Predictors of mortality in rheumatoid arthritis-associated interstitial lung disease.

Interstitial lung disease (ILD) is a common pulmonary manifestation of rheumatoid arthritis. There is lack of clarity around predictors of mortality and disease behaviour over time in these patients.We identified rheumatoid arthritis-related interstitial lung disease (RA-ILD) patients evaluated at National Jewish Health (Denver, CO, USA) from 1995 to 2013 whose baseline high-resolution computed tomography (HRCT) scans showed either a nonspecific interstitial pneumonia (NSIP) or a "definite" or "possible" usual interstitial pneumonia (UIP) pattern. We used univariate, multivariate and longitudinal analytical methods to identify clinical predictors of mortality and to model disease behaviour over time.The cohort included 137 subjects; 108 had UIP on HRCT (RA-UIP) and 29 had NSIP on HRCT (RA-NSIP). Those with RA-UIP had a shorter survival time than those with RA-NSIP (log rank p=0.02). In a model controlling for age, sex, smoking and HRCT pattern, a lower baseline % predicted forced vital capacity (FVC % pred) (HR 1.46; p<0.0001) and a 10% decline in FVC % pred from baseline to any time during follow up (HR 2.57; p<0.0001) were independently associated with an increased risk of death.Data from this study suggest that in RA-ILD, disease progression and survival differ between subgroups defined by HRCT pattern; however, when controlling for potentially influential variables, pulmonary physiology, but not HRCT pattern, independently predicts mortality.

Transgenic over-expression of YY1 induces pathologic cardiac hypertrophy in a sex-specific manner.

YY1 can activate or repress transcription of various genes. In cardiac myocytes in culture YY1 has been shown to regulate expression of several genes involved in myocyte pathology. YY1 can also acutely protect the heart against detrimental changes in gene expression. In this study we show that cardiac over-expression of YY1 induces pathologic cardiac hypertrophy in male mice, measured by changes in gene expression and lower ejection fraction/fractional shortening. In contrast, female animals are protected against pathologic gene expression changes and cardiac dysfunction. Furthermore, we show that YY1 regulates, in a sex-specific manner, the expression of mammalian enable (Mena), a factor that regulates cytoskeletal actin dynamics and whose expression is increased in several models of cardiac pathology, and that Mena expression in humans with heart failure is sex-dependent. Finally, we show that sex differences in YY1 expression are also observed in human heart failure. In summary, this is the first work to show that YY1 has a sex-specific effect in the regulation of cardiac pathology.

miRNA expression in pediatric failing human heart.

miRNAs are short regulatory RNAs that can regulate gene expression through interacting with the 3'UTR of target mRNAs. Although the role of miRNAs has been extensively studied in adult human and animal models of heart disease, nothing is known about their expression in pediatric heart failure patients. Different than adults with heart failure, pediatric patients respond well to phosphodiesterase inhibitor (PDEi) treatment, which is safe in the outpatient setting, results in fewer heart failure emergency department visits, fewer cardiac hospital admissions and improved NYHA classification. We have recently shown that pediatric heart failure patients display a unique molecular profile that is different from adults with heart failure. In this study we show for the first time that pediatric heart failure patients display a unique miRNA profile, and that expression of some miRNAs correlate with response to PDEi treatment. Moreover, we show that expression of Smad4, a potential target for PDEi-regulated miRNAs, is normalized in PDEi-treated patients. Since miRNAs may be used as therapy for human heart failure, our results underscore the importance of defining the molecular characteristics of pediatric heart failure patients, so age-appropriate therapy can be designed for this population.

Presence of Air Trapping and Mosaic Attenuation on Chest Computed Tomography Predicts Survival in Chronic Hypersensitivity Pneumonitis.

RATIONALE: Significant heterogeneity of computed tomography (CT) presentation exists within chronic hypersensitivity pneumonitis (HP). There are limited data aimed at delineating the prognostic value of specific CT features, distribution, and patterns in chronic HP. OBJECTIVES: To examine whether the presence of CT mosaic attenuation (MA) and air trapping (AT), and the distribution or patterns of fibrosis impact survival in subjects with chronic HP. METHODS: We retrospectively identified 110 consecutively enrolled, well-characterized, biopsy-proven adult subjects with chronic HP between 1982 and 2015 from the National Jewish Health interstitial lung disease research database. The first available CT scan of diagnostic quality from each subject was formally evaluated for specific CT findings associated with chronic HP and for overall CT pattern. A Cox proportional hazards model was used to identify independent predictors in time-to-death analysis, and bootstrap analysis was performed for internal model validation. RESULTS: Fibrotic HP (65%; 72/110) was most often peripheral in the axial plane and lower lung preponderant. The distribution of lung disease in those without fibrosis was most often axially and zonally diffuse. There was no association between survival and CT distribution or CT pattern in the whole cohort or within the fibrotic subset of subjects. After multivariate adjustment, AT/MA was independently associated with survival in the whole cohort (HR = 0.26; 95% confidence interval = 0.07-0.97). Results were similar after restricting the analyses to fibrotic HP cases. CONCLUSIONS: Among subjects with chronic HP, the presence of CT AT/MA may identify subjects with better prognosis.