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Dr. Timothy Werner Department of Health and Sports Sciences “Arterial Stiffness: Its Influence on Cardiovascular Disease and Therapeutic Interventions”
Salisbury University Research Day & Innovation Showcase 2016
Dr. Tim Werner • Arterial Stiffness: Its Influence on Cardiovascular Disease and Therapeutic Interventions
https://www.youtube.com/watch?v=6ORpJhjoUbQ
Dr. Clifton Griffin, Dean of Graduate Studies and Research
I’d like to welcome Dr. Tim Werner, from the Department of Health and Sport Sciences. He’s going to talk about his area of research on “Arterial Stiffness: Its Influence on Cardiovascular Disease and Therapeutic Interventions.” Coming from a family that has a long history of problems like this, I’m very interested in what he has to say.
Dr. Timothy Werner, Department of Health and Sports Sciences
Thank you all for your time and attention for this disease that I’ve been studying for a while now, but I want to preface this really early on, when I go about teaching Pathophys to my students, they all of a sudden start worrying about getting this disease, self-diagnosing, and it’s called “medical student syndrome.” I don’t want you to do this to yourself, so again, I’m not a medical doctor, so I cannot diagnose you with arterial stiffness. But, today I want to talk to you about what it is, what it isn’t, how does it become exacerbated and then what we can do to treat it and then some of my research behind this topic.
So, kind of the outline plan here, we’ll go through just some of the basic pathophys, I’m not going to get too brutal here, but I want to focus on what’s generating arterial stiffness, how I go about measuring arterial stiffness and then get into the therapeutic interventions behind solving this problem.
So, when I talk about arteriosclerosis, or excuse me when I talk about atherosclerosis, people automatically – or at least in my mind – think clotting of the artery. Well, arterial stiffness is not clotting of the arteries, it is actually strengthening of the arterial walls due to certain pressures. Many of these pressures are mechanical in nature, high blood pressure can generate this, inflammatory stress. There’s this notion that pro-inflammatory cytokines can stimulate the remodeling process inside the elastic arteries. Too much blood glucose – diabetics are at a higher risk for arterial stiffness and one of the reasons why this comes about is because the arteries trying to adapt to a change in environment, it’s trying to be resistant against these stressors. So, acutely, this is a great thing, this is protecting you from an ultimate rupture of the artery, but chronically it can wreak havoc on the heart, increasing your risk for heart disease, stroke, things like that.
Initially, we start off with very elastic arteries. Our arteries can expand and recoil as blood flows through it, and this is due to lots of elastin fibers inside most of the central arteries – these are the arteries that are coming off the heart. But as the artery goes through the stiffening process, these elastin proteins are changed with less compliant, stronger fibers, which we call collagen fibers, which allows the artery to resist these stressors like mechanical stress, inflammatory stress and blood glucose, but they’re less compliant. So, really what’s happening here is the artery is not able to expand and recoil like it could once and that’s going to wreak havoc on the cardiovascular system.
So, where this is really occurring inside the artery, if I were to just take a cross section of any artery right now, most of the stiffening process is right here in the muscular layer, which we call the tunica media. That’s where we see a lot of the protein reconfiguration going on.
So, let’s talk about what happens when your arteries become stiffer. Alright, so you’re going to see that the aorta’s buffering capacity is diminished. What I mean by that is, I can represent this with the illustration, when your heart is contracting, during what we call a systolic phase, it ejects blood into the atria, excuse me, into the aorta, and the aorta’s job is to expand and actually dissipate a lot of that strong force coming out of the ventricle. That strong force, if it were to reach the diastole capillaries, can actually wreak havoc and destroy some of the capillaries, and that’s one of the processes we actually see in someone who’s having stiffer arteries, we see an organ damage, damage in the capillaries, in the brain, the kidney. So, what the aorta is doing in a healthy individual is it’s buffering these strong pulsatile energies coming out of the ventricle. Again, the ventricle is creating pressures around 120 millimeters of mercury, which is not too terribly high, but the aorta is there to diminish some of those energies so that they don’t reach the delicate capillaries.
Alright, one of the changes that we do see occurring with stiffer arteries is that when people’s arteries become stiffer their systolic blood pressure, the top number that usually reported in blood pressure, is elevated and the bottom number, the diastolic blood pressure, actually reduces. And the difference between systolic and diastolic is sometimes called diastolic, excuse me, pulse pressure and pulse pressure will increase because of that.
Another consequence of stiff arteries has to do with the heart’s ability to receive its own blood flow, and I’ll talk more about that later. So, back to my model again, in a healthy person, you’re going to be able to expand while the heart is contracting, so the arteries are able to expand, but after the heart is done contracting, when it’s going back into resting mode, which we call diastole, these arteries are going to recoil. And, that recoil nature in a healthy artery is going to help push the blood even further out into the periphery. It actually helps the heart out.
In a stiffer model, one thing that we see is that when the ventricle is ejecting blood into the arteries here, you don’t get that expansion of the artery. So, those strong pulsatile energies are now reaching the delicate capillaries, destroying them. Also, because there’s no expansion during systole, there’s no recoil, and because of that diastolic blood flow is going to be reduced, making the heart work even harder.
So, to set you straight, in case your head is spinning right now, I’m going to give you a scenario to show you just how important this is. Imagine you’re 78 years old and you have no other cardiovascular risk factors, but you do have elevated systolic blood pressure. Is your chance of a cardiovascular event in your near future increased or decreased?
Who says increased?
Anyone for decreased?
Yeah, so systolic blood pressure, that top number is high, it is true. It’s going to increase your risk for a cardiovascular event in your near future.
Now let’s change the tables again. Again, same 78-year-old individual, you have no other risk factors for cardiovascular disease, but you do have elevated diastolic blood pressure. Is your chance of a cardiovascular event in the near future increased or decreased?
Interesting.
Who says decreased?
Who doesn’t know? (Werner and audience laugh)
So, what I want to show you, this is information from a colleague of mine from the Framingham study, Dr. Gary Mitchell. He put this together on a graph and what he’s showed here is the implication of stiffer arteries. So, first thing I want to show you is I have systolic on this upper X-axis and then diastolic blood pressure on the Y-axis here. And I want to hold diastolic blood pressure constant, so let’s imagine if you have a blood pressure 130 over 70, you have a hazard ratio of 1.2 – and again, a hazard ratio looks at risk factor or risk for a cardiovascular event in your near future. See my world, we like to play fortune teller. People always want to know what are my risks, how long do I have to live? So, we look for variables and outcomes that can predict, somewhat accurately, your chances of a cardiovascular event in the near future. So, when a hazard ratio is greater than one, you have an increased risk.
So, we have a blood pressure, 130 over 70, you have a risk of 1.2 or an elevated risk of a cardiovascular event in the near future. But, if the systolic blood pressure raises from 150, again holding diastolic blood pressure, that also your risk increases as well and it goes 170 and your risk increases as well. But, I want you to look at the graph going vertically now. Let’s hold systolic blood pressure constant. Alright, so we hold systolic blood pressure constant and we look at 130 over 70, your hazard ratio is 1.2, but now as the diastolic blood pressure increases your hazard ratio decreases. So, you can do this across any systolic blood pressure, 170 over 70 it’s 2.8, you go 170 over 100 it’s 1.7. So, your chances of a cardiovascular event in the near future is dropped.
And this is a game changer, this is a paradigm shift in the way we’re treating people right now because, typically, when people were brought to the doctor’s office and they notice that you have high diastolic blood pressure, you get treated for that. We’re saying wait a minute, let’s compare this to systolic before you do anything.
There’s another important physiological event about the arterial stiffness that I want to explain briefly because a lot of my work revolves around it, it’s to understand what we call “pulse wave.” Now every time your heart contracts it sends out a wave of energy that’s not blood flow and it travels much like a wave if I were to tie a rope to one of those doors knobs right now and fling it, you would see the wave of energy that travels along the walls of your arteries. And what happens is this wave of energy hits bifurcations, and bifurcations and impedances, and it’s actually going to hit these sites and it’s going to bounce back to the heart. So, this happens every time the heart beats. So, imagine if I were to fling my rope, that wave would come back and hit me soon enough. And a lot of times this is a good thing because in more compliant or less stiff arteries this helps to further perfuse the peripheral tissues. So, this wave actually helps to push blood further into the periphery, helping the heart out.
This also is very important for the heart to get its own blood supply. Due to physiological mechanisms that I’m not going to get into, the heart does receive most of its blood during diastole when it’s resting. So, we need this wave to come back to the heart when the heart is resting, this is how the heart gets 95% of its blood, from this wave motion and this is what happens in compliant arteries. I’m going to talk about what happens when things get stiffer. So, just to show you, I can measure the wave at different areas along the arterial system and the ways they change in configuration, but you’re going to notice the older we get, these waves do become faster and I’ll show you why here in a sec.
So, I want to talk about the problem with stiff arteries right now, and this is the big one. What happens here is when that wave gets sent out to the periphery, it travels very fast and then it comes back even faster. Much like if I were to take a wire now and tie it to a door knob and fling it, that wave would travel much faster than the rope I just had because it’s traveling through denser material. So, this wave will come back during the heart’s contraction period or systole. So, the heart right now, imagine is contracting. It’s trying to get blood out, trying to get it all out, but this wave comes back and hits it – head on collision – and that will increase the pressure that the heart now has to push against to get this blood out, and this is a great stimulus for left ventricular hypertrophy, which is a tell-tale sign of heart failure. Another problem with this is because that wave is coming back so early during systole, you can’t get that push of coronary blood flow or heart blood flow into the heart anymore. So, what’s happening now is the heart cells are becoming deprived of oxygen, which sets up sites of ischemia, which is low oxygen levels, which can lead to a heart attack.
So, again, when I talk about this with my students I know heads are spinning. So, just to illustrate what’s going on here, let’s imagine I have an artery and I sent out a wave. Here’s the time period during systole, this is diastole. This wave gets created in the ventricle and it gets sent out to the periphery. Now if there’s no site of bifurcation, that wave would go and never come back again. But, because it’s going to hit sites of impedance, it’s going to bounce back, and it’s going to come back in a less stiff, more compliant artery, usually during diastole, and it’s not going to have much of an impact on the overall pressure level here on the Y-axis. So, the heart’s not really pushing up against extra pressure. But, if I am dealing with stiffer arteries now, then that return wave is coming back during systole, when the heart is still trying to push more blood out. And that’s going to cause what we call augmentation. It’s going to augment the pressure, increasing the stress on the heart and the area in that curve represents “afterload” or something that we measure in the lab, looking at how much additional force this heart has to push against now, and it’s doing that every cardiac cycle, every, usually about 60 times a minute.
Now the other important part I want to point out about this is because of that early return on the wave, you miss out on this diastolic kickback. Remember we need this wave to come back during diastole. And it’s not in stiff arteries, so you lose out on the ability for the heart to get its own oxygen supply, which can set up sites of ischemia, and that can lead to increased heart malfunction.
So, what is arterial stiffness? Why should you care? Basically in three bullet points – again my colleague from the Framingham study, Gary Mitchell, he found that this was the best prognostic index that we have for predicting future cardiovascular events. A lot of people like to go off of lipid profiles, blood pressure; this one has the strongest predictive value that we can think of right now – so, in playing the fortune-telling game, knowing your arterial stiffness is something, I think, is pretty important. The issue right now, though and why you don’t see it when you go to your doctor’s office is because this is still early in the ball game, this has only been around for about 15 years. On average, to move something from a bench to the medical room it takes about, according to NIH statistics, it takes about 17 years to get real research being utilized inside a medical realm.
Again, another important part about arterial stiffness is that we are treating individuals who have high diastolic blood pressure, and we really shouldn’t be, having higher diastolic blood pressure is actually a good thing. And we also established that there are a couple of markers that we like to look for, for arterial stiffness. So, when you go to your doctors, at least, hopefully, in a few years, they’ll not only take your blood pressure, but also get an index of your stiffness by looking at how fast that pulse wave’s traveling, which we call pulse wave velocity. So, really quickly here, because I’m running out of time, the faster the pulse wave velocity or the faster that pulse is traveling, the stiffer the arteries and this is what Dr. Mitchell found. In that people that have the fastest pulse wave velocities, they have increased risk for a cardiovascular event in the near future.
Alright, what causes arterial stiffness? It’s basically the same stuff that causes everything else, right? Getting older, more exposure to inflammation, more exposure to high stress. Aging will definitely do it. Hypertension, high blood glucose, smoking, – smoking causes just about everything, but definitely people who smoke are at a higher risk – people that have a poor lipid profile, who have elevated cholesterol, also will have higher stiffness values, and, of course, physical inactivity, my realm. So, living a sedentary lifestyle will definitely predispose you to arterial stiffness.
So, usually, what I do in my lab is I measure arterial stiffness using tonometers and ultrasonography. So, a tonometer is basically – we just hook up an ECG on an individual or an EKG, and I put a probe on different areas of the arterial sites, so I can measure in the carotid, the brachial, the radial arteries and down a little bit lower in the limb. And with this I can actually figure out when the blood is leaving the heart with the ECG, and I can figure out when the blood is actually hitting the probe, and then I can calculate the velocity pretty quickly from that.
What can you do about arterial stiffness? Well, a lot of it’s been characterized already. You’re going to see that a lot of the blood pressure medicines that some of you might be on – the ACE inhibitors, the ARBs, diuretics, you know, your beta blocker – these are known de-stiffening agents. The problem with these, though, is they all have nasty side effects. Coughing, waking up at night, you know, using the restroom quite often. So, we are interested in looking at alternative measurements or alternative ways to treat this. And, so when I first got started with this – my lab – we looked at diet, and some of the studies that we found, that people actually lose weight by dieting can improve their stiffness scores. So, when you can actually cut calories, you’re going to see a reduction in your stiffness scores.
Exercise. Now this is an area that is really of my focus. We do know that aerobic exercise, exercise that involves a lot of cardiovascular work, is a great de-stiffening agent. It reduces inflammation, improves blood glucose function, it is an excellent tool for de-stiffening the artery, and if anyone can put exercise in a pill, they would be making a lot of money because exercise does more for arterial stiffness than most of these drugs combined. What I wanted to … So, the question that people might ask: How much exercise do I need? Well, just your basic exercise prescription plan that my agency, the American College of Sports Medicine, governs, you know, you’re supposed to exercise three to five days a week, moderate intensity, for about 30 to 60 minutes, and that’s what we’re looking for.
However, I want to switch the gears now to resistance training, this is where a lot of you probably have emails from me, or I always send out a last email to the students looking for a potential subject. There’s some controversy right now behind resistance training. When you’re doing resistance training your blood pressure goes up, right? And I already mentioned that high blood pressures generate stiffer arteries. So, there are five randomly controlled trials that have already been done that pulse wave velocity, arterial stiffness, increased in the cohorts. However, there are three randomly controlled trials that show nothing, and the difference really is how they approached it, their methodology was a little bit different. So, a lot of them didn’t use full-body workouts, a lot of them didn’t have control groups.
So, right now, I’m in the middle of this study where we’re looking at 30 individuals, and I’m separating them into three groups. I have a control group; I have a high-intensity group that’s training at a high percent of [inaudible] and other maximal repetition and then I also have a high-volume group who’s doing a lot of sets and reps. And I’m asking the question, one, can I illicit arterial stiffness in these individuals, and then, if so, which group, which type of training promotes it more? So, I’m only using males right now because it is a proof of concept study. If I do find something, we move it on to the female. And, again, this study is in collaboration with Dr. Pellinger. He’s doing the ultrasound tests for me.
Another area that’s booming, so to speak, is supplementation. So, we have a lot of athletes and a lot of students here doing supplements, and it hasn’t been characterized yet. So, I’m interested, in particular, in one supplement, creatine monohydrate, because a lot of individuals do take creatine. And so, this study we are submitting for IRB here soon, and what we will do is we’ll have a group of individuals on creatine and a group of individuals without creatine, and we’re just going to look at how creatine implementation influences arterial stiffness, at least acutely. And, if I see something I’ll move it to a chronic model for potentially six to 12 weeks to further draw things out.
So, in summary, I just want to finish up here. Arterial stiffness is a very, very powerful variable in the driving force for cardiovascular disease, and again, it’s just the remodeling of getting out those elastin fibers and putting in stronger collagen fibers so that the artery itself can maintain its integrity without rupturing. The same things that cause just about everything else – diabetes, heart disease – cause arterial stiffness. And then I talked a little bit about how we measure, it’s very non-invasive, so, it doesn’t hurt at all, there’s no side effects, and hopefully in the next few years, you’ll start to get your stiffness scores measured. Again, there’s many medications for this, but there’s unwanted side effects with every medication that you take. And, of course, the best treatment option, out of all, I can promote right now is aerobic exercise bar none. It has been shown to have the greatest impact on your arterial stiffness scores. I can’t say the same for resistance training. I’m still not convinced either way.
Thank you for your time (audience claps).
Audience Member One
I appreciate your presentation, and as you were describing some of the causal factors for this condition, it sounded very much like minority populations would be very much suspect to that. Is there a way – two-fold – in terms of thinking about this from a curriculum standpoint, it seems to me like this sort of research that you’re doing would be of an interest to minority populations, to interested populations of whatever hue here on campus and have that sort of a focus on those sort of communities. So, I would definitely invite you to consider, perhaps, crafting the work that you’re doing in providing for your students and adding, if it’s not there already, that sort of a component. And the second part of it is what about that outreach to communities to give them that heads up and to give medical folks in those communities a heads-up that, yeah, you need to be alerted to this and that this is a better predictor than some of the other things and probably better than, you know, a lot of the medicines that are being prescribed. Is there a way to target populations?
Dr. Werner
That’s the $64,000 question, right? How do we get people to wake up about this? Well, like I mentioned before, on average, it takes about 17 years for this to be brought. So, it’s just doing conferences and events like this that’s what’s going to take. So, this movement is growing. I can’t predict when and this will actually start to occur. Europe is already starting to measure arterial stiffness scores, but again I’m not in NIH or any of the major associations, so I can’t speak to what their voice is on this concern, but it is a very good point.
Thank you.
Audience Member Two
That was very interesting, Tim.
I’m just wondering from your lab research and the kind of protection of human subjects since you’re interested in inducing arterial … is it reversible, easily reversible? Or are there animal studies that you could draw upon to support doing this? And then the other question is why not approach it by seeking subjects that have stiff arteries and seeing if you can reverse them instead of inducing them?
So, that’s where my previous work was done, at Virginia Tech, we did all sorts of things. We made people gain weight, it was IRB approved (audience laughs), and we found that their stiffness scores went up. And then we had studies where we had them work with dieticians to lose weight, and their stiffness scores went down. So, that question, in my mind, has been answered or addressed effectively. So, I’m trying to look for a niche or areas that are not answered, and one of them, pretty big right now, is this controversy between resistance training in this world. Some people are on the fence that resistance training doesn’t do anything; some people are on the side of the fence that it can stimulate and put you at risk for arterial stiffness. Now, I’m a clinical exercise physiologist; I would never tell anyone not to do exercise, but people have a right to know that there’s something here. Exercise is an awesome tool to cure a lot of diseases. Do I think something’s here? I’m not convinced yet, but I’m not sold either. So, it’s kind of we’re in the middle of the ball game and I still don’t know what the score will be at the end.
Audience Member Three
Talking about the speed in which the wave travels, does height have an impact? The taller people versus shorter people?
(Laughs) Generally, you have to think it’s more of a relative question. So, if I have a politically correct way, say a shorter individual, vertically challenged, and a taller individual, but they both have the same stiff arteries; yeah, the shorter individual will have a higher pressure on the heart, they’ll have a higher afterload. But, in general, shortness, tallness really doesn’t influence – we don’t see too many discrepancies between someone who’s short or tall in your stiffness scores.
Thank you (audience claps).
Dr. Griffin
So, that concludes our presentation portion of 2016 SU Research Day. I do want to give the provost, Dr. Diane Allen, an opportunity to give a couple of comments, but first give a round of applause for all our speakers whether they’re here or not (audience claps).
Dr. Allen.
Dr. Diane Allen, Provost and Senior Vice President of Academic Affairs
Well, Clifton, that’s what I was going to say, let’s give a round of applause to all our presenters today. But, let me also applaud you for coming and spending time and learning what your colleagues across campus are doing. I love this event. I wish we could get more people here, but I love this event, and this is why I love it, because we have interesting people on this campus who are doing interesting work. And, you know, some of it I understand better than others. I’m going to spend time – Tim – this evening on WebMD, trying to figure out – I think I met all of your risk factors, except smoking, so.
But, the breadth of the things our faculty do is amazing to me, and I love hearing that. I love hearing them talk about their work because they’re so passionate about it. The other thing that I love about this event is we get to see how we interconnect to each other, and so, I heard that a lot today. You know, a speaker would talk about their work, about how they worked with someone over here or someone in this school, and I love that because it’s exactly what this building is supposed to promote. I love that the faculty are connecting their passion, their work, their scholarly effort to what they do in the classroom. Every single speaker talked about students, and so, that goes to what we talk about. We’re really proud of our teaching here, but I think good teaching is really tied to bringing your passion, your scholarly work, into the classroom, and so you can’t do them separately, you have to do them together.
So, I love coming here because that really just confirms for me everything I already believe about what we do here at SU. So, thank you again for being here today (audience claps).