Hypophosphatemia and sudden infant death syndrome (SIDS)—is ATP the link?

In their recent letter Van Kempen and co-workers presented an intriguing hypothesis linking hypophosphatemia and sudden infant death syndrome (SIDS) (1), founded on the work by Siren and Siren on the critical diaphragm failure being the cause of SIDS incidences (2,3). Van Kempen and coworkers argued that both etiology and symptoms of SIDS can be explained by low concentrations in erythrocytes of phosphate metabolites, mainly 2,3-biphosphoglycerate (2,3-BPG, also known as 2,3-diphosphoglycerate, 2,3-DPG), which in effect would impair muscle function (especially diaphragm) and lead to respiratory failure as Siren and Siren originally stated. We find the hypothesis interesting and definitely worth further investigation; however, we would assign the main role to ATP, not to 2,3-BPG. First of all, 2,3-BPGbindsweakly to fetalhemoglobin in comparison to adult hemoglobin (4). Analyses of oxygen equilibrium curves in infants indeed showed a correlation between P50 and 2,3-BPG concentration (5), but it was the so-called ‘functioningDPG fraction’, that is, amultiplicationof total red cell 2,3-BPGcontent and the percentage of adult hemoglobin. Fetal hemoglobin is being replaced by adult hemoglobinwithin the first few months of the infant’s life. However, its concentration does not seem to correlate with the lognormal distribution of age in SIDS incidents. Furthermore, the concentration of 2,3-BPG is tightly regulated assynthesisanddegradationareseparatedandcatalyzed by different enzymes (6). This process is one of the slowest in the whole metabolic system of the red blood cell (7). As a result, changes in the concentration of 2,3-BPG in erythrocytes in response to external stimuli (forexample,highaltitudeoracidosis (8,9))usually take several hours. Even more, in case of exchange transfusion with acid-citrate-dextrose (ACD) preserved blood in infants, adjustment of 2,3-BPG concentrations occurs over days not hours (10). It is hard to envision a sudden drop in the concentration of 2,3-BPG, but if it indeedoccurs itwill influencebloodoxygenaffinityonly inolder infantswhosebloodisalreadycomposedmainly of adult hemoglobin. That said, the hypothesis on the affected oxygen transport in SIDS is supported by the correlations between the levels of fetal hemoglobin and incidences of SIDS (11,12). However, we would like to extend the work of Van Kempen and co-workers by pointing in the direction of the major player in the regulation of oxygen delivery—ATP. In recent years a substantial body of evidence has accumulated for the hypothesis that erythrocytes themselves are the vascular controller adjusting blood flow on the basis of the local oxygen needs (reviewed in (13)). That regulation is executed mainly by an O2 saturation-dependent ATP release. However, the ATP signaling is not limited to vessel walls—it affects all rheological properties of blood. As shown recently, viscosity of blood is affected by cell-deformationdependent ATP release (14). In contrast to 2,3-BPG, the metabolism of ATP is fast (7), and similarly rapid is also its release (15). Therefore, effects of ATP on blood flow are also relatively quick.