Perspective: pathobiological paradigms in pulmonary hypertension, time for reappraisal.

For the past 120 years, there has been a progressive evolution of the pathobiological concepts underlying pulmonary hypertension. Conceptual frameworks, build around the paradigms of excessive vasoconstriction (vs. vasodilation) and, more recently, of the cancer-like hypothesis of pulmonary hypertension, have served to consolidate key discoveries; moreover, they have and continue contributing to innovative advances that have been translated into either successful or potential new therapies. However, those frameworks do not fully address the complexity and challenges facing pulmonary hypertension, particularly those involving the marked heterogeneity of disease presentation and the dynamic changes occurring over time in affected tissues and cells. This is particularly relevant in regards to the molecular pathways of pulmonary hypertension; the ever growing understanding of molecular and cellular pathways requires clarification if they drive distinctive pulmonary vascular lesions in a given lung and disease patients with the same group pulmonary hypertension. Novel methodologies and approaches can start dissecting this key challenge in the field as it is critical to address the key angle of heterogeneity of the disease and reappraisal of disease-modifying therapies.