Constrained Oxidative Reserve in Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is characterised by impaired physiological reserve despite preserved resting ejection fraction. Cardiac ³¹ P-MRS identifies abnormal myocardial high-energy phosphate states, but phosphocreatine-to-ATP reflects energetic state rather than oxidative ATP-generating flux. We propose constrained myocardial oxidative reserve as a testable physiological construct: a stress-dependent limitation in oxidative ATP provision that compromises the ability to sustain increasing energetic demand while maintaining adequate ATP hydrolysis free energy. Such limitation may contribute to impaired relaxation, myocardial reserve, and elevated filling pressures during stress. Potential constraints include intrinsic mitochondrial dysfunction and restricted oxygen delivery, which must be distinguished from excessive ATP consumption and impaired intracellular energy transfer. Human studies associate energetic abnormalities and altered oxidative metabolic responses with reserve failure but do not establish causal mediation. Static molecular profiles likewise do not define pathway flux, and current myocardial evidence is strongest in cardiometabolic HFpEF. Validation requires phenotype-stratified, stress-resolved assessment of oxidative metabolism, myocardial work, loading, oxygen delivery, and energetic stability, followed by targeted perturbation to establish causality.