Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure

Abstract

Despite existing therapy, patients with heart failure (HF) experience substantial morbidity and mortality, highlighting the urgent need to identify novel pathophysiological mechanisms and therapies, as well. Traditional models for pharmacological intervention have targeted neurohormonal axes and hemodynamic disturbances in HF. However, several studies have now highlighted the potential for ketone metabolic modulation as a promising treatment paradigm. During the pathophysiological progression of HF, the failing heart reduces fatty acid and glucose oxidation, with associated increases in ketone metabolism. Recent studies indicate that enhanced myocardial ketone use is adaptive in HF, and limited data demonstrate beneficial effects of exogenous ketone therapy in studies of animal models and humans with HF. This review will summarize current evidence supporting a salutary role for ketones in HF including (1) normal myocardial ketone use, (2) alterations in ketone metabolism in the failing heart, (3) effects of therapeutic ketosis in animals and humans with HF, and (4) the potential significance of ketosis associated with sodium-glucose cotransporter 2 inhibitors. Although a number of important questions remain regarding the use of therapeutic ketosis and mechanism of action in HF, current evidence suggests potential benefit, in particular, in HF with reduced ejection fraction, with theoretical rationale for its use in HF with preserved ejection fraction. Although it is early in its study and development, therapeutic ketosis across the spectrum of HF holds significant promise.

Keywords: fatty acids; glucose; heart failure; ketones; metabolism; sodium-glucose transporter 2.

Figure 1:. Pathways of Hepatic Ketogenesis and Myocardial Ketolysis

Exogenous fats are absorbed through the gastrointestinal tract (specifically, medium chain triglycerides can be hydrolyzed by lipases to generate medium chain fatty acids). In addition, free fatty acids generated by adipolysis are circulated to the liver, where they undergo fatty acid oxidation in the hepatic mitochondria to produce acetyl CoA. Subsequent ketogenesis ultimately produces two mature ketone bodies: acetoacetate and β-hydroxybutyrate (β-OHB). Export from the hepatocytes and import into the cardiomyocyte is accomplished via monocarboxylate transporters. In cardiomyocyte mitochondria, ketolysis produces acetyl CoA that can be used in the tricyclic acid cycle. Notably, circulating ketones that are not oxidized by tissue can be 1) used for lipid or cholesterol synthesis (acetoacetate only) or 2) eliminated through the urine or exhaled as acetone (derived from decarboxylation of acetoacetate). Therapies used to achieve ketosis are noted in red. Abbreviations: ACAT, acetyl-CoA acetyltransferase; BHB, β-hydroxybutyrate; BDH, BHB dehydrogenase; HMGCL, HMG-CoA lyase; HMGCS2, HMG-CoA synthase; MCT, monocarboxylate transporter; SCOT, succinyl-CoA:3 oxoacid-CoA transferase; TCA; tricyclic acid.

Figure 2:. Methods of Achieving Ketosis and Related Potential Cardiovascular Benefits

Popular, non-dietary ways of achieving ketosis include oral ketone ester drinks, intravenous ketone salt infusions, and SGLT2 inhibitors. Reported cardiovascular benefits related to the ketosis achieved are listed underneath with the corresponding patient population studied. Note that the role of ketosis as a mediator of the cardiovascular benefits observed with SGLT-2 inhibitors is speculative at this point. CV, cardiovascular; FA, fatty acid; HF, heart failure; LV, left ventricular; PVR, peripheral vascular resistance; SVR, systemic vascular resistance.