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Diastolic dysfunction in chronic hypoxia: IL‐18 provides the elusive link

The diastole is the phase of the cardiac cycle in which the ventricles fill with the blood deriving from the atria, ready to be pumped into the pulmonary or peripheral circulation during systole. The initial phase of the diastole is the myocardial relaxation, in which calcium reuptake in the sarcoplasmic reticulum and the release of the actin-myosin bonds allow for an energy-dependent elongation of the fibers allowing for a pressure gradient-dependent flow of blood from the atria to the ventricle. Abnormalities in the myocardial relaxation delay the rate of ventricular pressure decline leading to delayed opening of the atrioventricular valves, which, due to the gradual increase in atrial pressure, occurs at a higher value of ventricular pressure, and rapid equalization of the pressure limiting the gradient and limiting early ventricular filling. Late ventricular filling on the other hand is more dependent on the elastic properties of the ventricle (elastance=1/compliance). A hypertrophic or fibrotic left ventricle will oppose more resistance to filling, and thus impairs late ventricular filling. Impairment in the myocardial relaxation and/or of the ventricular compliance determines the presence of diastolic dysfunction. Diastolic dysfunction in the heart may occur as a result of normal ageing, but it more often is caused by metabolic or structural abnormalities in the myocardium, which are the substrate for diastolic heart failure (or heart failure with preserved ejection fraction – HFpEF) (Borlaug 2014). The pathophysiology of diastolic dysfunction and heart failure is poorly understood. In particular, it is not clear how acute metabolic changes, such as ischaemia, hypoxia or inflammation, cause impairment in myocardial relaxation (Butler et al. 2014). In this issue of Acta Physiologica, Hillestad and colleagues shed light on this field, by showing that Interleukin-18 (IL-18) mediates diastolic dysfunction secondary to ambient (alveolar) hypoxia in the mouse (Hillestad et al. 2014) (Fig. 1). Hypoxia to the heart may occur in the setting of a significant reduction of blood flow, which can be regional (ischaemia) or global (shock), or it may occur when low oxygen tension is found in the alveoli such as in the setting of high altitude (ambient hypoxia), chronic lung diseases or acute inflammation or infection of the lungs. Independent of the cause of hypoxia, the cellular stress response is activated and in the heart leads to impaired diastolic function. In this study, mice were exposed to chronic ambient hypoxia to artificially diminish oxygen tension. They found that the left ventricular relaxation time constant, Tau, and the isovolumetric relaxation time (IVRT) were increased following hypoxia, indicating diastolic dysfunction