By Phoebe Ingraham Renda
Stephen Chan, Vitalant Professor of Vascular Medicine and professor of medicine (Division of Cardiology) at the University of Pittsburgh School of Medicine. Photography by: Johnathan Wright
Back in 1995, when Stephen Chan, Vitalant Professor of Vascular Medicine and professor of medicine (Division of Cardiology) at the University of Pittsburgh, was a medical student, pulmonary arterial hypertension (PAH) was a death sentence—100% of patients died within two years of their diagnosis. Now, 30 years later, there are more than 20 approved drugs for PAH that can improve symptoms and increased the survival rate to 50% within five to seven years of a diagnosis. Unfortunately, there is still no cure for PAH.
Following the 2024 Food and Drug Administration approval of sotatercept, a drug that showed dramatic improvements in shortness of breath and pressures in the lungs and heart in patients with an inherited form of PAH, there was a sense of increased promise for treating PAH and achieving a cure.
However, caution may still lie in that promise.
In a research letter, published on Aug. 8, 2025, in the European Respiratory Journal, Stephen Y. Chan—director of the UPMC Comprehensive Pulmonary Hypertension (PH) Program and of the Vascular Medicine Institute—along with colleagues from five other U.S. PH centers of excellence, reported a significant rate of new or worsening pericardial effusions in PAH patients treated with sotatercept.
This Q&A has been lightly edited.
Health Sciences Strategic Communications: What is sotatercept and how does it work?
SC: Sotatercept works by inhibiting a pathway (activin signaling) that controls an inherited form of PAH. Some believe this is the first “disease-modifying” drug for pulmonary hypertension and is a “game-changer” in the treatment of PAH and the quest for a cure.
HSSC: What did you learn from your research that led to this letter?
SC: While some side effects were found in the clinical trials leading to sotatercept approval, other important side effects are now being recognized as associated with the use of this drug, such as GI bleeding, skin lesions and aberrant blood vessel formation that causes worsened oxygen levels. However, one important condition that, to a large extent, was not observed in the sotatercept clinical trials was the development of new or worsening pericardial effusion (collection of fluid around the heart). When that fluid accumulates, it can compromise heart function and reduce the ability of the heart to pump blood around the body. Untreated pericardial effusion, when large enough, can lead to hemodynamic collapse and major complications and even death.
HSSC: Can pericardial effusion occur in PAH patients not taking sotatercept?
SC: Pericardial effusion can occur in PAH patients, mostly in relation to worsening pressures in the heart and lungs. But, since it seems that sotatercept improves that pressure, the likelihood of new pericardial effusion forming after treatment with this drug was thought to be remote.
Yet, as sotatercept was first being used in clinical practice, another pharmaceutical company was initiating the testing of their competitor drug in the same class called cibotercept. Their Phase 2 human study stopped early due to new or worsening pericardial effusions in a significant number of their patients.
Based on those results, it became possible that pericardial effusions may not simply be a unique side effect of cibotercept, but rather a drug class effect that could be relevant to sotatercept as well.
HSSC: How were these effusions detected and determined to be potentially linked to activin signaling inhibitors?
SC: Typically, the way that pericardial effusions are detected early is through ultrasound images of the heart called echocardiograms. However, since most practitioners were not looking for new effusions, most centers were waiting between 6-12 months after starting sotatercept treatment to do any follow-up echocardiograms.
Our accredited UPMC PH program participated in the Phase 3 trials of sotatercept and was among the early adopters of prescribing it to our PAH patients. In that process, our program initiated a system to monitor for side effects, including early echocardiography, so we could detect any side effects not reported in the original clinical trial.
As such, our center was among the first to observe a significant rate of new or worsening pericardial effusions in PAH patients treated with sotatercept. In response, we coordinated with five other U.S. centers to compile a one-of-a-kind case series to report on the effusion rate. This letter is the first report of this clinically important connection to sotatercept use.
HSSC: What were the findings that were reported?
SC: Namely, in over 400 PAH adults who were consecutively treated with sotatercept as add-on therapy at six comprehensive care centers in the South, Midwest and Northeast United States, approximately 5% of these patients developed new or worsening pericardial effusions, some of whom had to undergo surgical drainage procedures. Historically, this is a much higher rate of effusions than what we have seen in our PAH patients, with more severe consequences.
HSSC: Is it known why this side effect is occurring?
SC: The exact mechanism underlying this connection of pericardial effusions to sotatercept therapy is unclear. We do not think it is due to the normal reasons why PAH patients develop disease, because most of these patients had improvements in heart and lung pressures.
We wonder if effusions could be specific to the mechanism by which this drug works—called an “on-target” effect, meaning that activin signaling simultaneously could control why the pressures get better and why these effusions develop.
There are a number of unknowns, mainly why some but not all patients develop this condition. It could be dose-dependent, or it could be related to other diseases that PAH patients have. For example, many of these cases were seen in PAH patients with autoimmune disease. Many cases also developed in patients being simultaneously treated with prostacyclin drugs, meaning drug interactions that have not been defined could be driving the condition.
HSSC: How will this report help patients?
SC: These findings are directly important to PAH patients being treated or considering treatment with sotatercept. We are very enthusiastic about the positive benefits that sotatercept could bring to our patients. But, this evolving clinical scenario calls for heightened vigilance for how we use this drug as well as for timely intervention from treating clinicians. Further research will be essential to determine if this drug is directly responsible for these pericardial effusions and to better define the mechanism and risk factors for this condition. Our comprehensive PH program is a Pulmonary Hypertension Association (PHA) accredited Center of Comprehensive Care and is at the forefront of this work and disease management.
Media contact: HSNews@pitt.edu