In this present study, a holistic approach with state-of-the-art cardiac function evaluation, tissue characterization and biomarker analysis was performed to evaluate myocardial function, thoracic and supra-aortic blood flow, and their changes during maximal individual apnoea. The major findings of our study are a stepwise (1) increase of LVEDV, LVESV, LVSV and an unchanged CO, (2) decrease of LVEF and FS at the end of apnoea, (3) increase of supra-aortic blood flow without concurring flow changes in the descending aorta, and (4) an elevated hs-cT and NT-pro-BNP levels.
Cardiac function
In the present study we were able to demonstrate a significant LV dilatation along with an increased LVSV, which is in line with a previous study [
17], where increased EDD and ESD, an increase in SV and CO and a reduction in contractile function after an apnoea time of 3.7 ± 0.3 min was reported. In contrast to our results, neither bradycardia nor increased calculated systemic vascular resistance were observed [
17], although both effects are part of the accepted concept of the diving response [
8]. In a more recent study by Batinic et al., cardiac parameters (i.e. HR, LV volumes, LVEF, LVCO) taken at two time points of apnoea (minute 1 and minute 3) were compared [
18]. These investigators found a significant increase in LVEDV and CO (112 ± 15 ml to 125 ± 15 ml; 5.4 ± 1.9 l/min to 6.0 ± 1.2 l/min), which was similar to our results (123 ± 24 ml to 177 ± 26 ml; 5.5 ± 1.6 l/min to 6.1 ± 1.7 l/min). In contrast to the previous results from Pingitore et al. [
17] and the results of the present study, no changes in SV were observed (69 ± 12 ml to 69 ± 8 ml), while HR increased from 80 ± 15 bmp to 87 ± 16 bmp during apnoea [
18].
Since the mammalian diving response to maximal voluntary apnoea considerably varies depending on the examined individual and the study setup, the at first apparently contradictory results of the three studies might be explained by the breath-hold duration [
5,
9,
19]. In contrast to previous studies focusing on physiological changes during apnoea, the breath-hold time in the present study was considerably longer (297 ± 99 s vs. 234 ± 66 s; 199 ± 11 s; 210 ± 70 s) [
5,
9,
19]. However, even though individual responses may vary, it is known that physiological changes are most notable at the end of apnoea [
9,
20,
21]. In this context it is important to mention that the previous studies [
17,
18] used predefined time points for data collection, which will not necessarily coincide with the individual maximum breath-hold duration of each athlete. We have therefore decided to use a minimal breath-hold duration of 270 s to eliminate the possible shortcomings of a too short apnoea duration in the previous studies [
5,
9,
19‐
21]. Therefore, one can speculate that the shorter breath-hold durations registered in both previous studies [
10,
17] are not suitable to push all compensatory mechanisms to their limits, and that a predefined time point might lead to undersampling. This is further supported by the fact that SpO
2 decreased more profoundly in our study compared to the study from Pingitore et al. (from 99 ± 1% to 74 ± 14% vs. 97 ± 0.2% to 84 ± 2%) [
17].
We found a relative increase in LVSV of 30 ± 48% during apnoea, but a decrease in FS and LVEF. FS depends on inter-ventricular dimensions and is affected by ventricular filling. Ejection fraction, in contrast, is a relatively load independent surrogate parameter for cardiovascular performance. In general, the efficiency of myocardial performance is determined by preload, afterload and contractility [
22,
23]. An increase in afterload will therefore result in decreased efficiency of myocardial performance. In case of prolonged breath-hold the peripheral chemoreflex regulation, the elevated sympathetic nerve activity and the increase in norepinephrine will lead to peripheral vasoconstriction and hypertension [
5,
24] and subsequently to bradycardia via the baroreflex [
25]. In accordance with this established physiological pathway, we observed a significant increase in norepinephrine levels to above the upper cut-off limit of > 420 pg/ml and a decrease in HR at the end of apnoea. Therefore, the HR decrease and the concommitant increase of both ventricles may be seen as an indirect visualization of the aforementioned baroreflex (Fig.
4).
Biomarkers
NT-proBNP was elevated early after maximal apnoea. Although some authors describe BNP as an “emergency” cardiac hormone against ventricular overload [
26], the observed elevations of pro-BNP were only minor and far from pathological levels. Nevertheless, in absence of other triggers even this small increase may be regarded as an indicator for LV wall stress. Although an increase in hs-cT was found in this study, the normal T2 relaxation times directly after apnoea may indicate that the increased hs-cT may be more attributable to the LV dilatation and not to acute and persistent myocardial damage. This may further be supported by the fact that elevated cardiac troponin (cT) levels are also commonly found in patients with dilated cardiomyopathy [
27].
In addition, myocardial perfusion and oxygen consumption is dependant on various parameters. At the end of apnoea, HR decreases while SV and systolic and diastolic blood pressure increase. These physiological changes translate into an increase of estimated oxygen demand in our study from 8.5 ml/min/100 g to 9.5 ml/min/100 g (i.e. only by 11%). However, this increase in demand may be assumed to be outweighed by a theoretical increase of approximately 40% of coronary perfusion due to increase of the diastolic blood pressure. It is of note that these theoretical considerations are based on healthy subjects without any coronary morbidities.
Clinical context
The human diving response (i.e. bradycardia, peripheral vasoconstriction, increased blood pressure) helps to preserve O
2 in case of apnoea [
28]. These protective mechanisms against hypoxia are triggered by apnoea per se and are augmented by face immersion [
29]. The constriction of intramuscular and dermal vessels results in an increased total peripheral resistance and thus in an increased blood pressure [
9,
30]. Due to peripheral vasoconstriction and reduced blood flow, the remaining circulating blood flow is redistributed to more hypoxia sensitive organs such as the brain [
19,
25]. In the present study, only minimal blood flow changes were seen in the descending aorta while blood flow in the ascending aorta and the carotid arteries massively increased, indicating that even the gastrointestinal tract is excluded from blood flow redistribution in the case of hypoxia. This perfusion preference of the cerebrum emphasises the efficiency of the body’s compensatory mechanism to avoid hypoxic damage of the brain. Accordingly, cerebral MRI showed no case of acute ischemia-induced brain injury, indicating the effectiveness of the compensatory mechanisms, even in case of breath-holds longer than 8 min (Table
1, subject 12).
Prolonged apnoea is not exclusively seen in breath-hold divers, also patients with obstructive sleep apnoea (OSA) show compensatory mechanisms to avoid brain damage [
31]. Patients with OSA show an increase in cerebral blood flow [
32,
33], elevated sympathetic activity [
34], elevated arterial blood pressure [
35], and an increase in norepinephrine levels [
31]. Interestingly, LV and right ventricular (RV) afterload are increased and cardiac arrhythmia is commonly seen [
36]. OSA is independently associated with coronary artery disease, atherosclerosis, hypertension, stroke, endothelial function and myocardial infarction [
37,
38]. A main problem in understanding the underlying pathophysiology stems from the lack of an adequate clinical model to simulate OSA [
39]. So far, hypoxic gas mixtures have been used to mimic hypoxia in humans [
40], but because of the resulting hyperventilation, these models are more representative for high altitude environments than for OSA. In addition, the transmissibility of animal models is also limited. Apnoea divers are mostly free of comorbidities, and our study shows that even a short episode of hypoxia affects the cardiovascular system. Therefore, voluntary extended breath-hold might be taken as a clinical relevant model to simulate short term changes due to hypoxia [
41], although the exposure levels to hypoxemia differ significantly [
41]. In this context it should be noted that this study was performed with trained athletes, and that a transfer of these findings to patients with cardiovascular diseases and obstructive sleep apnoea should be done with caution.
Patent foramen ovale has been demonstrated to have a higher prevalence in patients with obstructive sleep aponoea compared to healthy controls, and is suspected to inrease nocturnal oxygen desaturation in these patients [
42] and to enhance other pathologic conditions associated with OSA [
43]. In both scuba and apnoea divers knowledge about the implications of a patent foramen ovale regarding incidence and severity of decompression sickness is scarce [
44], especially because it is unkown if recurrent decompression sickness is a result of a patent foramen ovale, the inabiliy to adopt a more conservative diving style, or both [
45]. In the present study, no relevant changes of Qp/Qs (the stroke volume in the ascending aorta relative to the stroke volume in the pulmonary trunk) and thus no indication for a cardiac shunt, was found.
Cardiac dysrhythmia or irregular heartbeats (mainly premature ventricular excitations) were observed in 14 of 17 divers at the end of apnoea and during the early recovery phase (example shown in Additional file
1: Figure S1). It is tempting to speculate that the massive LV and RV dilatation triggers cardiac depolarization and repolarization. However, ECG quality was limited in this study and did not allow for a comprehensive analysis.
Limitations
Measurment accuracy (CMR and SpO2) might be limited at the end of apnoea due to e.g. motion artefacts (CMR), peripheral vasoconstriction (SpO2), and other technical restrictions. Blood pressure data is not available as invasive blood pressure measurement was not performed due to ethical considerations and automatic non-invasive blood pressure measurement failed due to the high and dynamic changes in blood pressure during apnoea. Due to the chosen CMR imaging protocol with only limited coverage of the RV, neither volumetric nor functional RV data are available. Future studies should also focus on effects of hypxoxia on pulmonary vasoconstriction and their effects on the RV function.