Background-We tested the hypothesis that right ventricular (RV) pressure overload affects RV function and further influences left ventricular (LV) geometry, which adversely affects LV twist mechanics and segmental function. Methods and Results-Echocardiographic

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and economic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of coexisting medical conditions, while the underlying mechanisms remain unclear. Furthermore, there are no approved therapies for COVID-19. This study aims to identify SARS-CoV-2 pathogenesis, disease manifestations, and COVID-19 therapies using network medicine methodologies along with clinical and multi-omics observations. We incorporate SARS-CoV-2 virus–host protein–protein interactions, transcriptomics, and proteomics into the human interactome. Network proximity measurement revealed underlying pathogenesis for broad COVID-19-associated disease manifestations. Analyses of single-cell RNA sequencing data show that co-expression of ACE2 and TMPRSS2 is elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn disease patients compared to uninflamed tissues, revealing shared pathobiology between COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and transcriptomics (bulk and single-cell) data from asthma patients indicate that COVID-19 shares an intermediate inflammatory molecular profile with asthma (including IRAK3 and ADRB2). To prioritize potential treatments, we combined network-based prediction and a propensity score (PS) matching observational study of 26,779 individuals from a COVID-19 registry. We identified that melatonin usage (odds ratio [OR] = 0.72, 95% CI 0.56–0.91) is significantly associated with a 28% reduced likelihood of a positive laboratory test result for SARS-CoV-2 confirmed by reverse transcription–polymerase chain reaction assay. Using a PS matching user active comparator design, we determined that melatonin usage was associated with a reduced likelihood of SARS-CoV-2 positive test result compared to use of angiotensin II receptor blockers (OR = 0.70, 95% CI 0.54–0.92) or angiotensin-converting enzyme inhibitors (OR = 0.69, 95% CI 0.52–0.90). Importantly, melatonin usage (OR = 0.48, 95% CI 0.31–0.75) is associated with a 52% reduced likelihood of a positive laboratory test result for SARS-CoV-2 in African Americans after adjusting for age, sex, race, smoking history, and various disease comorbidities using PS matching. In summary, this study presents an integrative network medicine platform for predicting disease manifestations associated with COVID-19 and identifying melatonin for potential prevention and treatment of COVID-19.

Pulmonary arterial hypertension (PAH) is a proliferative vasculopathy characterized by high circulating CD34 ؉ CD133 ؉ proangiogenic progenitors, and endothelial cells that have pathologic expression of hypoxia-inducible factor 1 ␣ (HIF-1␣). Here, CD34 ؉ CD133 ؉ progenitor cell numbers are shown to be higher in PAH bone marrow, blood, and pulmonary arteries than in healthy controls. The HIF-inducible myeloid-activating factors erythropoietin, stem cell factor (SCF), and hepatocyte growth factor (HGF) are also present at higher than normal levels in PAH blood, and related to disease severity. Primary endothelial cells harvested from human PAH lungs produce greater HGF and progenitor recruitment factor stromal-derived factor 1 ␣ (SDF-1␣) than control lung endothelial cells, and thus may contribute to bone marrow activation. Even though PAH patients had normal numbers of circulating blood elements, hematopoietic alterations in myeloid and erythroid lineages and reticulin fibrosis identified a subclinical myeloproliferative process. Unexpectedly, evaluation of bone marrow progenitors and reticulin in nonaffected family members of patients with familial PAH revealed similar myeloid abnormalities. Altogether, the results show that PAH is linked to myeloid abnormalities, some of which may be related to increased production of HIF-inducible factors by diseased pulmonary vasculature, but findings in nonaffected family suggest myeloid abnormalities may be intrinsic to the disease process. (Blood. 2011;117(13):3485-3493) IntroductionPulmonary arterial hypertension (PAH) is a vasculopathy of the pulmonary circulation characterized by arterial obliteration secondary to unchecked pathologic angiogenic processes. 1-3 An abundance of studies over the past decade provide evidence for the paradigm of lifelong interdependence between angiogenesis and hematopoiesis. [4][5][6] The concept of a common hematopoieticendothelial stem cell, that is, hemangioblast, with bidirectional, reversible gene transcription and persistence is well established in developmental biology. 7 In postnatal life to adulthood, hemangioblasts are readily identifiable in the bone marrow by the CD133-selective expression on a small subpopulation of CD34-positive hematopoietic stem cells. 8 Hemangioblasts give rise to all blood cellular components, but whether these cells give rise to endothelium during postnatal neovascularization is uncertain. 9,10 In contrast, studies clearly substantiate that CD34 ϩ CD133 ϩ progenitors are vital contributors to angiogenesis via proangiogenic effects on endothelial cells in vessels. [11][12][13][14][15][16][17][18] Our and other studies identify that CD34 ϩ CD133 ϩ progenitors are present at higher than normal levels in the circulation of PAH patients and are more proliferative than circulating progenitors of healthy controls. 19,20 The relationship of numbers of circulating CD34 ϩ CD133 ϩ cells to severity of PAH suggest that these cells may promote the angioproliferative vascular remodeling. 20 However, whether the source ...

Hematopoietic myeloid progenitors released into the circulation are able to promote vascular remodeling through endothelium activation and injury. Endothelial injury is central to the development of pulmonary arterial hypertension (PAH), a proliferative vasculopathy of the pulmonary circulation, but the origin of vascular injury is unknown. In the present study, mice transplanted with BM-derived IntroductionVascular endothelial injury with in situ thrombi is a typical pathologic finding in pulmonary arterial hypertension (PAH). Progressive disease is characterized by complex vascular malformations composed of disorganized proliferating monoclonal endothelial cells with neointima formation. 1 Although endothelial injury is hypothesized to account for the origins of PAH, the underlying mechanism of the vascular injury is unknown. Hematopoietic myeloid proangiogenic progenitors play a central role in endothelial injury and repair. We and others have reported that distinct 2-4 or indolent 5 myeloid abnormalities are present in the BM of the majority, if not all, of patients with PAH and even in unaffected family members 5 in familial cases of the disease. These findings and the unexplained high incidence of PAH among patients with myeloproliferative diseases 6,7 suggest a myelopulmonary pathophysiologic link. In support of this concept, competent hematopoietic progenitors are required for disease development in the monocrotaline-or hypoxia-induced murine models of pulmonary hypertension, and BM transplantation can transfer disease to healthy naive mice. 8 In contrast to developmental origins of blood cells and vascular endothelium from the common hemangioblast, hematopoietic stem cells in the adult do not differentiate into endothelium, but rather promote postnatal angiogenesis and homeostasis in a paracrine fashion. [9][10][11][12] In the hierarchy of adult hematopoietic stem cell differentiation, a small pool of pluripotent, BMresident stem cells exhibit self-renewal and long-term survival. 13 These stem cells proliferate and differentiate into relatively shortlived multipotent progenitors that give rise to common lymphoid and common myeloid progenitors. Common lymphoid progenitors further differentiate into B-or T cell-committed precursors. The common myeloid progenitors proliferate and differentiate into bipotent common erythroid/megakaryocyte progenitors and into multipotent monocyte/granulocyte progenitors. These lineagerestricted myeloid progenitors differentiate into mature blood cells via unilineage-committed intermediate precursors. The hierarchy of proliferation and differentiation is at each bifurcation strictly regulated by lineage-specific transcription factors. 13 In the BM, the cell-surface glycoprotein CD133 is highly expressed on immature progenitors, allowing CD133 expression to define the population of hematopoietic progenitors. Functional analysis of human BM-derived CD133 ϩ cells indicates that this fraction is enriched in primitive multilineage hematopoietic stem cells. 14 Early outgrowth pro...

ClinicalTrials.gov NCT01586156FUNDING. This project was supported by NIH R01HL115008 and R01HL60917 and in part by the National Center for Advancing Translational Sciences, UL1TR000439.

Women with asthma experience cyclic changes in airflow as well as gas transfer and membrane diffusing capacity supportive of a hormonal effect on lung function.

BackgroundNew 2-dimensional strain echocardiography enables quantification of right ventricular (RV) mechanics by assessing global longitudinal strain of RV (GLSRV) in patients with pulmonary arterial hypertension (PAH). However, the prognostic significance of impaired GLSRV is unclear in these patients.MethodsComprehensive echocardiography was performed in 51 consecutive PAH patients without atrial fibrillation (40 females, 48 ± 14 years old) with long-term follow-up. GLSRV was measured with off-line with velocity vector imaging (VVI, Siemens Medical System, Mountain View, CA, USA).ResultsGLSRV showed significant correlation with RV fractional area change (r = -0.606, p < 0.001), tricuspid annular plane systolic excursion (r = -0.579, p < 0.001), and RV Tei index (r = 0.590, p < 0.001). It showed significant correlations with pulmonary vascular resistance (r = 0.469, p = 0.001) and B-natriuretic peptide concentration (r = 0.351, p = 0.012). During a clinical followup time (45 ± 15 months), 20 patients experienced one or more adverse events (12 death, 2 lung transplantation, and 15 heart failure hospitalization). After multivariate analysis, age [hazard ratio (HR) = 2.343, p = 0.040] and GLSRV (HR = 2.122, p = 0.040) were associated with adverse clinical events. Age (HR = 3.200, p = 0.016) and GLSRV (HR = 2.090, p = 0.042) were also significant predictors of death. Impaired GLSRV (≥ -15.5%) was associated with lower event-free survival (HR = 4.906, p = 0.001) and increased mortality (HR = 8.842, p = 0.005).ConclusionGLSRV by VVI showed significant correlations with conventional echocardiographic parameters indicating RV systolic function. Lower GLSRV (≥ -15.5%) was significantly associated with presence of adverse clinical events and deaths in PAH patients.

Normal resting mean pulmonary artery pressure (PAP) is 8-20 mmHg. Pulmonary hypertension is defined as mean PAP of ≥25 mmHg. Borderline PAP levels of 21-24 mmHg are of unclear significance. We sought to determine the clinical characteristics and survival of subjects with mean PAP of 21-24 mmHg. We examined 1,491 patients enrolled in the Cleveland Clinic Pulmonary Hypertension Registry between February 1990 and May 2012 with baseline right heart catheterization. The relationship between PAP and all-cause mortality was assessed by Cox models and a tree-based analysis. Sixty-three patients had borderline PAP (underlying conditions: 12 left heart disease, 20 respiratory disease, 17 connective-tissue disease, 4 others, and 10 none). We then compared 3 groups: borderline PAP without heart or lung disease (n = 31), normal PAP without heart or lung disease (n = 51), and category 1 pulmonary arterial hypertension (PAH; n = 387). Borderline-PAP patients had levels of hemodynamic and functional compromise between those for normal-PAP patients and those for patients with PAH. Borderline PAP was associated with increased mortality compared to normal PAP (hazard ratio: 4.03 [95% confidence interval: 0.78-20.80], P = 0:099). A tree-based analysis demonstrated almost identical cut points in mean PAP (≤20, 21-26, and ≥27 mmHg) associated with differential survival (P < 0:001). Connective-tissue disease and an elevated transpulmonary gradient were predictors of worse survival in the borderline-PAP population. Borderline PAP elevation is associated with decreased survival, particularly in the context of connective-tissue disease and an elevated transpulmonary gradient.