Wesley Garza

Background: Pulmonary hypertension (PH) is a broad syndrome defined by a mean pulmonary arterial pressure >20 mmHg.¹ Regardless of subtype, mortality rates remain unacceptably high despite current treatments.² PH poses significant risks during surgical procedures, particularly with general anesthesia.^3,4 The etiology is unclear but includes genetic factors, associations with thrombophilia or other disease states in chronic thromboembolic PH (CTEPH), and heart and lung conditions such as CHF or COPD. Pathogenesis involves endothelial dysfunction, vascular remodeling, and inflammation.^{2, 5, 6} PH presents with nonspecific respiratory symptoms such as dyspnea, fatigue, or chest pain, and signs of increased right heart pressure such as edema, ascites, JVD, or tricuspid regurgitation. Diagnosis involves echocardiography and other cardiopulmonary imaging and can be confirmed by right heart catheterization.² From a surgical perspective, management is most successful with pulmonary endarterectomy in CTEPH. Other treatments may include balloon pulmonary angioplasty, atrial septostomy, or lung transplantation in severe cases.^{6, 7} Outside of CTEPH, patients are primarily medically managed.²

Objective: We explored emerging solutions to common problems in PH management, including understanding of disease mechanisms, novel procedural management, perioperative complications, and risk assessment.

Methods: A PubMed search from 2018-2024 was conducted using the keywords “pulmonary hypertension”, “anesthesia” “perioperative”, “pathogenesis”, and “REVEAL”.

Results: Research into pathogenesis revealed a link between a loss of function mutation of BMPR2 and an increase in ARRB2 resulting in aberrant proliferation and reduced contractility of pulmonary arterial smooth muscle cells. Silencing of ARRB2 was shown to prevent the development of pulmonary hypertension after a period of hypoxia in BMPR2 knockout mice.⁸ Considering management, vena cava backflow, a hallmark of PH, was shown to stem from right ventricular stiffening causing diastolic backflow. Because the major cause of death in PH patients is right heart failure, this stiffening is an area of prevention or repair to consider.⁹ New treatments are emerging to address the common disease source among all types of PH – the pulmonary arteries. Laser ablation has been shown to cause loss of S-100 expression in pulmonary arteries of sheep, suggesting denervation which may reduce vascular tone and arterial pressure.¹⁰ Considering perioperative management, reduced cardiac contractility with isoflurane and propofol was shown to stem from a loss of responsiveness to intracellular Ca²⁺ in myofibrils. With high concentrations of propofol, there is also a decrease in Ca²⁺ release from the sarcoplasmic reticulum.¹¹ Preoperatively, the REVEAL 2.0 calculator is used to stratify patient risk, but recent reports show abridged versions, such as the REVEAL Lite 2 calculator, may have comparable effectiveness in predicting patient survival.¹²

Conclusions: ARRB2 may be a promising biomarker and therapeutic target in PH. Preventing or repairing right ventricular stiffening may be an option to directly reduce heart failure and death in PH patients. Denervation procedures should be further researched and considered as a permanent solution in patients unresponsive to medical management. Therapies for perioperative complications may lie in targeting myofibrillar response to calcium or researching alternative anesthetic methods. Abridged calculators such as REVEAL Lite 2 may be invaluable tools when evaluating patient risk to dictate treatments.

Work Cited:

1. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. European Respiratory Journal. 2019;53(1):1801913. doi:10.1183/13993003.01913-2018
2. Mandras SA, Mehta HS, Vaidya A. Pulmonary Hypertension: A Brief Guide for Clinicians. Mayo Clinic Proceedings. 2020;95(9):1978-1988. doi:10.1016/j.mayocp.2020.04.039
3. Price LC, Martinez G, Brame A, et al. Perioperative management of patients with pulmonary hypertension undergoing non-cardiothoracic, non-obstetric surgery: a systematic review and expert consensus statement. British Journal of Anaesthesia. 2021;126(4):774-790. doi:10.1016/j.bja.2021.01.005
4. Smilowitz NR, Armanious A, Bangalore S, Ramakrishna H, Berger JS. Cardiovascular Outcomes of Patients With Pulmonary Hypertension Undergoing Noncardiac Surgery. The American Journal of Cardiology. 2019/05/01/ 2019;123(9):1532-1537. doi:https://doi.org/10.1016/j.amjcard.2019.02.006
5. Hassoun PM. Pulmonary Arterial Hypertension. New England Journal of Medicine. 2021;385(25):2361-2376. doi:10.1056/NEJMra2000348
6. Lang IM, Campean IA, Sadushi-Kolici R, Badr-Eslam R, Gerges C, Skoro-Sajer N. Chronic Thromboembolic Disease and Chronic Thromboembolic Pulmonary Hypertension. Clinics in Chest Medicine. 2021/03/01/ 2021;42(1):81-90. doi:https://doi.org/10.1016/j.ccm.2020.11.014
7. Xing C, Wang X, Pan X, et al. Outcomes of atrial septostomy and effect on long-term survival in patients with idiopathic pulmonary arterial hypertension: A single-center cohort. International Journal of Cardiology. 2023;373:118-123. doi:10.1016/j.ijcard.2022.12.002
8. Wang L, Moonen J-R, Cao A, et al. Dysregulated Smooth Muscle Cell BMPR2–ARRB2 Axis Causes Pulmonary Hypertension. Circulation Research. 2023;132(5):545-564. doi:10.1161/CIRCRESAHA.121.320541
9. Marcus JT, Westerhof BE, Groeneveldt JA, Bogaard HJ, Man FSd, Noordegraaf AV. Vena cava backflow and right ventricular stiffness in pulmonary arterial hypertension. European Respiratory Journal. 2019;54(4):1900625. doi:10.1183/13993003.00625-2019
10. Condori Leandro HI, Koshevaya EG, Mitrofanova LB, et al. An Ovine Model for Percutaneous Pulmonary Artery Laser Denervation: Perivascular Innervation and Ablation Lesion Characteristics. International Journal of Molecular Sciences. 2021;22(16):8788.
11. Meng T, Ren X, Chen X, et al. Anesthetic Agents Isoflurane and Propofol Decrease Maximal Ca(2+)-Activated Force and Thus Contractility in the Failing Myocardium. J Pharmacol Exp Ther. Dec 2019;371(3):615-623. doi:10.1124/jpet.119.259556
12. Benza RL, Kanwar MK, Raina A, et al. Development and Validation of an Abridged Version of the REVEAL 2.0 Risk Score Calculator, REVEAL Lite 2, for Use in Patients With Pulmonary Arterial Hypertension. Chest. Jan 2021;159(1):337-346. doi:10.1016/j.chest.2020.08.2069