Plasma myo-inositol elevation in heart failure: clinical implications and prognostic significance. Results from the BElgian and CAnadian MEtabolomics in HFpEF (BECAME-HF) research project

Abstract

Background: The metabolic environment plays a crucial role in the development of heart failure (HF). Our prior research demonstrated that myo-inositol, a metabolite transported by the sodium-myo-inositol co-transporter 1 (SMIT-1), can induce oxidative stress and may be detrimental to heart function. However, plasmatic myo-inositol concentration has not been comprehensively assessed in large cohorts of patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF).

Methods: Plasmatic myo-inositol levels were measured using mass spectrometry and correlated with clinical characteristics in no HF subjects and patients with HFrEF and HFpEF from Belgian (male, no HF, 53%; HFrEF, 84% and HFpEF, 40%) and Canadian cohorts (male, no HF, 51%; HFrEF, 92% and HFpEF, 62%).

Findings: Myo-inositol levels were significantly elevated in patients with HF, with a more pronounced increase observed in the HFpEF population of both cohorts. After adjusting for age, sex, body mass index, hypertension, diabetes, and atrial fibrillation, we observed that both HFpEF status and impaired kidney function were associated with elevated plasma myo-inositol. Unlike HFrEF, abnormally high myo-inositol (≥69.8 μM) was linked to unfavourable clinical outcomes (hazard ratio, 1.62; 95% confidence interval, [1.05-2.5]) in patients with HFpEF. These elevated levels were correlated with NTproBNP, troponin, and cardiac fibrosis in this subset of patients.

Interpretation: Myo-inositol is a metabolite elevated in patients with HF and strongly correlated to kidney failure. In patients with HFpEF, high myo-inositol levels predict poor clinical outcomes and are linked to markers of cardiac adverse remodelling. This suggests that myo-inositol and its transporter SMIT1 may have a role in the pathophysiology of HFpEF.

Funding: BECAME-HF was supported by Collaborative Bilateral Research Program Québec - Wallonie-Brussels Federation.

Keywords: HFpEF; Heart failure; Kidney; Metabolites; Myo-inositol; Prognosis.

Fig. 1

Plasma myo-inositol (MYO) levels in no HF individuals and patients with HF from the Belgian discovery (a, c) and Canadian confirmation (b, d) cohorts. a and b, myo-inositol concentrations in no HF individuals, patients with HFrEF or HFpEF. Scatterplot of myo-inositol concentrations in no HF individuals, patients with HFrEF or HFpEF. Black line represents the median with interquartile range (IQR, P25–P75, where P stands for percentile). Statistical analysis by one-way ANOVA with Bonferroni’s post-hoc test; c and d, myo-inositol concentrations among the different patient subgroups (no HF individuals, HFrEF, and HFpEF). Plasma myo-inositol level groups (tertiles): black square: low myo-inositol level, corresponding to 1st tertile; light grey square: intermediate myo-inositol level, 2nd tertile; dark grey square: high myo-inositol level, 3rd tertile. Statistical analysis by global subgroup Chi-square test, (no HF vs. HFrEF vs. HFpEF) is presented. MYO, myo-inositol; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction.

Fig. 2

Clinical parameters associated with myo-inositol. a, b correlation between eGFR and myo-inositol concentrations in the Belgian and Canadian cohorts; c, plasmatic myo-inositol level in no HF individuals and patients with HF, with or without renal dysfunction. no HF individuals and patients with HF were sorted according to eGFR. Statistical analysis by one-way ANOVA with Bonferroni’s post-hoc test; d, Plasmatic myo-inositol level in no HF individuals and patients with HF, with or without diabetes. c and d, Black line represents the median with interquartile range (IQR, P25–P75, where P stands for percentile). Statistical analyses by Wilcoxon rank-sum test; e, Linear regression between and MAGGIC risk score according to HF subgroup. Shaded area represents 95% confidence band. eGFR, estimated glomerular filtration rate; MYO, myo-inositol; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction.

Fig. 3

Prognostic impact of high myo-inositol (MYO) levels in HF. a, Kaplan–Meier curves for the 5-year composite endpoint in patients with HFrEF (left) or HFpEF (right) according to abnormal cut-off of plasma myo-inositol defined in no HF individuals from the Belgian discovery cohort; b, Spline curves between continuous MYO levels and the hazard ratio of composite endpoint (composite of HF hospitalization and all-cause mortality) in patients with HFrEF (left) or HFpEF (right). Dotted lines areas represent 95% confidence band; c, multivariable Cox regression, model for predicting the composite endpoint. BM, baseline model; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HR, hazard ratio. HFrEF, heart failure with reduced ejection fraction; eGFR, estimated glomerular filtration rate; MYO, myo-inositol.

Fig. 4

Correlation between plasma myo-inositol and cardiac biomarkers in no HF and HFpEF individuals. Simple linear regression of MYO and: a, NTproBNP (no HF individuals n = 67, HFpEF n = 132); b, Troponin (no HF individuals n = 83, HFpEF n = 130); c, FGF-23 (no HF individuals n = 94, HFpEF n = 136); d, Extracellular volume (no HF individuals n = 79, HFpEF n = 112). 69.8 μM MYO level cut-off is highlighted with a dotted line. MYO, myo-inositol; HFpEF, heart failure with preserved ejection fraction; NTproBNP, N-terminal pro b-type natriuretic peptide; FGF-23, fibroblast growth factor 23.