Ketone metabolism in the failing heart

Lopaschuk, Gary D.; Karwi, Qutuba G.; Ho, Kim L.; Pherwani, Simran; Ketema, Ezra Belay

doi:10.1016/j.bbalip.2020.158813

Cited by 57 publications

(50 citation statements)

References 142 publications

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“…Our study found that empagli ozin treatment signi cantly increased myocardial ATP levels, ketone bodies and mitochondrial activity after CA. Several recent studies have demonstrated that ketone body metabolism signi cantly protected the failing heart [45,46]. Therefore, our results suggested that the protective effects of empagli ozin on myocardial dysfunction after CA were mediated by ketone body metabolism.…”

Section: Discussionsupporting

confidence: 59%

“…Thus, a reduction of ATP level, decrease of mitochondrial complex activity, and accumulation of lipid droplets and lactate were observed in heart after CA in our study. Ketone bodies are an alternative fuel when energy is insu cient, and are more e cient than fatty acids on the basis of ATP produced per oxygen consumed (P/O ratio) [45]. Moreover, ketone bodies as a substrate for mitochondrial energy metabolism have no lactate production.…”

Section: Discussionmentioning

confidence: 99%

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Sodium–glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in rats after cardiac arrest

Tan¹,

Yu²,

Liang³

et al. 2021

Preprint

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Background: Sodium–glucose co-transporter 2 (SGLT2) inhibition reduces hyperglycaemia and has beneficial effects in heart failure. However, the effect of SGLT2 inhibition with empagliflozin on acute myocardial dysfunction after cardiac arrest (CA) remains unknown.Methods: Non-diabetic male Sprague–Dawley rats underwent ventricular fibrillation to induce CA, or sham surgery. Rats received 10 mg/kg of empagliflozin or vehicle at 10 minutes after return of spontaneous circulation by intraperitoneal injection. Cardiac function was assessed by echocardiography, histological analysis, molecular markers of myocardial injury, oxidative stress, mitochondrial ultrastructural integrity and metabolism. Results: Empagliflozin did not influence heart rate and blood pressure, but left ventricular function and survival time were significantly higher in the empagliflozin treated group compared to the group treated with vehicle. Empagliflozin also reduced myocardial contraction band necrosis, myocardial fibrosis, serum cardiac troponin I levels and myocardial oxidative stress after CA. Moreover, empagliflozin maintained the structural integrity of myocardial mitochondria and increased mitochondrial activity after CA. In addition, empagliflozin increased circulating and myocardial ketone levels as well as myocardial expression of the 𝛽-hydroxy butyrate dehydrogenase 1. Together these metabolic changes were associated with an increase in cardiac ATP production.Conclusions: Empagliflozin favorably affects cardiac function in non-diabetic rats with acute myocardial dysfunction after CA, associated with reducing glucose levels and increasing ketone body oxidized metabolism. Our data suggest that empagliflozin might be of benefit in patients with acute myocardial dysfunction after CA.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Sodium–glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in rats after cardiac arrest

Tan¹,

Yu²,

Liang³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Overall, our findings suggest that the KD has profound effects on cardiac metabolic pathways by downregulating genes involved in glucose and ketone body oxidation and upregulating genes involved in fatty acid uptake and beta-oxidation. Since hypertrophied and failing hearts are known to downregulate lipid metabolism, while concomitantly increasing glucose and ketone body metabolism [ 59 , 60 , 61 ], it is possible that the KD does not act by enhancing ketone body oxidation, but rather by normalizing the impaired lipid metabolism. Further studies evaluating the cardiometabolic consequences of the KD in the setting of cardiac hypertrophy and failure should help to elucidate this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Fasting or Ketogenic Diet on Endurance Exercise Performance and Metabolism in Female Mice

et al. 2021

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The promotion of ketone body (KB) metabolism via ketosis has been suggested as a strategy to increase exercise performance. However, studies in humans and animals have yielded inconsistent results. The purpose of the current study was to examine the effects of ketosis, achieved via fasting or a short-term ketogenic diet (KD), on endurance exercise performance in female mice. After 8 h of fasting, serum KB significantly increased and serum glucose significantly decreased in fasted compared to fed mice. When subjected to an endurance exercise capacity (EEC) test on a motorized treadmill, both fed and fasted mice showed similar EEC performance. A 5-week KD (90% calories from fat) significantly increased serum KB but did not increase EEC times compared to chow-fed mice. KD mice gained significantly more weight than chow-fed mice and had greater adipose tissue mass. Biochemical tissue analysis showed that KD led to significant increases in triglyceride content in the heart and liver and significant decreases in glycogen content in the muscle and liver. Furthermore, KD downregulated genes involved in glucose and KB oxidation and upregulated genes involved in lipid metabolism in the heart. These findings suggest that a short-term KD is not an effective strategy to enhance exercise performance and may lead to increased adiposity, abnormal endogenous tissue storage, and cardiometabolic remodeling.

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“…Inside the heart, monocarboxylate transporters (MCT1) transfer βOHB inside the mitochondria, where it is oxidized by βOHB dehydrogenase (BHD1) into acetoacetate. This intermediate molecule is further processed into acetyl-CoA for the TCA cycle [ 71 ]. Although ketone bodies do not contribute significantly to myocardial ATP synthesis, increased circulating levels of βOHB and ketone body uptake have been observed in heart failure patients [ 72 , 73 , 74 , 75 , 76 ].…”

Section: Mitochondrial Metabolism and Mitochondria-associated Disomentioning

confidence: 99%

Mitochondrial Homeostasis Mediates Lipotoxicity in the Failing Myocardium

Kretzschmar

Schulze

2021

IJMS

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Heart failure remains the most common cause of death in the industrialized world. In spite of new therapeutic interventions that are constantly being developed, it is still not possible to completely protect against heart failure development and progression. This shows how much more research is necessary to understand the underlying mechanisms of this process. In this review, we give a detailed overview of the contribution of impaired mitochondrial dynamics and energy homeostasis during heart failure progression. In particular, we focus on the regulation of fatty acid metabolism and the effects of fatty acid accumulation on mitochondrial structural and functional homeostasis.

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Ketone metabolism in the failing heart

Cited by 57 publications

References 142 publications

Sodium–glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in rats after cardiac arrest

Sodium–glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in rats after cardiac arrest

The Effects of Fasting or Ketogenic Diet on Endurance Exercise Performance and Metabolism in Female Mice

Mitochondrial Homeostasis Mediates Lipotoxicity in the Failing Myocardium

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