Atherosclerosis

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.