Breath acetone concentration: too heterogeneous to constitute a diagnosis or prognosis biomarker in heart failure? A systematic review and meta-analysis

Introduction: Exhaled breath acetone (ExA) has been investigated as a biomarker for heart failure (HF). Yet, barriers to its use in the clinical field have not been identified. The aim of this systematic review and meta-analysis was to assess the ExA heterogeneity and factors of variability in healthy controls (HC), to identify its relations with HF diagnosis and prognostic factors and to assess its diagnosis and prognosis accuracy in HF patients. Methods: A systematic search was conducted in PUBMED and Web of Science database. All studies with HC and HF patients with a measured ExA were included and studies providing ExA’s diagnosis and prognosis accuracy were identified. Results: Out of 971 identified studies, 18 studies involving 833 HC and 1009 HF patients were included in the meta-analysis. In HC, ExA showed an important heterogeneity (I²=99%). Variability factors were fasting state, sampling type and analytical method. The mean ExA was 1.89 times higher in HF patients vs. HC (782 [531-1032] vs. 413 [347-478] ppbv; p<0.001). One study showed excellent diagnosis accuracy, and one showed a good prognosis value. ExA correlated with New York Heart Association (NYHA) dyspnea (p<0.001) and plasma brain natriuretic peptide (p<0.001). Studies showed a poor definition and reporting of included subjects. Discussion: Despite the between-study heterogeneity in HC, the evidence of an excellent diagnosis and prognosis value of ExA in HF from single studies can be extended to clinical populations worldwide. Factors of variability (ExA procedure and breath sampling) could further improve the diagnosis and prognosis values of this biomarker in HF patients.

A Mediterranean-Based Ketogenic Diet Application Compared to a Calorie-Restricted Low-Fat Diet Application on Cardiometabolic Risk in Adults With Overweight or Obesity

Objectives To determine the effects of a Mediterranean-based ketogenic weight loss diet app paired with a breath acetone biofeedback device compared to a relevant comparator arm on blood biomarkers of cardiometabolic risk in a hands-off, real-world setting. Methods Participants (N = 155) with overweight/obesity (41 ± 11 years, BMI = 32 ± 9 kg/m2, 71% female) were randomized to one of two diet groups, with interventions delivered entirely via mobile app without in-person interaction with study staff: i) a Mediterranean-based ketogenic diet paired with a breath acetone biofeedback device (Keyto); or ii) a calorie-restricted low-fat diet (WW). Participants took daily weight measurements on an at-home wireless scale and a third-party laboratory obtained fasted blood samples at baseline and at 12 weeks. Results Based on intention-to-treat analysis, participants in the Keyto group lost more weight than those in the WW group (−3.1 kg; 95% CI, −4.6 kg to −1.5 kg; P &lt; 0.001). Likewise, those randomized to the Keyto app experienced greater improvements in markers of glycemic control (HbA1c; −0.2%; 95% CI, −0.3% to −0.1%; P &lt; 0.001) and hepatic function (alanine aminotransferase, alkaline phosphatase, globulin; P &lt; 0.01) compared to the WW group. In follow-up analyses accounting for baseline weight and change in body mass, the effects of group assignment on these cardiometabolic risk markers were found to remain significant independent of differences in weight loss between groups. No other differences in blood markers, including lipids and lipoproteins, were found. Conclusions Among adults with overweight or obesity, assignment to the Keyto app, as compared to the WW app, resulted in greater weight loss and cardiometabolic improvements that appeared to be independent of weight loss. These findings suggest that a Mediterranean-based ketogenic diet app paired with a breath acetone biofeedback device is effective at improving cardiometabolic health beyond weight loss in a real-world setting. Funding Sources Canadian Institutes of Health Research (CIHR), Michael Smith Foundation for Health Research (MSFHR), Mitacs Accelerate International with Keyto Inc. as the industry partner.

Metabolomics and a Breath Sensor Identify Acetone as a Biomarker for Heart Failure

Background Multiomics delivers more biological insight than targeted investigations. We applied multiomics to patients with heart failure with reduced ejection fraction (HFrEF). Methods 46 patients with HFrEF and 20 controls underwent metabolomic profiling, including liquid/gas chromatography mass spectrometry (LCMS/GCMS) and solid-phase microextraction (SPME) volatilomics in plasma and urine. HFrEF was defined using left ventricular global longitudinal strain, ejection fraction and NTproBNP. A consumer breath acetone (BrACE) sensor validated results in n=73. Results 28 metabolites were identified by GCMS, 35 by LCMS and 4 volatiles by SPME in plasma and urine. Alanine, aspartate and glutamate, citric acid cycle, arginine biosynthesis, glyoxylate and dicarboxylate metabolism were altered in HFrEF. Plasma acetone correlated with NT-proBNP (r = 0.59, 95% CI 0.4 to 0.7), 2-oxovaleric and cis-aconitic acid, involved with ketone metabolism and mitochondrial energetics. BrACE> 1.5 ppm discriminated HF from other cardiac pathology (AUC 0.8, 95% CI 0.61 to 0.92, P < 0.0001). Conclusion Breath acetone discriminated HFrEF from other cardiac pathology using a consumer sensor, but was not cardiac specific.

Acetone Bio-Sniffer (Gas-Phase Biosensor) for Monitoring of Human Volatile Using Enzymatic Reaction of Secondary Alcohol Dehydrogenase

We developed a highly sensitive acetone bio-sniffer (gas-phase biosensor) based on an enzyme reductive reaction to monitor breath acetone concentration. The acetone bio-sniffer device was constructed by attaching a flow-cell with nicotinamide adenine dinucleotide (NADH)-dependent secondary alcohol dehydrogenase (S-ADH) immobilized membrane onto a fiber-optic NADH measurement system. This system utilizes an ultraviolet light emitting diode as an excitation light source. Acetone vapor was measured as the fluorescence of NADH consumption by the enzymatic reaction of S-ADH. A phosphate buffer that contained oxidized NADH was circulated into the flow-cell to rinse the products and the excessive substrates from the optode; thus, the bio-sniffer enables the real-time monitoring of acetone vapor concentration. A photomultiplier tube detects the change in the fluorescence emitted from NADH. The relationship between the fluorescence intensity and acetone concentration was identified to be from 20 ppb to 5300 ppb. This encompasses the range of concentration of acetone vapor found in the breath of healthy people and of those suffering from disorders of carbohydrate metabolism. Then, the acetone bio-sniffer was used to monitor the exhaled breath acetone concentration change before and after a meal. When the sensing region was exposed to exhaled breath, the fluorescence intensity decreased and reached saturation immediately. Then, it returned to the initial state upon cessation of the exhaled breath flow. We anticipate its future use as a non-invasive analytical tool for the assessment of lipid metabolism in exercise, fasting and diabetes mellitus.