Exogenous ketone ester administration attenuates systemic inflammation and reduces organ damage in a lipopolysaccharide model of sepsis.

AIMS: Sepsis is a life-threatening condition of organ dysfunction caused by dysregulated inflammation which predisposes patients to developing cardiovascular disease. The ketone ß-hydroxybutyrate is reported to be cardioprotective in cardiovascular disease and this may be due to their signaling properties that contribute to reducing inflammation. While exogenous ketone esters (KE) increase blood ketone levels, it remains unknown whether KEs can reduce the enhanced inflammatory response and multi-organ dysfunction that is observed in sepsis. Thus, this study assesses whether a recently developed and clinically safe KE can effectively improve the inflammatory response and organ dysfunction in sepsis. METHODS AND RESULTS: To assess the anti-inflammatory effects of a KE, we utilized a model of lipopolysaccharide (LPS)-induced sepsis in which an enhanced inflammatory response results in multi-organ dysfunction. Oral administration of KE for three days prior to LPS-injection significantly protected mice against the profound systemic inflammation compared to their vehicle-treated counterparts. In assessing organ dysfunction, KE protected mice from sepsis-induced cardiac dysfunction as well as renal dysfunction and fibrosis. Furthermore, KE administration attenuated the sepsis-induced inflammation in the heart, kidney, and liver. Moreover, these protective effects occurred independent of changes to enzymes involved in ketone metabolism. CONCLUSION: These data show that the use of an exogenous KE attenuates the dysregulated systemic and organ inflammation as well as organ dysfunction in a model of severe inflammation. We postulate that this exogenous KE is an appealing and promising approach to capitalize on the protective anti-inflammatory effects of ketones in sepsis and/or other inflammatory responses.

Chronic exogenous ketone supplementation blunts the decline of cardiac function in the failing heart.

AIMS: Recent evidence has demonstrated that ketone bodies, particularly ß-hydroxybutyrate (BHB), are beneficial to the failing heart due to their potential as an alternative energy substrate as well as their anti-inflammatory and anti-oxidative properties. Exogenous supplementation of ketones also helps prevent heart failure (HF) development in rodent models, but whether ketones can be used to treat HF remains unexplored. Herein, we investigated whether chronic supplementation of ketones is beneficial for the heart in a mouse model of established HF. METHODS AND RESULTS: To elevate circulating ketone levels, we utilized (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate [ketone ester (KE)]. C57Bl/6N male mice were subjected to transverse aortic constriction (TAC) surgery. After developing HF, mice were treated with either 20% KE or vehicle via drinking water for 2 weeks. In another cohort, mice 3-4 weeks post-TAC received acute intravenous infusions of BHB or saline for 1 h and their cardiac function was measured. 20% KE significantly elevated blood BHB in mice (P < 0.01) without inducing ketoacidosis or altering other metabolic parameters. Mice with overt HF (30-45% ejection fraction) treated with 20% KE displayed significantly elevated circulating ketone levels compared with vehicle-treated mice (P < 0.05). The significant cardiac dysfunction in mice with HF continued to worsen after 2 weeks of vehicle treatment, whereas this decline was absent in KE-treated mice (mean difference 4.7% ejection fraction; P < 0.01). KE treatment also alleviated TAC-induced cardiomyocyte hypertrophy (P < 0.05) and reduced the TAC-induced elevated cardiac periostin (P < 0.05), a marker of activated fibroblasts. Cardiac fibrosis was also significantly reduced with KE treatment in TAC mice (P < 0.01). In another cohort, acute BHB infusion significantly increased the cardiac output of mice with HF (P < 0.05), providing further support that ketone therapy can be used to treat HF. CONCLUSIONS: We show that chronic treatment of exogenous ketones is of benefit to the failing heart and that chronic ketone elevation may be a therapeutic option for HF. Further investigations to elucidate the underlying mechanism(s) are warranted.