Plasma metabolomics identify hydroxyproline as a potential player in the pathophysiogy of HFpEF

Abstract

A better understanding of metabolic modifications occurring in heart failure with preserved ejection fraction (HFpEF) could elucidate pathophysiological pathways and reveal new biomarkers and therapeutic targets. To compare metabolic profiles of HFpEF patients with healthy controls. Plasma concentrations of 21 amino acids and 12 organic acids were assessed using gas chromatograph-mass spectrometry in 70 HFpEF patients (75 ± 7.2 years old, 57% women) and 44 “old” controls (65 ± 9.8 years old, 50% women). After adjustment for age, sex and batch effects in a linear regression model, hydroxyproline ( P = 8.19 × 10 −5 ) and cysteine ( P = 1.04 × 10 −6 ) were significantly upregulated in HFpEF compared to controls ( Fig. 1 A). In patients, hydroxyproline levels were correlated to BMI ( r = 0.29, P = 0.015), renal function ( r = −0.26, P = 0.028), septal E/e′ ( r = 0.29, P = 0.018), pulmonary pressures eSPAP ( r = 0.29, P = 0.015) and myocardial fibrosis measured by CMR extracellular volume (ECV) ( r = 0.28, P = 0.031, Fig. 1 B), but not with age, indexed LA volumes nor NTproBNP levels. In multivariate linear regression, hydroxyproline was independently associated with BMI and ECV. We did not find any significant correlation between cysteine and clinical characteristics (age, BMI, diabetes, renal function, LA volumes, E/e′ ratio, ECV or NTproBNP) ( Table 1 ). Hydroxyproline, formed by hydroxylation of proline by prolyl hydroxylase, is a key player in the synthesis and stability of collagen and may as such contribute to the myocardial structural changes in HFpEF. Hydroxyproline's specific role in HFpEF and diastolic dysfunction is intriguing, and may be relevant both as a biomarker and drug target.