Genetic Testing in Cardiovascular Disease

 

My name is a Atul Sachdev. I practice family medicine in Baytown, Texas. I've been affiliated with MDBIP since 2011, and I've been asked to talk to you today about how I use genetics in the setting of cardiovascular prevention. I'm going to keep this presentation relatively brief because I feel like we retain more when we're not inundated, inundated with information. And I really have to pee. So I've had a lot of success preventing heart attacks and strokes in a pretty high risk population in Baytown. It's a blue collar town, oil refinery town. And the reason I've had this success, I attribute quite a bit to the Bale Doneen method. So for those of you docs that have not had that training, haven't taken the Bale Doneen preceptorship course, I highly recommend it. One of the elements of their method, of course, is genetic testing so that you can tailor your approach to a specific patient according to their genetic makeup. And doesn't that make intuitive sense? Nothing in medicine is one treatment fits all. Is the reason sertraline works well in one patient and not at all in the next. It's the reason I don't do pap smears on men or prostate exams on women. Not just because the judge told me to stop doing that, but but it actually makes a lot of intuitive sense because our genetic makeup dictates our treatment. So if you're serious about preventing vascular events in your practice, which we should be, it's important that you understand this concept and that you applied in your practice. As you can imagine, there are a number of genetic markers that have implications with cardiovascular prevention, and I thought today I would discuss three of them that I've been using consistently for the past eight years, and I'll briefly introduced a few of them to you as well after the presentation. At the end of my presentation. Disclosures, basically I am a speaker for Quest slash CHL, and that's pretty much it. There is one more thing. I watched that movie The Notebook a few years ago and cried a lot. I was, uh, apparently my estrogen level is just fine. I was hoping you'd be more supportive than that. So that's pretty much all I'm going to be disclosing today. The the first gene I wanted to discuss is called the 9p21 gene. This gene has the most robust association with cardiovascular risk and is therefore referred to as the heart attack gene. It's located on the short arm of chromosome nine and it has two single nucleotide polymorphisms or snips that are associated with increased risk for coronary heart disease events. I was relieved to find out that the biology of this region was not only poorly understood by me, but also by a lot of smart people. It's usually just me that doesn't understand the biology. On a sad note, I actually majored in biology. So if you have a patient who's a non carrier of this 9p21 risk variant, they're at no higher risk than their other risk factors would dictate. This non carrier status occurs in about 27% of the population. About 50% of the population is heterozygous for this variant. These people have a 25% increased risk, relative lifetime risk of MI/CHD. They have almost a 50% increased risk for an early MI and a 36% increased risk for an abdominal aortic aneurysm. The remaining 23% of the population is essentially screwed. These people are homozygous for the variant. In other words, they got a heart attack, a gene gene from mom and one from dad. These people carry a 56% increased lifetime risk of MI, double the risk of an early MI and 74% higher risk of a AAA. The level of vascular risk associated with the 9p21 variant is comparable to that of smoking, LDL, HDL, age and LPa. So my question to you is, are you okay not knowing what your status is or maybe your patient's genetic status? It's akin to not asking your patient whether or not they smoke, which I admit, I need to start asking my patients that. I work in Baytown, so the answer's usually yes. But this is a pretty big deal. Has anyone here, just out of curiosity, had the 9p21 genetic tests performed? Few of you. I got tested myself and found out that I was part of the 50% of the population that is heterozygous. So in other words, I got one heart attack, gene. The test doesn't tell you whether you got it from mom or dad. But when I find out someone's not getting any more Christmas present. So. So what does all of this mean for you and your practice? First of all, it's important to note that the risk correlation has been noted to be most significant in the following populations of Caucasian, Chinese, Korean, Japanese, and also those from India. Now, both of my parents are from India, and I'm pretty sure they knew that when they decided to have kids and pass along 9p21 genes all willy nilly. So I apologize if I sound bitter. Basically, your knowledge of one's risk due to this genetic variant can basically allow you to detect things early to be more aggressive with monitoring and treatment and perhaps more aggressive with lifestyle and behavioral changes. In other words, this this test kind of indicates to you who you need to worry more about in your practice. As I'll show you in a little bit, the patient's knowledge of this risk may also motivate them to be more compliant. Another way to look at the impact of a particular risk factors by looking at its population attributable risk or PAR. The PAR is the measure of the fraction of disease burden in a population that would be eliminated if the risk factor was removed. So the PAR for 9p21 risk is substantial. As you can see, it's anywhere from 21% to 31%, depending on the specific complication, and it's due to the high prevalence of the 9p21 risk allele. It's present in 73% of our population. For comparison, the PAR of smoking and cardiovascular death is about 24%. So let's look at a patient. This is Jenny. Obviously, I use, you know, fake names to protect identity. Her real name is Jamie. So she's a 61 year old Caucasian female who is homozygous positive for the 9p21 Gene. She came to me from another physician with these initial labs. Her Lp-PLA2 activity was significantly elevated at 95. That means her arteries were on fire. She definitely had vulnerable plaque, putting her basically at a very high risk for an event. And again, this is something else that you guys will learn if you take this Bale Doneen preceptorship course, I promise you, if you're not checking Lp-PLA2 and some of these other markers that you're going to miss, heart attacks and strokes, things that could be prevented. So she also has familial hyperlipidemia with crazy LDL of 229. And this ad, the bottom one is actually the estimated amount of sweat that came pouring off of my body when I when I was still getting all these results. And honestly, again, if you understand this method, you should have the exact same reaction. It should be the same reaction as if, you know, you have a patient coming in with chest pain and they have ST elevations or you meet your daughter's new boyfriend for the first time. You know, you should get all aggressive and pumped up. And he's actually a pretty nice guy, but I'm still on guard. So when I saw her lab results, I did pretty much what most doctors would do. I asked her to leave my practice, but she keeps coming back, so I have to deal with this. See, the thing is, she told me that she and she's very well aware that she has a cholesterol problem. Her doctor, previous doctor did a good job of hammering that home. In fact, she told me that things were so bad, she was diagnosed with both hyperlipidemia and high cholesterol. So I could have said a lot of really smart things there. But I was being empathetic. That's what we do. She was very upset about her situation. And so I said, You know, dear God, we often don't see patients with both conditions at the same time. But I was being supportive. And and so the kicker here was she told me that she would rather die than try another statin medication. As you can see, she was about to get her wish. She said her previous physician tried her on all of the statins and they all caused severe myalgias, even though she tried CoQ10 and a lot of other measures. And when I explained to her about her heart attack, gene, she started crying. She said that her father had died of a massive heart attack in his forties. She told me about her younger brother who just had a triple bypass and she didn't want to end up the same way. So she softened her stance a little bit and we did some further digging and found out that her previous doctor tried 80 milligrams of Pravastatin, but not anything lower. And so she was willing to try 40 milligrams of Pravastatin combined with a Ezetimibe, which, by the way, was required by her insurance before they would consider a PCSK9 inhibitor, which she would be an ideal candidate for that. So we had to work on that. And this is what happened. So she had a pretty dramatic reduction in her LDL, still not at what some people might call a traditional goal, but way, way better. And if you understand everything we're talking about here today, you'll also understand that LDL is not the end game here. This is about inflammation and this is what happened to her inflammation. Her Lp-PLA2 activity now had come down to normal. In other words, we had an indication that her risk of an acute event just decreased dramatically. On top of that, she was tolerating this combination of Pravastatin and Ezetimibe very well. As a result my sweat level came back down to baseline. I am aware that 0.3 gallons is still pretty gross. You wouldn't believe how humid it is in Baytown. The next gene I wanted to talk to you about was it's called the Kinesin Family Member 6 or what we call the KIF6 gene. This gene basically encodes a member of a family of molecular motors which are involved in intracellular transport of protein complexes, membrane organelles, messenger RNA along microtubules. The gene is expressed in coronary arteries and other vascular tissue. This variant on the KIF6 where arginine gets substituted for a tryptophan, has a lot of implications regarding coronary heart disease risk and perhaps more importantly, response to certain statin drugs. There are a number of major trials that demonstrate the increased cardiovascular risk associated with the KIF6 gene variant, the Prove It Trials Care and WOSCOPS studies demonstrated that there was up to a 55% greater coronary heart disease risk associated with carriers of this variant. Like with the 9p21 gene, the risk conferred by the KIF6 variant is comparable to all the traditional risk factors like smoking, diabetes, hypertension. It's important to note that this risk is independent of other risk factors. The same studies also demonstrated that cardiovascular risk was significantly mitigated in those taking 40 milligrams of Pravastatin in carriers of the KIF6 variant, but minimally in those that didn't have the variant. This is an important thing to remember here, and I'll show you this in a second. So those who were carriers of the KIF6 variant experienced a 40 to 60% relative risk reduction with cardiovascular events, while the non carriers experienced as little as 6%. So big, big difference. The PROVE-IT-TIMI trial kind of demonstrated the same concept, but also with Atorvastatin 80 milligrams. This was a double blind trial of almost 1800 middle aged men with acute coronary syndrome treated with either 40 milligrams of Pravastatin or 80 milligrams of Atorvastatin. The endpoints were death and major CVD events. I would hate to be an endpoint in this study. The gist of this study is that the KIF6 carriers responded significantly better than the non carriers, which showed almost a negligible response If you can make out the graphs, there and again, just a whole list of studies that basically support what we're talking about. So didn’t just make this up. Because 60% of your patients are carriers of this variant, 60% of them carry a risk that's comparable to smoking that your you and your patient may not be aware of unless you're actually checking for this in your practice. There have been some more recent studies, by the way, that are challenging this concept, the degree of risk associated with the KIF6 variant. So you need to know that it is still a little bit controversial. But what that means is that 40% of the population basically are non carriers of the KIF6 gene and these people would not be expected to respond in terms of cardiovascular risk to either Pravastatin or Atorvastatin. And when you understand how often these statins are prescribed in general medicine, either by other people, cardiologists, they love Atorvastatin or maybe by you, it's very, very important to make sure that they have this KIF6 variant and that they'll respond to it. So this is Sharon. She's a 72 year old Caucasian female who came to me from a different provider on 80 milligrams of Pravastatin. She's diabetic, but very well controlled. Her blood pressure was normal without medication, and she's a nonsmoker. She didn't have periodontal disease because she has no teeth. Welcome to Baytown. Basically, if you're 40 or older in Baytown, you're not going to have any teeth. On the surface, it appears that she's being optimally treated. If you're looking at LDL, if you're an LDL doc, you're going to be fairly happy with this. But you see, my pulse rate down there is 140 beats per minute. And the reason is the Lp-PLA2 mass was 207 normal being less than 200. This was before we had the Lp-PLA2 activity that most of us are using now. So this lady had vulnerable plaque even though her LDL was near goal, she was on statin therapy. And the problem, as you just learned, was that she was KIF6 negative and wouldn't be expected to experience a significant risk reduction on the Pravastatin. So when I suggested to her that we switch her statin, she said, well, I like Pravastatin because I can get a 90 day supply for $10 at Walmart and I'm unwilling to pay more than that. Welcome to Baytown. And so the only other statin on that list was Lovastatin. So we went to that and she was able to get a 90 day supply for ten bucks. And this is what happened. Her LDL went up just a little bit from 75 to 80. But again, it's all about the inflammation. So her Lp-PLA2 decreased dramatically, basically indicating that her risk decreased dramatically and basically indicating that I'm a hero, as if you need to know anything else about me. My pulse rate came down to baseline, which is 75 beats per minute, which by the way, is the average pulse rate for a hero. Okay, So the last gene I thought I would talk about today, it's called the ApoE gene. It's kind of like a lifestyle gene. That's how I consider it. Basically, it serves as a ligand to LDL receptors and is therefore heavily involved in lipid metabolism. It plays a significant role in the exogenous endogenous and reverse cholesterol transport pathways in lipid metabolism, which is depicted in this slide. I was going to explain all of these steps in the slide to you, but out of the interest of time and the fact that I don't really know what's going on there, I thought I would go ahead. Now, does anybody want me to pause to take and take a picture? I just wanted to see if there are any nerds here today, so. Okay. So what you really need to know about ApoE is this basically there's three different isoforms, ApoE 2, 3 and 4. The ApoE 3 genotype is the most prevalent one and has an average affinity for hepatic LDL receptor. So there's no genotypic cardiovascular impact with this isoform. The ApoE 2 genotype actually has a decreased affinity for these hepatic LDL receptors and is associated with a slow conversion of IDL to LDL. This typically results in decreased LDL and elevated triglycerides. Then there's the ApoE 4 genotype, which is the one you need to worry about clinically. It has increased affinity for LDL receptors and limits HDL binding, thereby inhibiting this reverse cholesterol transport, which you heard a little bit about this morning. This genotype typically results in a lot of bad things elevated total cholesterol, elevated LDL, elevated triglyceride levels and decreased HDL. To make things worse, what's not on this slide, but warrants a lot of attention is the fact that ApoE 4, the genotype, has a strong association with the development of Alzheimer's disease, an association that was discovered in the 1990s. Since then, numerous studies have confirmed that possessing this ApoE 4 allele is basically the strongest genetic factor for Alzheimer's disease to date, as compared with individuals with no ApoE 4 allele. Patients who carry just one ApoE 4 allele have a 2 to 3 fold higher risk of developing Alzheimer's disease. Whereas those who are homozygous for the ApoE 4 allele carry 2 alleles have about a 12 fold increased risk for developing Alzheimer's disease. The ApoE 4 allele is also associated with an earlier age of Alzheimer's disease onset, and it's important to mention that those who carried the ApoE 2 allele seem to have a lower risk for Alzheimer's disease. So I'm not suggesting you tell your patients who carry the ApoE 4 allele that, you know, you better listen to me or you're going to develop Alzheimer's disease, Although that's been working really well for me in my practice. But you need to know that the incidence of Alzheimer's disease is actually relatively low in the population. Many patients who are carriers of this allele do not go on to develop Alzheimer's disease. Likewise, amongst the people that do have Alzheimer's disease, 40% of them carry this ApoE 4 Gene. So not all of them. So clearly, as you guys know, there are lifestyle and environmental factors involved there. Finally, there's one more important point about the ApoE 4 genotype, and it has to do with alcohol. There are studies that show that while alcohol, particularly red wine, can be cardioprotective, the 25% or so of the people who carry the ApoE 4 allele have an increased risk of cardiovascular disease and Alzheimer's disease when they consume alcohol. So if you recommend, for example, that to your patients that they drink 1 to 2 glasses of alcohol daily to ward off heart attacks, you may be actually worsening their situation if they have the ApoE 4 gene and you're not aware of it. This is a chart showing the breakdown of the possible ApoE genotypes, their population frequency associated to cardiovascular risk and dietary considerations. And you can see that a majority of the population, 62%, are of the ApoE 3 variety and do not carry increased risk and basically can be given your normal dietary guidelines. The carriers have the ApoE 2 genes which are also a relatively small percentage of the population, carry no cardiovascular risk and may even have a slightly reduced cardiovascular risk, can tolerate a moderate fat diet up to 35% of their caloric intake as fat. As I said earlier, the people you need to worry about are the carriers of the ApoE 4 genotype, particularly the ApoE 3 4 and the ApoE 4 4 patients. You see here that they will represent about a quarter of your patients and have an increased cardiovascular risk of 42% and should limit dietary fat intake to less than 20% of their caloric intake. So to summarize with regard to Alzheimer's disease, your ApoE 3 4 patients have about a 2 to 3 fold increased risk of developing Alzheimer's disease while the ApoE 4 4, which would be 5% of your patient population, will have up to a 12 fold higher risk of developing Alzheimer's disease. And these people should be told to avoid all alcohol intake because it may accelerate heart disease and Alzheimer's disease as well. So this is Ricky. His wife had been a patient of mine for a couple of years before he joined my practice. During those couple of years, his wife kept telling him that I mentioned to her because of her genotype and everything, that red wine would probably be beneficial if it was something that she would typically enjoy. By the way, we don't generally tell people to start drinking red wine if they're not drinkers to begin with. You can, you know, end up causing some other problems there. So he when he saw his wife doing that, decided it would probably be a good idea for him, too. So he started drinking two glasses of red wine every night in addition to his regular routine with bourbon and Coke. Welcome to Baytown. So when he joined my practice two years later, this is what his initial lab work showed. You can see his lab late to activity again, was very elevated at 93. Again, this means that his arteries were on fire. He's at high risk for having an event. His LDL was markedly elevated at 158. His LDL particle count by NMR was very high at 1,983. And because he tested, as an ApoE 3 4 I told him that drinking red wine, bourbon or any alcohol for that matter wouldn't be in his best interest, which really pissed him off. Yeah, he it’s scary telling people in Baytown not to drink. They, you know, we're in Texas and you're allowed to carry guns and stuff like that. So I was actually a little worried. But because of his LDL and particle count in the setting of his marked vascular inflammation, I also started him on Rosuvastatin when he came back in a few months. This is what we saw. You see, there's not a whole lot of change with his LDL there. When he came back, I asked if he was taking the Rosuvastatin because there was only a marginal decrease and he said, Well, I took it for a couple of days and stopped because I heard it can cause muscle pain and and I asked well, did it cause muscle pain? And he said, No. I said, You remember I told you to not stop it, you know, without calling me. And he said, Yeah, but I figured we'd just talk about it next time we met. So this is what happened to his particle count? Absolutely nothing. In fact, this is the first time I've ever seen a particle count be exactly the same from one visit to the next. So I advise him to play the lottery. It's very, very rare. But the point with this is his Lp-PLA2 activity did decrease substantially to 72 from 93, which is within normal limits, indicating that his arteries cooled off and I asked him, you know, I was very interested in this. I asked him what, if anything, he had done differently. And the only thing he pointed to was that he stopped drinking red wine and bourbon because he was afraid he would get Alzheimer's disease. I don't really tell people that every time, but that one really stuck with him. So this ended up kind of being a rare situation where this was kind of an isolated intervention of stopping alcohol. I always recommend a variety of things at every visit, which I'm sure you guys do as well, but out of all the things I asked them to do, the only thing he could pull off was stopping the alcohol. There was no fish oil, no vitamin D, no exercise, no dietary changes. So I'm not aware of any published literature, looking at Lp-PLA2 activity, alcohol intake in ApoE 4 people, but there are studies that suggest that vascular risk is increased by alcohol in these carriers, as I mentioned earlier. So this, in my opinion, is basically my end of one study in my practice. There could have been obviously other explanations for this, but it's rare to see a case where this particular intervention is isolated. It's been assumed for years that the increased risk associated with the ApoE 4 genotype is directly related to its role in modulating lipid metabolism. That chart I showed you earlier, however, there's been actually some more recent evidence suggesting that the impact of that genotype may be due in large part to the impact on oxidative stress, immuno modulation and anti-inflammatory properties of ApoE. So while this isn't mainstream thinking with regard to ApoE risk, I decided that I would just bring it to your attention. It was a very interesting case to me and I thought it might interest you. Judging by the awkward silence, it looks like a horribly midjudged that. But if any of you happen to have any experience with that and would like to make a comment, I'd love to hear from you during the maybe the Q&A session, particularly if you agree with me. If you don't, then just keep that to yourself, okay. So as I mentioned earlier, there are a few other genetic tests that you can consider. I do some of these myself. This is the 4q25 gene, which has implications with regard to risk of atrial fibrillation, which we heard about earlier. IL1 one which indicates a can indicate heightened response to inflammation. Haptoglobin, which is very useful for assessing cardiovascular risk in diabetics. LPA aspirin, cardiovascular risk and aspirin response and then LPA-Intron 25 an independent risk factor for cardiovascular disease related to LPa. And obviously there are more. This level of care is what we need to be providing to our patients every day. Unfortunately, as you know, people aren't naturally hardwired to focus on prevention. If we feel relatively well, we're not hurting or limited in any way, we tend to neglect things. Take things for granted, like your heart, your brain, your liver, your wife. So, you know, take it upon yourself to educate yourself and your patients about this. My advice is just to explain it to your patients. Let them make the choice. If they understand how this genetic testing might help tailor your recommendations, they may think it's important enough to pay for it, and you'll be surprising who will actually do that. Most of your patients recognize the value in prevention, and they're actually with you for that reason. If I can get my patients in Baytown to pay for this, then you can too. Remind your patients also, this is obvious to us, but since these are genetic tests, we only have to check it once. So it's not a recurring expense. And now most of my patients, Baytown, work at oil refineries, chemical plants, They're exposed to all kinds of things. So I could probably make a case. We're checking them weekly with genetic tests. But for most of you guys, it should just be once. So that basically concludes my presentation. I hope you enjoyed it, because I certainly didn't have a great day.