology you recommend for the NMR test, and the OGTT test does not measure insulin. It is confusing whether the other services (Walk in Labs, etc.) use the reliable technology that you recommend.

    I really want to get the right tests but am having a lot of trouble. Do you have any recommendations on where to find these tests?

    Seems like it should be easier to get such important tests done.

    I am very grateful to your generosity in providing information that can change lives and health.


  • Matt


    I’m at elevated risk and listen with interest to you and others (like Dr. D’Agostino) discuss this intervention. Just finished Mukherjee’s cancer tome which provides sobering reminder of cancer’s diabolical ingenuity.

    I realize you are not an oncologist, but I wonder whether it’s possible for cancers dependent upon glucose to somehow acquire the biochemical engineering to thrive on ketones — or if this is simply a physiological impossibility. After all, we know cancer cells can grow their own blood vessels, disable cell death mechanisms, migrate to other parts of the body, and evolve different shapes to stymie targeted drugs.

    Love to hear any thoughts you have, however speculative.

  • Benas

    Hi Peter,

    Recently I’ve been reading about the new toothpaste (livionex) that has EDTA calcium chelator as ingredient and found smth very interesting. Calcium in involved in the formation of tooth plaques, so that toothpaste chelated calcium (iirc) and thus plaque was unable to form on teeth, the results of study are incredible. The science behind it is in the video “Unprecedented Efficacy in Plaque Removal + Reduction in Bleeding Gums” on youtube, you can see the effectiveness charts from studies at around 16:30.

    Now from what I’ve read, atherosclerosis plaques in arteries involve calcium and other metals, and based on the toothpaste success in dealing with plaque, I think it is plausible that EDTA chelator IV therapy can actually remove the plaques in arteries. There also happens to be plenty of evidence for the effectiveness of EDTA chelation in atherosclerosis from many studies, for example here is a good summary: http://www.life-enhancement.com/magazine/article/78-edta-chelation-the-real-miracle-therapy-for-vascular-disease

    Have you heard of it, or perhaps know doctors who practise EDTA chelation? It’s a no1 cause of death, and I think logically it makes sense that metal chelation should be able to remove plaques from arteries, same as in teeth.

    What is your take on this?

  • Eric

    Dr. Attia,

    I just want to say thank you! I’ve learned a lot from you in the past two years since I found your website. After putting many things to practice I feel healthier and happier than ever! I truly appreciate all the time and thought you put into these blog posts, and clearly I’m not the only one who does.

    Best wishes to you and your family,


  • Owen

    How much of a role do you think diet plays in this equation? I’ve been basically doing the ketogenic diet as described by Dominic D’agostino and feel much better. Is a ketogenic diet something you think would help to lower ones risk for CAD?

    • There are 4 reasons LDL-P is elevated. Diet impacts 1.5 of them.

  • Rick

    Hello Peter,

    I am working my way through all of the great information you’ve provided on this site, but I have an urgent question that I hope you can answer. I recently had a blood test and was told that I have “high cholesterol” and a 6% chance of a “major event” in the next 10 years. I would like to find a good doctor that can give me good guidance that’s not based on the old paradigm of heart health (that you dispute so eloquently).

    Can you give me a few questions to ask prospective doctors to see if they are up to speed on some of the newer information, or red flags to look for when they begin giving me treatment guidance that might suggest they are not a good fit?

    • Here is my favorite: If your LDL-P (or LDL-C) is elevated, be sure the doctor knows the four possible reasons for it. If they can’t explain the four mechanisms by which apoB is elevated, they should not be treating it.

  • Laura

    I would like to chime in with those who requested a future post on hypothyroidism. Your comment at the beginning of this post was tantalizing–please do think about another post in 2016 and in this topic. It is just as misunderstood as so many of the topics you have already addressed so eloquently and efficiently. It would be great to see your usual treatment of this topic as well. Many thanks for your time and effort in bothering to keep this blog going.

  • Benas Zurauskas

    Hi Peter,

    Love your blog. I’ve done extensive research and now suspect that wide zinc deficiency (or low zinc:copper ratio) is the cause of all evil and health problems, not too many carbs in diet.

    Getting fat is a healthy and natural thing if you eat lots of carbs (think sumo wrestlers who eat tons of rice, but are otherwise healthy and without diabetes). I suspect that a person with good zinc:copper ratio will be able to tolerate any amount of carbs without insulin resistance. Might also explain why some skinny people have diabetes.

    Here is a good overwier http://universityhealthnews.com/daily/diabetes/benefits-of-taking-zinc-for-diabetes-natural-blood-sugar-control-and-more/

    Have a good weekend,

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  • Mihail

    So after all this HFLC diet its not as good as we thoguht? More fat into our blood stream more likely to get in trouble?

  • I have been on the LCHF diet for a month. I started when I was told i had diabetes. I have lost 12 lbs in a month, but for the past 6 days have not lost anything. Can you take a peek at my blog and perhaps tell my what I may be doing wrong? http://nocarbstonofat.blogspot.ca/

  • Tres

    Probably not the place to leave this comment, but I couldn’t find a “general comments/feedback” section, so…
    Peter, I am really glad to have found your blog! I have a PhD degree in Molecular & Cellular Physiology and teach biology at the university level. Much of what I’ve read about NK so far, while interesting, has been at a fairly basic level. I immediately realized you get into the science behind what’s happening in and to the body. I’m just starting to explore a ketogenic diet (mostly to increase performance, weight is fine) and this is what I’m currently craving.
    Thanks for writing this!

  • Evelyn Wong

    How can one achieve high LDL-C and low LDL-P?

  • Jessica Ackerman

    Lp(a)- what are your thoughts on elevated Lp(a)? I am a 38 year old female, a very active competitive athlete. My dad died at 46, his nephew at 43. I am being followed for elevated Lp(a) and I am interested in your thoughts on management in a general sense. PS- I am an open water swimmer in Narragansett, RI- we have some amazing ocean races, if you are on the east coast and want to join!
    Thank you in advance,
    Jessica Ackerman

    • Jessica, Lp(a) is a serious issue and must be addressed. I really need to put a post together on this topic, as it occupies much of my attention. You should absolutely be under the care of lipidologist.

  • Palak Kundu

    Dr. Attia, I actually tried vertical staples after your Easter Island podcast–game changer haha. Wish you had more airtime on the other topics though. Looking forward to the next one!

    • Glad you enjoyed it! I have lots more to say on such topics.

  • In the transplant donor study you cite to demonstrate that young adults and teenagers have atherosclerosis, the donor hearts were from a high percentage (77%) of smokers. i.e. there’s significant selection bias here. See donor characteristics on page 2. In military trauma victim autopsy studies, as smoking has decreased so has atherosclerosis in young people.


    Your citation:


    Also, note that some of the other links to studies aren’t working. Thank you for your time.

    • Correct, but note that the current study (2012) did not perform histologic exam–only gross exam, so while it shows a reduction in atherosclerosis for this population relative to the previous one, it don’t address the state of lesions in the detail I discuss. Remember, by the time you have a fatty streak (first visible sign) a lot has happened!
      Also, look at the actual paper and see table 1. If that doesn’t make the point of this article with respect to time/age, I don’t know what does.

  • steve

    4 possible reasons for elevated LDL-P ?
    1. body makes to much
    2. body absorbs to much of what it makes
    3. IR
    4. Diet
    Not a doc, so am i warm?
    What other than IR affects particle size? Know where i can learn about particle disorders, that are separate and apart from LDL disorder like FH? I and family members make to many particles no matter low or hi fat diet. On low fat they are extremely small. Statin and Zetia keeps level of LDL-P low, but if low fat diet they can get to be as low as 350, but very very small. No IR via traditional measurements and TRGs always low at 40-50 and if go VLC diet down to 20. All very interesting.
    Thanks for great work, and best regards,

    • 1. make too much
      2. absorb too much of that which is made
      3. too many TG competing for space
      4. poorly working LDL-R

  • Neil Cooper

    Peter, I just saw your reply to my August inquiry about your NYC practice where you suggest I contact you directly. How do I do that?

  • Brian E. Brumwell

    Hey Dr. A,
    What would you recommend for a 51 yr old man, 5.11, 215 lbs with a history of Brain injury and laziness?

  • pradeep

    Peter, can you elaborate on role of anti oxidants as atherosclerosis involves oxidized LDL C

  • Val

    Dr. Attia,
    I am new to your site. Ornish and Esselstyn have clinically reversed CAD. Why not just go on a plant-based diet with some nuts added? If you can follow that kind of diet (no refined carbs, limited complex carbs, very high veggies, beans, some fruit with meals, nuts, supplemented with B-12 and Omega 3s) is there any downside?
    Thank you,

    • Complicated question, which I’m generally loathe to answer in comments, but short answer is as follows:
      1. Esselstyn likely restricts fat too much (Dean doesn’t really go as extreme) for optimal health
      2. From an efficacy standpoint, this is obviously, much better than SAD
      3. From an effectiveness standpoint, not clear how many people can do this.

  • Regarding your point about age, are you basically saying that atherosclerosis is inevitable as we age? Isn’t this also selection bias? Meaning, in a pre-industrial or traditional society would we see the same increase in atherosclerosis as we age?

    Here’s a study with an average age of 50. These long-term calorie restricted people had excellent biomarkers (most notably, very low BP) and carotid IMT of 40% of controls with no evidence of atherosclerotic plaque. This probably would compare well with pre-industrial societies (who on average had much lower BMIs than modern people today).


    Isn’t it more likely that age is such a huge factor because as we age in modern society we are more likely to become insulin resistant? How many 50, 60 or 70 year olds in the US are lean and insulin sensitive? The typical American by middle age has a nice belly (and so is most likely insulin resistant).

    But that doesn’t mean that age is necessarily the issue. Age might just be a confounding variable with IR.

    • But they still have atherosclerosis. IMT reduction is one thing, but it tells us little about the histologic stages. This study just points out the obvious, but doesn’t refute the point that age=time is an independent risk factor.

  • Su-Chong Lim

    Another informative Post!

    Incidental non-sequitur: Just sat through the Easter Island retreat podcast with great enjoyment. Envious of your opportunity to enjoy intellectual stretching in a light hearted mutually respectful atmosphere among such well informed participants.

    The venue, of course, was significant as the site of the original source of the soil organism from which rapamycin was isolated. I was curious, though, in the lack of mention of anything about it during the podcast, whether there was any passing thought by the members of group, in such a devastated treeless landscape, of the pathos of the unintended ecological and cultural suicide that the prior rich Easter Island culture had inflicted upon themselves in their frantic efforts to quarry, transport, sculpt and raise their massive stone sculptures until all the trees were gone.

    • The locals would disagree with this assessment (Jared Diamond’s assessment), which is itself an interesting story.

  • Rodrigo

    Dear Peter,

    I am not sure in which one of your posts to ask you this, but I’ve come across a study that made me a little concerned about the high-fat diet because it mentions markers that I don’t really know. I don’t have access to it beyond the abstract, and I can’t really evaluate if it was properly done: https://www.ncbi.nlm.nih.gov/pubmed/11923038. I think that a post dedicated to such (perhaps less important) markers where high-carb seems to have an edge over high-fat meals would be very interesting, but a short answer would be greatly appreciated as well.

    I would also say that there doesn’t seem to be much concern about this paper, because the researchers mention that intake of vitamin C and E was sufficient to prevent the increase of the markers they mention after high-fat meals (TNF-alpha, IL-6, ICAM-1, VCAM-1). Also IL-6 stimulates CRP and I’ve only heard of people on ketogenic diets who accompany this marker having no problems with it. But still, from the way they write, the researchers seem to be a little biased towards low-fat (in the same way that I am probably biased towards low-carb), and I’d like to know if they have a point.

    Thank you for your blog,

    • Who funded this? What was composition of the high fat diet?

    • Zach

      From the paper:

      “The total energy content of the high-fat meal was 760 Kcal (3,180 J), with 58 g of carbohydrate, 50 g of fat, 20.4 g of saturated fat, 246 mg of cholesterol, 2.8 g of fiber and a total of 59.2 energy (%) from fat, 12.3 E% from protein and 28.5 E% from carbohydrates. It consisted of two sausages (80 g), six bread slices (90 g), a small egg (40 g), butter (15 g) and olive oil (5 g).”

      The high-fat meal included six pieces of bread. Not much more needs to be said.

      [Fat + low carbs] = good. [Carbs + low fat] = bad. [Carbs + fat] = the worst. In the presence of those six pieces of bread, your body wants to do nothing before getting rid of that garbage, so of course the fat from the other parts of the meal are immediately shunted aside.

      Also, Peter, there was no acknowledgement section but it says at the bottom of the paper that “This study was supported by a research grant from the Second University of Naples.”

  • Alejandro

    Hi Dr. Attía,

    First, I want to thank you for sharing the rigorous knowledge you have worked so hard to gain. Here is a question not related to the article.

    I have done some analysis of the brands of water more famous here in Spain, both with a TDS meter and a PH meter. I added the information I obtained to the content of minerals that appears on the labels and made an excel table that you can see here (https://doc.co/zz1LHT).

    I want to know which of the 4 brands I analyzed is the optimal with the goal of optimal physiological functioning and longevity. I have some general knowledge about the properties I have to look for (the higher the PH the better, the lower the TDS the better) but I ignore the importance of each of these factors and how to ponder them in order to obtain a general conclusion. I hope you do not mind to take a quick look and give me some guidance.

    Thank you very much in advance.

  • Steve

    Hi Dr. Attia,

    Good to find your blog. I heard you on TF show and really dug a lot of value. I was wondering about your thoughts on hemoglobin a1c being low on a higher fat diet. I say higher because I’m eating more fat but I don’t think a majority of my energy comes from fat. Probably closer to 50%? But in the mornings it’s only fat in coffee, until dinner. So there’s a separation. My blood tests showed twice, about a year apart, low a1c (~3). Everything else, cholesterol, triglycerides, etc, were “normal”. Doc said I was at risk for low energy because of this indicator of “low blood sugar”. However I let him know my energy was extremely high from my diet. Focus great, attention great, no cravings or hangry moods. I’ve been utilizing this “ketogenic” phenom for the last five years. However, I couldn’t find anything about low a1c values and whether this is a “bad” thing. I did hear on a podcast, from an MD, that low a1c is a good thing and it would be beneficial in general to lower it. I think it was Dom D’Agonisto, from guess who’s podcast.

    What do you think? Obviously I’m just one case, but have you seen this with others, and any implications of wellness?

    Thanks for your time,


    • A1C is directionally “reasonable” but not nearly as accurate as folks want to believe. I think I commented on my CGM vs. A1C elsewhere, but don’t recall where.

  • Philip Hellman

    Dr. Attia, and anyone else with an answer,

    I am a family doc in Silverton, OR. I’ve also found Dr. Dayspring and lecturepad.org to be a life boat. I’m yet to pursue the lipidology fellowship, but have started to incorporate advanced lipid testing into my practice. Dr. Tara Dall’s lecture, “Advanced Lipid Testing Comes Alive,” was the most cogent and clinically useful lecture that I’ve come across to date. Are there other lectures on lecturepad.org or elsewhere that deal directly with therapeutics and clinical decision-making in risk factor modification?

    Many thanks,

  • Ron

    Dr. Attia,

    I really thought you’d be part of this distinguished list:


  • Jan

    Hi Peter,

    Thank you so much for your amazing work. I read this article when it came out and have been anxiously awaiting to read about your work on Lp(a), because I too have this genetic problem along with APOE4. This morning I listened to your talk on the Fat Summit with Dr. Mark Hyman and it was so interesting. You mentioned that you are helping a patient with the same issues I am facing, but unfortunately you couldn’t go into the details of how you are approaching this. My doctor states that many specialists in my area don’t even do the NMR testing, can you believe it? Crazy! Thankfully, I have educated myself and knew what tests to ask for. So for that reason, I’m not sure if I should be seeing a lipidologist. I’m afraid they will want to put me on a statin. My main reason for writing to you was to see how the Lp(a) research is going? Again, loved the talk at the Fat Summit. Thank you again. Wish I had you, Dr. Dayspring and Dr. Kraus as my doctors!

    • The lp(a) world is really getting exciting with the ongoing development of ASO. These drugs are going to really change the way we thinking about lp(a) and prevention of CHD (and AS and even thrombosis) for patients with elevated lp(a).

  • Scott Miller

    Good post, as usual. Been reading your blog from month #1.

    For some 20 years I’ve been arguing with doctors and nutritionists that LDL and Total-C is a red-herring. But there’s a profitable drug for LDL, and so when your main tool is a hammer, you only focus on banging nails.

    There are actually a lot of well-studied natural supplements that play a tremendous role in the arterial health. I’m curious if you have researched any of them, such as pomegranate extract and resveratrol (both of which release nitric oxide). One human study showed a ~30% reversal in carotid thickness after a year of drinking pomegranate juice vs. a control group. (The study is easily found on Pubmed.)

    Vitamin K2 (along with D3) is a key regulator of arterial health.

    And there are others.

    My father had both terminal cancer and severe heart disease 12 years ago and was given less than a year to live. I got him to change his diet and take 15 supplements a day for both conditions, and his doctors now consider him a miracle case. But they showed no interest in hearing about the supplements (of course). Even though ALL of the supplements have numerous (sometimes 100’s) of confirming studies behind them.

    And such is one of the key problems with our profit driven (versus health driven) medical industry. Doctors are trained to make money, despite their Hippocratic Oath. (Yes, they can have great intentions, they just don’t realize they’re victims of a system that doesn’t align with their intentions.)

  • Jim Schmid

    Thanks for all the effort you put into communicating your knowledge and experience. I’m certainly enjoying learning about and practicing a new way of eating. I’m a teacher in a men’s prison and have been sharing information about insulin and low carb diets with my students. They don’t have much choice as to what is available to eat but they do have some. Their diets tend to be very simple carb heavy with a lot of potatoes (usually processed-think surplus French fries) and some rice as the main source of calories. My question for you is “what’s worse, simple carbs or trans fat from margarine?” They almost always have some margarine on their plates to make the calorie count high. 3 grams out of the 11 grams of fat in a Tbsp. serving are trans fat. The margarine is made from soybean oil and a bunch of other crap. If they are wanting to decrease insulin resistance should they consider eating this as opposed to more potatoes if they are still hungry?

    • Prison food is just the worst… so upsetting. I really don’t know what the best option, besides caloric restriction.

  • jw

    Why does ASO cause TG to go up (in mice) and is this a concern?


    • Probably a mouse thing… the human phase II in Lancet last month showed TG went down in both cohorts at dose escalation from 100 to 300 mg.

  • eric robinson

    Do you know which gene SNPs are “bad” with regards to the ABCG5/G8 and NPC1L1 (i.e. rs52815063, rs145297799,rs2072183, rs217434, rs217428 , etc) ? In particular, I’m wondering what the “normal” and “abnormal” patterns would be using the 23andme data.

    • I do not, and I’ve tried using Prometheus (unsuccessfully) to determine.

  • Hania

    I was trying to follow EFGT program and learned few things from your recent interview with Dr. Hyman. I finally got the doctor to issue a requisition for the NMR Lipo Profile which is not even done here in Canada. And the worse part is nobody knows what to do with it and the results are totally confusing to me…

    I need help with diagnosis and treatment, how I can contact you directly to become your patient.

  • John

    Hi, Peter.
    From the Quick FAQ: “Exercise is important for a number of reasons, but weight management and controlling disease risk are not on the list, at least according to the best available evidence.”

    Wait a second, wait a second: no reduction of disease risk? Any disease?

    What about strengthening of immune system (and prevention of many diseases as consequence)? What about depression? And isn’t strength training heart-protective?

    So I was unsure what you meant.

    • Actually, this was written in 2011, based on (if I recall correctly) a composite analysis from 2006 or 2007. Short answer, I would modify this view. The right kind of exercise certainly can help with weight management and disease risk.

  • John

    Adding to the above, a quote from Gary Taubes:

    “This is not to say that there aren’t excellent reasons to be physically active. We might just enjoy exercise. We may increase our overall fitness; we may live longer, perhaps by REDUCING OUR RISK of heart disease or diabetes”. (emphasis mine..)

  • Benas

    Hi Peter,

    Have you heard of Linus Pauling (2x Nobel winner) theory of what causes and how to stop/reverse cardiovascular disease?
    Briefly: unlike most animals, humans, monkeys and guinea pigs cannot produce Vitamin C in liver, which is necessary for collagen synthesis to repair arteries. Ascorbate deficiency leads to scurvy (like sailors bled to death before they started taking lime juice on trips), and cardiovascular disease is a weaker form of scurvy. Lp(a) and plaque in arteries is a compensatory mechanism which keeps arteries together as long as possible under ascorbate deficiency. Also, Lp(a) is found predominantly in species incapable of endogenous Vitamin C production.

    Here’s more on the theory:

    Here are published studies:
    https://www.ncbi.nlm.nih.gov/pubmed/26064792 – Deficiency of ascorbate increases serum levels of Lp(a) in mouse model with two characteristics of human metabolism: the expression of Lp(a) and the lack of endogenous ascorbate (vitamin C) production.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1823880/?page=3 – in guinea pigs atherosclerosis is reversible with vitamin C (in summary).

    There are plenty more. Also, animals that produce Vitamin C in liver make the equivalent of about 4g/day for a 70kg human.

  • Benas

    Here’s another study by different authors: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC15418/
    Aortic wall damage in mice unable to synthesize ascorbic acid (2000)

    Engineered mouse model unable to synthesize Vitamin C (like humans). Ascorbic acid deficiecy led to lower HDL and higher Total Cholesterol; Aortic damage was observed following Vitamin C deficiency.

  • John K.

    Any reason to believe that chamomile tea might improve blood lipids? My total cholesterol dropped 45 points (from 188 to 143, with an increase in “good” cholesterol and a decrease in “bad” cholesterol and triglycerides) after starting to drink 4 strong cups of chamomile tea per day for several months. Can’t think of other lifestyle or nutrition changes that could account for this drop.

  • John K.

    My latest lipid panel showed a substantial improvement since the last one six months ago, i.e., total cholesterol dropping from 187 to 143 (with an increase in “good” cholesterol and a decrease in “bad” cholesterol and triglycerides). I had only two lifestyle changes that could account for this drop. One was changing my 2-3 times weekly 30-minute treadmill exercise from steady brisk walking with maximum incline to intermittent walking and running (more walking than running) with no incline — a marginal change. The other was drinking 4 cups of strongly brewed chamomile daily for several months. I haven’t found any convincing research that the chamomile could have caused some or all of the improvement. Any thoughts?

    • ST

      John K – Four cups a day vs. zero before would probably fill me up – could it be that you consumed significantly less other calories and perhaps the quality of those disappeared calories that accounted for the changes? i.e. fatty acids?

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  • Most low-carb/keto sites gloss over keto flu.

    Many sites provide advice about fluids, minerals etc. If you begin vomiting when you think you have keto flu none of this advice will help you. And if you are using a drug from the SGLT2 group such as Invokana you could be susceptible to ketoacidosis.

    Ketoacidosis normally doesn’t affect type 2 diabetics and most websites tell you that nutritional ketosis is nothing to worry about. In the case of SGL2s accompanying a keto diet however this wrong! A family member is going through this. She assumed she had a bad case of keto flu and tried to wait it out. She has been in the hospital for a few days. She is not out of the woods yet but if she’s lucky will be discharged early next week. The vomiting and dehydration were eventually stopped. Mysterious, extremely painful, leg muscle pains continue. They are only relieved by standing up or with analgesics.

    SGL2-induced ketoacidosis in type 2 diabetes is not the same as the one that affects type 1 diabetics. In fact blood glucose levels can remain pretty normal throughout in the SGL2 variety. Government warnings about the role of SGL2s in ketoacidosis have been issued in Canada, the US and Europe. Documented cases so far are only in the hundreds so statistically this is small. I’m not a doctor but I don’t think anyone should try to reduce their carbs significantly while using an SGL2 drug

    I hate those Internet warnings that tell people to pass it on. This situation however might be one where you consider sharing the news. I’m hoping Peter will add his blessing/observation to validate this.

  • Ali

    Hi Peter,

    I’ve been quite intrigued by the findings and benefits of a high fat/low carb diet and decided to try it for myself three months ago. I recently did my blood work and as you may have guessed my cholesterol has raised some eyebrows.

    My question is – how do I engage a doctor to challenge their assumptions of LDL-C?

    For example, here’s an exchange I recently had with a family member who is a physician:

    Me: Based on what we chatted about, these were Attia’s views I was referring to…

    1. LDL-P (or apoB) is the best predictor of adverse cardiac events, which has been documented repeatedly in every major cardiovascular risk study.
    2. LDL-C is only a good predictor of adverse cardiac events when it is concordant with LDL-P; otherwise it is a poor predictor of risk
    Why? – Atherosclerosis is caused by an inflammatory response to sterols in artery walls. Sterol delivery is lipoprotein-mediated, and therefore much better predicted by the number of lipoprotein particles (LDL-P) than by the cholesterol they carry (LDL-C).

    Doc: I agree that LDL-P might be a better predictor, but LDL-C was found to be a risk factor for heart disease even before they were looking at LDL-P, meaning if you have an LDL-C over 4, your risk of a heart attack goes up 75%, and this is looking at all comers not even considering LDL-P. Framingham Paper.

    Not being a doctor, I figured that this may be a challenge for some of your readers who are having a difficult time to have an intelligent conversation with their doctor.

    Appreciate any insights or rebuttals in your arsenal.

    • LDL-C is a good predictor when it agrees with LDL-P, when it doesn’t, it’s not.

    • ST

      Dr. Dayspring (Lipidologist) says that if someone has an LDL-C of 200 or over they almost always have a correspondingly high LDL-P. Alternatively, some people have a perfectly in range LDL-C, but then have a very high LDL-P which warrants concern – at least that is my understanding.

      I’m in the same boat in that my cholesterol numbers rose considerably on keto. I suspect that far more than 30% of people experience this and few do enough testing to realize it. The conclusion I’m coming to is that if a modification in one’s diet has significantly raised the LDL-P to an unacceptable level, then something has to be done about it. Cut back on saturated fats, raise carbs etc… It is unclear to me whether these rises occur only during periods of weight loss and if they go back to normal during maintenance weight etc… The keto community seems to dismiss these rises by claiming that atherosclerosis is an all inflammation problem and not a cholesterol problem. The trouble is that all the luminary lipidologists regard that as absurd – they say it is both and that statins have saved more people than perhaps any other medical intervention. Personally, I cut back on saturated fats and will re-test in six months. I wouldn’t challenge the doctor on LDL-C numbers – rather seek to find out what the LDL-P is – if it’s high, which Dayspring suggests it will be if LDL-C is high, then consider changes. It seems that one rule of thumb that doctors go by (high LDL-C is likely a problem) is likely correct. That’s my current understanding from listening to interviews, reading case studies that these lipidoligists comment on.

  • Allen

    Peter – thanks for your blog posting.
    Any feedback on the comment regarding Linus Pauling & Lp(a) ?

    Looking forward to your Lp(a) article.
    much appreciated.

  • David Singer

    Thank you for all the public information you provide. I am enjoy watching your lectures. I am at a loss. Dr. Greger of Nutrutionalfacts.org claims a plant based diet is the only diet proven to increase longevity. What you say makes all the sense in the world, but how do we know it prove the test of time? If would be great if one day you and Dr. Greger would have a discussion to enlighten the public.
    One of the problems I have with the kenotic diet and most diets is that they don’t achieve the prober amount of nutrition. We all know the Gov’t RDA’s are meaningless. I have tried to contact Dr. Patrick and Dr. Ames about my concerns, but the best I got an email by Dr. Ame’s secretary suggesting I consult the Linus Pauling institute. The problem with that is Linus Pauling only discusses synthetic vitamins. Dr. Patrick on her videos recommends synthetic vitamins too. Its as if no one is aware there are some whole vitamins such, as My Kind produced by the Garden of life. Synthetic vitamins don’t have the bioavailability as a whole food vitamin. Its not even close.
    I believe supplements are very important since our soils are depleted. I am willing to bet that neither your or your wife consume close to the recommend (consensus) potassium for example which is about 4700MG. As you know 98% don’t of us don’t consume that much. Its seems to me that everyone is looking only at their slice of the pie but not trying to absorb everything.
    I have another question/concern. I recently watched a video where you said you consume about 20 grams of fiber daily! How did you determine the amount work for you? That seems awfully low. I am of the belief (proven or not) that we all have too many toxins and need to get rid of them ASAP, but at 20 grams it does not seem possible.
    Thanks again and hopefully if you don’t answer my concerns someone will.

  • Martin

    Hi Peter,

    Thanks a lot for a very informative blog. Really enjoy reading it and have read the majority of it. I’m very much into nutrition and exercising. Also a final year medical student in an European country.
    My goal is to become a surgeon, right now I’m a PhD student in the area of immunotherapy (hence I’ve met your supervisor S.R several times 🙂 ).

    However, I have a completely different question for you. What is your take on manual dexterity and surgery? I have asked around a lot and read different forums, and it all comes out 50-50, some believes it is important, some says it is one of the least important. But I like your thoughtful comments and would like to hear what you think. The problem my father seem to have developed a mild essential tremor at the age of 65 (it does not infer at all with his daily life even though I can see it when he holds a cup of coffee for example). I realize I cannot make life decisions on this, I have no idea if I will develop it or not (none of my grandparents have it..).
    On the same note, do you think you would have been able to stay on a ketogenic diet during your surgical residency?

    Again, thanks for your blog and hopefully it is OK I ask a question not regarding this post at all 🙂

    Best wishes

    • For most surgery it probably doesn’t matter much. For some specialties, though (e.g., cardiac, congenital cardiac, hepatobiliary) it probably matters a bit. Overall, though, less important than people think.

  • Esther

    I’m going to ask what everyone else is thinking – why do so many people who go on a ketogenic diet experience chest pain (including me)? Google “ketogenic diet chest pain”

  • Hi Peter,

    Excellent article for explaining how heart disease develops.

    It makes a good resource for referring doctors to.

    My mum suffered from strokes, and all the doctors were prescribing her was statin to lower cholesterol (as well as other medicines for blood pressure etc).

    They didn’t care about the diet at all, just eat less fat, and then eat whatever else you like.

    IF there was a post like this during that time, I would have passed it on them definitely.

  • Jennifer

    Hello Dr. Attia

    I’m not a doctor so I had to read this article several times to really understand it and I’m sure I am completely missing obvious implications as well. I have a question not about heart attacks and atherosclerosis but high blood pressure. My husband has moderately high blood pressure. Doctors want to put him on medications and told him to stop eating fat and salt. I know your feelings about fat restriction but what about salt? Does it impact blood pressure? Google returns many conflicting and confusing stances on this topic.

  • Allen

    Hi Peter,
    this may be an obvious point that I have missed, but are Lp(a) particle counts a subset of LDL-P particle counts ? For example if we measure Lp(a) at 100 nmol/L and LDL-P at 1000 nmol/L, does that combination indicate that a person really has a 900 LDL-P and 100 Lp(a) ?

    Looking forward to your Lp(a) article.
    best regards,

    • Good question. Yes, LDL-P includes lp(a)-P.

  • Vincent

    If the hypothesis of thermogenesis is caused by excessive LDP-P, then it should occur systematically in both of arteries and veins. Could you explain
    (1) What is the mechanism that LDL pass the healthy endothelial cell layers, such as by both of endocytosis and exocytosis?
    (2) why it actually occurs only in small segments, instead of major areas, of arteries and not in veins?

  • Allen

    Hi Peter,
    Two questions:
    (1) Is Lp(a)-P thought to be a linear function of LDL-P production ?
    (2) Your view on statistical representation of statin benefits
    as described in articles like this one:

    best regards,

  • Christine McCallum

    So, I might be missing this point but…If this process is normal in everyone, then where is the intervention point with diet?
    Does eating more MUFAs and PUFAs create more fuel for the infiltration (when the LDLs enter the epithelium)? I would think that High Healthy Fat programs (Eat Fat, Get Thin for example)REALLY compound this issue?
    Is it because when not eating “sugars” the body metabolizes the fats very quickly and there are not as many floating around to be transported?????
    And, regarding Coagulation factor VII, does eating healthy oils make this factor more active or provide an increased tendency of clots to develop. (From Dr. Esselstyn=”reverse heart disease”)

    Healthy Oils means to me: not heat or chemically processed: coconut, olive, avocado and grass fed butter-beef-chicken.
    Thank you,

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  • Don Pettibone

    I saw an article coauthored by Michael Hollick on a possible link between Vitamin K2 and CV disease that caught my eye. http://www.tandfonline.com/doi/full/10.4161/19381972.2014.968490
    The main point is that it may be that K2 keeps calcium where you want it, in bones and not in arterial linings. This looks pretty interesting. What do you think?

    BTW, I love this blog and look forward to reading your book. Regards,
    Don Pettibone

    • Problem with this logic, in my view, is that the data I find most compelling about atherosclerosis suggest it might actually be better to have calcium in the artery wall, if plaque exists. Very complex topic and not one I’ll address now, but be careful what you wish for. Calcium may reduce the risk of plaque rupture.

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  • Bill in Oz

    Dr Attia..I too love your blog. However the link provided by Don has this quote in it :
    “In the Rotterdam Study, a large-scale, population-based study with 4,807 Dutch women and men (age: 55+), the effect of dietary vitamin K1 and vitamin K2 over a 10-year period (1990 to 2000) was investigated with regard to the risk of coronary heart disease, arterial calcification and overall mortality. This study found that vitamin K1 (intake: ?250 ?g/day) had no protective effect on the cardiovascular system or overall mortality. Vitamin K2 (intake: ?25 ?g/day) reduced the relative risk of dying of heart disease by 57%. Vitamin K2 also markedly reduced the occurrence of coronary heart disease (by 41%) and overall mortality (by 36%). Vitamin K2 even reduced the risk of severe arterial calcification by 52% (OR: 0.48).43”..
    That seems fairly straight forward. However you express doubt about K2 supplementation. I would love to hear more from you on this.

    • 1. Pretty easy to K2 in diet
      2. This is not an experiment, therefore other confounders can explain benefit.

  • Bill in Oz

    Thanks for your very quick response Peter.
    You said that “Pretty easy to K2 in diet”.
    I assume that means that K2 is easy to obtain in the diet. However my reading elsewhere disputes this. I have read that in Japan Natto is a good source of K2 but pretty awful tasting and definitely an acquired taste even for Japanese. I have read also that dairy foods from dairy cows fed on grains ( as in dairy feed lot type situations ) instead of grass, also have negligible levels of K2. ( Source the Canadian, Rheaume-Bleue ” Vitamin K2 & the Calcium Paradox” pp. 50-56 ).

    Your second comment is ” This is not an experiment, therefore other ‘confounders’ could explain the benefits”. I understand. Yes the Rotterdam study is an observational study. So there may be confounders. And most of the other human studies on K2 I have seen cited are observational in character. I don’t know any human purely ‘experimental’ studies on K2. And I doubt any proposed studies would meet science ethics standards, as we know that K2 is essential.

    But Rheaume Bleue does cite a mice study which illustrates that K2 & GLA protein are essential in preventing calcification of the arteries. Luo G. Ducy P, McKee MD et al.”Spontaneous calcification of arteries & cartilage in mice lacking Matrix GLA protein” nature 1997, Mar, 386 (6620) :78-81

    But beyond all this is that you imply that calcium in arterial plaque serves a protective function, preventing rupture of the arteries. Now that is interesting and completely new to me. Is there any evidence for this ?

    Thanks again !

    • See Peter Libby re: progression of calcium scoring.

  • Bill in Oz
    • Bill In Oz

      Dr. Attia, I have just checked in a book by Dennis Goodman, MD and cardiologist in New York ( Vitamin K2, published in 2016, ) to see if he has any references to there being any danger if Calcium is ‘removed’ plaques using K2. On page 12 he says this
      ” Calcium reflects what cardiologists call ‘hard plaque’. Wherever you see hard plaque there is the more dangerous ‘soft plaque’ or vulnerable plaque. This can rupture and cause an immediate blood clot which leads to heart attack, stroke …Ironically hard plaque can protect us from this rupture ( ie it is part of the healing process) but it leads to a narrowing of the blood vessels and reduced blood flow.Oxygen and other vital nutriensts do not get to the heart which causes angina ( chest pain due to lack of oxygen” . Page 12.

      However Goodman still goes on to recommend that his patients take vitamin K2 because it reduces the accumulation of calcium in arterial plaque. He also quotes a study “Nutrition, Metabolism and Cardiovascular Diseases” Goodman staes that the risk of coronary heart disease dropped 9% for every 10 micrograms of Vitamin k2 subjects consumed..”…..Page 16

      So you have any comments ?

    • Bill In Oz

      Dr Attia, I did find a Peter Libbey article. However I think this one “Coronary artery calcification in clinical practice: what we have learned and why should it routinely be reported on chest CT?” by Joseph Shemesh is far more informative on calcium in arterial calcification. It outlines the character of the processes which you have hinted at


  • Debbie Christian

    Dear Dr. Attia,

    I am in graduate school and an writing a paper on ischemic heart disease. May I have your permission to use some of your images where applicable in my paper? My intro discusses cholesterol.

    Debbie Christian

    • Of course. Thanks for asking. Please note the figures are actually from a lecture by Tom Dayspring.

    • Debbie Christian

      Do I need to also get permission from Dr. Dayspring? I did a quick lookup and i am guessing that he is the Lipidologist ?

      Many Thanks,
      Debbie Christian

      • You should ask him. Yes he’s a lipidologist.

  • Debbie Christian

    One last thing, I will cite you for the images, unless you prefer I cite someone else…

  • Ken

    How can i get a NMR particle test? Cost? Ease?

  • Eric


    Great post – sorry I’m just learning of it now. As a 36 y/o last year I too was forced to face the realities of heart disease sooner than I would have anticipated although fortunately for me, as you phrased it I had this epiphany as well and do what I can to move the needle in my favor as it were.
    I’d be curious on your take on this paper (http://www.cell.com/cell/fulltext/S0092-8674(15)01574-3) and other research like it that focuses on the gut microbiome, specifically TMA–>TMAO production being a culprit for atherosclerosis and further that DMB may inhibit and/or attenuate choline and carnitine diet-enhanced atherosclerosis.
    Seems as though we need more research (and possibly more product) that has DMB in it, e.g., DMB infused water, to be consumed with all choline/carnitine rich meals. Unless of course we can convince our population to be vegan.
    Thoughts on this body of research?


    • I’m skeptical of this work. See work by Chris Kresser and Chris Masterjohn on this topic.

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  • Vanda

    I just found your videos on YouTube this weekend. As I listened, you said things that I myself have said and it gave me hope that after over 2.5 years of “eating right” and training for an Ironman I only became fatter and sicker, and slower. Disgusted at my appearance and my performance I have nearly spent my savings on every kind of doctor you can imagine to try to “fix” my problems. I’ve been trying to Keto adapt and think I am finally succeeding. Wonder why no one ever told me I was possibly insulin resistant or had metabolic syndrome. At the age of 36 I Was diagnosed with colon cancer. I weighed 200 lbs at that time. Then I drew a line in the sand. Once my treatment and surgery, I.decided to become a triathlete. I got down to 130lbs and I was fit and fast. Then slowly I began to gain the weight and there was nothing I could do to stop it! Despite training 5-8 hrs a day. INSANITY! I have almost lost my mind. Last year despite all of this, I made team USA in Aquabike and qualified for Worlds in Canada. I only have until late August to prepare and all my other docs are saying I shouldn’t do endurance sports. They are claiming some adrenal fatigue but NOW I believe otherwise! Can you help me? Is there anyway I could pay for phone consult so I could get some advice? I wish I could have found you 2 years ago. Any advice or help you could offer would be greatly appreciated and hopefully get me on a path moving back toward fitness and away from this mess I’m in. Thank you!

  • Steve

    Has the LP(a) article/post mentioned above been written or is it still a work in progress (I couldn’t find it if it exists).

    Generally speaking, for someone under 40 with a high calcium score (over 200) and high LP(a) (over 200 NMOL) but LDL-C, small LDL-P and particle number relatively under control via high dose statin/lifestyle changes, is there currently any other suggested treatment to lower LP(a) or is it a wait and see game for antisense drugs. Is Eztimbe and/or Niacin still recommended? It appears Niacin lost some of its luster after 2014 trial results but seems like there could still be some benefit for high LP(a) subset.

  • Vlad

    Hi Dr. Attia

    I was just about to ask what’s your take on Linus Pauling’s vitamin C theory regarding CVD when I noticed that the question was already asked by Benas in Nov 2016, but there’s no answer. So, what do you think?

  • Bill In Oz

    Peter any thoughts on this may 2017 Life Extension magazine article on preventing soft arterial plaque rupture using supplements made of extracts of Gotu Kola and French Maritime Pine ?


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  • Jan

    Hi Peter,

    I too was going to ask you again if you’ve written anymore regarding Lp(a), but I see that Steve just asked you. I watched (I’m a little behind in finding this out as I’m not a regular viewer of Dr. Oz) Bob Harper discussing that he has Lp(a) and was curious if this has sparked your interest to write more on the subject.
    Thank you.

  • Steve

    Regarding your LP(a) discussion for Chris Kesser, is there a way to access (even if behind a paywall)?

    • Yes, I believe the audio and transcript are available, but you’ll need to go to his site. I don’t have access.

  • Bill In Oz

    I read recently about the research work of Morrison in 1973 using Chondroitin sulfate. And then found this as well


    Any comment on C S ?

    Would love to read the book. Hope it is progressing well

    • Bill In Oz

      Lester Morrison’s 1973 research study into Cardio vascular disease treated with Chondroitin sulfate as reprinted online :

      A life saving supplement that has been completely ignored and forgotten about despite being researched for many years by Morrison in the 1960-70’s . Ignored because there is no money for pharmaceutical companies, in a natural supplement that cannot be patented. Ignored an forgotten by doctors as it an over the counter purchase rather than purchased via a prescription ?

  • John

    Hey Peter. Seems like many physicians are now stating that Cardio IQ, which uses ion mobility to measure LDL particle number and size, is more accurate than NMR Lipoprofile b/c it uses direct measurements.

    I know you’ve advocated for NMR – has your stance shifted at all from any new research?

  • Joe Scott

    Hi all. Curious to hear thoughts on folks with hypercholesterolemia and cholesterol intake.

    My cholesterol is 309 on the dot without statins. I could eat grass for every meal – still 309.

    Guidance from my doctors and cardiologists at Duke l (who are generally in the anti-statin boat) have advised me to stay on the statins. As statins were originally developed to treat hypercholesterolemia. They have also advised me to avoid cholesterol in my diet.

    But if cholesterol is not the culprit; what gives?

    • Dietary cholesterol plays virtually zero role in serum cholesterol levels. Amazing that in 2017 doctors don’t know this…

  • Nate

    Thanks so much for all the information you put out there, I find it so interesting an useful. I have been following some of the work of Chris Masterjohn and he had mentioned the role insulin plays in downstream signalling and its role in LDL receptor activity. My question is that on a very low carb diet, where insulin signalling is very low for long periods at a time, do you think there could be an eventual detrimental effect on health. This is assuming that the person has already used a low carb diet to improve body composition to close to ideal. If you get time to answer, thank you so much.

  • Leo Popovitch

    You should do the service of telling your customers about vitamin K2 (meniquinone 7) and vitamin D3 .
    When taken together they reverses plaque and calcium build up.
    Less plaque, less oxidation , less foam cells.

  • Andrey Che

    Are there any potential treatment that reverses existing plagues ?
    Ive read that Trodusquemine shown to reverse it in mice
    Is it real at all or is it a one way road and we could only hope to slowdown this process ?

  • Ben Gilsdorf

    Dr Attia
    Do you have any articles which show what a CT scan will show and what it will miss. I am guessing that one could have signicant plaque that would not show up in a CT scan.

  • John Steen

    Hey Peter,

    In the future will you discuss what tests one can do to determine the level of atherosclerosis one might already have, in order to assess their risk level of a a CVE/MI? (other than OGTT, LDL-p and LP(a) which seem to assess a more development risk)




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