Ketones with a twist: tipping the heart’s hat to fat

Ketones are readily oxidized by the heart and may have a beneficial effect on cardiac function because they produce energy more efficiently (at lower oxygen cost per ATP) than fatty acids (1). In this issue of Obesity, Luong and colleagues (2) conducted a randomized crossover study in eleven middle-aged men and women with obesity to test the hypothesis that a physiological increase in plasma ketones, induced by consuming a ketogenic diet, reduces myocardial oxygen consumption with direct functional consequences. Participants were assigned to either three weeks of a standard diet, containing 45% - 60% of energy as carbohydrates, 10% - 20% as protein, and 25% - 45% as fat, or three weeks of a ketogenic diet, containing 5% of energy as low-glycemic index carbohydrates, 20% as protein, and 75% as fat, with one week washout between the different diet periods. Compliance with the ketogenic diet was confirmed by daily plasma ketone monitoring. At the end of each diet period, dynamic cardiac positron emission tomography-computed tomography (PET/CT) imaging in conjunction with [¹¹C]palmitate, [¹¹C]acetate, and [¹⁵O]H₂O was performed to non-invasively evaluate myocardial fatty acid metabolism, oxygen consumption, external efficiency (stroke work in relationship to oxygen consumption), and flow reserve (increase in myocardial perfusion after adenosine administration). The ketogenic diet reduced myocardial fatty acid oxidation rate by about 30% but did not preserve oxygen or alter myocardial hemodynamics, myocardial external efficiency, or ejection fraction (Figure 1). However, the duration of the study (three weeks) may have been too short to observe functional consequences. The lower fatty acid oxidation rate on the ketogenic diet caused an imbalance between fatty acid supply (fatty acid delivery and uptake) and demand (oxidation) and a doubling of non-oxidative myocardial fatty acid disposal (Figure 1). In addition, ketones themselves may have contributed to the increase in myocardial lipids through increased lipogenesis (3). These data demonstrate that a ketogenic diet has potentially adverse cardiac effects because chronically elevated myocardial lipid content can cause cardiac lipotoxicity (4).

Figure 1.

Cardiac consequences of switching from a standard diet to a ketogenic diet in people with obesity.

The findings from this study have important clinical implications because ketogenic diets have become popular due to their weight loss-inducing effect and other presumed health benefits. In fact, during the ketogenic diet period, participants in the study by Luong (2) lost about 2 kg of body weight during just three weeks. Even a small (5%) body weight reduction induced by calorie restriction can have significant beneficial effects on cardiometabolic health (5). However, the initial weight loss when switching to a ketogenic diet represents primarily body water due to the carbohydrate restriction, not body fat (6). Nevertheless, blood glucose was lower even during overnight fasted conditions, suggesting a metabolic adaptation to the ketogenic conditions rather than merely a direct consequence of low glucose intake. Whether metabolic benefits of a ketogenic diet outweigh the potential cardiac risk is unclear.

A limitation of the study by Luong and colleagues (2) relates to the indirect evidence of increased ketone oxidation, because ketone metabolism itself was not measured. This is not a shortcoming of the experimental design but rather due to the fact that there are currently no ketone tracer methods available to evaluate ketone oxidation by imaging techniques. It is highly likely that during the ketogenic diet period ketones were oxidized at the expense of fatty acids, because the heart has a high capacity for oxidizing ketones and the rate of myocardial ketone oxidation is dependent largely on circulating ketone concentration (1). Based on the relative stoichiometry of fatty acid and ketone oxidation one would expect a lower oxygen consumption when the heart is fueled by ketones rather than fatty acids. However, Luong and colleagues (2) found no difference in oxygen consumption between the standard diet and ketogenic diet condition. Ketone provision in mouse and canine models of heart failure have shown improvements (i.e. increases) in myocardial oxygen consumption and heart function (7). Additionally, a study of acute ketone infusion in people with heart failure with reduced ejection fraction showed improved myocardial oxygen consumption - albeit no change in mechanical external efficiency (8). However, the effect of ketones on glucose oxidation in this study (8) was evaluated during a hyperinsulinemic-euglycemic clamp procedure when fatty acid concentration and oxidation are maximally suppressed. It is possible that this study (8) and the present study (2) were not sufficiently powered to detect the small (~5%) difference in oxygen consumption that in theory would have resulted if ketones replaced the oxidation of fatty acids. It is also possible that there was excessive/futile ketone oxidation (9). It is unlikely that there was a concomitant upregulation of carbohydrate oxidation, because the glucose “load” of a ketogenic diet is low and plasma glucose concentration during metabolic testing was lower. Moreover, ketones reduce glucose oxidation (10) and are an even more efficient substrate than fatty acids and ketones. It would be interesting to see the effect of ketones and a ketogenic diet on whole-body and cardiac substrate oxidation during postprandial conditions.

In summary, although the authors of the present study (2) report no functional cardiac consequences when switching to a ketogenic diet (possibly due to the short duration of the intervention), the observed shift from fat oxidation to fat storage is concerning and suggests ketogenic diets should be approached with caution. Longer-term intervention studies in both healthy people and people with cardiomyopathies are needed to better understand the effect of a ketogenic diet on the heart.