Benjamin H. Freed, MD, on Diffuse Right Ventricular Fibrosis in Patients With PH and HFpEF

In this podcast, Benjamin H. Freed, MD, answered our questions about his latest research on diffuse right ventricular fibrosis among patients with pulmonary hypertension (PH) and comorbid heart failure with preserved ejection fraction (HFpEF). 

Additional Resource:

• Patel R, Li E, Benefield BC, et al. Diffuse right ventricular fibrosis in heart failure with preserved ejection fraction and pulmonary hypertension [published online January 5, 2020]. ESC Heart Fail. https://doi.org/10.1002/ehf2.12565.

Benjamin Freed, MD, is an assistant professor of medicine in the Division of Cardiology at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

TRANSCRIPT:

Amanda Balbi:  Hello, everyone. Welcome to another installment of Podcasts360. I'm your moderator, Amanda Balbi with Consultant360 Specialty Network.

New research evaluated the extent and clinical correlates of diffuse right ventricular myocardial fibrosis among patients with comorbid pulmonary arterial hypertension, or PAH, and heart failure with preserved ejection fraction or HFpEF.

We are joined today by the lead author on the study, Dr Benjamin Freed, who is an assistant professor of medicine in the Division of Cardiology at Northwestern University Feinberg School of Medicine in Chicago, Illinois. Thank you so much for joining us today, Dr Freed.

Benjamin Freed: Thank you for this opportunity to share our recently published work with your listeners.

Amanda Balbi: To start, can you tell us more about your study and its findings?

Benjamin Freed: I do think that in order to better understand our study, it's important to understand why we decided to do it in the first place. A heart failure with preserved ejection fraction, or HFpEF, is a common type of heart failure. It makes up almost 50% of all patients with heart failure.

In fact, the prevalence of HFpEF relative to heart failure with reduced ejection fraction, or HFrEF, is increasing at a rate of about 1% per year. Many of these patients develop right ventricular or RV dysfunction, which is a known pathophysiologic predictor of adverse outcomes in this patient population. It's associated with a one‑year mortality of greater than 25%.

HFpEF is a syndrome that is in desperate need of research. What do we know about it? We know that many of these patients develop WHO Group 2 pulmonary hypertension, or PH, due to elevated left ventricular filling pressures.

In fact, a population‑based study of a little over 240 patients with HFpEF, 83% of these patients actually had PH. It's quite frequent in this patient population. We also know from previous MRI studies that patients with HFpEF develop diffuse fibrosis in the left ventricle.

This leads us to the question, which is the basis of our study, which is what exactly then is the mechanism for this RV dysfunction? Is it the pulmonary vascular resistance, like in patients with pulmonary arterial hypertension, or PAH, where the increase in RV afterload or the pulmonary vascular resistance is likely to cause the RV dysfunction? Could it be more intrinsic to the right ventricle, such as the buildup of diffuse fibrosis like we've seen in other studies that looked at this in the left ventricle?

To answer this question, we prospectively enrolled 14 patients with invasive hemodynamic‑proven HFpEF and PAH, 13 patients with PAH, and 8 controls to undergo cardiac MRI.

We performed a technique called T1 mapping using a high‑resolution sequence to quantify the extracellular volume or ECV. This is a surrogate of diffuse fibrosis on MRI. We calculated this in both the left and the right ventricle.

Here's what we discovered. Number one, RV‑ECV or diffuse fibrosis was similar between patients with PH‑HFpEF and patients with PAH. Number two, in that PH‑HFpEF group, RV‑ECV correlated strongly with worse RV structure and function which, by the way, was measured by RV strain in this case. But it was not correlated with total pulmonary resistance. However, in the PAH group RV‑ECV correlated strongly with total pulmonary resistance but not RV structure and function.

What we concluded was that diffuse fibrosis is present in the right ventricle in patients with PH‑HFpEF. And it is associated with adverse RV structural and functional remodeling, but not the degree of pulmonary vasculopathy.

What this suggests is that the RV dysfunction that we see in this PH‑HFpEF population is related more to intrinsic myocardial disease rather than changes in the pulmonary vasculature.

Amanda Balbi: Did any of these findings surprise you?

Benjamin Freed:  We were absolutely surprised by the degree of RV fibrosis present in patients with PH‑HFpEF. We thought it was likely greater than controls, but we weren't sure it would be to the same degree as PAH patients.

This is particularly true and surprising, because our PH‑HFpEF group wasn't significantly sick. Their average NYHA, or New York Heart Association, class symptoms was 2, which is not all that bad. They had a mean PA pressure of 34 millimeters of mercury, a wedge pressure of 18, but they had a normal cardiac output, normal LV function, and only mild RV dysfunction. We were surprised that this group had just as much RV fibrosis as our pulmonary arterial hypertension group.

Amanda Balbi:  The specific finding you discussed in your paper, is that diffuse right ventricular fibrosis is present among patients with comorbid PAH and HFpEF, and is associated with adverse right ventricular structural and functional remodeling? What do these findings, taken together, mean for clinical practice?

Benjamin Freed:  It's a good question. It's always important to understand the pathophysiologic mechanisms affecting our patients. This is particularly true in HFpEF, where we have tried to treat this syndrome with medications used in HFrEF but have had little success.

These types of heart failure are very different from each other from a pathophysiologic perspective. We need to do a better job figuring out what is driving HFpEF so we can find a treatment that actually works.

One important takeaway from this study for clinical practice is that RV dysfunction is very common in the HFpEF patient population. If you look at some of the previous major studies involving HFpEF, the prevalence was somewhere between 30 to 40%.

Given that RV dysfunction is a stronger predictor of poor outcomes compared to the standard diastolic parameters, which we commonly associate with HFpEF, we need to be aware of this pathophysiologic consequence.

I would also imagine that many physicians in practice presume that RV dysfunction is present in many patients with HFpEF as a direct result of pulmonary vascular resistance, just like in PAH rather than something else.

This study suggests that this isn't necessarily true. That might help explain why current therapies for PAH, like sildenafil, are not helpful in this patient population.

Amanda Balbi:  What are your tips for our listeners today who want to better manage their patients with PAH and HFpEF?

Benjamin Freed:  Well, my first tip is to not get discouraged. This is a very challenging disease with very sick patients. Despite this study, we still know very little from a treatment standpoint.

The second tip would be to not treat these patients with PAH medications, unless potentially they might have combined pre‑ and post‑capillary pulmonary hypertension. There might be a role for PAH medications in this population. But we simply don't have the data to support the use of PAH medications in this patient population.

In fact, the RELAX study by Maggie Redfield and colleagues from Mayo showed that in about 215 patients with stable HFpEF, 24 weeks of sildenafil therapy did not improve peak oxygen consumption. There is additional data suggesting that while sildenafil improved endothelial dysfunction in this patient population, it actually decreased LV contractility.

Of course, there's also the theoretical concern with pulmonary vasodilators like sildenafil and HFpEF that they can increase LA pressure with reduction in PA resistance. There are some ongoing clinical trials looking at different kinds of PAH medications and HFpEF such as macitentan, but there are no clear results yet.

My next tip is to be aware. Everyone needs to be aware that PAH in RV dysfunction is common in this patient population. Optimal images of the RV and the tricuspid regurgitant velocity on echo, which is used to record PA systolic pressure, is just as important, if not potentially more important than LV diastolic parameters.

Right heart catheterization is sometimes helpful in these patients, but it's not always necessary. If there is additional echo evidence to suggest WHO Group 2 pulmonary hypertension, such as grade 2 or higher diastolic dysfunction on the echo, an enlarged left atrium, these are things you're typically not going to see in your PAH patient population so you might not need the right heart catheterization. I would also say that despite our study, MRI for these patients is still not a part of the regular workup. I suspect it will be in the future, but we're not quite there yet.

Then, finally, my last tip is the mainstay of treatment is still diuretics. This might improve the PAH by reducing LV filling pressures, but as our study shows, it might not improve the RV fibrosis.

It's not clear at this time what might help, although there are some smaller studies suggesting that spironolactone, which was shown in the top trial to reduce heart failure hospitalizations in this patient population, might also have antifibrotic properties. We just need to stay tuned.

Amanda Balbi:  Absolutely. What is your next step in this research?

Benjamin Freed:  We didn't see a strong correlation in our study between RV‑ECV, which is our measure of RV fibrosis and RV ejection fraction. This suggests that RV‑ECV is a unique marker of RV remodeling. It seems to precede an actual decline in RV ejection fraction.

Given this, RV‑ECV might be an ideal measure for monitoring treatment success. One major next step in our research is to evaluate RV‑ECV before and after medical therapy in patients with HFpEF.

Unlike replacement fibrosis seen in infarcts, for example, diffuse fibrosis, which is what ECV is calculating, is potentially reversible in some of these therapies. Spironolactone perhaps might help decrease the amount of fibrosis. RV‑ECV might be a direct target for therapy as well.

We're also evaluating RV‑ECV and other types of PH. Our institution has a large population of patients with CTEPH or chronic thromboembolic pulmonary hypertension, who undergo pulmonary thromboendarterectomy surgery.

Currently, we're using cardiac MRI to examine RV‑ECV before and after surgery. We suspect that this intervention will improve RV perfusion and, in turn, decrease the amount of diffuse fibrosis.

Amanda Balbi:  Great. We'll definitely be on the lookout for that too. Thank you so much for speaking with me today and sharing your insights on your research.

Benjamin Freed:  Thank you very much for the opportunity again to present our research to your listeners. It was really a pleasure.