Ketone Therapy for Heart Failure and Inflammation
Creators: Soni, Shubham
Publisher: name: University of Alberta Library
Year: 2024

<p>Heart failure (HF) is complex syndrome in which the cardiac muscle is unable to sufficiently pump blood to the rest of the body. As a result, patients with HF experience several debilitating symptoms and a decreased quality of life. Despite recent advances in pharmacotherapies for HF, the burden of HF on patients and healthcare systems remains high. Therefore, there remains a need for additional therapeutic strategies that can improve cardiac function in patients with HF, and ultimately, their cardiovascular outcomes and quality of life. While the pathophysiology of HF is multifaceted, two important contributing factors are impaired myocardial substrate metabolism and increased proinflammatory signaling. Additionally, recent evidence has shown that the failing heart has increased ketone body utilization, and that these ketones may be important in providing an additional metabolic fuel for the failing heart. While having the ability to utilize ketones is necessary for the normal and the failing heart, the apparent benefit in cardiac function does not appear to be entirely due to an increase in ketone metabolism and subsequent increased energy production.</p>

<p>Ketones, or ketone bodies, are classically understood to be small metabolic molecules produced during states of carbohydrate deprivation, with the primary ketone body being β-hydroxybutyrate (βOHB). However, recent research has highlighted that ketones are far more than just metabolic substrates, and in fact, have several nonmetabolic signaling actions. As such, while most of this HF research has focused on the metabolic effects of ketones, their potential signaling effects on the failing heart have largely remained overlooked. Among their several beneficial signaling effects, ketones can inhibit the nucleotide-binding leucine-rich repeat receptor protein 3 (NLRP3) inflammasome and the resulting proinflammatory signals. Indeed, NLRP3-mediated inflammation is also implicated in the pathogenesis and progression of HF. Thus, this thesis tested the overall hypothesis that ketones, specifically βOHB, impart cardioprotective effects by inhibiting cardiac inflammation and improving cardiac function in the settings of HF and inflammation-induced cardiac dysfunction.</p>

<p>To determine whether ketones prevent the development of HF, we first used a genetic mouse model which endogenously increases ketone availability for the heart by ablating ketone utilization in skeletal muscle. These mice were then subjected to transverse aortic constriction surgery which results in pressure overload-induced HF, and their in vivo cardiac function was assessed via serial echocardiography for up to 5 weeks. To assess the direct effect of ketones on cardiac inflammation, hearts from healthy mice underwent ex vivo ischemia/reperfusion injury to assess how ketones affect cardiac function and inflammation. In the next set of experiments, mice with established HF received an exogenous ketone ester (KE) to determine whether ketone therapy can be used as a treatment for HF. Lastly, we injected mice with lipopolysaccharide to determine whether ketone therapy can be used to protect against inflammation-induced cardiac dysfunction, as well as systemic and multi-organ inflammation. </p>

<p>Our studies show that endogenously elevating circulating ketones blunted the development and progression of HF and reduced cardiac inflammation. Likewise, chronic exogenous KE treatment in mice with established HF prevented the decline in cardiac function. Similar to the effects of an NLRP3-specific inhibitor, βOHB improved functional recovery from ischemia/reperfusion injury in the isolated ex vivo heart and reduced cardiac inflammation, demonstrating the direct cardiac benefits of ketones. Lastly, ketone therapy with an exogenous KE protected against inflammation-induced cardiac dysfunction and reduced cardiac inflammation. Furthermore, KE therapy also robustly reduced systemic and multi-organ inflammation. Collectively, these findings highlight the importance of the nonmetabolic actions of ketone therapy in inflammation and HF. These promising results warrant further investigations for the potential clinical advancement of ketone therapy in order to ultimately help improve the cardiovascular outcomes and quality of life for patients with HF.</p>