Pericardial Effusion and Prostacyclin Analog Toxicity After Initiation of Sotatercept

ABSTRACT

Pulmonary arterial hypertension (PAH) is a disorder characterized by progressive remodeling of small pulmonary arteries, leading to increased pulmonary vascular resistance, right ventricular failure and premature death (1‐2). Over the past 30 years, significant advancements have been made in the treatment of PAH, including the recent approval of sotatercept, a first‐in‐class fusion protein that acts as a ligand trap for activins and growth differentiation factors, which are key players in the transforming growth factor β (TGF‐β) superfamily (3‐4). Sotatercept improves exercise capacity, as assessed by 6‐min walk distance and World Health Organization (WHO) functional class, reduces pulmonary vascular resistance and NT‐pro brain natriuretic peptide, and improves the simplified French risk score while extending the time to death or nonfatal clinical worsening (3). The 7th World Symposium in pulmonary hypertension recommends the addition of sotatercept as an option in PAH patients who have not achieved low risk despite combination therapy with at least an endothelin receptor antagonist and phosphodiesterase type‐5 inhibitor, in intermediate or high‐risk patients. The STELLAR study of sotatercept in PAH patients demonstrated the efficacy of this medication in patients receiving background therapy (3). In fact, 34% of the patients were on double and 60% of the patients on triple therapy. Interestingly 40% were on prostacyclin infusion therapy (3). Post‐hoc analysis of the stellar study showed a beneficial effect for those on double or triple background PAH therapy as well as those receiving prostacyclin infusion at baseline (1,5). It remains unclear if the addition of sotatercept to other PAH treatments may have unexpected complications. It is possible that by rebalancing the proliferative/antiproliferative effects in the pulmonary circulation, the effect of other treatments for PAH may become excessive, particularly when parenteral prostacyclin is used at high doses. This phenomenon may manifest with the typical characteristics of prostacyclin overdose, including enhanced side effects and high cardiac output heart failure. Hereby we describe a patient with PAH on triple PAH‐specific therapy, who after the initiation of sotatercept developed a large pericardial effusion and high cardiac output heart failure.

Abbreviation

ActRIIA‐Fc

activin receptor type IIA‐Fc

BMPR‐II

bone morphogenetic protein receptor type II

cAMP

cyclic AMP

CI

cardiac index

CTGF

connective tissue growth factor

ERA

endothelin receptor antagonist

GDFs

growth differentiation factors

IV

intravenous

MAP Kinase

mitogen‐activated protein kinase

NO

nitric oxide

PAH

pulmonary arterial hypertension

PASMCs

pulmonary artery smooth muscle cells

PCOP

pulmonary artery occlusion pressure

PDE5i

phosphodiesterase 5 inhibitor

PH

pulmonary hypertension

PKA

protein Kinase A

PTGIR

prostacyclin receptor

PVR

pulmonary vascular resistance

RHC

right heart catheterization

SMAD

mothers against decapentaplegic homolog

TGF‐β

transforming growth factor beta

WU

wood Unit

1. Background

Pulmonary arterial hypertension (PAH) is a disorder characterized by progressive remodeling of small pulmonary arteries, leading to increased pulmonary vascular resistance (PVR), right ventricular failure and premature death [1, 2].

Over the past 30 years, significant advancements have been made in the treatment of PAH including the recent approval of sotatercept, a first‐in‐class fusion protein that acts as a ligand trap for activins and growth differentiation factors, which are key players in the transforming growth factor β (TGF‐β) superfamily [3, 4]. Sotatercept improves exercise capacity, as assessed by 6‐min walk distance and World Health Organization (WHO) functional class, reduces PVR and NT‐pro brain natriuretic peptide, and improves the simplified French risk score while extending the time to death or nonfatal clinical worsening [3].

The 7th World Symposium in pulmonary hypertension recommends the addition of sotatercept as an option in PAH patients who have not achieved low risk despite combination therapy with at least an endothelin receptor antagonist and phosphodiesterase type‐5 inhibitor, in intermediate or high‐risk patients. The STELLAR study of sotatercept in PAH patients demonstrated the efficacy of this medication in patients receiving background therapy [3]. In fact, 34% of the patients were on double and 60% of the patients on triple therapy. Interestingly 40% were on prostacyclin infusion therapy [3]. Post‐hoc analysis of the stellar study showed a beneficial effect for those on double or triple background PAH therapy as well as those receiving prostacyclin infusion at baseline [1, 5].

It remains unclear if the addition of sotatercept to other PAH treatments may have unexpected complications. It is possible that by rebalancing the proliferative/antiproliferative effects in the pulmonary circulation, the effect of other treatments for PAH may become excessive, particularly when parenteral prostacyclin is used at high doses. This phenomenon may manifest with the typical characteristics of prostacyclin overdose, including enhanced side effects and high cardiac output heart failure. Hereby, we describe a patient with PAH on triple PAH‐specific therapy, who after the initiation of sotatercept developed a large pericardial effusion and high cardiac output heart failure.

2. Case

A 71‐year‐old woman with idiopathic PAH, diagnosed approximately two decades ago, had been receiving triple triple PAH‐specific therapy consisting of intravenous (IV) treprostinil, oral tadalafil and macitentan. Over these decades, her dose of treprostinil was gradually increased to 242 ng/kg/min given persistent symptoms and an intermediate‐high risk status. A right heart catheterization (RHC) showed a persistently elevated PVR at 7.2 Wood Unit (WU), with a cardiac index (CI) by thermodilution of 3.6 L/min/m². Given that the risk score continued to be inadequate, she was started on sotatercept SQ 0.7 mg every 3 weeks.

Approximately 6 months after initiating sotatercept, the patient developed worsening dyspnea along with fatigue, flushing, headache, nausea, vomiting, diarrhea and weight loss (8 kg in the previous 3 months). She presented as a WHO functional class IV. Interestingly, she reported that 2 weeks before admission, her IV pump had malfunctioned for approximately 4 h during which she experienced significant symptom relief and improvement in exercise capacity. An outpatient follow‐up echocardiogram showed a dilated right ventricle (RV) with moderate hypertrophy and moderately reduced RV function, which remained stable compared to prior studies (Figure 1). However, there was a significant increase in pericardial effusion measuring 2.9 cm adjacent to left ventricle, 1.4 cm at the right atrium and 1.6 cm adjacent to the right ventricle. This represented a marked progression from an echocardiogram done 6 months prior, which showed a small to moderate pericardial effusion measuring 1.5 cm adjacent to the left ventricle and 0.7 cm adjacent to the right atrium and the right ventricle. The right ventricular systolic pressure, degree of tricuspid regurgitation and tricuspid regurgitation jet velocity were stable on both exams. In the clinic she had a resting blood pressure of 89/43 mmHg and heart rate of 118 beats per minute. Taken together, this prompted admission to the medical intensive care unit. On admission, a repeat RHC which revealed RAP 13 mmHg, mPAP 57 mmHg, PCWP 23 mmHg, PVR of 5.07 WU, and a CI of 4.13 L/min/m². Treprostinil overdose was suspected, and tamponade physiology was excluded (Table 1).

Figure 1.

Echocardiogram images demonstrate pericardial effusion size before and after starting sotatercept.

Table 1.

Clinical, echocardiographic and hemodynamic parameters before and during treatment with sotatercept.

Variables	Before sotatercept	Six months after sotatercept before admission	Six months after sotatercept a week after admission	Seven months after sotatercept before admission	Seven months after sotatercept a week after admission
PAH treatment at the time of RHC
‐Tadalafil	40 mg/day	40 mg/day	40 mg/day	40 mg/day	40 mg/day
‐Macitentan	10 mg/day	10 mg/day	10 mg/day	10 mg/day	10 mg/day
‐Treprostinil IV	214 ng/kg/min	242 ng/kg/min	50 ng/kg/min	58 ng/kg/min	43 ng/kg/min
Dyspnea WHO	II	IV	III	IV	II
NT pro BNP (pg/mL)	490	1,472	1,173	3,063	447
Echocardiogram around the time of RHC
‐RV function	Moderately reduced	Mildly reduced	Mildly reduced	Mildly reduced
‐RV dilation	Moderate	Moderate	Normal size	Normal size
‐TAPSE (cm)	1.0	1.3	1.4	1.2
‐RVSP (mmHg)	75	65	65	86
‐Pericardial effusion	Small to moderate (1.5 cm)	Larger (2.9 cm)	No effusion	Moderate size (1.7 cm)
Right heart catheterization
‐RAP (mmHg)	12	13	11	13	12
‐mPAP (mmHg)	67	57	51	57	54
‐PAWP (mmHg)	21	23	17	20	18
‐CO (L/min)	6.4	6.7	6.2	7.7	4.9
‐CI (L/min/m2)	4.0	4.1	3.6	4.6	2.9
‐PVR (WU)	7.2	5.07	5.48	4.8	7.34

Note: Timeline of symptoms, hemodynamics and echo findings.

Our patient was closely monitored in the ICU with a pulmonary artery catheter and continuous hemodynamic assessment. When a small incremental decrease in treprostinil dose failed to produce a significant hemodynamic response, a more aggressive therapeutic approach was subsequently adopted. The treprostinil dose was decreased to 50 ng/kg/min with improvement of symptoms and without significant impact on the PVR, which remained at around 5 WU. The CI decreased to 3.6 L/min/m² (Table 1). The patient underwent pericardiocentesis of 200 mL of serosanguineous exudate with negative cytology and microbiology studies. This procedure was complicated by a left hemo‐pneumothorax and vasoplegia that required vasopressors. Over the course of the next week, she experienced significant clinical improvement and was discharged home with planned follow‐up in the PH clinic.

Two weeks after discharge the patient contacted her provider reporting new and significant lower extremity edema. She requested to increase her treprostinil, and therefore it was increased to 58 ng/kg/min. After this increase, the patient developed worsening dyspnea and was readmitted with findings of heart failure, cardiorenal syndrome and worsening hypoxemia requiring high‐flow supplemental oxygen. An additional RHC showed stable PVR of 4.8 WU with a CI of 4.6 L/min/m² (Table 1), which was confirmed by direct Fick methodology. The patient was again admitted to the medical intensive care unit and treprostinil was reduced to 43 ng/kg/min, in addition to the initiation of intravenous diuresis with furosemide. With these changes, the PVR remained largely unchanged, but the CI decreased to 2.9 L/min/m² and the patient's symptoms markedly improved and oxygen requirement returned to her baseline 2 L. She was discharged with IV treprostinil at a dose of 43 ng/kg/min plus the continuation of tadalafil, macitentan and sotatercept. One month after discharge, the patient was at intermediate‐low risk, with continued improvement in symptoms, exercise capacity and overall energy level. There was resolution of her lower extremity edema and normalization of her renal function.

3. Discussion

Current treatment pathways for PAH include agents that target four signaling pathways: endothelin, nitric oxide, prostacyclin, and activin/BMP pathways [6]. In PAH, there is an imbalance between the bone morphogenetic protein receptor type II (BMPR‐II)–Smad1/5/8 pathway and the activin receptor type IIA (ActRIIA)–Smad2/3 pathway. The BMPR‐II–Smad1/5/8 pathway is downregulated, leading to increased production of activin ligands such as activin A, GDF8, and GDF11. These ligands upregulate the ActRIIA–Smad2/3 pathway, promoting pro‐proliferative and antiapoptotic signaling, which contributes to pulmonary vascular remodeling [3, 4].

The currently available treatment that targets the activin/BMP pathway is sotatercept. Sotatercept is a ligand trap for certain transforming growth factor beta (TGF‐β) superfamily members, rebalancing growth‐promoting and growth‐inhibiting signaling, by inhibiting cell proliferation and promoting apoptosis in the pulmonary vasculature [3, 4]. This effect leads to reverse remodeling of the pulmonary arteries, improving hemodynamics and exercise capacity in patients with PAH [3, 4].

Sotatercept has demonstrated significant efficacy in improving pulmonary hemodynamics, exercise capacity, and time to clinical worsening. In the phase 2 PULSAR trial, sotatercept significantly reduced PVR and improved 6‐min walk distance in patients receiving background PAH therapy [4]. These findings were further supported by the phase 3 STELLAR trial, which confirmed the benefits of sotatercept in combination with standard PAH therapies [3]. Based on these studies, sotatercept received FDA approval on March 26, 2024. This medication is currently used in patients that do not achieve a low‐risk status on background PAH‐specific therapies, as suggested by the 7th World symposium in PH [7].

An open‐label study (SOTERIA) [1] evaluating long‐term safety, tolerability, and efficacy of sotatercept in patients who completed a prior sotatercept study was recently published. In this extension study, 286 out of 426 (67%) patients received prostacyclin therapy. Over the course of the study, during which the mean (standard deviation) of sotatercept exposure was 449 (173) days, 23 patients (5.4%) had a ≥ 10% reduction in prostacyclin dose, while 17 patients (4%) had a ≥ 10% dose increase [1]. A total of 163 patients (38%) were receiving parenteral prostacyclin therapy; among them, 15 patients (3.5%) were able to discontinue parenteral prostacyclin, and a smaller proportion (1.8%) transitioned to oral or inhaled formulations. Unfortunately, the SOTERIA study did not provide detailed information on the characteristics or clinical course of patients who successfully weaned off or significantly reduced parenteral prostacyclin therapy.

A post hoc analysis of the hemodynamic data for sotatercept revealed no significant increase in cardiac output, despite a marked reduction in PVR. While a decrease in PVR would be expected to result in an increase in cardiac output from a physiological and mathematical standpoint, the sotatercept studies did not demonstrate this, for reasons that remain unclear. This lack of correlation weakens the argument that the observed reduction in PVR directly accounts for the increase in cardiac output in our patient—particularly given that the study did not exclude patients receiving high doses of parenteral prostacyclin analogs (PCAs). These findings prompted us to consider alternative mechanisms to explain the observed outcomes.

Little is known about a potential interaction between the activin/BMP and the prostacyclin pathways; and how treatments that target one of them may affect the other. For instance, prostacyclin analogs, such as treprostinil and epoprostenol, have been shown to inhibit TGF‐β signaling. This inhibition occurs through the reduction of phosphorylation of SMAD2/3 and p38 MAP kinase, which are key mediators of TGF‐β signaling. This effect is mediated via a protein kinase A (PKA)‐dependent pathway, which is activated by increased cAMP levels [8, 9] (Figure 2).

Figure 2.

Model of crosstalk between the activin/BMP and prostacyclin pathways. (A) Under normal conditions, BMPR2 and activin signaling are balanced by the competition for SMAD4. Prostacyclin signaling activates PKA, which has been shown to inhibit activin pathway signaling by reducing SMAD2/3 phosphorylation. (B) In PAH, reduced BMPR2 signaling decreases SMAD1/5/8 phosphorylation while increasing phosphorylated SMAD2/3–SMAD4 activation. This imbalance promotes proliferation and inhibits apoptosis. The condition is worsened by elevated plasma activin levels and reduced expression of prostacyclin receptor (PTGIR), and adenylyl cyclase (AC), leading to diminished PKA activation and weakened inhibition of SMAD2/3 signaling. (C) Sotatercept treatment sequesters activin and related ligands, reducing activin pathway signaling. This restores balance by decreasing proliferation and increasing expression of PTGIR, AC, and Gαs, enhancing prostacyclin signaling. However, in the presence of prostacyclin or its analog treprostinil, this enhanced signaling can cause augmentation of the prostacyclin effect, necessitating a reduction in treprostinil dosage.

El‐Haroun et al. showed that TGF‐β1, along with other inflammatory cytokines, like IL‐1β and bradykinin, impair cAMP generation in response to prostacyclin analogs in pulmonary artery smooth muscle cells (PASMCs). This impairment is mediated through the downregulation of adenylyl cyclase isoforms 1, 2, and 4, and the upregulation of Gαi protein levels [10, 11]. Additionally, TGF‐β1 reduces prostacyclin receptor (IP receptor) mRNA expression, further decreasing cAMP formation (Figure 2). This may play a role in the tachyphylaxis phenomenon where the effectiveness of prostacyclin diminishes over time with continuous use, necessitating dose increases to maintain therapeutic efficacy.

Clinical evidence indicates that patients on chronic prostacyclin therapy often require upward dose titration to counteract the development of tolerance as seen in our patient. This is supported by studies showing that long‐term administration of epoprostenol leads to significant reductions in PVR and improvements in symptoms, but to sustain these benefits, the dose of epoprostenol must be increased over time [12, 13]. The American Heart Association and American Thoracic Society guidelines also note that up titration of epoprostenol is often necessary to maintain optimal effects [14].

The mechanism by which sotatercept contributed to apparent treprostinil overdose and high output heart failure remains unclear. One straightforward explanation is that sotatercept‐induced reduction in PVR led to an increase in CO in the setting of background triple PAH‐specific therapy, including high‐dose IV treprostinil. This hemodynamic shift may have unmasked or exacerbated features of prostacyclin overdose. An alternative hypothesis involves the impact of sotatercept on signaling within the TGF‐ß superfamily. TGF‐ß signaling may contribute to the development of tachyphylaxis to prostacyclin over time. Thus, by suppressing TGF‐ß ligands, sotatercept may inadvertently reverse this adaptation, leading to enhanced sensitivity to treprostinil (prostacyclins) and amplification of its vasodilatory and systemic effects. Additionally, sotatercept may promote vascular remodeling or endothelial changes that increase prostacyclin (IP receptor) expression and responsiveness, further potentiating the pharmacodynamic effects of treprostinil (Figure 2). This combined impact both on hemodynamics and receptor sensitivity—could explain the profound clinical response consistent with prostacyclin overdose observed in our patient [15].

Several potential mechanisms may explain the development of pericardial effusion in patients treated with sotatercept. First, immune and inflammatory modulation may play a role, as activin‐A one of the ligands inhibited by sotatercept has demonstrated anti‐inflammatory and pro‐resolving properties, which is a characteristics of molecules that actively promote the resolution of inflammation. Its suppression may disrupt immune homeostasis and trigger inflammatory cascades, potentially leading to serositis, including pericardial inflammation, particularly in susceptible individuals [16]. Second, the TGF‐β/activin pathway is known to contribute to vascular integrity; its inhibition may increase capillary permeability, resulting in fluid accumulation within the pericardial space [4]. Third, by improving PVR, sotatercept alters right heart loading conditions [3]. In patients with borderline right ventricular function or pre‐existing subclinical pericardial inflammation, this hemodynamic shift could unmask or exacerbate pericardial effusion. Finally, as a systemic biologic agent, sotatercept may exert off‐target effects on non‐pulmonary tissues, especially in patients with long‐standing PAH and chronic immune or vascular dysregulation [17]. Together, these factors may contribute to pericardial fluid accumulation in a subset of patients. Interestingly, the SOTERIA study did not report the development of large pericardial effusion or the development of high cardiac output heart failure in patients started on sotatercept; however, this phenomenon may develop in certain cases, such as in subjects receiving high doses of parenteral treprostinil like in the case presented [1].

As patients with PAH age and develop comorbidities—such as left heart disease, metabolic syndrome, or systemic hypertension—a transition from isolated pre‐capillary PAH to a mixed or combined pre‐ and post‐capillary pulmonary hypertension (Cpc‐PH) phenotype can occur [18]. This shift may alter baseline hemodynamics and influence therapeutic responses, particularly to agents like sotatercept that substantially reduce PVR. In our patient, who was diagnosed with idiopathic PAH over 16 years ago, the initial hemodynamic profile was consistent with pure Group 1 PAH (mPAP 42 mmHg, PCWP 8 mmHg, CO 2.5 L/min, and PVR 13.4 WU). However, over time, her phenotype evolved toward a combined pre‐ and post‐capillary form, evidenced by a persistently elevated PCWP and a significantly increased transpulmonary gradient. This underlying transition may have contributed to the development of pericardial effusion and clinical decompensation after the addition of sotatercept, particularly in the context of high‐dose prostacyclin therapy. The evolving Cpc‐PH physiology may have made the patient more susceptible to fluid shifts, hemodynamic perturbations, and inflammatory responses—factors that, when coupled with enhanced prostacyclin sensitivity or sotatercept‐induced vascular changes, could precipitate the constellation of findings observed in this case. Thus, this case underscores the need for careful hemodynamic monitoring and phenotype reassessment in long‐standing PAH patients undergoing treatment intensification, particularly when introducing novel agents like sotatercept alongside high‐dose parenteral prostacyclins.

4. Conclusions

In conclusion, we report an underrecognized phenomenon of clinically significant pericardial effusion and prostacyclin overdose in the setting of sotatercept treatment. Several mechanisms may explain this effect, but the specific origins require further investigation.

Author Contributions

Dany Tager: Participated in writing and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. Leora Haber: Participated in writing and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. Kulwant S. Aulak: Participated in writing, figure creating and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. Kristin Highland: Participated in writing and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. Adriano R. Tonelli: Participated in writing and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted.

Ethics Statement

The corresponding author confirms that all co‐authors have approved the submission and publication of the manuscript. All the patient's personal information has been removed to comply with HIPAA standards. The patient has provided written informed consent for the publication of their case details and any accompanying images. The work is original and has not been published elsewhere, nor is it under consideration for publication in another journal. All individuals who qualify for authorship have been listed as authors, and each has made a significant contribution to the work. No one who qualifies for authorship has been omitted. All potential conflicts of interest, both financial and nonfinancial, have been disclosed below. The authors have ensured that all data and materials are accurately represented, and that any material derived from prior work is properly cited.

Conflicts of Interest

ART participated in advisory boards of Jansen and Merck. KBH has grants/contracts, sits on a steering committee or advisory board, does consulting and/or is on the Speaker's Bureau for Atyr pharmaceuticals, Boehringer Ingelheim, Forsee Pharmaceuticas, Gossamer Bio, Johnson & Johnson (Jansen), Merk Sharp Dohme, Mitsubishi and United Therapeutics. The rest of the authors declare no relevant financial conflicts of interest.