During conditions that result in depleted circulating glucose levels, ketone bodies synthesized in the liver are necessary fuel substrates for the brain. In other organs, such as the heart, the reliance on ketones for generating energy in the absence of glucose is less important as the heart can utilize alternative fuel sources, such as fatty acids. However, during pathophysiological conditions, such as heart failure, cardiac defects in metabolic processes that normally allow for sufficient energy production from fatty acids and carbohydrates contribute to a decline in contractile function. As such, it has been proposed that the failing heart relies more on ketone bodies as an energy source than previously appreciated. Furthermore, it has been shown that ketone bodies function as signaling molecules that can suppress systemic and cardiac inflammation. Thus, it is possible that intentionally elevating circulating ketones may be beneficial as an adjunct treatment for heart failure. Although many approaches can be used for ‘ketone therapy’, each of these has their own advantages and disadvantages in the treatment of heart failure. Thus, we summarize current preclinical and clinical studies involving various types of ketone therapy in cardiac disease and discuss the advantages and disadvantages of each modality as possible treatments for heart failure.

Background: Doxorubicin (DOX) is a potent chemotherapy widely used in treating various neoplastic diseases. However, the clinical use of DOX is limited due to its potential toxic effect on the cardiovascular system. Thus, identifying the pathway involved in this toxicity may help minimize chemotherapy risk and improve cancer patients’ quality of life. Recent studies suggest that Endothelial-to-Mesenchymal transition (EndMT) and endothelial toxicity contribute to the pathogenesis of DOX-induced cardiovascular toxicity. However, the molecular mechanism is yet unknown. Given that arachidonic acid and associated cytochrome P450 (CYP) epoxygenase have been involved in endothelial and cardiovascular function, we aimed to examine the effect of suppressing CYP epoxygenases on DOX-induced EndMT and cardiovascular toxicity in vitro and in vivo. Methods and Results: To test this, human endothelial cells were treated with DOX, with or without CYP epoxygenase inhibitor, MSPPOH. We also investigated the effect of MSPPOH on the cardiovascular system in our zebrafish model of DOX-induced cardiotoxicity. Our results showed that MSPPOH exacerbated DOX-induced EndMT, inflammation, oxidative stress, and apoptosis in our endothelial cells. Furthermore, we also show that MSPPOH increased cardiac edema, lowered vascular blood flow velocity, and worsened the expression of EndMT and cardiac injury markers in our zebrafish model of DOX-induced cardiotoxicity. Conclusion: Our data indicate that a selective CYP epoxygenase inhibitor, MSPPOH, induces EndMT and endothelial toxicity to contribute to DOX-induced cardiovascular toxicity.

A plethora of studies have demonstrated that cardiomyopathy represents a serious source of morbidity and mortality in patients with diabetes. Yet, the underlying mechanisms of diabetic cardiomyopathy are still poorly understood. Of interest, cytochrome P450 2J (CYP2J) and soluble epoxide hydrolase (sEH) are known to control the maintenance of cardiovascular health through the regulation of cardioprotective epoxyeicosatrienoic acids (EETs) and its less active products, dihydroxyeicosatrienoic acids (DHETs). Therefore, we examined the role of the aforementioned pathway in the development of diabetic cardiomyopathy. Our diabetic model initiated cardiomyopathy as indexed by the increase in the expression of hypertrophic markers such asNPPA. Furthermore, diabetic cardiomyopathy was associated with a low level of cardiac EETs and an increase of the DHETs/EETs ratio both in vivo and in cardiac cells. The modulation in EETs and DHETs was attributed to the increase of sEH and the decrease of CYP2J. Interestingly, the reduction of sEH attenuates cardiotoxicity mediated by high glucose in cardiac cells. Mechanistically, the beneficial effect of sEH reduction might be due to the decrease of phosphorylated ERK1/2 and p38. Overall, the present work provides evidence that diabetes initiates cardiomyopathy through the increase in sEH, the reduction of CYP2J, and the decrease of cardioprotective EETs.

Anthracycline antibiotic is one of the most effective anti-tumor drugs used to manage certain types of breast cancers, lymphomas, and leukemias. However, anthracyclines induce a dose-dependent cardiotoxicity that may progress to heart failure. Thus, using a sensitive predictor of early cardiac dysfunction in patients treated with anthracyclines can help detect subclinical cardiac dysfunction early and help initiate interventions to protect these patients. Among parameters of myocardial measure, cardiac magnetic resonance (CMR)-measured native myocardial T1 mapping is considered a sensitive and accurate quantitative measure of early subclinical cardiac changes, particularly cardiac inflammation and fibrosis. However, to understand the quality and the validity of the current evidence supporting the use of these measures in patients treated with anthracyclines, we aimed to conduct a systematic review of clinical studies of this measure to detect early myocardial changes in cancer patients treated with anthracyclines. The primary outcome was the level of native T1 mapping. We performed fixed-effects meta-analyses and assessed certainty in effect estimates. Of the 1780 publications reviewed (till 2022), 23 were retrieved, and 9 articles met the inclusion criteria. Our study showed that exposure to anthracycline was associated with a significant elevation of native myocardial T1 mapping from baseline (95% CI 0.1121 to 0.5802; p = 0.0037) as well as compared to healthy control patients (95% CI 0.2925 to 0.7448; p < 0.0001). No significant publication bias was noted on the assessment of the funnel plot and Egger’s test. According to the Q test, there was no significant heterogeneity in the included studies (I² = 0.0000% versus healthy controls and I² = 14.0666% versus baseline). Overall, our study suggests that native myocardial T1 mapping is useful for detecting anthracycline-induced cardiotoxicity in patients with cancer.

Anthracyclines are effective antineoplastic drugs; however, their use is constrained by dose-dependent cardiotoxicity. Vascular endothelial dysfunction is an early independent event in cardiovascular diseases and may precede anthracycline-induced cardiotoxicity. Brachial flow-mediated dilation (FMD) is a non-invasive technique for evaluating vascular endothelial function. We evaluated the evidence on anthracycline-induced vascular endothelial dysfunction in cancer patients and survivors using FMD. Studies measuring FMD in anthracycline-treated active cancer patients or survivors were retrieved from inception to August 2024 using PubMed, Embase, and Scopus. The primary outcome was the difference in FMD between anthracycline-treated patients and healthy controls or baseline. We performed the meta-analysis using a random-effects model and evaluated the certainty in effect estimates. Overall, 18 studies (n = 841 patients) met the inclusion criteria. Compared to the baseline, a non-significant change toward a decline in FMD was observed. However, a significant reduction in FMD was observed in anthracycline-treated patients compared to healthy controls (standardized mean difference (SMD): − 0.6082; 95% CI: − 0.8963 to − 0.3201; p < 0.0001). Subgroup analyses revealed consistent significant reductions in FMD for childhood cancers (SMD: − 0.7189; 95% CI: − 0.9903 to − 0.4476; p < 0.0001), while adult cancers showed no significant difference. No significant publication bias was detected overall for healthy control comparisons. High heterogeneity was observed in the included studies (I² = 81.7808% versus healthy controls and I² = 75.6876% for childhood cancers subgroup analysis). Anthracyclines induce vascular endothelial dysfunction, indicated by lower FMD in cancer patients and survivors, particularly among those with childhood cancers, who might be at risk of long-term cardiovascular complications.