Atherosclerosis - Part II - Preventing, Treating, Reversing

Last week, we covered a lot of ground and got very technical.  

The etiology of atherosclerosis, the disease process underlying heart disease and stroke - the #1 cause of death and disability in Canada.

There were a number of takeaways that are worth reiterating:

• Atherosclerosis is a process that takes place over decades - and can be thought of as systemic, potentially affecting all arteries, starting in childhood.
• Thinking of heart disease as a “clogged pipe” problem is misguided as most atherosclerotic lesions that cause harm - heart attacks and death - are in arteries with minimal or moderate narrowing.
• Focusing only on arteries that are narrowed - through surgery and stents - can miss the point that atherosclerosis is a systemic process that needs to be dealt with systemically.​

• ​Atherosclerosis involves a reinforcing cycle of:
  
  • Endothelial dysfunction leading to the
    
  • Oxidation and retention of lipoproteins in the subendothelial space leading to
    
  • Inflammation resulting in further
    
  • Endothelial dysfunction​

• This deeper understanding of the disease helps us understand why most cardiac events happen in people with normal LDL cholesterol.  LDL particles (LDL-p) are necessary but not sufficient to cause disease.
• Higher LDL-p levels correlate with higher risk - because more LDL-p can get into the subendothelial space (ie. under the arterial lining),  where they can get stuck, oxidized and trigger the inflammatory process that underlies atherosclerosis.
• In a person with normal endothelial function, LDL-p go into, and out of the endothelial space all the time, without resulting atherosclerosis.  Some degree of endothelial dysfunction is therefore necessary for the trapping and oxidation of LDL-p and the resulting inflammatory cascade.
• Finally, it is the inflammatory response that causes all the damage.  Increased levels of systemic, chronic inflammation, amplify this effect.  Similarly, low levels of circulating inflammatory molecules and cells, decrease the proliferation of atherosclerotic lesions.

This week we will get very practical and provide a framework for understanding risk and treating, preventing or reversing atherosclerosis.

The first objective is to understand your risk.  Since atherosclerosis is a process involving:

• Endothelial dysfunction
• Oxidized LDL
• Inflammation

A perfect risk model would take all three into consideration.

The challenge is that we do not have perfect metrics, with enough evidence in relation to the hard outcomes of cardiac events to be definitive.

Here we can rely on some evidence-based risk calculators, like Framingham, that are based on large datasets.  These generally are a good place to start:

• Framingham - takes into account
  • Age - since the risk of atherosclerosis is a probabilistic time dependant function - age is the single biggest risk factor.  Expose endothelial cells to endothelial dysfunction, LDL-p and inflammation, long enough and the conditions for disease can be met.
  • BP - a metric of endothelial dysfunction - BP above 115/75 results in an almost linear degradation of endothelial function.
  • HDL cholesterol - this is a very indirect measure of oxidized LDL - HDL decreases the risk of LDL-p becoming oxidized and stuck in the subendothelial space.  Higher levels of HDL are thus generally thought of as protective. Unfortunately, what we measure with HDL is the quantity of cholesterol that the HDL lipoprotein is carrying - not the functional capacity of HDL - which is what we really want to measure and understand.
  • Total Cholesterol - this is a metric that, on it’s own, is virtually meaningless.  In the context for Framingham, total cholesterol serves as a very poor proxy for LDL-p.  Really the model underlying the Framingham calculation, does track non-HDL cholesterol which (Total C - HDL-C) and this represents that cholesterol that is carried in the ApoB100 containing particles - HDL, IDL and VLDL.  Generally speaking the cholesterol content of non-HDL-C particles is concordant with LDL particle count - which is what really correlates with risk.
  • Framingham also has modifications for smoking (endothelial function, diabetes - endothelial function, increased LDL-p and inflammation)
• Risks < 5% in Framingham are reassuring;
• Risks >7.5% need closer scrutiny for potential treatment.

In my practice - I start with Framingham, but also try and gather more data to support my understanding of the three ingredients:
Endothelial dysfunction - the biggest factors to consider are

• BP - is it optimal? 115/75
• Does the patient smoke?
• Are they obese?
• Do they exercise?
• What is their nutrition?
• What is their TG/HDL ratio?  This gives me an understanding of insulin resistance - which is associated with endothelial dysfunction as well as inflammation.
• I can also measure asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) - these toxic non proteinogenic amino acids are potent inhibitors of nitric oxide as a result cause endothelial dysfunction.

Oxidized LDL:

• What is their LDL-C?
• What is their Apo-B100 - this essentially tells me their LDL-p, as each LDL has a single ApoB100 protein.
• If there is a family history of premature heart disease, I will get an Lp(a) - more on this at another time…
• If we look at atherosclerosis causality having three legs to the stool - then this is the leg that I have the most definitive information.
• I can go further and measure oxLDL, a measure of circulating oxidized LDL cholesterol in circulation that correlates with LDL-C that has been oxidized in arteries.
• I can also measure myeloperoxidase (MPO) - an enzyme released by immune cells as part of the oxidation and inflammation process at the root of atherosclerosis.  MPO targets HDL - oxidizing the Apo-A1 protein and inhibiting HDL from protecting the LDL-p from oxidation.
• Similarly, I can measure lipoprotein-associated phospholipase A2 (Lp-PLA2) - another inflammatory enzyme involved in the development of atherosclerosis.
• (Some of these tests are only possible when the patient’s budget permits as not all of these tests are insured.)

Inflammation:

• What is the patient’s high sensitivity C-reactive protein (hsCRP)?  This is our best measure of chronic low grade inflammation. Unfortunately it does not tell us what is happening in the arteries.
• Fibrinogen and ferritin are also key markers of systemic inflammation that can help us further understand risk.

Testing allows us to understand risk at a personal level, from here, my objective is to align my patient’s behavior with optimizing and reducing the risk across the three dimensions of atherosclerosis causality.
The first place to start is with weight management - bringing the patient to normal levels of BMI, body fat and most importantly visceral fat will improve blood pressure, decrease insulin resistance, improve endothelial function, improve lipoproteins by increasing HDL-C and decreasing LDL-p, and decrease inflammation.
For weight management - we nutrition comes first.  Whole foods, mostly plant-based. We adjust and refine depending on response on our key biomarkers.
Next we increase exercise.  Our first goal is to get people to 150 minutes of moderate to vigorous exercise.  Nothing magic here - there is ample evidence to support this level of exercise as the minimal effective dose.  We adjust exercise across three components - aerobic, functional movement and resistance training. Again we adjust and refine depending on response of the patient’s biomarkers.
Inadequate sleep and chronic stress have both been shown to affect inflammation, immune response and endothelial function - so we need to have a strategy to get at least 7 hours of high quality sleep and reduce stress.
At Wellness Garage - we create month personalized lifestyle behavior action plans that we call “Precision Health Tune-ups”.  We reassess every 4 months, until we have optimized behavior and reduced risk.
If we see a patient’s measures of endothelial function, LDL and inflammation come to optimal levels with lifestyle measures we feel very comfortable that we have reduced their risk.
When risk remains, we are comfortable with using both specific supplements and drug therapies to normalize BP, address LDL-p and other key biomarkers - there is, we believe, enough evidence to support this approach.  In every case - this is a personal risk reduction conversation. Drug treatments are used to lower the probability of clinical atherosclerosis and carry a risk of adverse drug reactions. How much risk is too much on either side (disease vs drug reaction) of this decision is very individual - and can only be decided by a very well informed patient.

In summary,  atherosclerosis is a systemic, almost ubiquitous disease process with three major causal dimensions.  

• Endothelial function
• Oxidized LDL
• Inflammation

Understanding your risk of atherosclerosis depends on understanding these dimensions.
The place to start is with a medical assessment that measures at a minimum the key biomarkers for each dimension.  Know your numbers.

With this baseline, you will have an understanding of how your genes and current behaviors are working for you.

The next step is to optimize your behaviors - nutrition, exercise, sleep, stress tolerance all play a role. After several months of modified behaviors, checking to see your body’s response allows you to optimize your behaviors and reduce risk.

If, despite optimal behavior change, your risk does not seem to come down - supplements and medications may help.  This is something that you need to work through with your physician.
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At Wellness Garage - we take a precision health approach to atherosclerosis prevention, treatment and reversal, by working with our members throughout this process - Assess, Change Behaviors, Re-assess and Adjust.  
If you would like our help to take control of your health please books free consultation.