Genetics & Cardiovascular Disease: Getting to the Genetic Heart of the Matter with Daniel Judge, MD

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[00:00:04] Loretta Lynch-Reichert: Hello everyone and welcome back to the Medical University of South Carolina Science Cafe podcast, Science Never Sleeps. I am your host, Loretta Lynch-Reichert. We are once again partnering with our friends from the heart lecture series to help educate the public on the latest in heart and vascular care at the Medical University of South Carolina Health Heart and Vascular Center. Today our guest is Dr. Daniel Judge, professor of medicine in cardiology at MUSC and director of the Cardiovascular Genetics Program. Dr. Judge received his medical degree at the University of Pennsylvania and did his post-graduate work at Johns Hopkins. He’s board certified in cardiology and advanced heart failure transplant cardiology. Welcome, Dr. Judge.

[00:00:51] Daniel Judge, MD: Thanks very much for including me this morning.

[00:00:53] Lynch-Reichert: It’s our pleasure. You come to this conversation with an excellent reputation, so we are excited to have a conversation with you today. So I’d like to ask you a couple questions because I’ve read a few things, and this is what I understand: heart disease is still a leading cause of death in the U.S. Now a 2020 update from the American Heart Association indicates the age adjusted death rate attributable to cardiovascular disease is 219 per 100,000 people. On average someone dies of cardiovascular disease every 37 seconds in the U.S. and recently, we see that the mighty Arnold Schwarzenegger appears to have a congenital heart disease. I would’ve guessed that most of those cardiovascular events were related to lifestyle. You previously suggested that many cardiovascular disease events have a genetic component. Would you tell us more about inherited cardiovascular disease?

[00:01:55] Judge: Well certainly I’m biased, but I think that most things in cardiovascular disease have a genetic component. The way I look at it, there are things with a very strong genetic component – something that runs in the family where roughly half of the people have the condition or a genetic tendency – and other things have smaller genetic impact, but certainly those things add up together with environmental stressors to cause other cardiovascular conditions, like coronary artery disease and hypertension. It’s really sort of on the spectrum of the more common the condition is, the less strong the genetic factors are in impacting those, but they all add up to the final result.

[00:02:41] Lynch-Reichert: That’s fascinating. Would you happen to be able to hazard a guess how... what percentage of the population has some form of inherited cardiovascular disease?

[00:02:53] Judge: Well, that’s a hard one. We certainly know that the... if we include hypertension, for instance, or coronary artery disease, then the great majority have strong genetic factors impacting their development of these common conditions. On the other hand, the rare conditions, as defined by the National Order of Rare Diseases, as fewer than 200,000 Americans. Each of those is, by itself, quite rare, but when you add them up there’s a lot of them and they turn out to be a substantial number of people. For instance, it’s thought that roughly 25 to 30 million people in the U.S. have a rare condition, as defined by the National Order of Rare Diseases.

[00:03:40] Lynch-Reichert: As director of the Cardiovascular Genetics Program, you have extensive experience caring for individuals and families with the inherited forms of cardiomyopathy, aortic aneurysm, amyloidosis, and cardiac involvement from other genetic conditions, and I think this is what you were just speaking about. What... can you be more explicit about what those other genetic conditions are and do all inherited forms of cardiovascular disease mostly manifest later in life?

[00:04:09] Judge: Yeah, those are good questions. Let me start with the range of diseases and conditions that we think of as monogenic, or single gene disorders. Conditions where a strong genetic factor runs in the family and if someone has that condition, their offspring, their children have roughly a 50/50 chance of inheriting that. Includes as you mentioned cardiomyopathies, and cardiomyopathy as a technical term refers to a problem with the heart – cardio being heart and myopathy being it’s not working properly, it’s bad.

The most common reason for a heart to be weak or not to squeeze properly is blockage of the arteries. I look at the other conditions where we sometimes call it idiopathic, meaning we just don’t know why it’s occurred. If you look at people with an unexplained or idiopathic cardiomyopathy at least half of them have either a clear genetic factor that we can identify or affected family members, which means it runs in the family, we just haven’t identified the genetic factors in some of those circumstances. In terms of the age of onset, boy, it runs the full spectrum. There are clearly children, infants, with early onset forms of genetic heart disease, and then certainly things can be there for a long time and never show up until later adulthood.

Some conditions, you mentioned amyloidosis, typically start in later ages and it just relates to the genetic factors together with the environmental factors that really add up to a later onset of the condition.

[00:05:49] Lynch- Reichert: I think based on what you just said it seems to me that research could play a huge part in answering or resolving some of these questions and even finding new ways to deal with inherited heart disease. Can you share a little bit about the work that you do and I bring this up specifically because I know that MUSC has a very strong research component in heart disease and I know how closely you work with other researchers to translate that work into great clinical care, so can you just share with us some exciting news in that regard?

[00:06:24] Judge: Sure. Let me start with a point of common misconception. Sometimes people – when they hear about genetic heart disease, think that’s research, and really I think that identifying a genetic cause of a condition is no longer research that was 10 or 15 years ago that was sort of transitioned to something that was done in research laboratories like at MUSC and really now is a fairly standard clinical test to identify a genetic predisposition to heart disease or cancer or other common conditions.

In terms of the research that we’re doing now, and I think this is one of the things that excites me the most about genetic cardiovascular disease, if we can identify the genetic cause of a condition like aortic aneurysm or a weak heart or a thick heart and then figure out what other factors between the gene and the end result occur, we can sometimes impact those factors early on before the disease has manifest or at the earliest stages if we identify the genetic tendency.

On the other hand, there’s also a lot of excitement about genetic modifications. Even today, there’s clinically approved medications that will turn off a gene, silence that gene. That’s pertinent for two drugs that are approved for treatment of genetic forms of amyloidosis. And then finally, repairing those genes is something that’s not quite ready for primetime, but it’s something we all anticipate will be available in the future where we can use a therapy that will identify the gene where it has an error or change, something that shouldn’t be there or causes disease and fix that at an early stage and try to prevent the disease from occurring. That’s a big barrier to jump through but I think at this point I focus on the current clinical, translational research where we identify a gene, we identify a pathway, and we identify medications that can alter the trajectory of that gene abnormality.

[00:08:26] Lynch-Reichert: As I said, it’s lifechanging, it really is. Are any groups more inclined to inherit heart disease or any of these forms that we’ve just discussed?

[00:08:37] Judge: Honestly, no. Really there’s a lot of genetic heart disease in men and women of all races and we see it all over the world. There are a few exceptions to that rule. One of the conditions that I study, and I’ve mentioned a few times called amyloid has a genetic tendency for African Americans – 3.5% carry a genetic tendency to amyloid and it’s a condition that’s often not recognized when it’s present. So, many physicians or healthcare providers aren’t always thinking about amyloid because it’s considered a rare condition, but if there’s features that are concerning, like neuropathy or a thick, stiff heart, identifying a genetic contribution can lead to better therapies.

[00:09:25] Lynch-Reichert: Your discussion leads me to wonder about just general practice and how physicians are able to identify potential inherited genetic diseases when they don’t know the history of the family. How do they identify that just through an annual exam?

[00:09:48] Judge: Another great question and I certainly am working to train the next generation of physicians to understand and feel more comfortable with the use of genetic testing. But I would really divide genetic testing into two separate categories. There’s when you identify a condition – aortic aneurysm for example – when you see someone who has a completely unexplained aortic aneurysm and other features that suggest an inherited condition, we use a panel of genes, we look at that panel of genes and we ask ‘is one of them abnormal’ to explain this condition. That’s generally easier and a much higher yield than something called proactive genetic screening.

So I think what you’re referring to is a healthy person, or a person who isn’t known to have one of these questions asking ‘hey do I carry a genetic tendency to something like that?’ That’s now available, insurance doesn’t typically pay for that but it’s a few hundred dollars that would be proactively paid to identify genetic tendencies to cancer, to heart disease, and to a handful of other rare conditions.

One good example of this that’s commonly recognized among many people who've heard about Angelina Jolie and her exciting story of identifying a genetic tendency to breast cancer. She didn’t have breast cancer as I understand it – identified that she had a genetic predisposition to breast and ovarian cancer and then proactively had a mastectomy and oophorectomy to prevent the development of cancer. So that proactive approach is something that we hope to see more of as we extend beyond cancer into other cardiovascular conditions.

[00:11:38] Lynch-Reichert: You said that genetic testing has been around for awhile, but for cardiovascular disease it’s a relatively new discipline?

[00:11:49] Judge: Yeah it’s... I’m glad to be able to provide a history that’s spanned the spectrum from the research when it was really done just only in research laboratories to now being a fairly robust clinical test and I’d say it’s about 15 years ago that that transition started to occur. In the very early stages, we looked at one gene at a time with a very high cost and insurance, I think appropriately always said ‘well we’re not paying for it, it’s really not ready for primetime.’

On the other hand, today the costs are so much less and the size of the panel of genes that we can quickly look through and clearly look at changes and compare them to hundreds of thousands of people and see is it a common variation or a rare variation. The pace of research and the pace of understanding of genetics and the pace of technological improvement in genetic testing have led to it being less expensive than a routine test, like an echocardiogram or other imaging studies that we use for the heart or the blood vessels.

[00:12:57] Lynch-Reichert: That’s amazing and it’s lovely to hear that these are cost effective means of discovering issues. I love that. I’m sure the audience does too. So, if one has a genetic predisposition to heart disease, would engaging in a healthy lifestyle mediate the issue or is your fate sealed without medical intervention – and I think you and I had this conversation before. I relate this question to a friend who was seemingly incredibly healthy, did the annual stress test, knew about his heart history issues with the family, was robust in every way, and a week after a stress test, he died of a heart related issue and I’m wondering, what good then was the stress test and, you know, what do you do when you think you’re doing it right and these inherited diseases can still slay you?

[00:14:06] Judge: Yeah. There... that’s a very big concern for people, particularly like your friend whom you mentioned – I'm sorry to hear about his situation and I think stress tests are useful certainly, but they have to be applied in the right context. If you’re asking a question of ‘is there coronary artery disease’ a stress test is one of the best ways to answer that question. If you’re asking ‘is there a genetic tendency to the heart suddenly stopping’ it doesn’t answer that question in terms of... and I don’t know the cause of death of your friend and I think there’s a lot of different reasons that one could die suddenly from a heart condition – aortic aneurysm, arrythmia, an enlarged weak heart that has no blockage so it wouldn’t show up on a stress test as abnormal – all of those are relevant.

I think addressing the question of how can we identify people before they have a fatal initial presentation, well family history is maybe the most important part. As the holidays are approaching, it’s a good time to be asking family members ‘how did my grandfather die? How did my grandmother die? Are their cousins in the family who had something sudden, unexpected and potentially fatal, something that could be genetic and runs in the family?’ then it’s a harder question as you asked, ‘ well what do you do about it? And do you really want to know if it’s something that’s sealed, if your fate is sealed when you identify that gene... I disagree completely with that notion.

I think genetic information is important and it’s something one can really target rather than the unknown and the suddeness that can really strike people with these inherited conditions. Knowledge is power. Understanding that there's a genetic predisposition, one can then target it and if it’s an arrythmia, there are things like defibrillators for those at the highest risk that can be implanted to prevent sudden death. If it’s a medication issue or even a cholesterol issue – even getting your cholesterol checked is arguably a genetic test because high cholesterol runs in families. But when you identify it you can treat it and lower the risk accordingly.

[00:16:25] Lynch-Reichert: That’s very... that’s really heartening, pun intended, heartening news for those folks who think that there may not be any options. I know you deal mostly with adults but I think I read recently how, at least within athletes at high schools, they’re seeing a trend toward a higher level of athletes, at least male athletes, who die suddenly right after a strenuous football practice, or basketball or whatever. Is there truly a trend here?

[00:17:01] Judge: Well certainly any young high school student who dies suddenly and unexpectedly is a tragedy and it always makes the news, it always gets a lot of attention appropriately and I think that the actual incidence, fortunately, is quite low. It’s a little bit of a controversy because in some countries, for instance in Italy, if you are competing in high school, college level athletics, you are required to have an EKG, which is a very simple relatively inexpensive test, but if you applied that to every single high school athlete you’d have an awful lot of EKGs that are not necessary.

So the way I think about it or the way I look at it, particularly in the tragic situations where someone’s died suddenly is, was there a clue? Was there something in their family history that helps to understand that? Often that’s the case. Often the heart thick, that’s called hypertrophic cardiomyopathy and there have been more than a handful of athletes who have died suddenly or had life threatening events related to their activtiy and if you look carefully within the family and you identify that there’s others with a condition like that, you can target those individuals who are at the highest risk with not just an EKG, but an echo.

It’s the same with aortic aneurysm, conditions like Marfan’s Syndrome make people particularly tall, at times long bones grow longer, arms and legs can be very long so there are basketball players and volleyball players who have been identified on the basis of their skeletal features, their tall stature as having Marfan’s Syndrome and that’s a condition that predisposes to aortic aneurysm and aortic dissection. The aorta is the main blood vessel that comes out of the heart, if it tears suddenly it’s a life-threatening, often a fatal event. So understanding on the basis of family history or other skeletal features, is there an underlying genetic condition for a student athlete can really help to save lives.

[00:19:07] Lynch-Reichert: Well I wonder... I think it’s great advice and I hope our audience takes it to find out their health history within their families, but what symptoms would one want to be looking at with young adults as far as a potential heart disease?

[00:19:28] Judge: Yeah, fainting spells are maybe the most concerning. Lots of people faint. Fainting can be a benign condition, but if you’re having fainting spells, if you’ve fainted even once for no good reason, it certainly warrants a conversation with your physician and probably additional testing – EKG, probably an echocardiogram. The benign causes of fainting are quickly recognized and hopefully providing reassurance to people who have a fainting spell like that, but when we’ve looked at a condition called arrhythmogenic cardiomyopathy, a form of heart disease where the heart is prone to arrythmia, it’s worsened by athletic activity and one of the hallmark features is fainting spells. So identifying someone who has that condition and advising them not to be active with sports can really improve their chance of survival.

[00:20:30] Lynch-Reichert: What would you say in the next five years would be the most promising interventional discoveries to come out of cardiovascular research?

[00:20:44] Judge: Boy there’s a huge question [laughter]. I think... In my mind, the opportunity to understand disease pathogenesis – the cause of a condition like heart disease or aortic disease, vascular diseases – and then applying therapies that fix it. As you asked the question of the most important, you have to sort of step away from the very rare conditions, which have a very strong genetic factor to the more common conditions, like coronary artery disease or hyperlipidemias, high cholesterols. And we’re really focused very well, I think, on some of those conditions, but pushing things back towards the other genetic factors that contribute to these conditions, between the rare and the common, somewhere in between, to apply the best technology to a larger group of people who are at risk for these conditions.

[00:21:43] Lynch-Reichert: Tell me a little bit about yourself in regard to what brought you to this field in particular?

[00:21:50] Judge: Yeah. Boy it was a very natural connection for me to focus on genetic cardiovascular disease. As you mentioned, I trained in cardiovascular disease and focused on heart failure and heart transplant and the challenge for me, that was recommended by some of my mentors, was asking the question ‘why, why does this happen?’ and I found myself facing the question of unexplained cardiomyopathy or unexplained aortic aneurysm and being really just frustrated by that and figuring we have to be able to do better than that. It wasn’t... I didn’t have to look very far to identify that there was often a genetic predisposition and that led to a focus on those genetic factors and then naturally the transition from identifying the genetic factors that caused the condition to identifying treatments that would be available for people who are genetically predisposed to these conditions.

[00:22:52] Lynch-Reichert: So you’re very hopeful, I think, about the future. Yeah. We were talking a little bit about interventional discoveries. Within that realm, both pharmaceuticals, and would you suggest devices, also play an important part in resolution of any of these cardiovascular diseases and can you talk a little bit about them?

[00:23:17] Judge: I’m fortunate to have trained at the place where defibrillators were first discovered and the process of developing the first defibrillator was really quite a controversial one. Michele Morowski who was the electrophysiologist or cardiologist focusing on electric activity in the heart who had the dream and the vision that he could implant a defibrillator and he was mostly laughed at early in his career. So largely out of his own garage he was building these devices that have now become fairly routine for people to have a device implanted.
It monitors the heart and will shock the heart if it has life-threatening ventricular arrythmias. They don’t cure the condition, but boy do they save lives. Part of the challenge as you recognized and asked about is where do we draw the line? How do we say, ‘this is something that should be approved, is it safe, is it effective?’ And then where do we apply the cost, because they’re expensive, and who is at the greatest risk that should get one of these devices? I’m glad to be part of guidelines and committees to address those questions of who is at the greatest risk and who should have these defibrillators implanted, these devices, to help save their lives. They’re not for everybody, even for people who qualify. Some people who have these devices for awhile have been shocked a few times and really dread that shock more than anything. I think we have to be better at not only be identifying the right person to get one, but then coming up with alternative treatments to prevent their use. They’re a good backup, they’re a good system of saving lives, but they’re not something we should take lightly when someone gets a shock like that.

[00:25:09] Lynch-Reichert: Where can listeners go to learn more information or to offer their support of the work that you do?

[00:25:16] Judge: Well to learn more about this exciting research, or how you can get involved, please contact my philanthropic officer Leslie Brady at 843-637-5640 or visit judgeresearchlab@musc.edu.

[00:25:30] Lynch-Reichert: I would absolutely encourage our audience to do so. Dr. Judge, one of the reasons we have you on today is because you are not just renowned, I have several friends who are patients or have family members that are patients of yours and the repeated refrain is ‘compassionate, patient centered, thoughtful, diligent’ - you don’t rest until the answer is there for your patients and you are just another example of what makes MUSC so great, both your desire to help your patients and your community and to not just let the answers go by, to really dig deep for the answers for your patients and on behalf of the Medical University, thank you for the service that you provide. It really is impressive and I’m so grateful there are people like you working at MUSC to serve those of us.

[00:26:25] Judge: Thanks so much for your kind words.

[00:26:26] Lynch-Reichert: Absolutely. To our listeners, we hope you will join us again next month for another edition of Science Never Sleeps. Until then, please be safe and if you are joining the family for the holiday seasons, make sure you ask about your health history.

Thank you all again very much. We’ll see you soon.