Pathophysiology and the clinical relevance of pulmonary remodeling in pulmonary hypertension due to left heart diseases

Pulmonary hypertension (PH) in left heart disease (LHD), classified as Group II, is the most common form of PH that occurs in approximately 60% of cases of both reduced and preserved left ventricular ejection fraction. Although relatively much is known about hemodynamic stages (passive or reactive) and their consequences on the right ventricle (RV) there is no consensus yet on the best hemodynamic definition of Group II PH. In addition, the main pathways that lead to lung capillary injury and impaired biology of small arteries remodelling process are largely unknown. Typical lung manifestations of an increased pulmonary pressure and progressive right ventricular (RV)-pulmonary circulation uncoupling are an abnormal alveolar capillary gas diffusion, impaired lung mechanics (restriction) and exercise ventilation inefficiency. Out of several classes of pulmonary vasodilators currently clinically available, oral phosphodiesterase 5 inhibition, owing to its strong selectivity for targeting the cGMP pathway in the pulmonary circulation, is increasingly emerging as an attractive opportunity to reach hemodynamic benefits, reverse capillary injury and RV remodeling, and improve functional capacity. Guanylate cyclase stimulators offer an additional intriguing opportunity but the lack of selectivity and systemic effects may preclude some of the anticipated benefits on the pulmonary circulation. Future trials will determine whether new routes of pharmacologic strategy targeting aimed at targeting lung structural and vascular remodelling may effectively impact morbidity and mortality in LHD populations. We believe that this therapeutic goal rather than a pure hemodynamic effect may ultimately come out as an important challenge for the clinician.