The overlooked significance of plasma volume for successful adaptation to high altitude in Sherpa and Andean natives

In contrast to Andean natives, high altitude Tibetans present with a lower hemoglobin concentration that correlates with reproductive success and exercise capacity. Decades of physiological and genomic research have assumed that the lower hemoglobin concentration in Himalayan natives results from a blunted erythropoietic response to hypoxia (i.e. no increase in total hemoglobin mass). In contrast, herein we test the hypothesis that the lower hemoglobin concentration is the result of greater plasma volume, rather than an absence of increased hemoglobin production. We assessed hemoglobin mass, plasma volume and blood volume in lowlanders at sea level, lowlanders acclimatized to high altitude, Himalayan Sherpa and Andean Quechua, and explored the functional relevance of volumetric hematological measures to exercise capacity. Hemoglobin mass was highest in Andeans, but also elevated in Sherpa compared to lowlanders. Sherpa demonstrated a larger plasma volume than Andeans, resulting in a comparable total blood volume at a lower hemoglobin concentration. Hemoglobin mass was positively related to exercise capacity in lowlanders at sea level and Sherpa at high altitude, but not in Andean natives. Collectively, our findings demonstrate a unique adaptation in Sherpa that reorientates attention away from hemoglobin concentration and towards a paradigm where hemoglobin mass and plasma volume may represent phenotypes with adaptive significance at high altitude

Selection of endurance capabilities and the trade-off between pressure and volume in the evolution of the human heart

Chimpanzees and gorillas, when not inactive, engage primarily in short bursts of resistance physical activity (RPA), such as climbing and fighting, that creates pressure stress on the cardiovascular system. In contrast, to initially hunt and gather and later to farm, it is thought that preindustrial human survival was dependent on lifelong moderate-intensity endurance physical activity (EPA), which creates a cardiovascular volume stress. Although derived musculoskeletal and thermoregulatory adaptations for EPA in humans have been documented, it is unknown if selection acted similarly on the heart. To test this hypothesis, we compared left ventricular (LV) structure and function across semiwild sanctuary chimpanzees, gorillas, and a sample of humans exposed to markedly different physical activity patterns. We show the human LV possesses derived features that help augment cardiac output (CO) thereby enabling EPA. However, the human LV also demonstrates phenotypic plasticity and, hence, variability, across a wide range of habitual physical activity. We show that the human LV’s propensity to remodel differentially in response to chronic pressure or volume stimuli associated with intense RPA and EPA as well as physical inactivity represents an evolutionary trade-off with potential implications for contemporary cardiovascular health. Specifically, the human LV trades off pressure adaptations for volume capabilities and converges on a chimpanzee-like phenotype in response to physical inactivity or sustained pressure loading. Consequently, the derived LV and lifelong low blood pressure (BP) appear to be partly sustained by regular moderate-intensity EPA whose decline in postindustrial societies likely contributes to the modern epidemic of hypertensive heart disease

Stimulus-specific functional remodeling of the left ventricle in endurance and resistance-trained men

Left ventricular (LV) structural remodeling following athletic training has been evidenced through training-specific changes in wall thickness and geometry. Whether the LV response to changes in hemodynamic load also adapts in a training-specific manner is unknown. Using echocardiography, we examined LV responses of endurance-trained (n = 15), resistance-trained (n = 14), and nonathletic men (n = 13) to 1) 20, 40, and 60% one repetition-maximum (1RM), leg-press exercise and 2) intravascular Gelofusine infusion (7 mL/kg) with passive leg raise. While resting heart rate was lower in endurance-trained participants versus controls (P = 0.001), blood pressure was similar between groups. Endurance-trained individuals had lower wall thickness but greater LV mass relative to body surface area versus controls, with no difference between resistance-trained individuals and controls. Leg press evoked a similar increase in blood pressure; however, resistance-trained participants preserved stroke volume (SV; −3 ± 8%) versus controls at 60% 1RM (−15 ± 7%, P = 0.001). While the maintenance of SV was related to the change in longitudinal strain across all groups (R = 0.537; P = 0.007), time-to-peak strain was maintained in resistance-trained but delayed in endurance-trained individuals (1 vs. 12% delay; P = 0.021). Volume infusion caused a similar increase in end-diastolic volume (EDV) and SV across groups, but leg raise further increased EDV only in endurance-trained individuals (5 ± 5 to 8 ± 5%; P = 0.018). Correlation analysis revealed a relationship between SV and longitudinal strain following infusion and leg raise (R = 0.334, P = 0.054); however, we observed no between-group differences in longitudinal myocardial mechanics. In conclusion, resistance-trained individuals better maintained SV during pressure loading, whereas endurance-trained individuals demonstrated greater EDV reserve during volume loading. These data provide novel evidence of training-specific LV functional remodeling. NEW & NOTEWORTHY Training-specific functional remodeling of the LV in response to different loading conditions has been recently suggested, but not experimentally tested in the same group of individuals. Our data provide novel evidence of a dichotomous, training-specific LV adaptive response to hemodynamic pressure or volume loading

UBC-Nepal Expedition: Haemoconcentration underlies the reductions in cerebralblood flow observed during acclimatization to high-altitude

At high‐altitude, increases in haematocrit (Hct) are achieved through altitude‐induced diuresis and erythropoiesis, both of which result in increased arterial oxygen content (CaO2). Given the impact alterations in Hct have on CaO2, haemoconcentration has been hypothesized to partly mediate the attenuation of the initial elevation in cerebral blood flow (CBF) at high‐altitude. To test this hypothesis, healthy males (n = 13) ascended to 5050 m over nine days without the aid of prophylactic acclimatization medications. Following one‐week of acclimatization at 5050 m, participants were haemodiluted by rapid saline infusion (2.10 ± 0.28 L) to return Hct towards pre‐acclimatized levels. Arterial blood gases, Hct, global CBF (duplex ultrasound), and haemodynamic variables were measured following initial arrival to 5050 m, and after one‐week of acclimatization at high‐altitude, prior to and following the haemodilution protocol. Following one‐week at 5050 m, Hct increased from 42.5 ± 2.5 to 49.6 ± 2.5% (P < 0.001), and was subsequently reduced to 45.6 ± 2.3% (P < 0.001) following haemodilution. Global CBF decreased from 844 ± 160 to 619 ± 136 ml mi−1 n (P = 0.033) following one‐week of acclimatization and increased to 714 ± 204 ml mi−1n (P = 0.045) following haemodilution. Despite the significant changes in Hct, and thus CaO2, cerebral oxygen delivery was unchanged at all time points. Furthermore, these observations occurred in the absence of any changes in mean arterial blood pressure, cardiac output, arterial blood pH, or oxygen saturation pre‐ and post‐haemodilution. These data highlight the influence of Hct in the regulation of CBF and are the first to demonstrate experimentally that haemoconcentration contributes to the reduction in CBF during acclimatization to altitude

Electrocardiographic changes following six months of long-distance triathlon training in previously recreationally active individuals

Background: Clinical electrocardiographic (ECG) guidelines for athlete’s heart are based upon cross-sectional data. We aimed to longitudinally evaluate the influence of endurance training on the ECG and compare the prevalence of ECG abnormalities defined by contemporary criteria. Methods: A group of 66 training-naïve individuals completed a six-month training programme with resting ECGs and cardiopulmonary exercise tests performed at baseline, two and six months. Data were analysed using repeated measures analysis of variance and the prevalence of ECG abnormalities compared between proposed criteria. Results: Maximal oxygen consumption increased from 45.4 ± 7.1 to 50.3 ± 7.1 ml·kg−1·min−1 (p < 0.05) pre-to-post training. ECG changes included, bradycardia (60 ± 12 vs. 53 ± 8 beats·min−1; p < 0.05), shorter P wave duration (106 ± 10 vs. 103 ± 11 ms; p < 0.05), reduced QTc (413 ± 27 vs. 405 ± 22 ms; p < 0.05), and increased left ventricular Sokolow-Lyon index (2.45 ± 0.66 vs. 2.62 ± 0.78 mV; p < 0.05). 85% of individuals showed ≥1 ‘training-related’ ECG finding at six months vs. 68% at baseline. Using the 2013 Seattle Criteria, 4 ECGs were ‘abnormal’ at baseline and 3 at month six vs. 2 at baseline and 1 at month six, using the 2017 International Consensus. Prevalence of ‘borderline’ findings did not increase with training (11% at baseline and six months). Conclusion: Six-months endurance training leads to a greater prevalence of ‘training-related’ but not ‘borderline’ or ‘training-unrelated’ ECGs. ‘Borderline findings’ may not necessarily represent training-related cardiac remodelling in novice athletes following a six-month training intervention

Interaction between left ventricular twist mechanics and arterial haemodynamics during localised, non-metabolic hyperaemia with and without blood flow restriction

NEW FINDINGS: What is the central question of this study? Left ventricular (LV) twist is reduced when afterload is increased, but the meaning of this specific heart muscle response and its impact on cardiac output are not well understood. What is the main finding and its importance? This study shows that LV twist responds even when arterial haemodynamics are altered only locally, and without apparent change in metabolic (i.e. heat-induced) demand. The concurrent decline in cardiac output and LV twist during partial arterial occlusion despite the increased peripheral demand caused by heat stress suggests that LV twist may be involved in the protective sensing of heart muscle stress that can override the provision of the required cardiac output. Whether left ventricular (LV) twist and untwisting rate (LV twist mechanics) respond to localised, peripheral, non-metabolic changes in arterial haemodynamics within an individual's normal afterload range is presently unknown. Furthermore, previous studies indicate that LV twist mechanics may override the provision of cardiac output, but this hypothesis has not been examined purposefully. Therefore, we acutely altered local peripheral arterial haemodynamics in 11 healthy humans (women/men n = 3/8; age 26 ± 5 years) by bilateral arm heating (BAH). Ultrasonography was used to examine arterial haemodynamics, LV twist mechanics and the twist-to-shortening ratio (TSR). To determine the arterial function-dependent contribution of LV twist mechanics to cardiac output, partial blood flow restriction to the arms was applied during BAH (BAHBFR ). Bilateral arm heating increased arm skin temperatures [change (Δ) +6.4 ± 0.9°C, P 0.05), concomitant to increases in brachial artery blood flow (Δ 212 ± 77 ml, P 0.05). Subsequently, BAHBFR reduced all parameters to preheating levels, except for TSR and heart rate, which remained at BAH levels. In conclusion, LV twist mechanics responded to local peripheral arterial haemodynamics within the normal afterload range, in part independent of TSR and heart rate. The findings suggest that LV twist mechanics may be more closely associated with intrinsic sensing of excessive pressure stress rather than being associated with the delivery of adequate cardiac output

Factors affecting tear production and intraocular pressure in anesthetized chimpanzees (Pan troglodytes)

Measurements of intraocular pressure (IOP) and tear production are key components of ophthalmic examination. Chimpanzees (Pan troglodytes) were anesthetized using either tiletamine-zolazepam (TZ; 2 mg/kg) combined with medetomidine (TZM; 0.02 mg/kg), or, TZ alone (6mg/kg). Tear production was lower (P = 0.03) with TZM (5.63 ± 6.22 mm/min; n = 16) than with TZ (11.13 ± 4.63 mm/min; n = 8). Mean IOP, measured using rebound tonometry in an upright body position (n = 8) was 18.74 ± 3.01 mm Hg, with no differences between right and left eyes. However, positioning chimpanzees in left lateral recumbency (n = 27) resulted in higher IOP in the dependent (left) eye (24.77 ± 4.49 mm Hg) compared to the nondependent (right) eye (22.27 ± 4.65 mm Hg) of the same animal (P < 0.0001). These data indicate medetomidine anesthesia markedly lowers tear production in chimpanzees, and that body position should be taken into consideration when performing rebound tonometry

The influence of anesthesia with and without medetomidine on cardiac structure and function in sanctuary captive chimpanzees (pan troglodytes)

Dependent on timing of assessment, anesthetic agents and specifically medetomidinenegatively impact cardiac function in great apes. The aim of this study was todetermine the influence of tiletamine-zolazepam with and without medetomidine oncardiac structure and function in healthy chimpanzees ( Pan troglodytes ) during aperiod of relative blood pressure stability. Twenty-four chimpanzees living in an Africanwildlife sanctuary undergoing routine health assessments were stratified by age, sexand body mass and randomized to be anesthetized using either tiletamine-zolazepam(6 mg/kg; TZ; n=13; seven males and six females) or a combination of tiletamine-zolazepam (2 mg/kg) and medetomidine (0.02 mg/kg; TZM; n= 11; five males and sixfemales). During the health checks, regular heart rate and blood pressure readingswere taken and a standardized echocardiogram was performed 20-30 minutes post-induction. Data were compared between the two anesthetic groups using independentsamples T or Mann Whitney U tests. Whileheart rate (Mean ± S.D; TZ: 76 ± 10 bpm;TZM: 65 ± 14 bpm, P = 0.027), cardiac output (TZ: 3.0 ± 0.7 L/min; TZM: 2.4 ±0.7 L/min, P = 0.032) and mitral A wave velocities (TZ: 0.51 ± 0.16 cm/s; TZM:0.36 ± 0.10 cm/s, P = 0.013) were lower in the TZM group, there were no statisticallysignificant differences in cardiac structure or the remaining functional variablesbetween groups. Furthermore, there were no statistical differences in systolic (TZ114.6 ± 14.9 mmHg; TZM: 123.0 ± 28.1 mmHg; P = 0.289) or diastolic bloodpressure (TZ: 81.8 ± 22.3 mmHg, TZM: 83.8 ± 20.1 mmHg; P = 0.827) between thegroups during the echocardiogram. This study has shown that during a period ofrelative blood pressure stability there are few differences in measures of cardiacstructure and function between protocols using tiletamine-zolazepam with or withoutmedetomidine in healthy chimpanzees

The influence of anesthetic with and without medetomidine on cardiac structure and function in sanctuary captive chimpanzees (Pan troglodytes)

Dependent on timing of assessment, anesthetic agents and specifically medetomidine negatively affect cardiac function in great apes. The aim of this study was to determine the influence of tiletamine–zolazepam (TZ) with and without medetomidine on cardiac structure and function in healthy chimpanzees (Pan troglodytes) during a period of relative blood pressure stability. Twenty-four chimpanzees living in an African wildlife sanctuary undergoing routine health assessments were stratified by age, sex, and body mass and randomized to be anesthetized using either TZ (6 mg/kg; n = 13; seven males and six females) or a combination of TZ (2 mg/kg) and medetomidine (TZM; 0.02 mg/kg; n = 11; five males and six females). During health checks, regular heart rate and blood pressure readings were taken and a standardized echocardiogram was performed 20–30 min after induction. Data were compared between the two anesthetic groups using independent-samples t or Mann–Whitney U tests. Although heart rate (mean ± SD; TZ: 76 ± 10 bpm; TZM: 65 ± 14 bpm, P = 0.027), cardiac output (TZ: 3.0 ± 0.7 L/min; TZM: 2.4 ± 0.7 L/min, P = 0.032), and mitral A-wave velocities (TZ: 0.51 ± 0.16 cm/s; TZM: 0.36 ± 0.10 cm/s, P = 0.013) were lower in the TZM group, there were no statistically significant differences in cardiac structure or the remaining functional variables between groups. Furthermore, there were no statistical differences in systolic (TZ 114.6 ± 14.9 mmHg; TZM: 123.0 ± 28.1 mmHg; P = 0.289) or diastolic blood pressure (TZ: 81.8 ± 22.3 mmHg, TZM: 83.8 ± 20.1 mmHg; P = 0.827) between the groups during the echocardiogram. This study has shown that during a period of relative blood pressure stability, during the first 20–30 min after induction there are few differences in measures of cardiac structure and function between protocols using TZ with or without medetomidine in healthy chimpanzees