A very compelling read from a New York Times op/ed, making the point that we have made previously on our blog:  today's chronic diseases have their origin in the evolutionary mismatch between our current environment and behaviors and what our bodies evolved to be.

In this article, we learn how evolution set out to protect us from starvation, infections and injuries leaving us vulnerable to atherosclerosis - the disease process underlying heart disease.

​https://www.nytimes.com/2019/08/06/opinion/evolution-heart-disease.html?action=click&module=Opinion&pgtype=Homepage

At Wellness Garage - we take a precision health approach to atherosclerosis prevention, treatment and reversal, by working with our members through a structured change process: Assess, Change Behaviors, Re-assess and Adjust. 
 
Learn more about what it looks like to do a Precision Health Tune Up and take control of your health.

​For many physicians of my era (started practice in 1991) the story of hormone replacement therapy reflects the bandwagon nature of medicine.  In the mid-nineties as I opened my practice, we actively recommended that almost all menopausal women should take hormone replacement (HRT) or estrogen replacement therapy (if they had a hysterectomy).  As physicians we measured ourselves by our HRT percentage - feeling that if we were doing our jobs this should approach 100%.

​The reasons for our enthusiasm for estrogen replacement seemed clear.

In menopause, estrogen levels plummet to 1% of pre-menopausal levels.

Using estrogen to replace this loss, appeared to have significant benefits:

• Decreased menopausal symptoms (night sweats, hot flushes, joint/muscle pain, memory loss, etc.)
• Reduction in osteoporotic bone fractures - especially hip fractures
• Decreased heart disease
• Decreased dementia
• Decreased colon CA

...and while these benefits were offset by a small but real increased risk in venous blood clots - the benefits seemed overwhelming.

Then on July 17, 2002 the world of estrogen replacement came crashing down.  

The Woman's Health Initiative - the largest and most expensive trial ($1B)  ever done at that time was stopped because HRT increased the risk of breast cancer by 26%.

Overnight, physicians jumped off the bandwagon and rates of HRT fell dramatically.

Unfortunately most of us did not read the details of the study (once it was eventually released).

In the new book, "Estrogen Matters" by Dr. Avrum Bluming and Carol Tavris, the data from WHI is examined in the broader context.

Starting with the conclusion that HRT increases breast cancer by 26% - the first and most stunningly underappreciated fact was that this increase did not meet statistical significance, meaning that it did not clear the commonly accepted threshold that there has to be less than a 5% chance that this result could be random.

Next, even if you accepted that the result was real and not random, then it is important to understand the result.  There are two ways that the study could have shown an increased rate of breast CA, either the rate of breast CA actually increased in the treatment group OR the rate of breast CA went down in the control group.  Of course if the latter explanation is correct then the study is flawed.

Closer analysis of the WHI data has clearly shown that the reported increase rate of breast CA did not come from higher breast cancer rates than expected in the treatment group but resulted from the fact that the control group had a lower incidence of breast cancer than expected.  

Even more confusing was the fact that this reduction of breast cancer in the control group occurred because there was a significant number of woman who had been on HRT previously and in this group there was less breast cancer.

So the WHI concluded that HRT increases breast CA because previous HRT experience decreased the rate of breast CA in the control group - incredible!

The third thing to consider when reviewing the WHI findings is the absolute rate of the increase in breast cancer.

So even if you accept that the effect is real and not the result of randomness or a decreased rate in the control group the absolute increase in was 8 more breast cancer diagnoses per 10,000 patient years.

Taken together, this review significantly decreases, if not removes altogether, the concern that I have about estrogen causing an increase in breast cancer.

Bluming and Tavris then revisit the benefits and risks of HRT - providing links to the best available current evidence and in doing so provide perhaps the best single source of HRT information for anyone considering HRT.

Summary of the Risks and Benefits of Estrogen Replacement:

Benefits

• Effective treatment of menopausal symptoms - night sweats, hot flushes, joint/muscle pain, memory loss, etc.
  • especially vasomotor symptoms
• Reduction in fractures:  33-50% reduction of fractures (including hip fractures)
  • As we posted last week - nothing really works as well as estrogen replacement
  • It must be noted that a woman will need to take HRT for at least 10 years - and probably forever
  • ...and that fracture risk returns to normal within 6 years of stopping HRT.
  • Hip fractures are incredibly significant cause of suffering - approximately 21% of women who fracture their hip will die within a year of the hip fracture
    • In the US that number is approximately 40,000, which is similar to the number of women who die in this country of breast cancer every year
• Decrease in mortality from cardiovascular disease when started close to menopause - addition of 3-4 years of healthspan
  • This study by Nananda Col showed that if every woman in the United States do hormone replacement therapy (HRT) it would increase the median survival of women by 3.3 years in this country
  • Again it must be noted that there is a possible increased risk for women who begin HRT in their 60's with established atherosclerosis (at least in the first year) so HRT should be started at menopause.
  • When viewed from a numbers perspective the number of woman dying from heart disease is significantly greater than from breast cancer - so even if you accept that increased risk from the WHI study - the cardiovascular benefits will far outweigh that small absolute risk.
• Decreased risk of dementia from 24% to 65% if started at the onset of menopause - data is mixed with starting after menopause and may result in worsening of dementia
  • "If neurons are healthy at the time of estrogen exposure, their response to estrogren is beneficial for both neurological function and survival.  But if those neurons are not healthy when a woman starts estrogen or begins taking HRT ten or more years after menopause, estrogen may, over time make her condition worse" - Roberta Diaz Brinton.
  • Currently there is no treatment for Alzheimer’s
  • The one potential preventive medication is estrogen which can reduce the incidence of Alzheimer’s disease by between 20 and 50% depending upon the study you look at
  • Here’s one study
• Decreased colon CA - (oral HRT only)
  • Colon cancer mortality was reduced in the WHI and other studies
  • Interestingly while not as lethal as pancreatic or lung cancer, colon cancer is more lethal than breast cancer
• Decreased Ovarian CA
  • oral contraceptives decrease the rate of ovarian CA by up to 80% and the reduced risk persists with HRT

Risks

• Increased rates of breast CA - this is not supported by current evidence
  • The WHI which led to the conclusion that HRT increased breast cancer:
    • did not meet statistical significance
  • What about in women with pre-existing breast CA
    • neither increases (pregnancy) or decreases (oophorectomy) in physiological estrogen show changes in breast CA recurrence. 
    • Studies of HRT show no increased risk and may actually reduce the recurrence rate and prolong survival.
• Stroke
  • WHI showed higher rates of strokes, however when re-analyzed this looks to be an effect of starting HRT long after menopause in woman who were not healthy.
  • Further, the estrogen only arm was stopped because of a very small increased rate of 12 per 10,000 woman years - and these were using a very broad definition of stroke including TIA's
• Venous blood clots (pulmonary embolism and deep venous thrombosis
  
  • This risk is real but overall this is small and comparable to the accepted risk of oral contraceptives
• Gallstones
  • again - small but real risk.

Bottom Line:
For every woman going through menopause, HRT should be given personalized and individualized consideration.

I highly recommend this book to anyone who wants to review the data for themselves and make a fully informed decision.

As for my physician colleagues, I have already been recommending "Estrogen Matters"

For a great listen - check out Peter Attia's podcast. with Bluming and Tavris

This is the first of a two part series on atherosclerosis and will explain:

• What atherosclerosis actually is (and what it is not)
• Why it’s important, and
• What causes it

We will lay down a basic framework that will help you form a mental model so that next week we can cover what you need to know in order to prevent or reverse atherosclerosis.

What is atherosclerosis?
Atherosclerosis - commonly known as “ hardening of the arteries” refers to a disease process that causes damage to the arteries resulting in narrowing, blockage, occlusion and even rupture.
Atherosclerosis is the underlying cause of most cardiovascular disease (CVD) - including heart disease and stroke.

• Every 7 minutes a Canadian dies from heart disease or stroke
• Heart disease and stroke is the number one cause of death in Canada - accounting for 46% of all deaths; and also represent the single biggest cause of disability adjusted life years lost (DALY’s) - a measure of “lost healthy years”.
• 80% of premature heart disease and stroke can be prevented through healthy lifestyle choices
• Only 1 in 10 Canadians are in ideal heart health
• Over 90% of Canadians have at least one risk factor  

Atherosclerosis is both very common and very preventable.
Our view is that the key to prevention comes from really understanding how atherosclerosis develops.  This involves getting past some common misconceptions that have resulted from an oversimplification of the disease through the two dominant conceptual models used to explain atherosclerosis:

1. Clogged pipes (arteries) are the problem; and
2. Fat Clogs Arteries

The issue with each of these models is that they overlook some key facts and observations:

• Most cardiac events occur where there is minimal or moderate narrowing
• The cholesterol (fat) found in atherosclerotic lesions is not from the diet but produced by the liver.
• Most cardiac events occur in people with normal cholesterol levels

Before we go further here - let's back up and better understand the disease process:

• Low Density Lipoproteins (LDL) particles (the dominant transport vehicle for liver-produced cholesterol) enter the lining of the arteries - the subendothelial space.  
• Here LDL particles attach to proteoglycans molecules expressed in the lining of the artery.
• Once attached, the LDL particles, specifically, the phospholipds within, are prone to oxidation by reactive oxygen species.

At this stage - 3 things have happened:

1. LDL particles get in the lining of the arteries,
2. They get stuck and
3. They get oxidized.  

Oxidized LDL is toxic to the endothelial cells lining the arteries and this is the key step in the development of atherosclerosis.

• Endothelial cells, injured by oxidized LDL, now express molecules on their surface to mark their injury and trigger an immune response
• These molecules, vascular cell adhesion molecules, VCAM’s, attract monocytes, a type of white blood cell
• The now dysfunctional endothelial cells, also send out molecular messenger signals such as IL-6 and TNF-alpha which trigger liver cells to increase production of the inflammatory molecule C-reactive protein.
• The monocytes that attach to the endothelium, enter the subendothelial space, the intima and differentiate in macrophages - a specialized immune cell designed to inges toxic substances
• In this case the macrophages essentially eat up the oxidized LDL particles, and as these cells become full, stuffed with cholesterol, they are aptly named “foam cells”
• Multiple foam cells coalesce together to form a “fatty streak” in the artery wall - this is the hallmark of early atherosclerosis

Fatty streaks are almost ubiquitous and have even been found in utero!  This is the very earliest stage of atherosclerosis and almost all of us have disease at this stage.

• High Density Lipoprotein (HDL) - another lipid transport molecule - can enter the subendothelial space and take cholesterol from the foam cells, and subsequently distribute the cholesterol to other tissues in the body.
• Foam cells that do not get relieved of the cholesterol burden - produce a variety of molecules including angiotensin II, metalloproteinases, collagenases, elastases, and other proteins - all of which can further undermine the integrity and function of the endothelium
• At this point, the damage really begins.  The endothelial damage signals smooth muscle cells to the damaged area where they secrete a matrix to heal the arterial wall.  This matrix forms a fibrous cap that now can intrude into the lumen of the artery.

The atherosclerotic plaque, so formed, can become very large and can impede arterial blood flow to the extent in the heart that the muscle the artery serves can become starved of oxygen.  This narrowing and decreased blood flow, results in the the exertional chest discomfort known as angina.

• The metalloproteinases and collagenases produced by foam cells can also weaken the fibrous cap resulting in rupture of the plaque
• Rupture triggers a coagulation response - initially platelets accumulate, then fibrin forms, and clot can form.
• This process can occur rapidly and result in complete occlusion of the artery - even when the initial lesion did not produce significant narrowing - this occlusion occurring in a coronary artery is known as a myocardial infarction (MI) or more commonly referred to as a heart attack.

To summarize, atherosclerosis is caused by an inflammatory response to oxidized lipoproteins within the artery wall.  There are three main ingredients that trigger a lesion:

1. ApoB containing lipoprotein (mostly LDL) particles accumulating under the endothelial lining of arteries
2. Oxidation of the sub-endothelial LDL-particles, causes inflammation resulting in
3. Dysfunctional endothelial cells that trigger further immune response.

The developing process can be mitigated in its earliest phases by HDL-particles that take away the sub-endothelial cholesterol - even after it is taken up by the foam cells.

Evidence shows that the risk of atherosclerosis increases with increasing concentrations of LDL-particles in linear fashion - note this LDL-particle numbers, not LDL-cholesterol concentration. (while LDL-C and LDL-p are generally concordant, ie. they increase and decrease together, this is not always true - especially when insulin resistance is present).  LDL-cholesterol is what is commonly reported on the standard lipid panel.  A better test to understand your risk is the ApoB100 protein- which gives you the number of LDL-particles as each LDL-particle has one ApoB100

It must be stressed that LDL-P easily enter and exit the sub-endothelial space all the time - it is the oxidation of LDL-P that is key step in initiating atherosclerosis.  Only oxidized LDP-P is taken up by macrophages and foam cells.

What triggers the oxidation of the LDP-P?

Damaged, inflamed or dysfunctional endothelial cells create the conditions for LDL-P oxidation.
Common causes of endothelial dysfunction are:

• tobacco use,
• obesity,
• age,
• hypertension,
• hyperlipidemia,
• physical inactivity, and
• poor dietary habits or anything that results in low-grade chronic inflammation

Another key point is that the process that leads to an atherosclerotic lesion is systemic - so just identifying and treating lesions that cause blockage (ie. plumbing model) does not sufficiently decrease risk as there may be other non-obstructive lesions that can rupture and cause acute occlusion.

So in essence, with atherosclerosis we have a reinforcing cycle of:

• Endothelial dysfunction leading to the
• Oxidation and retention of lipoproteins in the subendothelial space leading to
• Inflammation that results in further
• Endothelial dysfunction

The take-home points to remember are:

• atherosclerosis is the number cause of death in Canada
• 80% of premature deaths from atherosclerosis are preventable
• the disease process is systemic and the conditions that lead to atherosclerosis affect all arteries
• because it is systemic - a systemic approach to prevention, treatment, and reversal of atherosclerosis is required
• atherosclerosis takes a long time to become symptomatic and most heart attacks occur in people who have had no prior symptoms
• atherosclerosis is caused by a combination of endothelial dysfunction that allows for the oxidation of LDL cholesterol in the lining of the artery, resulting in an inflammatory response that triggers further endothelial dysfunction.
• understanding an individual's
  • lipoprotein status
  • inflammation levels
  • endothelial function
• are essential in order to develop a coherent reduction strategy.

Next week - we will apply this framework to explain the Wellness Garage prevention and risk reduction strategy for atherosclerosis.

At Wellness Garage - we can help you understand and take control of your health.  Our comprehensive medical, fitness, nutritional and behavioral assessments give you baseline from which to measure your progress.  Our coaching helps you improve your behaviors, one habit at a time.

For more information - please book a free consultation.