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Altered profiles of lipids and eicosanoids predict survival rate in patients with de novo or acute decompensated heart failure

ABSTRACT: Background: Heart failure (HF) is becoming an increasingly common problem, especially in the ageing population. Lipids are closely related to cardiovascular disease (CVD) pathology. Lipidomics as a comprehensive profiling tool is showing to be promising in the prediction of events and death due to CVD. In this study, eicosanoids and lipid profiles were measured to predict survival in patients with de novo or acute decompensated HF. Methods: Our study involved 50 patients (16 females, aged 30-96 years, mean age 73 years and 34 males, aged 46-86 years, mean age 71 years) with de novo or acute decompensated chronic HF admitted to our tertiary cardiovascular centre with the median follow-up of 7 months. Lipids were semiquantified using targeted lipidomic LC-MS/MS analysis. The concentration of eicosanoids was determined by a commercially available sandwich ELISA assay. Results: From 736 lipids and 3 eicosanoids we selected 39 significant lipids (by using the Mann-Whitney U test after Benjamini-Hochberg correction) where the highest number of representatives belonged to polyunsaturated phosphatidylcholines (PC). PC 42:10 (p=1.44x10-4) was evaluated as the most statistically significant in the surviving group with receiver operating characteristics of AUC=0.84 (p=3.24x10-7). Conclusion: Although the cardioprotective effect of polyunsaturated fatty acids (PUFA) is well known, in the present study we described a trend in PUFA esterified in PC, which were systematically elevated in surviving patients with HF. Using multivariate supervised discriminant analysis, the groups of surviving and non-surviving patients were classified with 90% accuracy.

INSTRUMENT(S): QTRAP 6500+

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: David Friedecky

PROVIDER: MSV000090646 | MassIVE | Fri Nov 04 12:43:00 GMT 2022

REPOSITORIES: MassIVE

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Project description:Background: Organ fibrosis due to excessive production of extracellular matrix (ECM) by resident fibroblasts is estimated to contribute to >45% of deaths in the Western world, including those due to cardiovascular diseases such as heart failure (HF). Here, we screened for small molecule inhibitors with a common ability to suppress activation of fibroblasts across organ systems. Methods: High content imaging of cultured cardiac, pulmonary and renal fibroblasts was employed to identify non-toxic compounds that blocked induction of markers of activation in response to the profibrotic stimulus, TGF-β. SW033291, which inhibits the eicosanoid-degrading enzyme, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), was chosen for follow-up studies with cultured adult rat ventricular fibroblasts (ARVFs) and human cardiac fibroblasts (CFs), and for evaluation in mouse models of cardiac fibrosis and diastolic dysfunction. Additional mechanistic studies were performed with CFs treated with exogenous eicosanoids. Results: Nine compounds, including SW033291, shared a common ability to suppress TGF-β-mediated activation of cardiac, pulmonary and renal fibroblasts. SW033291 dose-dependently inhibited TGF-β-induced expression of activation markers (e.g. α-smooth muscle actin and periostin) in ARVFs and normal human CFs, and reduced contractile capacity of the cells. Remarkably, the 15-PGDH inhibitor also reversed constitutive activation of fibroblasts obtained from explanted hearts from patients with HF. SW033291 blocked cardiac fibrosis induced by angiotensin II (Ang II) infusion and ameliorated diastolic dysfunction in an alternative model of systemic hypertension driven by combined uninephrectomy (UNX) and deoxycorticosterone acetate (DOCA) administration. Mechanistically, SW033291-mediated stimulation of ERK1/2 mitogen-activated protein kinase signaling was required for SW033291 to block CF activation. Of the 12 exogenous eicosanoids that were tested, only 12-hydroxyeicosatetraenoic acid (12[S]-HETE), which signals through the G protein-coupled receptor (GPCR), GPR31, recapitulated the suppressive effects of SW033291 on CF activation. Conclusions: Inhibition of degradation of eicosanoids, arachidonic acid-derived fatty acids that signal through GPCRs, is a potential therapeutic strategy for suppression of pathological organ fibrosis. In the heart, we propose that 15-PGDH inhibition triggers CF-derived autocrine/paracrine signaling by eicosanoids, including 12(S)-HETE, to stimulate ERK1/2 and block conversion of fibroblasts into activated cells that secrete excessive amounts of ECM and contribute of HF pathogenesis.

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Altered profiles of lipids and eicosanoids predict survival rate in patients with de novo or acute decompensated heart failure

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