The Effect of High-Altitude Acclimatisation on Ultra-Short Heart Rate Variability.

Introduction: High-altitude (HA) exposure affects heart rate variability (HRV) and has been inconsistently linked to acute mountain sickness (AMS). The influence of increasing HA exposure on ultra-short HRV and its relationship to gold standard HRV measures at HA has not been examined. Methods: This was a prospective observational study of adults aged ≥ 18 years undertaking a HA trek in the Dhaulagiri region of the Himalayas. Cardiac inter-beat-intervals were obtained from a 10-s recording of supra-systolic blood pressure (Uscom BP+ device) immediately followed by 300 s single lead ECG recording (CheckMyHeart device). HRV was measured using the RMSSD (root mean square of successive differences of NN intervals) at sea level (SL) in the United Kingdom and at 3,619, 4,600, and 5,140 m at HA. Oxygen saturations (SpO2) were measured using finger-based pulse oximetry. The level of agreement between the 10 and 300 s RMSSD values were examined using a modified Bland-Altman relative-difference analysis. Results: Overall, 89 participants aged 32.2 ± 8.8 years (range 18-56) were included of which 70.8% were men. HA exposure (SL vs. 3,619 m) was associated with an initial increase in both 10 s (45.0 [31.0-82.0]) vs. 58.0 [33.0-119.0] ms) and 300 s (45.67 [33.24-70.32] vs. 56.48 [36.98-102.0] ms) in RMSSD. Thereafter at 4,600 and 5,140 m both 10 and 300 s RMSSD values were significantly lower than SL. From a total of 317 paired HRV measures the 10 and 300 s RMSSD measures were moderately correlated (Spearman r = 0.66; 95% CI: 0.59-0.72; p < 0.0001). The median difference (bias) in RMSSD values (300 s - 10 s) was -2.3 ms with a lower and upper limit of agreement of -107.5 and 88.61 ms, respectively with no differences with altitude. Overall, 293/317 (92.4%) of all paired HRV values fell within the 95% CI limits of agreement. Neither HRV method was predictive of AMS. Conclusion: Increasing HA affects ultra-short HRV in a similar manner to gold-standard 300 s. Ultra-short HRV has a moderate agreement with 300 s measurements. HRV did not predict AMS.

Relationship between coronary microvascular dysfunction and left ventricular diastolic function in patients with chest pain and unobstructed coronary arteries.

BACKGROUD: Diastolic dysfunction (DD) is reported to affect up to 35% of the adult general population. The consequence of progressive DD is heart failure with preserved ejection fraction (HFpEF). Coronary microvascular dysfunction (CMD) has been suggested as one of the pathologic mechanisms leading to HFpEF. We investigated whether there was an association between coronary microvascular function and echocardiographic indices of left ventricular diastolic function at rest in patients with chest pain and unobstructed coronary arteries (CPUCA). METHODS: This retrospective observational study recruited patients referred to cardiology clinics assessment of chest pain who subsequently underwent assessment via CT coronary angiogram (CTA). Coronary microvascular dysfunction was determined by myocardial blood flow reserve (MBFR; <2.0) using myocardial contrast echocardiography. Echocardiographic indices of diastolic function (septal mitral annular e'; septal mitral annular E/e', E/A ratio) were measured from baseline transthoracic echocardiogram. RESULTS: 149 patients (52% men) with a mean age 59.7(9.5) years were recruited. Mean (standard deviation) MBFR was 2.2 (0.51). 37% (55/149) had MBFR < 2.0. Median [interquartile range] septal mitral annular e' velocity and septal mitral annular E/e' were 7.6 cm/s [6.2, 8.9] and 9.5 [7.5, 10.8], respectively. Univariate regression analysis showed only age was a significant predictor of increasing septal mitral annular E/e' (ß = +0.20 95% CI 0.13, +0.28, P < .001) but not MBFR. Multivariable analysis also showed no association between these septal mitral annular E/e' and MBFR after adjustment for cardiovascular risk factors. CONCLUSION: There was no relationship found between echocardiographic indices of left ventricular diastolic function and coronary microvascular function at rest.

The Effects of Apnea Training, Using Voluntary Breath Holds, on High Altitude Acclimation: Breathe-High Altitude Study.

Introduction: There is evidence that intermittent hypoxic exposure (IHE) may improve high altitude (HA) performance. In this study, the effects of short-term IHE through voluntary apnea training on HA-related symptoms, including acute mountain sickness (AMS), were examined for the first time. Methods: Forty healthy adults were randomized to a self-administered apnea training (n = 19) or control (n = 21 no apnea training) group before ascent to an altitude of 5100 m in the Himalayas over 14 days. The apnea training was conducted at sea level (SL) and consisted of five breath holds per day in week 1, seven in week 2, followed by 10 per day from weeks 3 to 6 and until HA exposure. Saturation of arterial oxygen (SpO2), heart rate, sleep quality (Insomnia Severity Index [ISI]), rating of perceived exertion (RPE), blood pressure, and Lake Louise scores were measured at SL (in the United Kingdom) and at HA at 1400, 2700, 3400-3700, 4050-4200, 4800, and 5100-5200 m. Anxiety (Generalized Anxiety Disorder-7 [GAD-7]) scores were examined at SL, 1400, and 5100-5200 m. Results: Apnea training led to a significant increase in the mean longest breath-hold times from baseline (80.42 ± 32.49 [median 87.00] seconds) to the end of week 6 (107.02 ± 43.65 [113.00] seconds), respectively (p = 0.009). There was no significant difference in the prevalence of AMS (8/19 = 42.1% vs. 11/21 = 52.4%; RR 0.80; 95% confidence interval 0.41-1.57: p = 0.80) or in GAD-7, ISI and RPE, SpO2, heart rate, or blood pressure among the apnea versus control groups, respectively, at HA. Conclusions: Apnea training does not lessen HA-related symptoms in healthy adults traveling up to 5200 m. Larger studies using more challenging apnea protocols and at higher altitudes should be considered.

The Effect of Sex on Heart Rate Variability at High Altitude.

There is evidence suggesting that high altitude (HA) exposure leads to a fall in heart rate variability (HRV) that is linked to the development of acute mountain sickness (AMS). The effects of sex on changes in HRV at HA and its relationship to AMS are unknown. METHODS: HRV (5-min single-lead ECG) was measured in 63 healthy adults (41 men and 22 women) 18-56 yr of age at sea level (SL) and during a HA trek at 3619, 4600, and 5140 m, respectively. The main effects of altitude (SL, 3619 m, 4600 m, and 5140 m) and sex (men vs women) and their potential interaction were assessed using a factorial repeated-measures ANOVA. Logistic regression analyses were performed to assess the ability of HRV to predict AMS. RESULTS: Men and women were of similar age (31.2 ± 9.3 vs 31.7 ± 7.5 yr), ethnicity, and body and mass index. There was main effect for altitude on heart rate, SD of normal-to-normal (NN) intervals (SDNN), root mean square of successive differences (RMSSD), number of pairs of successive NN differing by >50 ms (NN50), NN50/total number of NN, very low-frequency power, low-frequency (LF) power, high-frequency (HF) power, and total power (TP). The most consistent effect on post hoc analysis was reduction in these HRV measures between 3619 and 5140 m at HA. Heart rate was significantly lower and SDNN, RMSSD, LF power, HF power, and TP were higher in men compared with women at HA. There was no interaction between sex and altitude for any of the HRV indices measured. HRV was not predictive of AMS development. CONCLUSIONS: Increasing HA leads to a reduction in HRV. Significant differences between men and women emerge at HA. HRV was not predictive of AMS.

Markers of physiological stress during exercise under conditions of normoxia, normobaric hypoxia, hypobaric hypoxia, and genuine high altitude.

PURPOSE: To investigate whether there is a differential response at rest and following exercise to conditions of genuine high altitude (GHA), normobaric hypoxia (NH), hypobaric hypoxia (HH), and normobaric normoxia (NN). METHOD: Markers of sympathoadrenal and adrenocortical function [plasma normetanephrine (PNORMET), metanephrine (PMET), cortisol], myocardial injury [highly sensitive cardiac troponin T (hscTnT)], and function [N-terminal brain natriuretic peptide (NT-proBNP)] were evaluated at rest and with exercise under NN, at 3375 m in the Alps (GHA) and at equivalent simulated altitude under NH and HH. Participants cycled for 2 h [15-min warm-up, 105 min at 55% Wmax (maximal workload)] with venous blood samples taken prior (T0), immediately following (T120) and 2-h post-exercise (T240). RESULTS: Exercise in the three hypoxic environments produced a similar pattern of response with the only difference between environments being in relation to PNORMET. Exercise in NN only induced a rise in PNORMET and PMET. CONCLUSION: Biochemical markers that reflect sympathoadrenal, adrenocortical, and myocardial responses to physiological stress demonstrate significant differences in the response to exercise under conditions of normoxia versus hypoxia, while NH and HH appear to induce broadly similar responses to GHA and may, therefore, be reasonable surrogates.

A comparison of two methods of heart rate variability assessment at high altitude.

Heart rate variability (HRV) is a useful index of autonomic function and has been linked to the development of high altitude (HA) related illness. However, its assessment at HA has been undermined by the relative expense and limited portability of traditional HRV devices which have mandated at least a minute heart rate recording. In this study, the portable ithlete™ HRV system, which uses a 55 s recording, was compared with a reference method of HRV which utilizes a 5 min electrocardiograph recording (CheckMyHeart™ ). The root mean squares of successive R-R intervals (RMSSD) for each device was converted to a validated HRV score (lnRMSSD × 20) for comparison. Twelve healthy volunteers were assessed for HRV using the two devices across seven time points at HA over 10 days. There was no significant change in the HRV values with either the ithlete (P = 0·3) or the CheckMyHeart™ (P = 0·19) device over the seven altitudes. There was also a strong overall correlation between the ithlete™ and CheckMyHeart™ device (r = 0·86; 95% confidence interval: 0·79-0·91). The HRV was consistently, though non-significantly higher with ithlete™ than with the CheckMyHeart™ device [mean difference (bias) 1·8 l; 95% CI -12·3 to 8·5]. In summary, the ithlete™ and CheckMyHeart™ system provide relatively similar results with good overall agreement at HA.

A Four-Way Comparison of Cardiac Function with Normobaric Normoxia, Normobaric Hypoxia, Hypobaric Hypoxia and Genuine High Altitude.

BACKGROUND: There has been considerable debate as to whether different modalities of simulated hypoxia induce similar cardiac responses. MATERIALS AND METHODS: This was a prospective observational study of 14 healthy subjects aged 22-35 years. Echocardiography was performed at rest and at 15 and 120 minutes following two hours exercise under normobaric normoxia (NN) and under similar PiO2 following genuine high altitude (GHA) at 3,375 m, normobaric hypoxia (NH) and hypobaric hypoxia (HH) to simulate the equivalent hypoxic stimulus to GHA. RESULTS: All 14 subjects completed the experiment at GHA, 11 at NN, 12 under NH, and 6 under HH. The four groups were similar in age, sex and baseline demographics. At baseline rest right ventricular (RV) systolic pressure (RVSP, p = 0.0002), pulmonary vascular resistance (p = 0.0002) and acute mountain sickness (AMS) scores were higher and the SpO2 lower (p<0.0001) among all three hypoxic groups (GHA, NH and HH) compared with NN. At both 15 minutes and 120 minutes post exercise, AMS scores, Cardiac output, septal S', lateral S', tricuspid S' and A' velocities and RVSP were higher and SpO2 lower with all forms of hypoxia compared with NN. On post-test analysis, among the three hypoxia groups, SpO2 was lower at baseline and 15 minutes post exercise with GHA (89.3±3.4% and 89.3±2.2%) and HH (89.0±3.1 and (89.8±5.0) compared with NH (92.9±1.7 and 93.6±2.5%). The RV Myocardial Performance (Tei) Index and RVSP were significantly higher with HH than NH at 15 and 120 minutes post exercise respectively and tricuspid A' was higher with GHA compared with NH at 15 minutes post exercise. CONCLUSIONS: GHA, NH and HH produce similar cardiac adaptations over short duration rest despite lower SpO2 levels with GHA and HH compared with NH. Notable differences emerge following exercise in SpO2, RVSP and RV cardiac function.

The Effects of Sex on Cardiopulmonary Responses to Acute Normobaric Hypoxia.

UNLABELLED: Boos, Christopher John, Adrian Mellor, John Paul O'Hara, Costas Tsakirides, and David Richard Woods. The effects of sex on cardiopulmonary responses to acute normobaric hypoxia. High Alt Med Biol. 17:108-115, 2016.- BACKGROUND: Acute hypoxia leads to a number of recognized changes in cardiopulmonary function, including acute increase in pulmonary artery systolic pressure. However, the comparative responses between men and women have been barely explored. METHODS: Fourteen young healthy adult Caucasian subjects were studied at sea-level rest and then after >150-minute exposure to acute normobaric hypoxia (NH) equivalent to 4800 m and again at sea-level rest at 2 hours post-NH exposure. Cardiac function, using transthoracic echocardiography, physiological variables, and Lake Louise Scores for acute mountain sickness (AMS) were collected. RESULTS: All subjects completed the study, and there was an equal balance of men (n = 7) and women (n = 7) who were well matched for age (25.9 ± 3.2 vs. 27.3 ± 4.4; p = 0.51). NH exposure led to a significant increase in AMS scores and heart rate, as well as a fall in oxygen saturation, systolic blood pressure, and stroke volume. Stroke volumes and cardiac output were overall significantly higher in men than in women, and acute NH heart rate was higher in women (80.3 ± 10.2 vs. 69.7 ± 10.7/min; p < 0.05). NH led to a significant fall in the estimated left ventricular filling pressure (E/E'), an increase in the septal A' and S' and septal and lateral isovolumic contractile velocities (ICVs), and a fall in the E'A'S' ratio. The mitral E, lateral ICV, and E' velocities were all higher in men. Acute NH led to a significant increase in right ventricular systolic pressure and pulmonary vascular resistance. There was no interaction between NH exposure and sex for any parameters measured. CONCLUSION: Despite several baseline differences between men and women, the cardiopulmonary effects of acute NH are consistent between men and women.

High Altitude and Acute Mountain Sickness and Changes in Circulating Endothelin-1, Interleukin-6, and Interleukin-17a.

INTRODUCTION: Hypoxia induces an inflammatory response, which is enhanced by exercise. High altitude (HA) leads to endothelial activation and may be proinflammatory. The relationship between endothelial activation, inflammation, and acute mountain sickness (AMS) and its severity has never been examined. METHODS: Forty-eight trekkers were studied during a progressive trek at 3833, 4450, and 5129 m at rest postascent (exercise), and then again at rest 24 hours later. Twenty of the subjects were also tested at rest pre- and postexercise at sea level (SL) at 6 weeks preascent. We examined plasma levels of the interleukin 6 (IL-6), 17a (IL-17a), and endothelin-1 (ET-1) along with oxygen saturation (SpO2) and Lake Louise scores (LLS). RESULTS: ET-1 (5.7 ± 2.1 vs. 4.3 ± 1.9 pg/mL; p < 0.001), IL-6 (3.3 ± 3.3 vs. 2.4 ± 2.3 pg/mL; p = 0.007), and IL-17a (1.3 ± 3.0 vs. 0.46 ± 0.4 pg/mL; p < 0.001) were all overall significantly higher at HA versus SL. There was a paired increase in ET-1 and IL-6 with exercise versus rest at SL, 3833, 4450, and 5129 m (p < 0.05). There was a negative correlation between LLS and SpO2 (r = -0.32; 95% confidence interval [CI] -0.21 to -0.42; p < 0.001) and a positive correlation between LLS and IL-6 (r = 0.16; 0.0-0.27; p = 0.007) and ET-1 levels (r = 0.29; 0.18-0.39; p < 0.001. Altitude, ET-1, IL-6, and SpO2 were all univariate predictors of AMS. On multivariate analysis, ET-1 (p = 0.002) and reducing SpO2 (p = 0.02) remained as the only independent predictors (overall r(2) = 0.16; p < 0.001) of AMS. ET-1 (p = 03) and SpO2 were (p = 0.01) also independent predictors of severe AMS (overall r(2) = 0.19; p < 0.001). CONCLUSIONS: HA leads to endothelial activation and an inflammatory response. The rise in ET-1 and IL-6 is heavily influenced by the degree of exercise and hypoxia. ET-1 is an independent predictor of both AMS and its severity.

The effects of exercise at high altitude on high-sensitivity cardiac troponin release and associated biventricular cardiac function.

BACKGROUND: It has been consistently shown that heavy exercise leads to cardiac troponin (cTn) release and variable changes in post exercise cardiac function. This relationship has not been explored at increasing or significant high altitude (HA). This study assessed the effects of exercise at progressively increasing HA on high-sensitivity (hs)-cTnT levels and their relationship to biventricular cardiac function and severity of acute mountain sickness (AMS). METHODS: Transthoracic echocardiograms, hs-cTnT levels and AMS scores were measured at rest at 1,300 m then repeated post exercise and 12 h later after progressive trekking to 3,440, 4,270 m and at 5,150 m (after trekking to 5,643 m) on 19 healthy subjects (age 35.4 ± years, 52.6 % males). RESULTS: There was a detectable increase (>5 ng/L) in post exercise hs-cTnT with exercise at HA which became significant at 5,150 m (5.84 % at 3,440 m, 5.2 % at 4,270 m and 56.3 % at 5,150 m; p = 0.0005). Compared with baseline, HA to 5,150 m led to a significant rise in post exercise Lake Louis AMS scores (p < 0.001) pulmonary artery systolic pressure (PASP) (23.7 ± 3.8 vs 37.9 ± 11.7 mmHg: p < 0.001), cardiac output (5.2 ± 1.2 vs 7.5 ± 1.3 l/min; p < 0.001) and a fall in SpO2 (96.1 ± vs 77.4 ± 12.0 %; p < 0.001). There was no change in stroke volume (p = 0.10) or estimated filling pressures (E/E') of the left (p = 0.50) and right ventricles (p = 0.4). On multivariate analysis increasing cardiac output (p = 0.02) and PASP (p = 0.04) and decreasing SpO2 (p = 0.01) were the only independent predictors of increasing cTnT levels (overall R (2) = 0.23, p < 0.0001). CONCLUSIONS: Moderate intensity exercise at significant HA influences the post exercise increase in hs-cTnT without overt deleterious effects on cardiac function.