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.

The purpose of this study was to examine the process of care in an interdisciplinary sleep clinic for patients with obstructive sleep apnea (OSA) and comorbid insomnia. A mixed-methods approach was used to examine clinical and patient-centered measures for 34 patients who received positive-airway pressure for OSA or cognitive-behavior therapy for insomnia. The results revealed baseline-to-follow-up improvements on several self-reported sleep parameters and measures of daytime functioning. Qualitative analyses from patient interviews revealed three themes: conceptual distinctions about each sleep disorder, importance of treating both sleep disorders, and preferences with regard to the sequence of treatment. These findings indicate that patients with OSA and comorbid insomnia encounter unique challenges. A dimensional approach to assessment and treatment is proposed for future research.

Pulmonary hypertension (PH) is associated with a metabolic shift towards glycolysis in both the right ventricle and lung. This results in increased glucose uptake to compensate for the lower energy yield of glycolysis, which creates a potential for 2-[18F] fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) to be a useful tool in the evaluation of participants with PH. We investigated the utility of PET for PH by comparing FDG-PET uptake in the right ventricle and lungs in 30 participants with PH and eight healthy controls and correlating these measurements with echocardiographic (ECHO) measurements and other traditional assessments commonly used in PH. All participants underwent gated FDG-PET scanning in the fasting state, ECHO, six-minute walk test (6MWT), and blood draw for NT-proBNP. Participants also completed the CAMPHOR questionnaire. Right ventricular (RV) end-diastolic and end-systolic volumes, RV ejection fraction, and FDG uptake by PET were significantly different between PH and healthy controls and strongly correlated with plasma NT-proBNP levels and RV ECHO parameters including TAPSE, RV systolic pressure, Tei index, and global peak systolic strain. In addition, lung standardized uptake value (SUV) was also found to be significantly higher in participants with PH than healthy controls. However, lung SUV did not show any significant correlations with NT-proBNP levels, 6MWT, or functional and pressure measurements by ECHO. In this study, we demonstrated the ability to evaluate both lung and right heart metabolism and function in PH by using a single gated FDG-PET scan.

Objective Sleep complaints are associated with adverse health consequences. We hypothesized that non-disabled older persons with more sleep complaints have an increased risk of developing disability. Methods Subjects included 908 older clergy participating in the Religious Order Study without clinical dementia, history of stroke or Parkinson’s disease. At baseline, participants rated their difficulty falling asleep, frequency of nocturnal awakenings, sleep efficacy, and napping frequency, from which a summary dyssomnia measure was derived. Self-report assessment of disability included instrumental activities of daily living (IADLs), basic activities of daily living (ADLs), and Rosow-Breslau mobility disability at baseline and at annual evaluations. Results Mean follow-up was 9.6 (SD=4.2) years. At baseline, more than 60% had 1 or more sleep complaints. In a series of Cox proportional hazards models controlling for age, sex, and education, a 1-point higher dyssomnia score at baseline was associated with about 20% increased risk of IADL disability (hazard ratio=1.20; 95% CI=1.04-1.39, x21=7.62, p<0.05), about 27% increased risk of ADL disability (hazard ratio=1.27; 95% CI=1.10-1.47, x21=12.15, p<0.01), and about 27% increased risk of mobility disability (hazard ratio=1.27, 95% CI=1.09-1.48, x21=11.04, p<0.01). These associations did not vary by age, sex, or education and remained significant after controlling for potential confounders including body mass index, chronic medical conditions, and several common medications. Controlling for depressive symptoms attenuated the association between sleep complaints and incident IADL and ADL disabilities but the association between sleep complaints and incident mobility disability remained significant. Conclusion Non-disabled older adults with more sleep complaints have an increased risk of developing disability.