A randomized crossover trial testing ketone ester supplementation in 20 adults with heart failure with preserved ejection fraction (HFpEF) found no improvement in peak oxygen consumption (10.4 vs 10.5 mL/kg/min) or exercise endurance time compared to placebo. While ketone esters increased cardiac output by 0.6 L/min and reduced peripheral resistance at rest, these cardiovascular changes vanished during exercise when they would matter most for performance. This finding challenges the hypothesis that metabolic fuel switching could address exercise intolerance in HFpEF, a condition affecting millions of older adults where few treatments exist. The negative result is particularly noteworthy given ketones' theoretical appeal as a more efficient cardiac fuel that requires less oxygen per ATP molecule generated. Previous animal studies suggested ketone supplementation could improve cardiac efficiency, but this human trial indicates the pathophysiology of HFpEF exercise limitation may be more complex than simple metabolic substrate availability. The study's crossover design and direct measurement of oxygen consumption provide robust evidence, though the small sample size of 20 participants limits broader generalizability. For the growing population with HFpEF, this adds to a series of disappointing therapeutic trials, suggesting that targeting metabolic pathways alone may be insufficient.