Pulmonary Arterial Hypertension Podcast

Classifications and Causes of Pulmonary Hypertension

Vallerie McLaughlin, MD; Raymond Benza, MD


June 23, 2022

This transcript has been edited for clarity.

Vallerie McLaughlin, MD: Hello, and welcome to this podcast series. I'm Dr Vallerie McLaughlin, the Kim A. Eagle Endowed Professor of Cardiovascular Medicine and director of the Pulmonary Hypertension Program at the University of Michigan Medical School in Ann Arbor, Michigan. I'm joined today by my dear friend and colleague, Dr Raymond Benza from Ohio State University Hospital.

Raymond Benza, MD: Good morning. It's a pleasure to be here today. As mentioned, I'm a cardiologist and I have large experience in the field of pulmonary vascular diseases. I've done many clinical trials in this area, and I do some primary investigative work in the genomics and risk stratification for this disease. Again, I'm very happy to be here to talk about the different classifications of pulmonary hypertension (PH) with you this morning.

McLaughlin: Thanks, Ray. That's what we're talking about: PH classification, and what are the causes? There's so many things that can cause PH. And of course, pulmonary arterial hypertension (PAH) itself is a rare disease. Ray, talk a little bit about the difference between PH and PAH in terms of definition.

Benza: That's a really great thing for people to understand because, as you just mentioned, PAH itself is rare but PH as a broader category is actually quite common. And some of the other causes of PH that we see in our clinic are much more common than those the patients that we see with PAH. I think understanding the classification is intimately important.

To start with, the definition of PH has changed a little bit since our last group meetings, in which we redefined some of these things. And PH as a whole is defined as a mean pulmonary artery pressure > 20 mm Hg as opposed to 25. And there are many reasons for having to change that classification, including really some good studies (study 1, study 2, study 3) in trying to understand what normal pulmonary pressures are in people, particularly as they age. This also allows us to diagnose disease earlier and watch patients over periods of time to see if it progresses, that older classic definition of PH and such.

PAH is defined by the same mean pulmonary artery pressure. But also there is a resistance definition to this: Many people with PAH have to have a pulmonary vascular resistance > 3 Wood units to be classified with that more rare form of the disease. Then, within the context of PH, we still have five groups within that classification that we'll discuss.

McLaughlin: That's right. Probably the most common type of PH, at least that I see in my clinic and probably in most patients, is group 2 PH due to elevated left heart filling pressures.

You are also a heart failure cardiologist. You're very experienced in this. And I tell you, people get in my door because of high pulmonary artery pressures on an echocardiogram, and on the echocardiogram, people understand systolic dysfunction. They see a low ejection fraction, and they understand that that can cause a modest elevation in pulmonary artery pressures and they get to treat the underlying heart failure.

But what a lot of people don't appreciate is diastolic heart failure. They see an elevated pulmonary artery pressure and a normal ejection fraction, and they think that it might be group 1 disease. Can you talk a little bit about diastolic heart failure — the risk factors for that and how that causes PH?

Benza: This is so incredibly important because heart failure with preserved ejection fraction (HFpEF) is really the PAH mimicker. And I think that a lot of people who have less experience in differentiating these types often confuse the two. That's really valuable to speak about.

HFpEF is really a constellation of diseases of heart failure in which the systolic function of the heart is normal. The relaxation properties of the heart are abnormal. And there are various phases of diastolic relaxation that allow us to differentiate the severity of that relaxation from mild to quite severe. Usually in the context of PH, the relaxation properties usually have to be somewhat in the mid- to severe range to cause pulmonary vascular disease or PH. So when we look at a patient who has normal systolic function and try to figure out if this person has HFpEF, the ordinary things are often very helpful — for example, questioning people about certain symptoms like orthopnea or paroxysmal nocturnal dyspnea, which is virtually never present in PAH, can be very common in a patient with group 2 PH. That's often a signal that you have to dive a little bit deeper, and then going into some of the risk factors for HFpEF is critical.

Say someone is of female gender and of an older age, with a history of hypertension, dyslipidemia, sleep apnea, coronary artery disease, and especially atrial fibrillation. Then you have to start thinking that this person may have HFpEF or group 2 PH. The more characteristics, the higher the likelihood. In that instance, I often will do a H2FPEF/HFA-PEFF calculation, using a validated scoring system. If that gives me a high percentage of being at group 2 PH or HFpEF, I am very careful about what I do next in terms of diagnostic strategies and particularly therapeutic strategies.

McLaughlin: That was a great summary, Ray. So some of the things you see in the office on physical exam and history, echo is really telling you too, right? Patients often have left atrial enlargement (LAE) and left ventricular hypertrophy (LVH), and all the Doppler signs have diastolic heart failure or diastolic dysfunction, but with normal right ventricles or maybe just a slightly big right ventricle or right atrium. I think that's a dead giveaway. We could actually harm those patients by treating them with PAH-specific therapy. So this delineation is really important.

Benza: I agree. The echo is my next step. Once I do that calculation and say, Oh boy, this person looks like they have HFpEF, I moved to the echo and the things that I look at the echo is I carefully evaluate left heart structure. I look to see if they have LVH. I look at the diastology, as you just mentioned, keeping really close attention to the E/e', the tissue Doppler characteristics. And then I, importantly, look at the left atrial volume index, which to me is one of the better signals. If someone has group 2 PH or signs related to HFpEF when the LAE starts getting > 30, I'm worried about it.

McLaughlin: I describe left atrial size as the A1c of left-heart filling pressures. If it's big, the left-heart filling pressures have been high for a long time. So group 2 PH is very common, and I think diastolic heart failure or HFpEF is the most common thing that we see these days, at least in my practice, but certainly valvular heart disease and others can cause it.

Let's go to group 3 disease. This is a really important area because now there's one specific type of group 3 disease that we have treatment options for. Let's briefly summarize the group 3 etiologies of PH.

Benza: When I think of these, I think of them in broad categories: obstructive lung diseases, restrictive lung diseases, and then the ever more common mixed etiology of obstructive and restrictive diseases. Sleep apnea is an important component of that group. Then there are a lot of less known diseases that can sneak in there — for example, very severe asthma, which I've seen rarely in PH but it's certainly a possibility if it's not controlled well.

The interesting thing about group 3 is that it's a mix of both the burden of parenchymal lung disease — distortion disease, I call it, if you have huge blebs that can compress pulmonary arteries — and the degree of hypoxia that you get with these individual diseases, which closely links with the degree of PH that I get.

McLaughlin: So group 3 PH is pretty common. Group 2 PH is the most common; group 3 PH is the next most common. A more rare but very important type of PH is chronic thromboembolic pulmonary hypertension (CTEPH), and we both have a passion for that. I think the one message that is most important to the audience is that when you're working someone up for unexplained dyspnea and PH, you have to do a ventilation-perfusion scan to rule out CTEPH. We want to get that message across.

Ray, you want to talk a little bit about what CTEPH is and why it's so important to differentiate from that more group 1 PAH?

Benza: You know, it's more common than we think. In people who, again, give a history of prior pulmonary emboli — particularly if they're bilateral and large — you really have to have a higher level of cognizance in terms of evaluating them for CTEPH.

The physiology of this disease is fascinating. Once we thought it was just the degree of obstruction of the pulmonary vessels by these fibrous masses that these clots become. But now that we know that it's actually a two-compartment syndrome and sometimes a three-compartment syndrome in which these fibrotic masses, which were once thought to be inert, are really chock-full of inflammatory cells that elaborate mediators that can remodel not only the vessels distal to the obstruction but also vessels that have not obstructed. So you can actually get a pulmonary artery vasculopathy in addition to the obstructed areas of the lung by these fibrous obstructions.

McLaughlin: And then group 5 disease — it's like the wasteland of where we put things that don't really belong in the other groups. Some of the rarer things, such as sickle cell disease and sarcoid (sarcoidosis-associated pulmonary hypertension [SAPH]), are in there. Although sarcoid, I think, of can go in lots of different spots, to be honest with you — some of the glycogen storage diseases, myelofibrosis, some of those rarer things.

But now let's go back to group 1 PH, kind of the heart of the matter. The prototype for group 1, PAH, is what we now call idiopathic PAH and what used to be called primary PH. It's a rare disease. We've also learned that many other diseases in group 1 have a pathobiology/pathophysiology and basic science mechanism very much like idiopathic PAH.

What we've learned so much about over the past decade or so is heritable PAH. We now have identified I don't know how many genes — probably 10, 12 genes that can cause heritable PAH. I know this is an interest of yours as well. Ray, do you want to tell us a little bit about heritable PAH?

Benza: The permissive phenotype in group 1 disease, like many others, is endothelial dysfunction, whereas in heritable PH, we actually know the trigger that causes this endothelial dysfunction. Usually, these are mutations in genes that deal with vascular remodeling — so smooth-muscle turnover, endothelial function — the most common is the BMPR2 mutation. You know that the BMPR2 mutation is a receptor for BMPR2. This receptor has a number of different mutations that affect the way the receptor binds to its ligand. The abnormality of this binding sets up a cascade in the cell that prevents the cell from dying, essentially; it prolongs the cell's life and makes it a more vasoconstrictive phenotype and also makes it proliferate unchecked. These mutations are probably, I would say, mostly grouped in these growth factor–like pathways that prevent the normal turnover of cells in the pulmonary artery and allow it to become a very large, resistant vessel.

McLaughlin: It's fascinating because we're learning more and more about these genes. We're also finding patients who don't have a family history and who, as you investigate them, have some of these genetic abnormalities, whether they're new spontaneous mutations or whether perhaps these genes, as you know, have some unusual characteristics. They can actually skip generations. They have incomplete penetrance, and it can make taking a family history very difficult. We now do the genetic series for the genes known to cause PAH on all of our patients with newly diagnosed idiopathic disease. And there's lots of literature that suggests you'll find 10%, 15%, 20% of those patients have a genetic abnormality.

Benza: We do something very similar in our clinic, and that's important, because genetic counseling is incredibly important to analog to these better understood subgroup of patients with group 1 disease.

McLaughlin: Next, let's move on to drugs and toxins. Probably when you and I were first starting out in PH in the mid- to late 1990s, all the rage was the epidemic of PAH caused by diet pills — fenfluramine, which eventually got pulled off the market. Now we don't see a lot of diet pill–induced PAH, but there are illicit drugs, such as methamphetamine, that can cause PH. So taking a good drug history is important in these patients.

Moving on to the associated causes, I have to say the one that's nearest and dearest to my heart is the connective tissue diseases, specifically scleroderma. Perhaps 10%-15% of patients with scleroderma develop PAH over the course of their disease. That's less common but can occur in all of the other connective tissue diseases. When a patient with scleroderma develops PA, they're more likely to die of that than anything else.

Ray, in the risk stratification work you've done with REVEAL, you identified connective tissue diseases as having a poor prognosis along with a couple of other heritable and portal, if I recall correctly. One of my passions is trying to screen these patients — those with connective tissue disease, and specifically those with scleroderma. You certainly can't screen all young women for idiopathic disease, but in a disease like scleroderma that has a prevalence as high as 10% or 15%, you can screen these patients. Our scleroderma program routinely uses the DETECT algorithm to screen these patients. Is that something that your practice does?

Benza: Absolutely. We have close connections with our rheumatology colleagues, and we have done a good job enforcing the use of the DETECT system and have found many patients with early PH by using it. I think that's critically important; when we have these high-risk categories, screening is essential because if we could find this disease at an early stage, we have a lot now that we can do to mitigate it. So these screening techniques are really important for this very prevalent subset of group 1 disease.

McLaughlin: I would also say that patients with scleroderma are really tough because multiple types of PH can be present within the same patient, right? So they have this risk factor for group 1 disease. We know that 10%-15% of them develop the vasculopathy that you described earlier that is consistent with group 1 disease. A lot of them have pulmonary fibrosis as well, so they're at risk for group 3 disease. And many of them are older with comorbidities and have some chronic HFpEF. So they're among the trickiest patients to treat, in my opinion.

Benza: Yeah, you really have to be careful with these people. You can't just say, oh, scleroderma: group 1 disease. We often do other studies. We look at their pulmonary function studies. We see if they have that restrictive pattern that you can be seeing when they have interstitial fibrosis. And I always look at their echocardiogram and their diastology, because it's a fibrotic disease and fibrosis in the heart is very common in patients with scleroderma, and they do get diastolic dysfunction. So it's really important to look at all three of those before you hang your hat just on the group 1 etiology.

McLaughlin: Moving on to portal hypertension. You and I have both been doing this for a long time, right? Twenty years ago, the most common call I would get is, we're in the OR. We are about to start a liver transplant. We put a Swan catheter in, and the mean pulmonary arterial pressure is 50. What should we do? I don't get those calls anymore because people understand the association between PH and portal hypertension, and all these patients get echos and are monitored very carefully.

Let's talk a little bit about portal hypertension. Ray, what are your thoughts?

Benza: I've never heard that call happen in at least 10 years, and that's because these patients were getting echos, and a lot of them were getting right-heart catheterizations before they're considered an absolute candidate for liver transplantation. That was a great screening tool for us — someone going to liver transplantation to identify these people. But I think, bringing that kind of clock backward and identifying patients who may not be going for liver transplant evaluations, unexplained dyspnea in a patient with a history of cirrhosis should be a trigger to think about group 1 disease. These people should have appropriate evaluations with echocardiography and right-heart catheterization, particularly if they have portal hypertension. That's the caveat that many people forget: In order to have group 1 disease in the setting of cirrhosis, patients should have established portal hypertension in addition to the cirrhosis. Because we know cirrhosis is a high-volume state, and when you catheterize these people, they often will have high cardiac outputs and could have a high pressure just from high flow. It's that resistance piece that we really must be attentive to.

McLaughlin: Moving on to congenital heart disease. We're getting so much better at taking care of these kids these days that many of them are surviving into adulthood with the residual and sequela of their congenital heart disease, and they develop PH. And every year we find a handful of patients who have an atrial septal defect (ASD) or a ventricular septal defect (VSD) or something that was missed in childhood. So we generally do a bubble echo on our initial echo to screen for that. And of course, we screen for these as well when we do the right-heart catheterization with saturation and try to pick up those patients. Often they tend to do better. The [people with unrepaired ASD or VSD] tend to do better, although sometimes we see patients who develop PH after a repair who don't do as well. This is something we have to be really cognizant of these days, because a lot of patients are getting clamshell closures of ASDs. Sometimes we have to be careful about who we choose for those procedures.

Benza: I agree, absolutely. Those are very challenging patients, and it depends on the shunt and the direction of the shunt. And the size of a hole, I think, is pretty critically important in trying to make those decisions. But you have to be very, very careful in those circumstances and make sure you're working with an expert in pulmonary vascular disease before you close those holes too prematurely.

McLaughlin: Patients with HIV have about 0.5% chance of having PAH, so we don't screen for it in them, but it's something to think about if they're symptomatic. And then there are those more rare but very complicated pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, which are challenging diseases. There are a lot of things to think about as we work up a patient with PH — a lot of different causes of it.

Ray, as we close our discussion today, I want to ask you something. You and I have been doing this for a long time. We've been through a lot, but it's a really exciting time in PH. Tell me what sorts of things you're most excited about that are likely to happen in the field in the next few years.

Benza: I think we've made a huge headway in the therapeutics for this disease, and I'm very excited about the new group of agents that are coming out that would focus on reversing the vascular remodeling we have in the disease — not just vasodilating blood vessels, but actually getting to the meat of the issue. And I think management techniques have also improved. We now know how to match patients according to their levels of risk with the type of medications that they have. I think that's going to really help us boost the survival that we've seen just with the new therapeutics.

McLaughlin: Ray, thank you for joining me for this podcast. It's always fun to chat with you, and I appreciate all the insight you've given to our audience.


Pulmonary Arterial Hypertension

The Definition of Pulmonary Hypertension: History, Practical Implications and Current Controversies

Pulmonary Hypertension

Group 2 Pulmonary Hypertension

Group 3 Pulmonary Hypertension

Group 4 Pulmonary Hypertension

Predicting Survival in Pulmonary Arterial Hypertension: Insights From the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL)

Evidence-Based Detection of Pulmonary Arterial Hypertension in Systemic Sclerosis: The DETECT Study

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