How a Blood Test Can Predict Abdominal Aortic Aneurysms

Podcast Transcript

Announcer:

Welcome to Love Your Heart, brought to you by Cleveland Clinic's Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute. This podcast will explore disease prevention, testing, medical and surgical treatments, new innovations and more. Enjoy.

Stanley Hazen, MD, PhD:

I'm Stanley Hazen, the Co-section Head of Preventive Cardiology at the Cleveland Clinic.

Scott Cameron, MD, PhD:

I'm Scott Cameron. I'm the Section Head of Vascular Medicine at the Cleveland Clinic.

Stanley Hazen, MD, PhD:

Today, we're going to talk to you about the connection between the gut microbiome and aortic aneurysms. Why don't we begin, Scott, with you telling us about aortic aneurysms? What are the risk factors, and what are some of the ongoing medical needs in that area?

Scott Cameron, MD, PhD:

Absolutely, Stan. This is a common question that sometimes comes from family members who may have had a relative with an aneurysm. An aneurysm in the abdomen is an abnormally shaped blood vessel. Blood vessels that are abnormally shaped or wider than they should be are more prone to developing tears in them. We call those dissections. The feared complication is that if an aneurysm becomes large enough, then it can rupture. That becomes a life-threatening emergency. Cleveland Clinic treats many patients on an annual basis for emergent surgeries who've had ruptured abdominal aortic aneurysms. One of the things that we like to do as physicians is try and predict who will have an aneurysm that may require surgery earlier than we would've anticipated.

We try and predict patients who may have a faster-growing aneurysm. Those are patients that we might want to tighten up their medications, for example. We might want to intervene earlier. Then, the last thing is, is there the possibility that we can develop a medical cure for aneurysms so that patients will no longer have to go for surgical procedures? That's part of the work that I do with Dr. Hazen.

We know that in a patient with an aneurysm, there are ultrasound-based techniques where we can look at the size of the aneurysm. Now, when I was training as a cardiology fellow, Stan, which seems like it was yesterday, but I guess it was about 14 years ago, I actually presented a journal club paper on one of your manuscripts where you showed there was a molecule called TMAO. TMAO can be made by a breakdown of certain animal products that we eat. You showed in that really elegant study, both in experimental animals but more importantly in humans, that that can lead to damage of arteries. Why don't you tell us a little bit about that discovery, and then we can come back to what that might mean for patients with an aneurysm?

Stanley Hazen, MD, PhD:

What Dr. Cameron is referring to is a compound called TMAO or Trimethylamine N-oxide. It's a mouthful. It's a compound that's made by the gut microbiome. What we were looking for is, could we identify a compound in blood that would predict the future development of atherosclerotic disease or heart disease? One of the chemical compounds that we detected in blood, in subjects who did not have disease but developed future disease, was this compound TMAO. We were able to show that higher levels of this compound, not only did they track with future development of arterial disease, but they also, when introduced into animal models, developed arterial disease like atherosclerotic disease.

Now, more recently, in collaborative studies with Dr. Cameron, we were able to observe that high levels of blood TMAO would predict increased risk for developing abdominal aortic aneurysms and also increased adverse outcomes in subjects who had a high level of TMAO in their blood, meaning worse outcomes like heart attack, stroke and death.

In collaborative studies, we then started to explore: was this connection causally linked to abdominal aortic aneurysm development? We're surprised to find that a high level of TMAO would literally drive, in multiple animal models, the development of aneurysm and then new drugs that we're in the process of developing to halt this process, new drugs being developed to lower TMAO levels in an animal model would halt disease progression and prevent the vessel from growing wider and from rupturing. More recently, this has now been extended to some human studies in collaboration with Dr. Cameron, who's the lead author on this manuscript that was just published in JAMA Cardiology. Why don't you tell us about that?

Scott Cameron, MD, PhD:

One of the problems in clinical medicine is that we're now quite good at fixing things, but we're not quite there yet when it comes to predicting who will have a disease. If you take a disorder like abdominal aortic aneurysms, the current guidelines tell me that I should only be screening men aged between 65 and 75 who've smoked in their life. Or if you have a patient with a first-degree relative who has an abdominal aortic aneurysm, that's considered reasonable. But one of the issues that we have with that is that data is based on what we call expert consensus. It's not really based on scientific data, but if you have a blood test that could predict the development of an aneurysm in the future or in a patient who has an established aneurysm, I would think that that would be a better thing for the patient because they're under a closer surveillance program.

So Dr. Hazen's work had shown initially in patients with coronary artery disease, so diseased blood vessels in the heart, cerebrovascular disease, diseased blood vessels in the brain, and then also peripheral artery disease, diseased blood vessels usually in the leg, that TMAO was causally related to those disorders and could sometimes predict adverse outcomes, for example, heart attack and stroke.

In my mind, it wasn't that much of a surprise when Dr. Hazen came and said, “I wonder if in patients with abdominal aortic aneurysms, TMAO could be showing something.”

Dr. Hazen was telling us about one of the studies in experimental animals where it was very clear that if you have TMAO elevated in the blood of those experimental animals, they would develop aneurysms and they're more likely to rupture. If you use certain medications to wipe out the production of TMAO, the aneurysm would literally stop growing. The initial study, in fact, showed that if you give broad-spectrum antibiotics to that experimental animal, the aneurysm would stop growing.

Dr. Hazen, could you maybe tell us a little bit about why antibiotics might stop an aneurysm growing and what that would mean for gut health, for example, and how that might impact blood vessels?

Stanley Hazen, MD, PhD:

The gut microbiome are microbes, bacteria that live in the intestines, and they actually eat our food in the same way that we do. One of the findings, that our group has been pushing, is the concept that after eating a meal, not only do we develop metabolites, but gut microbes, as waste products, will release compounds that then get absorbed by the host, by us, and can circulate in the blood and exert an effect. In this case, what was found is that this molecule called TMAO will actually cause vessels to dilate and aneurysms to grow and rupture.

If you give a cocktail of poorly absorbed antibiotics – the antibiotics that were given were ones that are usually given intravenously by injection, but this time they're given orally – they're very poorly absorbed. But what happens is they then suppress the intestinal microbes. This is not something we would be recommending as a therapy, but it is a good scientific tool. By doing it, you could show that it completely knocked out TMAO levels in the blood, and then that helped protect against the development of aneurysm growth.

But if you then put the compound in the drinking water and bypassed the intestines and just provided it directly, and after drinking it was absorbed, then aneurysm growth would return. Rupture and death, actually, was observed. What's interesting is that what we eat, the food we eat is the biggest environmental exposure that we have, and it's experienced through the filter of our gut microbiome.

Each person will experience a slightly different effect from their meal because the composition of the microbes in our intestine differs from one person to another. The level of how much TMAO is produced is, in large part, dependent upon the gut microbes a person has. But another component is the nutrients, the diet that we eat. The connection between the antibiotics was really a research tool to show that there was a gut microbial component. Other studies that have pretty much proven, that have shown you can take microbes from a high TMAO-producer or a bacteria that actually helps to make TMAO and transplant them into a recipient like a germ-free animal and literally transmit the ability to the recipient to make a high level of TMAO and have atherosclerosis or thrombosis or other effects that this pathway leads to.

Scott Cameron, MD, PhD:

So, one of the issues that patients will sometimes ask me if they see I'm ordering TMAO, they'll say, “Well, what are you going to do with the data”? And what I'll tell them, we see patients that come from all over the United States and sometimes other countries. It is a very good risk stratification tool. The current cutoff that we would use in our laboratory, and in fact the same cutoff that we found in our manuscript, is 6.2 micromolar. We know that there's an inflection point. If the TMAO concentration measured in your blood happens to be 6.2 or above, that's a patient who's at elevated risk.

Now I know what I tell patients when I detect that, especially if they have an aneurysm, the first thing that they'll say is, “is there a medication that I can take right now that would suppress it”? What would you tell your patients, Dr. Hazen? Would you first tell them about the dietary changes they can make, or would you tell them about what's in the pipeline, the exciting things we're doing at Cleveland Clinic?

Stanley Hazen, MD, PhD:

Well, we tell them a combination of both. There are medicines that are in the pipeline that have not yet been made available to humans, and we're still in the process of trying to see that happen. But there are lifestyle changes and some medications that do impact TMAO levels. When we see a TMAO level that's elevated in preventive cardiology, it does indicate, not just increased risk for aneurysm development, but heightened risk for clotting, like a heart attack or stroke and, long-term, the development of heart disease and even kidney disease because it leads to changes in the organ itself, the heart and the kidney that leads to what we call fibrosis, think like gristle in the steak.

It decreases the function long-term. How you can lower it, first and foremost, is with diet. The nutrient precursors, the parts of our diet that give rise to TMAO, tend to come from animal products. Adopting a more vegetarian-style diet will help lower TMAO levels. In particular, reduction or avoidance of red meat is important. Another thing that's important is to really read the labels and look, especially at health foods and energy drinks and energy-related processed foods and supplements. They often will have things like Phosphatidylcholine, lecithin, carnitine or choline listed in the label. It's thought to be a nutrient that is part of an energy drink. But on the other hand, chronically elevated levels are what get turned into TMAO. Some of the highest levels of TMAO we've seen have been in a vegan actually who was also having a lot of vegan energy drinks and was therefore getting a lot of lecithin in their diet.

Finally, there are some medications that we know, as a side effect, will lower TMAO levels a little bit, like 25% and a quarter here or there helps. If it's appropriate under the guidance of a doctor, some medications can help lower TMAO, such as low-dose aspirin has been seen in human studies to lower TMAO levels about 20 to 25%. Rosuvastatin, which is a statin called Crestor, also lowers TMAO levels partially, like 20, 25%. These aren't as strong as the drugs that have been developed in animal models that will lower TMAO by like over 95% to a 100%, just blocks it out to near zero. Those we’re working on, they're in the pipeline, and we hope to get them into humans in the next year in clinical studies.

Scott Cameron, MD, PhD:

Thanks for that perspective. I think one of the privileges, I find, and I know that you'll probably agree, Dr. Hazen, is that practicing medicine at Cleveland Clinic allows us to practice medicine very precisely. Patients are accustomed to getting imaging studies. That's part of what we do to look at blood vessel health. They're used to receiving medications. They're not always used to us talking and slowing down a little bit and asking about supplements. I think that that's something that we do especially well. We can use that information to make a real difference in that patient's life, which is a real privilege to do that.

Well, let me just switch gears a little bit and we'll talk about some of the work that's ongoing and what TMAO can do in terms of aneurysm care. Dr. Hazen, I think this may be the first time that there is a molecule that has been shown to be both causative in terms of growing aneurysms, but also as a marker that we can monitor the disease. I wonder if you could maybe tell us what your perspective would be for that. Do you think that we should continue looking for other molecules that both are causative for the disease and that they're markers for the disease? Or tell us what you think TMAO is going to be doing five or 10 years from now because many hospitals around the United States do offer this test now.

Stanley Hazen, MD, PhD:

It is widespread. It's offered throughout the United States. I think of it as something similar to a glucose or a cholesterol level or a triglyceride. These are all linked to disease processes. They're also all linked to compounds you can measure in blood and give guidance to a patient, how to personalize their dietary intervention. One person may be more sensitive to glucose elevations than another or triglyceride elevation or TMAO elevation. By seeing a high TMAO, for example, it gives us something to chase after in terms of saying, “Okay, for you, perhaps the amount of red meat you're eating should be cut back”. Oftentimes, rather than saying it needs to be complete avoidance or abstinence, we begin by saying, and especially in someone who's not too excited about changing their diet, say, why don't you try just one day a week doing a vegetarian diet and see how you like that? Usually, over time, you can increase the amount of vegetarian versus omnivore.

I think the ability to track after a therapeutic target is really the future of medicine because it allows you to titrate and personalize medical interventions to the individual. If your level isn't elevated, then you don't need it. Well, we already do this with cholesterol-lowering drugs or with diabetes drugs. We have not been doing this for diseases like thrombosis, a heart attack, stroke or with, for example, an aneurysm.

But many of the patients who you see in vascular medicine, you're doing routine surveillance monitoring and imaging. The question becomes, how frequently do you do this in the individual? In combination with TMAO, we now see that individuals with higher levels of TMAO are more likely to have a faster-growing aneurysm than those who have a low level. It just helps give yet another layer of preciseness in fine-tuning interventions and therapies to the patient, which I think everyone, both physicians and patients, are welcome to see.

Scott Cameron, MD, PhD:

Absolutely. Patients will sometimes ask me, what medical things should I be doing now? I can tell you, if you have an abdominal aortic aneurysm, it's a class one indication. That means it's not just a good idea, it's the law. We will control blood pressure, if a patient has high blood pressure. If we know that the patient has hyperlipidemia or elevated cholesterol, that's a class one indication to control that. Then sometimes, as Dr. Hazen was telling us, we'll put patients on aspirin, we have some data for that. We also know, as Dr. Hazen taught us, aspirin can decrease the concentration in TMAO.

But the medical guidelines right now, they're based on an absolute diameter, how wide the aneurysm is. I can tell you that for any patient that would come to us, if someone has an abdominal aortic aneurysm that's 5.5 centimeters or greater, that should be fixed either by doing a procedure, going through a blood vessel or doing an open surgical procedure to correct it.

It's considered reasonable to correct an aneurysm if the diameter is 5 to 5.4 centimeters. What we know in the medical literature is that's fine for men. We have lots of data. But because we know that women don't have aneurysms quite as frequently as men, we don't have the same degree of data for women. I can tell you that, although the guidelines are based on diameter, it's based on the principle that the wider a blood vessel is, the more pressure there is on the wall, so it's more likely to rupture. We know in our experience, and what's published in the medical literature, women with abdominal aortic aneurysms can actually tear and rupture at a smaller diameter. I think that that's the Achilles heel of the current guidelines. I'm told as a physician just to use imaging for what I would say is a risk profile.

Now, I can use TMAO in conjunction with imaging, and I have, in fact, recommended fixing an aneurysm at a slightly smaller diameter based on the data that we know. I think this is a really exciting time. We've talked about aneurysms and what causes them. We now know very clearly that the gut microbiome seems to affect blood vessels and blood vessel health. You've taught us about some of the strategies we can use with diet and medications, and I think this is just a really, really exciting time. I'm really, really hopeful that we can advance a therapeutic for TMAO and just have an impact on lots of arterial diseases, Dr. Hazen.

Stanley Hazen, MD, PhD:

Thank you. I agree. I also just want to emphasize, I know this is part of the way you and the entire vascular medicine team, as well as the preventive cardiology team, really emphasizes multidisciplinary care. It's not just simply giving a drug or measuring blood pressure. It's really the whole holistic approach. Nutrition interventions, diet interventions, smoking cessation, even behavioral health interventions can all impact a person's cardiovascular health.

All of these facets of a person's cardiovascular preventive portfolio are part of what we both recommend to our patients. This is just yet another new tool that we see as an up-and-coming area, not just for aneurysm development, but it will be important for all aspects of cardiovascular health. When I say “it” I mean the gut microbiome. It has a growing appreciation in multiple different aspects of our health, and it all comes down to our diet and exercise programs. They are equally important to a person's cardiovascular health, to the medications and the other interventions.

Scott Cameron, MD, PhD:

Fantastic summary there. Well, Dr. Hazen, thank you for joining me today and to our guests listening, thank you for listening to Love Your Heart.

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