Precision Medicine: Genetics in CVD Detection and Management

April 18, 2023
Guest: Carolyn Ho, MD

Guest Carolyn Ho, MD, discusses genetic testing and precision medicine. How can we improve the information we get as part of gathering family history? What role does genetic testing play in clinical practice–and how can we work collaboratively with our patients and their families to better understand the process and results?

Episode Resources

Welcome to Heart to Heart Nurses, brought to you by the Preventive Cardiovascular Nurses Association. PCNA's mission is to promote nurses as leaders in cardiovascular disease prevention and management.  

Geralyn Warfield (host): We're so excited for the opportunity today to talk to Dr. Carolyn Ho about precision medicine, and we have a lot to get to, but I'd first like to get to know Dr. Carolyn Ho. Could you introduce yourself to our audience, please?  

Carolyn Ho (guest): Thank you so much for inviting me to participate in this podcast. And it's also a real pleasure to be talking to the nurses because we know that the nurses are who gets it done for all of clinical medicine. And so, I am the Medical Director of the Cardiovascular Genetic Center at Brigham and Women's Hospital in Boston, Massachusetts. 

I have been fascinated by human genetics, you know, for my whole career, basically. And, you know, how understanding the genetic basis of disease, or how [00:01:00] mutations in certain genes can cause disease, gives us such an incredible leg up into understanding what's important in disease mechanisms, in disease biology, and then leveraging how we can use that information to improve the care of our patients, and our families, that suffer from these conditions. 

Geralyn Warfield (host): That sounds great. We're really looking forward to our conversation today. So, let's get started talking about how to assess for familial disease.  

Carolyn Ho (guest): So, familial disease can be present in all sorts of different cardiovascular conditions. So you can think about familial hypercholesterolemia, to familial cardiomyopathy, to familial rhythmic syndrome, even a familial sudden death syndrome.  

So, it's important to try to have, you know, your radar up a little bit, to see if that might be what's going on. And so, one easy way to do that is to try to make a, a pedigree or, you know, get a, a structured family history from patients that you might encounter that, that might have one of these potentially [00:02:00] genetic conditions.  

So, you start with your patient, and you ask them, systematically, you know, tell me about your parents, you know, how old they are, what conditions they might have, how old they are, when they might have passed away. 

And then you just work systematically through each side of the family. First, the maternal family. So, we usually say to do a three-generation pedigree. So you want to start with their parents, and then the kids, and then, you know, go up or down depending on where your particular patient sits in their family. 

And just, you know, try to go through each relative in, in turn. So, maternal aunts, uncles, and your maternal grandparents, paternal aunts, uncles, and paternal grandparents, and also their children.  And in that way, you might be able to pick out whether there might be a pattern of people having something that is suspicious or, you know, kind of helps group together. 

Geralyn Warfield (host): So, I like the idea of having that three [00:03:00] generations of information. I suspect that's not always an easy thing based on families. Is that right?  

Carolyn Ho (guest): Yes. And it's time-consuming. And that's, you know, why I think a lot of times, you know, in our rushed clinic environment where, you know, you're stacked up with patients and, you know, you only get 15 or 20 minutes for an encounter, it's really hard to fit in.   

And, you know, because we're very interested in this, we have a structure set up to send patients an email or a message through, through our EMR to say, “Before you come to your appointment, you know, try to fill in this information.”  So that can help with, with time-saving. 

And it's also, like you said, not always easy to get a family history. And you know what we've learned, and what has been proven throughout time is that women come from bigger families than men because, you know, women tend to remember about their, their families, and, you know, have a little bit more information. 

And so there's usually a person in the family [00:04:00] that, you know, is a family genealogist and kind of remembers stuff about the family. So, you know, giving your patients a little bit of warning, you know, allows them to, to contact that person and, you know, try to fill in the blanks a little bit if they don't have a great knowledge of their, their family history. 

So that's one way to try to do it or just, you know, trying to be as efficient as possible, in the clinic visit and, you know, giving the patients homework to, to report back, if, you know, they need to gather some more information if that would be helpful. 

Geralyn Warfield (host): That sounds like a great strategy in terms of giving them a little extra time so they aren't trying to think of it, as they're sitting in the clinical setting, maybe in their paper gown, and trying and trying to remember their family history. 

Carolyn Ho (guest): And then texting, you know, Aunt Fran who like knows everything, right?  

Geralyn Warfield (host): So, that's a great way to do that. So, the next step that we probably need to talk about is about genetic testing. So, could you talk a little bit about that process? 

Carolyn Ho (guest): Yeah. So if you could have somebody that has, you know, a [00:05:00] classically genetic disease or if your exploration of their family history, you know, suggests that there's  genetic disease, then you can think about offering genetic testing.  And, and, current day, this is arranged usually by phenotype or by disease type, and arrayed onto disease-based panel.  

So, if you have a patient that comes in with hypertrophic cardiomyopathy, you can think about ordering a hypertrophic cardiomyopathy genetic testing panel. And there are a handful of different genetic testing companies that offer these things that, you know, you can go through their various websites. They try to make it as easy as possible.  

And, you know, there's a set panel of genes that pretty much every company uses. And they're pretty much the same across all the different, all the different companies.  

But genetic testing is not the same as ordering a cholesterol level or a potassium [00:06:00] level. There’s a consent form that needs to be downloaded that the patient has to consent to having the genetic testing run. The provider can also provide consent in lieu of that, if you're doing some of these discussions virtually. And the results are much more complicated, than, you know, just saying your cholesterol is, you know, 200 or your potassium, or we need to give you more potassium, so that's another thing to think about.  

So, if you have the ability to work with a genetic counselor, or refer your patient to a provider like either cardiovascular genetics providers or just medical genetics provider, that can really be helpful. And also an important part of genetic testing is the pre-test, and post-test, genetic counseling. 

So, you want to make sure that, that the patient has the appropriate [00:07:00] expectations in terms of what genetic testing can tell us and what it can't tell us. And that can be, oftentimes, really well handled by working with, with genetic counselors to try to provide that information.  

But the logistics of performing it, you know, other than that, are relatively easy. 

The patient has a blood sample sent in, or they can even have saliva collected. All the genetic testing companies can provide saliva collection kits that, you know, the patient spit into it to a certain volume, it gets sent in, the genetic testing gets run, and results get returned. The genetic testing companies also try to make it as user friendly as possible for the provider and, and the patient, both in terms of logistics and cost. 

They usually have payment protection strategies in place so that the out-of-pocket costs can usually be defined upfront before testing is initiated. And it's usually somewhere in the neighborhood of, you know, $200 or less. [00:08:00] So it is much more accessible than it used to be in terms of, you know, when we were completely hampered by whether insurance would cover it or not, and when costs were really high. 

So, it is more accessible, but I think that one of the difficulties of genetic testing is just how complex the information is.

Geralyn Warfield (host): So, for patients who receive information from a genetic test that they are positive for a disease, let's say familial hypercholesterolemia or hypertrophic cardiomyopathy, at that point, then that would trigger a cascade screening. So, we'd be looking at other relatives getting information through a genetic test as well and going through that genetic process. Is that an accurate assessment? 

Carolyn Ho (guest):  Exactly. So the, the one of the most practical uses of genetic testing at this time is to, well, it's twofold really. One is that it can help us to precisely determine [00:09:00] the disease that's present and the initial relative, or the proband we call it, the first person in the family to be diagnosed with the disease. 

A lot of these conditions can have, you know, fairly low-resolution clinical phenotype that can span through several different distinct diseases. So, it can tell us you have, exactly, familial hypercholesterolemia caused by mutations in the LDL receptor. Or, you have hypertrophic cardiomyopathy caused by, you know, the classic sarcomere mutation—and you don't have cardiac amyloid, you don't have fibroid disease, you don't have other conditions that can, you know, cause, you know, a, a grossly similar phenotype. 

So, it can help clarify ambiguous diagnoses. 

And then it can help inform, and really refine, family management. So rather than saying, “You're at risk for having this condition because you're in a family where somebody has the condition,” we can, we can use [00:10:00] predictive genetic testing, testing a family member to see, yes/ no: did you inherit this mutation or not? to definitively identify those at risk.  

So, those relatives that did inherit the genetic variant can be counseled that they are at risk for developing disease. It's not a guarantee that they'll get it because the penetrance, or the likelihood that you will develop disease in the face of having a disease-causing mutation, is not a hundred percent. So, we can't say when—or even if—they'll get disease, or how severe it'll be, but we can say you are at risk for developing disease. We should follow you, 

And those that do not carry the variant can be reassured that they're not at risk. We can dismiss them from the longitudinal family follow-up that we would usually recommend, and we can reassure them that their children are not at risk. 

But because our knowledge of these things is not perfect, we always say, you know, “If you develop symptoms or if you develop any other features, down the road, you should come back and we should take [00:11:00] another look.” So, that's how genetic testing can really help us refine family management. 

Geralyn Warfield (host): We're with Dr. Carolyn Ho talking about precision medicine. We're going to take a quick break.  

 Geralyn Warfield (host): We are back with Dr. Carolyn Ho discussing precision medicine. And there's a lot more to genetic testing than just getting the results. So, why don't you lead us into the next step of what, what we would do with that information? 

Carolyn Ho (guest):  Yeah, so genetic testing is really kind of thorny and complicated. And, you know, it's important to make sure that people go into the testing understanding, you know, what we can and cannot learn. And that once the results are available, to make sure that we understand the results as best possible. 

So, genetic testing may not always crack the case. A lot of times, the genetic testing may be negative, meaning that no clinically-important variant was identified in that panel of, you know, [00:12:00] 12, 30, a hundred genes that was analyzed.  

But that doesn't necessarily mean that genetic disease is not present. It means that we weren't able to find it when we were looking at the usual suspects.  

So, genetic disease may still be present. If there's a family history of disease in the family, then that family should still undergo clinical follow-up. So, all at-risk relatives should still kind of, come forth for serial clinical screening for cardiomyopathy, or have their lipid panels checked if they're, you know, if there’s hypercholesterolemia or such. 

And genetic testing can also be ambiguous. We don't completely understand all of human genetic variation, so sometimes we can't firmly figure out whether a, a variant in a gene of interest is capable of causing disease or not. And so, that is flagged as a genetic testing companies as a variant [00:13:00] of uncertain or unknown significance, which is a plague to everybody, because it's an ambiguous result. That means, you know, there's something here. We're not sure if it’s important or if it's just part of the background genetic variation. 

And so, we cannot use that variant in predictive testing for the family. We counsel that the family should just be screened clinically. And then, because, you know, sometimes we do get smarter over time, we should reassess on at some regular basis, touch base with the genetic testing company, maybe have a genetic referral every few years to see if knowledge has progressed and that we're able to cleanly define the variant of either disease-causing or not.  

Geralyn Warfield (host): Great, wonderful information for our listeners and I, I'm hoping that you could focus in a little bit on new therapies that are available for some of these cardiovascular genetic conditions. Obviously, we're not going to have time to cover everything about everything, but maybe some highlights that you'd like to share.  

Carolyn Ho (guest):  Yeah, I mean, [00:14:00] it's a really fun and exciting time to be involved in cardiovascular genetics because for so many years we really didn't have anything and we would just repurpose what was being used to treat other cardiovascular disorders for, you know, our favorite conditions. 

But there are now disease-specific and disease-modifying therapies available for cardiac amyloidosis. There's been just, you know, a really exciting advance in therapies that help to stabilize transthyretin,  which is one of the main proteins involved in forming the amyloid fibrils. Transthyretin can either be the normal wild type, which for some reason goes off the rails, decides to form amyloid; or there can be mutations in, in the transthyretin gene that similarly cause transthyretin amyloidosis. And there are new stabilizers for that, and there's some gene-targeted therapies that have been developed. 

And for hypertrophic cardiomyopathy, better understanding of the mechanisms, [00:15:00] how the sarcomere is abnormal, you know, what is different about the sarcomere in patients with HCM? Or, you know, because of the genetic variants that has allowed us to understand,  that it's a more hyper-contractile or less energy efficient sarcomere, and myosin inhibitors have been developed to try to counteract  those fundamental pathophysiologic abnormalities, and those have been through clinical trial. A phase III trial was completed on a myosin inhibitor called mavacamten. It’s going to come before the FDA at the end of April [2022], and that might soon be clinically available. In the clinical trials, it was really quite beneficial, improving feel and function in patients with obstructive HCM.  

And there are new agents in development. And these myosin inhibitors may be effective for non-obstructive HCM because of [00:16:00] their ability to potentially improve diastolic function. And along the same lines, they might be effective for HFpEF, you know, and maybe we'll finally have  an effective treatment for some patients with, with HFpEF. 

And they're just, and they're also more agents in development that might more specifically target diastolic dysfunction and, and also target other components of the sarcomere, to really see if we can advance how we take care of these patients. 

Geralyn Warfield (host): Well, there certainly have been a lot of exciting advances that you've discussed with us today. 

If our listeners want to learn more, can you provide some resources that they could seek?  

Carolyn Ho (guest):  So, there's a primer on genetic testing that we published in JAMA Cardiology a few years ago. And the first author was Alison Cirino. And so I would recommend looking at that because it really helps to spell out how and when to think about implementing genetic testing.  

Geralyn Warfield (host): Great. Is there anything else that you'd like to add that I [00:17:00] forgot to ask? 

Carolyn Ho (guest):  This has been a great journey and it's been a really fun time talking to you about this.   

Geralyn Warfield (host): We have so enjoyed having you on our podcast today. Thank you so much for sharing your time and your expertise with us. 

We've been speaking with Dr. Carolyn Ho about precision medicine. I'm your host, Geralyn Warfield, and we will see you soon. 

Thank you for listening to Heart to Heart Nurses. We invite you to visit pcna.net for clinical resources, continuing education, and much more. 

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