Ultrasound neuromodulation of an anti-inflammatory pathway at the spleen improves experimental pulmonary hypertension

The study by Zafeiropoulos and colleagues on neuromodulation in experimental pulmonary hypertension presents groundbreaking findings that shed new light on the pathogenesis of this condition and offer potential therapeutic avenues for exploration.

The study's first notable contribution is its identification of the involvement of splenic innervation in the pathogenesis of pulmonary hypertension. Through the utilization of focused ultrasound, a noninvasive, widely available modality, the researchers targeted the spleen and successfully activated the splenic nerve, leading to the suppression of inflammation in a pulmonary hypertension model. Notably, focused ultrasound of the spleen (sFUS) achieved the normalization of immune cell populations, resulting in a less severe inflammatory environment within the lungs.

The study also reported remarkable reductions of 25-30% in right ventricular systolic pressure compared to sham-stimulation. Moreover, clinically relevant endpoints, including B-type natriuretic peptide, tricuspid annular plane systolic excursion, right ventricular free wall thickness, and autonomic function indices, showed significant improvements. Morphometric and histological analyses of lung and heart tissue further demonstrated a reduction in vascular remodelling, including apoptosis and proliferation, immune cell infiltration, and fibrosis.

Of particular interest, the study revealed a dose-dependent effect and a sustained benefit of sFUS even after treatment discontinuation, suggesting a potentially disease-modifying effect rather than a temporary one. Additionally, single-cell RNA-sequencing analysis of lung tissue highlighted the downregulation of various inflammation-related genes and pathways, showing overlap with established human pulmonary arterial hypertension (PAH)-associated genes and pathways.

While these findings are undoubtedly impressive, several crucial questions must be addressed to facilitate the clinical translation of this study. Determining the optimal dosage, frequency, and duration of sFUS treatment is imperative. Additionally, identifying the feasibility of delivering this treatment via portable devices within patients' homes or in outpatient healthcare settings is essential.

The success of Sotatercept in restoring the balance between pro-proliferative and anti-proliferative signaling has paved the way for novel therapeutic pathways in the treatment of PAH. It is our hope that in the future, sFUS may serve as an adjunctive anti-inflammatory treatment, supplementing PAH-specific therapies.

In conclusion, Zafeiropoulos and colleagues' study significantly contributes to our understanding of pulmonary hypertension pathogenesis and introduces the potential of neuromodulation as a therapeutic approach. Further investigation is warranted to address the remaining questions and uncover the full clinical potential of this exciting treatment modality.