Beyond the Heart‐Lung Axis: A Review of the Crosstalk Between the Hemodynamic, Neurohormonal, and Immune Systems in Pulmonary Hypertension

Investigating systemic interactions involving interorgan crosstalk in pulmonary arterial hypertension (PAH) may elucidate the underlying mechanisms that drive pathogenic processes. Further understanding of the disease process through communication pathways at the broader physiological level can inform advancements in novel therapeutic approaches. This article is a comprehensive summary of our current knowledge surrounding the heart‐lung axis in PAH as well as systemic pathophysiological contributions and their methods of communication through neurohormonal, inflammatory, metabolic, and extracellular mediated pathways. Neurohormonal crosstalk encompasses the renin‐angiotensin‐aldosterone system (RAAS) and sympathetic nervous system (SNS), both of which modulate communication between the heart and lung. Inflammation, within the heart‐lung axis and at the systemic level, is characterized by cytokine signaling and chemokine recruitment. Extrapulmonary mediators of inflammation in PAH include the liver, chronic kidney disease (CKD), adipose tissue, insulin resistance, and bone marrow‐derived cells. Extracellular vesicles mediate proximal to distal communication pathways, spanning from localized crosstalk between the heart and lungs to peripheral interorgan signaling. Emerging studies have revealed broader physiological contributions across multiple organ systems in PAH pathogenesis, such as pulmonary vascular remodeling and endothelial cell dysfunction, suggesting systemic interorgan crosstalk with the heart and lungs influences the disease phenotype.