Talking Tall Rounds: Chronic Thromboembolic Pulmonary Hypertension

Podcast Transcript

Announcer:

Welcome to the Talking Tall Rounds series, brought to you by the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute at Cleveland Clinic.

Michael Tong, MD:

Good morning. It's my honor and pleasure to be with you today. We have a great program for you today. To all those in our audience and those online, we'll be talking about the management and diagnosis of CTEPH. This is a underdiagnosed condition, but one where we can cure the pulmonary hypertension for these patients. It is an extremely rewarding group of patients to take care of. They come in very sick. Often, they've been misdiagnosed for a long time and we have the potential to cure their disease. I have with me today a panel of world experts on this condition, and to get us started, first I'd like to introduce Dr. Juan Umana, who is one of our upcoming chief residents who will start with a case presentation.

Juan Umana-Pizano, MD:

Good morning. We have a case presentation of a 36-year-old male who had a prior history of GERD and epilepsy and then started having progressive shortness of breath six months prior to the admission here at the hospital. And workup showed extensive PE. He was started on anticoagulation and oxygen and was transferred to the center for management. So we see the CT PE here, which you're going to see that there's a lot of clot burden in the main pulmonary arteries, inter lobar and lobar arteries and some subsegmental occlusions, so significant disease, a dilated PA. And then here you start seeing all of the clot burden in the main pulmonary arteries tracks down into the inter lobars and submental occlusions. Mostly lower lobe. You see some middle lobe on the right and upper lobe on the left.

So then we see the V/Q scan here. This is the anterior-posterior view. You have the ventilation on your left and the perfusion on the right, and you see that it's mostly a predominantly lower lobe disease with some middle lobe involvement and upper lobe on the left. So then the echo, we saw that there was good left ventricular function with the severely dilated RV with moderate dysfunction and 3+ TR. You can see here the images. In the right heart catheterization, the right atrium pressure was 10 with a pulmonary artery of 87 over 40 with a mean of 54 with an index of 2.39 and a calculated total coronary resistance of 12.08.

And so we decided to go forward with a bilateral pulmonary thrombectomy and a tricuspid valve repair. Here's a picture of the specimen that was gotten out in the OR, and then you can see that the postoperative V/Q scan, there's a significant improvement of the perfusion on both lower lobes and middle lobe on the right and upper and the left. And then postoperative echocardiogram and also the RV recovered. It's now mildly dilated with mild dysfunction and trace TR, and postoperative hemodynamics are significantly better with a right atrial pressure of four, pulmonary artery pressures of 28/8 and a mean of 16 with an index of 3.2, and now a calculated total pulmonary resistance of 2.6. He was discharged home on postoperative day six on room air and doing pretty good.

Michael Tong, MD:

Great. Thank you. Next I would like to introduce Dr. Nick Smedira. Dr. Smedira taught me how to do this operation and he's been a mentor to all of us. And what's really unique about our practice is that we work together as a team. And this team was started by Dr. Nick Smedira over 10 years ago, and he'll tell you about how we are organized together and how we manage these patients.

Nick Smedira, MD:

Good morning, everybody. I thought I'd give you a quick historical perspective of how we got where we are, and then my colleagues will take you into the modern era. So this is an old slide deck that's dated November of 2005. I want to give you a perspective of where this field started, and then the team here will give you where we are. And as an introduction and an interest in the history of cardiothoracic surgery, I put this slide in, and if it wasn't for a pulmonary embolus, we might not be doing the five to 6,000 cases we do every day, and our perfusionists are here. It was John Gibbons who was at the Mass General and watched a young woman die from a massive pulmonary embolus and began to think through how one could take the blood, oxygenate it, remove the carbon dioxide, and then bring it back. And maybe if we had something like that, we could have saved this young patient's life.

So he began to do a lot of this work in his garage. And you can see the first screen oxygenator, and these things were massive. They were the size of a couple refrigerators. They took tens and tens and tens of units of blood to prime, quite complex. And the work was all started in the '30s and came to fruition in the '50s. And think about that, 20 years of struggling to get this from the thought to the bedside. So that's all because of a pulmonary embolism.

I think the team here will show you about the surgery. So when I started to do it, I took over from Dr. Cosgrove in the mid '90s. We were doing these endarterectomies. The anatomic approach was quite simple, but the physiologic management of these patients with profusion and how we manage them in the intensive care unit was critical. Here's just a figure of mobilization of the cava. I used a cold fibrillatory approach. I didn't typically arrest the heart. Others in San Diego have arrested the heart. But one of the key things that really changed what we did is that in '91, Pat O. Daily out of San Diego published in The Annals the instruments they used, and it sounds kind of silly, but the instruments, at least in my mind, were critical. And they had these suction dissectors that they had developed and they had a small opening that allowed you to suck the blood that would always return during the operation and also use it as a dissector when you were in the plane and doing the endarterectomies.

So our team here took these prototypes and actually developed these suction dissectors. I don't know if you guys are still using them, but this was developed from the San Diego group in the '90s, and then I just stole their concept, or borrowed it, and we used it. But this was really critical to our ability to do endarterectomies deep in the pulmonary artery. So that was critical. So this article was '93. The outcomes were challenging. Reperfusion injury 10%, delirium and mental status dysfunction 11%, mortality nearly 10%. And a lot of it was related to how we perfuse the patient, and then with Gus's help, I think we really started to understand the reperfusion injury and the hyperperfusion management of the patient in the postoperative period.

We learned a lot from the guys in San Diego, Jameson, and then Madani, who took over. They focused on their last 500 in this article in 2003, and our goal at this time was to drive towards their results, really trying to get better. They broke it down into a couple of different categories. You guys still use this type? So this is all out of San Diego, where it is, and then the results of how well patients did depended on how easy it was. So central clot and scar, you could extract that at relatively low risk, and as you got the more diffuse, it was a higher mortality.

Now, during this time, I felt like I was the lone ranger doing these operations. And what I really needed was a partner on the medical side because so much of the outcome was dependent upon the preoperative evaluation. A lot of these patients had COPD. They had other medical disorders that led to pulmonary hypertension, and you can imagine if somebody's sick and they have X disorder and they're sitting around, they get pulmonary emboli. But what is really the main cause? So understanding V/Q scans, perfusion abnormalities, which wasn't in my sweet spot, came along, Gus came along.

I think when Dr. Herasi came and really helped on the medical side, we developed this partnership. He helped me in the intensive care unit. We fought regularly about anticoagulation postoperatively, whether to give heparin or not. But through that relationship we started to get a better understanding and we got better at the preoperative management. We had the instruments for intraoperative management, and then postoperative management. Also at that time, Tory McGrath came. He was a cardiac anesthesiologist that trained in San Diego, and he brought the anesthesia, anesthetic management, the steroids, the various things that they were given that I didn't know in detail about, and we started to use the San Diego intraoperative management for lung protection and brain protection that we needed to reduce that delirium and the reperfusion injury.

So around the late 2000s, we really had the right team in place. We had cardiac anesthesia, we had the profusion technology, I had developed a deeper understanding of how to find the right surgical plane. We had the right instruments and we had the medical team. The last, I think, step in our developing the multidisciplinary team was really having a dedicated imaging specialist and interventionalist that could begin to help us understand where the scar was and then begin with some of the balloon angioplasty for the really distal lesions.

So over the course of about 20 years, we were able to bring this team together. And as I think my colleagues will show you, the results are absolutely phenomenal. And the extent of scar that they're tackling now is at that type four that was really challenging for us to manage 20 years ago. So it's been a great pleasure to work with everybody here and it's been fascinating and fantastic results.

Michael Tong, MD:

Next I'd like to introduce Dr. Gustavo Heresi. He's the medical director of our CTEPH program, and he's going to be talking about the pathophysiology of this disease.

Gustavo Heresi, MD:

Thank you, Mike. Good morning. And I should acknowledge, I mean, all credit goes to Nick. I mean, I think we wouldn't be here without your pioneer work and your leadership. And yes, we had a lot of fights. I think I lost most of those. But we're going to talk about CTEPH pathophysiology now. So yeah, we do think that CTEPH starts with one or more episodes of acute pulmonary embolism that failed to resolve, right? But the mechanisms that mediate this transition from acute clot to chronic clot are really not well understood. They probably involve things like impaired fibrinolysis, impaired angiogenesis, which are critical for clot recanalization, and also an enhanced inflammatory milieu at the level of the pulmonary vasculature.

How frequent is CTEPH after PE? The best data out there I show you there, it's about three percent of survivors of PE. And this study also gave us a couple of important risk factors from the clinical perspective. Recurrent PE and unprovoked PE are things that should enhance our suspicion for the development of CTEPH after a PE. However, when you look at these epidemiologic studies, and also in clinical practice, you need to be mindful that unfortunately the recognition of CTEPH lesions that you can see there to your right is frequently not done. So people are not trained in teasing out what chronic clot looks like, and it's not uncommonly mischaracterized as acute PE.

So patients presented with clot in the pulmonary vasculature and right ventricular strain are labeled as acute PE with RV strain, but they may be CTEPH all along. And so it requires a special expertise to pick those up. And in fact, several studies have documented this. I'm showing you the very last one where out of a group of 300 patients during follow-up over two years, five of them developed CTEPH. But when the authors went back and looked at the index CT scan, four out of those five had already CTEPH lesions on the index CT scan.

So I think this is an interesting phenotype of this disease that presents acutely in our PERT team and in the CTEPH team, we frequently see these cases, and obviously you can imagine that the management would be quite different if you already know that CTEPH is present there. Of course, we all have seen acute PE evolve to chronic PE, and I show you an example there where, to your right, classic retraction stenosis after an acute PE. Our group actually has shown that that type of acute PE that you see there, completely occlusive disease, is associated with a greater than threefold increased odds of CTEPH development after an acute PE. So again, simple imaging phenotype that should enhance your suspicion of CTEPH development after an acute PE.

Now, CTEPH may represent the tip of the iceberg. We do know that there is a larger number of patients out there with cardiopulmonary limitations after an acute PE. Some of those patients have the classic CTEPH lesions on imaging, but don't have pulmonary hypertension at rest, at least. We call those CTEPH, or more recently, chronic thromboembolic pulmonary vascular disease without pulmonary hypertension. And those patients, after careful phenotyping with invasive cardiopulmonary exercise testing, frequently benefit from our interventional and even sometimes medical therapies.

Which brings me to why people with CTEPH are limited, and they're limited or functionally impaired by two reasons. The first one is increased dead-space fraction. And in this slide I show you data even compared with patients with pulmonary arterial hypertension. So the dead-space fraction of CTEPH patients is way beyond what you observe in patients with pulmonary arterial hypertension. And of course, the reason is this massive ventilation perfusion mismatch that these patients have.

The second reason, of course, is right ventricular failure, and this is due to increased right ventricular afterload due to the disease in the level of the pulmonary vasculature. But here comes another key pathophysiologic concept in CTEPH. So when you look at imaging studies, and this is data from nuclear medicine comparing acute PE in orange versus CTEPH in yellow, you see that for any level of pulmonary vascular occlusion, the pulmonary resistance in CTEPH is much higher than what you would anticipate compared to acute PE.

And the only reason this is possible is because all these patients with CTEPH, in addition to the proximal occlusive thrombo-fibrotic process, they also have microscopic vasculopathy. And when you look at the microscopic vasculopathy under the microscope, it looks exactly the same as that that we observe in our patients with group one pulmonary arterial hypertension, or what we used to call primary pulmonary hypertension. This microscopic vasculopathy is key to understanding what happens with these patients. This is likely the reason why some of them don't respond well and they're left with residual pulmonary hypertension. Some of this is likely the reason why some of these patients bleed in the operating or in the ICU after endarterectomy.

And of course, the operation works, as you will see later. So this microscopic vasculopathy regresses, but the degree and how fast it regresses can be quite variable. And I think that we still don't understand some of these phenotypes, and that's part of the research that we're trying to do here. So again, dual compartment disease. CTEPH is featured by both large vessel obstruction, but microscopic vasculopathy. And this occurs both in areas distal to open arteries, and this is due to overflow induced vasculopathy. Basically, what you see in patients with left to right shunt where they have all these cardiac output going through the pulmonary vasculature over a long period of time that leads to vasculopathy. There may be some growth factors also produced by the ischemic lung that some data has shown contribute to this as well.

And vasculopathy distal to occluded areas, this is likely due to lung ischemia, low shear stress that has been demonstrated that leads to endothelial dysfunction, and systemic collateral. Of course, the body reacts by trying to bypass these obstructions and perfuse the distal pulmonary artery. And this is something actually that two of these slides are courtesy of Nick, the video that is really cool. This collateral coming out of the right coronary artery perfusing the right lung. And the other picture is our surgeons see these collaterals in the lungs, in the chest wall, and on imaging to your left, we see it also. And this is really another important concept because this is the reason why you will hear patients require circulatory arrest during the operation.

So this is my last slide. So just to remind you that CTEPH is a condition that affects the length of the pulmonary vasculature, and this is why we have different treatment modalities to address the large vessel thrombo-fibrotic process and medical therapy to address the microscopic vasculopathy. And frequently, we think about these patients as requiring one or more of these therapies. Thank you for your attention.

Announcer:

Thank you for listening. We hope you enjoyed the podcast. Like what you heard? Visit TallRounds online at clevelandclinic.org/tallrounds and subscribe for free access to more education on the go.