cardiovascular genetics: am i at risk? webcast february 8...

www.patientpower.info ihealth.nmh.org © 2010 Northwestern Memorial Hospital All Rights Reserved

Cardiovascular Genetics: Am I At Risk? Webcast February 8, 2011 Hossein Ardehali, M.D., Ph.D. Kathryn Schmahl Please remember the opinions expressed on Patient Power are not necessarily the views of Northwestern Memorial Hospital, its medical staff or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you. Introduction Andrew Schorr: There are millions of people who have or are developing coronary heart disease, and it can be caused by so many things. But what role does genetics play, and how do you find out? Who should be tested, and what can you do with that information. Coming up a leading cardiologist from Northwestern Memorial Hospital will discuss genetic testing for heart issues, how it should be used and if it's right for you. It's all next on Patient Power. Hello and welcome to Patient Power sponsored by Northwestern Memorial Hospital. I'm Andrew Schorr. Well, as you know, one of the most prevalent conditions that affects us all is heart disease, and whether it's about our diet, our cholesterol, a variety of factors, whether you smoke, all of that could play a role. And unfortunately, it is our biggest killer, really, things that affect our heart. So we all think about it a lot. But when we think about it, we say, well sure, we should quit smoking, lose weight. We want to make sure our numbers are good, if we have diabetes especially, monitoring that number. But what if mom or dad or grandpa or a brother or sister had a heart event at an early age? Does it run in the family, and how do you know? And maybe you're familiar with this whole human genome project, and they're identifying genes that could put us at higher risk. Well, what about are we at risk for heart problems, coronary artery disease, where the arteries that supply the heart muscle get blocked? Are we more likely to have high cholesterol that could play a role there? Kathryn’s Story Well, we're going to talk about that in this Patient Power program with an expert at Northwestern Memorial Hospital and the Bluhm Cardiovascular Institute who is focusing on that and helping patients learn more and if needed genetic tests that could provide helpful information. Let's meet someone who has been taking advantage of that, consulting with that expert. It's actually somebody who works at Northwestern Memorial. Kathryn Schmahl is 27 years old, an active woman, and recently married. And Kathryn, tell us about heart events in your family that sort of put it on your radar, if you will, to say, could there be something going on genetically here?

2

www.patientpower.info ihealth.nmh.org NMH020811/0210/AS/jf © 2011 Northwestern Memorial Hospital All Rights Reserved

Kathryn: Sure. On one side of my family there is a lot of heart disease and heart trouble, and so I had cause to be concerned. My grandfather had two heart attacks before he was the age of 40. My uncle has had heart issues, as well as an aunt and two cousins, all on the same side of the family. Andrew Schorr: So you're a young, active person. You've been thinking about this. Usually people in their 20s say, well, I'm immortal, you know, and nothing is going to happen to me. What got you thinking about this where you say, maybe I should investigate this further? Kathryn: Well, it had always sort of been in the back of my mind, but I work at Northwestern and I had the opportunity to see Dr. Ardehali speak about this, and so that intrigued me to look into my risk factors. Andrew Schorr: Now, I know that, like a lot of us, sometimes something happens, you go to the emergency room. Wasn't it something at the emergency room that got you thinking about your heart as well? Kathryn: Yes. I had a spell of dizziness after running, and I was having sort of a history of unexplained, you know, just headaches. Anyway, I did end up in the emergency room, and they did an EKG, and the doctor who reviewed it with me looked at it and he said, you know, there's this one little spot, it's a little irregular, but it's nothing. And I also was sent for testing, I did the stress test on the treadmill, and the person who did the test said I've never seen anyone take this long to get to the heartbeat we're looking for. You're in very good shape. So I was pleased with that, but that always was in the back of my mind, that little irregularity. Did that mean anything? Andrew Schorr: Right. So you went to see Dr. Ardehali. Kathryn: Yes. Andrew Schorr: And you've gone through some testing and may go through some more. Is it starting to give you some peace of mind? Kathryn: Well, yes. It's great to know that some of the behaviors and lifestyle that lead to heart disease are not in my lifestyle. I know those are some that can really affect your risk. But, yes, I do want to know more about my risk genetically.

3


Andrew Schorr: Okay. And I know that's something you've been discussing with him, is actually having genetic tests to see if there are genes that are affected that put you at higher risk. Kathryn: Yes. The Human Genome Project Andrew Schorr: Okay. So the story continues. We will talk more about that. Let's meet your doctor and this cardiologist who focuses on this, and that is, as you mentioned, Dr. Hossein Ardehali. Dr. Ardehali is director of the program for cardiovascular genetics at the Bluhm Cardiovascular Institute at Northwestern Memorial Hospital. Also he's an associate professor of medicine in molecular pharmacology and biological chemistry, and so he thinks about this a lot. Dr. Ardehali, so I mentioned the Human Genome Project, so just a word about genes. We've spent maybe billions of dollars to map the genes that help our body work and create cells and tell the cells what to do and how to operate, and now we're sort of on the cusp of learning about which genes do what. We have a ways to go, but we're starting to unlock some of the secrets. Am I right? Dr. Ardehali: Yes, that's correct. We have focused on modifiable risk factors for coronary disease for the past 50, 60 years. We know what contributes to coronary disease, and we have always had this observation in the back of our mind that patients who have family history of coronary disease, they are also at high risk of getting coronary disease, but we haven't been able to identify the genes that contribute to this disorder. Andrew Schorr: So where are we now? Are we beginning to get a clue? Dr. Ardehali: Yes. So in 1990 the Human Genome Project was started, and the plan at the time was to sequence the whole human genome in 15 to 20 years. So the idea was to finish it by the year 2007, I believe, or 2010. But fortunately the project was finished in 2003, and the reason that it was finished earlier than the expected was mostly because of our progress in the technologies that we were employing and using to sequence the human genome. Just to give you an example, Andrew, when I was a graduate student in the 1990s at Vanderbilt, for a year every day I went to the lab, I poured these big gels, and my project was to clone one of the genes in our genome, and it's called hexokinase II. So for a year I basically poured these gels and read the sequence, and every couple of days I obtained about 200 nucleotides. So to get, let's say, you know, if you want to sequence a gene that is

4


100,000 nucleotides you have to do it over and over, and it takes a long time. But the technology improved in a way that basically the year that I spent sequencing for my Ph.D. now can be done in a day, which is-- Andrew Schorr: Wow. Dr. Ardehali: --actually, yes. It's amazing how much technology has improved. And the Human Genome Project was finished, again, in 2003, and since then we have obtained a lot of information that has helped us look for genes that may contribute to various disorders like diabetes, high blood pressure, and coronary artery disease. The Role Genes Play in Cardiovascular Disease Andrew Schorr: Now, some people have said, well, high cholesterol runs in my family, so I know I have to lower the bad cholesterol because that could lead to the blockage of arteries and a heart attack, and, sure, there are medicines but they're just not working very well for me. Am I right? Because I know we're talking about pharmacogenetics too. Could somebody have a family history where they just sort of create cholesterol? Dr. Ardehali: Yes, absolutely. Again, our body makes cholesterol, and if cholesterol is evil, if it is bad for us it should go away. Nature should select against it, but we still make cholesterol. And why do we make cholesterol. Because we need cholesterol. Our cell membranes need a precursor that is cholesterol to make the cell membrane, so every cell in our body needs cholesterol. We need cholesterol for sex hormones. We need cholesterol for some vitamins and also for biliary salts, so cholesterol is an essentially part of our body. But too much of it is bad for us, and that's why our body actually makes cholesterol and the cholesterol is mostly synthesized. The majority of cholesterol in our body is synthesized in the liver through a very extensive, extensive enzymatic reaction pathway. And one of the enzymes that is involved in this pathway is called HMG-CoA reductase, and that's the enzymes that statins, like Lipitor, Zocor, Crestor, you know, the drugs that we use to reduce our cholesterol. They target that specific enzyme and by doing that they reduce the levels of cholesterol in our body by reducing the synthesis of cholesterol. So to answer your question, yes, our body makes cholesterol, and some of us make more than others. Some of us absorb more cholesterol from our digestive tract than others.

5


Andrew Schorr: So in other words the genes could determine how well you synthesize, how well you absorb, and there could be some people where you're just left with too much. Dr. Ardehali: Absolutely. The genes in our body can determine many of the phenotypes or the symptoms that we have, and other environmental factors can also contribute. So just to use the example of coronary artery disease, we know a lot of factors, environmental factors contribute to coronary artery disease. Examples of that are smoking. We know that bad diet can contribute to coronary artery disease. High cholesterol diet can contribute to coronary artery disease. High blood pressure, diabetes, all these things can contribute to coronary artery disease. But we also know that there are patients who also have a genetic component that can contribute to coronary artery disease. Andrew Schorr: Now, let's talk about that, and let's go back to Kathryn's case. So Kathryn says I have these relatives who had bad heart events at a relatively early age. Would that be an indication that genetics may have been at work? Because I know a lot of times you sit down with your doctor, maybe it's a new visit, and they take you through your family history, and they're often asking what happened to a parent or a brother or sister, grandfather, grandmother, at an earlier age rather than a later age. So does the age of an event, heart event matter as far as a clue that genetics could be at work? Dr. Ardehali: The answer is yes. We usually look at family members, male family members if they had a cardiac event or heart attack prior to the age of 50 or 55, and usually in females, female family members, if there's a cardiac event before the age of 60 we are concerned. So there is a gender difference between family members. So males who are younger than 50 and females who are younger than 60, that's when we get concerned about positive family history. Andrew Schorr: And Kathryn, you were saying grandpa, 40, age 40? Kathryn: He died at age 40. Andrew Schorr: Wow. Kathryn: Both of those, or 42, I should say, so both of those occurred before that time. Andrew Schorr: Wow. Okay.

6


Kathryn: He was very young. Andrew Schorr: So that's sort of a blinking light, a warning light there. So, Doctor, so we were talking about the modifiable factors. So we start with that is, like in Kathryn's case she was saying--Kathryn, you jog, don't you? Kathryn: Mm-hmm. Andrew Schorr: Okay. And you're a pretty active person. Do you smoke? Kathryn: No. Andrew Schorr: How is your weight? Kathryn: Good. Andrew Schorr: Okay. So good weight, doesn't smoke, no diabetes, right? Kathryn: Right. Andrew Schorr: I sound like a doctor here doing a family history. Okay. So those are modifiable factors, and, Dr. Ardehali, Kathryn looks good on that. So tell us about genetic testing. Is it a blood test? And where are we now with the genes that you look for to then counsel a patient related to risk? Dr. Ardehali: Yes. So let me answer your first question first, what's the method of doing these tests. And there are different ways of doing it. Of course we try to stay away from very invasive techniques like going and doing a biopsy of the heart, so we have basically gone away from doing those kinds of tests. We don't do biopsy basically to make a diagnosis. So we usually get blood samples and get DNA from blood samples, or there are some tests where we can also do buccal swab, and getting samples from the mouth and getting genetic information from the DNA that we get from these samples. So the tests are very simple. It's either a blood test or a buccal swab, and it goes to the lab, and the results come back, and we go over the results with the patients and explain to them what they mean.

7


Now, going to your second question, I think you were asking me how those genetic tests actually help. Is that what you were asking me? Andrew Schorr: Yes. Well, actually what are you looking for? So you mentioned certain genes that relate to sort of processing of cholesterol, so is that one we can identify now, that, hey, you don't process cholesterol so well because of your genetic makeup, so do we have to take that into consideration? What are you able to observe today? Dr. Ardehali: Right. So that's a good question, and, Andrew, before I answer that question let me just give a couple of interesting facts from the Human Genome Project which will help us answer this question a little better. Andrew Schorr: Sure. Sure. Dr. Ardehali: So the Human Genome Project showed us that we have 2.85 billion base pairs… Andrew Schorr: Oh, my. Dr. Ardehali: …in our genome. That's a big sequence, and that basically refers to nucleotides that are present, present in our genome. And we have four different nucleotides based on the structure of the base that is present in that nucleotide. So we either have adenine, thymine, guanine or cystocine. And again that's dependent on the base that is present in the nucleotide. Now, so we have 2.85 billion base pairs, and if you actually write those base pairs on a piece of paper it takes 400,000 pages to fill it up. So you can imagine how difficult it was to sequence the human genome, and that's why it took a long time. Andrew Schorr: So this is the code that makes up an individual's body and their cells. Dr. Ardehali: Exactly. Now, this 2.85 billion base pairs, it encodes for only 20- to 25,000 genes in our genome, and that accounts for 100,000 difficult proteins that we make. So as you remember from our basic biology classes, DNA makes RNA, and RNA makes protein, so this genome codes for proteins that are synthesized in our body, and only 100,000 proteins are made. Now, that 20- to 25,000 genes that I mentioned, that's only 50 percent more than what a worm has. A worm or a fly has 10 to 15,000 genes. So we only have 50 percent more, or one has 50 percent less than our genes.

8


Andrew Schorr: I thought we were much more highly evolved than a worm. Dr. Ardehali: Exactly. That's quite surprising, and it has been surprising to many people. We thought we had a lot more genes in our genome that could explain the complexity of our body, but it appears that we are not that much different, at least at our genetic level, from very primitive organisms. Andrew Schorr: And just to help people understand, Dr. Ardehali, so when we talk about genes, though, we're really talking about the blueprint for our body, for living. So if I've got it right, it's the whole blueprint, it's the instructions for what cells we make, how they divide, what proteins they have, what their behavior is, what their function is. It's the base blueprint for everything. That all comes out of the genes. Dr. Ardehali: Exactly. So a gene, the definition of a gene is that it is a unit of heredity in a living organism. So it basically contains the information to build and maintain an organism's cell and also to pass the genetic information to offspring. So that's basically what a gene is. And if you look at other definitions, it's basically a stretch of DNA, and DNA again is deoxyribonucleic acid, and that's basically the code that I was telling you earlier, sequence of different nucleotides that contain different bases, four different bases. What Scientists Have Learned About Genes Andrew Schorr: So we went through our science lesson, and I think I understand that. So again where we are with our understanding of that complexity, although only 50 percent more complex than a worm, related to the genes that affect different issues for the heart and coronary artery disease, you said you could do a blood test. You could swab our mouth. What are you going to look at in that DNA that could be helpful? Dr. Ardehali: Yes. So one thing we learned from the Human Genome Project is that you and I, Andrew, are 99.9 percent similar at our genomic, genetic level. That means only one nucleotide out of 1,000 to 1200 base pairs are different between two human beings. And these small differences, only one in 1,000 to 1200, explain why we are different, why I look different from you or from anybody else. And also it explains why I'm more susceptible to some diseases than other people or some other people are more susceptible to other diseases. These differences at the genetic bases explains not only are the way we look it also determines how we respond to different diseases and different insults, different injuries throughout our lives. So after the Human Genome Project was completed the goal was to figure out what genes contribute to different disorders. Now, basically the genetic diseases can be

9


divided into three different categories. One is chromosomal disorders, and we all know about Down syndrome and trisomy 21. That's basically when a chromosome is abnormal, and these disorders have been discovered for many, many years we have known about this. There's also a group of diseases called simple inherited disorders, and an example of that is cystic fibrosis or sickle cell anemia. And in those disorders there is basically a mutation in a specific gene that causes the disease. So if you have that mutation in that specific gene, you get the disease. If you don't have it, you don't get the disease. So there is a one or zero answer, you know. If you have the mutation, you get the disease. If you don't have the mutation you don't get the disease. What has been challenging to us in the genetic field is what we call complex disorders like diabetes, coronary artery disease, cancer, obesity, and high blood pressure. These are not due to one single gene mutation. We know that there are multiple genes that contribute to these disorders, and there are environmental factors. So, for example, let's say we discover four different genes to be involved in cancer. I'm just using that as an example. So genes A, B, C, and D. So if you have the mutation in gene A you may have a 30 percent chance of getting the disease if you’re, let's say, Korean, if you are from a Chinese race, but if you have a mutation in the B gene you may have a different chance of getting the disease if you are from that race. And the numbers may be completely different if you are a Caucasian. So it is not just one gene causing a disease. It's multiple genes that can contribute to a certain disease, and they're all affected by other factors, environment, race, and other things that can contributed to the disease. Andrew Schorr: Wow. This is going to take a little deeper discussion for us to understand the detective work you're starting to do in cardiology now to help people like Kathryn. Let's take a brief break. When we come back we're going to continue understanding what you're doing now in your clinic to help give information to people like Kathryn and what they can do with that information to lower their risk of some of these inherited heart conditions. We'll be back with more Patient Power sponsored by Northwestern Memorial Hospital right after this. Andrew Schorr: Welcome back to Patient Power. Andrew Schorr here with Dr. Hossein Ardehali, who is director of the program for cardiovascular genetics at the Bluhm Cardiovascular Institute at Northwestern Memorial. Also with us is his patient who is inquiring about her genetic connection with heart disease, and that's Kathryn Schmahl. All right. Dr. Ardehali, where we left off was in understanding that there may be several genes at work when it comes to coronary artery disease, not just one as

10


there might be in cystic fibrosis, or I personally have known some people with Huntington's disease, an inherited condition where they've identified a gene. So in heart disease how many genes do you think are at work? Dr. Ardehali: That's a good question and I wish I had the answer to that question. I don't think anyone knows at this point, and that's why we are doing all these different studies. And so far I can tell you there are maybe three or four genes, or I should say that is referring to the location within our genome that probably contribute to coronary artery disease, and they have been confirmed by different studies. The problem we are having is that sometimes people find a mutation or a defect in part of our genome and other people cannot replicate. So it's very critical that the information that has been published can be replicated by other people and other investigators. And so far I would say three or four are available that we can test. Information Provided by the Genetic Test Andrew Schorr: All right. So you do the blood test, you swab the mouth. Let's say, with Kathryn, so when and if you do a test there, what would some information that might come back? Would it be one would be this example that you have a gene that affects your production or processing of cholesterol? What would be useful information that might come back? Dr. Ardehali: So I think we can categorize the information into several different categories. The first one is this test helping us to make a diagnosis. Not a diagnosis but providing information as far as what the risk of the patient is to have coronary disease or some other cardiovascular disorders. So for example we know that one location within our gene that has been shown to correlate with early-onset coronary disease and incidence of myocardial infarction, which is another name for heart attack, is a region called chromosome 9p21. And this chromosome 9p21 is a region within the chromosome of 9 that has been shown to correlate with coronary disease, and if there is a mutation in the specific location of that chromosome the chance of getting coronary disease if you have two of these goes up by twofold, so you have a twofold higher chance of getting early-onset coronary disease if you have these mutations. So that's one category. We can basically use this test to identify the risk of having early-onset coronary disease for our patients. The other thing that it can help us is to guide us as far as our treatments. There are some tests that we can do, and based on those tests we can tell whether or not our patients would benefit from a specific drug. For example there is a gene called LPA, and that's lipoprotein A, and we know that if there is a mutation in that gene, or I should say a polymorphism or a change in the sequence of the gene, patients who have that mutation have a 56 percent relative risk reduction in another

11


cardiovascular event if they take aspirin. So it's very critical for these patients to take their aspirin, and we've got to be very careful to make sure that these patients take their aspirin no matter what. And there are some other tests. We know that there is test called KIF6, and that stands for kinesin-like protein 6, and if you have that mutation you have a higher likelihood that you would benefit from a statin drug. And statins are the drugs I mentioned earlier, and those are drugs that inhibit an enzyme involved in cholesterol synthesis, and examples of statins are Lipitor, Crestor and Zocor. So when we identify these patients we want to be more aggressive as far as giving them the drugs. Andrew Schorr: I think of an example and a lot of people can relate to concerns, let's say, in women about breast cancer, so if mom had breast cancer at an early age her daughter with no sign of breast cancer might start mammography earlier, right? So that would be screening earlier, for example. That would be a valid example, correct? Dr. Ardehali: Yes, that would be a good example. And I basically emphasize how these tests can help us with our diagnosis and risk stratifying our patients and also guide us as far as our treatment. But one other area that these tests can help us is, let's say, a patient comes to me and I do these genetic tests and I identify the patient to be at higher risk of coronary disease. So I go back to the patient and I explain to the patient that, you know, listen, you may not have high blood pressure, you may not have diabetes, you may not be a smoker, but you have this genetic disorder or this genetic defect that increases your risk of having coronary disease. Now, this is the patient's choice and if the patient wants to have further tests we would be happy to provide those tests. We can do noninvasive imaging of the coronary vessels in the heart and identify whether or not the patient has any blockage, and if they do then we are going to be more aggressive as far as preventing further blockage in the coronaries. And if there is any indication we would go ahead and open up the vessels. So, as you said, like breast cancer these tests in cardiology can also help us identify patients who may have coronary disease and perform more tests to identify whether or not the patient has blockage in the coronary vessels. Andrew Schorr: Right. And then of course the other side of it is too that, let's face it, we have an obesity problem in this country. Dr. Ardehali: Right.

12


Andrew Schorr: We have an epidemic of diabetes, and although a lot of people have quit smoking there are still millions of people who have not, so if you identify these genetic risks and that person did have these other factors, they're kind of skating on thin ice, perhaps, are they? Dr. Ardehali: Yes, exactly. So this test can also motivate our patients to be more careful about their health. If they don't have any other risk factors but they have this genetic defect that is not visible unless the test is done, and when the test is done it identifies the patient to be at high risk, I personally feel if I have that information I would like to be more careful. That means at an earlier age I may start taking an aspirin. I may take cholesterol medication to reduce my cholesterol. I may want to take fish oil to make sure that my good cholesterol goes up. And things like that. I may exercise more. So this may be a motivator for our patients to take better care of themselves knowing that they have a risk factor and they didn't know about it, and that is because it was hidden inside their cells, and the information cannot be obtained until we do these tests. Andrew Schorr: Well, let's play this out if you don't mind. Kathryn, so you've been listening. You haven't quite had all these tests yet or the conversation with Dr. Ardehali, but let's do a little role play because you're listening, you're saying, well, gee, what do I think about this. You have the test, he comes back, and he says, yes, you run, and, yes, you're physically fit, and you're youthful and active and you're not overweight and you eat right and you do all these good things, but, you know what, here is this gene that we can tell that is changed, and we have information that puts you at a double risk of a heart attack perhaps at an earlier age. And he says maybe you should take some fish oil or take aspirin or whatever. What do you say? What's your thinking about that? Kathryn: Absolutely. I would be absolutely willing to make the changes to address the risk that's there. Andrew Schorr: Okay. Now let's say he walks back in the room and he says Kathryn, you know what, I know you had these family members where bad things happened at relatively young ages, but at least what we can see in the genes now, we don't spot it with you. That would be a sense of relief, wouldn't it? Kathryn: Absolutely.

13


Andrew Schorr: Yeah, I think that would be a great peace of mind. So, Doctor, let's talk about that, where we are with what we know about genes. And, again, I'm familiar with that breast cancer example, a lot of people are. My family is Ashkenazic Jewish and there was a high risk there, and they've identified some genes that are even more prevalent in that group of people women who might be at higher risk for breast cancer or ovarian cancer even though that's the minority of breast and ovarian cancer patients. But they know that there are other genes at work in breast cancer, and probably there are other genes at work that you haven't identified in heart disease. So if you sort of come back and give Kathryn a clean bill of health on what you can observe, that doesn't necessarily that there aren't other genetic factors, right? Dr. Ardehali: Absolutely. And the point I want to emphasize here is that if a patient comes to me and I do the test and go back to the patient and say, well, everything is okay. You don't have any mutations, that doesn't mean the patient should come out of my office and go get a box of donuts and eat donuts. It doesn't mean that the patient doesn't have a high risk of having coronary disease. It's very critical to emphasize that the patient is not at high risk of getting coronary disease. So the lack of these tests, if the tests are not positive it doesn't mean that the patient should forget about lifestyle modifications and not exercise. That doesn't mean that. We should always emphasize lifestyle, good lifestyle, not smoking, eating good, good diet and all that, but these tests also identify patients who are at high risk. So if you have mutations in these genes it doesn't mean you have coronary disease. It just means that you are at two times higher risk of getting coronary disease. It doesn't identify blockage into coronaries. Andrew Schorr: Let's talk about, you know, what runs in families. So, you know, if you're chatting with somebody and you get to know them over time and someone says, well, cancer runs in my family, heart disease runs in my family. Do we know when people say that are we really talking about the genes or maybe the lifestyle that family had. They ate really fatty foods, nobody exercised, you know. I mean, it's hard to say, isn't it? We're beginning to understand that but, it could be I think you say in the medical field multifactorial, right? Dr. Ardehali: Exactly. Yes. And that's a good point. You know, I have had many patients who came to me and said, you know, my dad had a heart attack at age 55, but he's still alive. And I ask them did he smoke? And they say, yeah, he was a smoker, he had diabetes, he had high blood pressure, and he had very high cholesterol, so that reduces my suspicion as far as thinking that this patient has a family history. Because the person who is smoking and has high blood pressure, has diabetes and has high cholesterol, that person has all these modifiable risk factors,

14


environmental risk factors that contribute to coronary disease, and even if they don't have a genetic predisposition, those factors can still contribute to coronary disease. Andrew Schorr: All right. Let me take this a little further. Because, Kathryn, do you and your husband have plans to have children some day? Kathryn: Yes. Andrew Schorr: Okay. So let's just say that Kathryn has tests with you, and they come pack positive, and she's ready to take the fish oil or do ever what she needs to do. And let's just say that, what's your husband's name, Kathryn? Kathryn: Andy. Andrew Schorr: Oh, nice name. There you go. Some people call me Andy. Okay. So let's say that Andy had the same concern and maybe he had a genetic test and it was positive, too, so he's doing everything he can so he does not have coronary artery disease, and Kathryn is doing that too. And they have a baby. Do we know about the genetic transmissibility, if you will, of genes that relate to a higher risk of earlier heart events? Dr. Ardehali: So we are not at that point, able to screen newborns for coronary disease. Our research hasn't got to a point that we can do that. However, I want to mention what I think the future will be like, and again I can't guarantee the future will be like this, but this is what I think will happen in the future. So I think like 50, 60 years from now if I go to an emergency room, I will have a card with me with my picture and with my ID, and the card, I give it to the doctor. He goes and puts it into the computer and the sequence of my genome will show up on the computer. Not the whole, you know, 2.85 million base pairs, but the information that the doctor needs to see what diseases I'm at high risk of and what medications I should be taking. At this time we are more relying on population medicine. We do studies in let's say 20,000 patients and we compare drug X versus drug Y and we say, okay, drug X works better, so we should give drug X to our patients with coronary disease. In the future medicine will be more personalized because we will have the genetic code of our patients, and we will know whether or not our patients should be taking drug X based on the specific genome sequence of that patient and whether or not the patient should be taking drug Y. You know, if we do the study in 20,000

15


patients drug Y may not work as well as drug X, but in specific patients in that group of 20,000 patients it may work better. So in the future we will have this information, but at this point we are not there yet. But we are making very good progress. The Human Genome Project has helped us significantly, and this will help us to revolutionize medicine from population medicine or population-based medicine to individualized medicine. Who Should be Tested? Isn’t a Family History Enough? Andrew Schorr: So what about the concern, though, that Andy and Kathryn could have is could they pass on genes that would put their baby at higher risk? Do we have any sense of that in cardiology now? Dr. Ardehali: So if a newborn baby has these mutations, and again I don't think that newborns should be tested, but in the future if he is tested and he has these mutations that suggests that the patient has a high risk of getting coronary disease, so that person would probably have to make lifestyle modifications and take other medications. But at this point again we are not at a point to screen newborns to see whether or not they will have coronary disease in the future. Andrew Schorr: Okay. So we've got people listening, including our producer, Jamie wonders about it because Jamie has had family members who, actually, Jamie's mother passed away of a heart attack at age 49. And Jamie wrote me and said that her maternal grandfather had two bypass surgeries. I'm not sure at what age, but she thinks about this in her family. Somebody would say, well, who should be tested? So at your clinic and referrals at the Bluhm Cardiovascular Institute who is a candidate to really maybe come in and see you where you say, you know, it makes sense? Dr. Ardehali: I would categorize those patients into four different categories. The first category is patients who don't have any risk factors and they're concerned about getting coronary disease, and Kathryn is a good example of that. She's in her 20s. She wants to see whether or not she has a genetic predisposition to coronary disease, and that will lead her to have a change in her lifestyle and maybe take medications early. Maybe when she turns 40 she may take cholesterol medications even though that's not really indicated for someone at that age, but she may think that that may help her. Or she may take fish oil. So those are things that those patients do. Now, the second category would be patients who have other risk factors, let's say high blood pressure, diabetes or they have high cholesterol or they are smokers, and they want to see if they have an additional risk factor, which is the genetic predisposition. And they come in and we test them and if we identify an additional risk factor that even increases their likelihood of getting coronary disease even--increases that to a higher level. And those patients, again we would become

16


more aggressive with those patients and try to make sure that they get the best possible treatment. They may have these noninvasive methods to look at their coronary vessels, and so those are patients that would also benefit from such tests. Now, the third category of patients would be patients who have a family history, and again that would probably refer to the case that Kathryn has, and if patients who have a family history, they want to make sure that the family history translates to these clinical or these genetic abnormalities. And we do those tests and I think it also helps those patients to motivate them to conduct a healthier lifestyle. And finally patients who have coronary disease if we do these genetic tests we can identify patients who would benefit from specific medications that they are taking, and we would be more aggressive with those medications. One thing we do in our patients is after we do cardiac catheterization we give them a medication called Plavix. Now, the thing about Plavix is that Plavix by itself doesn't do any good things to our body. It has to be metabolized in the liver to a different drug--to a different molecule. That's why we call Plavix as a pro-drug, and we know that there are some patients who are poor metabolizers of Plavix. So if you give them 75 milligrams not much of that becomes transformed to an active form that helps their body, so those patients need to probably get a higher dosage of Plavix, or they may need to get a different medication. So we can do those tests to identify patients who should be getting a different dosage or a different medication to help make sure that their coronary vessels don't close up again. So again in all these four categories I think the genetic tests can help our patients. Andrew Schorr: That last area you were talking about, about how does someone process a medicine, is that what you call pharmacogenetics? Dr. Ardehali: Yes. So pharmacogenetics is a very big area of medicine now, and that's basically what I was talking about earlier. I think pharmacogenetics one day will be to all of us having our genetic information help us identify how pharmacological therapy or, you know, medications, how these medications can help us. And that's what I was talking about earlier, that our genetic code will someday be available to all of us to our physicians. Andrew Schorr: Wow. This is so cool. Well, we're going to discuss this a little bit more and look into the future and help our listeners understand what's right for them and maybe a little guidance from Kathryn as to the thought process she went through and what she might recommend to others. All that as we continue our Patient Power discussion on the heart and genetics sponsored by Northwestern Memorial. We'll be right back.

17


The Future of Genetic Testing Andrew Schorr: Welcome back to Patient Power as we continue our discussion on, really, where medicine is headed, and that is us having our whole genome personally sequenced, and it's becoming much less expensive and someday not far off may be standard, you know, when you go to the doctor, as Dr. Ardehali was saying, you have that card and it has your genetic sequencing right there and knowledge from that of not just what you're at higher risk for but also which medicines might be effective given the blueprint for your biology. So, Dr. Ardehali, let's talk about that. You said 50 years from now you could imagine going in with the card, but you also mentioned that the whole human genome was sequenced much faster than anybody expected as computing power got ramped up and all that. So maybe the pace of change is increasing. You're doing some testing at Northwestern now to help people make decisions, like Kathryn, but where are you going to be next year or two years or three years from now? Let's have sort of that nearsighted crystal ball. Dr. Ardehali: Sure. So when I said 50 years I was giving you a very conservative estimate. Andrew Schorr: Yes, you were. Dr. Ardehali: That's basically how we all thought about the Human Genome Project it would take a long time, and the information would not be available for a long time, but we saw that we were all wrong, and things improved very quickly because of our progress in our technologies. So what has happened since we sequenced the human genome was that basically that was from one person. Now the idea is to sequence the genome from multiple people, from several people around the world and with different diseases and identify what genetic mutations caused the disease. And that's basically where we are now with the human genome, and basically we have a lot of information. We have 2.85 billion base pairs of information, but we want to see which one of them contribute to different diseases. And that will take a few years, and I don't think we will have all the answers probably for maybe a couple of decades. But in the next few years we will have more information. You know, it's amazing how much we have learned over the past four or five years as far as the genes that have been identified to be mutated in the complex diseases like coronary disease, diabetes, cancer and high blood pressure. And I think very soon we will--the price will go down significantly. So the price of getting our genome, our genes sequenced will probably be in somewhere between $1,000 to $5,000 and same

18


price as doing maybe, you know, an MRI or a CAT scan. So our patients when they go to the hospital they may as one of the routine tests they may get their genome sequenced. Now, we can't--we don't have all the information what to do with that information at this point. Again, it will take a couple of decades, but that can still help us identify those who are at high risk based on what we know at this point and what we will know four years from now. So I think the genetic aspects of medicine is going to revolutionize medicine, and I think we will pay more and more attention to the genetic codes of our patients in the next few years. We are basically at a point now that the future of medicine, as I said earlier, is going to be transformed into individualized medicine, and we are going to see that in the next couple of years. Andrew Schorr: Right. I actually got to be the master of ceremonies at the Personalized Medicine World Conference just last week, and that's what they were all saying, geneticists there and companies that make these sequencers, there's a lot of work going on. And they actually believe that all of us will have a much more personalized approach, and that will be part of the dialogue with our doctor, and I know you as a scientist and a clinician welcome this. Now, here's the question that a lot of us just out there in the public wonder. You know, often we might have the attitude, I really don't want to know. I don't mean like necessarily being like an ostrich who puts his head in the sand, but basically, I'm feeling okay, life's going all right, I maybe don't want to think about it, A. Or, if there is testing, genetic testing, and it brings back these answers maybe I do want to know, but I don't want it generally known. So obviously the concern is, could I lose my job, could I be discriminated against, could the insurance company insist on charging me more money for my risk of heart disease even though I don't have it now? Where are we with protections, Doctor, and what would you say about people's concern about that privacy, if you will? Dr. Ardehali: Sure. So my answer to the first group of patients who basically say I don't want to know is that we only have one heart, and if the heart goes our body goes, so I emphasize to all of my patients that, listen, I want to take very good care of your heart because I know your body depends on your heart. I would do anything that is needed to make sure that you get very good care of your heart. And so if there is information that can help us take better care of our heart I would go ahead and do it and not say, well, I don't want to know. So that's my answer to the first group of patients. But the other group of patients that you mentioned are patients who are concerned that this information may act against them and may cause their health insurance premium to go up. But there is a Genetic Information Nondiscrimination Act of 2008. It has already passed the congress, and President Bush signed it in 2008, and it appears that this bill prohibits the improper use of genetic information in

19


health insurance and employment. So the concerns that people have was the concern that our lawmakers had too. They spent billions of dollars funding the Human Genome Project, and they don't want to get to a point saying, well, the scientists and physicians cannot use the information because patients don't want to have the information since it may act against them. So they have passed this law, and the law provides us with the peace of mind that it will not be used against us. Andrew Schorr: Kathryn, so you've been listening. You've actually thought about all that, right? Kathryn: Yes. Andrew Schorr: What would you do with the information and would it be useful. So it sound like you're eager as a 27-year-old to really get a clear picture of your health status and the genes that your mom and dad gave you. Kathryn: Yes. Andrew Schorr: So what would you say to other people? So, you know, there are people out there, and they are worried. Like my friend Dennis, his dad died of a heart attack at age 40 and as he approached his 40th birthday he was just extremely anxious. And when he was 40 years old and one day, he thought he was on borrowed time and two days, more borrowed time without any knowledge. And at that point, this was a few years ago, there was not the science to try to look at his genes. Some people are still there even though the science has moved on. What would you say to them if they have concerns? What do you think people might want to do? Kathryn: Well, I think that we know that early detection is the key to a lot of the health risks that are there, and so if we know that there is a risk already existing that gives me peace of mind when I talk to Dr. Ardehali and we talked about doing the genetic testing. If there was a genetic predisposition, I said what do we do about that? He said, well, we will check in with you more often to see how you're doing. So that gives me peace of mind that if there is an increased risk that I have the opportunity to have detection take place earlier so that anything what needs to be done can be done more quickly. Andrew Schorr: Right. And I think that's so important for people. And I know my friend, Dennis, the guy who's dad died in early age, this kind of gives him some confidence as well. Dr. Ardehali, so you're having some interesting discussions with people who come to see you now as you go into this genetic world because it really is the leading edge of medicine, isn't it?

20


Dr. Ardehali: I think so. Again, personalized medicine will be the future of medicine, and I think the mission of the National Institute of Health is also to help physicians and scientists go through that transition and transformation, and I think more of us will be emphasizing personalized medicine in the future. Andrew Schorr: Now, let's talk about its role at the Bluhm Cardiovascular Institute. So the leaders there asked you to start this, right? There is not this sort of genetics clinic at every medical center around the corner. You're really a leader in this, aren't you? Dr. Ardehali: Yes. So not every medical center around the country has this. We have all the cutting-edge tests that are available. We work with different companies to provide all the available tests to our patients, and this is something that the leaders here at Northwestern had on their mind, and they wanted to be ahead of the curve when it comes to this transition from population-based medicine to personalized or individualized medicine. Andrew Schorr: All right. So if somebody is listening and they say I want to find out more, can they self-refer? Can they talk to their primary care doctor? If they already have a cardiologist but the cardiologist doesn't do this, how do they get to you? Dr. Ardehali: Yes. So they can either be referred to us or they can call us, and we would be happy to make an appointment. And they can see me in clinic. My information is available on the website, but I take patients in my clinic, and I would be happy to see the patients and help them with their genetic disorders. Andrew Schorr: So somebody comes, you sit down with them, you talk through family history first, right? Dr. Ardehali: Yes, absolutely. Andrew Schorr: And then where does the testing come in, and then when does further testing, you know, beyond blood testing or the mouth swab, when do like a heart scan or any of that come in? How does that proceed? Dr. Ardehali: So after we get the information I usually ask the patient to come back. I explain to them what it means, and I tell them what I think should be done next, and I try to

21


make sure that this decision, the next decision is more of a team decision, both of us, me and the patient together talk about it and see where it goes next. And I give them my recommendation and we go from there. Andrew Schorr: Okay. Well, it sounds like you are a man who can really help us understand, look into our bodies like never before, and our heart, and, as you said, we only have one heart so we have to honor it and pay attention to it. So, Kathryn, are you feeling confident going forward that whether the answers to tests are positive or negative that you can go forward and really play an active role in maintaining your heart health? Kathryn: Yes, I do. Andrew Schorr: Okay. Well, I'm going to look for you jogging there, with Andy, in Chicago and maybe not too far down the road pushing a baby carriage. That will be fun. I wish you well. Thank you for being with us, Kathryn Schmahl, and really helping us to understand how family history comes into play when somebody thinks about it and wanting if understanding what's going on in their genes kind of unlocks some secrets. And Dr. Hossein Ardehali, director of the program for cardiovascular genetics in the Bluhm Cardiovascular Institute, thanks for what you do and in the work I know that will still unfold. And thanks to your institute also for helping to lead the way because I'm convinced it is where medicine is now, but is going to do a lot more down this road in the future, personalized medicine for our whole body and certainly for our heart. Thank you, Doctor. Dr. Ardehali: Thank you. Thanks for having me on your program. Andrew Schorr: Oh, sure. Well, this is what we do on Patient Power. This is something I think we're going to be discussing a lot more is genetics. Certainly we talk about it in cancer, we talk about it now in heart issues too, and as you can hear, a lot of groundbreaking work is being done. Thank you so much for joining us on Patient Power. Remember, knowledge can be the best medicine of all. I'm Andrew Schorr. For more information or to schedule an appointment with a Northwestern Memorial physician, please contact our Physician Referral Service at 1-877-926-4664 or visit us online at www.nmh.org. Please remember the opinions expressed on Patient Power are not necessarily the views of Northwestern Memorial Hospital, its medical staff or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

cardiovascular genetics: am i at risk? webcast february 8...

Documents