Atherosclerosis: Risk Factors

00:02 All right, we've had an overview of atherosclerosis, we understand that atherosclerosis is a gruel like atheromatous core with an overlying sclerotic, fibrous cap.

00:15 How do we get there? Let's talk about risk factors.

00:19 And maybe you'll rethink your lifestyle after this particular session.

00:24 Here's where we are on the roadmap, we will eventually build on these risk factors to talk about pathogenesis and plaque morphology.

00:31 And actually, a lot of that falls out of the risk factors driving the process.

00:38 Beginning in the 1950s, there was a study that came out of Framingham, Massachusetts, which is just about 15 minutes down the road from where I'm currently standing.

00:49 That was the Framingham Heart Study.

00:51 And that was the very first time that we identified the major cardiac risk factors.

00:57 So on the left hand side, we have the major risk factors.

01:00 And those the five main ones identified by the Framingham Heart Study.

01:05 The traditional ones are hypertension, so high blood pressure, hypercholesterolemia, so elevated cholesterol, diabetes, whether it's type one or type two, smoking, and family history.

01:18 Age and gender, also clearly play into this.

01:22 So as you get older, you will have more atherosclerotic burden.

01:27 And if you happen to be of the male persuasion, you will tend to have more atherosclerosis, up until a point where women undergo the menopause, and don't have the protection of estrogens.

01:41 So age and gender are identified as risk factors.

01:46 But the traditional five are the first five on the left hand side.

01:49 Important point here, for those of you paying attention, the first four, you can do something about.

01:55 We have medications, we have lifestyle changes, and you can materially impact your cardiac risk factors.

02:04 Family history, you can't change who you were born to.

02:07 So you're stuck with that one.

02:08 But even then we're beginning to understand some of the genetic changes that are driving the development of atherosclerosis.

02:16 Now, there are a variety of secondary risk factors, these are not quite as strongly associated.

02:23 And then some cases may be even related to those that are described on the left hand side.

02:28 So obesity in the metabolic syndrome, very tightly linked with diabetes, inactivity.

02:34 So if you don't exercise regularly, that affects things like blood pressure, hypercholesterolemia, and diabetes.

02:41 A type A personality, this is very controversial.

02:44 And most of you watching this are of a type A personality, just because you're in medical school.

02:50 I'm not so sure that, that is exactly a major risk factor.

02:54 But something that's always cited.

02:57 Diet, including saturated fatty acids, outside of whether or not you have elevated cholesterol levels, is also driving potentially some of the cardiac risk.

03:08 And whether you are have particular isoforms of lipoprotein a.

03:13 And infectious agents have begin, it's kind of controversial, not clear, these are actually driving atherosclerosis, but are just part and parcel of an atherosclerotic plaque and once it develops, for the reasons.

03:25 I would have you pay attention to the ones on the left hand side, the major ones.

03:30 And I'm going to add one more major factor in just a little bit, so stay tuned.

03:37 Shown here are what happens with cardiovascular risk, as we increase the number of risk factors that you have.

03:46 So the Y axis shows the estimated rate of cardiovascular events that will occur in the next decade.

03:53 And you can see that those numbers in this starts with patients, I believe, at age 50, and says what is the risk of them having a major stroke or coronary artery event in the next decade.

04:08 So we're going to add on a variety of risk factors one by one and look at the relative risk of a bad event happening in the next decade.

04:16 So the first column on the left hand side just shows normal blood pressure, normal cholesterol, normal high density lipoprotein, so the good cholesterol, diabetes, cigarette use, and left ventricular hypertrophy by electrocardiogram.

04:32 If you are good in all of those, normal, you still have about an 8% risk of something adverse happening to you within the next decade.

04:41 Just a fact of life.

04:43 So if we move over to the next column, and I just give you elevated blood pressure, that increases your risk by actually almost twice.

04:52 Everything else is normal within the normal range.

04:55 And then if I add on in the third column over cholesterol, elevated cholesterol, bad cholesterol, low density lipoprotein, I increase the risk a little bit more.

05:05 And in the next column, if I reduce the good cholesterol, the high density lipoprotein, the risk goes up a little bit more.

05:11 If I have diabetes, the risk goes up.

05:14 If I smoked cigarettes, the risk goes up even more.

05:17 And finally, the last column is if I have left ventricular hypertrophy, that's probably driven by long standing hypertension, but that also shows an increased risk.

05:27 Now, even with all those bad things, all of the Framingham Heart Study risk factors identified there.

05:36 I'm still only, I have 40% of patients overall, who don't have an adverse event in that decade.

05:44 But I also have a significant number of people that do have adverse events that are in this category.

05:51 Okay? So, the important point, and this is the final risk factor that didn't come out in the Framingham Heart Study.

05:59 Important to understand that 20% of all cardiovascular events, heart attack and stroke occur in the absence of the known traditional risk factors.

06:10 Hypertension, hypercholesterolemia, diabetes, cigarettes, family history.

06:16 And in fact, 75% of cardiovascular events in healthy women occur with normal cholesterol levels, low density lipoprotein.

06:24 So the fact that we had always thought of atherosclerosis is being driven by fat and cholesterol, not entirely true.

06:32 The final kind of risk factor that we need to be thinking about is inflammation.

06:37 And your inflammatory status.

06:39 And we're not all created equal, some have a high thermostat set for inflammation, some have a relatively low thermostat.

06:46 The more inflammatory your setpoint, the more likely is that you'll have complications related to atherosclerosis.

06:54 So how do we measure that? How do we assess that? There have been a number of markers suggested, it turns out that one of the cheapest and most easily measured is something called C-reactive protein.

07:06 It's shown on the right hand side, it is a pentamer.

07:10 It's called pentraxin.

07:12 It is normally made by the liver and its normal role is to bind up to various microbes, and help them be identified as invading so that we can get the inflammatory response to get rid of them.

07:26 But CRP can be used as a surrogate to reflect the systemic inflammatory status.

07:32 That's all it is. It's just a marker.

07:34 It doesn't cause inflammation.

07:37 But it says where your setpoint is, in terms of your inflammatory, inflammatory mediator production.

07:44 There are several other markers that we could look at.

07:47 Interleukin 6 is one, we could look at adhesion molecules made by endothelial cells as surrogates for inflammation.

07:54 It turns out that the cheapest and one of the easiest is C-reactive protein.

08:01 And it turns out that elevations and C-reactive protein, as a surrogate for inflammation are completely independent risk factors compared to everything else that we've talked about, for heart attack and stroke.

08:14 So it's really important to add that to your list.

08:21 Indeed, we can look at, we can take the entire population of the world and look at their levels of CRP.

08:29 And then we can break that population down into quartiles.

08:33 So the lowest quartile is number one, and then the next level up, we'll have a certain amount of inflammation, the next level of the next amount, and we can break the population down into four separate groups, depending on how much CRP they have, or where their trend or where their setpoint is.

08:50 And it turns out that as you go to higher and higher levels of CRP, your risk of having a myocardial infarct, or a stroke goes up and this is now everybody else has been stratified for cholesterol levels and for hypertension and for diabetes and everything else.

09:07 So this is to make the point that inflammation is an independent risk factor for cardiovascular events.