Chronically Elevating Circulating Ketones Can Reduce Cardiac Inflammation and Blunt the Development of Heart Failure

Byrne, Nikole J.; Soni, Shubham; Takahara, Shingo; Ferdaoussi, Mourad; Batran, Rami Al; Darwesh, Ahmed M.; Levasseur, Jody; Beker, Donna L.; Vos, Dyonne; Schmidt, Mya A.; Alam, Abrar S.; Maayah, Zaid H.; Schertzer, Jonathan D.; Seubert, John M.; Ussher, John R.; Dyck, Jason R.B.

doi:10.1161/circheartfailure.119.006573

Cited by 72 publications

(54 citation statements)

References 50 publications

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“…Chronic elevation of circulating ketones by knockout of succinyl-CoA:3-ketoacid-CoA transferase (SCOT)1 in mouse skeletal muscle suppressed pressure overload-induced cardiac inflammation and cardiac dysfunction. Infusion with β-hydroxybutyrate into isolated hearts inhibited NLRP3 inflammasome activation (Byrne et al, 2020b). Inhibiting of sodium-glucose cotransporter (SGLT)2 increased β-hydroxybutyrate and decreased serum insulin in patients with type 2 diabetes compared to sulfonylurea, and inhibited activation of the NLRP3 inflammasome in isolated macrophages (Kim et al, 2020).…”

Section: Preclinical Experiments On Inflammasome Inhibitionmentioning

confidence: 99%

The Role of the Inflammasome in Heart Failure

Dong

Zhang

et al. 2021

Front. Physiol.

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Inflammation promotes the development of heart failure (HF). The inflammasome is a multimeric protein complex that plays an essential role in the innate immune response by triggering the cleavage and activation of the proinflammatory cytokines interleukins (IL)-1β and IL-18. Blocking IL-1β with the monoclonal antibody canakinumab reduced hospitalizations and mortality in HF patients, suggesting that the inflammasome is involved in HF pathogenesis. The inflammasome is activated under various pathologic conditions that contribute to the progression of HF, including pressure overload, acute or chronic overactivation of the sympathetic system, myocardial infarction, and diabetic cardiomyopathy. Inflammasome activation is responsible for cardiac hypertrophy, fibrosis, and pyroptosis. Besides inflammatory cells, the inflammasome in other cardiac cells initiates local inflammation through intercellular communication. Some inflammasome inhibitors are currently being investigated in clinical trials in patients with HF. The current evidence suggests that the inflammasome is a critical mediator of cardiac inflammation during HF and a promising therapeutic target. The present review summarizes the recent advances in both basic and clinical research on the role of the inflammasome in HF.

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Section: Preclinical Experiments On Inflammasome Inhibitionmentioning

confidence: 99%

The Role of the Inflammasome in Heart Failure

Dong

Zhang

et al. 2021

Front. Physiol.

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“…Another study found that the anti-inflammatory effect of ketogenic diet may be attributed to the β-OHB-mediated inhibition of Nlrp3 inflammasome formation (Youm et al, 2015). Increasing the circulating β-OHB levels by SCOT knockout in skeletal muscle reduced cardiac Nlrp3 inflammasome activation upon heart failure (Byrne et al, 2020). Endoplasmic reticulum (ER) stress can induce Nlrp3 inflammasome.…”

Section: β-Ohb Is An Endogenous Nlrp3 Inflammasome Inhibitormentioning

confidence: 99%

Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts

2021

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One of the characteristics of the failing human heart is a significant alteration in its energy metabolism. Recently, a ketone body, β-hydroxybutyrate (β-OHB) has been implicated in the failing heart’s energy metabolism as an alternative “fuel source.” Utilization of β-OHB in the failing heart increases, and this serves as a “fuel switch” that has been demonstrated to become an adaptive response to stress during the heart failure progression in both diabetic and non-diabetic patients. In addition to serving as an alternative “fuel,” β-OHB represents a signaling molecule that acts as an endogenous histone deacetylase (HDAC) inhibitor. It can increase histone acetylation or lysine acetylation of other signaling molecules. β-OHB has been shown to decrease the production of reactive oxygen species and activate autophagy. Moreover, β-OHB works as an NLR family pyrin domain-containing protein 3 (Nlrp3) inflammasome inhibitor and reduces Nlrp3-mediated inflammatory responses. It has also been reported that β-OHB plays a role in transcriptional or post-translational regulations of various genes’ expression. Increasing β-OHB levels prior to ischemia/reperfusion injury results in a reduced infarct size in rodents, likely due to the signaling function of β-OHB in addition to its role in providing energy. Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been shown to exert strong beneficial effects on the cardiovascular system. They are also capable of increasing the production of β-OHB, which may partially explain their clinical efficacy. Despite all of the beneficial effects of β-OHB, some studies have shown detrimental effects of long-term exposure to β-OHB. Furthermore, not all means of increasing β-OHB levels in the heart are equally effective in treating heart failure. The best timing and therapeutic strategies for the delivery of β-OHB to treat heart disease are unknown and yet to be determined. In this review, we focus on the crucial role of ketone bodies, particularly β-OHB, as both an energy source and a signaling molecule in the stressed heart and the overall therapeutic potential of this compound for cardiovascular diseases.

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“…Deletion of succinyl-CoA:3-ketoacid-CoA transferase 1 (SCOT) In a mouse model increased circulating ketones and reduced the cardiac inflammasome preventing heart failure caused by increased afterload (30).…”

Section: Discussionmentioning

confidence: 99%

Metabolomics and a Breath Sensor Identify Acetone as a Biomarker for Heart Failure

Young¹,

Gladding

Cooper³

et al. 2021

Preprint

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Background Multiomics delivers more biological insight than targeted investigations. We applied multiomics to patients with heart failure with reduced ejection fraction (HFrEF). Methods 46 patients with HFrEF and 20 controls underwent metabolomic profiling, including liquid/gas chromatography mass spectrometry (LCMS/GCMS) and solid-phase microextraction (SPME) volatilomics in plasma and urine. HFrEF was defined using left ventricular global longitudinal strain, ejection fraction and NTproBNP. A consumer breath acetone (BrACE) sensor validated results in n=73. Results 28 metabolites were identified by GCMS, 35 by LCMS and 4 volatiles by SPME in plasma and urine. Alanine, aspartate and glutamate, citric acid cycle, arginine biosynthesis, glyoxylate and dicarboxylate metabolism were altered in HFrEF. Plasma acetone correlated with NT-proBNP (r = 0.59, 95% CI 0.4 to 0.7), 2-oxovaleric and cis-aconitic acid, involved with ketone metabolism and mitochondrial energetics. BrACE> 1.5 ppm discriminated HF from other cardiac pathology (AUC 0.8, 95% CI 0.61 to 0.92, P < 0.0001). Conclusion Breath acetone discriminated HFrEF from other cardiac pathology using a consumer sensor, but was not cardiac specific.

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Chronically Elevating Circulating Ketones Can Reduce Cardiac Inflammation and Blunt the Development of Heart Failure

Cited by 72 publications

References 50 publications

The Role of the Inflammasome in Heart Failure

The Role of the Inflammasome in Heart Failure

Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts

Metabolomics and a Breath Sensor Identify Acetone as a Biomarker for Heart Failure

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