April 18, 2022

Cardiovascular Disease

#203 – AMA #34: What Causes Heart Disease?

Not everybody dies from atherosclerosis, but… everybody dies with it.” — Peter Attia

Read Time 29 minutes

In this “Ask Me Anything” (AMA) episode, Peter dives deep into the topic of atherosclerotic cardiovascular disease (ASCVD)—the number one killer in the developed world. Peter argues for the importance of paying attention to and understanding ASCVD given its ubiquity and inevitability. He goes into great detail about the development of atherosclerosis and how it can take hold at a very early age, the role of cholesterol, and the causal factors of ASCVD that determine prevention strategies. Additionally, he discusses the important metrics and biomarkers found in blood work, as well as diagnostic tests such as coronary artery calcium scores (CAC) and CT angiograms which help to determine the level of arterial damage present. Finally, Peter lays out the keys to understanding and interpreting calcium scores before wrapping up the conversation with his key takeaways regarding prevention.

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We discuss:

  • The importance of understanding atherosclerosis early in life [2:15];
  • Defining atherosclerotic cardiovascular disease (ASCVD), its causes, and the role of cholesterol [9:00];
  • The process of developing ASCVD, part 1 [15:00];
  • The process of developing ASCVD, part 2 [24:00];
  • The process of developing ASCVD, part 3 [32:45];
  • How early in life ASCVD can start to develop [40:30];
  • Case studies of atherosclerosis and figures showing real pathology [43:00];
  • Coronary artery lesions present in autopsies of different age groups [49:15];
  • The causal factors of ASCVD that determine prevention strategies [52:15];
  • Labs to identify biomarkers of ASCVD [59:00];
  • Diagnostic tests to determine the level of arterial damage present—CAC, CTA, CIMT, and more [1:00:30]
  • Calcium scores: keys to understanding and interpreting a CAC score and/or CTA results [1:05:15];
  • Is there a risk from cholesterol levels being too low? [1:13:00];
  • Key takeaways regarding prevention [1:15:45];
  • More.


The importance of understanding atherosclerosis early in life [2:15]

 Atherosclerosis is ubiquitous

  • It’s the only disease that is inevitable, and it limits human longevity
  • Cancer and dementia, also diseases of old age are not inevitable the way atherosclerosis is

Not everybody dies from atherosclerosis, but… everybody dies with it”— Peter Attia

  • You want to understand this because the impact is huge and the tools we have are also huge
  • Extending lifespan comes down to delaying the onset of chronic disease, and atherosclerosis is the most common chronic disease

2 main paths to atherosclerosis

Risk factors

  • Smoking, a behavioral risk factor (we’ll put this aside for the moment)
  • 1 – Hypertension
  • 2 – High blood and lipid abnormalities (we’ll focus on this one)
    • This leads to atherosclerotic cardiovascular disease (ASCVD)

Studies of pathology show ASCVD begins at a young age

What is the most common presentation for a 1st heart attack?

  • Sudden death
  • A 1st heart attack in over 50% of people is fatal; today this number is a little less but still staggering

What is the age distribution of people who have their 1st major adverse cardiac event?

  • Adverse cardiac events are a heart attack or a stroke (or death)
  • Figure 1 shows the incidence of cardiovascular events for both males and females in the US

Figure 1.  Incidence of cardiovascular events by age and sex.  Credit JAMA Cardiology 2016

  • The graph on the right shows total annual events
    • The 1st 2 sets of bars show the number of events for people under 65
    • Men are shown in the darker bars comprising slightly below 25% and slightly above 25% of all cardiac events
      • The implication is that 50% of men who are going to have a cardiac event in their life will have it before the age of 65 
    • For women, a third of women will have their 1st cardiac event before the age of 65 
  • The total annual events is not the whole story; it’s important to understand how long it takes for this disease to take hold
    • Early prevention is key
  • Almost 25% of these events are in men younger than 54
  • When you think of someone who is 45, 50, this disease didn’t start 2 years before

When you see these stats laid out, it creates a shift in your mind around why you should care about this


Defining atherosclerotic cardiovascular disease (ASCVD), its causes, and the role of cholesterol [9:00]

ASCVD is disease state characterized by the deposition or the buildup of cholesterol (sterols) in the artery wall

  • It begins with a fatty streak that later consolidates into plaques that can ultimately lead to a reduction in blood flow
  • Reduction in blood flow is called ischemia 
  • Ischemia results in tissue damage to the heart and this is what results in a heart attack 
  • A heart attack can be fatal depending on the amount of cardiac tissue that is damaged from loss of oxygenation

Causes of ASCVD

  • You don’t have to be obese or have high blood pressure

It’s really a question of the cholesterol in your blood. That’s really what defines the disease.”— Peter Attia

  • Atherosclerosis is defined by the presence of cholesterol in the artery wall
    • This is not necessarily related to the measurement of cholesterol in circulation
  • Patients with cholesterol in their arteries do not necessarily have to have co-aggravating factors such as: high blood pressure, diabetes, obesity, family history, smoking
    • All these things that exacerbate ASCVD

Cholesterol explained

  • Cholesterol is an organic molecule, a type of lipid
    • It is not soluble in water
    • It is a hydrophobic molecule
    • Picture pouring oil into water and you would immediately see what it means to have a hydrophobic substance in contact with something that is hydrophilic (water)
      • They repel each other

Cholesterol is about one of the most important molecules in the body

  • You would die without it
  • Rare genetic conditions that impair the ability to make cholesterol are fatal
  • Cholesterol is used for 2 main things:
  • 1 – The cell membrane of every cell in the body contains cholesterol
    • Cholesterol contributes to the fluidity of the cell membrane, important for membrane channels that allow things in and out of the cell
  • 2 – Synthesis of many hormones begins with cholesterol, including: cortisol, estrogen, testosterone
    • It is also essential for the creation of bile acids, necessary to digest food

Where does cholesterol come from?

  • Most people think of cholesterol as something that comes from eating certain foods
    • This is true, eggs contain cholesterol
  •  But the cholesterol in your bloodstream has little to do with the cholesterol in foods you eat 
    • The reason is, the cholesterol we eat in esterified, it has a chemical bond that swings between an intermediary oxygen and another side chain
    • This cholesterol is too large for the receptors in our gut to absorb
    • Most of the cholesterol we eat is excreted

Most of the cholesterol we will discuss [in our bloodstream] is made in our body and transported between cells through lipoproteins 


The process of developing ASCVD, part 1 [15:00]

Anatomy of blood vessels

{end of show notes preview}

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  1. I think as far as treatment is concerned, a healthy diet is not described, and rarely if ever prescribed as at least as essential as the drugs, stents, etc. As an integrative health registered dietitian, and 77 year old faculty at a college, I teach a whole person approach to feeding yourself, exercise, and a lifestyle that promotes spiritual/emotional aspects to reduce stress.
    A vegetarian DASH or Mediterranean Diet, and elimination of glysophated foods, and ultra processed foods, is what I would call a healthy diet. It can lower cholesterol as well as statins. And the anti-inflammatory qualities of eating this way does wonders for arteries. The pre and probiotic foods that should be included do so much for our immune system that resistance to communicable disease is reduced. All of the statements above have been researched, and shown to be effective. Michelle Scott, MA, RD, IBCLC (lactation consultant)
    PS Did my last triathlon in 2017, and still run 2-3 miles every week. Yoga daily as well.

  2. Where is periodontal disease mentioned?
    Oral DNA probes?
    What about CIMT?
    Oxidative stress?
    Glycemic index?

  3. Can cholesterol be too low? I am 72and take a lot of omega-3 fatty acids for my arthritis (and I know it is beneficial because I did my doctoral thesis on this very subject). These long chain omega-3 fatty acids will be incorporated into the phospholipid layer of cell membranes and make them more fluid, whereas the cholesterol part of cell membranes make them more solid or structured. If I lower my cholesterol dramatically (my non-HDL is 157 mg/dL, my HDL is 75 mg/dL and my CAC is 0), for example with a statin, will the balance of fluidity to structure in cell membranes change such that the membranes become more fluid and thus possibly more “leaky”, to carcinogens, for example?

  4. Thank you Nick and Peter for such an amazing AMA on causes of heart disease. The information you provided in this podcast is in stark contrast to the information I’d gotten from my previous cardiologists, who would talk about “Bad Cholesterol” as if it were the boogie man. Their advice was comically simplistic: cut stress, red meat consumption and take statins. The oversimplification and unwillingness to get into the nuance [i.e. Apo B, LP (a), and the drivers like uric acid, hyperinsulanemia, elevated glucose or homocysteine levels] is just a slap in the face. It turns out that exercise is much more important than anything, and dietary cholesterol is not really the issue as much as whether I’m eating lots of sugar (or processed foods). It also turns out that continuing to raise statin dosage is contraindicative to someone with high LP (a), yet most cardiologists rarely test for this. My point is that you’ve done more in one podcast than many mainstream cardiologists do on a daily basis. I can’t wait to hear the AMA on LP (a) and I hope that you continue to explore the myriad reasons that lead to heart disease, and the best paths forward to help avoid death from a cardiac event (I think I’ve heard all the previous podcasts on this subject). Yes, I know, no doctor/patient relationship has been established, and none was assumed, but all the same, I prefer to be better educated when I talk to my doctors and your podcast is an amazing course. And PS: I’ve found a GREAT cardiologist now. She’s a lipidology specialist, and it makes all the difference in the world because she is insanely thorough and talks to me like an adult. Thanks again.

  5. is ASCVD reversible? i had a triple bypass last year but understand from my research into possible treatments, that there were drugs under testing that could potentially dissolve the plaque.

  6. I too am very interested in comments in how to reverse atherosclerosis. Have read several studies that showed dietary changes made a significant difference in a certain percentage of people, but others were not affected much or at all. Would love to see a podcast on “how to” reverse. Given its prevalence, I think there would be a lot of interest. Thanks !

    • To be clear, I’m looking to be “aggressive” Peter puts it: reducing LDL from 150 to <100 & ApoB from 100 to <60. (56yo ♂, athletic, plant based).

  7. Thanks for this session. The video made it much easier to follow. Please prioritise the Lp(a) deepdive. I would like to understand it better. If someone could point me to any materials I could start reading/listening I would appreciate. My result is 5x the upper bound ( 1400 mg/l) and I would like to understand if I am in that 10% mentioned during this AMA. Keep up the good work!

  8. This was fantastic! Could you talk more on the target/ideal Apo-B values? You posted on Twitter that Apo-B should be below 30mg/dl. But my lab’s normal ranges are between 104-202 mg/dl… so I woould need to be at 30% of the minimum?
    also I read in other sources that the Apo-B targets seem to be different according to individual risk. It would be great if you could include more details on that in a follow up session.

  9. This video should just be released for free as a public service. I am an otherwise healthy 46 year-old who was just diagnosed with a CAC of 106, which was a bit of a shock. Though not exactly encouraging this video gave me a great understanding of the process that has led up to where I am at now. Like others have said, I would love a few deeper dives into the role of diet in slowing CAD. I already eat healthy, but I’d love to have more info on where the current nutritional science is at in this area. I’s also love a deep dive into statins since you seem fairly positive about them but in general, people just seem to say they are worthless, cause cancer, and leave you crippled with muscle pain. Thanks for all the great content!

  10. Great one as always

    I try to count it figure 27 – lipoproteins is 1.42 g/70 kg.

    Assuming that the volume of blood for a human being is 5 L (50 dL), then with the value of 1.42 g (1420 mg) the result for given parameters will be 28.4 mg/dl

    Is this total cholesterol? Am I making a mistake somewhere in my reasoning, counting?

  11. The concept of Lipoproteins entering the subendothelial space from the circulation to form atherosclerotic plaques requires a mechanism to transport the particles across the endothelial glycocalyx and the endothelial cell, or through the tight junctions between the endothelial cells. As far as I know there isn’t one.
    Fatty streaks form in the outer vessel wall from an early age, and not the subendothelial space (see Subotin: https://doi.org/10.1016/j.drudis.2016.05.017), and can’t be implicated in subendothelial plaque.
    The thrombogenic theory of atherosclerosis makes much more sense mechanistically as it ties all the factors that damage the glycocalyx/ endothelium (eg diabetes, smoking, hypertension etec) into a single causative process. Thrombus forms on areas of damaged glycocalyx and endothelium. New endothelium, derived from endothelial progenitor cells in the circulation (derived from the bone marrow) covers the thrombus. The cholesterol found in atherosclerotic plaques is derived from the degenerated red cell membranes in the endothelial thrombus, not from cholesterol carried by circulating lipoproteins. All explained really well in Malcolm Kendrick’s book, “The clot thickens”. Highly recommended to those interested in this topic. In the spirit of “..a firm conviction, held loosely” it would be great to see a podcast with Dr Kendrick

  12. Statins certainly lower LDL, but have minimal effect on survival (days, over a 5 year follow-up), and the side effects of statins are under-reported. See the following two references. The marginal beneficial effects of statins may be related to a beneficial effect on endothelial nitric oxide production.

    The effect of statins on average survival in randomised trials, an analysis of endpoint postponement
    Kristense, Christensen, Hallas; BMJ Open 2015:5e007118

    How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease
    Diamond, Ravnskov; Expert Rev. Chin Pharmacy. Early online, 1-10 (2015)

    In fact, is seems that higher LDL-cholesterol in the elderly is associated with lower all cause mortality. Possibly due to LDL’s role in the innate immune system. See below
    Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review
    Ravnskov et al; BMJ Open 2016;6:e010401. doi:10.1136/bmjopen-2015-010401

    What about lowering cholesterol in Familial Hypercholesterolaemia? Seems that if there is no linked hypercoagulabilty defect, the high LDL does not result in early mortality. See below:
    Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolaemia
    Ravnskov, de Lorgeril, Kendrick, Diamond
    Medical Hypotheses 121 (2018) 60-63

    High apoB count/ density includes LDL, HDL, and VLDL (aka Triglyceride). If you accept that lowering LDL cholesterol doesn’t reduce mortality, then lowering apoB won’t either if the raised apoB is a result of raised VLDL. The raised VLDL is a proxy for metabolic dysfunction secondary to excessive dietary carbohydrate intake. There are no drugs to lower Triglycerides, and in any event treatment should address input not just consequences. Raised TG is a dietary problem, and the treatment should be dietary, in the same way that “type 2 diabetes is a dietary disease requiring a dietary treatment” (Jason Fung’s words).

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