Non-invasive Multimodality Cardiovascular Imaging of the Right Heart and Pulmonary Circulation in Pulmonary Hypertension

Sotatercept May Reduce All-cause Mortality In Pulmonary Arterial Hypertension Patients, Finds Research

A new study published in The New England Journal of Medicine showed that for high-risk patients with pulmonary arterial hypertension (PAH), adding sotatercept (Winrevair) to the therapy regimen helped postpone major complications.

Vascular remodeling is a major pathogenic aspect of the illness that is not immediately addressed by current therapies, which instead concentrate on vasodilation. A new experimental treatment, sotatercept is intended to address this underlying condition. The fusion protein called sotatercept binds to activin A and other transforming growth factor-beta (TGF-β) superfamily ligands and neutralizes them. The vascular remodeling that takes place in PAH is linked to this route. For individuals with WHO functional class II or III pulmonary arterial hypertension, sotatercept increases exercise capacity and postpones the onset of clinical deterioration.

In patients with developed pulmonary arterial hypertension and an elevated likelihood of mortality, the effects of add-on sotatercept are not well understood. Thus, this study by Marc Humbert and team evaluated the effectiveness of sotatercept in patients with pulmonary arterial hypertension.

The patients receiving the maximum tolerated dose of background therapy who had pulmonary arterial hypertension (WHO functional class III or IV) and a high 1-year risk of death (Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management Lite 2 risk score, ≥9) were randomly assigned to receive either a placebo or add-on sotatercept (elevated to target dose, 0.7 mg per kilogram) every three weeks. A time-to-first-event analysis was used to determine the primary end point, which was a composite of hospitalization (≥24 hours) for worsening pulmonary arterial hypertension, lung transplantation, and death from any cause.

There were 172 patients in all, 86 in each of the placebo and sotatercept groups. The effectiveness findings of a predetermined interim analysis led to the early termination of the experiment. 15 patients (17.4%) in the sotatercept group and 47 patients (54.7%) in the placebo group experienced at least one main end-point incident.

A total of 7 patients (8.1%) in the sotatercept group and 13 patients (15.1%) in the placebo group died; 1 patient (1.2%) and 6 patients (7.0%) received lung transplants; 8 patients (9.3%) and 43 patients (50.0%) were hospitalized due to worsening pulmonary arterial hypertension. Telangiectasia and epistaxis were the most frequent side effects of sotatercept.

Overall, sotatercept treatment reduced the risk of death, lung transplantation, and hospitalization (≥24 hours) for worsening pulmonary arterial hypertension in high-risk adults receiving the maximum tolerated dose of background therapy when compared to placebo.

Reference:

Humbert, M., McLaughlin, V. V., Badesch, D. B., Ghofrani, H. A., Gibbs, J. S. R., Gomberg-Maitland, M., Preston, I. R., Souza, R., Waxman, A. B., Moles, V. M., Savale, L., Vizza, C. D., Rosenkranz, S., Shi, Y., Miller, B., Mackenzie, H. S., Kim, S. S., Loureiro, M. J., Patel, M. J., … ZENITH Trial Investigators. (2025). Sotatercept in patients with pulmonary arterial hypertension at high risk for death. The New England Journal of Medicine. Https://doi.Org/10.1056/NEJMoa2415160

Role Of Right Atrial Reservoir Strain In Detecting Pulmonary Hypertension In Systemic Sclerosis

Photo Credit: daveberk

The following is a summary of "Right atrial reservoir strain as an early predictor of pulmonary hypertension development in Systemic Sclerosis: a single center pilot study," published in the April 2025 issue of Rheumatology by Codullo et al. 

Regular screening for pulmonary hypertension (PH) is essential in systemic sclerosis (SSc) for early pulmonary arterial hypertension (PAH) detection. Right atrial (RA) function may reflect early right heart overload from pulmonary pressure rise. 

Researchers conducted a retrospective study to assess RA reservoir strain as a marker of early right heart overload and predictor of PH in SSc. 

They enrolled 113 patients with SSc from May 2010 to April 2022 who underwent echocardiography, including systolic pulmonary artery pressure (PASP), the measurement of tricuspid annular plane systolic excursion (TAPSE), TAPSE/PASP, and RARs measurements. 

The results showed that during a median follow-up of 43 months, 11 patients underwent RHC and PH were confirmed in 10. RARs was the only independent predictor of PH (HR 0.85, 95% CI 0.75–0.96, P=0.01). The optimal RARs cut-off was 39.6 (AUC 0.7, P=0.04, sensitivity 70%, specificity 60%). 

Investigators found that RARs were a sensitive echocardiographic parameter to predict PH development in patients with SSc. 

Source: academic.Oup.Com/rheumatology/advance-article-abstract/doi/10.1093/rheumatology/keae628/8109436

Pulmonary Hypertension: When Cell Teamwork Turns Toxic

Cells rely on cues from their environment to develop and work properly. Yet this interdependence can turn perilous when one cell goes rogue, triggering an unchecked cascade of dysfunction. For decades, understanding these toxic cellular relationships has been hindered by a fundamental challenge: the inability to simultaneously study molecular details and tissue-wide interactions. Earlier studies often prioritized one scale at the expense of the other and, because of this, missed critical connections.

A striking biological example is the cellular interplay in pulmonary hypertension. This life-threatening disease, defined by an increased pressure in the blood vessels of the lungs, often ultimately leads to heart failure and death (Humbert et al., 2019). At its roots, pulmonary hypertension arises from the toxic interaction between multiple cell types compromising each other's normal function (Frid et al., 2020). Under healthy conditions, smooth muscle cells in the arteries of the lungs (known as PASMCs) contract and dilate, regulating flow and pressure in the lung vasculature. Their counterparts, the fibroblast cells that form the vessel's outer layer (or PAAFs), protect PASMCs and mediate communication between the two cell types (Stenmark et al., 2018).

In pulmonary hypertension, however, this partnership turns lethal. PAAFs start remodeling their external environment and secrete signals that cause PASMCs to lose their ability to contract, depriving them of their main function (Park et al., 2022). Instead, the PASMCs start stiffening, causing a cascade of irreversible vascular changes that represent a cornerstone in the development of pulmonary hypertension (Crnkovic et al., 2022).

With PAAFs and PASMCs at the forefront of this disease, many questions remain unanswered. What triggers PAAF activation? How do PASMCs lose their contractility? Is there an underlying shared mechanism linking PAAF and PASMC dysfunction? Crnkovic et al., 2022 Answering these questions could lead to new and more effective therapies for a number of deadly diseases.

Now, in eLife, Grazyna Kwapiszewska, Vinicio de Jesus Perez and colleagues at various research institutes in Austria, Germany and the United States – including Slaven Crnkovic and Helene Thekkekara Puthenparampi as joint first authors – report how PAAFs force PASMCs into a diseased state (Crnkovic et al., 2025).

Crnkovic et al. Isolated PAAFs and PASMCs from both healthy donors and pulmonary hypertension patients, comparing the gene activity and protein levels between these two groups. They found that diseased PAAFs produced more collagen, which stiffens tissues, while simultaneously underproducing laminin, a protein that provides structure for collagen deposition (Figure 1). This collagen-laminin imbalance created a rigid environment, similar to a building with too much concrete and not enough scaffolding. The mechanical stress from the stiffened matrix forced PASMCs to abandon their contractile function, a hallmark of their healthy state (Crnkovic et al., 2022).

Progression from healthy pulmonary artery adventitial fibroblasts (PAAFs) and pulmonary artery smooth muscle cells (PASMCs) to pulmonary hypertension (PH) phenotype.

In healthy arteries (left), PASMCs are dynamic cells that regulate flow and pressure in the lung vasculature by contracting and dilating, while the fibroblasts on the vessel's outer layer (PAAFs) protect PASMCs (green triangles). In pulmonary hypertension, PAAFs overproduce collagen and harmful proteins (red triangles) that cause PASMCs to become rigid. Imbalanced protein dynamics and mitochondrial dysfunction in both cell types further contribute to the diseased state (right). Created with BioRender.Com.

In a parallel mechanism, diseased PAAFs exacerbated dysfunction by overproducing harmful signals while downregulating protective proteins, thus reprogramming PASMCs into a dysregulated state. As dynamic cells require constant energy, PASMCs rely heavily on mitochondria, especially in times of added cellular stress (Qin et al., 2023). Given the central role of mitochondria in generating cellular energy, regulating harmful molecules, and maintaining an adequate intracellular balance – all of which are affected in pulmonary hypertension – Crnkovic et al. Investigated the mitochondria's role in reprogramming PAAFs and PASMCs (Chan et al., 2009).

Next, mitochondrial function was evaluated by measuring membrane potential, oxygen consumption and levels of harmful reactive species, which linked the observed mitochondrial compromise to subsequent DNA damage. This analysis revealed that mitochondrial dysregulation occurred when both cell types transitioned to a diseased state. Mitochondria are crucial in protecting the cell's DNA by neutralizing harmful molecules, especially in diseased states. However, because the mitochondria were damaged, the DNA suffered additional stress, worsening cellular injury.

In pulmonary hypertension, microenvironment stiffness and mitochondrial dysfunction are two sides of the same coin. The rigid environment forces PASMCs into a state of mechanical stress, overloading their mitochondria. In turn, dysfunctional mitochondria, while unable to protect the DNA, also leak harmful molecules, worsening cellular remodeling. This vicious cycle, where mechanics and metabolism unite, traps the cells in a diseased state leading to irreversible vascular damage. By uncovering these pathways, Crnkovic et al. Revealed that targeting PAAF signaling has the potential to reverse PASMC dysfunction in pulmonary hypertension. Halting toxic crosstalk and mitochondrial damage could thus reverse vascular stiffening, a potential therapeutic breakthrough for this disease.

While this study advances our understanding of pulmonary hypertension, certain limitations must be acknowledged. First, by focusing only on samples from patients with an established disease, early markers of disease triggers remain unexplored (Stacher et al., 2012). Second, the study only focused on PASMCs and PAAFs, potentially excluding other significant but understudied cell types in the progression of the condition (El Kasmi et al., 2014). Third, the origin of the reported mitochondrial dysfunction, whether a cause or a consequence of pulmonary hypertension, remains unclear.

By evaluating the interplay between different cell types while pinpointing precise genetic targets, Crnkovic et al. Highlight the transformative potential and inherent challenges of studying genes and protein profiles in pulmonary hypertension. Leveraging this approach in future work, researchers may be able to shed light on pulmonary hypertension's full story and provide a therapeutic road map to restore healthy cell states for a disease with no current cure.

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