Elevated plasma β-hydroxybutyrate predicts adverse outcomes and disease progression in patients with arrhythmogenic cardiomyopathy

Song, Jiangping; Chen, Liang; Xiao, Chen; Ren, Ji-Hua; Zhang, Ningning; Tirasawasdichai, Tiara; Hu, Zhenliang; Hua, Wei; Hu, Yiran; Tang, Huiru; Chen, Huei-Sheng Vincent; Hu, Shengshou

doi:10.1126/scitranslmed.aay8329

Cited by 59 publications

(52 citation statements)

References 46 publications

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“…30 Furthermore, it has recently been shown in the mouse model Myh6-Cre: Dsp w/f that ketogenesis occurs in heart muscle before the development of HF, during early stages of arrhythmogenic cardiomyopathy. 31 The current study revealed a difference in the association of β-OHB with HF between men and women. Besides the well-known differences in the clinical presentation of HF between men and women, with preserved ejection fraction being more frequently observed in women, 32 ketone body metabolism also shows important sex-based differences with a higher production of β-OHB in women.…”

Section: Discussionmentioning

confidence: 55%

Association of beta‐hydroxybutyrate with development of heart failure: Sex differences in a Dutch population cohort

Flores‐Guerrero

Westenbrink

Connelly

et al. 2020

Eur J Clin Investigation

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Background: In the failing heart, energy metabolism is shifted towards increased ketone body oxidation. Nevertheless, the association of beta-hydroxybutyrate (β-OHB) with development of heart failure (HF) remains unclear. We investigated the association between plasma β-OHB and the risk of HF in a prospective populationbased cohort. Design: Plasma β-OHB concentrations were measured in 6134 participants of the PREVEND study. Risk of incident HF with reduced (HFrEF) or preserved (HFpEF) ejection fraction was estimated using multivariable-adjusted Cox regression models. Results: During median follow-up for 8.2 years, 227 subjects were diagnosed with HF (137 with HFrEF; 90 with HFpEF). Cox regression analyses revealed a significant association of higher β-OHB concentrations with incident HF (HR per 1 standard deviation increase, 1.40 (95% CI: 1.21-1.63; P < .001), which was largely attributable to HFrEF. In women, the hazard ratio (HR) for HFrEF per 1 standard deviation increase in β-OHB was 1.73 (95% confidence interval (CI): 1.17-2.56, P = .005) in age, BMI, type 2 diabetes, hypertension, myocardial infarction, smoking, alcohol consumption, total cholesterol, HDL-C, triglycerides, glucose, eGFR and UAE adjusted analysis. In men, in the same fully adjusted analysis, the HR was 1.14 (CI: 0.86-1.53, P = .36) (P < .01 for sex interaction). In N-terminal pro-brain natriuretic peptide (NT-proBNP)-stratified analysis, the age-adjusted association with HF was significant in women with higher NT-proBNP levels (P = .008). Conclusions: This prospective study suggests that high plasma concentrations of β-OHB are associated with an increased risk of HFrEF, particularly in women. The mechanisms responsible for the sex differences of this association warrant further study. K E Y W O R D Sbeta-hydroxybutyrate, heart failure, ketone bodies, sex differences 2 of 11 | FLORES-GUERRERO Et aL.*P values represent the significance of difference across the tertiles of plasmatic β-OHB. P values were determined using a one-way analysis of variance for normally distributed data, Kruskal-Wallis test for skewed distributed data, and chi-square test for categorical data.

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Section: Discussionmentioning

confidence: 55%

Association of beta‐hydroxybutyrate with development of heart failure: Sex differences in a Dutch population cohort

Flores‐Guerrero

Westenbrink

Connelly

et al. 2020

Eur J Clin Investigation

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“…Ehd1 (Eps15 homology domain-containing protein 1) is recently identified as a novel interactor of Cx43 in the heart and plays a critical role in the pathological remodeling of gap junctions (39). Hmgcs2 is a ketone metabolic enzyme, and the level of Hmgcs2 in patients with arrhythmogenic cardiomyopathy is elevated, which leads to elevated plasma beta-hydroxybutyrate (β-OHB) and predicts major adverse cardiovascular events (MACE) (40). The altered m6A peaks in HFpEF have been associated with several protein processing by GO enrichment and KEGG pathway analyses, such as protein folding, ubiquitin, and protein binding, which means that the dysfunctional m6A methylation of the protein process plays a vital role in the development of HFpEF.…”

Section: Discussionmentioning

confidence: 99%

Alteration of m6A RNA Methylation in Heart Failure With Preserved Ejection Fraction

Zhang

Cui

et al. 2021

Front. Cardiovasc. Med.

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Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disease, in which its pathogenesis is very complex and far from defined. Here, we explored the N6-methyladenosine (m6A) RNA methylation alteration in patients with HFpEF and mouse model of HFpEF.Methods: In this case–control study, peripheral blood mononuclear cells (PBMCs) were separated from peripheral blood samples obtained from 16 HFpEF patients and 24 healthy controls. The change of m6A regulators was detected by quantitative real-time PCR (RT-PCR). A “two-hit” mouse model of HFpEF was induced by a high-fat diet and drinking water with 0.5 g/L of Nω-nitro-l-arginine methyl ester (L-NAME). MeRIP-seq was used to map transcriptome-wide m6A in control mice and HFpEF mice, and the gene expression was high-throughput detected by RNA-seq.Results: The expression of m6A writers METTL3, METTL4, and KIAA1429; m6A eraser FTO; and reader YTHDF2 was up-regulated in HFpEF patients, compared with health controls. Furthermore, the expression of FTO was also elevated in HFpEF mice. A total of 661 m6A peaks were significantly changed by MeRIP-seq. Gene Ontology (GO) analysis revealed that protein folding, ubiquitin-dependent ERAD pathway, and positive regulation of RNA polymerase II were the three most significantly altered biological processes in HFpEF. The pathways including proteasome, protein processing in the endoplasmic reticulum, and PI3K-Akt signaling pathway were significantly changed in HFpEF by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.Conclusions: The expression pattern of m6A regulators and m6A landscape is changed in HFpEF. This uncovers a new transcription-independent mechanism of translation regulation. Therefore, our data suggest that the modulation of epitranscriptomic processes, such as m6A methylation, might be an interesting target for therapeutic interventions.

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“…reprogramming described in diverse cancers which involve the overexpression of both HMGC2 (28,29) and PGC-1α transcripts (24). Overexpression of HMGC2/PGC-1α has been observed in high-grade colorectal cancer (30), colitisassociated cancer (31), clear cell renal cell cancer (32,33), ovarian (34), liver (35), oral squamous cell carcinoma (36) and high-grade prostate cancer (37), and is reflective of recurrence and poor prognosis (38).…”

Section: Discussionmentioning

confidence: 99%

Whole-transcriptome Analysis of Fully Viable Energy Efficient Glycolytic-null Cancer Cells Established by Double Genetic Knockout of Lactate Dehydrogenase A/B or Glucose-6-Phosphate Isomerase

Mazzio

Badisa

Mack

et al. 2020

Cancer Genomics Proteomics

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Background/Aim: Nearly all mammalian tumors of diverse tissues are believed to be dependent on fermentative glycolysis, marked by elevated production of lactic acid and expression of glycolytic enzymes, most notably lactic acid dehydrogenase (LDH). Therefore, there has been significant interest in developing chemotherapy drugs that selectively target various isoforms of the LDH enzyme. However, considerable questions remain as to the consequences of biological ablation of LDH or upstream targeting of the glycolytic pathway. Materials and Methods: In this study, we explore the biochemical and whole transcriptomic effects of CRISPR-Cas9 gene knockout (KO) of lactate dehydrogenases A and B [LDHA/B double KO (DKO)] and glucose-6-phosphate isomerase (GPI KO) in the human colon cancer cell line LS174T, using Affymetrix 2.1 ST arrays. Results: The metabolic biochemical profiles corroborate that relative to wild type (WT), LDHA/B DKO produced no lactic acid, (GPI KO) produced minimal lactic acid and both KOs displayed higher mitochondrial respiration, and minimal use of glucose with no loss of cell viability. These findings show a high biochemical energy efficiency as measured by ATP in glycolysis-null cells. Next, transcriptomic analysis conducted on 48,226 mRNA transcripts reflect 273 differentially expressed genes (DEGS) in the GPI KO clone set, 193 DEGS in the LDHA/B DKO clone set with 47 DEGs common to both KO clones. Glycolytic-null cells reflect up-regulation in gene transcripts typically associated with nutrient deprivation / fasting and possible use of fats for energy: thioredoxin interacting protein (TXNIP), mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), PPARγ coactivator 1α (PGC-1α), and acetyl-CoA acyltransferase 2 (ACAA2). Other changes in non-ergometric transcripts in both KOs show losses in "stemness", WNT signaling pathway, chemo/radiation resistance, retinoic acid synthesis, drug detoxification, androgen/estrogen activation, and extracellular matrix reprogramming genes. Conclusion: These findings demonstrate that: 1) The "Warburg effect" is dispensable, 2) loss of the LDHAB gene is not only inconsequential to viability but fosters greater mitochondrial energy, and 3) drugs that target LDHA/B are likely to be ineffective without a plausible combination second drug target. Common features across diverse mammalian tumors include the rapid glycolytic activity, greater expression of lactate dehydrogenases (LDH) and subsequent overproduction of lactic acid, occurring regardless of the presence of oxygen (Warburg effect) (1,2). This unique trait of cancer has been studied for decades, where researchers have geared off original focus from its role in metabolism to its role in acidification of the tumor microenvironment (TME), a formidable driving force for tumor growth, metastasis, aggressiveness, chemo/radiation resistance and loss of immune surveillance (3-8). This loss of immune surveillance 469 This article is freely accessible online.

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Elevated plasma β-hydroxybutyrate predicts adverse outcomes and disease progression in patients with arrhythmogenic cardiomyopathy

Cited by 59 publications

References 46 publications

Association of beta‐hydroxybutyrate with development of heart failure: Sex differences in a Dutch population cohort

Association of beta‐hydroxybutyrate with development of heart failure: Sex differences in a Dutch population cohort

Alteration of m6A RNA Methylation in Heart Failure With Preserved Ejection Fraction

Whole-transcriptome Analysis of Fully Viable Energy Efficient Glycolytic-null Cancer Cells Established by Double Genetic Knockout of Lactate Dehydrogenase A/B or Glucose-6-Phosphate Isomerase

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