METABOLOMICS ANALYSIS DISCRIMINATES HEART FAILURE PATIENTS ACCORDING TO PULMONARY HYPERTENSION: A PROOF-OF-PRINCIPLE STUDY
CCC ePoster Library. Ruiz M. 10/26/19; 280523; 288
Matthieu Ruiz
Matthieu Ruiz
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Abstract
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BACKGROUND: Heart failure (HF) is a major cause of morbidity and mortality. One important determinant of prognosis in HF is the development of pulmonary hypertension (PH), classified as group II PH. Unfortunately, its pathogenesis is misunderstood. Mass spectrometry (MS)-based metabolomics offer a potential to identify new biomarkers and underlying mechanisms that may be associated with poor prognosis in diseases. We recently reported, using MS analyses in plasma from human HF with reduced ejection fraction (rEF) recruited at the Montreal Heart Institute (MHI), disturbed lipid metabolism and especially enhanced circulating acylcarnitines (ACs) as markers of impaired fatty acid (FA) oxidation. Our objective is to assess whether PH-HF patients exhibit a distinct metabolic profile in a retrospective analysis of the above-mentioned MHI cohort.

METHODS AND RESULTS: Echocardiographic data was reviewed in 74 HFrEF patients to classify 27 subjects as noPH (sPAP ≤ 40 mmHg) and 33 subjects as HF-PH (sPAP ≥ 40 mmHg) in comparison to 72 healthy subjects. The metabolites included in the analyses comprised Krebs cycle intermediates (4), ACs (12), amino acids (12) and FAs (29). Using principal component analyses, we noticed that while ACs were the most discriminant to segregate HF-PH from healthy subjects, the FA profile was more useful to discriminate HF-noPH from healthy subjects. Interestingly, ANOVA analyses pointed to a specific signature characterizing HF-PH compared to noPH: (increased) citrate and fumarate (p < 0.05 and p < 0.01, respectively), acetylcarnitine and long chain ACs (p < 0.05), saturated FAs (C14:0, p < 0.05; C16:0 p < 0.05) and monounsaturated FAs (C18:1n9, p < 0.01; C18:1n7, p < 0.05; C20:1n9, p < 0.05). This specific signature was refined following covariance analyses for age, sex, HOMA-IR (indicator of insulin resistance) and eGFR (indicator of kidney function) and only comprised fumarate (p < 0.05), acetylcarnitine (p < 0.05), saturated FAs (p < 0.01) and monounsaturated FAs (p < 0.05). Finally, we performed interaction analyses using NT-proBNP as a classical marker of prognosis with the latter metabolites and found a significant association only in the HF-PH group. In particular, while in HF-PH patients a signification correlation was observed between NT-proBNP and i) acetylcarnitine (p=0.0039), ii) the long chain AC 18:2 (p=0.007), or iii) C18:1n9 FA (p=0.002), none of these correlations were reported in HF-noPH.

CONCLUSION: The metabolic profile, and particularly acetylcarnitine, long chain ACs as well as saturated and monounsaturated FAs are differentially affected in a population of PH due to LHD and may be related to poor outcome. This supports validations in larger prospective cohorts and exploration of roles of these biomarkers on PH.
BACKGROUND: Heart failure (HF) is a major cause of morbidity and mortality. One important determinant of prognosis in HF is the development of pulmonary hypertension (PH), classified as group II PH. Unfortunately, its pathogenesis is misunderstood. Mass spectrometry (MS)-based metabolomics offer a potential to identify new biomarkers and underlying mechanisms that may be associated with poor prognosis in diseases. We recently reported, using MS analyses in plasma from human HF with reduced ejection fraction (rEF) recruited at the Montreal Heart Institute (MHI), disturbed lipid metabolism and especially enhanced circulating acylcarnitines (ACs) as markers of impaired fatty acid (FA) oxidation. Our objective is to assess whether PH-HF patients exhibit a distinct metabolic profile in a retrospective analysis of the above-mentioned MHI cohort.

METHODS AND RESULTS: Echocardiographic data was reviewed in 74 HFrEF patients to classify 27 subjects as noPH (sPAP ≤ 40 mmHg) and 33 subjects as HF-PH (sPAP ≥ 40 mmHg) in comparison to 72 healthy subjects. The metabolites included in the analyses comprised Krebs cycle intermediates (4), ACs (12), amino acids (12) and FAs (29). Using principal component analyses, we noticed that while ACs were the most discriminant to segregate HF-PH from healthy subjects, the FA profile was more useful to discriminate HF-noPH from healthy subjects. Interestingly, ANOVA analyses pointed to a specific signature characterizing HF-PH compared to noPH: (increased) citrate and fumarate (p < 0.05 and p < 0.01, respectively), acetylcarnitine and long chain ACs (p < 0.05), saturated FAs (C14:0, p < 0.05; C16:0 p < 0.05) and monounsaturated FAs (C18:1n9, p < 0.01; C18:1n7, p < 0.05; C20:1n9, p < 0.05). This specific signature was refined following covariance analyses for age, sex, HOMA-IR (indicator of insulin resistance) and eGFR (indicator of kidney function) and only comprised fumarate (p < 0.05), acetylcarnitine (p < 0.05), saturated FAs (p < 0.01) and monounsaturated FAs (p < 0.05). Finally, we performed interaction analyses using NT-proBNP as a classical marker of prognosis with the latter metabolites and found a significant association only in the HF-PH group. In particular, while in HF-PH patients a signification correlation was observed between NT-proBNP and i) acetylcarnitine (p=0.0039), ii) the long chain AC 18:2 (p=0.007), or iii) C18:1n9 FA (p=0.002), none of these correlations were reported in HF-noPH.

CONCLUSION: The metabolic profile, and particularly acetylcarnitine, long chain ACs as well as saturated and monounsaturated FAs are differentially affected in a population of PH due to LHD and may be related to poor outcome. This supports validations in larger prospective cohorts and exploration of roles of these biomarkers on PH.
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