Jordan Morningstar

Dimethylguanidino valeric acid is a marker of liver fat and predicts diabetes

Unbiased, “nontargeted” metabolite profiling techniques hold considerable promise for biomarker and pathway discovery, in spite of the lack of successful applications to human disease. By integrating nontargeted metabolomics, genetics, and detailed human phenotyping, we identified dimethylguanidino valeric acid (DMGV) as an independent biomarker of CT-defined nonalcoholic fatty liver disease (NAFLD) in the offspring cohort of the Framingham Heart Study (FHS) participants. We verified the relationship between DMGV and early hepatic pathology. Specifically, plasma DMGV levels were correlated with biopsy-proven nonalcoholic steatohepatitis (NASH) in a hospital cohort of individuals undergoing gastric bypass surgery, and DMGV levels fell in parallel with improvements in post-procedure cardiometabolic parameters. Further, baseline DMGV levels independently predicted future diabetes up to 12 years before disease onset in 3 distinct human cohorts. Finally, we provide all metabolite peak data consisting of known and unidentified peaks, genetics, and key metabolic parameters as a publicly available resource for investigations in cardiometabolic diseases.

Identification of specific metabolic pathways as druggable targets regulating the sensitivity to cyanide poisoning

Cyanide is a potent toxic agent, and the few available antidotes are not amenable to rapid deployment in mass exposures. As a result, there are ongoing efforts to exploit different animal models to identify novel countermeasures. We have created a pipeline that combines high-throughput screening in zebrafish with subsequent validation in two mammalian small animal models as well as a porcine large animal model. We found that zebrafish embryos in the first 3 days post fertilization (dpf) are highly resistant to cyanide, becoming progressively more sensitive thereafter. Unbiased analysis of gene expression in response to several hours of ultimately lethal doses of cyanide in both 1 and 7 dpf zebrafish revealed modest changes in iron-related proteins associated with the age-dependent cyanide resistance. Metabolomics measurements demonstrated significant age-dependent differences in energy metabolism during cyanide exposure which prompted us to test modulators of the tricarboxylic acid cycle and related metabolic processes as potential antidotes. In cyanide-sensitive 7 dpf larvae, we identified several such compounds that offer significant protection against cyanide toxicity. Modulators of the pyruvate dehydrogenase complex, as well as the small molecule sodium glyoxylate, consistently protected against cyanide toxicity in 7 dpf zebrafish larvae. Together, our results indicate that the resistance of zebrafish embryos to cyanide toxicity during early development is related to an altered regulation of cellular metabolism, which we propose may be exploited as a potential target for the development of novel antidotes against cyanide poisoning.

Association of Acylcarnitines With Left Ventricular Remodeling in Patients With Severe Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement

Importance Clinical practice guidelines currently endorse a reliance on clinical symptoms of overt left ventricular (LV) failure to time aortic valve replacement for severe aortic stenosis; however, delayed aortic valve replacement can result in irreversible LV injury and adverse outcomes. Blood metabolomic signatures possess prognostic value in heart failure; this study assesses whether they are informative in aortic stenosis. Objective To evaluate the value of metabolomic signatures in reflecting the extent of maladaptive LV remodeling in patients with end-stage aortic stenosis undergoing transcatheter aortic valve replacement, and to assess whether this procedure reverses metabolomic aberrations. Design, Setting, and Participants This study of 44 patients with symptomatic severe aortic stenosis who underwent transfemoral transcatheter aortic valve replacement at a single-center tertiary care hospital. Liquid chromatography–mass spectrometry-based metabolomic profiling was performed on blood samples collected before and 24 hours after the procedure, and analyses were conducted to identify metabolites related to the measures of LV remodeling. Main Outcomes and Measures We evaluated LV ejection fraction, LV mass index, and relative wall thickness, as well as levels of the acylcarnitines C16, C18:1, C18:2, C18, C26, choline, and kynurenine. Results We enrolled 44 patients with severe aortic stenosis with a mean (SD) age of 81.9 (8.5) years, of whom 23 (52%) were women. The mean (SD) LV ejection fraction was 56.7% (18.2%), mean (SD) LV mass index was 117.3 (41.4) g/m2, and relative wall thickness was 0.53 (0.14). The mean &bgr; values of acylcarnitines C16, C18:1, C18:2, C18, and C26 were independently associated with LV mass index (C16: mean, 19.24; 95% CI, 5.48-33.01; P = .008; C18:1: mean, 26.18; 95% CI, 14.04-38.32; P < 1.0 × 10-4; C18:2: mean, 17.42; 95% CI, 3.40-31.43; P = .02; C18: mean, 25.25; 95% CI, 10.91-39.58; P = .001; C26: mean, 19.93; 95% CI, 4.41-35.45; P = .01), even after adjustments for age, sex, diabetes status, renal function, and B-type natriuretic peptide (BNP). Circulating levels of C18:2 acylcarnitine were associated with LV ejection fraction before and after multivariable adjustment (mean, −6.11; 95% CI, −10.88 to 1.34; P = .01). Blood metabolite levels did not independently relate to relative wall thickness. Within 24 hours of transcatheter aortic valve replacement, circulating levels of C16 decreased by 30.2% (P = 7.3 × 10-6), C18:1 by 42.7% (P = 3.7 × 10-8), C18:2 by 37.3% (P = 5.1 × 10-6), and C18 by 38.3% (P = 3.4 × 10-5). Conclusions and Relevance In symptomatic patients with severe aortic stenosis undergoing transcatheter aortic valve replacement, circulating levels of long-chain acylcarnitines were independently associated with measures of maladaptive LV remodeling, and metabolic perturbations lessened after procedure completion. Further efforts are needed to determine the clinical applicability of these novel biomarkers.