Proteoglycan accumulation is a hallmark of medial degeneration in thoracic aortic aneurysm and dissection (TAAD). Here, we defined the aortic proteoglycanome using mass spectrometry, and based on the findings, investigated the large aggregating proteoglycans aggrecan and versican in human ascending TAAD and a mouse model of severe Marfan syndrome. The aortic proteoglycanome comprises 20 proteoglycans including aggrecan and versican. Antibodies against these proteoglycans intensely stained medial degeneration lesions in TAAD, contrasting with modest intralamellar staining in controls. Aggrecan, but not versican, was increased in longitudinal analysis of Fbn1mgR/mgR aortas. TAAD and Fbn1mgR/mgR aortas had increased aggrecan and versican mRNAs, and reduced expression of a key proteoglycanase gene, ADAMTS5, was seen in TAAD. Fbn1mgR/mgR mice with ascending aortic dissection and/or rupture had dramatically increased aggrecan staining compared with mice without these complications. Thus, aggrecan and versican accumulation in ascending TAAD occurs via increased synthesis and/or reduced proteolytic turnover, and correlates with aortic dissection/rupture in Fbn1mgR/mgR mice. Tissue swelling imposed by aggrecan and versican is proposed to be profoundly deleterious to aortic wall mechanics and smooth muscle cell homeostasis, predisposing to type-A dissections. These proteoglycans provide potential biomarkers for refined risk stratification and timing of elective aortic aneurysm repair.

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Background & Aims Selected-ion flow-tube mass spectrometry (SIFT-MS) can precisely identify trace gases in the human breath, in the parts-per-billion range. We investigated whether concentrations of volatile compounds in breath samples correlate with the diagnosis of alcoholic hepatitis (AH) and the severity of liver disease in patients with AH. Methods We recruited patients with liver disease from a single tertiary care center. The study population was divided those with AH with cirrhosis (n=40) and those with cirrhosis with acute decompensation from etiologies other than alcohol (n=40); individuals without liver disease served as controls (n=43). We used SIFT-MS to identify and measure 14 volatile compounds in breath samples from fasted subjects. We used various statistical analyses to compare clinical characteristics and breath levels of compounds among groups, and test the correlation between levels of compounds and severity of liver disease. Logistic regression analysis was performed to build a predictive model for AH. Results We identified 6 compounds (2-propanol, acetaldehyde, acetone, ethanol, pentane and trimethylamine [TMA]) whose levels were increased in patients with liver disease compared with controls. Mean concentrations of TMA, acetone, and pentane were particularly high in breath samples from patients with AH, compared to those with acute decompensation or controls (for both, P<.001). Using receiver operating characteristic curve analysis, we developed a model for the diagnosis of AH based on breath levels of TMA, acetone, and pentane (TAP). TAP scores of 36 or higher identified the patients with AH (AUC=0.92), with 90% sensitivity and 80% specificity. The levels of exhaled TMA had a low level of correlation with the severity of AH based on model for end-stage liver disease score (r=0.38; 95% confidence interval, 0.07–0.69; P=.018]. Conclusion Based on levels of volatile compounds in breath samples, we can identify patients with AH vs patients with acute decompensation or individuals without liver disease. Levels of exhaled TMA moderately correlate with the severity of AH. These findings might be used in diagnosis of AH or in determining patient prognosis.

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