Pulmonary Arterial Hypertension Podcast

Diagnosis of PAH: What Are the Causes and Why Does It Take So Long?

Vallerie McLaughlin, MD; Paul Forfia, MD

Disclosures

June 23, 2022

This transcript has been edited for clarity.

Vallerie McLaughlin, MD: Hello. I'm Dr Vallerie McLaughlin, the Kim A. Eagle Endowed Professor of Cardiovascular Medicine at the University of Michigan in Ann Arbor. I would like to welcome you to today's Medscape InDiscussion series on pulmonary arterial hypertension (PAH). This is episode 2: diagnosis of PAH. What are the challenges and why does it take so long?

First, I'm thrilled to introduce my guest Dr Paul Forfia, who is professor of medicine at Temple University in Philadelphia. Paul, welcome. Tell me a little bit about your journey into pulmonary hypertension.

Paul Forfia, MD: Thanks, Val. I appreciate it.

I started my cardiology training just like anyone else and ended up finishing my training in heart failure transplantation. But all the while, I had an interest in pulmonary hypertension and in particular, right heart function. And it was really my overlap training between heart failure transplant and focused interest in the pulmonary circulation in the right heart that got me into seeing patients with all forms of pulmonary hypertension.

McLaughlin: Today we're talking about the diagnosis, and you and I have both been doing this a long time. We have had the privilege of seeing so many medications approved and seeing our patients do so much better once their disease is diagnosed. But sadly, despite all these advances, it still takes so long for these patients to come to medical attention and get the correct diagnosis. Paul, why do you think that is? What sorts of things contribute to that delay from onset of symptoms to the diagnosis of pulmonary hypertension?

Forfia: There's no doubt that we tend to see patients in the later stages of their condition, and I think there are multiple factors that contribute to that phenomenon. On the patient-related side, as we've both experienced for patients with a heart or lung or a combined cardiopulmonary process who have exercise intolerance and shortness of breath with exertion, it is not uncommon that they will delay their own presentation. So this is a pretty common phenomenon, that patients are less likely to seek therapy when their symptoms begin. They'll often rationalize their symptoms away, and in our patients who are overweight and or have other chronic background medical problems, they will often ascribe their own symptoms to maybe their preexisting condition or their own overweight status.

McLaughlin: I hear that a lot, too. "Oh I'm getting older. I expect this."

Forfia: Right. And so we'll call that the patient-related factors. But I think the patient-related factors are baked into the overall process. I don't think that that's fundamentally changed in the past 20 years. That's more human nature.

Now we'll talk about disease-related factors. PAH, as you know, is a condition that presents in an overlapping way, where features of cardiac dysfunction are often present. But features of pulmonary, vascular, and respiratory dysfunction are also often present, so patients can often present with a mix of signs and symptoms that look something like heart disease, something like lung disease. It really does often present as this overlapping condition. As a result, to a nonexpert clinician who is seeing the person for the first time, they may not pinpoint the diagnosis a first or second or even a third time because of the fact that there's overlapping presentations to the illness.

McLaughlin: And giving these physicians the benefit of the doubt, common things happen commonly, right? It makes sense for the primary care provider who sees many patients with shortness of breath to think about other, more common diagnoses — coronary disease, ischemia, COPD — before they start thinking about pulmonary hypertension.

Forfia: There's no question about it. When you have an overlapping condition that is relatively uncommon, the more common explanations for dyspnea will often be credited as the cause of their shortness of breath from the beginning. And what I'll call physician-related factors, I think relate to training. In standard cardiology fellowship training and in standard pulmonary disease fellowship training, there is often not a significant emphasis on the diagnosis of PAH or other pulmonary hypertensive syndromes, like chronic thromboembolic pulmonary hypertension.

So it's almost like the perfect storm, if you will, in that the disease itself can present with overlapping features, and the physicians who are seeing the patient are not trained in a focused manner on PAH. And so as a result, the way I explain it to patients is that patients with PAH will often walk right in between the cardiologist and the pulmonologist, and they keep on going with their undiagnosed PAH until they ultimately find the right provider who can recognize that oftentimes very quickly.

McLaughlin: It's unfortunate that we both see way too many patients who have advanced symptoms and advanced hemodynamics by the time they get to us, for all these reasons.

Paul, there are probably some patient populations who are appropriate for more aggressive screening. Or we should think about pulmonary hypertension from the get-go, when they might start having some exercise intolerance. Do you want to highlight the few groups in whom we might be more aggressive in terms of screening and early diagnosis?

Forfia: Certain preexisting medical conditions put patients at significantly higher risk of developing PAH. The most obvious example would be any form of connective tissue disease, but in particular, scleroderma. If we think about connective tissue disease as an overarching or categorical diagnosis, limited scleroderma confers the highest risk of developing PAH in that patient's lifetime.

Ranked just underneath that would be the condition that you and I are well familiar with, which is often referred to as mixed connective tissue disease (MCTD). In our patients with MCTD, very often they have a strong scleroderma feature to their MCTD presentation.

Then, of course, there are other connective tissue diseases, like lupus and Sjögren syndrome — and again, these overlaps between lupus and Sjögren syndrome or lupus and scleroderma. So clearly, the connective tissue disease population is at risk, and we should always maintain a high index of suspicion in those patients.

These are not the only high-risk patients, though. Patients with chronic HIV infection are at lifetime increased risk of developing PAH. In a patient who has known HIV who presents with new onset and progressing dyspnea, PAH should always be on the differential diagnosis.

Similarly, if a patient has known liver pathology in particular, if they have liver cirrhosis with preexisting portal hypertension again, they are at lifetime increased risk of developing PAH — known, of course, as portopulmonary hypertension.

Another important category would be patients with congenital heart disease and, in particular, systemic-to-pulmonary shunt conditions, like an atrial septal defect, a ventricular septal defect, or a patent ductus. These are three subsets of systemic pulmonary shunt where PAH is at increased risk.

Then the last one I would raise would be toxin exposures. Historically, it was a particular type of anorexigen, but nowadays it seems that recreational methamphetamine use seems to confer a very strong risk of developing PAH.

Those would be some of the ones I could think of off the top of my head, Val.

McLaughlin: Then there's people with a family history — someone with a known heritable form of PAH in a first-degree relative — we might consider those folks as well.

So the patients present with often nonspecific symptoms: dyspnea, fatigue. Sometimes the physical exam findings are subtle: a loud P2, the RV heave. Sometimes when they're more advanced, we see the jugular venous distention and lower-extremity edema and more ominous signs of right heart failure. But early on, some of the physical exam findings can be subtle. You know, I don't blame the frontline physicians for thinking of the common things, but something I always emphasize to them is if the patient has these symptoms of these cardiopulmonary symptoms we both described, and it's not those things that you thought of as a more common diagnosis, please get an echocardiogram so that we can start raising the suspicion for pulmonary hypertension or at least evaluating that possibility.

Paul, I know this is a passion of yours. Can you please review for the audience the salient findings of pulmonary hypertension on the echocardiogram and how you use some of these findings to go down that diagnostic pathway in patients?

Forfia: This is one of the most important areas within the diagnostic workup: how to use your noninvasive imaging, which is mostly the transthoracic echocardiogram, to hone in on whether there is or is not the condition of PAH. Sometimes what happens with the echo is that the clinician thinks that the primary role of the echo is to detect pulmonary hypertension. But in fact, what we're really looking for on the echo first and foremost is to look for signs of PAH and other pulmonary vascular forms of pulmonary hypertension, where the pulmonary vascular resistance is high. And whether there was a true increased afterload onto the right side of the heart. It is often misunderstood that a high pressure in the lung causes a high afterload, and that all forms of pulmonary hypertension will have the same effect on the heart. But that couldn't be further from the truth.

For the listening audience out there, to understand how pulmonary hypertension affects the echo, you first have to understand that pulmonary pressure is not afterload, but pulmonary vascular resistance being elevated is afterload. Therefore, what we're really looking for on any echo is any evidence of a high pulmonary vascular resistance. If you can do that, you'll be able to spot the overwhelming majority of patients who have the features of PAH right away.

What are those features? PAH is a condition of abnormal pulmonary blood vessel function, narrowing obliteration remodeling with a very high pulmonary vascular resistance (PVR), but at the exclusion of left-heart disease. So one of the things that you will not see from the outset in the echo of a patient with PAH is that they have left-heart disease. Their left atrium will be normal in size or even small. Their left ventricular cavity size will be normal or small. Their left ventricular ejection fraction will be normal or even elevated because their cavity dimensions are reduced. They won't have aortic valve disease, nor will they have mitral valve disease. These features unto themselves are very, very important because the pulmonary vascular resistance is so elevated in these patients. For those who are not familiar with the magnitude, the average patient with PAH will present with a PVR that's six to 10 times normal at their initial presentation. As a result, the right side of the heart must change in its size, shape, septal position, and function in the presence of such high PVR.

So how does that manifest? What you'll see classically on the apical four-chamber view is that the right ventricle (RV) is enlarged and is often as large or typically significantly larger than the left ventricle (LV). So your RV/LV ratio will be far greater than 1. You'll often find that the distal third of the RV is just as wide as the basal third, what we call the base/apex ratio. You'll see that that RV apex is quite open or dilated. And often the right ventricle and the left ventricle will co-occupy the apex of the heart. There will very often be right ventricular dysfunction, and the average patient with PAH at the outset of diagnosis will have moderate right ventricular dysfunction. You may or may not see tricuspid regurgitation. You'll often see right atrial enlargement, and then on your short axis, you'll see that the interventricular septum is flattening from right to left in systole. These are all classic features of increased size, decreased function, and increased septal flattening of the right side of the heart.

McLaughlin: I agree, Paul — that short axis view, the way the RV and LV interact, that's the key view for me. You're doing a great job and explaining the echo, but I also want to focus on what everybody else thinks about when they order an echo, and that's the estimated right ventricular systolic pressure (RVSP). Honestly, what you just described is way more important than the estimated RVSP. But can you remind the audience of some of the pitfalls of estimating the RVSP on echo?

Forfia: As Dr McLaughlin pointed out, and for the listening audience, you probably have seen that I didn't mention the RVSP right from the beginning. I did that on purpose because it's the last thing that I look at. You have to be very careful here. The Doppler estimation of pulmonary artery systolic pressure is typically done by measuring your peak TR jet velocity, your place in continuous wave Doppler across the tricuspid valve, getting the highest velocity across the tricuspid valve. Then you plug that into what's called the modified Bernoulli formula, where you then take your velocity peak as a number; let's say it's 3 m/sec. You square that, multiply it by 4, and then you add an estimate of right atrial pressure. If you just think about that math for a second, you are entirely dependent on whether the peak TR jet velocity that you obtain is accurate. If you miss it, then you're putting either no number or a low number into your 4 multiplied by (TR jet velocity)2 + RA pressure equation. If you overestimate it, you're putting an overestimated number into that equation.

OK, so the Bernoulli formula is correct, but there are many scenarios where you will not have an accurately obtained peak TR jet velocity, and then you will have the wrong number come out at the end of the equation. Numerous studies have now shown that when you do a right-heart catheterization and a Doppler estimated PA systolic pressure within short proximity of each other (meaning minutes of each other), you will often find that there is not a high amount of agreement between what the Doppler provided and what the cath provided. That's because you can't always get these perfect TR jet velocities to put into the equation. Therefore, you have to be careful about being overly reliant on your Doppler estimated pulmonary artery systolic pressure (PASP). If your PASP is 80 and you have all of those features I described — dilated, dysfunctional, right-heart septal flattening, something called a notched pattern in the RV outflow tract Doppler — you've got it, right? You've got a patient who has severe pulmonary hypertension. That's high PVR in nature, and you're well on your way to diagnosing PAH.

However, if the person has a normal TR jet velocity or you don't have any signal to measure at all, but they still have a dilated, dysfunctional right heart, you still have to suspect PAH with a very high degree of certainty and move on to your next diagnostic tests.

McLaughlin: That was a great summary of echo, which is really critical in raising the suspicion or at least telling us whether we need to go down the further diagnostic pathway — whether they have all the signs that you mentioned or whether there have just some of them, and we need to investigate further. Of course, there's lots of other diseases that can cause pulmonary hypertension. We always have to think about left-heart disease. And Paul, you nicely summarized some things that we might see on echo that lead us that way.

Obstructive lung disease, restrictive lung disease, even obstructive sleep apnea — we need to get pulmonary function tests (PFTs) and at least consider the possibility of sleep apnea with a screening tool. We routinely do some blood tests, look at antinuclear antibodies (ANAs) and try to find connective tissue disease; every once in a while, I find some cases before a rheumatologist has.

Another really important test in the diagnostic algorithm for pulmonary hypertension is the ventilation-perfusion scan. Paul, do you want to briefly highlight the importance of that test?

Forfia: In any patient who presents with dyspnea of unknown cause and or significant pulmonary hypertension, particularly the form that looks like PAH, a ventilation-perfusion scan should be done as a screening tool to rule out the presence of chronic thromboembolic disease. This is a disease that, as I've written about before, can hide in plain sight. A person has a known history of a pulmonary embolism (PE). They're short of breath 3 years after their PE. They have evidence of pulmonary hypertension on their echocardiogram. Yet a ventilation-perfusion scintigraphy (V/Q) scan has not been performed. And so the V/Q scan occupies a critical role as a screening tool for the presence or absence of chronic thromboembolic pulmonary hypertension (CTEPH). If the V/Q scan is truly normal, then it is very unlikely that someone has chronic thromboembolic disease. If the V/Q scan is abnormal, then we keep going in our diagnostic algorithm and then go to our next imaging test, which is CT pulmonary angiography.

McLaughlin: Right, and that's a diagnosis you don't want to miss as you work these patients up because it's potentially curable with a surgery.

And of course, the diagnostic algorithm concludes with right-heart catheterization. You cannot make a diagnosis of pulmonary hypertension without right-heart catheterization. Paul, very briefly, do you want to highlight some of the most important hemodynamics that we get at the time of a right-heart catheterization?

Forfia: As you pointed out, the right-heart catheterization is absolutely necessary to make your confirmatory diagnosis of pulmonary hypertension and PAH. When we do a right-heart catheterization, we are going to obtain direct pressure recordings within the right atrium, the right ventricle, and the pulmonary artery and get some form of left atrial pressure assessment. In most cases, we can get the left atrial pressure assessment using what we call a pulmonary artery occlusion pressure — also affectionately referred to as the wedge pressure — but sometimes that's either technically challenging or is fraught with some interpretive issues and will require a brief left-heart catheterization for left ventricular and diastolic pressure to be sure what your left-heart filling pressure is.

In addition, on the right-heart catheterization, we measure cardiac output, which can be done either through a thermodilution technique or through Fick estimations of cardiac output. Once we have our pressure and our flow, we then can derive our resistances. We can develop our pulmonary vascular resistance from these numbers, as well as our systemic vascular resistance.

And then not to be minimized is our ability to screen for the presence of systemic-to-pulmonary shunt conditions. When we perform a right-heart catheterization in any patient with pulmonary hypertension, we always at least do what we call a partial saturation run, where we measure the superior vena cava (SVC) saturation and the pulmonary artery (PA) saturation. If they're within 7 percentage points absolute of each other, then you've excluded a systemic-to-pulmonary shunt straight away. If there is a 7 percentage point or greater difference between your SVC and your PA sat, then we'll do a full saturation run to determine where the step-up is coming from. So that last part, which is to exclude a shunt condition, is also an important part of the pulmonary hypertension assessment in the cath lab.

McLaughlin: I'd like to close by asking you: What are you most excited about that's likely to happen in pulmonary hypertension in the next 5 years or so?

Forfia: I'll give you two quick ones. One is that there is an increase in evidence and traction of the use of cardiac imaging to directly assess the risk of patients with PAH who are on medical therapy. What we're seeing now is literature showing that cardiac imaging should have been and probably will be in the risk assessment tools that we use moving forward. I look forward to that because I think that risk assessment tools that incorporate right ventricular size and function will be a more refined instrument for assessing risk than our current instrument tools that don't use cardiac imaging.

The second thing I'm looking for, which is a little bit out there still, is really transformative PAH medical therapy that causes regression and reverse remodeling of the pulmonary circulation itself and truly reverses the disease that we have not yet seen. But I think we're getting closer.

McLaughlin: Great. Paul, thanks for joining me. As always, it's a pleasure to work with you.

Forfia: Same, Val. Thank you so much for the opportunity to contribute to this.

Resources

Pulmonary Arterial Hypertension

The 'Great Wait' for Diagnosis in Pulmonary Arterial Hypertension

Systemic Consequences of Pulmonary Hypertension and Right-Sided Heart Failure

Management of Coronary Artery Disease and Chronic Stable Angina

What Is Myocardial Ischemia?

Chronic Obstructive Pulmonary Disease (COPD)

Group 4 Pulmonary Hypertension

Pulmonary Arterial Hypertension in Connective Tissue Disorders: Pathophysiology and Treatment

Scleroderma

Pulmonary Hypertension Phenotypes in Patients With Systemic Sclerosis

Mixed Connective-Tissue Disease (MCTD)

Systemic Lupus Erythematosus (SLE)

Sjogren Syndrome

Pulmonary Arterial Hypertension in Patients Infected With the Human Immunodeficiency Virus

Portal Hypertension

Liver Abnormalities in Pulmonary Arterial Hypertension

Pulmonary Hypertension in Adults With Congenital Heart Disease

Atrial Septal Defect

Anorexigens and Pulmonary Hypertension in the United States

Methamphetamine and the Risk of Pulmonary Arterial Hypertension

Echocardiography in Pulmonary Arterial Hypertension: Comprehensive Evaluation and Technical Considerations

Echocardiography

Echocardiography Can Identify Patients With Increased Pulmonary Vascular Resistance by Assessing Pressure Reflection in the Pulmonary Circulation

Pulmonary Resistance

Right Heart Adaptation to Pulmonary Arterial Hypertension: Physiology and Pathobiology

RV Systolic Pressure (TR Jet)

Modified Bernoulli Formula

Limitations and Strengths of Doppler/Echo Pulmonary Artery Systolic Pressure-Right Heart Catheterization Correlations: A Systematic Literature Review

Unraveling the RV Ejection Doppler Envelope: Insight Into Pulmonary Artery Hemodynamics and Disease Severity

Lung Ventilation/Perfusion Scintigraphy for the Screening of Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Which Criteria to Use?

Group 4 Pulmonary Hypertension Workup

Cardiac Output - Fick

Emerging Role of Cardiovascular Magnetic Resonance Imaging in the Management of Pulmonary Hypertension

A Clinical Approach to Multimodality Imaging in Pulmonary Hypertension

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