Every year, the American Thoracic Society (ATS) organizes a conference in which ideas are exchanged and the latest research developments in the field of respiratory medicine are presented. Despite coronavirus disease 2019 (COVID-19) restrictions, the 2020 conference went ahead virtually and was, by all accounts, a major success.
Medical conferences such as these, besides allowing participants to broaden their network, allow key stakeholders in respiratory medicine to be informed about promising new developments in clinical research that may soon change how patients are diagnosed and treated. Inevitably, some clinical trials are more promising than others, and some will fail. However, medical conferences allow participants to at least be aware of where the world of medical research is heading, as well as the kind of therapeutics that are under investigation.
A group of North American researchers selected 11 of the best abstracts on pulmonary circulation and the current challenges in treating pulmonary arterial hypertension (PAH) from the 2020 ATS conference. Their review, published in Pulmonary Circulation, will form the basis of this article. We will particularly be focusing on new research regarding right ventricular failure in PAH.
Why the Right Ventricle Fails
The authors of the study started by providing a rather thorough definition of PAH that deserves mention: “Pulmonary arterial hypertension specifically refers to disease processes, which result in vasoconstriction and stiffening of the small arteries in the lungs secondary to cell proliferation, fibrosis, as well as the development of in situ thrombi or plexiform lesions.” From this definition, it is clear that a simple aberration in normal pulmonary anatomy—the remodeling of the pulmonary vasculature—triggers a cascade of pathologies that eventually results in death if left untreated.
Researchers have known the value of right ventricular function as a prognostic indicator in PAH for a long time. However, at present, there are no drugs that specifically target right ventricular function. In addition, the right ventricle usually starts adapting to changes caused by PAH, but at some point, those adaptations fail and right ventricular failure occurs.
Read more about PAH diagnosis
How the right ventricle goes from a compensated state to a decompensated one is still poorly understood. The good news is that this is precisely what clinical researchers are trying to understand. The current questions the research community is asking are: What are the pathophysiological changes that occur in PAH-associated right ventricular failure, and can they be stopped or even reversed?
Let’s revise what usually happens in the right ventricle under normal circumstances. It derives 60% to 90% of its energy requirements from fatty acid oxidation; the remaining 10% to 40% is obtained from glucose oxidation and glycolysis. The “Warburg effect” is when the right ventricle pathologically increases its reliance on glycolysis for its energy requirements. Studies have suggested that this metabolic shift results in pathological changes in the metabolism, fibrosis, and proliferation of the pulmonary vasculature.
As for the change from compensated to decompensated right ventricular failure, studies have suggested that increased poly ADP-ribose polymerase 1 (PARP1) expression is partly to blame. Increasing PARP1 expression is caused by the sustained activation of DNA damage signaling responses, one of which is the nuclear translocation of pyruvate kinase muscle isozyme M1 (PKM1). Therefore, it can be postulated that the induction and nuclear localization of PKM2 and PARP1 stimulate proinflammatory DNA damaging signaling pathways that result in decompensated right ventricular function.
A relatively recent finding as it relates to right ventricular function in PAH is that 17β-Estradiol (E2), the predominant sex hormone in women of reproductive age, may play a protective role in the right ventricle. The estrogen receptor α (ERα) has even been associated with improved systemic vasculature. In mouse models, a loss of ERα is associated with a more severe phenotype, while the administration of an ER agonist reverses those changes. This suggests that alterations in normal ERα signaling pathways may be the cause of the female bias commonly observed in PAH.
Read about more PAH prognosis
In addition, scientists have turned their attention to the effect of long noncoding RNAs (lncRNAs) on right ventricular function. Particularly, scientists have singled out the lncRNA H19 as a novel target that also functions as a prognostic indicator in PAH-associated right ventricular failure. Scientists have found a correlation between H19 and right ventricular hypertrophy and fibrosis in both humans and rat models, as well as that the silencing of H19 improves right ventricular function in vivo. This suggests that H19 is an epigenetic driver of certain pathways that lead to right ventricular failure and thus correlates with a poorer prognosis. Fortunately, the discovery of the role of this lncRNA in PAH-associated right ventricular failure means that therapies can be developed to silence or minimize its effects in patients with PAH.
A Missing Piece of the Puzzle
The review went on to identify a host of other factors that contribute to PAH, such as inflammatory pathways and the role of genetics and epigenetics in its pathophysiology. However, an entire section devoted to exploring how right ventricular failure is triggered in PAH is encouraging because it is a subject that is sometimes taken for granted in clinical research.
As we have seen in this article, decompensated right ventricular failure can quickly lead to a worsening prognosis since its proper function is vital in the body. Indeed, the identification of the pathways that cause decompensated right ventricular function in PAH opens up a new world of therapeutic possibilities that target this pathology in a highly specific way, thus improving clinical outcomes.
Potus F, Frump AL, Umar S, Vanderpool RR, Al Ghouleh I, Lai YC. Recent advancements in pulmonary arterial hypertension and right heart failure research: overview of selected abstracts from ATS2020 and emerging COVID-19 research. Pulm Circ. 2021;11(3):20458940211037274. doi:10.1177/20458940211037274
Vonk Noordegraaf A, Chin KM, Haddad F, et al. Pathophysiology of the right ventricle and of the pulmonary circulation in pulmonary hypertension: an update. Eur Respir J. 2019;53(1):1801900. doi:10.1183/13993003.01900-2018