Current and future prospects in treatment of pulmonary hypertension

In recent years, great progress has been made in understanding the cellular and molecular mechanisms driving pulmonary vascular remodeling in various forms of pulmonary hypertension (PH), including pulmonary arterial hypertension (PAH), pulmonary hypertension associated with left heart disease, pulmonary hypertension associated with chronic disease lungs and hypoxemia, and chronic thromboembolic pulmonary hypertension. Nevertheless, survival rates for all these forms of PH remain unsatisfactory, highlighting the crucial need to implement innovative scientific knowledge more effectively into existing therapeutic protocols. The results of translational research on the potential of new therapeutic strategies reveal the importance of gender and the interaction of genetic polymorphism with environmental factors, showing a higher prevalence of PH in women, with a ratio ranging from 2.3:1 in PAH to 9:1 in PH-related to connective tissue diseases. Furthermore, the penetrance of PAH-related mutations is higher in women at 42% compared to 14% in men. This relationship is consistent with incidence rates found in prospective follow-up studies of asymptomatic gene bone morphogenetic protein receptor type 2 (BMPR2) mutation carriers, revealing an incidence of 0.99% per year in men and 3.5% per year in women. However, the prognosis for men diagnosed with PAH is less favorable, primarily due to variations in the adaptation of the right ventricle to afterload. What appears to be significantly evident is that estrogens play a dual role in PAH, exerting local effects that trigger pulmonary vascular remodeling, contributing to the intensity of PAH while simultaneously offering systemic protection and improving right ventricular adaptation. On the other hand, newly discovered genes associated with PAH have been shown to interact with estrogens and molecular agents derived from sex chromosomes, including long non-coding RNA of the X chromosome and the sex-determining region I gene on chromosome I, causing phenotypic sex differences. In light of new therapeutic strategies, there is a critical need to expand the existing range of biomarkers of PH activity. This expansion could enable a more personalized and effective approach to treatment. Moreover, it is crucial to better understand the mechanisms of action of new PAH therapies, with activin signaling inhibitors at the forefront, but they should also be evaluated in other forms of PH. Particular attention should be paid to potential side effects of therapy in patients with PAH who are already at increased risk of epistaxis and telangiectasia, such as those carrying ACVRL1, BMP10, GDF2, and ENG mutations. Alternative models and animal studies are crucial in unraveling these aspects, highlighting the imperative need to strengthen their relevance. Therapeutic improvements can be implemented by including the randomization of animals, considering both sexes and introducing blinded protocols for observations related to hemodynamic and structural endpoints of the final effect. Implementing preclinical findings into the clinical setting presents a unique challenge for a rare, complex, and multifactorial disease such as PH. Through this approach, we can improve treatment approaches, quality of life, and potentially reverse or stop the progression of this destructive disease.