Patent foramen ovale: a leaking radiator?

At birth, the first breath increases left atrial pressure beyond right atrial pressure and forces the septum primum against the septum secundum. This in effect prevents right to left blood flow through the foramen ovale, and forces blood to navigate through the lungs where it can participate in gas exchange. In most, the foramen ovale eventually fuses creating the fossa ovalis. In approximately 25–35% of people, however, this fusion is incomplete, and a patent foramen ovale (PFO) is formed. The magnitude of the blood flow shunt is dependent on the size of the PFO, and is accentuated when right atrial pressure exceeds left (e.g. during a Valsalva manoeuvre or coughing). The presence of a PFO in most is completely benign. Nevertheless, a large pathophysiological shunt may require surgical closure (albeit the benefits of surgical PFO closure remain debatable), and its potential role in certain pathology (e.g. cryptogenic stroke, migraine and hypoxaemia) and physiology (e.g. arterial-alveoli gradients) continues to be characterized (Dattilo et al. 2013). In a recent novel publication in The Journal of Physiology, Davis et al. (2015) add to the growing body of literature demonstrating that subjects with a PFO (PFO+) are warmer by an average of ∼0.4°C (oesophageal), than subjects without a PFO (PFO−). Convincingly, the magnitude of the temperature difference is proportional to the estimated size of the PFO (measured using the agitated saline bubble score technique), and persists throughout incremental intensity exercise. Sex, anthropometric levels and fitness levels were appropriately matched between PFO+ and PFO− groups, minimizing the potential for competing thermal determinants. The purpose of this Journal Club article is to (1) discuss the potential underlying mechanisms for the temperature differences in PFO+ vs. PFO− subjects (while being cognizant to not over-speculate), (2) propose areas for future research, and (3) since a 0.4°C difference in core temperature is not trivial, highlight the significance of these findings in thermal physiology. Given the above calculation, it follows that in combination with environmental factors (ambient temperature and humidity), changes in respiratory heat loss are largely affected by metabolism, via changes in pulmonary blood flow (cardiac output), core temperature and minute ventilation. However, in the presence of a PFO, respiratory heat loss may be lower for a given cardiac output, where a proportion of blood bypasses the respiratory radiator (pulmonary circulation). To probe the impact of respiratory cooling differences in PFO+ vs. PFO− subjects, Davis et al. had subjects exercise while breathing cooled air (∼2°C). In keeping with the notion that PFO+ subjects have a reduced respiratory cooling capacity, the increase in oesophageal temperature during exercise was attenuated in the PFO− group during cold air breathing, relative to the room air temperature breathing, but was not in the PFO+ group. Again, the magnitude of the temperature difference between groups was proportional to the estimated size of the PFO. Equivocally, however, a biophysical estimation of changes in respiratory heat transfer with a PFO does not entirely align with the differences in measured core temperature. For example, assuming the proportion of blood flow passing through the PFO is equal to 5% of cardiac output, Davis et al. estimated that body core temperature would be elevated by ∼0.1°C (see Appendix in Davis et al.). The theoretical calculations of differences in respiratory heat loss only explain ∼25% of the difference in actual resting core temperature measurements in PFO+ vs. PFO− subjects. Therefore, assuming these theoretical calculations accurately reflect true differences in respiratory heat transfer, other interacting mechanisms must be involved. Although not significantly different, resting was on average ∼10% higher in PFO+ vs. PFO− subjects (0.42 ± 0.08 vs. 0.38 ± 0.09 L min−1, respectively). Using the reported values for and respiratory exchange ratio (RER), the calculated resting metabolic heat production is similarly ∼10% greater in the PFO+ (130 W) vs. PFO− (144 W) subjects. Given an average specific heat capacity of human tissue at ∼3.5 J g−1 °C−1 and the average participant mass of 77 kg, this ∼14 W difference in metabolic heat production would equate to a ∼0.19°C h−1 body core temperature difference. It may therefore be that the elevated core temperature in PFO+ compared to PFO− subjects is in part explained by the elevated metabolic heat production. However, as highlighted in Davis et al., quantifying only one component of the human conceptual heat balance equation precludes any conclusion for whole-body heat balance, and ultimately temperature. For example, aerobically trained and heat acclimated persons are cooler than their unfit or un-acclimated counterparts, regardless of resting metabolism. Ultimately, thermal balance is best described from the interaction of independent feedforward and feedback thermoeffector loops. Partitioning the biophysical components of human balance – that is, metabolic heat production, heat exchange at the skin (via conductance, convection, radiation and evaporation), and respiratory heat loss – may help provide the much needed insight into the thermoregulatory properties responsible for the ∼0.4°C temperature difference in PFO+ vs. PFO− subjects. An obvious sequential study to follow Davis et al. is one that quantifies respiratory heat loss. Here, the temperature and absolute humidity of inspired (ambient) and expired (at the mouth) air would be measured. Under conditions of identical ambient conditions, core temperature (via pre-heating), and ventilation (via paced breathing), potential differences in respiratory heat loss between PFO+ and PFO− can be quantified, with respiratory heat loss described as a ratio of cardiac output. Potential confounding factors may be total lung capacity and dead space, which should be corrected for. As an adjunct to measuring respiratory heat loss, to rule out other differential thermoregulatory properties between PFO+ and PFO− subjects, a viable study may be to measure whole body and local sweat rate (for sweating onsets and thermosensitivity), skin blood flow, and skin temperature. Of note, the physiological differences between PFO+ and PFO− subjects in Davis et al. closely resemble those of heat acclimated and non-acclimated subjects, respectively. That is, a lower resting core temperature and heart rate in the PFO− vs. PFO+ subjects. Therefore, to rule out any confounding influence of heat acclimation and/or aerobic fitness, future study may require a full heat acclimation protocol, prior to and following thermoregulatory testing. Indeed, although the difference was small and insignificant, PFO− subjects had a that was on average 4 ml kg−1 min−1 higher (∼5%) than their PFO+ counterparts. Following further study, if negligible differences in respiratory or other thermoregulatory effector responses are observed, it may be that the presence of a PFO is in part determined by resting core temperature, rather than vice versa. Measuring resting core temperature in patients prior to and following surgical PFO closure may shed light on this chicken or the egg hypothesis (i.e. if PFO closure does not proffer changes in resting core temperature). Although completely speculative, future study may in turn suggest a role for the prevailing body temperature in the aetiology of the fusion between the septum primum with the septum secundum. Regardless of mechanism or aetiology, Davis et al. convincingly show that those with a PFO are on average 0.4°C warmer than those without a PFO. It follows that those with a PFO may be more susceptible to heat related illnesses. Pre-screening for PFO+ before thermal stress may be of benefit for future thermoregulatory study, or even in the field. Given the ominous consequence of even small (0.5°C) increases in core temperature following cerebral stroke (den Hertog et al. 2011), it may also be of benefit for clinicians to pay special attention on core temperature, particularly following cryptogenic stroke where the cause may result from emboli that travel from the extremities to the brain, via the PFO. In summary, Davis et al. provide unique and convincing data of core temperature differences in PFO+ vs. PFO− subjects. Their study should provide a framework for work to come. None declared.

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