Establishing a balloon pulmonary angioplasty program for chronic thromboembolic pulmonary hypertension: A United States single-center experience.

INTRODUCTION: Balloon pulmonary angioplasty (BPA) is a less invasive treatment alternative for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are unable to move forward with pulmonary thromboendarterectomy. This report describes a single-center experience with a nascent BPA program in the United States (US). METHODS: All patients who underwent BPA between August 2018-2021 were included in this retrospective, single-center observational cohort. Pre- and post-procedure clinical information was collected, along with procedural characteristics. RESULTS: Thirty patients began their BPA series during the study period. The majority of patients had segmental disease (n = 25, 83.3%). A total of 135 BPA procedures were performed on 417 segments. On average, patients completed 4.5 sessions and the majority of patients (n = 23, 76.7%) underwent more than 2. There were 24 episodes of hemoptysis and 20 procedural events that required treatment, typically with either heparin reversal or balloon tamponade. Of 26 participants with completed series, mean PA pressure (-6 mmHg, 95% CI -9 to -4 mmHg, p = 0.0001), PVR (-1.9 Wood units, 95% CI -2.9 to -1.0, p = 0.0002), and pulmonary compliance (-1.0 mL/mmHg, 95% CI -1.5 to -0.5, p = 0.0002) improved. Improvement was also seen in NYHA functional classification and walk distance (p = 0.01). Two deaths occurred, with one death peri-procedurally. CONCLUSION: This paper describes an early experience with BPA at a single US center. Improvement in non-invasive and invasive metrics were seen without adding a significant morbidity to an already high-risk patient population.

Circulating markers of inflammation and angiogenesis and clinical outcomes across subtypes of pulmonary arterial hypertension.

BACKGROUND: Subtypes of pulmonary arterial hypertension (PAH) differ in both fundamental disease features and clinical outcomes. Angiogenesis and inflammation represent disease features that may differ across subtypes and are of special interest in connective tissue disease-associated PAH (CTD-PAH). We compared inflammatory and angiogenic biomarker profiles across different etiologies of PAH and related them to clinical outcomes. METHODS: Participants with idiopathic PAH, CTD-PAH, toxin-associated PAH (tox-PAH), or congenital heart disease-associated PAH (CHD-PAH) were enrolled into a prospective observational cohort. Baseline serum concentrations of 33 biomarkers were related to 3-year mortality, echocardiogram, REVEAL score, and 6-minute walk distance (6MWD). Findings were validated using plasma proteomic data from the UK PAH Cohort Study. RESULTS: One hundred twelve patients were enrolled: 45 idiopathic, 27 CTD-PAH, 20 tox-PAH, and 20 CHD-PAH. Angiogenic and inflammatory biomarkers were distinctly elevated within the CTD-PAH cohort. Six biomarkers were associated with mortality within the entire PAH cohort: interleukin-6 (IL-6, HR:1.6, 95% CI:1.18-2.18), soluble fms-like tyrosine kinase 1 (sFlt-1, HR:1.35, 95% CI:1.02-1.80), placental growth factor (PlGF, HR:1.55, 95% CI:1.07-2.25), interferon gamma-induced protein 10 (IP-10, HR:1.44, 95% CI:1.04-1.99), tumor necrosis factor-beta (TNF-ß, HR:1.81, 95% CI:1.11-2.95), and NT-proBNP (HR:2.19, 95% CI:1.52-3.14). Only IL-6 and NT-proBNP remained significant after controlling for multiple comparisons. IL-6, IP-10, and sFlt-1 significantly associated with mortality in CTD-PAH, but not non-CTD-PAH subgroups. In the UK cohort, IP-10, PlGF, TNF-ß, and NT-proBNP significantly associated with 5-year survival. CONCLUSION: Levels of angiogenic and inflammatory biomarkers are elevated in CTD-PAH, compared with other etiologies of PAH, and may correlate with clinical outcomes including mortality.

Association of soluble Flt-1 with heart failure and cardiac morphology: The MESA angiogenesis study.

BACKGROUND: Soluble Fms-like tyrosine kinase 1 (sFlt-1) may inhibit angiogenesis. Higher levels of sFlt-1 are associated with worse prognosis in prevalent heart failure patients. The aim of this study was to better understand the role of sFlt-1 in heart failure pathogenesis by characterizing relationships between sFlt-1, cardiac morphology, and the composite outcome of incident heart failure or cardiovascular (CV) death in in a multiethnic cohort free of CV disease at baseline. METHODS: sFlt-1 was measured in 1,381 participants in the Multi-Ethnic Study of Atherosclerosis Angiogenesis sub-study. Linear regression was used to estimate the association between sFlt-1 and cardiac morphology and Cox proportional hazard regression was used to estimate associations with incident heart failure or CV mortality. RESULTS: Over a median follow-up of 13.1 years, higher sFlt-1 levels were associated with incident heart failure or CV mortality independent from CV risk factors or NT-proBNP levels (HR 1.17, 95% CI 1.10-1.26, p < 0.001). Higher sFlt-1 levels were also associated with greater baseline left ventricular (LV) mass by cardiac MRI and increased loss of LV mass over the 10 years following the baseline exam (p-value 0.02 for each), but this association was no longer statistically significant after adjustment for baseline NT-proBNP (p = 0.11 and 0.10 respectively). CONCLUSIONS: Baseline sFlt-1 levels are associated with incident heart failure and cardiovascular mortality independent of traditional CV risk factors or NT-proBNP. An association was also found with cardiac mass but was no longer significant after adjustment for NT-proBNP.

WNT5A from the fetal liver vascular niche supports human fetal liver hematopoiesis.

The human fetal liver is a critical organ for prenatal hematopoiesis, the study of which offers insights into niche signals that regulate the fates of hematopoietic stem and progenitor cells (HSPCs) during fetal development. Here, we demonstrate that human fetal liver endothelium uniquely supports the maturation and expansion of multilineage HSPCs. Specifically, co-culture of fetal liver-derived immature CD43+CD45- hematopoietic cells with human fetal liver endothelial cells (ECs) led to a profound increase in the numbers of phenotypic CD45+CD34+ HSPCs and multilineage colony-forming progenitors generated in vitro, when compared to co-culture with ECs derived from other organs. We further identified a supportive role for EC-derived WNT5A in this process via gain- and loss-of-function studies within ECs. Our study emphasizes the importance of the organ-specific endothelial niche in supporting hematopoietic development and provides novel insight into signals that may facilitate HSPC expansion in vitro for clinical applications.

Reconstructing the Human Renal Vascular-Tubular Unit In Vitro.

Engineered human kidney-on-a-chip platforms show tremendous promise for disease modeling and drug screening. Outstanding challenges exist, however, in reconstructing the complex architecture, cellular make-up, and matrix composition necessary for the proper modeling of kidney function. Herein, the first fully tunable human kidney-on-a-chip platform is reported that allows the reconstruction of the native architecture of the renal endothelial-epithelial exchange interface using entirely cell-remodelable matrix and patient-derived kidney cells. This platform consists of a double-layer human renal vascular-tubular unit (hRVTU) enabled by a thin collagen membrane that replicates the kidney exchange interface. It is shown that endothelial and epithelial cells lining their respective lumens remodel the membrane in culture into a ≈1 µm thick exchange interface composed of native basement membrane proteins. This interface displays sufficient mechanical integrity for media flow and blood perfusion. As a proof of principle, it is demonstrated that the hRVTU performs kidney-specific functions including reabsorption of albumin and glucose from the epithelial channel. By incorporating multiple cell populations from single donors, it is demonstrated that the hRVTU may have utility for future precision medicine applications. The success of the system provides new opportunities for the next generation of organ-on-a-chip models.