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  1. Barry A Borlaug
  1. Correspondence to Professor Barry A Borlaug, Department of Cardiovascular Medicine, Mayo Clinic Minnesota, Rochester MN 55906, USA; Borlaug.Barry{at}mayo.edu

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Heart failure with preserved ejection fraction (HFpEF) afflicts millions worldwide and clinical trials have failed to identify effective treatments.1 This failure is related partly to pathophysiological heterogeneity and partly to incomplete pathophysiological understanding of the different phenotypes. Elevation in left ventricular filling pressures during exercise is the one pathophysiological component that is shared by all HFpEF phenotypes,1 2 but high filling pressures do not appear to explain everything that goes wrong in people with this syndrome.

In order to perform work, mitochondria in skeletal must generate ATP through oxidative metabolism.3 As the work of exercise increases, there is matching increase in the amount of oxygen consumed (VO2) to provide fuel. Increases in VO2 are achieved by enhancing O2 delivery through several integrated steps involving multiple organ systems. The lungs are responsible for oxygenation of erythrocytes, and the heart accelerates these erythrocytes through the circulation to the tissues in a process termed convective O2 transport. This ‘bulk transfer’ step is analogous to shipment of a package from the central post office to the local post office closer to the recipient’s home. The convective impairment in O2 transport (the ability to increase cardiac output, Qc) is typically impaired in patients with HFpEF.1–5

But that is not the end of the story (or the postal metaphor). After being ejected from the heart through the conduit and resistance arteries, the O2-rich erythrocytes then need to be distributed to capillary beds in skeletal muscle, where O2 will diffuse from haemoglobin molecule to skeletal myocyte to be utilised by mitochondria. This step in the O2 pathway is analogous to transport of our package from the destination post office to the recipient’s doorstep (capillary), where it is then opened and read by the recipient …

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