Introduction to Atherosclerosis

by Richard Mitchell, MD, PhD

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    00:00 Welcome. In the next set of slides and sessions, we're going to talk about a very important cause of pathology, that is atherosclerosis.

    00:11 And the most common complication related to atherosclerosis, which is infarction, the death of tissues that are being now blocked because of a vascular occlusion.

    00:22 Atherosclerosis is going to be a major cause of morbidity and mortality around the world.

    00:29 Much more than 50% of people will ultimately die as a result of coronary artery disease or stroke related to atherosclerosis.

    00:40 So with that preface, let's get started.

    00:43 Here's the roadmap, and we're going to have a number of blocks after this as we work our way through the various aspects of atherosclerosis.

    00:53 We'll talk about risk factors, we'll talk about how a plaque actually gets formed.

    00:59 We will talk about how the plaque looks and the complications related to that morphology.

    01:04 It's not just simply a plaque, but in fact how it is assembled that will have implications for outcomes.

    01:13 We'll talk about how we can diagnose and potentially treat atherosclerotic disease.

    01:19 And then finally we'll talk about complications.

    01:21 That's our roadmap. Lots of fun along the way.

    01:25 First, an overview of atherosclerosis.

    01:29 So, what is atherosclerosis? Let's start with your typical arterial wall, and we're starting mostly with arteries, because atherosclerosis is typically predominantly a disease of arteries, not of veins, although you can get venous atherosclerosis under some circumstances.

    01:50 You've learned in your basic anatomy and your basic physiology how vessels are assembled.

    01:57 There is an outer layer of loose connective tissue and fat that's called the adventitia.

    02:03 The next layer in is the media, and it's largely composed of smooth muscle cells with a little bit of extracellular matrix.

    02:11 And that smooth muscle media is going to be an important source of cone and integrity to the vessel wall.

    02:17 So when I talk about tone, if that smooth muscle relaxes, the wall dilates, and if that smooth muscle contracts, the wall constricts, and we can control blood pressure in that way, we can control flow into the tissues in that way.

    02:31 The next layer in from the smooth muscle media is going to be the intima, and the intima usually has very little connective tissue, and it's basically an endothelium sitting on a basement membrane and just a little bit of extracellular matrix.

    02:49 That's the normal situation, and that's the normal vessel.

    02:53 Now, let's do atherosclerosis.

    02:56 And in atherosclerosis, we have an artery that has been narrowed by an atherosclerotic plaque.

    03:02 Well, that still doesn't tell us what that's about, but atherosclerosis, the name is actually quite good.

    03:09 It comes from the Greek.

    03:11 The "athero" actually means gruel like.

    03:14 Gruel as in porridge or oatmeal like.

    03:17 And the central core, the atheromatous core in an atherosclerotic plaque is fat and necrotic debris, old red cells, a whole variety of things. It's kind of a mush, and it looks a little bit like gruel.

    03:31 Hence that was the name that was given to it.

    03:34 The sclerosis part is scarring.

    03:37 So atherosclerosis is scarring overlying gruel, and that is the typical atherosclerotic plaque.

    03:48 Now, sometimes we have more fibrous scarring in the fibrous cap composed of extracellular matrix and smooth muscle cells, and sometimes we have less.

    03:58 And sometimes we have a big old atheromatous core with lots of necrotic debris and fat and cholesterol, and sometimes not so much.

    04:06 So the relative components of the fibrous cap versus the atheromatous core will also determine kind of the outcomes associated with atherosclerotic plaque.

    04:16 Now, there are multiple players that are in here.

    04:19 This very broad kind of overview captures those.

    04:24 So, dysfunctional endothelium on the surface is going to be a major driver for the production of atherosclerosis.

    04:32 And we'll talk about that when we talk about risk factors and we talk about how a plaque is formed.

    04:37 So, endothelium over an atherosclerotic plaque, not normal.

    04:41 It's an unhappy endothelium.

    04:43 It's prothrombotic, it's proinflammatory, it's dysfunctional.

    04:47 We have recruited smooth muscle cells, and the smooth muscle cells have come largely from the media.

    04:54 They can also come from circulating precursors.

    04:57 And those smooth muscle cells that are part of the atherosclerotic plaque and scar are also important players in the process.

    05:05 And the last important player in this are macrophages, elements of innate immunity.

    05:12 So, for many, many years, we thought of atherosclerosis as a fat related disease, a cholesterol driven process.

    05:21 In fact, now we know that it's really largely driven by innate immunity, by macrophage activation and recruitment.

    05:30 Okay, so we've got kind of the general feeling for what an atherosclerotic gruel and scar plaque is all about.

    05:39 So why is atherosclerosis so bad? Well, in small vessels, this is showing a coronary angiogram, we have small vessel occlusion.

    05:49 Remember, that plaque is growing, growing, and it is blocking blood flow.

    05:53 So in a coronary, in a small vessel, maybe 50%, 60% of the vessel lumen is blocked by the growth of this plaque.

    06:03 And now we're not getting adequate flow into the distal vasculature.

    06:06 So the two arrows are indicating areas of narrowing in the coronary.

    06:13 In larger vessels, atherosclerosis can lead to abnormal endothelial cell function leading to thrombosis, but can also lead to the production of plaques, which are friable. They break up.

    06:29 So what we're looking at here is an aorta.

    06:33 Off to the left would be the head, down to the right would be the legs.

    06:38 And this lumen of the aorta is filled up with grummus, friable, thrombus, platelets, and fibrin, and inflammatory debris and necrotic debris.

    06:51 And all of this is because of atherosclerosis that had led to very easily fragmented plaque in the lumen of this large vessel.

    07:04 Another complication associated with larger vessels as well is that the recruitment of the macrophages as part of the atherosclerotic plaque growth is also going to lead to the production of proteases that are going to degrade the extracellular matrix of the media.

    07:23 So we're looking at angiogram reconstruction.

    07:27 Again, at the top would be the head, and at the bottom are going to be the legs.

    07:31 And there is this kind of bulbous dilation just above the iliac bifurcation.

    07:36 This is an abdominal aortic aneurysm occurring as a result of the recruitment of macrophages into the area of a growing atherosclerotic plaque.

    07:46 And those macrophages, elaborating elastases that break down the matrix and cause the wall to thin and therefore dilate.

    07:54 As we talked about in our thrombosis and hemostasis sessions, that abnormal bulbous dilation also causes aberrant flow.

    08:05 And as part of Virchow's Triad, we'll get a thrombus in that.

    08:09 So, here's why atherosclerosis is so bad.

    08:12 Small vessels, we block them.

    08:14 Large vessels, we get friable atherosclerotic plaque and vessel wall destruction and aneurysm.

    08:21 With that, we've had our overview, and I look forward to seeing you again when we talk about all the details related to the development of atherosclerosis.

    About the Lecture

    The lecture Introduction to Atherosclerosis by Richard Mitchell, MD, PhD is from the course Atherosclerosis.

    Included Quiz Questions

    1. ...endothelial cells.
    2. ...smooth muscle.
    3. ...fibrous connective tissue.
    4. ...calcified matrix.
    5. ...adipose tissue.
    1. Fibrous cap
    2. Normal endothelial cells
    3. Calcium phosphate crystals
    4. Epitheloid cells
    5. Fibrin clot
    1. Innate immunity
    2. Cholesterol
    3. Triglycerides
    4. Fibrin activators
    5. Fatty acids
    1. Thromboembolism
    2. Complete occlusion
    3. The collapse of the vessel
    4. Accumulation of fibrin
    5. Loss of elasticity of the vessel wall

    Author of lecture Introduction to Atherosclerosis

     Richard Mitchell, MD, PhD

    Richard Mitchell, MD, PhD

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