Ryan Tedford, MD, on the Impact of the New PH Definition on Heart Transplant Outcomes

In this podcast, Ryan Tedford, MD, answers our questions about his team's latest study, which assessed the impact of the new definition of pulmonary hypertension (PH) on heart transplant outcomes. Pulmonary artery pressure and survival rates were evaluated.

Additional Resources:

• Crawford TC, Leary PJ, Fraser III CD, et al. Impact of the new pulmonary hypertension definition on heart transplant outcomes: expanding the hemodynamic risk profile. CHEST. 2020;157(1):151-161. https://doi.org/10.1016/j.chest.2019.07.028.
• Maron BA, Hess E, Maddox TM, et al. Association of borderline pulmonary hypertension with mortality and hospitalization in a large patient cohort: insights from the veterans affairs clinical assessment, reporting, and tracking program. Circulation. 2016;133(13):1240-1248. https://doi.org/10.1161/circulationaha.115.020207. 

Ryan J. Tedford, MD, FACC, FAHA, FHFSA, is an associate professor of medicine, chief of heart failure, and medical director of adult cardiac transplantation in the Division of Cardiology, Department of Medicine, at the Medical University of South Carolina in Charleston.

TRANSCRIPT:

Amanda Balbi:  Hello, everyone. Welcome to another installment of Podcasts360, your go‑to resource for medical news and clinical updates. I'm your moderator, Amanda Balbi with Consultant360 Specialty Network.

Last year, the definition of pulmonary hypertension, or PH, was updated to include lower pulmonary artery pressures in the setting of elevated pulmonary vascular resistance, or PVR. In a new analysis, a team of researchers analyzed 32,465 patients registered in the United Network for Organ Sharing database, who had underwent heart transplant from 1996 to 2015.

Patients were categorized based on mean pulmonary artery pressure, and 30‑day and 1‑year survival characteristics were recorded.

To gain more insight on the findings of the study, we're speaking with the study's lead author, Dr Ryan Tedford, who is an associate professor of medicine, chief of heart failure, and medical director of adult cardiac transplantation in the Division of Cardiology, Department of Medicine at the Medical University of South Carolina in Charleston.

Thank you so much for joining me today, Dr Tedford. Let's dive into your study. To start, can you tell us more about the new definition of PH?

Ryan Tedford:  Sure. If you look at very large population studies of normal individuals, the average mean pulmonary artery pressure is around 14 millimeters of mercury. If we assume that about 2 standard deviations from that should define an abnormal population, this would lead us up to an upper limit of normal of about 20 millimeters of mercury.

The experts that came up with the original definition of mean pulmonary pressure 25 were aware of this data but they chose to really maximize the specificity of this definition so that there was not an overdiagnosis of pulmonary hypertension.

Part of the reason for that is that we didn't have a lot of treatment for this condition at that time. We were excluding a lot of people that actually had abnormal physiology.

In the last 3 to 4 years, there's been multiple large population studies, many of which were led by Brad Maron at Brigham and Women's Hospital, that have shown us that lower pulmonary artery pressures are associated with excess mortality. In fact, that increased risk starts early on, probably around 18 millimeters of mercury.

Based on Brad's work and others, the World Symposium in Pulmonary Hypertension recognized this and therefore chose to change the definition to highlight this increased risk that happens at lower pulmonary pressures.

We also chose to incorporate a pulmonary vascular resistance cutoff to define abnormal, and that cutoff was 3 wood units. Although, this is somewhat arbitrary. We'll be hearing a lot more about that cutoff and surrounding data in the next couple of years.

We should be very clear however, that this definition does not represent a treatment threshold, but rather a definition of what is abnormal and normal within pulmonary pressures.

Amanda Balbi:  How has the new definition of PH impacted heart transplant outcomes for patients with PH?

Ryan Tedford:  That's a great question. I would say at this point, it's a little bit unclear because the new definition is so new. Like many good clinical research questions, this original idea for the study came out of a true clinical case.

I was sitting in one of our heart transplant selection meetings and we had an individual who had low pulmonary pressures, but an elevated PVR. There was a lot of debate about was that significant? Many of us felt that the PVR was high just because the cardiac output of this individual is low. Why is that?

Well, we know that PVR theoretically should be a flow independent metric of vascular resistance. However, as cardiac output declines mean pulmonary artery pressure does not necessarily fall in a proportional manner. Therefore, there's an increase in pulmonary vascular resistance due to this nonlinear relationship.

That's due to, at least theoretically, decreased vascular distensibility at lower flow. Perhaps also, there was a contribution of the critical closing pressure exceeding left atrial pressure, when that left atrial pressure is actually low. That's called the waterfall effect. We weren't sure that that was actually going to be significant.

We were, in fact, so much surprised when we did the analysis to find that individuals with an elevated PVR and low pulmonary pressures still had very similar risk to those with elevated pressures.

We saw that PVR was associated with outcome as a continuous variable. Although we also defined the cut point to look at risk association, that indeed lower pulmonary vascular resistance may be associated with a worse outcome. Further risk stratification in that PVR 2 to 3 range should be the focus of our future study.

Amanda Balbi:  Among your findings was that elevated PVR remains associated with a significant increase in the hazard for a 30‑day mortality after cardiac transplantation, even in the setting of lower pulmonary artery pressures. How might this finding inform clinical practice in how cardiac transplantations might be managed among patients with PH in the future?

Ryan Tedford:  There was several things that we learned from the study. One, that in our cardiac transplant population, it's very common to have mean pulmonary pressures that are below 25. In fact, in this large cohort from UNOS, 38% of individuals actually had a low mean pulmonary artery pressure.

As you stated, we did find that PVR remained associated with increased mortality, even in the setting of lower pulmonary pressure and importantly, after controlling for other comorbidities and unknown risk factors. At least within the controlling for those variables, it did appear that this was an independent association.

Clinically, this tells us that these individuals should receive vasodilator or vasoreactive testing to determine if they're responsive and lower that pulmonary vascular resistance. This is something that we routinely do in individuals with pulmonary hypertension and high pressures to see if we can reverse that PVR prior to transplant. But I would say, if people have low pulmonary pressures, it's not routinely done. That certainly has changed my practice. Then we also have to consider this when we're selecting donors and perhaps individuals who have this elevated PVR with lower pulmonary pressures. We want to make sure that we're not under‑sizing the donor that's been selected for those individuals.

It's important to keep in mind that although there is a clear increased risk of 30‑day mortality that the absolute risk is still relatively modest. It's around 2%. Although, that is the same risk that is if your pulmonary pressures were high. It's also similar to other many comorbid conditions that influence our decision‑making. For example, the presence of diabetes or obesity. It is clinically relevant, but not prohibitive.

Finally, this really adds to the support of the newer definition that in fact, an elevated PVR is clinically relevant in these individuals with lower pulmonary pressures. That supports the definition change from the World Symposium.

Amanda Balbi:  How else has this new definition of PH impacted clinical practice? Has it truly improved patient care?

Ryan Tedford:  Other than risk recognition, it has not, and I think it should not at this point. We're really just defining what is abnormal and what's associated with increased risk. The next step would be to study this population, the lower pulmonary pressures with an elevated PVR or subpopulations, to see if targeting to pulmonary circulation with specific therapies would improve outcomes.

It's very important though as we do this, as we make these diagnoses, as we think about designing clinical trials, that we have an impeccable quality control of the hemodynamics. I do have concerns about a decrease in specificity of this diagnosis as we introduce these lower pulmonary pressures.

Amanda Balbi:  Absolutely. What is the overall key take‑home message from your study today?

Ryan Tedford:  First, I would say we cannot ignore PVR when the mean pulmonary pressure is less than 25 in the pre‑transplant population. That is a population that deserves a vasodilator challenge and increased awareness of that risk. Secondly, the new definition of pulmonary hypertension is clinically relevant and defines an abnormal population. Then lastly, the review of heart transplant outcomes provides an important and unique research platform for the study of pulmonary vascular disease. Adverse outcomes of the PH naive heart found to be independently associated with a PH defining hemodynamic profile, really suggests that that profile itself is abnormal.

We only found increased risk at 30 days. Those who survived 30 days, there was no difference in 1‑year mortality against adjusting that there was an early mortality signal, and perhaps these individuals were succumbing to complications from that pulmonary hypertension.

Amanda Balbi:  Thank you again so much for sharing your insights with me today.

Ryan Tedford:  Amanda, it was a pleasure to be here with you today and share my thoughts about our study.