This is the first report from the PVDOMICs study, an NIH funded multicenter project designed to better understand the clinical, biological and genetic features and differences between all forms of pulmonary hypertension. This initial paper describes the clinical features of over 1000 subjects in Groups 1-5 pulmonary hypertension. The notable findings include 1) there is often a mixture of etiologies in each of the groups; 2) DLCO is depressed in Groups 1-3; 3) Right atrial volume is enlarged in Groups 1-4 even when the right ventricle is not; 4) Group 1 patients frequently have ground glass findings on Chest CT scan and nocturnal desaturation; 5) Survival is poorest in Group 3.
The finding that there is right atrial enlargement before it is right ventricular enlargement is particularly relevant to the numerous reports that increased right atrial pressure is a powerful predictor of survival in PH, and that the mechanism appears to be associated with increased stressed blood volume. These data provide support for the potential of levosimendan as a fundamental treatment of pulmonary hypertension.
This landmark study used a machine learning approach to identify transcriptome associated endophenotypes of patients with heritable and idiopathic PAH. They defined five distinct clinical subgroups based on clinical presentation, severity and survival. The three largest subgroups displayed significantly different clinical characteristics, severity and survival outcomes suggesting that a molecular classification for PAH may be possible. The dysregulation of immunoglobulin genes (NOG and ALAS2), were most predictive of the subgroups with the best and worst prognosis, suggesting that these genes are key in determining patient outcome, and may therefore represent future drug targets but also a tool to identify patients responsive to current treatments. The identification of genetic signatures in PAH has been a hope for several decades and is now becoming a reality. As this field progresses one may expect that treatments will follow patient specific genetic biomarkers as is done in oncology.
This is a report of preclinical research that studied the role of K+(V.7) channels in PAH. Unlike other K+ channels that appear to be downregulated in PAH, the Kv7 channel function was preserved whereas the KCNE4 subunit was upregulated. This research highlights the complexities behind K+ channel control over the pulmonary circulation and the impact of their actions.
This authoritative review from eminent translational researchers in this field demonstrates the diversity of K+ channels which regulates the pulmonary arterial and venous circulations. It raises the question as to why there has not been the development of K+ channel activator drugs as a treatment, as there appears to be an extraordinary opportunity and need for such therapies.
Interesting research demonstrating that the loss of BMPR2 signaling, an established fundamental mechanism underlying PAH, is mediated by downregulation of K+ channels of the voltage regulated family. This implies that K+ downregulation may be a cause of pulmonary vasoconstriction and that K+ channel activators may be a promising treatment.
This authoritative review from a leading authority in the field explains the complex pathophysiology behind the development of pulmonary hypertension which may apply to all of the 5 groups of clinical pulmonary hypertension.
An outstanding and comprehensive review of PAH by experts in the field. This review summarizes the epidemiology, diagnostic evaluation, and treatment of PAH. It also examines recent advances in basic science, noting potential therapeutic targets and future research questions.
Unbiased meta-analysis of the approved pulmonary vasodilator therapies for PAH. The authors improved upon two previous meta-analyses by addressing some of the limitations in those analyses. By pooling the available literature, they sought to determine the effect of the classes of medication on total mortality and secondarily to assess their impact on other clinical endpoints, including dyspnea, exercise tolerance, hemodynamics, and adverse effects
Authoritative review of the pathology of PAH, with a focus on the impact of modern treatments by leading experts. They show that in patients with advanced disease there is a distinct spectrum of pulmonary vascular and nonvascular pathologies, including localized interstitial and perivascular inflammation. In this set of patients who were being treated with the modern drug therapies, the appearance of classical pulmonary vascular lesions related to the disease was unaffected.