In this episode, Andrew Perry, MD, discusses pulmonary hypertension with Murali Chakinala, MD, who specializes in pulmonary vascular diseases at Washington University School of Medicine in St. Louis. During the course of the conversation, they cover the diagnosis and disease groupings related to this condition, as well as the available treatments.
A transcript of the podcast follows:
Perry: Maybe first let’s start with you maybe saying your name and your title, and then I’ll describe that case that I encountered.
Chakinala: I’m Murali Chakinala. I’m a member of the pulmonary division at Washington University. I’m a Professor of Medicine, and I direct our Pulmonary Hypertension Care Center.
Perry: Thank you for meeting with me today. This is actually a few months ago, starting with a patient case. I was rotating through the cardiothoracic ICU as an elective, and we had a gentleman come up from the OR with a mitral valve repair from mitral stenosis. Past medical history also included lupus with some low-dose prednisone. He had some history of cirrhosis from alcohol and a DVT, but no PE. He came up with a Swan-Ganz catheter in place and his pressures, they were 134/47, which is huge.
One of my first questions when I was seeing him, knowing he had multiple reasons to have pulmonary hypertension, primarily this mitral stenosis that had been repaired, but that just seemed so out of proportion to maybe what you would normally see or experience. For a patient like that, it’s complicated. What would be your approach for him and then we’ll kind of talk about the overall groupings of pulmonary hypertension.
Chakinala: What you’re asking, really, is how do you approach sort of severe pulmonary hypertension like in this case? It really is tricky and it depends on the context by which you come across that patient. When people come to you in the office with that kind of pulmonary hypertension and they’re not acutely ill, obviously, you know they’ve been like this for a long time. You don’t develop pulmonary hypertension like that out of the blue. It’s something that takes a long time to develop those kind of pressures. You have to really have the historical frame of reference of why or what led to where they are and what are the comorbidities or underlying causes.
The scenario you’re describing with somebody who just had, well, first off, they had mitral valve disease for a long period of time, and so they certainly could have developed pulmonary hypertension, but then you’re catching them fresh post-op, presumably still intubated or on a lot of vasoactive medicines, and the context or the background or the setting that you’re in will certainly influence a lot of those pressures.
Like in a lot of other diseases, it’s really important to understand sort of the pace and the tempo of quality in the case of when and how it developed over time. Then you alluded to a lot of comorbidities and underlying factors that could lead to pulmonary hypertension beyond the mitral valve disease. They had previous venous thromboembolism or at least DVTs and how sure are you that they didn’t have pulmonary emboli and chronic thromboembolic disease and you mentioned they have cirrhosis, so that puts them at risk as well, too.
We certainly want to think about all of those things, but obviously, at that moment where you’re in the ICU taking care of somebody, you’re really focused on the acute situation and how much of an impact that it’s directly having on their blood pressure and organ perfusion and whatnot. I think that’s sort of just preliminary approach, but I always want to think about how long or how chronic is the hypertension, the pace with which it’s presented, and what are the relevant comorbidities that may cause it as we try to figure out what the true etiology or true diagnosis is.
Perry: We should take a second and just kind of define what pulmonary hypertension is, so that we start on the same page.
Chakinala: Sure. Just like hypertension meaning high blood pressure, we’re now focusing on the arterial side of the vascular tree in the lung, so essentially the vasculature, the blood vessels that are responsible for transmitting blood from the right side of the heart to the lungs and remind everybody that’s the deoxygenated blood that has to make it to the capillary level so that we can transport or pick up oxygen that the lungs have respired in and deliver it to the rest of the body. When you’re dealing with pulmonary hypertension, it’s the pressure being elevated in those vessels on the arterial side of the tree, and there are many reasons for people to develop pulmonary hypertension. Just aging in itself will lead to a modest rise in the pressures, but not to the level of what we call pulmonary hypertension.
To define pulmonary hypertension, the mean pulmonary artery pressure has to be at least 25 mm Hg. Any time you have that, then you’re dealing with pulmonary hypertension. But as you mentioned a few minutes ago, the different groupings and whatnot, that is really the beginning and I always tell people pulmonary hypertension isn’t a diagnosis by itself. It’s more of a physiologic finding, a condition, if you will, but the ultimate diagnosis has to be drilled down further to get to. Think of PH in five different groups. Group 1 is pulmonary arterial hypertension. Group 2 is classic left heart disease that leads to pulmonary hypertension like your patient who had mitral valve disease. That would be your big concern. Group 3 is patients who have underlying bronchial lung diseases, whether it be airways disease, interstitial lung disease, you name it, anything, sleep apnea, anything that can affect the lung, parenchyma that can then ultimately affect gas exchange can also lead to pulmonary hypertension. Group 4 is rare, but very important and that’s chronic thromboembolic disease, previous pulmonary emboli that failed to completely resolve and lead to diffuse remodeling of the vasculature that ultimately causes pulmonary hypertension.
Then Group 5 is more of a miscellaneous category of a bunch of different diseases, where either we don’t quite know why they develop PH or there may be multiple reasons and one disease in one patient for them to have pulmonary hypertension. Classic examples might be sarcoid, for instance, or patients who have chronic kidney disease on dialysis. These are patients where multiple things can be going on simultaneously to lead to pulmonary hypertension.
But Group 1, which I quickly mentioned, is the one that probably we talk about the most because, in some ways, it’s the most lethal disease, and this is PAH or pulmonary arterial hypertension, where it’s really a problem at the level of the small arteries of the lungs. It’s in these tiny vessels that normally should offer very little resistance that became progressively narrowed and maybe even occluded because of vascular remodeling and some vasoconstriction. It’s a group of diseases that also are interesting because they can come from a variety of other disciplines like autoimmune diseases, like scleroderma, cirrhotic patients who develop portal hypertension, folks born with congenital heart defects that also go on to affect the pulmonary vasculature, drugs and toxins in the environment or that are available like anorexigen compounds, certain chemotherapeutic agents. All of these entities act like the classic, quintessential example, which is idiopathic pulmonary arterial hypertension and the heritable form of it as well.
In all these conditions, you can develop a severe vascular disease or really an arteriopathy, with the rest of the lung essentially being unremarkable or normal. That’s why it’s a special group because there really isn’t a significant heart disease that’s causing the PH or a significant lung disease that’s causing the PH. At the same time, these are patients who can develop some of the most severe forms of pulmonary hypertension. When you’re in that group, your symptoms, your clinical presentation, your natural history is pretty much determined by the fate of your pulmonary hypertension.
Perry: I find that having cared for a few patients with pulmonary hypertension, I find that generally folks with left side heart failure or chronic obstructive pulmonary disease, that their pulmonary hypertension is usually pretty mild. That’s talking mean pressures up in the 30s or low 40s. I would once ask you at what point is your threshold to then suggest even with these other comorbidities that they have, their pulmonary pressures are out of proportion to what I would expect and maybe I should consider this a coexisting Group 1 pulmonary arterial hypertension in combination to those?
Chakinala: Yeah, that’s a great question and we wring our hands a lot at some of these patients because the patients don’t come to us like they’re out of the textbook where they have one problem. Sometimes they do, but most often they don’t. Before I answer you, I want to just say that our patients can easily have multiple things going on at the same time, where more than one condition they have may produce pulmonary hypertension, and sometimes that can have an additive effect.
For example, people who have chronic lung disease like COPD or interstitial lung disease, they can certainly develop pulmonary hypertension, typically mild like you were suggesting, and I’ll give you some numbers in a minute, but in that patient, they also have undiagnosed obstructive sleep apnea. The two things together can lead to a more robust pulmonary hypertension because the driving factors that are causing the vascular changes, some of the remodeling, and the hypertension is more aggravated because a COPDer who also has sleep apnea, in all likelihood, has worse gas exchange and lower oxygen levels and higher carbon dioxide levels at night when they sleep as opposed to the COPDer without sleep apnea or the sleep apneic who doesn’t have COPD.
You have to think that the added effect of some of these conditions can certainly make it worse, but in general, what I worry any time I see a patient where the mean pulmonary artery pressure is above 40, even sometimes 35, the mean now, not the systolic, I think when you’re getting up into that range, again, certainly above 40 and maybe even above 35, you’re really talking about rare examples of pulmonary hypertension. Now all that means to me, though, is that I really want to pay attention and do a thorough workup to see if I can identify what might be the cause. Sometimes it still winds up being these common conditions, but it’s just a snowball effect. They’ve got heart failure, preserved ejection fraction, untreated sleep apnea, and COPD and they haven’t been wearing oxygen because they don’t like to wear it. You still have to think about all those things, but certainly my ears perk up when I hear a mean PA pressure greater than 40, that I want to be sure I’m not missing something else.
Lo and behold, I’ve been fooled thinking on first glance or first look that, “Oh, this is probably just COPD pulmonary hypertension,” and then we wind up finding out that, “You know what? They have scleroderma.” Until we did the digging, we didn’t see it. Or they have chronic thromboembolic disease or they have a bad mitral valve or an aortic valve. I think it’s really important that those patients, that we carefully look at them and thoroughly evaluate them with our standard workup for pulmonary hypertension any time you have a mean PA pressure certainly above 40.
Perry: Okay, and maybe just to rephrase what you’d also mentioned. But those common groups could also result in that degree of hypertension. It’s maybe a matter of them being inadequately treated for many, many years, and then they develop this remodeling and now their pressures are that high, even without…
Chakinala: Right, and there’s a lot about the pulmonary vascular biology we still don’t know. I mean we’ve identified certain genes that can lead to heritable pulmonary arterial hypertension. We’re still learning more, but it’s possible that maybe there are lesser pathways or more common pathways or polymorphisms in certain genes that may trigger a more robust pulmonary vascular response to a trigger that’s quite common. They have HFpEF, heart failure with preserved ejection fraction, like millions of people in our country, but they get a more severe form of pulmonary hypertension, and while we don’t have proof yet of what those other pathways are, you still wonder, “Why does this person in their 70s have such bad PH?” We know they have all these issues and they have HFpEF, but they also have this exaggerated pulmonary hypertension.
A lot of us have speculated that maybe some of the pathways that are relevant for primary pulmonary vascular diseases may also spill over as a lesser pathway, may also be present in the HFpEF patient, in the mitral valve patient or something. We have to be very careful not to lump them just with the other Group 1 patients and say, “Here’s drug A, B, and C. Go at it.” Some of these patients, when they have more of these comorbidities, even though the PH may be severe, you can’t treat them necessarily the same way, and you still have to recognize and optimize the underlying other issues, whether it’s valve disease, HFpEF, sleep apnea, and whatnot.
Perry: You’re in a bit of a unique position in that you’re here at a tertiary, quaternary referral center for seeing patients with pulmonary hypertension that come to see you. But what’s the common story that you generally see from patients that are coming to present to you?
Chakinala: Patients with pulmonary hypertension, whether it’s strictly from the pulmonary hypertension or it’s because of the other underlying things that cause Group 2 and Group 3 disease, almost the universal complaint we hear is that they’re short of breath. Their exercise capacity is down, and then if it gets far enough along, then we start seeing signs of right-sided heart failure. These are the scenarios and the presentations, I think, that patients generally present with. Then it’s really an issue of how the medical system around them handles them.
I mean ideally what we’d like to see is patients who have pulmonary hypertension or at least unexplained dyspnea where PH may be a possibility, that they’re carefully evaluated by their physicians, often involving pulmonologists, cardiologists to look for all these other issues. When you look at the PH universe, 85% of patients are going to be Group 2, 3, and a little bit of 5. There’s that thin 15% sliver that is either PAH or Group 4, which is chronic thromboembolic disease, that really requires sort of special attention and focused therapies. There are going to be some patients in 85% who are sort of the more severe end of PH, even though it’s from other reasons like we talked about. They may require special attention, too, because they’ve got significant right-sided heart failure.
But the vast majority of patients need a good, thorough workup to look for lung diseases, heart diseases, make sure they don’t have blood clots, and when you find any of these underlying explanations, the focus should really be on that underlying problem. Is there heart failure? Is their HFpEF adequately controlled? Are they on the proper bronchodilators? Are they on potentially antifibrotic therapies if they have interstitial lung disease? I mean we can’t lose sight of the fact that that’s probably why their short of breath more so than the pulmonary hypertension in most of those patients.
We definitely like to see patients evaluated and worked up appropriately for those underlying problems. I think the patients that deserve consideration for coming to a center like ours, that has a lot of expertise and all the equipment and tools to evaluate these patients, are the ones where you really think they’re in that 15% where you can’t explain it off to other heart or lung problems, or that patient, yes, they have these comorbidities, but gosh, their PH is really severe. I just, for instance, yesterday, saw a gentleman who has COPD, has HFpEF and Afib, and his local doctors have been working on him for a couple of years and doing everything appropriately, but he’s just really dyspneic still and out of proportion. There’s clearly something abnormal about him, and he does have moderate pulmonary hypertension. That’s the kind of patient that I think is served best by being referred to a center, at least for a second opinion and re-evaluation to make sure that nothing is missed and are they a candidate for maybe specific PAH therapies for either an underlying, missed PAH diagnosis, or perhaps, they’re one of these rare patients where they have a more exaggerated vascular response to those other conditions, and we might enroll them in a clinical trial or, on rare occasion, try off-label therapy from the Group 1 cache of drugs that are out there. But that shouldn’t be something done routinely or in a willy-nilly basis in the community. I think those things really should be done at centers who know how to manage those medicines.
Perry: Sure, okay. Now I think we’ve done a good job overviewing the broader approach to pulmonary hypertension, maybe narrowing down a bit more on the folks of that 15% of pulmonary arterial hypertension. But first, before we get there, I had a specific question regarding coronary thromboembolic pulmonary hypertension. Pulmonary embolism is fairly common. One thought is that we don’t always give these folks thrombolytics, so one question I had is there’s some evidence to help improve right heart function if you give thrombolytics at the time of a submassive PE. I’m wondering if there’s any information about thrombolytics and the use for PE and the end results for developing CTEPH later on. That question may not be answered, but what are your thoughts?
Chakinala: It’s a good question and it’s something I get asked not infrequently. Every time another thrombolytics article comes out, it seems like that invariably gets asked. I think that at this point, there’s no data to support that practice of using thrombolysis in submassive PE simply for the treatment goal of preventing chronic thromboembolic disease. The decision to give thrombolytics, I think, should squarely be on whether there’s felt to be an acute need for the thrombolysis. In other words, a patient who’s sick, too tenuous to where the need to acutely lower the RV afterload is crucial for maintaining perfusion and their survival.
That’s why massive PE with hemodynamic consequences, there’s little, if any, doubt that people feel like they should give thrombolytics. It’s just with submassive PEs, it’s more controversial because many of those patients will do just fine if you just support them through those first few hours. The problem is that, and sorry to throw some numbers at you, but the incidence of chronic thromboembolic pulmonary hypertension is probably no more than 2% of PE survivors. That may even be a generous number. In fact, some of the best studies, including one from Italy from about 10 years ago, showed that maybe the numbers, if I recall, were as high as 4% by two years. But I think the problem, or in hindsight, what people have appreciated, is that the patients that were entered into studies like that had already a bias towards having pulmonary hypertension, and it was more likely they had acute PE on top of previous pulmonary embolism. There’s already an element of chronicity there, and so it’s not the same population.
The reason I say that is because if you do the mental math of how many people in our country have pulmonary embolism, and you then apply, okay, 4% are going to get CTEPH, chronic thromboembolic pulmonary hypertension in two years, there would be tens of thousands of patients with CTEPH out there. There just aren’t that many. I’m sure we’re missing some, but I don’t think we’re anywhere close to that. My point is that the incidence of CTEPH is still pretty low, probably in the order of 1% to 2% of PE survivors.
You have a condition that, in years down the road, 1% to 2% of patients may get. If your goal is prevent that, do you really want to expose patients to a treatment where the incidence of severe bleeding, including intracranial hemorrhage, may be as high as 2% to 3% in the span of the days of giving thrombolytics. When you think about it in those terms, do I want to take a chance of 2% to 3% of having an intracranial hemorrhage to prevent something that I have a 1% to 2% chance of getting in the next five to 10 years? I think just the math doesn’t add up.
That’s why I would caution anybody listening. Please don’t give thrombolytics, no matter what the burden of clot that you see on imaging is, simply, if your goal is to prevent CTEPH. That shouldn’t be the reason of the trigger to pull or the trigger to give thrombolytics. It should be that this patient is in shock and is in extremis, is a high risk of going into that dreaded spiral towards death in the setting of an acute PE.
Now if you want to believe some of the studies and say even submassive PE with RV strain should get thrombolytics, I mean, I think it’s debatable, but some people do that. I tend to be more conservative and want harder reasons or goals for why I’m giving thrombolytics in those patients. But it definitely shouldn’t be to prevent CTEPH. Sorry, I kind of got us off topic there, but I think it’s a good question that people do ask.
Perry: Yeah, it’s come up a couple of times on the wards for me. No, I appreciate you elaborating on that. Now for the rest of the time, I want to focus primarily speaking about Group 1 PAH. In my reading prior to this, they’re maybe somewhat poorly understood, but there’s a lot of environmental and genetic factors. I’m wondering if you could talk about some of the etiologies that we know behind PAH and that complex interplay between environmental exposures like we’re talking anorexigens, grapeseed oil, and then underlying genetic factors as well.
Chakinala: I kind of alluded to it a little bit earlier, and again, there’s a lot we still don’t understand about this disease. It is still rare and we know a lot of potential exposures that are out there. Now, I think we’re up to seven genes that have been linked. I mean more are popping up smaller in numbers and probably more significance than the granddaddy, which is the BMPR2 gene, bone morphogenetic protein receptor II. That was discovered over 10 years ago, and it’s a cell-surface receptor that helps modulate TGF-beta signaling on endothelial and smooth muscle cells of the lung. It’s a pathway that’s really critical for the endogenic development, and it has expression in other parts of the body too, but as far as I’m aware of, it’s only been linked to disease in the lung, in the pulmonary circulation.
But we know that about 75% to 80% of people with heritable PAH are going to have a mutation in BMPR2. There’s several other less common genes. We’re talking probably, at most, 1% of the heritable population that probably have these other genes that can be affected. But the crazy thing is even in families with BMPR2, the penetrance is very low. It’s roughly about 10%, so that 1 in 10 family members who have a BMPR2 mutation, as best as we know, go on to develop PAH. That’s why it’s this classic kind of multi-hit process where genes play a role, but there’s probably other pathways and potentially other triggers, environmental, that we may not even know. Again, sort of other co-pathways that might have to be affected as well for BMPR to be expressed. Some have even speculated about certain infections. We know HIV is one of those triggers. There was a lot of interest in the human herpes virus 8 years ago. Is there a response to virus or inflammatory response that then unleashes BMPR2? We don’t know, really, but clearly the penetrance is low. We think there’s multiple hits that have to occur.
The same thing applies for other things, too. A lot of people used anorexigen compounds back in the 90s, drugs like fen-phen and Redux and Pondimin, but only a small percentage of them went on to develop pulmonary arterial hypertension. Even now, the big toxin that we see is methamphetamines. That’s overtaken everything else in our country, and it’s a sliver of the methamphetamine user population that go on to develop this. There’s clearly more than just the exposure, and it undoubtedly has something to do with the vascular biology. Maybe some of the other main pathways that we know are involved in the pathogenesis like the nitric oxide pathway or the endothelin pathway or the process cyclin pathway. There may be polymorphisms for receptors or intracellular messengers that modulate those pathways, and depending on the polymorphism, maybe you’re one of these people who have underexpression of nitric oxide in the lung, and then you take a drug like methamphetamine and something snaps, and now you’ve got a PAH syndrome.
That same idea could be applied as we were talking about earlier. You have somebody with HFpEF, but boy, they have really severe pulmonary hypertension, or they have mitral valve disease and they have really severe pulmonary hypertension, or they have COPD and emphysema, but out of proportion pulmonary hypertension. Again, it’s something else, maybe a lesser pathway that we still need to unlock that may explain why they go on to get it.
Perry: Now let’s take an example for a case. I have somebody coming to me with pulmonary hypertension, and I’ve done the workup to investigate other causes for their pulmonary hypertension. Their VT scan looked for CTEPH with echo and verify it on a cath, did my sleep study and their PFDs as well. I’ve determined yeah, they truly have Group 1 pulmonary hypertension. What is then your stepwise approach with medical management for those patients?
Chakinala: Yeah, and we’re blessed that even with a rare disease like PAH, that we have so many therapies now. I think we’re up to 14 FDA-approved therapies, which for a rare disease, is just unheard of. That’s great. Patients have lots of options, but the challenge there becomes, as you said, what’s the stepwise approach and what therapy and how do you begin to decide what therapy to put them on?
I think I can tell you some more general principles now, but we’ve always thought that the more severe the presentation, the more aggressive we need to be, just because this is a lethal disease, and sometimes people can die within months of diagnosis, so we don’t have a lot of time to waste. In general, the more severe the disease, the more aggressive we’re going to want to be. Another general principle nowadays is that we’ve known that this is a very difficult and refractory disease, and we’ve got many studies now that have shown that what we’ll call combination therapy treating with multiple drugs, at least two, maybe three drugs, early on or right off the bat is going to achieve more robust improvement and better, longer-term outcomes.
Most PAH patients nowadays, again, truly PAH patients, when they’re diagnosed, will be started on a dual therapy, two drugs. Now, how we decide, again, comes back to our initial evaluation. We have risk scores that we generate based on the data that we collect during the initial evaluation, things to inform us about, well, first just demographics. For instance, men do worse with this disease than women, comorbidities like scleroderma and cirrhosis certainly make the risk greater, the pace and severity of their symptoms, and how functionally impaired they are. The higher the functional class, I should say, the worse they are. Their exercise capacity, we usually use the six-minute walk test. We might use a peak VO2 doing an exercise study, but the worse those numbers are, the worse their prognosis.
Then really critical, though, is the state of their right ventricle. The condition of the right ventricle drives our decision-making probably more than anything. If you think about it, that also answers or feeds into other things like how their exercise capacity is, how symptomatic they are, whether they’re having syncope or not. That’s really all driven by right ventricular function. We look at things like BNP values, hemodynamics, echo imaging parameters, but we look at a whole host of things and there are well-characterized, validated risk tools that we have, like the REVEAL risk score is one of the ones that was developed in our country, and then there are some more simplified European risk models.
We take into account multiple pieces of data to sort of risk stratify our patients, and based on that risk stratification, then we can decide about therapy. Certainly patients who are in a high-risk category, where we think their chance of dying within the year may be as high as 10% or 20%, those are patients that not only are we going to treat with combination therapy, but unless they are unable to do it or unwilling to do it, they are the patients who are going to go on our advanced therapies, which are parenteral prostacyclin analogs, drugs like epoprostenol, treprostinil in our country. Oftentimes, the parenteral agent coupled with one or two oral agents in the other classes of therapies is how we’re going to hit them hard and aggressively.
I would say the majority of our patients fall into a slightly less risky category of presentation, what we call intermediate risk. It’s a pretty broad category, but in most cases, those are patients we would typically start with two oral medications such as an endothelin-receptor antagonist plus a PD5 inhibitor, a phosphodiesterase 5 inhibitor or an endothelin-receptor antagonist and another class called the soluble guanylate cyclase stimulator, or a non-parenteral prostacyclin analog. They are available now in inhaled and oral formulations, too. That’s four classes of therapies I just mentioned: ERAs, PD5 inhibitors, SGC stimulators, and non-parenteral prostacyclins.
I think most of us, for the intermediate-risk patients, would pluck two drugs from those four and start patients on therapy. If you truly have somebody that’s low risk, maybe he was an incidental planning on an echo or a screening protocol for a scleroderma patient where you found the PH pretty early on, they’re still quite functional. Their RV is almost normal. Those are patients that maybe you might treat with one drug, but even then, the threshold to treat with two drugs has really sort of been drilled into our heads based on some of the trial data that we have.
Perry: Gotcha, okay. Very interesting. These patients can be tenuous, as I’m sure you know, and so they can come in in an acute decompensated state. Wondering about other considerations to help optimize their function and management decisions to consider when you’re seeing a patient acutely in the hospital in right ventricular failure.
Chakinala: Are you specifically talking about sort of the prevalent patient who’s been on therapy and has slipped into right heart failure or just even somebody sort of a new diagnosis that presents in pretty bad right heart failure?
Perry: I guess I was thinking more of the person who had been stable and has slipped into it.
Chakinala: Good, sure. The first thing we always want to know what tipped them over, just like any disease state, whether it’s congestive heart failure or COPD. We have our list of things that we think about as precipitators of right heart failure. First and foremost, we always want to make sure there’s been no sort of gaps in their care or lapses in their medications, and unfortunately, it’s becoming more and more common as patients are struggling to get medicines or access to therapies. That’s always first. We want to make sure there isn’t any gaps or lapse in their medications. We want to make sure there’s no complications of the medications, specifically the patients on parenteral therapy. If there’s a catheter infection or dislodgement and they aren’t getting their medicine, that can really sort of put people into a bad position.
There are some other less common things like a comorbidity like an acute pulmonary embolism, endocrinopathies like thyroid disease, pregnancy. These are also on our list of things and the differential arrhythmias, I shouldn’t forget about that. Atrial arrhythmias, in particular, can really set our patients back. These are all some of the other things we think about.
Then there’s always the concern of disease progression. People are getting worse. Hopefully and I’d like to think that when they’re followed closely at a center like ours, that’s less likely to just all of a sudden lead to hospitalization, that their disease is just progressing so rapidly. That is less often likely to occur, but certainly patients who may not be getting the closest of care, they can be slipping at home and then show up in bad right-sided heart failure. We always want to go through that mental exercise of what’s the trigger for the decompensation and address whatever might be the inciting issue there.
But in terms of management of these patients, it comes down to a lot of basics just like in managing left-sided heart failure. You want to think about it in terms of preload, afterload, and contractility. I mean what are things you can do to adjust either of those things? I mean preload is a big thing, and a lot of times these patients are just really volume overloaded, and they need a diuresis. We shouldn’t be afraid to diurese them even when their blood pressure is a little soft. We may need help to support their blood pressure, but they need diuresis because that right ventricle can get so big, it tends to encroach upon the left ventricle. You don’t fill the left ventricle and your cardiac output really goes down. If you can properly diurese, the right ventricle decreases in volume, the left ventricle now can actually receive blood and you improve cardiac output that way.
So optimizing preload, the RV afterload. Unfortunately, we struggle there. We don’t have a lot of great drugs that are potent, acute vasodilators to the lungs because of the disease itself, but we certainly want to make sure we’re properly utilizing their home PAH therapies and potentially even adding more PAH therapies. Sometimes it calls for acute interventions, like in the ICU, inhaled vasodilators like epoprostenol or nitric oxide, if you’re in a really tough spot. Then I think something that’s real important that we rely heavily upon are inotropic agents like dobutamine and milrinone. These are drugs that can really help tremendously when you have decompensated patients in the hospital and you’re struggling to diurese them and improve organ perfusion and get them out of renal failure and decompress their liver and right side.
That’s the careful introduction of these interventions. It’s really critical. You obviously want to also avoid doing things that can harm these patients, using indiscriminate vasodilators like calcium channel blockers and lowering their blood pressure. Intubation and mechanical ventilation can be very tough on these patients. We try to avoid doing that as much as possible. Anything that might injure their kidneys, nephrotoxic agents like non-steroidals or even ACE inhibitors and angiotensin receptor blockers can be really tough on these patients and put them into kidney failure or really drop their GFR, and now they’re not able to properly diurese, so you have to be careful to avoid things like that.
Then in the really extreme cases, there are some interventions that we sometimes have to do. Atrial septostomy is a procedure that our colleagues in cardiology can sometimes do in the cath lab where they create essentially a PFO, a patent foramen ovale, so that they offload the right ventricle. They create a popoff so that blood can go from the right side directly to the left side, even though it’s bypassing the lungs and you’re delivering deoxygenated blood. But by enhancing delivery to the left side, you’re increasing cardiac output. If it’s done properly, even with the lower saturation, oxygen delivery can actually go up because cardiac output goes up. That’ll help or perfuse the brain, so prevent syncope, perfuse the kidneys so you can avoid getting into severe renal failure, and it can also help decompress the right side to offload the liver and the site ease and whatnot.
We do maybe one or two of those a year at our center. It’s not often that you have to do it. ECMO support is something that is certainly an option in certain cases, but I won’t say too much about it except to say that patients with severe pulmonary hypertension and right heart failure, they really need VA-ECMO. They won’t benefit from VV-ECMO, really, so it’s a much bigger deal, but ECMO is one of those things that you never want to start unless you have a good exit strategy, a viable exit strategy. What I mean by that, you’ve got somebody that’s waiting for a lung transplant or waiting to have endarterectomy surgery if they have CTEPH. Or maybe a new patient who’s treatment naïve, and while you’re trying to get them started and ramp up PH medications, they’re really in trouble. You can support them for a little while with ECMO as you introduce medications that have a chance to really turn the disease around. It buys you time.
But taking the really advanced end-stage PAH patient who has no viable, long-term options and putting them on VA-ECMO doesn’t make a lot of sense because you’re not going to be able to now likely get them off VA-ECMO. Those are some of the more rare and heroic things that we sometimes do, septostomy, ECMO, and of course, transplantation for patients that are eligible is certainly another possibility as well.
Perry: Gotcha. Going back to inotropic support. I know there’s a theoretical difference between dobutamine versus milrinone. Milrinone may have some pulmonary vasculature dilation. Has that born out or is that a practice that you subscribe to?
Chakinala: Yeah, I’ve heard that before, too, and there certainly haven’t been any great head-to-head studies have shown that. I use both. I tend to prefer dobutamine more. Part of the problem is a lot of our patients have renal insufficiency and milrinone is challenging to use, then, but I’ve had some good success with milrinone, too. I really don’t count on much of the pulmonary vasodilation effect of that. Maybe you see that in people who don’t have such severe pulmonary hypertension or these patients’ vasculature is very different than other people, but I think the main reason we resort to those drugs is purely for the inotropic effect, and I think both work similarly.
Perry: Very good. We have talked about a lot of different things, and I think we’ve covered pretty much all the things I wanted to talk about. Maybe you can give us a glimpse for where the field is heading and what are the exciting things right now?
Chakinala: We’ve come a long way since I started doing this in the early part of the 2000s, over the last decade. I think, though, I will say I feel like we’ve hit a little bit of a lull or a staleness in that we haven’t really developed any great, new therapies or new pathways to look back. We’re sort of stuck with the same three pathways that we’re modulating with multiple drugs and a lot of second- and third-generation drugs. We still have questions to answer. Don’t get me wrong on the timing, how aggressive should we be upfront, when should we be switching, or when should be adding therapies. There’s still a lot to resolve, but we really still see patients do poorly with this disease and sometimes people still succumb to the disease, not too infrequently, so we really need new therapies that work completely differently, that are not so much vasodilators, that really do something about trying to reverse remodel the vasculature, do something about the cellular dysfunction, the bioenergetics. We also need drugs to support the right ventricle.
Then there’s a lot that’s still uncovered about the cellular mishaps that are going on in these patients beyond just what I’ve described with the vascular remodeling and whatnot. There’s a lot still in terms of mitochondrial dysfunction, disruption of the basic metabolic pathways. There’s a lot to the disease that we still don’t know. There’s a lot of interest and some exciting candidate drugs that work completely differently, that are really focusing more at some of those basic pathways and mitochondrial dysfunction. Maybe drugs that work on the right ventricle and maybe even the peripheral musculature or peripheral skeletal muscle, even. Things that I think are also not normal in these patients that we haven’t really looked at.
I think it’s really important for us to try to develop these drugs. The biggest challenge or another big challenge we’re having, though, is that we have so many therapies, much like in left heart failure, where until you saw the development and availability of sacubitril, Entresto, you went through this long lull where there was nothing new coming along in left heart failure. I think that’s where we are in pulmonary hypertension. We have all these drugs. We have multiple pathways, and we know we’re combining drugs and we’ve made a lot of inroads, but in order to get to the next level, in order for us to have our Entresto, it’s going to take some time and real investment to find other therapies that can add to what we’re already doing to make a difference in these patients.
I think that’s really important. There’s always this talk about personalized medicine. I’m a little bit of a naysayer in that I would love for that to come about. I just don’t know if we’re going to have the number of patients to really understand and analyze who’s going to respond to what drug better than others, and we should really be using this drug in this patient. Unlike what we say are now doing in lung cancer and some other areas of medicine would be really nice to have that personalized medicine in pulmonary hypertension. I just don’t know if we’re going to have that. I also think that, getting back to what we talked about earlier, there are a lot of people out there with pulmonary hypertension that is Group 2 and Group 3, and there may be subsets of patients there that, while we may not fix everything, we may still impact them positively in a subset of these patients by treating the pulmonary hypertension aspect of their disease. Who do we identify and what therapies because right now the PAH drugs have been kind of a bust when we try to expand and look at Group 2 and Group 3.
There’s been a renewed interest to study those other groups, but there, again, the clinical trials, we have to study the right patients, and then pick the right therapy, and have the right endpoints to show that treating the PH aspect makes sense and actually improves outcomes and that patients either feel better, they function better, or they live longer. Those are the three things that your audience needs to understand, certainly regulatory bodies. When you’re going to try a new therapy, you have to prove one of those three things. Maybe there is a subset of patients with COPD or HFpEF that also have significant hypertension in the lungs that clearly makes them even sicker, but there’s a drug now that maybe it treats the HFpEF and the pulmonary hypertension or it treats the pulmonary hypertension without worsening the HFpEF that might actually help that patient. Those are areas we’re also very interested in as well.
Perry: Gotcha. Very cool. Thank you, again, for your time. I really appreciate it.
Chakinala: Sure. Thanks for asking and your interest, and it’s an exciting field and I’ve been at it almost 20 years, and I still feel like there’s a lot to learn and a lot to improve upon.
Perry: Thank you for listening to this episode of AP Cardiology. This series is cosponsored by MedPage Today and by the Division of Medical Education at Washington University in St. Louis School of Medicine.
Andrew Perry, MD, is a resident physician at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis.