Description: Alterations in extracellular matrix (ECM) have been implicated in the pathophysiology of pulmonary hypertension. Here, we have undertaken a compartment-specific study to elucidate the expression profile of collagens and their processing enzymes in donor and idiopathic pulmonary arterial hypertension (IPAH) pulmonary arteries. Predominant intimal, but also medial and perivascular, remodeling and reduced lumen diameter were detected in IPAH pulmonary arteries. Two-photon microscopy demonstrated accumulation of collagen fibers. Quantification of collagen in pulmonary arteries revealed collagen accumulation mainly in the intima of IPAH pulmonary arteries compared with donors. Laser capture-microdissected pulmonary artery profiles (intima+media and perivascular tissue) were analyzed by real-time PCR for ECM gene expression. In the intima+media of IPAH vessels, collagens ( COL4A5 , COL14A1 , and COL18A1 ), matrix metalloproteinase (MMP) 19 , and a disintegrin and metalloprotease (ADAM) 33 were higher expressed, whereas MMP10 , ADAM17 , TIMP1 , and TIMP3 were less abundant. Localization of COLXVIII, its cleavage product endostatin, and MMP10, ADAM33, and TIMP1 was confirmed in pulmonary arteries by immunohistochemistry. ELISA for collagen XVIII/endostatin demonstrated significantly elevated plasma levels in IPAH patients compared with donors, whereas circulating MMP10, ADAM33, and TIMP1 levels were similar between the two groups. Endostatin levels were correlated with pulmonary arterial wedge pressure, and established prognostic markers of IPAH, right atrial pressure, cardiac index, 6-min walking distance, NH 2 -terminal pro-brain natriuretic peptide, and uric acid. Expression of unstudied collagens, MMPs, ADAMs, and TIMPs were found to be significantly altered in IPAH intima+media. Elevated levels of circulating collagen XVIII/endostatin are associated with markers of a poor prognosis.

Description: Background Pregnancy and tuberculosis treatment or prophylaxis can affect efavirenz pharmacokinetics, maternal human immunodeficiency virus type 1 (HIV-1) treatment outcomes, and mother-to-child transmission (MTCT) risk. Methods We evaluated a prospective cohort of pregnant, HIV-infected women with and without tuberculosis in Soweto, South Africa. Pharmacokinetic sampling was performed at gestation week 37 and during the postpartum period . Efavirenz trough concentrations (C min ) were predicted using population pharmacokinetic models. HIV-viral load was measured at delivery for mothers and at 6 weeks of age for infants. Results Ninety-seven women participated; 44 had tuberculosis. Median efavirenz C min during pregnancy was 1.35 µg/mL (interquartile range [IQR], 0.90–2.07 µg/mL; 27% had an efavirenz C min of 〈 1 µg/mL), compared with a median postpartum value of 2.00 µg/mL (IQR, 1.40–3.59 µg/mL; 13% had an efavirenz C min of 〈 1 µg/mL). A total of 72% of pregnant women with extensive CYP2B6 genotypes had an efavirenz C min of 〈1 µg/mL. Rifampin did not reduce the efavirenz C min . Isoniazid (for prophylaxis or treatment), though, reduced the rate of efavirenz clearance. At delivery, median durations of ART were 13 weeks (IQR, 9–18 weeks) and 21 weeks (IQR, 13–64 weeks) for women with and those without tuberculosis, respectively; 55% and 83%, respectively, had a viral load of 〈20 copies/mL ( P = .021). There was 1 case of MTCT. Conclusions Pregnancy increased the risk of low efavirenz concentrations, but MTCT was rare. A detectable HIV-viral load at delivery was more common among pregnant women with tuberculosis, in whom ART was generally initiated later.

Description: BACKGROUND Renal sympathetic denervation (RSD) represents an effective treatment option for patients with resistant arterial hypertension (HT). Extracellular matrix (ECM) turnover and deposition are essential processes in HT-related cardiovascular remodeling, fibrosis, and cardiac hypertrophy and contribute to hypertensive heart disease. OBJECTIVES The primary aim of the present study was to examine the effect of RSD on increased collagen turnover as reflected by serum levels of amino-terminal pro-peptides (PINP, PIIINP) and a carboxyl-terminal pro-peptide (PICP), specific biomarkers for cardiac ECM turnover and cardiovascular fibrosis. METHODS A total of 100 consecutive patients (mean age: 65.9±10.1 years) undergoing RSD were included in this study. A therapeutic response was defined as an office systolic blood pressure (SBP) reduction of 〉10mm Hg 6 months after RSD. Venous serum samples for measurement of PICP, PINP, and PIIINP were collected prior to and 6 months after RSD. RESULTS A significant reduction in the office SBP of 24.3mm Hg (SBP baseline: 166.9±14.3mm Hg ( P 〈 0.001) was documented 6 months after RSD. At this time point, the serum levels of PICP, PINP, and PIIINP ( P 〈 0.01) were significantly decreased compared to baseline values in patients with an increased collagen turnover, showing significant differences comparing BP responders and nonresponders. CONCLUSION In addition to the effective blood pressure reduction in response to RSD, this study demonstrates a positive effect of RSD on biomarkers reflecting cardiovascular ECM turnover and deposition. These results suggest a beneficial effect of RSD on cardiovascular fibrosis, hypertensive heart disease, and end-organ damage in high-risk patients.

Description: Over past years, a critical role for the immune system and, in particular, for mast cells in the pathogenesis of pulmonary hypertension (PH) has emerged. However, the way in which mast cells promote PH is still poorly understood. Here, we investigated the mechanisms by which mast cells may contribute to PH, specifically focusing on the interaction between the innate and adaptive immune response and the role of B cells and autoimmunity. Experiments were performed in Sprague-Dawley rats and B cell-deficient JH-KO rats in the monocrotaline, Sugen/hypoxia, and the aortic banding model of PH. Hemodynamics, cell infiltration, IL-6 expression, and vascular remodeling were analyzed. Gene array analyses revealed constituents of immunoglobulins as most prominently regulated mast cell-dependent genes in the lung in experimental PH. IL-6 was shown to link mast cells to B cells, as 1 ) IL-6 was upregulated and colocalized with mast cells and was reduced by mast-cell stabilizers and 2 ) IL-6 or mast cell blockade reduced B cells in lungs of monocrotaline-treated rats. A functional role for B cells in PH was demonstrated in that either blocking B cells by an anti-CD20 antibody or B-cell deficiency in JH-KO rats attenuated right ventricular systolic pressure and vascular remodeling in experimental PH. We here identify a mast cell–B cell axis driven by IL-6 as a critical immune pathway in the pathophysiology of PH. Our results provide novel insights into the role of the immune system in PH, which may be therapeutically exploited by targeted immunotherapy.