Association between admission plasma 2-oxoglutarate levels and short-term outcomes in patients with acute heart failure: a prospective cohort study

Abstract

Background 2-oxoglutarate (2OG), an intermediate metabolite in the tricarboxylic acid cycle, has been found to associate with chronic heart failure (HF), but its effect on short-term adverse outcomes in patients with acute HF (AHF) is uncertain. Methods This prospective cohort study included 411 consecutive hospitalized patients with AHF. During hospitalization, fasting plasma samples were collected within the first 24 h of admission. Plasma 2OG levels were measured by hydrophilic interaction liquid chromatography-liquid chromatography tandem mass spectrometry (HILIC-LC/MS/MS). All participants were followed up for six months. Multiple logistic regression was used to determine the odds ratio (OR) and 95% confidence interval (CI) for primary outcomes. Results The AHF cohort consisted of HF with preserved ejection fraction (EF) (64.7%), mid-range EF (16.1%), and reduced EF (19.2%), the mean age was 65 (±13) years, and 65.2% were male. Participants were divided into two groups based on median 2OG levels (μg/ml): low group (< 6.0, n = 205) and high group (≥6.0, n = 206). There was a relatively modest correlation between 2OG and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels (r = 0.25; p < 0.001). After adjusting for age, sex, and body mass index, we found that the progression of the NYHA classification was associated with a gradual increase in plasma 2OG levels (p for trend< 0.001). After six months of follow-up, 76 (18.5%) events were identified. A high baseline 2OG level was positively associated with a short-term rehospitalization and all-cause mortality (OR: 2.2, 95% CI 1.3–3.7, p = 0.003), even after adjusting for NT-proBNP and estimated glomerular filtration rate (eGFR) (OR: 1.9, 95% CI 1.1–3.4, p = 0.032). After a similar multivariable adjustment, the OR was 1.4 (95% CI 1.1–1.7, p = 0.018) for a per-SD increase in 2OG level. Conclusions High baseline 2OG levels are associated with adverse short-term outcomes in patients with AHF independent of NT-proBNP and eGFR. Hence plasma 2OG measurements may be helpful for risk stratification and treatment monitoring in AHF. Trial registration ChiCTR-ROC-17011240 . Registered 25 April 2017.

Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice

“…Changes in specific plasma metabolites, including AKG, in HF patients were shown to act as metabolic biomarkers with clinical applications for diagnostic and prognostic purposes. Previous clinical studies showed circulating AKG levels to be elevated in in AHF and CHF patients [ 5 , 6 , 12 , 13 ]. In contrast, in an animal experiment, no significant change in circulating AKG was observed in mice with pressure overload-induced cardiac hypertrophy, but an obvious decrease in circulating AKG was observed in mice with ischaemic HF [ 37 ].…”

“…Interestingly, the changes in circulating AKG levels reported in previous studies on HF metabolites are inconsistent. Some clinical studies have shown that an increase in circulating AKG levels in HF patients is associated with HF severity (NYHA classification) and adverse short-term outcomes and that circulating AKG levels thus can be used as a metabolic biomarker and contribute to the diagnosis and prognostic assessment of HF [ 5 , 6 , 12 , 13 ]. Another examination of the plasma metabolome in HF patients revealed no significant change in AKG [ 38 ].…”

“…The HILIC-LC-MS/MS system consisted of an Agilent 6460 Triple Quadrupole LC-MS/MS system with an ESI interface, as described previously [ 28 ]. Measurements were carried out as described in a previous study [ 13 ].…”

“…The circulating AKG concentration was found to decrease with ageing [ 8 ] and is elevated under fasted states [ 9 ], after acute exercise [ 10 ] and resistance exercise [ 11 ], and in HF [ 5 , 6 ]. Clinical studies showed that a high circulating AKG level was associated with HF severity (NYHA classification) and adverse outcome in acute HF (AHF) and chronic HF (AHF) patients [ 12 , 13 ]. As a circulating metabolic marker of HF, AKG may play a special role in risk stratification, prognostic evaluation, and treatment guidance for HF.…”

Identification of metabolomic profile related to adult Fontan pathophysiology

“…cis -aconitic acid and 2-oxoglutarate are major intermediates in the TCA cycle that perform a central role in energy metabolism [26] . Serum 2-oxoglutaric acid has been associated with a poor prognosis in heart failure patients, which was characterized by alterations in energy metabolism [27] , [28] . Recent findings using metabolomics to investigate protein alterations during cardiac ischemia have also shown decreases in several constituents of the TCA cycle [29] .…”