The Roles of S100A4 and the EGF/EGFR Signaling Axis in Pulmonary Hypertension with Right Ventricular Hypertrophy

Pulmonary hypertension (PH) is characterized by increased pulmonary arterial pressure caused by the accumulation of mesenchymal-like cells in the pulmonary vasculature. PH can lead to right ventricular hypertrophy (RVH) and, ultimately, heart failure and death. In PH etiology, endothelial-to-mesenchymal transition (EndMT) has emerged as a critical process governing the conversion of endothelial cells into mesenchymal cells, and S100A4, EGF, and EGFR are implicated in EndMT. However, a potential role of S100A4, EGF, and EGFR in PH has to date not been elucidated. We therefore quantified S100A4, EGF, and EGFR in patients suffering from chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH). To determine specificity for unilateral heart disease, the EndMT biomarker signature was further compared between PH patients presenting with RVH and patients suffering from aortic valve stenosis (AVS) with left ventricular hypertrophy. Reduced S100A4 concentrations were found in CTEPH and iPAH patients with RVH. Systemic EGF was increased in CTEPH but not in iPAH, while AVS patients displayed slightly diminished EGF levels. EGFR was downregulated in all patient groups when compared to healthy controls. Longitudinal data analysis revealed no effect of surgical therapies on EndMT markers. Pulmonary thrombo-endarterectomized samples were devoid of S100A4, while S100A4 tissue expression positively correlated with higher grades of Heath–Edwards histopathological lesions of iPAH-derived lung tissue. Histologically, EGFR was not detectable in CTEPH lungs or in iPAH lesions. Together, our data suggest an intricate role for S100A4 and EGF/EGFR in PH with right heart pathology.

Frequency of Thrombotic Risk Factors in Patients with Chronic Thromboembolic Pulmonary Hypertension and Acute Pulmonary Embolism: A Case-Control Study

Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious complication of acute pulmonary embolism (PE) which remains underdiagnosed. A better understanding of risk factors for CTEPH would improve our ability to predict which PE survivors are at risk. Several medical conditions—including malignancy, splenectomy, thyroid hormone supplementation, the presence of an intravascular device, inflammatory bowel disease, osteomyelitis, and non-O blood group—have been associated with increased risk of CTEPH, primarily in studies comparing patients with CTEPH to individuals with non-thrombotic conditions. Because many of these conditions increase thrombosis risk, it remains unclear whether their association with CTEPH reflects a general effect on thrombosis risk, or a specific effect on the risk of developing CTEPH as an outcome of thrombosis. We performed a case-control study comparing the frequencies of these conditions in patients with CTEPH versus patients with acute PE who did not develop CTEPH. The conditions studied were equally frequent in the CTEPH and PE cohorts, although there was a trend towards an increased frequency of splenectomy and non-O blood group among the CTEPH cohort. Thus, other than the possible exceptions of splenectomy and non-O blood group, the investigated medical conditions do not appear likely to increase the risk of CTEPH as an outcome of acute PE, and thus are unlikely to be useful in predicting CTEPH risk among PE survivors.

Examining the Development of Chronic Thromboembolic Pulmonary Hypertension at the Single-Cell Level

Background: The mechanism of chronic thromboembolic pulmonary hypertension (CTEPH) is known to be multifactorial but remains incompletely understood. Methods: In this study, single-cell RNA sequencing, which facilitates the identification of molecular profiles of samples on an individual cell level, was applied to investigate individual cell types in pulmonary endarterectomized tissues from 5 patients with CTEPH. The order of single-cell types was then traced along the developmental trajectory of CTEPH by trajectory inference analysis, and intercellular communication was characterized by analysis of ligand-receptor pairs between cell types. Finally, comprehensive bioinformatics tools were used to analyze possible functions of branch-specific cell types and the underlying mechanisms. Results: Eleven cell types were identified, with immune-related cell types (T cells, natural killer cells, macrophages, and mast cells) distributed in the left (early) branch of the pseudotime tree, cancer stem cells, and CRISPLD2+ cells as intermediate cell types, and classic disease-related cell types (fibroblasts, smooth muscle cells, myofibroblasts, and endothelial cells) in the right (later) branch. Ligand-receptor interactions revealed close communication between macrophages and disease-related cell types as well as between smooth muscle cells and fibroblasts or endothelial cells. Moreover, the ligands and receptors were significantly enriched in key pathways such as the PI3K/Akt signaling pathway. Furthermore, highly expressed genes specific to the undefined cell type were significantly enriched in important functions associated with regulation of endoplasmic reticulum stress. Conclusions: This single-cell RNA sequencing analysis revealed the order of single cells along a developmental trajectory in CTEPH as well as close communication between different cell types in CTEPH pathogenesis.

The Role of Pulmonary Artery Wedge Pressure on the Incidence of Atrial Fibrillation and Atrial Tachycardias in Patients With Isolated Pre-capillary Pulmonary Hypertension

Atrial fibrillation and atrial tachycardias (AF/AT) have been reported as a common condition in patients with pulmonary hypertension (PH). As yet, limited data exists about the significance of the borderline post-capillary pressure component on the occurrence of AF / AT in patients with isolated pre-capillary PH. We retrospectively studied the prevalence of AF / AT in 333 patients (mean age 61±15 years, 44 % males) with pre-capillary idiopathic / familiar pulmonary arterial hypertension, and inoperable chronic thromboembolic pulmonary hypertension. The prevalence of AF / AT was analyzed in different categories of pulmonary artery wedge pressure (PAWP). In the study population overall, the mean PAWP was 10.5±3 mmHg, median of 11 mmHg, range 2-15 mmHg. AF / AT was diagnosed in 79 patients (24 %). The proportion of AF / AT among patients with PAWP below the median (≤11 mmHg) was lower than in subjects with PAWP between 12 and 15 mmHg, 30 (16 %) vs. 46 (35 %), p=0.0001. Compared to the patients with PAWP≤11 mmHg, subjects with PAWP between 12 and 15 mmHg were older (65±13 years vs. 58±16), with more prevalent arterial hypertension [100 (70 %) vs. 106 (55 %)] and diabetes mellitus [50 (35 %) vs. 48 (25 %)], showed larger size of the left atrium (42±7 vs. 40±6 mm), and higher values of right atrium pressure (12±5 vs. 8±5 mmHg), p<0.05 in all comparisons. The prevalence of AF / AT in the group studied increased with the growing post-capillary component.