Cardiogenetics: Genes and Heart Health

Welcome to the Texas Heart Institute educational programs and podcast series on the topic of the latest advances in pharmacogenetics. My name is Juan Uribe I'm clinical professor in cardiology at Baylor College of Medicine and interventional cardiologist at Texas Heart Institute Baylor St. Luke's Medical Center in Houston, Texas. Our guest today is uh Dr. Silvana Miskovic from Split, Croatia. She works at Analiza Lab in Split, Croatia. Now, we know from previous publication that every person reacts differently to drugs medica- and medications. According to estimates, approximately 7% of patients suffer from severe adverse reactions and about 0.4% suffer from fatal consequences related to a variety of drugs. Adverse reactions to drugs are the fifth most frequent cause of death in developed world. In most cases, these reactions are determined by inherited genetic variations or mutations, environmental factors, and also certain drug interactions. Dr. Miskovic has a great expertise in the area of genetics and she is a graduate of the European School of Genetic Medicine in Bologna, Italy. She also published extensively on this topic and is an author of a book Genetic Counseling in Practice. Since 2005, she's working in the field of immunology, oncology, and preventive genetics. Dr. Miskovic, welcome again to this podcast on genetics and pharmacotherapy. >> Uh Professor Kreutzer, thank you for your invitation. It's a pleasure and honor for me to be guest in your podcast. And uh please accept a warm greetings from the split and also from Annalisa clinic. >> Thank you. How does genetic testing and pharmacotherapy help us in avoiding side effects from various medications? >> Uh the first based of our genetic analysis that we call the pharmacosensors, uh pharmacosensor is our personal identification card about our uh how to how we reacted to some medicine. Uh based of this genetic information that provide information how we metabolize some medication, which medication is appropriate for us, which medication causes the side effect in our organism, and which dose is appropriate for us. Uh when we know all of about this information, uh the pharmacosensor is very important for our for us for clinicians and also for our patient to make a right decision about the medicine for better outcome of our patient and with avoiding of side effects. >> Excellent. Including here is the list of studied cardiac pharmacosensors on a specific patients. You might want to comment briefly on this uh particular uh table that's listed. >> Uh this is two genes connected with the increased risk of heart diseases. Uh you can see uh the name of the gene, also the relevant polymorphism, three type of genotypes, the population prevalency, and also uh the risk lab results for our patient. Uh for example, uh when we speak about the cadherin 13, uh this patient uh is a carrier of GG genotype. The population prevalency is 59% and this genotype is connected with a 2.23 higher risk of uh heart diseases than in compared with the TT genotype. Uh also, when we speak about the coronary heart disease susceptibility to age, the person is a carrier of GC genotype with population prevalency of 45%, which is uh connected with a 1.47 higher risk of heart disease uh in compared with a GG genotype. Uh both of these genes are connected with the scientific references uh because the scientific references give us credibility when we speak about the gene, relevant polymorphism, genotype, and results of our patient. >> Thank you very much for this interpretation. Are the current analysis of cardio pharmaco sensors addressing all major cardiovascular risk factors? >> Uh absolutely. Uh all pharmaco sensors including information about the lipid metabolism, homocysteine metabolism, uh regulation of the blood pressure, iron channel uh functioning, uh muscle structure, uh and but I must tell you, uh till these days we don't have genes which are force patient to start uh to um stop smoking and starting with exercise. >> Are all currently used pharmacosensors adequately studied and reported in scientific publications? >> I I really I don't know. Lots of laboratories and lots of um firms offer the pharmacosensors, but our pharmacosensor is adequately studied and reported in scientific publications. >> So now, this is a very important question that I have to deal with on a regular basis. Should every patient undergo genetic testing prior to initiation of any prescribed medication? >> Uh absolutely. It would It would be great. It would be wonderful for both, for physician and also for the patient, because when the physician establish adequate the diagnosis based on pharmacosensors, he he or she choosing adequate medication and our patient in the first step receive adequate medication for better outcome and avoiding the side effects. Because you know, as a physician, we hear lots of times in between the our patient, they change three to four medication without effect, and some of that medication provide some side effects in the organism, but fifth medication is absolutely good. Uh the fifth medication is not miracle, is just medication based of our genetic information. And that type of fifth medication is based of proper proper type of genetic connection. So, that is a reason why I tell you about the patient in the first step receive adequate medication. >> Now, one very useful information that you provide uh in your analysis uh and genetic report includes three studied variables. Drug effect, drug breakdown, and drug dose. What is this based on and how to use this information in drug selection? Let's start with a drug effect first. >> All of this information are based of analyzing of 14 14 genes involved in medication uh in metabolism of the medication, relevant metabolism, and also also the genotype of our patient. Uh for example, when we speak about the drug effect, in the first line you see the patient which is normal metabolizer, which is mean the breakdown and is absolutely okay, and there is no need to adjustment of the dose. Uh in the second line, you see the patient who is faster metabolizer. The body activates this medication too quickly, and the clinical implication is start with a lower dose of medication. Uh in the third line, you see the patient who is a slow metabolizer. That is mean the body activates this medic medication too slowly, and a higher dose of medication is absolutely needed to achieve adequate effect. And in the fourth line, you see the body is unable to sufficient activate the drug. So, my recommendation is try with alternative medication. >> Yeah, this is very, very important information. Now, this is not the only information you provide, but you also look at the drug dose as far as dose selection is concerned. Maybe you can comment on this as well. >> Absolutely. The drug dose is a second variable in our Pharmacosensor. It is connected with drug breakdown. Also, in the first line, you see the normal metabolizer, which is mean the breakdown of medication is absolutely okay. The So, we can prescribe the standard dose of medication. In the second line, you can see the patient who is a fast faster metabolizer, which is mean the breakdown is too fast, which is lead to a lower dose of medication in the blood. So, the suggestion is start it with with the standard dose and slightly elevated that dose. In third line, you can see the patient who are slower metabolizer, which is mean the breakdown of medication is too slow. The higher concentration of medication is in the blood, and the clinical implication is started with a low dose of medication a low dose of medication. And the fourth line, there is a the patient is poor metabolizer, so there is no effect of breakdown. And in this case, I suggest taking of alternative medication. >> Now, let's talk about drug breakdown. Again, >> Yes, and that is a connected with a drug dose. Uh in the first line, you see the normal metabolizer with a normal breakdown of medication. Uh so, you can prescribe for that patient a standard dose of medication. Uh in the second line, you see the faster metabolizer, which is uh mean the breakdown is too fast, so the level of medication in the blood is too low. Uh the uh the clinical implication is uh started with the standard dose, and then the slightly elevated under physician um uh under physician looking. Uh the third line is a slower metabolizer, which is mean uh the breakdown is slower, the concentration of medication is too high in the blood, and the clinical implication is please prescribe the lower dose of medication. And uh the fourth line, uh the body's unable to sufficient breakdown, and it's much better to take alternative drug. >> So, here are Here is one of the examples of uh pharmacogenetic testing in your lab. And uh can you uh explain this pretty complex uh scheme that you have related to cytochromes, which are very important in metabolism. Now, I think that the most of the drugs or great majority of drugs uh are being metabolized through uh cytochrome P450, but there are other ones that play a significant role. So, maybe you can comment on this as well. >> Uh when we speak about the drugs in cardiovascular medicine, uh the most of drugs are uh connected with uh CYP3A4, CYP3A5, with a connection with a CYP2C19, CYP2C9, and also CYP2D6. Uh for clinician, this is I'm sorry. Uh for clinician, this picture is very important because uh when clinician want to prescribe some medication which pharmacokinetics is connected with CYP2D6 or CYP3A5, uh my suggestion is avoiding that medication. Why? The patient is a poor metabolizer, which is mean the breakdown and activation of the drugs via these genes is absolutely insufficient. But, in the second case, when the physician want to prescribe some medication which is pharmacokinetics is connected with a CYP2C19, the patient is a faster metabolizer, so the clinical implication is start with a standard dose, and then slightly elevated. But, in third case, when the physician want to prescribe some medication which is pharmacokinetics is connected with CYP2B6, the patient is slow metabolizer, which is mean that medication have slow breakdown, uh the high concentration of medications appear in the blood, so the clinical implication is started with a lower dose. But, if the patient if the physician want to prescribe some medication based of um VKORC1, the suggestion, please please avoid this type of medication. For example, VKORC1 is connected with the metabolism of warfarin, uh so suggestion, please avoid this type of medication because this genetic uh variation lead us uh to immediately appearing uh of side effect. >> Very good. So, uh of course, there are a lot of pharmacogenetic genes that play a significant role, and you already discussed this uh quite extensively. Uh here is a for instance, a specific example of variety of drugs that we use not only in uh cardiovascular diseases, but others as well. And on the basis of the information that you just provided as far as uh uh breakdown is concerned, uh dose and effect, uh here you can get an information that's clearly shown that which drug should be used and which drug should be used or there should be certain caution when we use certain drug that is listed here, and we can go through this list uh following uh many many drugs that are available. Now, what we would like to see as a cardiologist uh is actually just specifying on the drugs that are related to cardiovascular diseases. However, we as physicians provide many different drugs, so it is meaningful to add everything that is included in here and here we can see through the list and you might want to comment on one of them and just mention when you have X there that means it's not a good idea to use the drug in general, correct? >> Uh correct. I want to see the first picture, please. Can you return on the first picture? For example, it's the drug is carvedilol if I see correct. >> Yeah. >> For all of these genes you understand. You understand some genetic principle, but when you look the carvedilol you think oh, it's something wrong with this with this medication. You see the breakdown is a slow, but effect of the drug is absolutely insufficient. What is a happened with the drug with that drug? That is that is a beautiful part of pharmacogenetics because that is explained that pharmacokinetics of one medication is not connected with only one specific cytochrome genes. When we speak about carvedilol the pharmacokinetics of carvedilol is connected with functioning of I think four genes. For example, cytochrome 2D6, cytochrome 2C9 with contribution of cytochrome 2 sorry cytochrome 3A4 and cytochrome 2C19. And when we get all information about four genes, we can make decision for the patient. And the decision for this patient it's not please take some lower dose. >> Right. >> For decision for this patient is please take the alternative drug. >> Good. So the last few questions that are important and I know you are involved in this evaluation as well. Which is separate from what we have discussed so far, but you provide that analysis. What is the food intolerance or allergy related to and how is it mediated? >> The food intolerance is immunological reaction based of IgG antibodies to the food proteins and allergy is also immunological reaction based on IgE antibodies to some allergens. For example, food, drug, pollen and I'm sorry they are not mediated because they part of different part of the spectrum of immunological reaction. The food intolerance is IgG antibody and allergy is IgE antibody. >> Can it be quantified or is it only a qualitative assessment as far as food intolerance is concerned? >> Absolutely quantified because the immunological reaction. We want to see how much antibodies our our body produce to some proteins or some allergens. I don't know in the different laboratory, but in our laboratory is absolutely quantified. >> Well, Dr. Miskovic, this was extremely informative, educational, and well-presented. I thank you for your expertise and your cooperation working with us uh for this type of a analysis for patients with not only with cardiac conditions, but many other medical conditions. Thank you very much for your participation in this uh podcast. >> Uh thank you Professor Kreitzer for invitation. >> You're more than welcome.