[On-screen text: Anjali Vaidya, MD, FACC, FASE, FACP, Professor, Medicine, Lewis Katz School of Medicine, Temple University Hospital, Philadelphia, Pennsylvania]

[Part 3 title: Imaging in Clinical Practice, Anjali Vaidya, MD, FACC, FASE, FACP]

Dr. Anjali Vaidya:

I'm really excited to continue this conversation today. Thank you so much. Dr. Ryan nicely took us through the pathophysiology of pulmonary arterial hypertension followed by the treatment goals in pulmonary arterial hypertension. This is a huge topic. 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. 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, 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.