Aims Recent evidence has demonstrated that ketone bodies, particularly β‐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.

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:Cytochrome P450 1B1 (CYP1B1) is known to be involved in the pathogenesis of several cardiovascular diseases, including cardiac hypertrophy and heart failure, through the formation of cardiotoxic metabolites named as mid-chain hydroxyeicosatetraenoic acids (HETEs). Recently, we have demonstrated that fluconazole decreases the level of mid-chain HETEs in human liver microsomes, inhibits human recombinant CYP1B1 activity, and protects against angiotensin II–induced cellular hypertrophy in H9c2 cells. Therefore, the overall purpose of this study was to elucidate the potential cardioprotective effect of fluconazole against cardiac hypertrophy induced by abdominal aortic constriction (AAC) in rats. Male Sprague–Dawley rats were randomly assigned into 4 groups such as sham control rats, fluconazole-treated (20 mg/kg daily for 4 weeks, intraperitoneal) sham rats, AAC rats, and fluconazole-treated (20 mg/kg) AAC rats. Baseline and 5 weeks post-AAC echocardiography were performed. Gene and protein expressions were measured using real-time PCR and Western blot analysis, respectively. The level of mid-chain HETEs was determined using liquid chromatography–mass spectrometry. Echocardiography results showed that fluconazole significantly prevented AAC-induced left ventricular hypertrophy because it ameliorated the AAC-mediated increase in left ventricular mass and wall measurements. In addition, fluconazole significantly prevented the AAC-mediated increase of hypertrophic markers. The antihypertrophic effect of fluconazole was associated with a significant inhibition of CYP1B1, CYP2C23, and 12-LOX and a reduction in the formation rate of mid-chain HETEs. This study demonstrates that fluconazole protects against left ventricular hypertrophy, and it highlights the potential repurposing of fluconazole as a mid-chain HETEs forming enzymes' inhibitor for the protection against cardiac hypertrophy.

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Numerous existing full-spectrum cannabis extract products have been used in clinical trials for the treatment of various diseases. Despite their efficacy, the clinical use of some of these full-spectrum cannabis extracts is limited by behavioral side effects such as cognitive dysfunction and impaired motor skills. To better understand what constitutes cannabis-induced behavioral effects, our objective was to identify a novel panel of blood-based metabolites that are predictive, diagnostic, and/or prognostic of behavioral effects.At 8 weeks of age, male rats were randomly assigned to groups and were gavage fed with full-spectrum cannabis extract (tetrahydrocannabinol/cannabidiol (THC/CBD) along with all other cannabis compounds, 15 mg/kg), broad-spectrum cannabis extract (CBD along with all other cannabis compounds, 15 mg/kg), or vehicle oil. Four hours after being gavage fed, behavioral assessments were determined using the open field test and the elevated plus maze. Following these assessments, serum was collected from all rats and the serum metabolites were identified and quantified by LC–MS/MS and 1H NMR spectroscopy.We found that only rats treated with full-spectrum cannabis extract exhibited behavioral changes. Compared to vehicle-treated and broad-spectrum extract–treated rats, full-spectrum extract–treated rats demonstrated higher serum concentrations of the amino acid phenylalanine and long-chain acylcarnitines, as well as lower serum concentrations of butyric acid and lysophosphatidylcholines. This unique metabolomic fingerprint in response to cannabis extract administration is linked to behavioral effects and may represent a biomarker profile of cannabis-induced behavioral changes. If validated, this work may allow a metabolomics-based decision tree that would aid in the rapid diagnosis of cannabis-induced behavioral changes including cognitive impairment.