INTRODUCTION

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THE AMPLITUDE of the T wave (A_Tw), which represents the repolarization phase of the electrical activity of the heart, has been shown to change during diving in many studies (20-22, 26, 30). Tall, peaked T waves have been observed in native-diving animals (20, 21), in breath-holding, non-native-diving animals (30), and in freely breathing animals in dry hyperbaria (22). The reason for this change has not been satisfactorily explained, nor has it been determined whether this change in A_Tw is associated with a change in cardiovascular performance (22, 26). We studied the electrocardiograms (ECG) of guinea pigs breathing mixtures of helium (He) or hydrogen (H₂) and oxygen (O₂) (heliox and hydrox, respectively) in a hyperbaric chamber, as well as the O₂ consumption rate (O₂) of these animals, to determine whether there was a correlation between A_Tw and whole-animal O₂ relative to heart rate.

Electrical conduction in the heart occurs in a complex manner in three physical dimensions and over time; only a small part of all the depolarization and repolarization events is recorded in the ECG waveform of a single lead placement (29). Thus cardiologists are wary of overinterpreting ECGs (5). Nevertheless, useful information can be gathered from ECGs by associating characteristic changes in waveform with changes in the cardiovascular health status of the subject (5). The tall, peaked T waves previously reported in diving subjects are not convincingly associated with any particular pathology, because they usually occur without any other obvious ECG anomalies or overt signs of cardiovascular distress, such as ischemia or electrolyte imbalance (6, 22, 26). In recent years, there has been a growing interest in studying subtle changes in electrical activity of the heart, including variation in beat-to-beat time intervals (3, 11) and in A_Tw (12, 22, 26). These subtle changes do not necessarily reflect a pathological condition, but they are of interest if they can be linked to physiological events. Such a linkage has been shown, for example, for a change in the relative sympathetic vs. parasympathetic nervous system influence (11, 12) and the influence of the renin-angiotensin system on heart function (3).

Changes in heart rate are a classic response in diving animals and are believed to reflect a redistribution of blood flow to conserve O₂ (17, 21). Bradycardia has been noted in freely breathing human divers compressed in a dry chamber (4, 26, 32), but the magnitude and duration of bradycardia are apparently highly variable (4), and its cause is unknown. Reductions in electrical conduction velocity and excitability by compression of critical sites on membranes associated with myocardial beating frequency have been proposed (14). Cold, exercise, and general stress are additional factors often present in diving that may have a significant effect on heart rate and metabolism. Narcosis may counteract some of these effects (15, 19). To differentiate among these factors, it is useful to compute heart rate relative to metabolic rate. The total volume of O₂ consumed by an animal per heart beat, known as the O₂ pulse, is important, because a change in this ratio implies a change in cardiovascular performance (2, 8, 18, 23, 28, 33). This change in performance must in turn be caused by changes in stroke volume or O₂ extraction, or a combination of these, relative to a given heart rate.

In a previous study, Kayar and Parker (24) measured O₂ pulse in guinea pigs breathing either heliox or hydrox at 10-60 atm and over a chamber temperature range of 26-36°C. The O₂ pulse was found to be correlated with body surface area (S), core body temperature (T_core), and chamber temperature (T_cham) and pressure (P), and these correlations were different for animals in heliox vs. hydrox. This earlier study concluded that, in order to analyze O₂ pulse, multiple factors had to be taken into consideration simultaneously. The present study builds on this earlier work. Using the same animals as in the previous study (24), but including A_Tw as an additional variable, we used stepwise multivariate regression analysis to determine whether A_Tw also correlates significantly with O₂ pulse. This correlation would demonstrate that changes in A_Tw in hyperbaria are predictive of a change in cardiovascular performance, as expressed by O₂ pulse.

Guinea pigs were instrumented with radiotelemeters to transmit electrical signals from the heart. The animals were placed in a dry chamber that was pressurized to generate hyperbaric conditions of up to 60 atm (atmospheres absolute pressure, equivalent to a dive to 590 m) of either heliox or hydrox. The O₂ of the animals was measured by gas chromatographic analysis of the chamber gas throughout the dive. T_cham was varied from 25 to 36°C as a means of generating a range of O₂ values and heart rate at each pressure. The radiotelemeters also transmitted body temperature from their implant site in the abdomen.

Measured values of O₂ pulse were mathematically modeled as a function of A_Tw, body S, T_core, T_cham, and chamber P. Multivariate regression analysis allowed us to clearly demonstrate the relationship between O₂ pulse and A_Tw by separating the simultaneous effects of the other measured variables.

	MATERIALS AND METHODS

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Animal preparations. Male guinea pigs (Cavia porcellus, Hartley strain; n = 19) were housed in an accredited, professionally staffed animal care facility and had ad libitum access to food and water before experiments.

Dive protocol. Animals were selected randomly for diving in the He [n = 10, 761 ± 43 (SE) g mean body mass] or H₂ (n = 9, 766 ± 29 g) gas mixtures. The animals in the heliox group were identical to those described previously by Kayar and Parker (24). Seven of the nine animals in the hydrox group were included in the earlier study (24). However, in three of the ten animals in the hydrox group from the original study, the ECG was not sufficiently clear to measure T waves. Two new hydrox animals with clearer ECGs were added to the present study. The new animals were in the same weight range and exposed to temperatures similar to the animals they replaced.

Statistical analysis. Data were analyzed by stepwise least squares regression (9). Regressions were compared with each other by F-tests, with significant difference assigned at the P = 0.05 level. For consistency with our previous study (24), all data from each gas mixture were analyzed separately to generate a multivariable model of O₂ pulse, using A_Tw, T_cham, chamber P, T_core, and body S as the variables. For least squares regressions of the model, these terms were analyzed sequentially, starting from only the y-intercept term and adding each successive variable in order of greatest statistical significance (forward step). After the addition of each variable, an F-test was performed to determine whether there had been a significant improvement. To test the robustness of the fit, we then started with all variables and eliminated any that were not significant (backward step). There was no difference in the best-fit parameter estimates in the forward vs. backward step analyses. The functions fitted in the analysis were of the form y = a + bx.

	RESULTS

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The A_Tw values for all animals appear in Fig. 1. While the animals were breathing 1 atm air before the start of the experiments, 12 of the animals had T waves that were positive, and the remaining 7 animals had T waves that were negative. In one animal in the heliox group, the polarity of its T wave reversed between 1 atm air and 10 atm heliox (Fig. 1). In one animal (animal 19) in the hydrox group, the T wave reversed from a moderately sized positive value at 40 atm to a negative value at 60 atm that was >10 SD from the mean value of all other A_Tw values in the study. Data from animal 19 at 60 atm were consequently deleted from all further analyses but will be discussed in greater detail later. The A_Tw values from animal 19 at 10, 20, and 40 atm were within 3 SD of the mean of all A_Tw values, and, therefore, they were not discarded. However, all statistical tests were performed with and without the data from this animal at 10-40 atm as a test of the influence of these data points; including these data did not change any conclusions.

View larger version (20K): [in this window] [in a new window]   Fig. 1.   Amplitude of T wave of electrocardiograms of guinea pigs breathing either 2% O2 in He (heliox; n = 10) or 2% O2 in H2 (hydrox; n = 9) at 10-60 atm. T-wave amplitudes for these same animals breathing 1 atm air are also included. Data from each animal at the different pressures are linked by line segments.

The polarity of the T wave in each animal included in the study remained the same from 10 to 60 atm. To rectify the polarity differences among animals, we used the absolute value of A_Tw measurements in all subsequent calculations. All P waves and R waves (depolarization of the atria and ventricles, respectively) were positive.

Mean A_Tw (absolute value) in the animals in the heliox group was the same as that of animals in the hydrox group measured in 1 atm air before the start of the experiments (93 ± 15 and 93 ± 19 µV, respectively). The A_Tw did not change significantly with increasing pressure for animals breathing either heliox (P = 0.21) or hydrox (P = 0.34; Table 1). In heliox, the mean A_Tw increased with increasing pressure, but the between-animal variability was too great for this trend to be statistically significant (Fig. 1; Table 1). The nonsignificant trend for animals in hydrox was for A_Tw to decrease with increasing pressure (Fig. 1; Table 1). Some sample ECGs from animals in the two gas mixtures at 10 and 60 atm are given in Fig. 2.

View larger version (18K): [in this window] [in a new window]   View larger version (23K): [in this window] [in a new window]   Fig. 2.   Sample electrocardiograms (lead II configuration) from 2 selected guinea pigs used in the present study. A and B: animal breathing heliox at 10 and 60 atm, respectively; C and D: animal breathing hydrox at 10 and 60 atm, respectively.

To examine the influence of the chosen variables on the relationship between O₂ pulse and A_Tw, and to consider the differences in this relationship between animals in heliox vs. hydrox, we constructed a multivariable regression model. As in the previous study (24), we reasoned that the heat drain of a small animal in hyperbaria should have a major impact on metabolism, heart rate, and potentially on O₂ pulse. The most complex model with statistically significant parameters that we identified was the following

(1)

where S (in m²) is estimated body surface area of an animal [computed from body mass (M_b, in g) as 9 × 10⁴ M ^2/3_b] (16), T_cham is chamber temperature (°C) measured inside the animal's box, T_core is the temperature (°C) registered by the telemeter in the peritoneal cavity, P is chamber pressure (in atm), and A_Tw is the absolute value of the amplitude of the T wave (in µV). The -parameters were estimated by fitting Eq. 1 to data from animals in the two gases separately (Table 2).

For animals breathing heliox, O₂ pulse increased with decreasing T_cham, decreasing P, and increasing A_Tw [P < 0.0001; R² = 0.70; residual sum of squared errors (RSSE) = 0.398 × 10⁸; Table 2]. Neither T_core nor body S were significant variables (P = 0.39 and 0.17, respectively; Table 2). For animals in hydrox, O₂ pulse increased with decreasing T_cham and decreasing A_Tw (P < 0.0001; R² = 0.57; RSSE = 0.228 × 10⁸; Table 2). There was also a trend for O₂ pulse to increase with decreasing pressure (P = 0.06) in hydrox, but T_core (P = 0.16) and body S (P = 0.14) were not significant variables (Table 2).

We tested whether two separate parameter estimates of _ATw in heliox and hydrox were justified within the model, in comparison to a single parameter estimate for _ATw in both gases. Separate values provided a significantly better fit to the data [F(1,66) = 27.15; P < 0.0001]. When data in heliox and hydrox were combined, no significant value (P = 0.55) for a parameter estimate for _ATw was obtained. We also tested whether the data were better fit by a model with separate _ATw parameters for each of the 19 animals, to account for differences among individuals. Inclusion of 19 additional parameter estimates was not justified [F(17,49) = 1.63; P > 0.09]. Of the ten individual _ATw parameter estimates computed for heliox animals, nine were of positive slope. Of the nine individual _ATw parameter estimates computed for hydrox animals, eight were of negative slope. Thus the correlations described in Table 2 between O₂ pulse and A_Tw are supported by data from individual animals as well as by a fit to all animals in each gas mixture.

	DISCUSSION

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The volume of O₂ consumed per heart beat was found to correlate with A_Tw in guinea pigs in a hyperbaric chamber at various ambient temperatures and pressures and in two different gas mixtures (Table 2). This suggests that a change in A_Tw is not merely an artifact of diving (26) but is related to physiological events associated with cardiovascular function. The correlation between O₂ pulse and A_Tw was positive for animals breathing heliox but negative for animals breathing hydrox (Table 2). That is, taller T waves were correlated with higher O₂ pulse in heliox and with lower O₂ pulse in hydrox. This indicates that repolarization events in the heart are affected by the choice of breathing gas mixture, in a manner that ultimately is connected to whole body O₂ relative to heart contraction rate.

The most accurate way to present the relationships between O₂ pulse and A_Tw is as shown in Table 2; i.e., as multidimensional relationships, explicitly listing the other variables that have been shown to be significantly correlated, and their numerical values in the regression. There is also a way to illustrate some of the information in Table 2 graphically. We plotted O₂ pulse vs. A_Tw for animals in each gas mix and separated by pressure (Fig. 3). At each of the four pressures sampled, there was a positive correlation between these variables in heliox but a negative correlation in hydrox, just as shown by the multidimensional analysis (Table 2). Note that the slopes of these regressions decrease systematically with increasing pressure in heliox, whereas there is no consistent trend between slope and pressure in hydrox. This is illustrative of the interactions of pressure and O₂ pulse shown in Table 2. With the use of data collected at all temperatures and pressures together, the positive correlation between O₂ pulse and A_Tw was significant in heliox (P = 0.02), and the negative correlation between these variables was significant in hydrox (P < 0.001), even when the other significant variables in the model were not included.

View larger version (26K): [in this window] [in a new window]   Fig. 3.   O2 pulse vs. amplitude of T wave (absolute value) for guinea pigs breathing heliox () or hydrox () at 10, 20, 40, and 60 atm, over chamber temperature range from 25 to 36°C. Lines, least squares linear regression that best fits data in each gas mixture at each pressure. If data points at 200 and 300 µV in hydrox are excluded, outcome of analysis is not altered.

We also measured the amplitude of the R wave (A_Rw) in these animals (data not shown) and found that A_Rw did not fit into the model as a substitute for A_Tw for animals in either heliox (P = 0.41) or hydrox (P = 0.47). This indicates that changes in electrical depolarization events in the heart, as illustrated by lead II configuration A_Rw, are not associated with changes in O₂ pulse in a manner analogous to lead II configuration A_Tw changes under the conditions of these experiments. That is, the phenomena we are observing (Table 2) are specific to electrical repolarization events as viewed from this orientation of electrodes.

Our model can now be used to predict differences in guinea pigs under the conditions of our experiments. Consider a guinea pig at a selected temperature and pressure in each of these two gas mixtures. From the raw data, we find that 34°C is a T_cham that will allow a guinea pig in both heliox and hydrox at 60 atm to maintain a stable T_core near its normal value of 38.8°C. At 34°C and 60 atm, the mean A_Tw of two guinea pigs measured in heliox (80 and 250 µV) was 165 µV, and the A_Tw in one guinea pig in hydrox was 80 µV. From the parameters in Table 2, we compute the O₂ pulse for animals at this temperature, pressure, and respective A_Tw values to be 64.8 and 76.8 nl O₂ · g¹ · beat¹ in heliox and hydrox, respectively. Thus we predict that normothermic animals breathing hydrox at 60 atm have an O₂ pulse ~20% higher than those breathing heliox [(76.8  64.8)/64.8]. Because A_Tw is predictive of O₂ pulse (Table 2), some of the difference in O₂ delivery may lie in the heart itself, i.e., may reflect a subtle difference in stroke volume between animals in heliox vs. hydrox at 60 atm.

The O₂-pulse-model analysis we performed previously (24) was identical to the present analysis minus the A_Tw term (Eq. 1). In that earlier analysis, we demonstrated that there were significant differences in O₂ pulse for animals breathing heliox vs. hydrox, with these differences attributable to heat loss and pressure effects. In heliox, O₂ pulse increased with decreasing body S (_surf = 0.52 × 10³ ± 0.22 × 10³), decreasing T_cham (_cham = 0.23 × 10⁵ ± 0.84 × 10⁶), decreasing T_core (_core = 0.46 × 10⁵ ± 0.17 × 10⁵), and decreasing P (_P = 0.42 × 10⁶ ± 0.12 × 10⁶). In hydrox, O₂ pulse increased with decreasing body S (_surf = 0.68 × 10³ ± 0.27 × 10³) and decreasing T_cham (_cham = 0.31 × 10⁵ ± 0.56 × 10⁶), with parameter values for these two variables not significantly different from those of heliox animals. Neither T_core nor pressure was a significant variable in hydrox, using the analysis for which we had the strongest statistical support (Eq. 1, Ref. 24). We speculated that animals in heliox were experiencing a decline in cardiovascular performance with increasing pressure, as a symptom of high pressure neurological syndrome (HPNS), whereas animals in hydrox were not experiencing this decline because of narcotic suppression of HPNS by H₂.

Including A_Tw in Eq. 1 provided a significantly better fit to the data, as assessed by smaller RSSE of the regressions (Eq. 1, Ref. 24; 2% smaller RSSE in heliox with 1 less parameter, and 17% smaller RSSE in hydrox with the same number of parameters). In addition, more of the variance in O₂ pulse was explained for animals in each gas mixture when changes in O₂ pulse were correlated with changes in A_Tw in addition to the other variables considered. The regression R² was closer to 1 for the new model with A_Tw (R² = 0.701 in heliox and 0.570 in hydrox) compared with the old model (R² = 0.693 in heliox and 0.480 in hydrox).

Including A_Tw in the model allowed a trend for a negative effect of pressure on O₂ pulse to be apparent for animals in hydrox (Table 2). The magnitude of this pressure effect was less than that for animals in heliox (_P = 0.181 × 10⁶ vs. 0.303 × 10⁶, respectively; Table 2). In our earlier study (24), we found some statistical support for a second O₂-pulse model for animals in hydrox. In this model, O₂ pulse increased with increasing pressure at 10-40 atm but decreased with increasing pressure at 40-60 atm. In the present study, in which we substituted two new animals in hydrox, this alternative "pressure maximum" model was no longer found to have statistical support (P = 0.08). However, it remains possible that there are more complex terms involving pressure that explain more of the variance in O₂ pulse or in A_Tw than we have found thus far.

In heliox, the addition of A_Tw made both T_core and S insignificant as variables, and in hydrox, the addition of A_Tw made S insignificant (Table 2). Body S was included as a model variable because we wanted to normalize for differences in body size among animals by using a variable that could be related logically to the heat-exchange S of an animal. Because A_Tw substitutes for T_core and/or S in this model, this suggests that there is a connection between changes in A_Tw and temperature effects. There was an animal in hydrox (animal 19; see Fig. 1) with a T wave that changed both polarity and amplitude dramatically between 40 and 60 atm, to the extent that the A_Tw for this animal at 60 atm (Fig. 4) was discarded to avoid bias in the analysis. A depression of the S-T segment was also noted in this waveform (Fig. 4). At 60 atm, this animal had an unusually low T_core of 34.1°C. Hypothermia is known to be associated with a variety of changes in ECG waveforms and with inconsistent changes in A_Tw (7). We speculate that more dramatic changes in T wave, either in amplitude or in polarity, might have been found if animals had been permitted to become more severely hypothermic.

View larger version (17K): [in this window] [in a new window]   Fig. 4.   Electrocardiogram (lead II configuration) for guinea pig 19 in the present study, breathing hydrox at 10 atm, 33°C (left) and at 60 atm, 30°C (right). Note dramatic reversal of T wave and S-T segment depression at this high pressure and low temperature. Data from this aberrant animal at 60 atm were deleted to avoid bias.

Thus the interconnections between A_Tw and O₂ pulse are likely to be multifaceted, with temperature and pressure exerting pivotal influences. Although our mathematical approach is appropriate for identifying correlated variables and calculating relative values, it cannot explain the underlying physiological mechanisms that cause the interconnections. The roles of such critical factors as myocardial contractility, stroke volume, arteriovenous O₂ extraction, and blood flow distribution are unknown. Further experimentation is needed to determine causality, now that it is clear that changes in A_Tw during diving are indeed likely to have a physiological significance to cardiovascular function. We can, however, speculate that changes within the heart, such as myocardial contractility or stroke volume, are likely, given that a change in an electrical component of the cardiac cycle is predictive of a change in O₂ pulse.

Gennser and Örnhagen (15) demonstrated that the beating frequency of isolated atria of rats declined in response to environmental pressure and that beating frequency increased after superfusion with solutions containing H₂. Superfusing with He caused only a slight increase in beating frequency (15). This partial reversal of bradycardia by H₂ was attributed to its narcotic properties, which in turn are generally attributed to the relative solubility of H₂ in the lipid component of nerve tissues (15). H₂ is more soluble in lipids than is He, and one of the perceived benefits of diving with hydrox is the observed reduction in symptoms of HPNS (1, 13, 24). Thus there is support for the idea that different breathing gases can have differing effects on myocardial function, and, specifically, that narcotic suppression of HPNS by H₂ may ameliorate the effects of pressure on the heart. Gennser and Örnhagen (15) speculated that pressure and inert gas mixtures might have either synergistic or opposing effects on cardiac electrical activity, and they proposed that a study of ECGs in hyperbaria be undertaken.

Numerous previous diving studies (20, 21, 30, 31, 34), including a study with three human subjects and five dogs in hyperbaric H₂ (22), have reported finding taller T waves with increasing pressure. We found no such correlation for guinea pigs under the conditions of our study. Lafay et al. (26) also found no significant changes in A_Tw during compression of three human subjects breathing varying mixtures of He and H₂; however, Lafay et al. did report a significant rightward shift in the T-vector axis during compression and a decrease in A_Tw in these subjects during decompression.

The varying results of these studies and the present study may indicate that there is an underlying effect on the wavefront of cardiac repolarization events that is associated with hyperbaria. However, it may be too simplistic to expect that this effect will always be manifested as an increase in A_Tw with increasing pressure in all species and all individuals, given the complexity of the electrical events in four dimensions and the limited view of these events presented by T waves. In 7 of the 19 guinea pigs in the present study, the T waves were negative at 1 atm, whereas with a conventional lead II configuration in humans, positive T waves are typical (22, 26, 29). This suggests that anatomic differences between human and guinea pig hearts, or minor variation in electrode placements among individuals, may affect the amplitude or polarity of the T wave under any circumstances. In the present experiment, the deliberate inclusion of cold as well as two different gas mixtures appears to have added further confounding influences on T-wave appearance.

Joulia et al. (22) reported that changes in A_Tw were dependent on the density of the breathing mixture, but they found no specific effects that were attributable to whether the inert gas portion of the breathing mixture contained He, H₂, or N₂. This is in contrast with the finding in the present study that the relationship between A_Tw and O₂ pulse was dependent on whether the breathing mixture was heliox or hydrox (Table 2; Fig. 3).

The guinea pigs in the present study were exposed to more stresses than hyperbaria, cold, and differing inert gas mixtures that may have had additional effects on the heart. Increasing PO₂ from 0.2 to 1.2 atm with increasing chamber pressure may also have led to an alteration in electrical conduction. Hyperoxia is known to affect cardiac output and blood flow distribution to the heart and many other tissues (19). Changes in T-wave configuration have been seen in human divers as PO₂ changed from 0.2 to 0.3 atm (34). Because we used a constant 2% O₂ in our exposures, dependence of O₂ pulse on PO₂ would be 100% correlated with ambient pressure (P in Eq. 1) and thus would not be distinguishable from pressure effects. The work of Hordnes and Tyssebotn (19) showed that both heart rate and cardiac output are reduced under the combined effects of high PO₂ and high ambient total pressure. This makes it difficult to speculate on how O₂ pulse should be affected by hyperbaric hyperoxia.

We have no evidence that the changes we measured in A_Tw are an indication of myocardial pathology in diving. Changes in A_Tw in two or more leads are considered to reflect nonspecific changes, primarily in oxygenation or electrolyte balance of the endocardium of the left ventricle (6). These changes are of clinical concern only when they are coupled with a number of other ECG abnormalities, such as S-T segment depression, elevation, or prolongation (5, 27). We did not systematically measure these other features of the ECG waveforms, but such changes were not overtly present in the animals included in our analysis (Fig. 2; also note the S-T segment depression in the excluded animal 19 in 60 atm hydrox, Fig. 4). Similarly, the increases in A_Tw reported by Joulia et al. (22) were not regarded by them as consistent with a pathological state. We have some measurements of heart rate (25) and O₂ (24) taken from normothermic guinea pigs breathing 1 atm air, although these two variables were not measured in the same individuals. From these data, we compute that O₂ pulse in a resting 750-g guinea pig at 25°C breathing 1 atm air is on the order of 50 nl O₂ · g¹ · beat¹ (O₂ = 0.73 ml O₂ · g¹ · h¹ and f_H = 243 beats/min). All of the O₂-pulse values in this study were higher than this 1-atm air estimate (Fig. 3), suggesting that cardiovascular function, as assessed by whole body O₂ per heart beat, is not impaired by breathing either He or H₂ gas mixtures in hyperbaria, despite the associated changes in A_Tw.

We conclude that there is a difference in the amount of O₂ consumed per heart beat in guinea pigs in a hyperbaric H₂ vs. He environment and that A_Tw and ambient temperature and pressure are associated with this difference. Taller T waves were correlated with higher O₂ pulse for animals breathing heliox, but shorter T waves were correlated with higher O₂ pulse for animals in hydrox. Inclusion of A_Tw in our model explained more of the observed variance in O₂ pulse than did inclusion of T_core and body S for animals in heliox or body S alone for animals in hydrox. This suggests that body heat loss is involved in changing A_Tw. These results demonstrate that the changes in A_Tw found in these experiments in hyperbaric He and H₂ are correlated with events that are significant to cardiovascular function. The underlying physiological mechanisms for these correlations remain to be elucidated.