Novel assessment of haemodynamic kinetics with acute exercise in a rat model of pulmonary arterial hypertension.

NEW FINDINGS: What is the central question of this study? The acute effect of exercise at moderately high intensity on already-elevated pulmonary arterial pressures and right ventricular wall stress in a rat model of pulmonary arterial hypertension (PAH) is unknown. What is the main finding and its importance? We show, for the first time, that in a rat model of PAH, exercise induces an acute reduction in pulmonary artery pressure associated with lung endothelial nitric oxide synthase activation, without evidence of acute right ventricular inflammation or myocyte apoptosis. Haemodynamic measures obtained with traditional invasive methodology as well as novel implantable telemetry reveal an exercise-induced 'window' of pulmonary hypertension alleviation, supporting future investigations of individualized exercise as therapy in PAH. Exercise improves outcomes of multiple chronic conditions, but controversial results, including increased pulmonary artery (PA) pressure, have prevented its routine implementation in pulmonary arterial hypertension (PAH), an incurable disease that drastically reduces exercise tolerance. Individualized, optimized exercise prescription for PAH requires a better understanding of disease-specific exercise responses. We investigated the acute impact of exercise on already-elevated PA pressure and right ventricular (RV) wall stress and inflammation in a rat model of PAH (PAH group, n = 12) induced once by monocrotaline (50 mg kg(-1) , i.p.; 2 weeks), compared with healthy control animals (n = 8). Single bouts of exercise consisted of a 45 min treadmill run at 75% of individually determined aerobic capacity (V̇O2max). Immediately after exercise, measurements of RV systolic pressure and systemic pressure were made via jugular and carotid cannulation, and were followed by tissue collection. Monocrotaline induced moderate PAH, evidenced by RV hypertrophy, decreased V̇O2max, PA muscularization, and RV and skeletal muscle cytoplasmic glycolysis detected by increased expression of glucose transporter-1. Acute exercise normalized the monocrotaline-induced elevation in RV systolic pressure and augmented pulmonary endothelial nitric oxide synthase activation, without evidence of increased RV inflammation or apoptosis. Real-time recordings of pulmonary and systemic pressures during and after single bouts of exercise made using novel implantable telemetry in the same animal for up to 11 weeks after monocrotaline (40 mg kg(-1) ) corroborated the finding of acute PA pressure decreases with exercise in PAH. The PA pressure-lowering effects of individualized exercise associated with RV-neutral effects and increases in vasorelaxor signalling encourage further development of optimized exercise regimens as adjunctive PAH therapy.

17ß-Estradiol attenuates hypoxic pulmonary hypertension via estrogen receptor-mediated effects.

RATIONALE: 17ß-Estradiol (E2) attenuates hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension (HPH) through an unknown mechanism that may involve estrogen receptors (ER) or E2 conversion to catecholestradiols and methoxyestradiols with previously unrecognized effects on cardiopulmonary vascular remodeling. OBJECTIVES: To determine the mechanism by which E2 exerts protective effects in HPH. METHODS: Male rats were exposed to hypobaric hypoxia while treated with E2 (75 µg/kg/d) or vehicle. Subgroups were cotreated with pharmacologic ER-antagonist or with inhibitors of E2-metabolite conversion. Complementary studies were performed in rats cotreated with selective ERα- or ERß-antagonist. Hemodynamic and pulmonary artery (PA) and right ventricular (RV) remodeling parameters, including cell proliferation, cell cycle, and autophagy, were measured in vivo and in cultured primary rat PA endothelial cells. MEASUREMENTS AND MAIN RESULTS: E2 significantly attenuated HPH endpoints. Hypoxia increased ERß but not ERα lung vascular expression. Co-treatment with nonselective ER inhibitor or ERα-specific antagonist rendered hypoxic animals resistant to the beneficial effects of E2 on cardiopulmonary hemodynamics, whereas ERα- and ERß-specific antagonists opposed the remodeling effects of E2. In contrast, inhibition of E2-metabolite conversion did not abolish E2 protection. E2-treated hypoxic animals exhibited reduced ERK1/2 activation and increased expression of cell-cycle inhibitor p27(Kip1) in lungs and RV, with up-regulation of lung autophagy. E2-induced signaling was recapitulated in hypoxic but not normoxic endothelial cells, and was associated with decreased vascular endothelial growth factor secretion and cell proliferation. CONCLUSIONS: E2 attenuates hemodynamic and remodeling parameters in HPH in an ER-dependent manner, through direct antiproliferative mechanisms on vascular cells, which may provide novel nonhormonal therapeutic targets for HPH.

The relationship between caffeine and blood pressure in preadolescent African American girls.

BACKGROUND: While high caffeine consumption has been shown to be associated with increased blood pressure in controlled experiments, the relationship between caffeine consumption and blood pressure in preadolescent (ages 6-11 years) and adolescent (ages 12-19 years) children has not been well studied. The primary objective of this study was to assess the cross-sectional relationship between caffeine intake and blood pressure in 8- to 10-year-old African American girls who eat an unrestricted diet. METHODS: Demographic, 24-hour dietary recall, and blood pressure data collected at baseline from 303 African American girls aged 8-10 years in the Girls health Enrichment Multisite Studies (GEMS) cohort were analyzed by using linear and multiple regression models. RESULTS: Dietary caffeine intake was not associated with either systolic or diastolic blood pressure (P=.33 and P=.36, respectively). However, consistent with the literature, height and body mass index were each positively and independently associated with systolic blood pressure (both P<.0001). Height and amount of sodium intake were positively associated with diastolic blood pressure (P=.01 and P=.02, respectively). CONCLUSIONS: Dietary caffeine intake in low amounts is not associated with elevated blood pressure in 8- to 10-year-old African American girls who eat an unrestricted diet.

Predictors of recurrent esophageal food impaction: a case-control study.

BACKGROUND: Esophageal food impaction (FI) is a distressing condition requiring urgent endoscopic intervention, with a reported recurrence rate between 10% and 20%. Knowledge of factors predisposing to recurrent FI may enable preventive measures to minimize the risk of recurrence. OBJECTIVE: To identify risk factors associated with recurrent FI. DESIGN: Retrospective case-control study. SETTING: Tertiary referral center. PATIENTS: A prospectively maintained database and medical records of all patients undergoing emergent endoscopy for FI from 1989 to 2000 were reviewed. Cases were defined as those presenting with more than 1 episode of FI, whereas controls were defined as those without recurrence within 5 years of the index episode. Several demographic, clinical, endoscopic, and follow-up variables were extracted. Statistical analysis included chi2 tests and t tests for univariate analysis, and stepwise logistic regression for multivariate analysis. INTERVENTIONS: NA. MAIN OUTCOME MEASUREMENTS: Predictors of recurrent FI. RESULTS: A total of 52 cases and 124 controls were identified (recurrence rate 30%). Presence of a diaphragmatic hernia [odds ratio (OR) 2.65; confidence interval (CI) 1.19-5.89], disimpaction by piecemeal extraction (OR 2.32; CI 1.09-4.97), and acquisition of esophageal biopsies (OR 3.69; CI 1.42-9.66) increased odds for recurrent FI. Physician follow-up after FI decreased the odds for recurrent FI (OR 0.38; CI 0.18-0.80). LIMITATIONS: Retrospective study. CONCLUSIONS: The presence of a diaphragmatic hernia, complexity of endoscopic disimpaction technique, and lack of follow-up increased risk for recurrent FI. Collection of esophageal biopsies as a risk factor suggests a visibly more severe esophageal disorder as a potential cause for recurrent FI.

Safety of infliximab and other biologic agents in the inflammatory bowel diseases.

In many ways, infliximab has drastically altered expectations for medical therapy in IBD, and it is expected that adalimumab and certolizumab pegol with ultimately have a similar role. Patients initiating such therapy should be made cognizant of the potential risks of serious infection including opportunistic ones, such as TB and histoplasmosis; demyelinating disorders; CHF; and lymphoma. Proper selection of candidates for anti-TNF-alpha therapy is critical in maintaining a proper benefit-to-risk ratio.