[On-screen text: John Ryan, MD, MB, BCH, BAO, Cardiologist]

[Title: Pathophysiology of the Right Heart in PAH]

Dr. John Ryan:

Thank you to those who are joining us today to learn more about the right heart and the role that it plays in pulmonary arterial hypertension. So the particular focus that I'm going to have is the pathophysiology of the right heart in pulmonary arterial hypertension. We all know that pulmonary arterial hypertension causes increased resistance in the pulmonary vasculature. You go from a healthy endothelium, thin-walled and relaxed pulmonary artery, and a large capillary network that produces a low-volume, normal pulmonary vascular resistance and normal perfusion within the lungs, specifically within the pulmonary arterial system of the lungs.

Then as pulmonary arterial hypertension evolves and progresses, the endothelium becomes abnormal, the walls become constricted and stiff, you actually lose some vessels, so you lose microvasculature, which results in the increase in pulmonary vascular resistance, and contributes to a moderate decrease in perfusion in the pulmonary vascular bed. And again, as the disease progresses further, it is notable that you get further constriction and now accompanied with cell proliferation and an obstructive vasculopathy, due to obliterative remodeling that results in severe increases in pulmonary vascular resistance and a severe decrease in perfusion.

This is not happening in a vacuum. The changes in the pulmonary vasculature then have effects on the right ventricle, and the right heart in general, and ultimately lead to changes in the right heart. Normally, the right ventricle is a thin-walled structure with a normal cardiac output. Although there are changes in the pulmonary vasculature that we've already alluded to, you may not be symptomatic, or you may not be dramatically symptomatic because, for a while at least, you can compensate. Now how long a while is, is variable. For some people, it's a couple of months, for some people it's a couple years. So it is variable. But ultimately, the right ventricle becomes hypertrophied and the cardiac output can actually be sustained. When you transition from compensated to decompensated, that largely occurs through changes in the right ventricle, where the right ventricle now becomes dilated, the cardiac output decreases, even the walls might now actually become thinner, and some people would even refer to it as a burnt-out right ventricle.

In 2022, the only way to diagnose pulmonary arterial hypertension is by doing a right heart catheterization. That is it. There are no other ways. Other imaging modalities and other tests can give you ideas about prognosis, et cetera, and we will touch on some of them shortly. And the diagnostic criteria for pulmonary arterial hypertension have actually changed in recent years. One is the pulmonary capillary wedge pressure needs to be low, needs to be less than 15 millimeters of mercury. The reason for that is that if we gave any of us a large-volume bolus, our PA pressures would go up. So, what we're trying to rule out with the wedge being less than 15 millimeters of mercury, is that this is not secondary to volume overload—left-sided heart failure, in essence.

The average PA pressure in normal humans, and in fact, in every land-living species in the animal kingdom, the average PA pressure, the average mean PA pressure is 14 millimeters of mercury, one-four. Now we define the upper limit of normal as 20 millimeters of mercury. So when Dr. Vaidya and I were younger, we used to diagnose pulmonary hypertension by having a mean PA pressure greater than 25, but because, as I mentioned, the normal PA pressure is actually 14, 25 is very far away from 14. So the cutoff got changed. So the cutoff now is a mean PA pressure of greater than 20.

Pulmonary vascular resistance has not changed. Normal pulmonary vascular resistance is 1 Wood units. And to diagnose pulmonary arterial hypertension, you need a pulmonary vascular resistance of greater than 3 Wood units. Some argue that remains too high, but those are the diagnostic criteria, once more, for pulmonary arterial hypertension: mean PA pressure greater than 20, pulmonary capillary wedge pressure of less than 15, and pulmonary vascular resistance of greater than 3.

After diagnosis, you have someone in your clinic, and you know that they have pulmonary arterial hypertension. Well, now, the right ventricle is going to give you important insights into the disease progression, and how your right ventricle progresses and how your right ventricle responds ultimately determines how your disease will progress and how your disease will respond. And here you have, from left to right, you have a normal-sized right ventricle with a normal-sized left ventricle. Then as the disease progresses, as represented by the arrow, as the disease progresses, even to an untrained eye, you can now see that the right ventricle is getting bigger and is actually bigger than the left ventricle. The right ventricle should never be bigger than the left ventricle.

Finally, then, as the disease worsens, you end up in a scenario, which to any cardiologist will portend signs of imminent doom. You see that the right ventricle is very big, and actually perhaps more ominously, the left ventricle is compressed. Right ventricle is compressed in the left ventricle, and it does not take a lot to imagine that your cardiac output is going to be quite low in this setting. Other ominous features on this echocardiogram, we've talked a lot so far about the right ventricle. There's also great deal to be learned from the right atrium. And in this disease progression slide, you can see that the right atrium goes from being enormous size on the first screen capture to being quite enlarged on the last screen capture.

And then, most ominous of all, the echocardiographic finding that is more ominous than any of this is the pericardial effusion. Having fluid outside the heart in the setting of pulmonary arterial hypertension has the worst prognosis of any imaging finding. Now we've represented this as disease progression, that top arrow. This can also be used to show a better improvement with PH therapies, where you can actually go in the opposite direction, and particularly if the right atrium can get smaller, the pericardial effusion can go away with adequate therapy.

In this study, which is a retrospective analysis of enrolled patients with pulmonary arterial hypertension, 22 patients overall, small study, 12 of whom remain stable during follow-up and 10 experienced late progression leading to death or lung transplant. In this study, of what you can see, the patients who are stable are this gray color with the circles; the patients who progressed are represented by squares. 6 minute walk distance, not much of a change, not a big surprise. A lot of criticism over the years with 6-minute walk distance. No change between those who are stable and unstable.

New York Heart Association stayed lower in the stable group, stayed a little bit lower, but the big things that were dramatically different were the right ventricular end-diastolic volume, so the size of the right ventricle. And you can see that on the stable population, the right ventricle end-diastolic volume remained stable, whereas in those who got sicker, in those who progressed, as we said, even to death or lung transplantation, the right ventricle end-diastolic volume got bigger. And correspondingly with that, the right ventricle ejection fraction, not a commonly used measure, but the right ventricle ejection fraction got worse, decreased, whereas those who remain compensated, the right ventricular ejection fraction remained stable. So this makes a compelling argument that monitoring the right heart can anticipate clinical worsening.

Appropriately so, we put a large emphasis on Functional Class in 6-minute walk distance, but they actually lag in the setting of clinical indicators as to how the disease is progressing. And actually, harmful changes to the right heart can happen weeks, even 12 weeks, before you actually see clinical changes such as changes in 6-minute walk distance or change in Functional Class. The changes in the right heart are the first things that will occur, and we don't necessarily have good ways of evaluating that, other than echocardiogram. Even these changes in the right heart will precede changes in N-terminal proBNP. A lot of us depend on N-terminal proBNP clinic, following patients longitudinally. Then you'll get a change in 6-minute walk, then you'll get a change in weight, then you'll get a change in Functional Class, and then you'll get hospitalization.

So, we don't want to change in Functional Class or change in hospitalization. We want to capture this early. When someone changes their Functional Class, it is very hard to get them back to their previous Functional Class. When someone has been hospitalized, it gets even harder. So, performing a routine Echo may help catch patients whose pulmonary arterial hypertension is progressing before the symptoms are evident, arguably even before the BNP. Managing by symptoms alone may be a detriment to patients. In a retrospective analysis of Functional Class 2 patients, more than half were classified as intermediate or high risk after risk calculation.

In this study, retrospective chart analysis of 153 Functional Class 2 patients, on 1 or 2 drugs, and the healthcare providers were surveyed to obtain an assessment of patient risk, which may have been informed by formal assessment. Patient risk was then calculated independently, using COMPERA, French registry, or REVEAL 2.0. Of patients considered to be low risk by gestalt, so the regular old reliable, "I look at you, I determine you to be low risk," of those patients who were considered to be low risk by gestalt, 4 to 28% of them were characterized as high risk when objective measures were used. All of this reflects that if we wait for symptoms to worsen before adjusting our patient's treatment regimen, the opportunity to minimize functional impairment may be lost.

[On-screen text: John Ryan, MD, MB, BCH, BAO, Cardiologist]

[Title: Right Heart Treatment Goals]

Dr. John Ryan:

We've emphasized this functional impairment. Now let's talk about the actual treatment goals, which are functional improvement. Patients who achieve low-risk status within 1 year of diagnosis have improved survival. We can see this from the graph at the right, which is the impact on survival per change in risk category in the COMPERA Registry. Within the COMPERA Registry, patients were assessed with an abbreviated version of 6 risk factors, from the ESC and ERS guidelines. These risk variables were WHO Functional Class, which we've talked about a lot so far, 6-minute walk distance, and N-terminal proBNP and BNP, right atrial pressure, cardiac index, and SvO2. Survival, then, was estimated based on risk category.

As you can see in this graph on the right, stable lower-risk patients are represented by the dark green, and as you can see at 1 year, if you are stable, low risk, by 5 years, your survival is about between 80 and 90%. This is higher than the stable intermediate risk, which is the dotted light orange line, where you can see that, again, if you get to stable intermediate risk at 1 year, your survival is somewhere between 50 and 60% at 5 years. The worst prognosis, then, in this data from the COMPERA Registry, is the stable high risk represented by the solid red line. Therefore, treatment should be escalated if patients do not achieve low-risk status.

In conjunction with a low risk, what we also want is near normalization of right heart function. This is another important treatment goal. We have seen over and over and over, on the slides today, that the right heart, as I say, is the key to the whole game. And if we get near normalization of the right heart, then we are in a really good spot to give the patients the best possible outcomes that they can have, acknowledging, of course, that we do not have a cure for this disease, but at least we can let patients know that you are as low risk as possible. So what is that, and how does that pertain to the right ventricle?

Well, this, based on the European Society of Cardiology and the European Respiratory Society and Risk Score, N-Terminal proBNP, you want that to be less than 300, you want BNP to be less than 50. We measure those every time we see a patient in clinic. Clinical signs of right heart failure, you do not want to see them. You have to look for them, but you don't want to see them. What's that? Increased JVP, enlarged liver, lower extremity edema. Syncope is a sign of right heart failure. If patients are having syncopal episodes, then that is a high-risk characteristic. If patients are not, and they're low risk.

Now the next does require invasive hemodynamics. Low right atrial pressure, normal cardiac index, and SvO2 of greater than 65%, all of these reflect good prognostic indicators, and all of these are reflective of the right ventricle. Then, with imaging, we want to see a right atrial area that is small, and as I mentioned earlier, we do not want to see a pericardial effusion. Improvement to the right heart is one of the most important considerations to get people to low-risk status and improving survival.

Treatment guidelines recommend serial echocardiograms for routine surveillance. You get them at baseline. You likely should get it 3 to 6 months after changing or starting therapy. You should get it in the case of clinical worsening. And then there are many who do it, even in stable patients, every 6 months.

The importance of frequent Echo is shown in this retrospective study. This was a chart analysis of 150 Functional Class 2 patients who were on 1 or 2 medicines for their pulmonary arterial hypertension, and the healthcare providers were surveyed to obtain an assessment of patient risk, which had been informed by formal risk calculators. The patient's risk was calculated then using COMPERA, the French registry, and REVEAL 2.0. So, the congruence of gestalt and formal risk assessment, based on this Echo frequency, was that in those who got echocardiograms every 3 months, 82% of those patients were congruent with the risk calculation that was used; 18% were not. In those whose echocardiograms were obtained every 7 to 12 months, 46% were congruent with their risk calculations; whereas 54% were not. So, the take-home point from this study is that physicians who ordered Echoes more frequently every 3 months were more likely to accurately assess their patient's risk status.

The Echo evaluations help stratify patients. Intermediate risk is a vast category of patients. Here's one patient, 42 years of age, Functional Class 3A, 6-minute walk distance 405, BNP 21, or sorry, BMI 21, and hemoglobin is 14. So, some normal aspects here, some intermediate-risk aspects. Ultimately, it comes down to being an intermediate-risk patient. This patient here, 45-year-old female, Functional Class 3A, 6-minute walk distance is the same at 410, BMI is 20, and hemoglobin is 13. So again, couple of intermediate-risk aspects there. Both right ventricles are enlarged, one on the right, patient 2 has pericardial effusion and has that left ventricle be compressed.

So, the Echo may assist with determining the treatment regimen needed to help a patient achieve a low-risk status because, in hindsight, looking at these Echos, although both patients fell into an intermediate-risk category, looking at these Echos, in particular, the one on the right, these patients are at high risk of complications, and we want to get patients to low risk.

[On-screen text: Anjali Vaidya, MD, FACC, FASE, FACP, Cardiologist]

[Title: Imaging in Clinical Practice]

Dr. Anjali Vaidya:

We're going to transition now into focusing, in a little more detail, on the imaging and clinical practice in pulmonary arterial hypertension. The emphasis of course, being on echocardiography. This is a critical component of patient care in PAH as a screening tool. It can be very helpful, if a patient is suspected to have pulmonary hypertension to evaluate the probability of PAH. Echo is not sufficient alone, but wow, it can tell us a lot more than I think was previously appreciated, and we'll talk about how to do that. And then of course, as a monitoring tool, meaning once someone already has a diagnosis of PAH, the monitoring is really critical, and it should be done with high frequency to identify early recognition of a patient's clinical status that's declining.

So, the Echo really is a highly available and helpful noninvasive assessment that can give us information truly on the hemodynamic right ventricular burden that measures RV structure and function. So, it's a first-line screening tool, and it really can help predict if a pulmonary vascular resistance is elevated. It can take it a step further and give us really direct clues to discriminate between pulmonary venous hypertension or PVH that's WHO Group II or left-sided filling pressure is being elevated. That's what Dr. Ryan referred to when the wedge pressure is elevated and discriminate between that versus PH due to pulmonary vascular disease, which is when that pulmonary vascular resistance is elevated in the context of normal left heart filling pressures. So, there are quite a few clues. This slide very nicely shows one that is really kind of prominent to the eye. So, this is the apical 4-chamber view of the echocardiogram.

You can see the focus on the right side of the heart being the very large chamber on the picture, on the left of your screen, which is PH due to pulmonary vascular disease, or what would represent PAH. And you can see here that the right ventricle is bigger than the left ventricle, but specifically I want to bring your focus to the apex of the right ventricle itself. And you can see that first of all, the right ventricle is forming the apex of the entire heart, but more specifically, the angle of the right ventricular apex is wide open. And, when you see that red line sort of measuring the diameter in the apical 4-chamber of the heart, and it's measuring close to the apex of the heart, that red line is truly almost as wide as the dimension of the base of the right ventricle.

You could even argue that they're about equal. Now in contrast, the Echo on the right side of your screen is pulmonary venous hypertension. The pulmonary pressures may be equally high in both of these hearts, but the patient on the right side of your screen has high pulmonary pressure is not on the basis of a high pulmonary vascular resistance. Instead, it's on the basis of high left-sided filling pressures, and it looks vastly different. The apex of the right ventricle is normal here. It is narrow, the apical angle, relative to the base of the right ventricle, which has a much broader dimension. So, the base-to-apex ratio in somebody with a normal pulmonary vascular resistance or a right ventricle that has not been chronically exposed to a high after load, that base-to-apex ratio remains high, certainly greater than one, even greater than one and a half.

And this was studied and published in our group a few years ago, in contrast to those again, with pulmonary arterial hypertension on the left, where that base-to-apex ratio is much lower. The apical dimension is much wider. So, if that base-to-apex ratio is less than one and a half, or even more simply stated, you look at that heart and the apex of the right ventricle is wide open, you're immediately thinking this is an elevated PVR, and you're going down that road of urgent hemodynamic assessment.

The imaging can show improvement in therapy and deterioration before patients really clinically worsen. So, we've talked about this kind of graph before where the pulmonary pressures go up and you start to see these other changes on Echo. The RV wall starts to thicken end diastolic volume increases. And we start to uncouple the right ventricle in the pulmonary artery and really worsen our contractility efficiency in that coupling. And with that maladaptation, you see in the blue line, that cardiac output really falls on the basis of a reduced stroke volume.

So, these are some of the morphologic metrics that are indicative of a significant remodeling from PAH. To put some of these concepts together—there's that open RV apex, that apical widening that you see on the left side of the screen. RV hypertrophy is a sign of chronic remodeling—when the RV wall is greater than 0.5 centimeters in thickness. The RV-to-LV ratio, which is seen really nicely here in the apical 4-chamber, it should be less than kind of two-thirds or so, 0.6, 0.7. When you measure the dimension at the base of the ventricles, just above the valve plane, and that RV is greater than LV, that's a right ventricle that's at least moderately enlarged. The presence of the pericardial effusion gets a lot of attention in PAH, and it's critically important to recognize, but unfortunately, we can't rely solely on this because it is a marker of late disease.

So, it does correlate with mortality. And the reason that a pericardial effusion happens in PAH is because it represents impaired venous drainage into the right side of the heart, which happens via the coronary sinus, very large thin-walled venous structure that runs through the posterior AV groove alongside the circumflex artery. When you have such chronic and severe congestion and pressure elevation in the right heart, it impairs that venous drainage from the coronary sinus into the right heart. As such, it then leads to a transudative effusion that builds up as a representation of this. It's what I call RV pitting edema, but it's not actually the effusion that's dangerous, it's that the effusion is a marker of severity of disease. Now the right atrial area has also been shown to correlate with outcome and mortality and so you can get this sense here when it's measured in end atrial diastole, that area is greater than 18, that's a really high risk.

In the parasternal short axis. This is that septal flattening in systole is key. And just a reminder, when you see that D-shaped septum in systole, it's not just for all versions of high pressure. You won't see that as commonly or at all when PH is purely on the basis of pulmonary venous hypertension, but when the pulmonary vascular resistance is high, you will see that. So that can be really significant and notable.

TAPSE is a marker on Echo of right heart function. It stands for a tricuspid annular plane systolic excursion. It is a measurement of longitudinal contraction of the right ventricle, which in native hearts that have not been operated on, represent 70 to 75% of RV contraction. So, while there are some limitations in this measurement, it's been shown to be the most kind of reproducible with inter-rater reproducibility and reliability. It's quite simple and easy to obtain and can be obtained quite quickly in measurement. So, it's really been a valuable thing to monitor serially. This is a paper our group published a few years ago, showing that if you achieve a normal TAPSE or TAPSE greater than 2 centimeters on pulmonary hypertension medical therapy at 1 year, your survival is much greater than if you did not achieve that. And I think it's really important to emphasize here that it's not the RV function or the TAPSE at initial diagnosis that's the most predictive. It's how you respond to therapy and really being progressive with therapy to try to achieve this goal of a TAPSE greater than 2 in this study that predicted mortality at 1 year.

So, in summary, there are a lot of concepts to go over today that we discussed, but a really important goal and concept is that we're trying to achieve near normalization of the right heart. However, the right heart performance can be measured, those are the parameters we are trying to generally achieve to achieve a low-risk status for our patients and improve long term survival in PAH. So, we're evaluating the structure and function of the right heart. This is needed at the time of diagnosis and frequently throughout treatment. We want to frequently monitor this and supplement it with our kind of integrated Echo Doppler assessment to help inform our treatment decisions.

It might guide us to be more proactive and progressive in our treatment escalation, than if we solely relied on Functional Class and 6-minute walk. We know that these changes to the right heart can often occur before the subjective changes, or the functional capacity may definitively change, and we certainly see that time and time again in our clinical practice. And it's really important to note that while patient symptoms are so important for them and for us, if we wait for them to worsen before we adjust their treatment regimen, we may miss an opportunity to improve their functional impairment. So, I'll stop there with this topic of discussion and really grateful to have the opportunity to discuss all of this. And we'll transition into more Q&A. Thank you.

[On-screen text: John Ryan, MD, MB, BCH, BAO, Cardiologist]

[On-screen text: Anjali Vaidya, MD, FACC, FASE, FACP, Cardiologist]

[Title: Echo for Monitoring PAH]

Dr. John Ryan:

So at this point, I want to bring in Dr. Vaidya to cover some of these aspects and cover how to implement these aspects in clinical care. So, Dr. Vaidya, I touched on the issues of echocardiogram incorporating into your treatment algorithm, diagnostic algorithm, et cetera. How often are you doing your echocardiograms?

Dr. Anjali Vaidya:

Thanks, John. I think that's a great question. And I'm asked this quite a lot, actually, when I speak to folks. So I'm going to be really interested to hear about your program's practice also. I really want to emphasize some of the data that you so nicely presented about how, if we do our Echos more frequently, then our clinical gestalt tends to be more in line with a formal validated objective risk assessment. And I think that point is really key. So, I always tell my fellows and my residents, "The Echo doesn't lie," whereas you just nicely presented a case where 6-minute walk and Functional Class could represent such a wide range of actual cardiac performance. So it's a long-winded way of saying more frequent is better.

For me, if a patient has WHO Group 1 pulmonary arterial hypertension and there's any change in their clinical status, there's change in their functional capacity, there's change in their physical exam, their jugular venous pressure is up, they're retaining fluid, they're having presyncope, their BNP or NT-pro starts to rise, then I'm immediately getting an echocardiogram at that clinical assessment, regardless of when the last one was because we know, you so nicely presented in the beginning, how this is a progressive disease, and you showed that pathophysiology, and it's amazing how some patients, it can happen slowly and gradually, and some patients can seemingly have no progression, and then it can suddenly happen quickly.

So, any sign of a clinical change in a relatively urgent Echo, if I'm escalating therapy, or if I've recently changed their therapy, then I'm not waiting more than 3 months for my next echocardiogram. And then I would say in the ideal, what we all strive for, for our patients, the patients that have had truly low-risk status that has maintained for quite a long period of time, and we're objectively looking at all of those parameters, then I may stretch it out to 6 months. In my opinion, 12 months is far too long. This is a progressive disease that cannot wait that long for such a careful objective assessment. So that's kind of my take on it. How do you approach it?

Dr. John Ryan:

We're exactly the same, but we'll emphasize the 6-month issue that you bring up, yes. So, we also do it every 6 months.

Similarly, then, as you said, when you're up-escalating therapy, then again, that's where you want to see that response. That patient, you're seeing more frequently and you want to see a response. You want to incorporate that along with everything else that you're seeing to show that, "I have done the right thing." You always feel you've done the right thing for the most part, but I am actually seeing response and I can rest on my laurels here because 12 weeks after changing therapy, I've got them down to low risk. I've got their Echo looking better.

But one of the things that I emphasize with our fellows, is that the right ventricle can fool you. You and I measure TAPSE all the time, but TAPSE can fool you. We don't touch on TAPSE here. But TAPSE, just to clarify, is movement of the tricuspid annulus with each compression, or each contraction, rather, with the idea being that the more that your right ventricle moves, the better it is. That can fool you. That can trick you. And you've done a lot of the work on TAPSE. Right ventricular size can fool you. The right ventricle that's dilated, it stays dilated. The right atrium is very adaptive, and I feel that the right atrium is...

It is my favorite chamber. We've lots of chambers to choose from, Dr. Vaidya, the right atrium is my favorite chamber because the right atrium will get bigger as you get sicker and will get smaller as you get better. And getting Echo techs in any lab is not a criticism. This is not ivory tower or elitism but getting Echo techs to look at the right ventricle can be challenging because we are so LV centric. Getting Echo techs to look at the right atrium can be even more challenging, but that is ultimately where I think the truth lies, is what is the right atrium doing?

Dr. Anjali Vaidya:

That's interesting. I like to look at that as well, and certainly right atrial area, atrial diastole has been shown to correlate with mortality and PAH. And I think what you are describing reminds me of, I think, an easy-to-remember concept, which is I'll often say, "Any parameter that represents performance of the right side of the heart has likely been studied, and more importantly, shown to correlate with outcomes and pulmonary arterial hypertension." I'm very grateful that, in the years that we've been in this career and taking care of PAH, that the attention to the right heart has really exploded in a favorable way, finally, in the right direction, although it's taken some time. But I think it's important to note that the assessment on Echo, really, is an integration of multiple parameters, like you're alluding to, the congestion on the right side of the heart, which can be shown in that IVC. The degree of tricuspid regurgitation we haven't alluded to yet, but is a representation of that as well.

I really like that you mentioned about the right ventricle not necessarily changing or reversing, and I've struggled with that. And I think what I've come to appreciate is that there are some patients, and I think chronicity plays a big role in this, there are some patients where their right ventricular size and shape and function might reverse with therapy, and that is the most satisfying thing, I think, for us when we're taking care of patients. But there are other patients who have the same looking or similar looking initial Echo features that you described with that enlarged right ventricle, dysfunctional right ventricle, the shape might be abnormal, and on treatment, they feel better and their BNP falls, and they walk further, and you look at their echocardiogram and part of your brain is saying that right ventricle still looks really abnormal, right? And you can kind of wonder, "What do we do with this?"

And what I've come to appreciate is the distinction between RV size and RV function, and I think it's a really real phenomenon, and this is where patients that have had very chronic remodeling and chronic severe disease, sometimes that right ventricle may not fall in size or shape. It may not reverse as much as we'd like to see, but the function absolutely can. But it takes a really discerning eye to make that distinction, and I don't think you said this yet, but your expertise alludes to this, that there's a lot of value when risk assessing these patients to look at those pictures yourself. Do you have a similar experience in your practice? Because I love that you said, "The Echo kind of trumps everything else. I want to know what that Echo looks like." So does that mean you're looking at the pictures in your practice, in your clinic, or just going by the reports and the risk assessment?

Dr. John Ryan:

The feature of the exam that I said that I don't care about can actually be replicated in Echo as well. We had a patient recently, one of our patients, myelofibrosis with pulmonary arterial hypertension in the setting myelofibrosis. She came in, exertion of dyspnea. She came into one of the urgent care, like the oncology acute care, which is essentially the same as the ER. They got an Echo.

One of our faculty, this is not a criticism of one of our faculty, but it's just instructive as to how you can just hang your hat too much on one thing. One of our faculty who read the Echo, right ventricle is big, right atrium is big, pulmonary artery was big, the tricuspid they estimated RVSP, came out at 25. Word got back, both to me as well as to the acute care, saying, "Not pulmonary hypertension. Don't worry about it. Must be something else." Pulled up the Echo, true enough, right atrium was big, right ventricle was big, pulmonary artery was big. I didn't care what the tricuspid regurgitation was. I didn't care what the estimated right ventricular systolic pressure was, because again, none of this is happening in a vacuum, and everything is about the company it keeps. What is the company it keeps?

And in that setting, we took her to the lab. Sure enough, estimated RVSP was 45, got her on extra therapy. So with that in mind, we've talked a lot about the right ventricle. For most people who don't do this for a living, right ventricular assessment is RVSP. Right ventricular systolic pressure, tricuspid regurgitation. And I guess the question I have for you is, what role do the pressures play? What role does RVSP play in your assessment of right heart function or pulmonary hypertension in general on Echo?

Dr. Anjali Vaidya:

That's great. I'm so glad you brought that up, and I think that's a perfect point to end on for this discussion. So, there is so much variability and error in the RVSP estimation for a variety of Echo Doppler technique issues, and this has been shown time and time again, particularly some data that show up to 50% of patients will have a 10 millimeter of mercury error in the Echo Doppler estimation of pressure relative to the directly measured hemodynamics.

So, the bottom line is the pressure is never the answer. It's never the answer in the diagnosis. It's never the answer in the risk assessment, even less so. It's meant to raise awareness to look closer. And once you have a suspicion of it, we have to look at all of the right heart parameters, right ventricular size, structure, function, tricuspid regurgitation, right atrial size and shape, IVC collapse, and all of those things. And so I've really enjoyed this discussion with you, Dr. Ryan. Thank you so much.

[On-screen text: Anjali Vaidya, MD, FACC, FASE, FACP, Cardiologist]

[Title: Examine the Virtual Echocardiography Screening Tool (VEST)]

Dr. Anjali Vaidya:

Let's take that step further and kind of add to our toolbox now, of clues that can give us a sense to predict if this is pulmonary arterial hypertension, pulmonary vascular disease, PVD, or left heart disease. This is the Echo score paper that we published about 10 years ago now. And this is a culmination of work looking at several different Echo Doppler parameters that represent the right heart, hemodynamics, the left heart, size, Doppler features, and it's simplified here.

These were the parts of the score that were most predictive of the hemodynamic profile. And it's a very simple score. This warrants looking at the Echo pictures directly. I'm going to start with the features on the top of the table, which represent what the most common scenario is in all of our clinical practice, which is left heart failure, WHO Group II, pulmonary venous hypertension. So, the features that would help you predict that when you're looking at Echo pictures are features that correlate with high filling pressures on the left side of the heart. So, all the cardiologists know that when you're looking at an Echo that transmitral-to-tissue Doppler ratio, that E-to-E prime, if it's elevated, this is a well-established marker of high left heart filling pressures. Of course, all of our pulmonary colleagues who are experts in pulmonary hypertension know this as well.

And this has become a really helpful tool that all of us can recognize. So, when the E-to-E prime is high or greater than 10, that predicts high left heart filling pressures. This would be more consistent with pulmonary venous hypertension or WHO Group II PH. Similarly, when a patient is presenting with shortness of breath, dyspnea, and it's on the basis of pulmonary hypertension that you're seeing is elevated on the Echo, if their left atrium is enlarged, that also would correlate with pulmonary venous hypertension, which is literally left atrial hypertension. So very simply, very early on when you're looking at an Echo, you're looking at left atrial size and that E-to-E prime ratio. If they're enlarged or elevated, you're already thinking this is more likely to be pulmonary venous hypertension. Now, the flip side to that is what gets us really excited in the context of pulmonary arterial hypertension.

You have a patient who has shortness of breath. Their pulmonary pressure is estimated on Echo, but again, that doesn't tell you what's really wrong with the patient—you have to look further. So, when you look at that and you see that the left atrium is normal in size, that sort of tells you that, wow, this patient can't have pulmonary hypertension on the basis of left atrial hypertension. If their left atrium is small. So that's already a clue that this may be more likely a pulmonary vascular disease problem. Now, the other parameter exists in the pulse wave Doppler in the RV outflow tract. And what we're talking about here is when you eject out of your RV outflow tract through the pulmonic valve in systole, and you have a high afterload, a high pulmonary vascular resistance, you get a reflected wave back into your RV outflow tract before that pulmonic valve closes at the end of systole.

When that happens, that reflected wave back causes an indentation or a notch in that pulse wave Doppler profile. And that also correlates with a rapid peak at acceleration. So, a shortened acceleration time. So, the flip side of pulmonary venous hypertension on an Echo report would be features of pulmonary arterial hypertension, a high pulmonary vascular resistance, meaning a notch in the RV outflow tract, or a reduced acceleration time in the context of a normal or small left atrium.

So, let's put that into a little bit more perspective. Let me show you some more data about how that pans out. The score, if it's positive is highly suggestive, again, of pulmonary arterial hypertension, pulmonary vascular disease, and you really need to move quicker for hemodynamic assessment. You'll see that when the score goes from negative to positive, that wedge pressure falls, the transpulmonary gradient increased, and the pulmonary vascular resistance increased. Now, a simpler way to look at this, if you don't have access to the actual direct Echo images is what we call the virtual Echo screening tool. This is a paper we published in 2020, looking at just the routine Echo reports that can help predict the hemodynamic profile and pulmonary arterial hypertension.

For all of our colleagues and friends who may not have easy, readily accessible pictures to look at, just look at your routine Echo report. Look at that E-to-E prime that's automatically populated into the report when our technicians obtain it. If you don't have the tissue Doppler, E prime just look at that E velocity. You can use 90 centimeters per second as a cutoff. Look at the qualitative description of left atrial size if it's at least moderately enlarged. Look at that presence of the D-shaped septum, the interventricular septal flattening that correlates with RV pressure overload. We've all been taught this. Please remind yourself and your trainees that, that's specific to high resistance, it's not just pressure. So, when you see the D shaped septum and the left atrium is normal or only mildly enlarged, and that E-to-E prime is low, or that transmitral E velocity is low.

You get positive points for all of those, and that all correlates with pulmonary arterial hypertension, or pulmonary vascular disease. Those 3 parameters, very simply on a routine Echo report in VEST can identify patients with WHO Group 1 PAH. That's the graph on the left of your screen. You can see it's highly discriminatory to distinguish between Group 1 and Group 2 PAH, as opposed to kind of the tempting downfall of relying too heavily on the PA systolic pressure. And you can see when doing that in the same cohort of patients with pulmonary hypertension, there's a little ability to discriminate at all between WHO Group 1 and WHO Group 2. So positive VEST score has a higher sensitivity and specificity for WHO Group 1, pulmonary arterial hypertension than simply PASP.

And so any patient with a VEST score that's greater than zero should be referred really quickly for right heart cath to complete an additional PAH evaluation and the goal here to recognize patients sooner and really get them to their accurate diagnosis, much faster than our current standard, unfortunately, which is up to two and a half or 3 years and waiting for patients to already be Functional Class 3 or 4.

Apical four-chamber imaging provides a view of all cardiac chambers, enabling assessment of size, shape and function. This view is also important to estimate pulmonary artery pressures.

In PAH, these are critical factors in diagnosing disease, monitoring disease, and making informed treatment decisions.

Parasternal long-axis imaging offers a longitudinal slice through the heart, visualizing the left ventricle, left atrium, aortic valve, and mitral valve.

In PAH and other pre-capillary forms, this view helps rule out left-sided heart disease, a critical consideration in distinguishing pulmonary arterial hypertension and other forms.

The parasternal short-axis view provides cross-sectional images, allowing assessment of ventricular wall motion, valve morphology, and chamber dimensions.

In PAH, this view allows for evaluation of hallmark signs of right ventricular pressure overload. These insights are essential for developing an informed treatment plan.

Subcostal four-chamber imaging provides a view of all heart chambers obtained from beneath the rib cage.

In PAH, this view is useful for assessing the size and collapsibility of the inferior vena cava to estimate right atrial pressure, and for identifying interatrial shunting, which can complicate the diagnosis of PAH.

As a reminder, echo cannot diagnose PAH. Instead, echocardiography serves as a screening tool, helping to raise suspicion when multiple findings suggest elevated pulmonary pressures and right heart strain.

Ultimately, only a right heart catheterization can provide a definitive diagnosis of PAH.

Normally, the right ventricle is smaller in diameter than the left ventricle.

A right ventricular to left ventricular diameter ratio greater than 1.0 suggests right ventricular dilation and possibly PAH.

Right ventricular fractional area change, or RVFAC, is an important marker of right ventricular function. Tricuspid annular plane systolic excursion (TAPSE) and pericardial effusion are other important markers of right ventricular function. These parameters have prognostic significance.

Changes in right ventricular size and function over time provide crucial insights into disease progression, right ventricular adaptation, and treatment response once the disease is diagnosed.

Normally, tricuspid annular plane systolic excursion, or TAPSE, is generally greater than 18 millimeters.

In PAH, TAPSE is typically less than 18 millimeters, indicating reduced right ventricular systolic function and right heart impairment.

TAPSE can be divided by the systolic pulmonary arterial pressure to determine the degree of coupling between the pulmonary artery and right ventricle. A higher ratio is associated with improved prognosis.

Normally, the right and left atria are similar in size, with the left atrium appearing slightly larger.

In the apical four-chamber view, right atrial area exceeding 19 cm² may suggest sustained right-sided pressure elevation and right ventricular dysfunction.

Elevations in right atrial pressure, estimated from size and collapsibility of the inferior vena cava, may also signal PAH or worsening disease.

Normally, the inferior vena cava varies with respiration, measuring less than 21 mm in diameter and collapsing greater than 50% with inspiration.

In PAH, the inferior vena cava appears dilated, exceeding 21 mm, with minimal respiratory collapse.

This suggests elevated right atrial pressure and right heart strain.

Normally, the pressure in the left ventricle pushes the interventricular septum into the right ventricle. Increases in right ventricular systolic pressure from PAH may flatten the septum.

Septal flattening is quantified using the Eccentricity index measured in systole. Increased eccentricity index indicates abnormalities of the right ventricle.

Normally, tricuspid regurgitation velocity, or TRV, is less than 2.8 meters per second, corresponding to a pulmonary artery systolic pressure of less than 36 mmHg when summed with estimated right atrial pressure.

TRV elevated above 2.8 meters per second signals increased right ventricular systolic pressure and possible PAH.

Let’s review some common issues and tips when performing right heart echoes.

Probe placement. Be sure to adjust your probe settings based on your patient's body habitus.

Interference issues. The ribs, lungs, air, or body tissue can interfere with the echo quality. When necessary, use a contrast liquid to help provide a more accurate view.

Limited experience assessing the right heart. If your clinical practice focuses on left heart failure, the nuances of right-sided heart disease and pre-capillary PH may not be fully appreciated. Ensure that you and your team have the best information to fully assess right heart function, particularly as it relates to possible PAH.

As a reminder, echo cannot diagnose PAH. Instead, echocardiography serves as a screening tool, helping to raise suspicion when multiple findings suggest elevated pulmonary pressures and right heart strain.

Ultimately, only a right heart catheterization can provide a definitive diagnosis of PAH.

Tricuspid regurgitation velocity, or TRV, is important to estimating systolic pulmonary artery pressure.

On subcostal view, right atrial pressure is estimated from diameter and collapsibility of the inferior vena cava. Elevated TRV and right atrial pressure signal elevated systolic pulmonary artery pressure, raising suspicion of PH.

Views of heart chamber size and shape are important in estimating likelihood of pre-capillary PH.

In 4-chamber view, the likelihood of pre-capillary PH may be estimated by: an RV to LV ratio greater than 1.0 may suggest pre-capillary PH; a decreased RV base-to-apex systolic ratio may suggest pre-capillary PH; an enlarged RA, where the area exceeds 18 centimeters squared; and on short-axis view, a flattened interventricular septum and decreased left ventricular eccentricity index are suggestive of RV pressure elevation. To learn more about these parameters go to the ECHO section.

When TRV is elevated, different echo parameters have been combined into a simple risk assessment tool called VEST.

Using just left atrial size, trans-mitral E to e prime at the lateral mitral annulus, and the presence of interventricular systolic septal flattening help discriminate pre-capillary from post-capillary PAH. A VEST score of +3 is specific for PAH.

VEST is important because it allows early detection of PAH by more than 6 months before PAH is detected at a PH referral center.

Estimating the probability of pre-capillary PAH versus post-capillary PH is enhanced by visualizing heart chamber size and shape, in conjunction with the VEST score.

VEST can be integrated into an EMR-based algorithm to identify PAH hemodynamics for referral for right heart catheterization.

Ultimately, only a right heart catheterization can provide a definitive diagnosis of PAH.

Echo is important not only to suspect PAH or PH, but in risk stratification after a diagnosis of PAH is made. High-risk echo parameters include presence of pericardial effusion, elevated TR, and elevated RAP, the latter suggestive of worsening venous congestion. Patients with intermediate or high risk echocardiographic probability of PH should be referred for right heart catheterization.

Once PAH is diagnosed, risk assessment is integral to risk-based goal-directed approaches in managing disease.

Echocardiogram parameters are included in many risk methods, and in many cases, can stand alone or augment the prognostic accuracy of tools that rely less on echo data.

REVEAL 2.0 and 2022 ESC/ERS guidelines are 2 common methods of assessing risk of mortality in PAH.

Echo parameters in REVEAL 2.0 include pericardial effusion, estimated right atrial pressure, and pulmonary vascular resistance, the latter estimated from right ventricular outflow notching.

2022 ESC/ERS guidelines incorporate pericardial effusion, right atrial area, and the ratio of TAPSE to systolic pulmonary artery pressure.

Echo parameters representing right heart function may outperform current risk methods. A method incorporating TAPSE, tricuspid regurgitation grade, and inferior vena cava diameter was effective in stratifying risk of mortality in PAH.

In another study of stand-alone echo parameters used in risk assessment, combining estimated right atrial pressure, tricuspid regurgitation, and pericardial effusion accurately characterized risk of mortality. Estimated RAP greater than 15 mm Hg, TR greater than moderate, and presence of pericardial effusion were highly prognostic. Methods and approaches like this help identify patients earlier to therapy escalation.

Once diagnosed with PAH, regular echocardiographic follow-up is recommended as frequently as every 3 to 6 months. Tracking changes in chamber shape, size, and function is vital to monitoring the effect of therapeutic interventions and determine when therapy escalation is required to achieve low risk.

Echo is important not only to suspect PAH or PH, but in risk stratification after a diagnosis of PAH is made. High-risk echo parameters include presence of pericardial effusion, elevated TR, and elevated RAP, the latter suggestive of worsening venous congestion. Patients with intermediate or high risk echocardiographic probability of PH should be referred for right heart catheterization.

The hemodynamic definitions of pre-capillary and post-capillary PH have recently been updated by the seventh World Symposium on Pulmonary Hypertension.

All three hemodynamic criteria must be met to distinguish pre-capillary from post-capillary PH in the course of right heart catheterization.

Right atrial pressure is a key hemodynamic parameter, reflecting right ventricular preload and overall right heart function.

Normal right atrial pressure ranges from 2 to 6 mmHg, indicating adequate venous return and normal right atrial compliance.

In PAH, elevated right atrial pressure suggests right heart strain, impaired right ventricular function, and venous congestion. Monitoring right atrial pressure over time helps assess disease progression and treatment response.

Mean right ventricular pressure reflects overall right ventricular workload, which increases in PAH due to elevated pulmonary vascular resistance. Right ventricular pressures are equal to pulmonary artery pressures when there is no obstruction in the right ventricular outflow tract or RVOT.

Right ventricular systolic pressure represents the peak pressure the right ventricle generates during systole, closely correlating with pulmonary artery systolic pressure. Elevated right ventricular systolic pressure in PAH indicates increased right ventricular afterload, which can lead to hypertrophy, dilation, and eventual failure.

Mean pulmonary artery pressure normally ranges from 8 to 20 mmHg. In PAH, the mean pulmonary artery pressure value by definition, is greater than 20 mmHg.

Systolic pulmonary artery pressure represents the peak pressure during right ventricular systole, while diastolic pulmonary artery pressure reflects residual pressure during diastole.

Pulmonary artery systolic pressures are equal to right ventricular pressures when there are no obstructions in the RVOT.

In a normal heart, pulmonary capillary wedge pressure is typically less than or equal to 15 mmHg. This definition must be met to help determine whether a patient has a form of pre-capillary PH such as PAH.

In pre-capillary PAH, PCWP stays at or below 15 mmHg despite increased pulmonary artery pressures, confirming that the condition originates from elevated pulmonary vascular resistance and not from left-sided heart failure or valvular issues.

A PCWP greater than 15 mmHg may suggest a post-capillary form of pulmonary hypertension secondary to left-sided conditions such as heart failure or valvular disease.

Cardiac output, cardiac index, and stroke volume index are essential for assessing overall right heart function and prognosis.

Cardiac output and cardiac index typically range from 4 to 8 liters per minute and 2.5 to 4 liters per minute per millimeters squared, respectively.

In PAH, cardiac output and cardiac index may decrease as right ventricular function deteriorates due to increased pulmonary vascular resistance or right ventricular afterload.

Since stroke volume index is determined from the cardiac output and heart rate, a decrease in cardiac output is typically associated with a decrease in stroke volume.

Stroke volume index is typically between 33 and 47 milliliters per millimeter squared, with less than 33 milliliters per millimeter squared suggesting PAH.

Of importance, pulmonary vascular resistance is calculated from the transpulmonary pressure gradient divided by the cardiac output. Pulmonary vascular resistance greater than 2 Wood Units must be met as part of the hemodynamic definition of PAH.

Right heart catheterization is the gold standard for diagnosing PAH and is required for all patients with suspected disease.

In the standard procedure, a Swan-Ganz catheter is introduced through a central vein and guided towards the right atrium.

Prior to positioning in the right atrium, a small balloon is inflated to help blood flow pull the catheter along the path of blood flow. Right atrial pressure is measured when the catheter position is confirmed.

The catheter is then advanced into the right ventricle and right ventricular pressures are measured.

The balloon is deflated and the catheter is advanced into a distal artery branch. The balloon is then reinflated to form a tight seal in the wedge position to measure pulmonary capillary wedge pressure. The balloon is then deflated and the catheter is retracted to measure pulmonary artery pressures and collect a mixed venous oxygen saturation sample.

Alternatively, some clinicians will assess the wedge pressure after the pulmonary artery pressure and mixed venous oxygen saturation are determined.

Finally, cardiac output is assessed using either the thermodilution or Fick method, providing essential data for evaluating pulmonary hypertension and heart function.

The over or under-estimation of the PCWP or volume status:

This measurement should be recorded at end-expiration when the mitral valve is open, and LAP is equal to LVEDP.

You should measure mPAP and PCWP at the same point in the respiratory cycle.

A properly wedged catheter will yield an SaO2 greater than 90–95%. If an accurate PCWP cannot be obtained via RHC, a LHC must be performed to rule out LH disease.

Pressure waveforms are dampened due to air bubbles in the pressure tubing:

Be sure to flush the catheter and tubing to ensure no air is in the pressure system.

Improper placement of the pressure transducer relative to the patient's heart can result in inaccurate hemodynamic pressure readings.

Placement too high will lead to underestimation of pressures. Placement too low will lead to overestimation of pressures.

Improper or untimely inflation and deflation of the Swan-Ganz catheter balloon can cause complications. Balloon inflation can cause pulmonary infarction or artery perforation, especially with prolonged inflation or in patients with PH. Air embolism can also occur, requiring immediate intervention. Likewise, damage to the heart valves may occur if the balloon is not deflated before retracting the catheter from the distal pulmonary artery branch.