John Giacona (UT Southwestern Medical Center): So at this point I will pass it off to Lauren. She will start with Setting the Stage: The Unique Role of APPs in Optimizing PAH Care.

[0:07:32]

Lauren Eyadiel (Wake Forest University School of Medicine): Thank you so much John. I do think it requires a PhD to be able to pronounce my last name. So very impressive work there. So my name is Lauren Eyadiel and I'm going to really kind of set the stage for us as APPs in the PAH care space. We really sit at the center of PAH care transformation between our day to day decisions, as well as kind of our shared decision making with our patient. this is super imperative in our patients’ outcomes, their adherence to therapy, as well as their quality of life.

So one of our goals today is really to connect guideline-based recommendations from the bench to the bedside. So to begin, let's get started with why is this even important and why is this a unique role for APPs.

[0:08:26]

So when we think about the epidemiology and the etiology of PAH, we know that over the past 30 years, the global prevalence of the disease has increased by about 100,000 patient. this is also based on registry data, so there's a chance that this is really also underestimating the number of individuals who are living with and suffering from pulmonary arterial hypertension.

So when we consider the causes of pulmonary arterial hypertension, if you look to the right side of this slide, we can think of these in some big buckets, like associated, which means this type of PAH is associated with an underlying disease, a known underlying disease. And this accounts for about half, about 50% of patients with PAH.

Then we have patients who have idiopathic PAH. And alarmingly this is about 46% give or take of patients with PAH. And so there is a large group of people who have PAH that we really do not understand or know why this happens to them.

But when we think about associated PAH, this is by far most commonly caused by connective tissue disease. So in your patients, even if you are practicing in a more generalist setting, in your patients who have connective tissue disease, it is incredibly important that you have a high index of suspicion that these patients may go on to develop PAH. So for patients with connective tissue disease and who have associated PAH, this accounts for about 50 to 67% of all associated PAH. So this is something that is really, really important for us to consider.

in addition, PAH is more common in older adults between the ages of 50 to 65, which is interesting, because in a prior registry, this actually showed that there was a younger age of onset. I think this is likely really related to techniques where we can better identify and diagnose patients in this space.

[0:10:52]

So with the who and the what in mind, for patients with PAH, let's kind of talk a little bit about what competencies define the power of the APP impact in patients with PAH. So when we think about key competency domains these are separated into 5 subsections: patient centered care, interprofessional collaboration, systems based practice, your medical knowledge and your ability to practice based learn or learn on the job and grow, and then your professionalism and communication.

So these are tenets that really exist for APPs in all areas of practice, but are uniquely important in the PAH space as this disease has significant complexity and a bit of a unique need for really multidisciplinary approach where you have pharmacy, you have cardiology, pulmonology, oftentimes rheumatology when we think of connective tissue disease as well, involved in the patient's care. So we really want to focus on making sure that the patient is central to their care model, and that we are using shared decision making in them to provide the best outcomes. in addition, centering our care on the patient is really important for their adherence with these morbidity, mortality and quality of life improving therapies.

We also always, as we practice, want to use our guidelines. So in the PAH space we're talking about the ESC ERS guidelines from 2024, that really guide and define what a PAH Center of Excellence looks like.

In addition, we want to continue to grow our knowledge. We are all lifelong learners in this space. And so that's very important. And as with any multidisciplinary care, our communication amongst other providers is very important in the team based care.

[0:12:44]

So when we think about guideline-based management of PAH, we have this here on this slide formatted as kind of this nice table, looks very stepwise right. But I would like for you to think of this more as kind of a flow chart that is surrounded by the clinical care team. So that last point on this chart, really think of that as more of an overarching thing that is really almost supporting the patient through the entirety of the guideline-based principles and care.

So we cannot treat something if we don't know the diagnosis. Right. So the most important thing for us to do initially is to confirm the diagnosis. And we do this using right heart catheterization, which Brian will talk with you a little bit more about what these diagnostic criteria look like, but that is our gold standard for diagnosing group 1 pulmonary arterial hypertension. Then we use risk scores such as the ESC, ERS, 4-strata risk stratification and the REVEAL calculator to guide our therapy. That helps us decide exactly what we're going to do and what risk level the patient is that defines what level of therapy is needed.

We start with combination therapy, utilizing an ERA, an endothelin receptor antagonist, as well as a PDE-5 inhibitor, and then escalate our care into triple and quadruple therapy in patients who are higher risk profiles. We have some novel pathways we're going to talk more about as the intensive goes forward this morning. So stay tuned. Hold on to your hats. We've got lots of great news in that space. And then it's very important, as with all disease, that even once we get our patients well controlled, right, we're continuing to follow up with them every 3 to 6 months to ensure that they're not having decline, and ensure that they are on optimized therapy.

[0:14:45]

So what is a PAH Center of excellence? So PAH happens in rural settings and urban settings and across all areas where APPs practice. So when the diagnosis is made for PAH it is recommended that patients are referred to a PAH Center of Excellence. When they are referred to these centers it has been shown to improve outcomes for these patients. And that's really because these centers of excellence are defined by the guidelines as comprehensive care models for patients with PAH. It's very similar, in a sense, to sending someone with advanced heart failure to a tertiary care center where advanced heart failure therapies like LVAD and transplant are an option.

That said, if you look at this map to the right side of your screen, you will notice that there are many areas that do not have access to a center of excellence. In the state of North Carolina we have 1 singular center, right? But if you look through the Midwest there, it could take someone a significant amount of travel to reach a PAH center of excellence. So there are lots of barriers in access for our patients to these spaces and so we need to all know about and know how to manage patients with PAH in the event that they can't make it to a PAH center of excellence and really cultivate relationships with our local centers of excellence or our regional centers of excellence in some spaces. Unless, of course, you're in the northeast, it does look like there's quite a few up there. but we need to cultivate relationships for shared care models to really improve outcomes for our patients.

So now I will hand it over to Brian, who's going to really kind of get into the nuts and bolts of pulmonary arterial hypertension.

[0:16:39]

Brian Rose (Reid Heart Center): Thank you, Lauren. again, I would just like to underscore the thanking the planners for inviting me to talk about this topic that's very near and dear to me. so I want to kind of get down into the nitty gritty so to speak, talking about pathophysiology and the importance of symptom progression reversal for these patients, which Lauren kind of already touched on in terms of risk stratification, what we're shooting for.

[0:17:12]

So hopefully this may be review for a lot of folks, but it's really important that we're all talking the same language when we discuss pulmonary hypertension, and we use the World Health Organization or WHO classification groups. So group 1, which is really what we're talking about today, is pulmonary arterial hypertension. and when we get into discussion of hemodynamics based on the right heart catheterization, which you see here, that is what really defines pulmonary arterial hypertension and distinguishes it from the other groups among other factors. So I'm going to kind of hold off on what those exact hemodynamic parameters mean and why they're important to us until later in our presentation.

Group 2, which was discussed during some of the pretest, is due to left heart disease. And this can include both valvular heart disease as well as heart failure with reduced ejection fraction or heart failure with preserved ejection fraction.

Group 3 is pulmonary hypertension that is due to intrinsic lung disease or hypoxic lung disease.

Group 4 is due to what is called CTEPH, or chronic thromboembolic pulmonary hypertension, or blood clots in the pulmonary arterial system.

And group 5 is what I like to commonly call the catchall group. It's etiologies that are not really clear or multifactorial mechanisms.

[0:18:57]

So our focus today, like I alluded to, was on group 1 or pulmonary arterial hypertension. So what's really happening here is we're having narrowing of the pulmonary arteries leading to increased RV overload, which results in right ventricular failure. And there's multiple different reasons this can happen. it can be due to genetic predispositions. There's some environmental exposures and underlying conditions. And what the World Symposia did last year as well as the ESC guidelines, which Lauren alluded to, is to try and tease out subcategories within group 1.

So we talked about idiopathic pulmonary arterial hypertension. And a subset among those folks are responders to calcium channel blockers, and that would be indicative during right heart catheterization. There are patients that have heritable pulmonary arterial hypertension. Associated with drugs and toxins like methamphetamine use which we see, I practice on the East, the eastern United States, we don't see a whole lot of methamphetamine use, but colleagues that are practicing on the West Coast, where there is a methamphetamine epidemic, so to speak, see this quite commonly.

The associated subset of patients, which Lauren showed in that pie chart earlier can be due to connective tissue disease, HIV infection, portal hypertension, congenital heart disease or schistosomiasis. There’s also patients that have PVOD involvement and then also persistent PH of the newborn.

[0:20:56]

So I alluded to what is going on in terms of RV dysfunction and patients specifically with left heart disease, once they have RV remodeling and RV dysfunction, that is associated with a worse prognosis in that group. And what exactly is going on is the increase in the pulmonary congestion, the vasoconstriction, and then you get vascular remodeling as a result. And remember left heart disease, this is not only patients with heart failure—so HFrEF, HFpEF—but also those with left-sided valve disease, aortic stenosis or regurgitation, and mitral stenosis or regurgitation.

[0:21:50]

In patients with group 3 or pulmonary hypertension associated with lung disease, you can see remodeling of the airways, the lung parenchyma and the vessels. And one way I tell my patients to think about this is it's almost like a garden hose mentality. You've got something going on in the lungs, and it's like someone's turned the garden hose on and put a kink in it. So in this instance, the lung disease is causing the kink. It's causing that backwards remodeling of the airways, lung parenchyma and vessels. And this can be due to chronic obstructive pulmonary disease and emphysema, patients with interstitial lung disease like pulmonary fibrosis. And what we see is that as patients develop more remodeling of their vessels, their pulmonary vascular resistance increases significantly and those patients do worse over time and have a high incidence of morbidity and mortality. And these are patients that we can often see in clinic that may that have intrinsic lung disease. COPD is fairly common. We see lots of patients in our offices with COPD. But these are patients that will have a significant amount of hypoxemia at rest or with even mild levels of exercise.

[0:23:20]

So distinguishing the type of PH is important. But I want to back up for a second and really point out that we have to have a high index of suspicion for these patients. So being able to detect symptoms or being able to detect pulmonary hypertension early based on symptoms is key. So some of the early symptoms that patients will have, classically dyspnea with activity. They can have fatigue and rapid exhaustion, dyspnea with bending forward or something called bendopnea. Palpitations, hemoptysis. Exercise-induced abdominal distension and nausea. Weight gain due to fluid retention. And syncope, both shortly after or during physical exertion.

Some of the later findings that we will see once they've had that pulmonary remodeling is exertional chest pain, and this comes from dynamic compression of the left main coronary artery. Patients can have hoarseness or dysphonia due to compression of the left laryngeal recurrent nerve. This is something called Ortner's syndrome. Shortness of breath. Wheezing. Coughing. Atelectasis due to compression of the bronchi.

[0:24:46]

So some of the clinical signs of PH: central, peripheral or mixed cyanosis; an insinuated pulmonary component of the second heart sound; an RV third heart sound; a systolic murmur of tricuspid regurgitation; or diastolic murmur or pulmonary regurgitation. Similarly, signs that point to an underlying cause of pulmonary hypertension. So patients that have digital clubbing, signs of cyanotic congenital heart disease, fibrotic lung disease, bronchiectasis, PVOD, or liver disease. Auscultatory findings like crackles, wheezing, murmurs can point to underlying intrinsic lung disease or heart disease. patients that have a prior deep venous thrombosis or venous insufficiency, we get suspicious for CTEPH. Telangiectasias. Sclerodactyly, Raynaud's phenomenon, digital ulceration, GERD, we worry about connective tissue disorder.

So those are signs. What about when things are maybe a little bit more advanced? So signs of RV backward failure. So, distended and pulsating jugular veins, abdominal distention, hepatomegaly, ascites and peripheral edema. Now, these are signs that obviously have some overlap with other underlying conditions as well. So I do want to point that out.

What about signs of RV forward failure? So peripheral cyanosis, dizziness, pallor, cool extremities and prolonged capillary refill.

[0:26:37]

Brief Overview of Workup

So this is a busy slide, but let's break this down. So when you have a patient who you're suspecting pulmonary hypertension in, your echocardiogram is your first line. It's a quick, inexpensive, easily accessible test for most patients. And we're able to use the ECHO to give us some clues. Now remember, this is not definitive for determining someone has, let's say, pulmonary arterial hypertension but this is a good way to further that index of suspicion and really make sure, are we working this patient up properly?

So the ECHO is allowed to give us information like TAPSE, which is looking at excursion of the tricuspid annulus; the right atrial area; something called the eccentricity index; the RV, RV LSS and RV FAC. So we're able to hone in on that right ventricle by looking at the estimated pulmonary arterial arterial systolic pressure. What's the RV function doing during systole? What's the size? What's the severity of the tricuspid regurgitation? Is there pericardial effusion or is there evidence of shunting?

Similarly we have to work up the lungs as well. We have to make sure that the patient doesn't have CTEPH. If we're going down the rabbit hole to diagnose pulmonary arterial hypertension, we must make sure that there's no CTEPH. And we do that by VQ scan.

We will get a lot of serologic testing specifically to look at connective tissue disease, HIV, etc. if we suspect portal hypertension we'll get an abdominal ultrasound. We need pulmonary function testing with diffusion capacities to be able to look at their lung function. Are we dealing with someone that has hypoxic lung disease? Is there an intrinsic lung disease like ILD or pulmonary fibrosis?

But ultimately we have to get the right heart catheterization for confirmatory diagnosis by getting those critical hemodynamic parameters.

[0:29:08]

So as I alluded to previously we’re able to distinguish some of the classification based on right heart catheterization. So pulmonary hypertension, just a patient that you get an ECHO on and it shows an elevated pulmonary artery systolic pressure, let's say estimated at 45%. We take that patient for right heart catheterization. What defines PH on the right heart catheterization is a mean pulmonary arterial pressure of more than 20mm of mercury. That is true for all classes of pulmonary hypertension. Group 1 through 5, you must have that mPAP of more than 20.

Now, when we add the pulmonary arterial wedge pressure and the pulmonary vascular resistance is where we start seeing differentiation. So precapillary pulmonary hypertension or truly group 1, PAH, is the mPAP more than 20, a wedge less than or equal to 15 and a PVR of more than 2 Woods units. When we have isolated post-capillary, pulmonary hypertension, we have the mPAP more than 20, but our wedge is more than 15. So these are patients that are classically group 2 in etiology and their PVR is less than 2. However, you can have patients that have a combined pre and post-capillary component. And that's where their wedge is more than 15 but their PVR is more than 2. So they've had some of that backwards remodeling.

And lastly, just for the sake of completeness, but you know, a little bit outside of the direction of this talk, is exercise induced PH, and we calculate that based on the mPAP and cardiac output slope.

[0:30:59]

7th World Symposium Algorithm for PAH

So the seventh World Symposium gave this algorithm for pulmonary arterial hypertension. So we have good clear cut therapies for patients that have group 1 PH. And this includes patients that have idiopathic pulmonary arterial hypertension, hereditary, connective tissue disease, among others. So we do our initial risk assessment. We work the patient up as we saw a few slides ago and we determine their risk because their risk helps us identify what therapies they need.

So patients that are not deemed at high risk, based on whatever risk assessment model you use, will get combination therapy with an ERA and a PDE-5 inhibitor. But those that are deemed at high risk will look at utilizing an ERA and a PDE-5 plus either a subcutaneous or IV prostacyclin.

[0:32:08]

Treatment Based on Risk Stratification

Treatment based on risk stratification is key, as I said previously, and you can pick. There are a lot of great risk stratification markers to use not only at time of diagnosis, but also at time of follow up, because every time we evaluate a patient with pulmonary arterial hypertension who is on therapy, we're wanting to make sure we have achieved low risk. If we have not, we're looking at ways to escalate their therapy to achieve low risk, because by achieving low risk, we're improving their outcomes. We're improving their functional class and we're improving mortality.

[0:32:52]

Screening and Diagnosis Summary

So in summary, we have to have a high index of suspicion, a thorough and complete diagnostic evaluation that ranges all the way from a thorough physical exam to an echocardiogram, serologic testing, VQ scan, and ultimately right heart catheterization. We have to exclude thromboembolic disease. This is a critical pitfall that people can fall into is they think that they have a case of pulmonary arterial hypertension, but in reality it may be CTEPH, in the right patient with the right risk factors.

We need to evaluate potential causes and contributing issues. Remember, the vast majority of patients that have pulmonary arterial hypertension have it associated to another underlying cause.

The right heart catheterization is required prior to initiating PAH therapy. We must get those critical hemodynamic parameters in order to decide on therapy, and not only to decide on therapy, but to make sure that we are treating the patient correctly, because not doing so can lead to potential harm.

We have to do some baseline functional evaluation. We need to know what the patient’s risk is, what their risk profile is not only at time of initiation of therapy, but also on subsequent follow up. Do we need to be escalating therapy?

And lastly, if we do identify a patient that has a heritable cause, we need to make sure that there's genetic testing and counseling available not only for them but for their family members as well.

And with that, I will pass it back to Lauren.

[0:34:45]

John Giacona: So actually I will I will take it back.

Brian Rose: Okay.

John Giacona: Thank you so much. Thank you, Brian, and thank you, Lauren. That was amazing. so we'll take a little halfway section here, to talk about a case study.

[0:35:02]

Patient: Angela, 48-Yr-Old Woman

And so here we have Angela. She's a 48 year old woman. Her chief complaint is worsening shortness of breath and fatigue over the past 3 months. She reports new ankle swelling and disrupted sleep. She also reports great adherence to her current therapy, but feels that it isn't helping like it used to. Her current therapy is here. It's macitentan 10mg and tadalafil 40mg. Her past medical history: Idiopathic pulmonary arterial hypertension, WHO group 1 diagnosed 18 months ago, no significant cardiopulmonary comorbidities. On physical exam, she has mild right atrial dilation, right ventricular enlargement, TAPSE 15, trace pedal edema, accentuation of P2 heart sound. Recent findings: she had an NT-proBNP of 780, which is up from 420 previously. She has a 6-minute walk test of 320, which is down from 385.

[0:36:04]

Poll 3

So with that in mind, we have our poll number 3. Which mechanism is most likely the primary driver of Angela's disease progression?

1. Increased endothelin-mediated vasoconstriction and vascular remodeling
2. Reduced nitric oxide production leading to impaired vasodilation
3. Decreased prostacyclin synthesis reducing antiproliferative signaling
4. Progressive right ventricular remodeling secondary to vascular change

Excellent. Thank you very much for taking the time to answer.

[0:37:00]

Let’s Discuss: From Pathophysiology to Practice

 So, we can discuss a little bit from pathophysiology to practice. So what's happening with this patient is obviously she's experiencing endothelial dysfunction. and that can be characterized as vasoconstriction, proliferation and remodeling, as Lauren and Brian talked about. she's also experiencing progressive right ventricular strain, which is showing up and manifesting as functional decline and increasing in her symptoms. non-adherence worsens vascular remodeling and outcomes.

And so what are some things that we can do? again, many of these were discussed by Brian and Lauren, and I'm about to bring them back in to discuss, but we can repeat right heart catheterization and reassess her hemodynamics, which is recommended by the 2022 ESC/ERS guidelines. We can evaluate for add on therapy, right. We might be able to add on sotatercept. We can reassess every 3 to 6 months or should be reassessing every 3 to 6 months, and using patient-first communication and shared decision making, specifically when we're talking about potential non-adherence to medications.

And so I'm going to bring our faculty back in so that they can kind of talk about how we how we approach patients who are feeling discouraged and how we can get them back on track with their treatment. So Lauren and Brian, would you guys like to join me back in and kind of discuss how you would approach this?[0:38:21]

Brian Rose: Absolutely. unfortunately, this is, you know, a conversation we have more often than we probably would like with these patients. you know, pulmonary arterial hypertension at its core is a progressive disease. it is something we always have to be very attentive to, which I think this case really underscores the need for continual risk stratification. You know, this patient is getting clinically worse, due to a multitude of reasons. but, you know, it's very important to stay positive when people—and this predates me, but if you talk to a lot of the original, you know, the OGs of of pulmonary arterial hypertension, you know, 10, 15 years ago, there was not a lot of therapies. I mean, we wouldn't be talking about a lot of these therapies. now our toolkit is getting pretty full. so patients that do have clinical worsening, we do have options. And I think that's important to underscore we have options to change therapy. You know, the goal here is to make sure that they feel better, and that they're more functional. and that we also have a way to measure that. So being able to let them know that there are options, and sometimes it's not a failure if we have to change course. those are critical discussions that I have with my patients often. Lauren?

Lauren Eyadiel: I think too, kind of a real focus on empowering your patient, you know, these are funny named medications, medications that are hard to understand, but it's really our job, as the providers, as the APPs in their care, to really be able to explain it in a way that they understand so that they kind of have an underlying understanding and why this medication is important. Why do I need to take it when I need to take it? You know, especially with parenteral therapies, a lot of times it's a bit more difficult, right, to get people on board with that, or inhaled therapies that require multiple times of daily dosing. And so I think really empowering your patients to take some ownership of that and have good understanding of their disease process, as well as these kind of funky-named therapies that might be difficult for them to understand. really kind of getting that down at the level that our patients can understand and then be empowered to adhere with therapies.

John Giacona: Thank you both for those incredible insights. I mean, I completely agree, non-judgmental language. And being a hypertension specialist, we often talk about, you know, adhering to therapy and hypertension worsens with age and so similar, very similar sort of patient focused, patient centered language, comes in all in all of our cardiology discussions. So thank you both for that.

For the sake of time, I will move on to our next section. so that will be poll number 4.

[0:41:37]

Poll 4

So for the audience, how would you respond to a patient like Angela who says, I've been taking my medicines, but I feel worse. Does this mean they're not working?

1. It might take more time for your medicines to work, so let’s just keep monitoring
2. Your symptoms suggest your PAH may be progressing — we’ll review your results and adjust your plan together
3. That can happen sometimes; you should probably rest more and see if things improve
4. You may need to stop one of your medicines if they’re making you feel worse

Excellent. Thank you all for for for responding.

[0:42:27]

Poll 5

So last poll for this session. Poll 5. So take a moment to reflect on what this case brought up for you. What's one area you'd like to strengthen in your in your pulmonary arterial hypertension care? Is it:

1. Patient education and adherence support
2. Earlier diagnostic or RHC follow-up
3. Integrating QoL and mental health screening
4. Enhancing communication and shared decision-making

Excellent. Thank you.