Angiotensin II blockade and aortic-root dilation in Marfan's syndrome

Background: Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor (beta) (TGF-(beta)) that can be mitigated by treatment with TGF-(beta) antagonists, including angiotensin II-receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan's syndrome who had severe aortic-root enlargement. Methods: We identified 18 pediatric patients with Marfan's syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs. Results: The mean (+/-SD) rate of change in aortic-root diameter decreased significantly from 3.54+/-2.87 mm per year during previous medical therapy to 0.46+/-0.62 mm per year during ARB therapy (P<0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P<0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan's syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P<0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan's syndrome, was not affected by ARB therapy. Conclusions: In a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial

Dedicated JPSS VIIRS Ocean Color Calibration/Validation Cruise

The NOAA/STAR ocean color team is focused on “end-to-end” production of high quality satellite ocean color products. In situ validation of satellite data is essential to produce the high quality, “fit for purpose” remotely sensed ocean color products that are required and expected by all NOAA line offices, as well as by external (both applied and research) users. In addition to serving the needs of its diverse users within the U.S., NOAA has an ever increasing role in supporting the international ocean color community and is actively engaged in the International Ocean-Colour Coordinating Group (IOCCG). The IOCCG, along with the Committee on Earth Observation Satellites (CEOS) Ocean Colour Radiometry Virtual Constellation (OCR-VC), is developing the International Network for Sensor Inter-comparison and Uncertainty assessment for Ocean Color Radiometry (INSITU-OCR). The INSITU-OCR has identified, amongst other issues, the crucial need for sustained in situ observations for product validation, with longterm measurement programs established and maintained beyond any individual mission. Recently, the NOAA/STAR Ocean Color Team has been making in situ validation measurements continually since the launch in fall 2011 of the Visible Infrared Imaging Radiometer Suite (VIIRS) aboard the Suomi National Polar-orbiting Partnership (SNPP) platform, part of the U.S. Joint Polar Satellite System (JPSS) program. NOAA ship time for the purpose of ocean color validation, however, had never been allocated until the cruise described herein. As the institutional lead for this cruise, NOAA/STAR invited external collaborators based on scientific objectives and existing institutional collaborations. The invited collaborators are all acknowledged professionals in the ocean color remote sensing community. Most of the cruise principal investigators (PIs) are also PIs of the VIIRS Ocean Color Calibration and Validation (Cal/Val) team, including groups from Stennis Space Center/Naval Research Laboratory (SSC/NRL) and the University of Southern Mississippi (USM); City College of New York (CCNY); University of Massachusetts Boston (UMB); University of South Florida (USF); University of Miami (U. Miami); and, the National Institute of Standards and Technology (NIST). These Cal/Val PIs participated directly, sent qualified researchers from their labs/groups, or else contributed specific instruments or equipment. Some of the cruise PIs are not part of the NOAA VIIRS Ocean Color Cal/Val team but were chosen to complement and augment the strengths of the Cal/Val team participants. Outside investigator groups included NASA Goddard Space Flight Center (NASA/GSFC), Lamont-Doherty Earth Observatory at Columbia University (LDEO), and the Joint Research Centre of the European Commission (JRC). This report documents the November 2014 cruise off the U.S. East Coast aboard the NOAA Ship Nancy Foster. This cruise was the first dedicated ocean color validation cruise to be supported by the NOAA Office of Marine and Air Operations (OMAO). A second OMAO-supported cruise aboard the Nancy Foster is being planned for late 2015. We at NOAA/STAR are looking forward to continuing dedicated ocean color validation cruises, supported by OMAO on NOAA vessels, on an annual basis in support of JPSS VIIRS on SNPP, J-1, J-2 and other forthcoming satellite ocean color missions from the U.S as well as other countries. We also look forward to working with the U.S. and the international ocean community for improving our understanding of global ocean optical, biological, and biogeochemical properties.JRC.H.1-Water Resource

A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome

Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCβ) as a critical mediator of this pathway and demonstrate that the PKCβ inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCβ and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents. DOI: http://dx.doi.org/10.7554/eLife.08648.00

Recent advances in understanding Marfan syndrome: should we now treat surgical patients with losartan?

OBJECTIVE: Marfan syndrome is a systemic connective tissue disorder caused by mutations in the fibrillin-1 gene. It was originally believed that Marfan syndrome results exclusively from the production of abnormal fibrillin-1 that leads to structurally weaker connective tissue when incorporated into the extracellular matrix. This effect seemed to explain many of the clinical features of Marfan syndrome, including aortic root dilatation and acute aortic dissection, which represent the main causes of morbidity and mortality in Marfan syndrome. METHODS: Recent molecular studies, most based on genetically defined mouse models of Marfan syndrome, have challenged this paradigm. These studies established the critical contribution of fibrillin-1 haploinsufficiency and dysregulated transforming growth factor-beta signaling to disease progression. RESULTS: It seems that many manifestations of Marfan syndrome are less related to a primary structural deficiency of the tissues than to altered morphogenetic and homeostatic programs that are induced by altered transforming growth factor-beta signaling. Most important, transforming growth factor-beta antagonism, through transforming growth factor-beta neutralizing antibodies or losartan (an angiotensin II type 1 receptor antagonist), has been shown to prevent and possibly reverse aortic root dilatation, mitral valve prolapse, lung disease, and skeletal muscle dysfunction in a mouse model of Marfan syndrome. CONCLUSION: There are indicators that losartan, a drug widely used to treat arterial hypertension in humans, offers the first potential for primary prevention of clinical manifestations in Marfan syndrome

Murine model of surgically induced acute aortic dissection type A

This study aimed at developing a murine model of surgically induced acute aortic dissection type A for investigation of the formation and progression of acute aortic dissection and to test whether this system could be used for biomarker discovery

Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism

Angiotensin II (AngII) mediates progression of aortic aneurysm, but the relative contribution of its type 1 (AT1) and type 2 (AT2) receptors remains unknown. We show that loss of AT2 expression accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan syndrome (MFS). The selective AT1 receptor blocker (ARB) losartan abrogated aneurysm progression in the mice; full protection required intact AT2 signaling. The angiotensin-converting enzyme inhibitor (ACEi) enalapril, which limits signaling through both receptors, was less effective. Both drugs attenuated canonical transforming growth factor-β? (TGFβ) signaling in the aorta, but losartan uniquely inhibited TGFβ-mediated activation of extracellular signal-regulated kinase (ERK), by allowing continued signaling through AT2. These data highlight the protective nature of AT2 signaling and potentially inform the choice of therapies in MFS and related disorders.5 page(s