Ketone body metabolism and cardiovascular disease

Cotter, David G.; Schugar, Rebecca C.; Crawford, Peter A.

doi:10.1152/ajpheart.00646.2012

Cited by 353 publications

(276 citation statements)

References 241 publications

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“…We noticed a dramatic upregulation in the expression of CoA synthetic enzymes that prompted us to take a closer look at these steps of the pathway. The CoA pool is known to be limiting for several metabolic processes, including the TCA cycle, ketogenesis, lipogenesis, and mitochondrial fatty acid import and ␤ -oxidation ( 21,26,33 ). Although we did not probe all of these pathways, our data support a model where CoA is limiting in the face of caloric excess, reducing animal fi tness by contributing to metabolic lipotoxicity.…”

Section: Discussionmentioning

confidence: 57%

CoA protects against the deleterious effects of caloric overload in Drosophila

Musselman¹,

Fink

Baranski

2016

Journal of Lipid Research

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Section: Discussionmentioning

confidence: 57%

CoA protects against the deleterious effects of caloric overload in Drosophila

Musselman¹,

Fink

Baranski

2016

Journal of Lipid Research

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“…In in vitro systems, b-hydroxybutyrate has been shown to suppress oxidative stress (44) by inhibiting histone deacetylases. Finally, ketone bodies have been shown to upregulate mitochondrial biogenesis and, by stabilizing cell membrane potential, to exhibit antiarrhythmic potential (45).…”

Section: Rationalementioning

confidence: 99%

“…Starting from the evolutionary role of ketosis (26), other biology of ketone bodies (e.g., their effects on cardiac remodeling, oxidative stress, and mitochondrial biogenesis [42][43][44][45]) has generated some enthusiasm for their therapeutic exploitation (68-70). Low-carbohydrate ketogenic diets are still widely used, mainly for weight loss, but their long-term impact on CV function is still uncertain and controversial (71).…”

Section: Caveatsmentioning

confidence: 99%

CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

2016

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The striking and unexpected relative risk reductions in cardiovascular (CV) mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) observed in the EMPA-REG OUTCOME trial using an inhibitor of sodium-glucose cotransporter 2 (SGLT2) in patients with type 2 diabetes and high CV risk have raised the possibility that mechanisms other than those observed in the trialdmodest improvement in glycemic control, small decrease in body weight, and persistent reductions in blood pressure and uric acid leveldmay be at play. We hypothesize that under conditions of mild, persistent hyperketonemia, such as those that prevail during treatment with SGLT2 inhibitors, b-hydroxybutyrate is freely taken up by the heart (among other organs) and oxidized in preference to fatty acids. This fuel selection improves the transduction of oxygen consumption into work efficiency at the mitochondrial level. In addition, the hemoconcentration that typically follows SGLT2 inhibition enhances oxygen release to the tissues, thereby establishing a powerful synergy with the metabolic substrate shift. These mechanisms would cooperate with other SGLT2 inhibition-induced changes (chiefly, enhanced diuresis and reduced blood pressure) to achieve the degree of cardioprotection revealed in the EMPA-REG OUTCOME trial. This hypothesis opens up new lines of investigation into the pathogenesis and treatment of diabetic and nondiabetic heart disease.First among cardiovascular (CV) end point trials of glucose-lowering agents (1), the EMPA-REG OUTCOME trialdusing 10 or 25 mg/day sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin against placebo in 7,020 patients with type 2 diabetes (T2D) who were at increased CV riskdreported a 14% reduction in major CV events and marked relative risk reductions in CV mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) over a median time period of 2.6 years (2). Of note, all the pathologic categories of CV death (ischemic, pump failure, arrhythmic, embolic) contributed to the overall reduction in CV death in a patient cohort well treated with the use of renin-angiotensin-aldosterone inhibitors, statins, and acetylsalicylic acid. Furthermore, separation of the cumulative incidence functions between pooled-dose groups and placebo was already evident months after randomization. This unusual time course and the discrepancy between the relative risk reduction of the primary end point (nonfatal myocardial infarction, stroke, and CV mortality) and CV mortality itself suggests that active treatment affected case fatality rates more than event rates. In other words, empagliflozin treatment appeared mostly to rescue patients from impending cardiac decompensation. This interpretation is supported by the recent post hoc analyses of heart failure, documenting a large benefit in first and recurrent heart failure hospitalization across virtually every patient subgroup (3). Despite the fact that the diagnosis of heart failure was based on investigator reporting, th...

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“…BCL-2-associated agonist of cell death (BAD), a member of the Bcl-2 proteins that govern apoptotic cell death, was found to mediate a switch in the oxidative metabolism of glucose versus ketone bodies, as neurons which makes it an important regulator of mitochondrial NAD + /NADH status ( 73 ). In the second reaction of ketone body oxidation, ACA is then converted to acetoacetylCoA by succinyl-CoA3-oxoacid CoA transferase in a reaction that transfers a molecule of CoA from succinyl-CoA and therefore also yields succinate.…”

Section: Crmentioning

confidence: 99%