Inflammatory Basis of Pulmonary Arterial Hypertension

Implications for Perioperative and Critical Care Medicine

Neil M. Goldenberg, M.D., Ph.D.; Marlene Rabinovitch, M.D.; Benjamin E. Steinberg, M.D., Ph.D.


Anesthesiology. 2019;131(4):898-907. 

In This Article

Abstract and Introduction


Pulmonary hypertension, defined as a resting mean pulmonary artery pressure greater than or equal to 25 mmHg, results from a myriad of conditions. The Fifth World Symposium on Pulmonary Hypertension proposed a classification system that organizes pulmonary hypertension into five groups based on common hemodynamic, pathophysiologic, and therapeutic parameters.[1] This review focuses on pulmonary arterial hypertension (Group 1 pulmonary hypertension), a disease in which progressive pulmonary vascular obstruction, remodeling, and destruction lead to increased right ventricular afterload and hypertrophy, right heart failure, and death. On a cellular level, the dysregulated proliferation of endothelial, smooth muscle, and immune cells predominates within the diseased vessels.[2] Hemodynamically, pulmonary arterial hypertension can be defined as a mean pulmonary artery pressure greater than 25 mmHg, a pulmonary capillary wedge pressure less than 15 mmHg, and a pulmonary vascular resistance (PVR) greater than 3 Wood units in the absence of a more common cause such as left heart disease, chronic venothromboembolic disease, or lung disease. Like pulmonary hypertension in general, pulmonary arterial hypertension can result from multiple causes, including infectious and autoimmune pathologies. In this review, our focus will be on pulmonary arterial hypertension specifically (World Health Organization Group 1), predominantly comprising idiopathic and heritable pulmonary arterial hypertension, as well as pulmonary arterial hypertension associated with connective tissue disease, congenital heart disease, or other systemic conditions.

Major pulmonary hypertension clinical registries report pulmonary arterial hypertension incidence rates between 1.1 to 7.6 cases of pulmonary arterial hypertension per million adults per year with a prevalence ranging from 11 to 26 cases per million adults.[2] The disease demonstrates a gender bias, occurring four times more frequently in women, but with worse survival in male patients.[3] Although pulmonary arterial hypertension is a relatively rare disease, it has a grim prognosis with mortality 5 yr after diagnosis as high as 60%.[1] However, the preceding decades have seen significant improvement in the survival of patients with pulmonary arterial hypertension,[4] likely attributable to a combination of increased awareness, improved management of right heart failure, and access to pulmonary arterial hypertension therapies and anticoagulation. As a result, patients with pulmonary arterial hypertension are increasingly presenting for noncardiac surgery.

Pulmonary arterial hypertension remains an indolent, progressive disease without a cure. Current therapies delay clinical worsening and improve quality of life, but generally have not been shown to decrease mortality. Therapeutic approaches include both supportive and disease-specific measures. Supportive measures include salt and fluid restriction, supplemental oxygen to maintain systemic arterial oxygen saturation greater than 90%,[5] exercise training, and consideration of diuretics for venous congestion attributable to right heart failure. In some patients, anticoagulation with warfarin is prescribed to mitigate thrombosis in resistance pulmonary arteries; however, its benefit appears contingent on the underlying type and cause of pulmonary arterial hypertension.[6] The role of new oral anticoagulants remains unknown.

Current pulmonary arterial hypertension therapies work through dilating the pulmonary vasculature, and thereby offset the elevated right ventricular afterload. These temporizing measures may neglect the underlying mechanism of disease pathogenesis, and new approaches are wanting. To that end, pulmonary arterial hypertension has more recently been associated with dysregulated and aberrant inflammation independent of the underlying cause.[7,8] In this narrative review, we delineate the immunologic basis of pulmonary arterial hypertension, highlighting biomedical and clinical evidence, and review ongoing clinical trials targeting the immune system in pulmonary arterial hypertension, as well as potential immunomodulatory therapeutic strategies for future study. Throughout, we emphasize the implications for perioperative and critical care specialists, beginning with a discussion of the perioperative management of patients with pulmonary arterial hypertension.