American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Feb 2014
Practice GuidelineAn official american thoracic society statement: pulmonary hypertension phenotypes.
Current classification of pulmonary hypertension (PH) is based on a relatively simple combination of patient characteristics and hemodynamics. This limits customization of treatment, and lacks the clarity of a more granular identification based on individual patient phenotypes. Rapid advances in mechanistic understanding of the disease, improved imaging methods, and innovative biomarkers now provide an opportunity to define PH phenotypes on the basis of biomarkers, advanced imaging, and pathobiology. This document organizes our current understanding of PH phenotypes and identifies gaps in our knowledge. ⋯ Accurate phenotyping of PH can be used in research studies to increase the homogeneity of study cohorts. Once the ability of the phenotypes to predict outcomes has been validated, phenotyping may also be useful for determining prognosis and guiding treatment. This important next step in PH patient care can optimally be addressed through a consortium of study sites with well-defined goals, tasks, and structure. Planning and support for this could include the National Institutes of Health and the U.S. Food and Drug Administration, with industry and foundation partnerships.
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Am. J. Respir. Crit. Care Med. · Feb 2014
Evidence for Right Ventricular Lipotoxicity in Heritable Pulmonary Arterial Hypertension.
Shorter survival in heritable pulmonary arterial hypertension (HPAH), often due to BMPR2 mutation, has been described in association with impaired right ventricle (RV) compensation. HPAH animal models are insulin resistant, and cells with BMPR2 mutation have impaired fatty acid oxidation, but whether these findings affect the RV in HPAH is unknown. ⋯ These data demonstrate that Bmpr2 mutation affects RV stress responses in a transgenic rodent model. Impaired RV hypertrophy and triglyceride and ceramide deposition are present as a function of RV mutant Bmpr2 in mice; fatty acid oxidation impairment in human HPAH RVs may underlie this finding. Further study of how BMPR2 mediates RV lipotoxicity is warranted.
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Am. J. Respir. Crit. Care Med. · Feb 2014
Simultaneous Targeting of Interleukin-1 and -18 is Required for Protection against Inflammatory and Septic Shock.
Sepsis is one of the leading causes of death around the world. The failure of clinical trials to treat sepsis demonstrates that the molecular mechanisms are multiple and are still insufficiently understood. ⋯ Our data point toward the therapeutic potential of neutralizing IL-1 and IL-18 simultaneously in sepsis, rather than inhibiting the upstream inflammatory caspases.
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Am. J. Respir. Crit. Care Med. · Feb 2014
Regulation of Hypoxia-Induced Pulmonary Hypertension by Vascular Smooth Muscle HIF-1alpha.
Chronic hypoxia induces pulmonary vascular remodeling, pulmonary hypertension, and right ventricular hypertrophy. At present, little is known about mechanisms driving these responses. Hypoxia-inducible factor-1α (HIF-1α) is a master regulator of transcription in hypoxic cells, up-regulating genes involved in energy metabolism, proliferation, and extracellular matrix reorganization. Systemic loss of a single HIF-1α allele has been shown to attenuate hypoxic pulmonary hypertension, but the cells contributing to this response have not been identified. ⋯ These results indicate that HIF-1α in smooth muscle contributes to pulmonary vascular remodeling and pulmonary hypertension in chronic hypoxia. However, loss of HIF-1 function in smooth muscle does not affect hypoxic cardiac remodeling, suggesting that the cardiac hypertrophy response is not directly coupled to the increase in pulmonary artery pressure.