Circulating acylcarnitine profile in human heart failure: A surrogate of fatty acid metabolic dysregulation in mitochondria and beyond

Matthieu Ruiz, François Labarthe, Annik Fortier, Bertrand Bouchard, Julie Thompson Legault, Virginie Bolduc, Odile Rigal, Jane Chen, Anique Ducharme, Peter A. Crawford, Jean Claude Tardif, Christine Des Rosiers

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Heart failure (HF) is associated with metabolic perturbations, particularly of fatty acids (FAs), which remain to be better understood in humans. This study aimed at testing the hypothesis that HF patients with reduced ejection fraction display systemic perturbations in levels of energy-related metabolites, especially those reflecting dysregulation of FA metabolism, namely, acylcarnitines (ACs). Circulating metabolites were assessed using mass spectrometry (MS)-based methods in two cohorts. The main cohort consisted of 72 control subjects and 68 HF patients exhibiting depressed left ventricular ejection fraction (25.9 ± 6.9%) and mostly of ischemic etiology with ≥2 comorbidities. HF patients displayed marginal changes in plasma levels of tricarboxylic acid cycle-related metabolites or indexes of mitochondrial or cytosolic redox status. They had, however, 22-79% higher circulating ACs, irrespective of chain length (P < 0.0001, adjusted for sex, age, renal function, and insulin resistance, determined by shotgun MS/MS), which reflects defective mitochondrial β-oxidation, and were significantly associated with levels of NH 2 -terminal pro-B-type natriuretic peptide levels, a disease severity marker. Subsequent extended liquid chromatography-tandem MS analysis of 53 plasma ACs in a subset group from the primary cohort confirmed and further substantiated with a comprehensive lipidomic analysis in a validation cohort revealed in HF patients a more complex circulating AC profile. The latter included dicarboxylic-ACs and dihydroxy-ACs as well as very long chain (VLC) ACs or sphingolipids with VLCFAs (>20 carbons), which are proxies of dysregulated FA metabolism in peroxisomes. Our study identified alterations in circulating ACs in HF patients that are independent of biological traits and associated with disease severity markers. These alterations reflect dysfunctional FA metabolism in mitochondria but also beyond, namely, in peroxisomes, suggesting a novel mechanism contributing to global lipid perturbations in human HF.

Original languageEnglish (US)
Pages (from-to)768-781
Number of pages14
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume313
Issue number4
DOIs
StatePublished - Oct 11 2017

Fingerprint

Mitochondria
Fatty Acids
Heart Failure
Peroxisomes
Tandem Mass Spectrometry
Sphingolipids
Citric Acid Cycle
acylcarnitine
Brain Natriuretic Peptide
Firearms
Proxy
Liquid Chromatography
Stroke Volume
Oxidation-Reduction
Insulin Resistance
Comorbidity
Mass Spectrometry
Carbon
Kidney
Lipids

Keywords

  • Acylcarnitines
  • Heart failure
  • Lipid oxidation
  • Metabolomics
  • Peroxisomes

Cite this

Circulating acylcarnitine profile in human heart failure : A surrogate of fatty acid metabolic dysregulation in mitochondria and beyond. / Ruiz, Matthieu; Labarthe, François; Fortier, Annik; Bouchard, Bertrand; Legault, Julie Thompson; Bolduc, Virginie; Rigal, Odile; Chen, Jane; Ducharme, Anique; Crawford, Peter A.; Tardif, Jean Claude; Des Rosiers, Christine.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 313, No. 4, 11.10.2017, p. 768-781.

Research output: Contribution to journalArticle

Ruiz, Matthieu ; Labarthe, François ; Fortier, Annik ; Bouchard, Bertrand ; Legault, Julie Thompson ; Bolduc, Virginie ; Rigal, Odile ; Chen, Jane ; Ducharme, Anique ; Crawford, Peter A. ; Tardif, Jean Claude ; Des Rosiers, Christine. / Circulating acylcarnitine profile in human heart failure : A surrogate of fatty acid metabolic dysregulation in mitochondria and beyond. In: American Journal of Physiology - Heart and Circulatory Physiology. 2017 ; Vol. 313, No. 4. pp. 768-781.
@article{10a9855e2dd1441e87541d02fe9335b8,
title = "Circulating acylcarnitine profile in human heart failure: A surrogate of fatty acid metabolic dysregulation in mitochondria and beyond",
abstract = "Heart failure (HF) is associated with metabolic perturbations, particularly of fatty acids (FAs), which remain to be better understood in humans. This study aimed at testing the hypothesis that HF patients with reduced ejection fraction display systemic perturbations in levels of energy-related metabolites, especially those reflecting dysregulation of FA metabolism, namely, acylcarnitines (ACs). Circulating metabolites were assessed using mass spectrometry (MS)-based methods in two cohorts. The main cohort consisted of 72 control subjects and 68 HF patients exhibiting depressed left ventricular ejection fraction (25.9 ± 6.9{\%}) and mostly of ischemic etiology with ≥2 comorbidities. HF patients displayed marginal changes in plasma levels of tricarboxylic acid cycle-related metabolites or indexes of mitochondrial or cytosolic redox status. They had, however, 22-79{\%} higher circulating ACs, irrespective of chain length (P < 0.0001, adjusted for sex, age, renal function, and insulin resistance, determined by shotgun MS/MS), which reflects defective mitochondrial β-oxidation, and were significantly associated with levels of NH 2 -terminal pro-B-type natriuretic peptide levels, a disease severity marker. Subsequent extended liquid chromatography-tandem MS analysis of 53 plasma ACs in a subset group from the primary cohort confirmed and further substantiated with a comprehensive lipidomic analysis in a validation cohort revealed in HF patients a more complex circulating AC profile. The latter included dicarboxylic-ACs and dihydroxy-ACs as well as very long chain (VLC) ACs or sphingolipids with VLCFAs (>20 carbons), which are proxies of dysregulated FA metabolism in peroxisomes. Our study identified alterations in circulating ACs in HF patients that are independent of biological traits and associated with disease severity markers. These alterations reflect dysfunctional FA metabolism in mitochondria but also beyond, namely, in peroxisomes, suggesting a novel mechanism contributing to global lipid perturbations in human HF.",
keywords = "Acylcarnitines, Heart failure, Lipid oxidation, Metabolomics, Peroxisomes",
author = "Matthieu Ruiz and Fran{\cc}ois Labarthe and Annik Fortier and Bertrand Bouchard and Legault, {Julie Thompson} and Virginie Bolduc and Odile Rigal and Jane Chen and Anique Ducharme and Crawford, {Peter A.} and Tardif, {Jean Claude} and {Des Rosiers}, Christine",
year = "2017",
month = "10",
day = "11",
doi = "10.1152/ajpheart.00820.2016",
language = "English (US)",
volume = "313",
pages = "768--781",
journal = "American Journal of Physiology - Cell Physiology",
issn = "0363-6143",
publisher = "American Physiological Society",
number = "4",

}

TY - JOUR

T1 - Circulating acylcarnitine profile in human heart failure

T2 - A surrogate of fatty acid metabolic dysregulation in mitochondria and beyond

AU - Ruiz, Matthieu

AU - Labarthe, François

AU - Fortier, Annik

AU - Bouchard, Bertrand

AU - Legault, Julie Thompson

AU - Bolduc, Virginie

AU - Rigal, Odile

AU - Chen, Jane

AU - Ducharme, Anique

AU - Crawford, Peter A.

AU - Tardif, Jean Claude

AU - Des Rosiers, Christine

PY - 2017/10/11

Y1 - 2017/10/11

N2 - Heart failure (HF) is associated with metabolic perturbations, particularly of fatty acids (FAs), which remain to be better understood in humans. This study aimed at testing the hypothesis that HF patients with reduced ejection fraction display systemic perturbations in levels of energy-related metabolites, especially those reflecting dysregulation of FA metabolism, namely, acylcarnitines (ACs). Circulating metabolites were assessed using mass spectrometry (MS)-based methods in two cohorts. The main cohort consisted of 72 control subjects and 68 HF patients exhibiting depressed left ventricular ejection fraction (25.9 ± 6.9%) and mostly of ischemic etiology with ≥2 comorbidities. HF patients displayed marginal changes in plasma levels of tricarboxylic acid cycle-related metabolites or indexes of mitochondrial or cytosolic redox status. They had, however, 22-79% higher circulating ACs, irrespective of chain length (P < 0.0001, adjusted for sex, age, renal function, and insulin resistance, determined by shotgun MS/MS), which reflects defective mitochondrial β-oxidation, and were significantly associated with levels of NH 2 -terminal pro-B-type natriuretic peptide levels, a disease severity marker. Subsequent extended liquid chromatography-tandem MS analysis of 53 plasma ACs in a subset group from the primary cohort confirmed and further substantiated with a comprehensive lipidomic analysis in a validation cohort revealed in HF patients a more complex circulating AC profile. The latter included dicarboxylic-ACs and dihydroxy-ACs as well as very long chain (VLC) ACs or sphingolipids with VLCFAs (>20 carbons), which are proxies of dysregulated FA metabolism in peroxisomes. Our study identified alterations in circulating ACs in HF patients that are independent of biological traits and associated with disease severity markers. These alterations reflect dysfunctional FA metabolism in mitochondria but also beyond, namely, in peroxisomes, suggesting a novel mechanism contributing to global lipid perturbations in human HF.

AB - Heart failure (HF) is associated with metabolic perturbations, particularly of fatty acids (FAs), which remain to be better understood in humans. This study aimed at testing the hypothesis that HF patients with reduced ejection fraction display systemic perturbations in levels of energy-related metabolites, especially those reflecting dysregulation of FA metabolism, namely, acylcarnitines (ACs). Circulating metabolites were assessed using mass spectrometry (MS)-based methods in two cohorts. The main cohort consisted of 72 control subjects and 68 HF patients exhibiting depressed left ventricular ejection fraction (25.9 ± 6.9%) and mostly of ischemic etiology with ≥2 comorbidities. HF patients displayed marginal changes in plasma levels of tricarboxylic acid cycle-related metabolites or indexes of mitochondrial or cytosolic redox status. They had, however, 22-79% higher circulating ACs, irrespective of chain length (P < 0.0001, adjusted for sex, age, renal function, and insulin resistance, determined by shotgun MS/MS), which reflects defective mitochondrial β-oxidation, and were significantly associated with levels of NH 2 -terminal pro-B-type natriuretic peptide levels, a disease severity marker. Subsequent extended liquid chromatography-tandem MS analysis of 53 plasma ACs in a subset group from the primary cohort confirmed and further substantiated with a comprehensive lipidomic analysis in a validation cohort revealed in HF patients a more complex circulating AC profile. The latter included dicarboxylic-ACs and dihydroxy-ACs as well as very long chain (VLC) ACs or sphingolipids with VLCFAs (>20 carbons), which are proxies of dysregulated FA metabolism in peroxisomes. Our study identified alterations in circulating ACs in HF patients that are independent of biological traits and associated with disease severity markers. These alterations reflect dysfunctional FA metabolism in mitochondria but also beyond, namely, in peroxisomes, suggesting a novel mechanism contributing to global lipid perturbations in human HF.

KW - Acylcarnitines

KW - Heart failure

KW - Lipid oxidation

KW - Metabolomics

KW - Peroxisomes

UR - http://www.scopus.com/inward/record.url?scp=85031089909&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85031089909&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00820.2016

DO - 10.1152/ajpheart.00820.2016

M3 - Article

C2 - 28710072

AN - SCOPUS:85031089909

VL - 313

SP - 768

EP - 781

JO - American Journal of Physiology - Cell Physiology

JF - American Journal of Physiology - Cell Physiology

SN - 0363-6143

IS - 4

ER -