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

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 ...

Circadian Phase Assessments at Home, http://clinicaltrials.gov/show/NCT01487252, NCT01487252.

We hope that this perspective will stimulate interdisciplinary activity toward uncovering the pathway for more effective interventions for chronic headache patients.

A proliferation of mast cells around the small pulmonary blood vessels and the alveolar septae has been noted in models of pulmonary hypertension, and in plexiform lesions of pulmonary arterial hypertension (PAH) in patients. Here, we hypothesize that total mast cell numbers and activation are increased in PAH and that they contribute to vascular remodeling through cellular and soluble proangiogenic effectors. To test this, blood and urine were collected from patients with PAH (N=44), asthma (N=18) and healthy controls (N=29) to quantitate biomarkers of total body mast cell numbers and activation (total and mature tryptase, N-methyl histamine, leukotriene LTE4 and prostaglandin PGD-M). Serum total tryptase was higher in PAH than that in controls suggesting greater numbers of mast cells, but indicators of mast cell activation (mature tryptase, LTE4 and PGD-M) were similar among PAH, asthma, and controls. Immunohistochemistry of lung tissues identified mast cells as primarily perivascular and connective tissue chymase+ type in PAH, rather than mucosal phenotype. Intervention with mast cell inhibitors cromolyn and fexofenadine was performed in 9 patients for 12 weeks to identify the influence of mast cell products on the pathologic proangiogenic environment. Treatment decreased total tryptase and LTE-4 levels over time of treatment. This occurred in parallel to a drop in vascular endothelial growth factor (VEGF) and circulating proangiogenic CD34+CD133+ progenitor cells, which suggests that mast cells may promote vascular remodeling and dysfunction. In support of this, levels of exhaled nitric oxide, a vasodilator that is generally low in PAH, increased at the end of the 12-week mast cell blockade and antihistamine. These results suggest that mast cells might contribute to the pulmonary vascular pathologic processes underlying PAH. More studies are needed to confirm their potential contribution to the disease.