Frank Cikach

Single Exhaled Breath Metabolomic Analysis Identifies Unique Breathprint in Patients With Acute Decompensated Heart Failure

To the Editor: Acute decompensated heart failure (ADHF) is the most common indication for hospital admission, particularly in the elderly, yet the identification of those with impending decompensation using conventional clinical methods is unreliable and frequently leaves insufficient lag time for

Metabolomic analysis of breath volatile organic compounds reveals unique breathprints in children with inflammatory bowel disease: a pilot study.

Breath testing is becoming an important diagnostic method to evaluate many disease states. In the light of rising healthcare costs, is important to develop a simple non‐invasive tool to potentially identify paediatric patients who need endoscopy for suspected inflammatory bowel disease (IBD).

The Breathprints in Patients With Liver Disease Identify Novel Breath Biomarkers in Alcoholic Hepatitis

BACKGROUND & AIMS Selected-ion flow-tube mass spectrometry 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 between 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 control subjects (n = 43). We used selected-ion flow-tube mass spectrometry 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 to 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 control subjects. Mean concentrations of TMA and pentane (TAP) were particularly high in breath samples from patients with AH, compared with those with acute decompensation or control subjects (for both, P < .001). Using receiver operating characteristic curve analysis, we developed a model for the diagnosis of AH based on breath levels of TAP. TAP scores of 36 or higher identified the patients with AH (area under the receiver operating characteristic curves = 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). CONCLUSIONS 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.

Analysis of breath volatile organic compounds as a noninvasive tool to diagnose nonalcoholic fatty liver disease in children

Objective Nonalcoholic fatty liver disease (NAFLD) is one of the most common complications of childhood obesity. Our objective was to investigate the association of breath volatile organic compounds with the diagnosis of NAFLD in children. Methods Patients were screened with an ultrasound of the abdomen to evaluate for NAFLD. Exhaled breath was collected and analyzed per protocol using selective ion flow tube mass spectrometry (SIFT-MS). Results Sixty patients were included in the study (37 with NAFLD and 23 with normal liver). All children were overweight or obese. The mean age was 14.1±2.8 years and 50% were female. A comparison of the SIFT-MS results of patients with NAFLD with those with normal liver on ultrasound revealed differences in concentration of more than 15 compounds. A panel of four volatile organic compounds can identify the presence of NAFLD with good accuracy (area under the receiver operating characteristic curve of 0.913 in the training set and 0.763 in the validation set). Breath isoprene, acetone, trimethylamine, acetaldehyde, and pentane were significantly higher in the NAFLD group compared with normal liver group (14.7 ppb vs. 8.9 for isoprene; 71.7 vs. 36.9 for acetone; 5.0 vs. 3.2 for trimethylamine; 35.1 vs. 26.0 for acetaldehyde; and 13.3 vs. 8.8 for pentane, P<0.05 for all). Conclusion Exhaled breath analysis is a promising noninvasive method to detect fatty liver in children. Isoprene, acetone, trimethylamine, acetaldehyde, and pentane are novel biomarkers that may help to gain insight into pathophysiological processes leading to the development of NAFLD.

Shot-noise Limited Faraday Rotation Spectroscopy for Detection of Nitric Oxide Isotopes in Breath, Urine, and Blood

Measurement of NO and/or its metabolites in the various body compartments has transformed our understanding of biology. The inability of the current NO measurement methods to account for naturally occurring and experimental NO isotopes, however, has prevented the scientific community from fully understating NO metabolism in vivo. Here we present a mid-IR Faraday rotation spectrometer (FRS) for detection of NO isotopes. The instrument utilizes a novel dual modulation/demodulation (DM) FRS method which exhibits noise performance at only 2 times the fundamental quantum shot-noise level and provides the record sensitivity in its class. This is achieved with a system that is fully autonomous, robust, transportable, and does not require cryogenic cooling. The DM-FRS enables continuous monitoring of nitric oxide isotopes with the detection limits of 3.72 ppbv/Hz1/2 to14NO and 0.53 ppbv/Hz1/2 to15NO using only 45 cm active optical path. This DM-FRS measurement method can be used to improve the performance of conventional FRS sensors targeting other radical species. The feasibility of the instrument to perform measurements relevant to studies of NO metabolism in humans is demonstrated.

Breathprints of childhood obesity: changes in volatile organic compounds in obese children compared with lean controls.

The objective of this study was to investigate changes in volatile organic compounds (VOCs) in exhaled breath in overweight/obese children compared with their lean counterparts.

Breath Analysis in Pulmonary Arterial Hypertension

BACKGROUND Pulmonary arterial hypertension (PAH) is a progressive and devastating condition characterized by vascular cell proliferation and is associated with several metabolic derangements. We hypothesized that metabolic derangements in PAH can be detected by measuring metabolic by-products in exhaled breath. METHODS We collected breath and blood samples from patients with PAH at the time of right-sided heart catheterization (n=31) and from healthy control subjects (n=34). Breath was analyzed by selected ion flow tube-mass spectrometry in predetermined training and validation cohorts. RESULTS Patients with PAH were 51.5±14 years old, and 27 were women (85%). Control subjects were 38±13 years old, and 22 were women (65%). Discriminant analysis in the training set identified three ion peaks (H3O+29+, NO+56+, and O2+98+) and the variable age that correctly classified 88.9% of the individuals. In an independent validation cohort, 82.8% of the individuals were classified correctly. The concentrations of the volatile organic compounds 2-propanol, acetaldehyde, ammonia, ethanol, pentane, 1-decene, 1-octene, and 2-nonene were different in patients with PAH compared with control subjects. Exhaled ammonia was higher in patients with PAH (median [interquartile range]: 94.7 parts per billion (ppb) [70-129 ppb] vs 60.9 ppb [46-77 ppb], P<.001) and was associated with right atrial pressure (ρ=0.57, P<.001), mean pulmonary artery pressure (ρ=0.43, P=.015), cardiac index by thermodilution (ρ=-0.39, P=.03), pulmonary vascular resistance (ρ=0.40, P=.04), mixed venous oxygen (ρ=-0.59, P<.001), and right ventricular dilation (ρ=0.42, P=.03). CONCLUSIONS Breathprint is different between patients with PAH and healthy control subjects. Several specific compounds, including ammonia, were elevated in the breath of patients with PAH. Exhaled ammonia levels correlated with severity of disease.

Sublingual microcirculation in pulmonary arterial hypertension

RATIONALE Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy that leads to failure of the right ventricle and premature death. OBJECTIVES To determine whether the sublingual microcirculation is affected in patients with PAH compared with healthy age- and sex-matched control subjects. METHODS Using the CapiScope Handheld Video Capillaroscope we measured the sublingual microvasculature density, flow index, tortuosity, and curvature. Videos were acquired immediately after right heart catheterization, and determinations were made off-line by investigators blinded to the group assignment or hemodynamics. MEASUREMENTS AND MAIN RESULTS In this cross-sectional pilot study, we included 26 patients with PAH (age, mean ± SD, 56.7 ± 10 yr; 77% women) and 14 healthy control subjects (age, 53.1 ± 12 yr; 71% women). Sublingual microvasculature flow index was lower (2 ± 0.66 vs. 2.7 ± 0.37, P < 0.001) with higher heterogeneity index (0.63 ± 0.63 vs. 0.25 ± 0.25, P = 0.04) in patients with PAH than control subjects. Microvasculature density was similar between the groups, but tortuosity was more pronounced in patients than control subjects (tort 0: 45 ± 19 vs. 23.6 ± 12, P = 0.001 and tort 1: 0.2 ± 0.16 vs. 0.06 ± 0.04, P < 0.001). CONCLUSIONS Patients with PAH showed lower sublingual microvasculature flow index and higher tortuosity compared with healthy age- and sex-matched control subjects. Further investigations are needed to assess whether this methodology can provide information on disease prognosis and/or response to therapy in this condition.

Analysis of breath volatile organic compounds in children with chronic liver disease compared to healthy controls

Breath testing is increasingly being used as a non-invasive diagnostic tool for disease states across medicine. The purpose of this study was to compare the levels of volatile organic compounds (VOCs) as measured by mass spectrometry in healthy children and children with chronic liver disease (CLD). Patients between the ages of 6 and 21 were recruited for the study. Control subjects were recruited from a general pediatric population during well-child visits, while patients with CLD were recruited from pediatric gastroenterology clinic visits. The diagnosis of CLD was confirmed by clinical, laboratory, and/or histologic data. A single exhaled breath was collected and analyzed by means of selected-ion flow-tube mass spectrometry per protocol. A total of 104 patients were included in the study (49 with CLD and 55 healthy controls). Of the patients with CLD, 20 had advanced liver fibrosis (F3-F4). In the CLD cohort, levels of exhaled 1-decene, 1-heptene, 1-octene and 3 methylhexane were found to be significantly higher when compared to the control population (p < 0.001, p = 0.035, p < 0.001 and p = 0.004, respectively). Exhaled 1-nonene, (E)-2-nonene, and dimethyl sulfide levels were found to be significantly lower in patients with CLD patients when compared to controls (p < 0.001, p < 0.001 and p = 0.007, respectively). By utilizing a combination of five of the VOCs, the accuracy for predicting the presence of CLD was excellent (AUROC = 0.97). Our study demonstrates that children with CLD have a unique pattern of exhaled VOCs. Utilization of a combination of these VOCs represents a promising non-invasive diagnostic tool and may provide further insight into the pathophysiologic processes and pathways leading to pediatric liver disease. Further analysis of these compounds in external cohorts are needed to validate our findings.

Combined aortic root replacement and mitral valve surgery: The quest to preserve both valves

Objectives: Coexisting aortic root and mitral valve pathology is increasingly recognized among patients undergoing surgery. We characterized the pathology and surgical outcomes of patients with combined aortic root and mitral disease. Methods: From 1987 to 2016, 118 patients (age 52.40 ± 17.71 years) underwent concomitant aortic root and mitral procedures (excluding aortic stenosis, endocarditis, and reoperations). Aortic root pathologies included degenerative aneurysm (94%) and aortic dissection (6%). The aortic valve was bicuspid in 15% of patients and had normally functioning tricuspid leaflets in 23% of patients. Marfan syndrome was present in 34 patients (29%). Degenerative mitral disease predominated (78%). Mitral procedures were repair (86%) and replacement (14%), and root procedures were valve‐preserving root reimplantation (36%), Bentall procedure (47%), and homograft root replacement (17%). In the last 10 years, the combination of valve‐preserving root reimplantation and mitral repair has increased to 50%. Kaplan–Meier and competing risk analyses were used to estimate survival and reoperation. Results: There were 2 (1.7%) operative deaths with survival of 79% and 71% at 10 and 15 years, respectively, and reoperation rates of 4.7% and 12% after 5 and 10 years, respectively. There were no operative deaths in patients with combined valve‐preserving root reimplantation and mitral repair, with survival of 89% and reoperation rate of 7.8% at 10 years. Among patients with Bentall/homograft and mitral operation, survival was 73% and reoperation was 9.8% at 10 years. Conclusions: In patients with aortic root and mitral pathology, combined surgical risk is low and valve durability is high. When possible, valve‐preserving root reimplantation and mitral repair should be considered to avoid prosthesis degeneration, anticoagulation, and lifestyle limitations.