Patterns of Early Coronary Artery Changes in Pediatric Heart Transplant Recipients Detected Using Optical Coherence Tomography.

BACKGROUND: Cardiac allograft vasculopathy, the leading cause of graft failure in pediatric heart transplant recipients, is characterized by diffuse and concentric coronary intimal thickening. Early treatment yields better outcomes. While coronary angiography is the standard for cardiac allograft vasculopathy screening and diagnosis, it only identifies luminal narrowing, which occurs in more severe disease. Coronary optical coherence tomography (OCT) is a high-definition intravascular imaging modality that may offer earlier diagnosis. We used OCT to investigate coronary intimal thickening in pediatric transplant recipients and examined its (1) location (ie, vessel type and location) and (2) nature (ie, characteristics of cross-sectional and longitudinal thickening). METHODS: Sites collected coronary angiography and OCT data from participants (N=258 vessel segments from 73 individuals; median age: 11.5 years [8.4-15.3]; 55% male). Images were collected from the left anterior descending, left circumflex, and right coronary arteries, and location (ie, proximal, middle, and distal) were classified using coronary angiography. RESULTS: OCT identified 32 vessel segments meeting criteria for significant thickening, 88% of which were angiographically silent. Longitudinal thickening was segmental rather than global in 88%, and cross-sectional thickening was 48% eccentric and 52% concentric. Intimal thickening prevalence and severity measures did not consistently differ between coronary artery type (P=1.000) or location (P=0.248) but increased with time since transplant and age at transplant and OCT procedure. CONCLUSIONS: In pediatric transplant recipients, we observed a surprisingly high prevalence of segmental and eccentric intimal thickening. Insights from intravascular imaging suggest these patterns of coronary vascular changes may precede overt cardiac allograft vasculopathy. Identifying early changes may offer opportunity for enhanced surveillance and earlier intervention.

Cardiovascular responses to progressive hypoxia in ducks native to high altitude in the Andes.

The cardiovascular system is critical for delivering O2 to tissues. Here, we examined the cardiovascular responses to progressive hypoxia in four high-altitude Andean duck species compared with four related low-altitude populations in North America, tested at their native altitude. Ducks were exposed to stepwise decreases in inspired partial pressure of O2 while we monitored heart rate, O2 consumption rate, blood O2 saturation, haematocrit (Hct) and blood haemoglobin (Hb) concentration. We calculated O2 pulse (the product of stroke volume and the arterial-venous O2 content difference), blood O2 concentration and heart rate variability. Regardless of altitude, all eight populations maintained O2 consumption rate with minimal change in heart rate or O2 pulse, indicating that O2 consumption was maintained by either a constant arterial-venous O2 content difference (an increase in the relative O2 extracted from arterial blood) or by a combination of changes in stroke volume and the arterial-venous O2 content difference. Three high-altitude taxa (yellow-billed pintails, cinnamon teal and speckled teal) had higher Hct and Hb concentration, increasing the O2 content of arterial blood, and potentially providing a greater reserve for enhancing O2 delivery during hypoxia. Hct and Hb concentration between low- and high-altitude populations of ruddy duck were similar, representing a potential adaptation to diving life. Heart rate variability was generally lower in high-altitude ducks, concurrent with similar or lower heart rates than low-altitude ducks, suggesting a reduction in vagal and sympathetic tone. These unique features of the Andean ducks differ from previous observations in both Andean geese and bar-headed geese, neither of which exhibit significant elevations in Hct or Hb concentration compared with their low-altitude relatives, revealing yet another avian strategy for coping with high altitude.

Cardiovascular responses to progressive hypoxia in ducks native to high altitude in the Andes.

The cardiovascular system is critical for delivering O2 to tissues. Here we examine the cardiovascular responses to progressive hypoxia in four high-altitude Andean duck species compared to four related low-altitude populations in North America, tested at their native altitude. Ducks were exposed to stepwise decreases in inspired partial pressure of O2 while we monitored heart rate, O2 consumption rate, blood O2 saturation, haematocrit (Hct), and blood haemoglobin concentration [Hb]. We calculated O2 pulse (the product of stroke volume and the arterial-venous O2 content difference), blood O2 concentration, and heart rate variability. Regardless of altitude, all eight populations maintained O2 consumption rate with minimal change in heart rate or O2 pulse, indicating that O2 consumption was maintained by either a constant arterial-venous O2 content difference (an increase in the relative O2 extracted from arterial blood) or by a combination of changes in stroke volume and the arterial-venous O2 content difference. Three high-altitude taxa (yellow-billed pintails, cinnamon teal, and speckled teal) had higher Hct and [Hb], increasing the O2 content of arterial blood, and potentially providing a greater reserve for enhancing O2 delivery during hypoxia. Hct and [Hb] between low- and high-altitude populations of ruddy duck were similar, representing a potential adaptation to diving life. Heart rate variability was generally lower in high-altitude ducks, concurrent with similar or lower heart rates than low-altitude ducks, suggesting a reduction in vagal and sympathetic tone. These unique features of the Andean ducks differ from previous observations in both Andean geese and bar-headed geese, neither of which exhibit significant elevations in Hct or [Hb] compared to their low-altitude relatives, revealing yet another avian strategy for coping with high altitude.

Control of breathing and respiratory gas exchange in high-altitude ducks native to the Andes.

We examined the control of breathing and respiratory gas exchange in six species of high-altitude duck that independently colonized the high Andes. We compared ducks from high-altitude populations in Peru (Lake Titicaca at ∼3800 m above sea level; Chancay River at ∼3000-4100 m) with closely related populations or species from low altitude. Hypoxic ventilatory responses were measured shortly after capture at the native altitude. In general, ducks responded to acute hypoxia with robust increases in total ventilation and pulmonary O2 extraction. O2 consumption rates were maintained or increased slightly in acute hypoxia, despite ∼1-2°C reductions in body temperature in most species. Two high-altitude taxa - yellow-billed pintail and torrent duck - exhibited higher total ventilation than their low-altitude counterparts, and yellow-billed pintail exhibited greater increases in pulmonary O2 extraction in severe hypoxia. In contrast, three other high-altitude taxa - Andean ruddy duck, Andean cinnamon teal and speckled teal - had similar or slightly reduced total ventilation and pulmonary O2 extraction compared with low-altitude relatives. Arterial O2 saturation (SaO2 ) was elevated in yellow-billed pintails at moderate levels of hypoxia, but there were no differences in SaO2  in other high-altitude taxa compared with their close relatives. This finding suggests that improvements in SaO2  in hypoxia can require increases in both breathing and haemoglobin-O2 affinity, because the yellow-billed pintail was the only high-altitude duck with concurrent increases in both traits compared with its low-altitude relative. Overall, our results suggest that distinct physiological strategies for coping with hypoxia can exist across different high-altitude lineages, even among those inhabiting very similar high-altitude habitats.

Validation of a Pulse Oximetry System for High-Altitude Waterfowl by Examining the Hypoxia Responses of the Andean Goose (Chloephaga melanoptera).

Hypoxia at high altitudes constrains O2 supply to support metabolism, thermoregulation in the cold, and exercise. High-altitude natives that somehow overcome this challenge-who live, reproduce, and sometimes perform impressive feats of exercise at high altitudes-are a powerful group in which to study the evolution of physiological systems underlying hypoxia resistance. Here, we sought to determine whether a common pulse oximetry system for rodents (MouseOx Plus) can be used reliably in studies of high-altitude birds by examining the hypoxia responses of the Andean goose. We compared concurrent measurements of heart rate obtained using pulse oximetry versus electrocardiography. We also compared our measurements of peripheral arterial O2 saturation (SaO2) in uncannulated birds with published data collected from blood samples in birds that were surgically implanted arterial cannulae. Responses to acute hypoxia were measured during stepwise reductions in inspired partial pressure of O2. Andean geese exhibited very modest breathing and heart rate responses to hypoxia but were nevertheless able to maintain normal O2 consumption rates during severe hypoxia exposure down to 5 kPa O2. There were some minor quantitative differences between uncannulated and cannulated birds, which suggest that surgery, cannulation, and/or other sources of variability between studies had modest effects on the hypoxic ventilatory response, heart rate, blood hemoglobin, and hematocrit. Nevertheless, measurements of heart rate and SaO2 by pulse oximetry had small standard errors and were generally concordant and well correlated with measurements using other techniques. We conclude that the MouseOx Plus pulse oximetry system can be a valuable tool for studying the cardiorespiratory physiology of waterfowl without the deleterious effects of surgery/cannulation.

Divergent respiratory and cardiovascular responses to hypoxia in bar-headed geese and Andean birds.

Many high-altitude vertebrates have evolved increased capacities in their oxygen transport cascade (ventilation, pulmonary diffusion, circulation and tissue diffusion), enhancing oxygen transfer from the atmosphere to mitochondria. However, the extent of interspecies variation in the control processes that dictate hypoxia responses remains largely unknown. We compared the metabolic, cardiovascular and respiratory responses to progressive decreases in inspired oxygen levels of bar-headed geese (Anser indicus), birds that biannually migrate across the Himalayan mountains, with those of Andean geese (Chloephaga melanoptera) and crested ducks (Lophonetta specularioides), lifelong residents of the high Andes. We show that Andean geese and crested ducks have evolved fundamentally different mechanisms for maintaining oxygen supply during low oxygen (hypoxia) from those of bar-headed geese. Bar-headed geese respond to hypoxia with robust increases in ventilation and heart rate, whereas Andean species increase lung oxygen extraction and cardiac stroke volume. We propose that transient high-altitude performance has favoured the evolution of robust convective oxygen transport recruitment in hypoxia, whereas life-long high-altitude residency has favoured the evolution of structural enhancements to the lungs and heart that increase lung diffusion and stroke volume.

High-altitude champions: birds that live and migrate at altitude.

High altitude is physiologically challenging for vertebrate life for many reasons, including hypoxia (low environmental oxygen); yet, many birds thrive at altitude. Compared with mammals, birds have additional enhancements to their oxygen transport cascade, the conceptual series of steps responsible for acquiring oxygen from the environment and transporting it to the mitochondria. These adaptations have allowed them to inhabit a number of high-altitude regions. Waterfowl are a taxon prolific at altitude. This minireview explores the physiological responses of high-altitude waterfowl (geese and ducks), comparing the strategies of lifelong high-altitude residents to those of transient high-altitude performers, providing insight into how birds champion high-altitude life. In particular, this review highlights and contrasts the physiological hypoxia responses of bar-headed geese (Anser indicus), birds that migrate biannually through the Himalayas (4,500-6,500 m), and Andean geese (Chloephaga melanoptera), lifelong residents of the Andes (4,000-5,500 m). These two species exhibit markedly different ventilatory and cardiovascular strategies for coping with hypoxia: bar-headed geese robustly increase convective oxygen transport elements (i.e., heart rate and total ventilation) whereas Andean geese rely predominantly on enhancements that are likely morphological in origin (i.e., increases in lung oxygen diffusion and cardiac stroke volume). The minireview compares the short- and long-term cardiovascular and ventilatory trade-offs of these different physiological strategies and offers hypotheses surrounding their origins. It also draws parallels to high-altitude human physiology and research, and identifies a number of areas of further research. The field of high-altitude avian physiology offers a unique and broadly applicable insight into physiological enhancements in hypoxia.

Respiratory mechanics of eleven avian species resident at high and low altitude.

The metabolic cost of breathing at rest has never been successfully measured in birds, but has been hypothesized to be higher than in mammals of a similar size because of the rocking motion of the avian sternum being encumbered by the pectoral flight muscles. To measure the cost and work of breathing, and to investigate whether species resident at high altitude exhibit morphological or mechanical changes that alter the work of breathing, we studied 11 species of waterfowl: five from high altitudes (>3000 m) in Perú, and six from low altitudes in Oregon, USA. Birds were anesthetized and mechanically ventilated in sternal recumbency with known tidal volumes and breathing frequencies. The work done by the ventilator was measured, and these values were applied to the combinations of tidal volumes and breathing frequencies used by the birds to breathe at rest. We found the respiratory system of high-altitude species to be of a similar size, but consistently more compliant than that of low-altitude sister taxa, although this did not translate to a significantly reduced work of breathing. The metabolic cost of breathing was estimated to be between 1 and 3% of basal metabolic rate, as low or lower than estimates for other groups of tetrapods.

Altitude matters: differences in cardiovascular and respiratory responses to hypoxia in bar-headed geese reared at high and low altitudes.

Bar-headed geese (Anser indicus) fly at high altitudes during their migration across the Himalayas and Tibetan plateau. However, we know relatively little about whether rearing at high altitude (i.e. phenotypic plasticity) facilitates this impressive feat because most of what is known about their physiology comes from studies performed at sea level. To provide this information, a comprehensive analysis of metabolic, cardiovascular and ventilatory responses to progressive decreases in the equivalent fractional composition of inspired oxygen (FiO2 : 0.21, 0.12, 0.09, 0.07 and 0.05) was made on bar-headed geese reared at either high altitude (3200 m) or low altitude (0 m) and on barnacle geese (Branta leucopsis), a low-altitude migrating species, reared at low altitude (0 m). Bar-headed geese reared at high altitude exhibited lower metabolic rates and a modestly increased hypoxic ventilatory response compared with low-altitude-reared bar-headed geese. Although the in vivo oxygen equilibrium curves and blood-oxygen carrying capacity did not differ between the two bar-headed goose study groups, the blood-oxygen carrying capacity was higher than that of barnacle geese. Resting cardiac output also did not differ between groups and increased at least twofold during progressive hypoxia, initially as a result of increases in stroke volume. However, cardiac output increased at a higher FiO2  threshold in bar-headed geese raised at high altitude. Thus, bar-headed geese reared at high altitude exhibited a reduced oxygen demand at rest and a modest but significant increase in oxygen uptake and delivery during progressive hypoxia compared with bar-headed geese reared at low altitude.

Oxygen in demand: How oxygen has shaped vertebrate physiology.

In response to varying environmental and physiological challenges, vertebrates have evolved complex and often overlapping systems. These systems detect changes in environmental oxygen availability and respond by increasing oxygen supply to the tissues and/or by decreasing oxygen demand at the cellular level. This suite of responses is termed the oxygen transport cascade and is comprised of several components. These components include 1) chemosensory detectors that sense changes in oxygen, carbon dioxide, and pH in the blood, and initiate changes in 2) ventilation and 3) cardiac work, thereby altering the rate of oxygen delivery to, and carbon dioxide clearance from, the tissues. In addition, changes in 4) cellular and systemic metabolism alters tissue-level metabolic demand. Thus the need for oxygen can be managed locally when increasing oxygen supply is not sufficient or possible. Together, these mechanisms provide a spectrum of responses that facilitate the maintenance of systemic oxygen homeostasis in the face of environmental hypoxia or physiological oxygen depletion (i.e. due to exercise or disease). Bill Milsom has dedicated his career to the study of these responses across phylogenies, repeatedly demonstrating the power of applying the comparative approach to physiological questions. The focus of this review is to discuss the anatomy, signalling pathways, and mechanics of each step of the oxygen transport cascade from the perspective of a Milsomite. That is, by taking into account the developmental, physiological, and evolutionary components of questions related to oxygen transport. We also highlight examples of some of the remarkable species that have captured Bill's attention through their unique adaptations in multiple components of the oxygen transport cascade, which allow them to achieve astounding physiological feats. Bill's research examining the oxygen transport cascade has provided important insight and leadership to the study of the diverse suite of adaptations that maintain cellular oxygen content across vertebrate taxa, which underscores the value of the comparative approach to the study of physiological systems.

Effects of fatty acid provision during severe hypoxia on routine and maximal performance of the in situ tilapia heart.

The ability to maintain stable cardiac function during environmental hypoxia exposure is crucial for hypoxia tolerance in animals and depends upon the maintenance of cardiac energy balance as well as the state of the heart's extracellular environment (e.g., availability of metabolic fuels). Hypoxic depression of plasma [non-esterified fatty acids] (NEFA), an important cardiac aerobic fuel, is a common response in many species of hypoxia-tolerant fishes, including tilapia. We tested the hypothesis that decreased plasma [NEFA] is important for maintaining stable cardiac function during and following hypoxia exposure, based on the premise that continued reliance upon cardiac fatty acid metabolism under such conditions could impair cardiac function. We examined the effect of severe hypoxia exposure (PO2 < 0.2 kPa) on routine and maximum performance of the in situ perfused tilapia heart under conditions of routine (400 µmol L(-1)) and low (75 µmol L(-1)) [palmitate], which mimicked the in vivo levels of plasma [NEFA] found in normoxic and hypoxic tilapia, respectively. Under both concentrations of palmitate, the in situ tilapia heart showed exceptional hypoxic performance as a result of a high maximum glycolytic potential, confirming our previous results using a perfusate without fatty acids. We additionally provide evidence suggesting that non-contractile ATP demand is depressed in tilapia heart during hypoxia exposure. Cardiac performance during and following severe hypoxia exposure was unaffected by the level of palmitate. Thus, we conclude that hypoxic depression of plasma [NEFA] in fishes does not play a role in cardiac hypoxia tolerance.

Exceptional cardiac anoxia tolerance in tilapia (Oreochromis hybrid).

Anoxic survival requires the matching of cardiac ATP supply (i.e. maximum glycolytic potential, MGP) and demand (i.e. cardiac power output, PO). We examined the idea that the previously observed in vivo downregulation of cardiac function during exposure to severe hypoxia in tilapia (Oreochromis hybrid) represents a physiological strategy to reduce routine PO to within the heart's MGP. The MGP of the ectothermic vertebrate heart has previously been suggested to be ∼70 nmol ATP s(-1) g(-1), sustaining a PO of ∼0.7 mW g(-1) at 15°C. We developed an in situ perfused heart preparation for tilapia (Oreochromis hybrid) and characterized the routine and maximum cardiac performance under both normoxic (>20 kPa O(2)) and severely hypoxic perfusion conditions (<0.20 kPa O(2)) at pH 7.75 and 22°C. The additive effects of acidosis (pH 7.25) and chemical anoxia (1 mmol l(-1) NaCN) on cardiac performance in severe hypoxia were also examined. Under normoxic conditions, cardiac performance and myocardial oxygen consumption rate were comparable to those of other teleosts. The tilapia heart maintained a routine normoxic cardiac output (Q) and PO under all hypoxic conditions, a result that contrasts with the hypoxic cardiac downregulation previously observed in vivo under less severe conditions. Thus, we conclude that the in vivo downregulation of routine cardiac performance in hypoxia is not needed in tilapia to balance cardiac energy supply and demand. Indeed, the MGP of the tilapia heart proved to be quite exceptional. Measurements of myocardial lactate efflux during severe hypoxia were used to calculate the MGP of the tilapia heart. The MGP was estimated to be 172 nmol ATP s(-1) g(-1) at 22°C, and allowed the heart to generate a PO(max) of at least ∼3.1 mW g(-1), which is only 30% lower than the PO(max) observed with normoxia. Even with this MGP, the additional challenge of acidosis during severe hypoxia decreased maximum ATP turnover rate and PO(max) by 30% compared with severe hypoxia alone, suggesting that there are probably direct effects of acidosis on cardiac contractility. We conclude that the high maximum glycolytic ATP turnover rate and levels of PO, which exceed those measured in other ectothermic vertebrate hearts, probably convey a previously unreported anoxia tolerance of the tilapia heart, but a tolerance that may be tempered in vivo by the accumulation of acidotic waste during anoxia.