Samrudhi Mishra

Background:  Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by elevated pulmonary arterial pressure, pulmonary vascular remodeling, and eventual right ventricular failure. Current therapeutic strategies primarily target vasoconstriction through pharmacologic vasodilators; however, these treatments fail to reverse disease progression or adequately address the inflammatory and immune-mediated mechanisms involved in PH pathogenesis.^1,2 Recent research has identified the spleen as a key regulator of systemic inflammatory signaling, leading to growing interest in noninvasive neuromodulatory therapies that target neuroimmune pathways.³ Focused ultrasound stimulation of the spleen (sFUS) has emerged as a potential therapeutic modality capable of modulating inflammatory responses without significant systemic side effects.^3,4

Objective:  This narrative review explores the therapeutic potential of ultrasound neuromodulation of splenic anti-inflammatory pathways as a future noninvasive treatment strategy for pulmonary arterial hypertension and other inflammatory disease processes.

Methods:  A literature review was conducted using PubMed and peer-reviewed journal databases. Search terms included “pulmonary hypertension,” “focused ultrasound,” “ultrasound neuromodulation,” “splenic stimulation,” “anti-inflammatory pathway,” “pulmonary vascular remodeling,” and “neuroimmune modulation.” Primary emphasis was placed on preclinical and translational studies evaluating splenic focused ultrasound stimulation in pulmonary hypertension and systemic inflammatory disease models.

Results:  Studies demonstrated that sFUS significantly reduced right ventricular systolic pressure, pulmonary vascular remodeling, inflammatory cytokine expression, and right ventricular hypertrophy in monocrotaline and Sugen/hypoxia animal models of pulmonary hypertension.³ Therapeutic effects were abolished following splenic denervation, supporting the role of an intact splenic neuroimmune pathway.³ Additional studies in healthy human subjects showed that sFUS reduced lipopolysaccharide-induced tumor necrosis factor production without adverse clinical or hematologic effects, providing translational evidence for immune modulation in humans.⁴Other inflammatory disease models, including intra-abdominal sepsis, demonstrated prolonged survival and reduced systemic inflammation following splenic ultrasound stimulation.⁵ Furthermore, alternative nontraditional therapeutic approaches targeting inflammatory and remodeling pathways, such as mineralocorticoid receptor antagonism and Notch3-HES5 signaling modulation, have also demonstrated improvements in pulmonary vascular remodeling and pulmonary hypertension severity.^6,7 Collectively, these findings suggest that ultrasound neuromodulation may attenuate inflammatory signaling and vascular remodeling involved in pulmonary hypertension progression.

Conclusion:  Focused ultrasound neuromodulation represents a promising noninvasive therapeutic strategy that extends beyond traditional vasodilatory treatment approaches in pulmonary hypertension. By targeting splenic neuroimmune pathways, sFUS may reduce inflammation, improve cardiopulmonary function, and potentially modify disease progression without systemic adverse effects associated with pharmacologic therapies. Further clinical studies are needed to evaluate long-term safety, therapeutic efficacy, and broader applications of ultrasound neuromodulation in pulmonary hypertension and other inflammatory disorders.

Works Cited

1. Johnson S, Sommer N, Cox‐Flaherty K, Weißmann N, Ventetuolo CE, Maron BA. Pulmonary Hypertension: A Contemporary Review. Am J Respir Crit Care Med. 2023;208(5):528-548. doi:https://doi.org/10.1164/rccm.202302-0327SO
2. Estrada RA, Sahay S, Tonelli AR. Treatment of pulmonary hypertension after seven world symposia. Ther Adv Respir Dis. 2025;19. doi:https://doi.org/10.1177/17534666251342898
3. Zafeiropoulos S, Ahmed U, Bekiaridou A, et al. Ultrasound neuromodulation of an anti-inflammatory pathway at the spleen improves experimental pulmonary hypertension. Circ Res. 2024;135(1):41-56. doi:https://doi.org/10.1161/CIRCRESAHA.123.323679
4. Zanos S, Ntiloudi D, Pellerito J, et al. Focused ultrasound neuromodulation of the spleen activates an anti-inflammatory response in humans. Brain Stimul. 2023;16(3):703-711. doi:10.1016/j.brs.2023.04.003
5. Zhang A, Charles EJ, Xing J, Sawyer RG, Yang Z. Pulsed ultrasound of the spleen prolongs survival of rats with severe intra-abdominal sepsis. J Surg Res. 2021;259:97-105. doi:10.1016/j.jss.2020.11.005
6. Tu L, Thuillet R, Perrot J, et al. Mineralocorticoid receptor antagonism by Finerenone attenuates established pulmonary hypertension in rats. Hypertension. 2022;79(10):2262-2273. doi:10.1161/HYPERTENSIONAHA.122.19207
7. Chen X, Zhou W, Hu Q, Huang L. Exploration of the Notch3-HES5 signal pathway in monocrotaline-induced pulmonary hypertension using rat model. Congenit Heart Dis. 2019;14(3):396-402. doi:10.1111/chd.12733