Metabolic perturbations underlie a variety of cardiovascular disease states; yet, metabolic interventions to prevent or treat these disorders are sparse. Ketones carry a negative clinical stigma as they are involved in diabetic ketoacidosis. However, evidence from both experimental and clinical research has uncovered a protective role for ketones in cardiovascular disease.

Growing evidence suggests that ketones may be beneficial for patients with cardiovascular disease (CVD). Interventions that enhance circulating ketone levels result in increased myocardial ketone oxidation and improved cardiac function.

In addition to the expected role of ketones as an efficient substrate for (cardiac) metabolism, as they require less oxygen per molecule of ATP generated, ancillary cardioprotective effects of ketone bodies beyond energetics have also recently been identified.

Cardiac diseases are associated with loss of metabolic flexibility. Even in early stages of structural heart diseases, substrate utilization switches from fatty acids to glucose utilization, and oxidative metabolism is reduced. This metabolic reprogramming results in a fuel preference pattern that is similar to the fetal state. The majority of evidence indicates that the reduced capacity to utilize fatty acids sets the stage for myocardial energy starvation, contributing to the pathogenesis of heart failure (HF). Intriguingly, in the context of reduced fatty acid oxidation, the failing heart appears to reprogram metabolism to increased reliance on ketone bodies as a fuel source.

Strategies to induce ketosis relevant to heart failure:

In general, a BHB level ≥0.5 mmol/l has been considered as a cut-off point for entry into ketosis.

Ketosis can also be achieved by a ketogenic diet (KD) or by ingesting ketone precursors, such as 1,3-butanediol or medium-chain triglyceride (MCT). Alternatively, exogenous sources of ketones, such as ketone salts (KS) or ketone esters (KE), can be ingested. The KD has become extremely popular, both within and outside of the medical arena. KD consists of a very low-carbohydrate and high-fat diet that forces the body into endogenous ketosis. Although sustained KD can raise blood βOHB to 2 to 4 mmol/l, long-term compliance is low, often due to gastrointestinal (GI) distress (Figure 1).

SGLT2i induced ketosis and cardiovascular benefits:

Sodium-glucose cotransporter inhibitors (SGLT2i) are drugs that stimulate urinary glucose excretion and have recently received considerable interest because of their cardiovascular benefits in HF patients with and without diabetes. SGLT2i reduce insulin levels and stimulate lipolysis, which in turn drives ketone production in the liver. Accordingly, SGLT2i induce mild ketosis in both diabetic and nondiabetic subjects. Some authors have suggested that CV benefits during SGLT2i are mediated by the increases in circulating ketone bodies.

Ketone Bodies: Pleiotropic Effects Beyond Cardiac Energetics:

Besides the effects of ketones on (cardiac) energetics, several pleiotropic effects of ketones have been identified that may provide additional CV benefit (Figure 2)

Summary:

Evidence for benefits of ketone bodies in subjects with cardiovascular disease is rapidly emerging. In addition to the role of ketones in provision of an ancillary fuel for the failing heart, ketone bodies may also exert a myriad of pleiotropic effects. Ketone bodies may improve endothelial function, ameliorate oxidative stress, improve mitochondrial function, exert anti-inflammatory actions, and mitigate cardiac remodeling. Other systemic extracardiac effects on body weight, blood pressure, glycemia, and lipid profile may also benefit patients with CVD. Regardless of the pathway to achieve ketosis, ketone bodies have potential clinical applications that require further exploration, including new therapeutic approaches to harness the beneficial effect of ketosis. In the coming years, we will learn whether ketone bodies can be beneficial and optimized to be used in treatment and prevention of CVD.