¶ Understanding Pulmonary Hypertension Classifications
You're listening to Medscape's in Discussion series on pulmonary arterial hypertension, a podcast where thought leaders and clinical experts share their diverse insights and practical ideas for optimizing patient care. This series is hosted by Dr. Valerie McLaughlin, MD.
Kim A. Eagle MD, Endowed Professor of Cardiovascular Medicine, and Director of the Pulmonary Hypertension Program, University of Michigan Medical School in Ann Arbor, Michigan. Relevant disclosures can be found with the episode show notes on Medscape.com. The topics and discussions are planned. produced and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals.
Hello and welcome to this podcast series. I'm Dr. Valerie McLaughlin, the Kim A. Eagle Endowed Professor of 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.
Well, good morning. It's a pleasure to be here today. As mentioned, I am a cardiologist and uh have large experience in the field of pulmonyvascular diseases, done many clinical trials in this area and and do some primary investigative work. uh in the genomics and risk stratification for this disease. Again, very happy to be here to talk about the different classifications of pulmonary hypertension with you this morning.
Yeah, so thanks, Ray. That's what we're talking about. PH classification. What are the causes? And there's so many things that can cause pulmonary hypertension. And of course, pulmonary arterial hypertension itself is a rare disease. So Ray, talk a little bit about the difference between pH and pH.
Any
In terms of definition.
I think this is a really great thing for people to understand because as you just mentioned, pulmonary arterial hypertension itself is rare, but pulmonary hypertension as a broader category is actually quite common. And uh some of the other causes of pulmonary hypertension that we see in our clinic are much, much, much, much more common.
than the patients that we see with PEH. So I think understanding the classification is uh intimately important. So d to start with, uh the definition of pulmonary hypertension has changed a little bit since our last group meetings. in which we redefine some of these things. And pulmonary hypotension as a whole is defined as a mean pulmonary artery pressure greater than 20 millimeters of mercury.
as opposed to 25. And there are many reasons for having to change that classification, including really some good studies in trying to understand what normal pulmonary pressures are in people, particularly as they age. And this also allows us to diagnose people earlier, to watch them through periods of time to see if this progresses to the older classic definition of pulmonary hypertension as such.
So pulmonary arterial hypertension is defined by the same mean pulmonary artery pressure, but also there is a resistance definition to this. So many people with pulmonary arterial hypertension have to have a pulmonary vascular resistance greater than three Woods units to be classified with that more rare form of the disease. And then within the context of pulmonary hypertension, we still have five groups within that classification that we'll discuss.
¶ Group 2 PH: Heart Failure and Diastolic PH
Yeah, that's that's right. And I think probably the most common type of pulmonary hypertension, at least that I see in my clinic and and probably most patients, is group two pulmonary hypertension due to elevated left heart filling pressures. And you are also a heart failure cardiologist. You're very experienced in this. And and I tell you, people get in my door because of high PA pressures on an echo. And on the echo, 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 they think that it might be group one. Can you talk a little bit about diastolic heart failures, the risk factors and for that and how that causes pulmonary hypertension?
Yeah, I think that is so incredibly important because heart failure preserved ejection fraction is really the PAH mimicker. And I think a lot of people who have a little less experience in differentiating these types. often confuse the two. So I think that's really valuable to to speak about. Heart failure preserved ejection fraction is really a constellation of diseases of heart failure in which the systolic function of the heart is normal.
But the relaxation properties of the heart are abnormal. And there are very various phases of diastolic relaxation that allows us to differentiate the severity of that relaxation abnormality from mild to quite severe. And usually in the context of pulmonary hypertension, the relaxation of the properties usually have to be somewhat in the mid to severe range.
To really cause uh pulmonary vascular disease or pulmonary hypertension. And so when we look at a patient who has normal systolic function and Try to figure out if this person has heart failure preserved ejection fraction. The ordinary things are often very helpful. So questioning people about uh certain symptoms like orthopnea or PND, which is virtually never present in a PAH patient, can be very common in a group two patient. So that's often a signal that you have to dive a little bit deeper.
And then going into some of the risk factors for heart failure preserved ejecture fraction is critical. So someone is a female gender of an older age that has 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 heart failure preserved ejection fraction or group two pulmonary hypertension. And the more characteristics, the higher the likelihood.
And in that instance, I often will do uh a hef pef. calculation using a a validated scoring system. And if that gives me a high percentage of being a group two or a heart failure preserved ejection fraction, I am very careful about what I do next in terms of diagnostic strategies. And particularly therapeutic strategies.
Yeah, and I also think um that was a great summary, Ray. So some of the things you see in the office on physical exam and history. I think echo is really telling too, right? You know, they often have left atrial enlargement and L VH and all the Doppler signs of diastolic heart failure or diastolic dysfunction.
but with normal right ventricles or maybe just a little big right ventricle, right atrium. So I think that's a dead giveaway. And we can actually harm those patients by treating them with PAH specific therapy. So this delineation is really important.
Yeah, I agree. Uh the echo is my next step. So once I do that calculation and I say, oh boy, this person looks like they have FPF, I move to the echo. And the things that I look at the echo is I I carefully evaluate left heart structure. I look to see if they have left ventricular hypertrophy.
I look at the diastology, as you just mentioned, keeping really close attention to the EE prime, 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 two pulmonary hypertension or related to heart failure preserved ejection fraction. When the lobby starts getting greater than 30, I'm worried about it.
You know, I kind of describe the the left atrial size as sort of the hemoglobin A1C of left heart filling pressures. If it's if it's big, the left heart filling pressures have been high for a long time. So Yeah, so group two is really very common. And I think diastolic heart failure or F-PEF 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.
¶ Group 3, 4, 5 PH: Diverse Etiologies
Let's go to group three disease, because I think this is a really important area because now there's one specific type of group three disease that we have treatment options for. So let's just briefly summarize the group three etiologies of pulmonary hypertension.
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 a important component of that group. And then there are a lot of uh less known diseases that can sneak in there. Very severe asthma, rarely I've seen pulmonary hypertension with, but it's certainly a possibility if it's not.
controlled well. And the the interesting thing about group three, I think it's a mix of both the burden of parenchymal lung disease or or distortion disease, I call it, if you have huge blebs that can actually compress uh pulmonary arteries and or the degree of hypoxia that you get with uh these individual diseases, which closely links with the degree of pulmonary hypertension that I get.
So group three is pretty common. Um group two is the most common. Group three is next most common. Uh a more rare but very important type of pulmonary hypertension is chronic thromboembolic pulmonary hypertension. And we both have a passion for that. And I and I think the one message that is most important
to the audience is that when you're working someone up for unexplained dyspia and pulmonary hypertension, you have to do a ventilation perfusion scan to rule out chronic thromboembolic pulmonary hypertension. So we want to get that message across. Ray, you want to talk a little bit about what chronic thrombolic pulmonary hypertension is and why it's so important to differentiate from that more group one pulmonary arterial hypertension?
Yeah, uh you know, it's more common than we think. And in people who again give a history of prior pulmonary emboli, particularly if they're bilateral and large, are people that you really have to have a higher level of cognizance about in terms of evaluating them for CTEF. And so, you know, the the physiology of this disease, I think it's fascinating. You know, once we just thought it was 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 for the disease, 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 remodel vessels that have not obstructed.
And so you can actually get a pulmonary artery vasculopathy in addition to the obstructed areas of the lung by these fibrous obstructions.
And then group five disease, it's like the wasteland of where we put things that don't really belong in the other group, some of the rare things, you know, sickle cell disease, sarcoid is in there, although sarcoid I I 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 more rare things.
¶ Group 1 PAH: Etiologies, Screening, and Future
But now let's go back to group one, kind of the heart of the matter. So the prototype for group one pulmonary arterial hypertension is what we now call idiopathic pulmonary arterial hypertension, what used to be called Primary pulmonary hypertension. And it's a rare disease. And we've also learned that many other diseases in group one. have sort of a pathobiology, pathophysiology, and basic science mechanism very much like idiopathic PAH.
You know what we've learned about so much 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. Uh as well, Ray. Do you want to tell us a little bit about heritable pulmonary arterial hypertension?
The permissive phenotype in group one disease, like many others, is endothelial dysfunction. Whereas in heritable pulmonary hypertension, we actually know the trigger. that causes this endothelial dysfunction. And usually these are mutations. uh in genes uh that deal with uh vascular remodeling. So smooth muscle turnover, endothelial function, the most common which is the BMPR2 mutation. You know, BMPR2 mutation is a receptor.
uh for BMPR2. And this receptor has a number of different mutations that affect the way the receptor binds to its ligand. And the abnormality of this binding sets up a cascade in the cell that prevents the cell from dying, essentially. It it prolongs the cell's life. It uh makes it a more vasor constrictive phenotype. And also makes it proliferate unchecked. And so these mutations are probably, I would say, mostly grouped in these growth factor-like pathways that really prevent.
The normal turnover of cells in the pulmonary artery and allow it to become a very large resistant vessel.
Right. And it's 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. who as 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.
Um, they have incomplete penetrance and it can make taking a family history really very difficult. We now actually do the genetic series for the the genes known to cause pulmonary chural hypertension on all of our newly diagnosed idiopathic patients. And and there's lots of literature that suggests you'll find 10, 15, you know, 20% of those patients actually have a genetic abnormality.
Yeah, we do something very similar in our clinic, and I think that's important because genetic counseling is incredibly important analog to these really better understood subgroup of Group One patients.
Next, let's move on to drugs and toxins. Probably when you and I were first starting out in pulmonary hypertension in the mid to late 1990s, there was all the rage, the epidemic of pulmonary arterial hypertension that were caused by diet pills, phenfluoramine. Which eventually got pulled off the market. And so now we don't see a lot of diet pill-induced pulmonary arterial hypertension.
There are other illicit drugs, metamphetamine, that can cause pulmonary hypertension. So doing a a good drug history is important in 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. So perhaps 10 to 15% of patients with scleroderma.
develop pulmonary arterial hypertension over the course of their disease. That's less common, but can occur in all of the other connective tissue diseases. And when a patient with scleroderma develops pulmonary arterial hypertension, they're more likely to die of that than anything else. Ray, in in the wrist ratification 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, actually, if I recall correctly. So one of my passions is trying to screen these patients, the connective tissue disease patients. specifically the scleroderma patients. You certainly can't screen, you know, all young women for idiopathic disease, but in a disease like scleroderma that has a prevalence as high as 10 or 15%.
Uh you can screen these patients and our scleroderma program routinely uses the detect algorithm to screen these patients. Is that something that your your practice does?
Absolutely. We have close connections with our uh rheumatology colleagues. And we have uh done a good job enforcing the use of the detect system and have found many patients with early pulmonary hypertension using that. And I think that's critically important because when we have these. High risk categories.
screening is essential because if we can 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 one disease.
Yeah, now I would also have to say that the the scleroderma patients are really tough patients because they can also have multiple types of pulmonary hypertension within the same patient, right? So they have this risk factor for group one disease. We know that 10 to 15% of them develop that, you know, the vasculopathy that you described earlier that is consistent with group one disease.
Lot of
of them have pulmonary fibrosis as well. So they're at risk for group three disease. And many of them are older with comorbidities and have some chronic heart failure with preserved ejection fraction. So they're amongst the trickiest patients to treat, in my opinion.
Yeah, you really have to be careful with these people. You can't just say, oh, scleroderma group one. So 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 itcytial fibrosis. And I always look at their echocardiograms 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 one etiology.
Moving on to portal hypertension, I'll tell you, you and I have both been doing this for a long time, right? So 20 years ago, the most common call I would get is uh we're in the OR, we are about to start a liver transplant, we put a swan in, and the mean PA pressure is. 50. What should we do? I don't get those calls anymore because people understand the association of pulmonary hypertension and portal hypertension. And all these patients get.
echoes and are monitored very carefully. Let's talk a little bit about portal hypertension, Ray. What are your thoughts?
I've never heard that call happen in at least ten years. And that's because these patients were getting echoes and a lot of them are getting right heart catheterizations before they're considered an absolute candidate for liver transplantation. And that was actually a great screening tool for us.
Is someone going to a liver transplantation to identify these people? But I think bringing that kind of clock backwards and identifying those patients who may not be going for liver transplant evaluations. Yeah, unexplained dyspia in a patient with a history of cirrhosis should trigger.
Uh, someone to think about group one disease. And then these people should have appropriate evaluations with echocardiography and right-heart catheterization, particularly if they have portal hypertension. And I think that's the caveat. that many people forget that in order to have group one disease in the setting of cirrhosis.
They should have established portal hypertension in addition to the cirrhosis, because we know cirrhosis is a high volume state. And if when you calf these people, they often will have high cardiac output. and could have a high pressure just from high flow. It's that resistance piece that we really gotta be attentive to.
Moving on, congenital heart disease. So we're getting so much better at taking care of these kids these days that many of them are surviving into adulthood with the residua and sequella of their congenital heart disease and they develop pulmonary hypertension. And of course, you know, every year we find a handful of patients who have an ASD or a VSD or something that was missed in childhood.
So we generally do a bubble echo on our initial echo to kind of screen for that. And of course we screen for this as well. when we do the right heart catheterization with saturation runs. So we try to pick up those patients. Often they tend to do better. The unrepaired tend to do better, although sometimes we see patients who develop pulmonary hypertension after a repair.
who actually don't do as well. And this is something we have to be really cognizant of these days because a lot of patients are getting clamshell closures of ASTs. And you know, sometimes we have to be careful about who we choose for those procedures.
Yeah, I I agree absolutely. And and those are very challenging patients. And it depends on the shunt and the direction of the shunt and the size of the hole, I think, is important. pretty critical important in trying to make those decisions, but you had to be very, very careful in those circumstances and really make sure you're working with an expert in pulmonovascular disease before you close those holes too prematurely.
HIV has point five or so percent 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 of course there are those more rare but very complicated pulmonary veno occlusive disease and PCH, which are challenging diseases. But a lot of things to think about as we work up a patient with pulmonary hypertension, a lot of different causes of it.
So Ray, as we close our discussion today, I wanna ask you, you know, 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 pulmonary hypertension. Tell me in the next few years what what sorts of things you're most excited about that are likely to happen in the field.
Well, like I, you know, 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 really 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 then I think management uh techniques have also improved. You know, we now know how to match.
Patience.
according to their levels of risk with the type of medications that they have. And I think that's going to really help us boost the survival that we've seen just with the new therapeutics.
Well, 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.
Thanks for listening to Medscape's Indiscussion Pulmonary Arterial Hypertension Podcast Series with our host, Dr. Valerie McLaughlin. Be sure to look for more Indiscussion episodes wherever you get your podcasts. Check out Medscape.com for show notes, links, and more information on pulmonary Primary arterial hypertension.
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