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Dr. Evans received his DPM from the Temple University College of Podiatric Medicine and has a BS in Pharmacy from the University of Connecticut. He is board-certified by the American Board of Foot and Ankle Surgery (Foot and Ankle) and is Chief of Podiatry at Corewell Health (Beaumont) Medical Center in Dearborn, Michigan.

He is Chair-Emeritus of the APMA Health Policy and Practice Committee and has served as a Medicare Carrier Advisory Committee (CAC) representative for over 20 years. He is active with the American Board of Foot and Ankle Surgery, having served on multiple committees including their Board of Directors for eight years, and is the immediate Past-Chair of their Communications Committee. He is the 2018 recipient of the APMA Award of Excellence and is the Podiatric representative to the PAD Guidelines Writing Committee of the American Heart Assn. and American College of Cardiology.

Dr. Evans is a nationally recognized speaker on a variety of topics including Peripheral Arterial Disease, the Diabetic Foot, Limb Salvage and Preservation, Physician Burnout, Dealing with the Difficult Patient, and Mindfulness in Medicine. Dr. Evans is in private practice in southeast Michigan.

Dr. Evans 02:50 Discusses his journey into PAD

I really started looking at it about more about 25 years ago when I was doing a lot of wound care, and realizing this was a major reason why wounds wouldn't heal. So, looking into it more that way. And at that time, I started working with some interventionists in my area, and so started learning a little bit more about what they did. And based on that, it kind of became just an interest that I would look into. Then a number of years ago, our National Association, the American Podiatric Medical Association asked me to be a representative to the American Heart Association and American College of Cardiology. They were in the process of revising their peripheral arterial disease guidelines and They appointed me to be part of that working group to construct the new guidelines. Okay? And that was for a PMA? Yes. Okay. APMA was asked to be part of this group, gotcha, which was great for us, because we had never been part of this, this large Association before developing guidelines. So, I had the opportunity to start working with about 25 of the top vascular experts in the country on devising these guidelines. So, it took a deep dive, then what I realized was, the majority of the literature that I was researching for these guidelines, was new to me. Okay, and I thought I had a pretty good grasp on vascular disease and such because, you know, that's what we do, right. But I realized that unless you were reading the vascular literature, a lot of the information wasn't there. Really, in the last 25 years, the whole science of how peripheral arterial disease develops has changed. And unless you were steeped in the more modern research, which certainly someone who graduated from medical school in the 80s, I wasn't. And I didn't read the vascular literature itself, I basically looked at what had come into either primary care or into the pediatric literature. There was a lot of stuff going on, that I wasn't aware of. So, once I started realizing that I didn't know about this, I thought, well, there's a good chance that a lot of my colleagues aren't either. Right. So really, over the last, we've been working on these guidelines for three years now. And the research around it, for me started in depth about five or six years ago. I just wanted to take the information that I thought was interesting, and, and unique, and to share it with our colleagues, and ideally, primary care to so we can start looking for a lot of these problems that can develop right.

Dr. Barrett 07:18

Well, it makes a lot of sense. I mean, it's something that you're looking at every day. And if you change the mental perspective a little bit, there's the same, the eyes can't see what the mind doesn't know. And so, we're seeing this all of the time. But once you're able to put it into a perspective that oh, yeah, now I'm seeing this and it makes sense. That I think is going to be great. Now, are these guidelines published yet?

Dr. Evans 07:48

No, they are not. The newest guidelines were published in 2016. Okay, with any luck, the new guidelines will be published in the spring of 2024. Okay, we're getting close. But until, you know, we still have a few months to go before the actual Newman's are there.

Dr. Barrett 08:11

That'll be very interesting. And hopefully, you know, before we wrap up later, for this episode, that maybe we can give the practitioners a few little bullet points to put in their hat, so to speak, and change the way they're evaluating these people next week.

Dr. Evans 08:28

That would be very helpful.

Dr. Barrett 08:31

I think it would be great. So, I know you have some really good PowerPoints that we can dive into this. And so why don't you go ahead and share your screen and let's go into it.

Dr. Evans 08:42

Thank you for your patience.

Dr. Evans 08:54

Thank you. Well, I think where we should start, Stephen is how big a problem is peripheral arterial disease. The typical statistics you're going to hear is that it's in the United States. It involves about eight to 10 million adults. But this was based on data that was developed in around 1985. Based on diabetic information that was available then. And since then, it's just keeps showing up in the literature. So that's pretty much the standard number, you'll see eight to 10 million. More recently, evaluations have been done. And the newer numbers are probably between 21 and up to 26 million of American adults have PAD. So, this is well over 200 million globally, people have this vascular insufficiency issue. So is quite large and odd this, around 10% of them have the more severe level of this, which we would call chronic limb threatening ischemia or critical limb ischemia. This is a just a percentage of the people who have PAD, but they're the ones who are at most risk of having amputation or even dying from it, and who require treatment. The cost to the healthcare system is immense, over $21 billion a year. And you talk about poly vascular disease. peripheral arterial disease is actually a component of atherosclerotic disease, which covers not just the legs, but also the heart and the brain. So, when there are different segments of the arterial flow are involved. We call it poly vascular. And about one out of five patients who have PAD, also have either coronary disease or cerebrovascular disease. And when that happens, the risks get much worse.

Dr. Barrett 11:05

Hey, John, let me interrupt you there because I've heard something. And I don't know if this is true or not. But I heard it stated that if a patient has peripheral arterial disease that is demonstrative, without a doubt they have coronary artery disease, is that not true?

Dr. Evans 11:24

It, it has a kernel of truth to it. Okay. Patients who have coronary artery disease, about 25% of them will have PAD, between 20 to 35%. Well, patients who have PAD, have between 50%, and up to even 90%, who will also have coronary artery disease. Now, the problem with these things, there's an overlapping between the three groups. But when you look at different vascular studies that have been done, you'll find some of the more recent ones, when they're looking at PAD, only 25 to 40% of them had coronary disease also. So, it's kind of hard to say exactly where the lines are drawn. But they're all arteries, and it just matters where they are in the body. And there is some overlap between the different groups. But certainly, coronary disease is the most common. It's also the one that we've developed the most efficient treatments for. So, one of the things we look at is if a patient does have coronary artery disease, if they've had an MI, if they've had a stent or bypass or something like that, you really need to be on the lookout, that there's a good chance they're going to have PAD also.

Dr. Barrett 12:58

Well, let me let me interject another question here for you. Because in my clinical experience, I can't tell you how many folks I've seen that that will relay in their history that they have no coronary vascular disease whatsoever, but they clearly have PAD, when you evaluate them. You told me that unless I misunderstood between what 50 to 90% of the people with PAD will also have coronary artery disease. Is that true?

Dr. Evans 13:25

Yeah. Although some of the studies have shown, you know, only 30% of them may have it, there's a death.

Dr. Barrett 13:33

But that's, but that's enough of a percentage. What I'm trying to do here is, is see if it's prudent or not, if you make a diagnosis of PAD and somebody who has who relates a history of no coronary vascular disease, but you diagnose PID, aren't you under the gun a little bit that now you have to say, Listen, we gotta get you evaluated from a coronary vascular standpoint, because that's the stuff that people drop dead with.

Dr. Evans 14:04

You're right. It's a good point. It's arguable whether it's, that is an absolute, that would be malpractice if you didn't. But here's something to think about. There's there are some new studies that have been done that look at calcium scoring of the heart, right? And looking at vessel calcification in the lower legs and foot. Right. And there has been an association between the two that there is there is a significant risk factor for people who have calcification legs that they very well may have a higher calcium score of a heart. And we're finding that there'll be a few articles will be published within the next year or so to talk about that.

Dr. Barrett 14:54

So, John, let me jump in here. Again. I'm not trying to imply that it's malpractice at all. But it might be optimal practice, that if you make a diagnosis and somebody with peripheral that has peripheral arterial disease, and they say that they don't have coronary vascular disease, it might be prudent to get them worked up, at least by their cardiologist, or, you know, they can go next door to the imaging center, and for 99 bucks get a CT coronary calcium scan. It's super simple.

Dr. Evans 15:27

You're right, you're right. And, and I actually agree with you. I look at it, when I sit down with a patient for the first time or even when I'm just reviewing their charts with them, I go over the medications that they're on. And I look at that, because the majority of patients 60% of patients in my practice are diabetic. Now, that's a high-risk factor, right? There are some things that I look at the medications they're on, and there's a good chance that they're on a diuretic, something that's going to reduce their blood pressure, they're probably on some sort of lipid lowering therapy. And at this point, I'm hitting some of the top risk factors for them. And if I see somebody that just on all of these medications, but they don't necessarily have PAD,  I assume they've got a high chance of having PAD unless it's ruled out. So, my concern would be if you find somebody with PAD, you really need to look a little bit deeper on their medical history, because there's a good chance they're going to have some of the other risk factors that will we'll talk about in just a minute or two. But you're absolutely right, we should think of the different anatomic locations of the arteries as being somewhat related. They're not going to work in a vacuum.

Dr. Barrett 17:04

That’s right, exactly.

Dr. Evans 17:10

We talk about diabetes, a lot, certainly in our profession. And basically, 1/3 of patients with diabetes, who are over 50 will have PAD. And we know that the majority of amputations that people have are done. They also have a diagnosis of diabetes. And when you put them together, someone who has diabetes and peripheral arterial disease, they have a five times greater risk of losing that limb, and a three times greater risk of dying earlier than what they would have. Certainly, with diabetes, the overlap and the risk of having one of these subsequent terrible activities is really high. Now if somebody is diagnosed with PAD, the risk of these other cardiovascular events goes way up. They talk about major cardiovascular events as being a heart attack, stroke or dying of vascular cause. And after someone's diagnosed with PAD, by year for, they have an almost 20% Chance increasing of having one of these cardiovascular events that are life changing. And by year two, about 6% of these patients will have a limb event which means they've either suffered an amputation or they've had to have some sort of intervention. So, when you are diagnosed with PAD and affect your life changes, you need to be on the on the scan for these other terrible things that can happen not just in the legs, but either a heart attack or a stroke.

Dr. Evans 19:04

PAD tends to get worse, the longer you have it. Now, we don't think about people have peripheral arterial disease until they actually present with symptoms. But the atherosclerotic process actually begins when they're teenagers, and gradually worsens. The problem is we don't diagnose it until they become symptomatic. It would be nice to know if you're on that pathway before you get to the point that you're symptomatic. And yet, the majority of patients who have PAD are asymptomatic. But five years later, they're going to likely have claudication 1/5 of them will or 15% will have had some sort of more severe condition or even dying. And the claudication symptoms also did increase after five years, the risk of that goes way up the critical limb ischemia or chronic limb threatening ischemia, people who have that severity of PAD, at one year 30%, will them have had an amputation, and a quarter of them will have died, as well. And there's a category we'll talk about in a few minutes. That's acute limb ischemia. And this is this is an emergent event where all of a sudden, your arteries have been clogged up. And really, at one month, a third of these patients will have had to have undergone an amputation and a quarter of them are dead. Wow. So, it's a progressive disease. That it, it doesn't have to follow the asymptomatic declassification. And gradually worsening stage sometimes we just aren't aware of how bad it is until there is one of these acute limb ischemic events.

Dr. Evans 21:06

But one of the problems we see with PAD is that the majority of patients have no symptoms, or they have symptoms, but they're attributed to, oh, you've got arthritis, or Oh, you're just getting old. Right. But only a small fraction of the patients who have PAD, have the typical symptoms of ischemia. This would be they would come in, they'd have claudication symptoms, which is the muscle pain that's caused by poor arterial flow that's aggravated by activity or exercise, the ones who walk and then after a block, they have to stop because their, their calves, or their thighs or buttocks are hurting. And they rest and then it goes away. Kind of a little bit like you would see in the heart, if we're talking about that, right. But really, only less than 15% of patients have those typical symptoms. So, if you wait until someone has symptomatic, meaning they either have claudication, or they have wounds that won't heal on their legs or feet. If you wait for that, you're going to miss up to 90% of the people who have PAD. So again, this is something it would be nice to know, before it got to that level. And yet, unless you're really, really looking for it, it's likely to be missed.

Dr. Barrett 22:58

I think that, you know, our discussion of PAD here indicates how the slide that you just showed, if you wait for, you know, that they demonstrate intermittent claudication. And that's your definition of PAD. Of course, there's a lot of, you know, a lot that's flying underneath the radar. And even if you're, you know, kind of up on a lot of this stuff, you only think of smoking diabetes primarily. And then if they've had some cardiovascular event, antecedent to them presenting to you. But no, I think your point is that a higher degree of understanding what we're talking about today is going to lead to a higher degree of diagnosis, because so much of this is asymptomatic.

Dr. Evans 23:44

I totally agree. And unfortunately, there's a lot of risk factors that are involved with PAD. And here is one schematic illustration of them, that really, probably the top risk factor that we see is age, because every decade, your risk goes up. So as long as you're living, it's going to gradually get worse along those lines. But the highest risk factors that we see are people who are smokers, or have a history of diabetes. And more recently, we are seeing that renal insufficiency is also high on this list, along with hypertension, or these lipid disorders that we would consider dyslipidemia, which is basically for most people who would be your LDL is high. So, these are things to look at. And one of the things that I think about when I see a patient is I'm looking through their medical history and they may not be aware I have the fact that they have dyslipidemia, or renal insufficiency. But if I look at their medications, it gives me an idea of what doctors are treating them for. And, you know, it's kind of up to us to put the pieces together and saying, you know, you've got a lot of risk factors here. But you know, of all of them. Smoking is probably the one that they have the greatest control over. And I'm sure you've seen this with your patients. Smoking is so difficult to get that addiction under control. Right, and yet it causes so many repercussions down the road.

Dr. Barrett 25:43

Right? No, I totally agree. It's a very powerful addiction, and not so easy to treat. Now, looking at this graph, John, these, these risk factors have to be cumulative as well, right. So, if I'm a male, and I'm diabetic, and I smoke, and I have high blood pressure, and my, my lipids are askew, and probably if I have all of those, my homocysteine is going to be high, you can see where this is all going.

Dr. Evans 26:12

You're right, they are interrelated. And this, you know, this graph really doesn't separate. How it would be when you do get the additive or, and cumulative effect of a number of these pathologies together. So yeah, these are the things to watch for. And something I really wasn't that aware of is that the public awareness of peripheral arterial disease is quite low. A minority of US population, people are aware that PAD is pretty dangerous. Most of the think it's just, you know, it's not that bad. We know that. cancer, heart disease, we understand that these are major life-threatening conditions to understand, but the peripheral arterial disease doesn't make the list. And even when you look at primary care physicians, studies have been done that show that a lot of them are unaware of whether their patients have a PAD diagnosis, a major study was showing less than half of the physicians were aware. And as you can imagine, if your primary care team isn't aware of the diagnosis, then they're not going to be treating appropriately with all the guidelines directed medical therapy that they could to help stem, you know, the development of worsening of this problem.

Dr. Barrett 27:54

So, what you're saying here, John, to be clear, is that even physicians who are aware of PAD only diagnosis 50% of the time?

Dr. Evans 28:03

This study looked at primary care physicians around 2000. Okay, it was a major trial called the partners trial. And when they were looking at this, and they were interviewing and going through talking to patients in their primary care physicians, PAD, was not showing up as one of their diagnoses of patients who had it less than half the time. So, it's one of these things that I can't really hang my hat on it as that's how it is. But it, it pretty much implies the fact that PAD is not within the top 10 things physicians are looking for, unless you're going to a specific physician for that problem. Right. And yet, it probably shouldn't be for the, for the mortality and morbidity of the problem.

Dr. Barrett 29:03

Right. And I'm going to ask you at the end here about early testing, early diagnosis, because this is a pretty big segment of the population to just ignore until they have a symptom.

Dr. Evans 29:17

Oh, you're right, absolutely. But just to talk a little bit about the different types of arterial disease. The arteries come in different sizes. I mean, you've got the aorta, which is huge. And then you've got the capillary bed, we've got these micro vascular vessels where the, the actual oxygen transfer into the tissue occurs. And so most of when we're talking about PAD, we're talking about the macro vascular component. These are the arteries, the ones that we can either visualize or use when we're taking blood pressure and such like this. And the majority of our treatments certainly are interventions, which are many. And they're amazing how we can actually go in and clean out arteries, or do bypasses and such like this, they have to do with the larger arteries, the macrovascular. You know, so we're talking about bait, typical atherosclerotic changes, or if there's somebody throws an envelope, or they have inflammation of these large vessels due to different inflammatory situations, or the blockage of these little blood vessels that we call thrombophlebitis. obliterans is to type thing that we see that we talked about, okay, these are vascular events. But what we don't talk about are the changes that go on in the micro vascular vessels. And actually, this is where PAD develops, from these, this microscopic this cellular level, where the endothelial cells that line the vessels stop working well, or the there's arterial remodeling, that occurs that isn't helpful to the vessels, these type of things. Now, we don't talk about microvascular changes much, because until recently, we really couldn't measure them. And we really didn't know how to treat it. But that is changing, as we'll see down the line, but the macrovascular disease is often overlooked. These are the tiny vessels, you know, the 100 micrometers in diameter. I mean, these are like 10 times smaller than even the small vessels that we talk about, that we look at. But one out of six people who have an amputation have micro vascular disease without the macro vascular component. And this is not necessarily a direct component of atherosclerosis, but it is part of the early development, how it occurs. And we see it when we're talking about these major disease problems of peripheral neuropathy, or retinopathy in the eye and nephropathy in the kidneys, which are major health concerns that physicians deal with and you know, this even you're, you're one of the national experts in neuropathy. You know, how difficult and how, how life changing these conditions can be.

Dr. Barrett 32:34

Yeah, absolutely, John, and this. This slide brings to mind a couple of things that I wanted to drill down on a little bit more because the average person that's evaluating PAD is taking their dorsalis pedis and posterior tibial pulse. It's like Alright, great, got pulses, I feel it, all's good but then you've got skin that is xerotic, and then loss of hair growth, all this other stuff just because you palpate the pulses doesn't mean they don't have this macular microvascular disease.

Dr. Evans 34:49

You're right. You're right and up to recently we really didn't have ways of looking at the macrovascular component. Fortunately, now we actually do, there's a few products on the market that look at the actual tissue, oxygenation of the dermis, which is where we tend to see the, the actual transfer of oxygen from the arterioles, to the venules, and then into the tissue that occur. And they're out there now. It's just that there are people who really aren't using them that much unless they're doing research, or they may have a specialized wound clinic, or they're using them more in dialysis centers now, to basically look for these concerns. But at least we have ways now looking at measuring how this can occur. And because of that, we're going to be able to develop new treatments that work at the root development of atherosclerosis.

Dr. Barrett 35:51

So, John, let me ask you a couple of questions. I'm assuming that you're talking about maybe spy technology, where they're using some type of an indocyan green? Or what about, what about that? What about thermography? TCP O2? What about those diagnostic modalities?

Dr. Evans 36:15

No, they're useful, they are the problem with them has been other than say with thermography. And looking at TCP co2 levels, a lot of them are either difficult to reproduce, or, as far as the partial pressure, it tends to be evaluator bias. So, you couldn't necessarily reproduce their vessels like that. But there's, there's a couple of newer technologies out that involve Near Infrared Spectroscopy, or spatial frequency domain imaging, which are both devices that measure the oxygenation of the dermis, they look at hemoglobin levels that are either oxygenated or deoxygenated. And they can actually determine the levels between the superficial and deep dermis, just with by taking a three second scan noncontact holding a device, you know, about, you know, a foot or so from the extremity, in our case, the foot, and just taking a snapshot. So, there's a couple of devices out. One is called Snapshot by Kent, is the company that does it. Others clarify, that's the company module. And these give incredible information on this level. And more and more research is coming out talking about it, and certainly within our profession, and within the wound care. They spectrum, we're seeing these technologies utilized to help determine, because face it, if somebody's got a great superficial femoral artery, or a great posterior tibial pulse, it really doesn't matter if the oxygen can't get to the tissue. So, this is a way of being able to look at that. Is it so at least we have a couple of clinical aids that are on the market now that we can utilize, and we'll be seeing them become more and more available to clinicians?

Dr. Barrett 38:39

Is there any merit in thermography? Because that's relatively inexpensive.

Dr. Evans 38:44

It is tremendous. But thermography, it's because it's, it's not really specifically related to oxygenation. It's what, at least what my own perception of the great benefit has been in developing areas of at risk for ulceration or to determine if there is a major difference in in perfusion between one side or the other, just depending on warmth. So, it's not just circulation, but you're also basically your expertise in the neurological component of the autonomic system and regulation of vasodilation. Such, what are your thoughts on that?

Dr. Barrett 39:29

Well, my thoughts are that thermography is pretty valuable, because it's objective. It's, you know, it takes out anybody saying, well, it's a placebo effect or, you know, like people are using a visual analogue scale for pain. Well, those are super subjective. But if somebody says, My foot is really cold all of the time, and you have thermography that shows the foots really cold all the time, then, you know, it's pretty hard to argue with that. But it's more of a at least In my mind, right now it's more of an academic interest, because it's not widespread in the average practice. Maybe it will be once they get more parameters, but I see David Armstrong talking a lot about thermography. And, and its value. And I think there's definite value there. It's just how do you position it? How do you quantify it? How do you actually take it? You know, I mean, what's the temperature of your room one day versus another day? I mean, there's a lot of variables that you have to take into consideration, but I still think it has some merit for future investigation and, and implementation because it is very inexpensive. I mean, you can get a pretty darn good thermography camera for, you know for under a $1,000. That is pretty darn accurate. So, I think there's a future in it, but maybe not just yet.

Dr. Evans 40:47

I totally agree. And, in fact, a lot of the remote therapeutic options, one area they've been looking at, has been the utilization of thermography on a home use. Because it is objective. And it's modifiable. And as long as you're, you know, you've got a way of being able to put things into perspective. As you mentioned, with room temperature and with different environments and such. It's very useful. Right.

Dr. Barrett 41:21

Right. Well, I would love to talk a little bit about the at this, because you've touched on the microvascular disease. I think this plays a lot in the peripheral neuropathy that we deal with frequently. And a lot of the peripheral neuropathy, these that are categorized as idiopathic, really are, I think, you know, you just have to keep turning over the rocks, and you find that there is a cause. But regardless, I don't know of any peripheral neuropathic condition that doesn't have some element of neuro inflammation, and some element of microvascular impairment at the, let's call it the vascular neural interface. And so, if you break down peripheral neuropathy is into compressive versus non- compressive. And people will say, Well, what the hell is that? And the answer is, well, there are certain neuropathy is like diabetic peripheral neuropathy, that a lot of the symptoms are caused by the edematous nature of the nerve getting, you know, the nerve gets fat and swollen in a tight tunnel. And you have this focal compression, well, where you have any focal compressions, you're going to have a decrease in circulation. So, you're adding this, this negative synergistic effect of okay, I've got maybe microvasculature, that is impaired and not putting more pressure on the microvasculature. And these are these are lumens, they're, they're, they're tubes. And if the tube is compressed, and it also has disease, then it's kind of intuitive that that's going to be more of a problem than somebody that didn't have a tube that was diseased and maybe only partially compressed. So that's, I think there's a lot of interplay here. And I don't think that if you really, ultimately want to treat patients the best with neuropathic conditions, you have to pay attention to the vascular component. And I think you could say the other way around people with PAD, we should really be looking at the vascular or at the neuropathic, or the neurogenic aspect of what's going on with them, because they may indeed have both things against them.

Dr. Evans 43:33

I totally agree. We're seeing it a lot, even in dementia research, of vascular dementia as being a major component of what we may be calling aspects of Alzheimer's, or even the development of Alzheimer's very well. A number of researchers are saying, look, there's a significant vascular component to that affecting the nerves. Right. So, you're right, I think it's hard to separate the two because they're so intertwined. You can't have one without the other. I totally agree.

Dr. Barrett 44:10

So, let's go into this slide about the combinations of the PAD and the microvascular versus the macrovascular.

Dr. Evans 44:20

Yeah, this just talks about the, the fact that they work together in a synergistic in a way that with microvascular disease, if they have that alone, just this this microvascular ischemia, they have a seven times greater risk of having an amputation. If they have strictly macro vascular disease. They have a 20 times greater risk of having an amputation. But if they combine the two, which is what face it most people have is a combination of both except to 60 times greater risk of, of losing a limb. So, there's a synergistic relationship between these two. And so even though we really only have ways of measuring micro or the macrovascular, the larger vessels at this point, we need to take into consideration that, you know, if we don't do something about the micro cars, we're not going to get as good. As a result, when it comes to treatment, there's a lot of new research is going into genetics, and working on cellular modifications to deal with microvascular. It's pretty much now it's all academic. But it's all pretty exciting. And we'll be seeing more and more of it.

Dr. Evans 45:47

But at the end stage of peripheral arterial disease, the more serious aspect that will develop is something that we call critical limb ischemia, CLI or more modern term would be chronic limb threatening ischemia. CLTI, you'll see these terms used. And they're basically interchangeable, but they're more or less leaning towards CLTI is being what we're talking about here. Okay. And these are patients that will have chronic ischemic rest pain, that have been going on for over two weeks. So, this isn't just ischemia, or claudication symptoms on exertion. This is without exertion, they're just hurting because this tissue doesn't get enough oxygen and the nerves are screaming, or patients have developed ulcers that won't heal in the legs or the feet, or they have developed some degree of gangrene. So, this CLTI, is about somebody that falls into this more serious component. And it's kind of like the end stage of the chronic development of disease and about 2% of PAD patients will have this at any time, but if you have PAD, about 11% of patients will progress to this more severe level. And unfortunately, this is usually when treatment begins. This is what we'll see people being referred for interventions or something along those lines, right. Now, see, LTI is not good to have people who have it after four years, between 1/3 and two thirds of these patients will have had an amputation of a leg. And at one year, 25% of them will have died and over 60% will have passed by five years. So this is this is a very dangerous disease to have. And yet when we look at the mortality rates compared with those of your more common cancers, really, it's more dangerous than all of them except lung cancer, and possibly pancreatic cancer. But, you know, knowledge of this really isn't that well known. But we should be thinking about, you know, what's going to kill people, you know, CLTI is up near the top.

Dr. Barrett 48:25

But nobody's talking about it. Yeah. Right. Yeah, that's, that's a pretty big statement, when you go back and look at that graph, where CLTI is compared to some of the things that are tremendously in the top of mind.

Dr. Evans 48:42

You're right, you'd think we would have a better understanding or at least awareness of the dangers of it. But somehow it hasn't. It's just not that popular.

Dr. Barrett 48:56

No, I look at that. And I it, it makes me think that, you know, in one of your earlier slides, you talked about how I think it was only 21% of the population even knows about PhD. And I was wondering, well, maybe that's because Big Pharma hasn't gotten this million dollar, or multi-million dollar drug to advertise on the news every night that in I mean, we we get commercials for all of these different diseases that were never talked about before. You know, that's just maybe some sarcasm there.

Dr. Evans 49:30

Well, no it's true. And a little later, I'll talk about one medication that's on the market now that's, that has been developed, and has been shown to make a significant reduction in these, these events. But you're right there. There's not a lot out there. But to talk a little bit about how peripheral arterial disease develop because this is something that I don't remember learning along my educational pathway. And yet, I think it's, I think it's really interesting. So, I'm hoping other people feel the same. But it's how, why is pediatric development, it's not just like your arteries get clogged up, and then once they get too clogged up, you know, you start having ulcers, right. But there's there are four large groups that we talked about when how pa develops. And the first is inflammation. Inflammation is very, very common for many of the disease states, we see certainly with diabetes, it's made worse by smoking, and certain other conditions that just have detrimental effects on health. But an inflamed artery is one of the precursors to all this happening in the first place. And the next is the inner lining of the arteries become diseased, and we call this the endothelial. So, once you develop endothelial dysfunction, the process has a chance to to worsen, and to speed up to the next level. And one of the worst things we had to deal with are lipids, these cholesterol type and triglyceride chemicals in the blood that we talked about as being LDL, or HDL. And it's a little bit more involved than just those, but it's extremely common, especially in the standard American diet, that we have high levels of unhealthy lipids within our system. And lipids are one of the processes that drive the development of atherosclerosis. And the fourth aspect is something that really doesn't get a whole lot of screen time. And that's the effect of thrombin. In the body. thrombin is part of the clotting system that we use, it's very, very important. So our blood clots, so we don't have excessive bleeding. And it's extremely important in the regulation of how our body works. But thrombogenesis, this, this formation of thrombin is one of the key factors that leads to the severity of atherosclerosis. And again, it's something that has gotten much more research recently than in the past, where we have talked about these other three items a lot. But it's very, very important for the development, and also for the treatment options that are available to us now. So, first is inflammation. Because basically, atherosclerotic heart disease is an inflammatory condition. Again, we talked about, there's a number of inflammatory components to this, that I won't really get into now. But we know that inflammation is extremely important to a number of the disease states that we tend to see nowadays. We also know that it's extremely popular in modern medicine, as to one of these health degrading concerns that we're trying to take medications that might reduce inflammation in our bodies. We talk about it being bad. But inflammation, ultimately is one of the process that keeps us alive. It helps us fight infection, it helps us to heal wounds and such like this, but it also has the other side where it can drive some of these pathologies to a greater level. So, trying to keep inflammation in a healthy balance is extremely important.

Dr. Barrett 53:58

It all breaks down from acute inflammation to chronic inflammation.

Dr. Evans 54:07

That's an excellent point. You're right.

Dr. Barrett 54:08

You gotta have the acute (inflammation) to get to get healthy and your wounds to heal but you can't have it become chronic because that's the harbinger of disease.

Dr. Evans 54:20

That's very, very well stated. You're right. But within the arteries, the inner lining is called the endothelial there's tends to be three different levels of cells, the lion, the arteries, and the intima is the endothelial this very, very thick, only one or two cells thick, but line the arteries themselves. And it's extremely important because when they're healthy, it your arteries are able to dilate and constrict, and they're able to allow certain types of healthy chemicals to come through it to get into the inside of the artery. and such, and certain development of hydration and fluidity within the blood is important for this. But over time, the endothelial becomes damaged. And this happens from smoking, inflammation will do it. Too much glucose levels will damage it. But what happens is this protective lining that tries to let good things in and keep bad things out becomes damaged to the point that it can't act in a healthy manner. And when this happens, we find that things can get into the artery that are not so healthy, that we'll speak about just a minute. But also, the endothelial is extremely important for the formation of a chemical called nitric oxide, which probably even you've spoken about this before, you've looked into how important nitric oxide is for a number of different systems of the body. And when it's reduced, and the endothelial is one of the major parts of the body that forms this nitric oxide. For vascular health, if it's not getting if nitric oxide is not created enough, it can't function. The vessels can't function in a healthy manner.

Dr. Barrett  56:24

Yeah, absolutely. John, had the more I learned about nitric oxide--it may be one of the most important molecules to human health.

Dr. Evans 56:36

That's an excellent point. I know with your research in in neuropathy and its effect, you've also pointed out how important it is for that problem also.

Dr. Barrett 56:47

Well, I mean, it's unbelievable how, you know, you, I think you're gonna show a slide here about how your body as you age just makes less, there you go less each decade, you're producing less nitric oxide. So, at age 40, you're really probably everybody should be supplementing to, you know, with something to increase their nitric oxide, in my opinion. And we've had a couple of great episodes on nitric oxide. But go ahead, I think this is that fantastic.

Dr. Evans 57:23

No, and I would refer people back to those episodes that you've spoken about, because nitric oxide is something we hear about through the lay literature a lot. But I don't really hasn't entered into the standard medical discussions of how important it is. And yet, specifically, when we talk about just the arteries, we see that every decade, there's a significant reduction in the formation, the ability to form nitric oxide within these arteries. And that one factor drives the development of atherosclerosis in a way we'll talk about a little bit. So, these endothelial cells are important, because they allow chemicals to come in and out of the artery of the walls of the artery. And they also have a lot to do with a protective function. And there are chemicals called free radicals that develop that are extremely dangerous to our health. And usually there are ways that these can be mitigated or reduced. But as the endothelial is damaged, we see a significant increase in these reactive, these ROS. The oxygenation is reactive oxidative agents that cause this, these concerns that lead to chronic inflammation. And these cytokines that are released these inflammatory substances from the cells. And they also increase the ability for white blood cells to adhere to the vessel itself. And we'll talk about this in just a minute with one of the blood cells, platelets. But the artery is just not able to react in a healthy manner. And so the endothelial the longer you've lived, it will become more and more damaged. And if you smoke, or if you have high glucose levels, all of these things can affect them along with high blood pressure, which just physically damages the cells itself. So, all these things kind of go together. But the add up when we're talking about the development of atherosclerosis