The Oxygen Transport Triad in High-Altitude Pulmonary Edema: A Perspective from the High Andes

Acute high-altitude illnesses are of great concern for physicians and people traveling to high altitude. Our recent article “Acute Mountain Sickness, High-Altitude Pulmonary Edema and High-Altitude Cerebral Edema, a View from the High Andes” was questioned by some sea-level high-altitude experts. As a result of this, we answer some observations and further explain our opinion on these diseases. High-Altitude Pulmonary Edema (HAPE) can be better understood through the Oxygen Transport Triad, which involves the pneumo-dynamic pump (ventilation), the hemo-dynamic pump (heart and circulation), and hemoglobin. The two pumps are the first physiologic response upon initial exposure to hypobaric hypoxia. Hemoglobin is the balancing energy-saving time-evolving equilibrating factor. The acid-base balance must be adequately interpreted using the high-altitude Van Slyke correction factors. Pulse-oximetry measurements during breath-holding at high altitude allow for the evaluation of high altitude diseases. The Tolerance to Hypoxia Formula shows that, paradoxically, the higher the altitude, the more tolerance to hypoxia. In order to survive, all organisms adapt physiologically and optimally to the high-altitude environment, and there cannot be any “loss of adaptation”. A favorable evolution in HAPE and pulmonary hypertension can result from the oxygen treatment along with other measures.

The Oxygen Transport Triad in High Altitude Pulmonary Edema: a Perspective from the High Andes

Acute high altitude illnesses are of great concern for physicians and people traveling to high altitude. High Altitude Pulmonary Edema (HAPE) can be better understood through the Oxygen Transport Triad which involves the Pneumo-Dynamic Pump (Ventilation), the Hemo-Dynamic Pump (Heart and circulation), and Hemoglobin. The two pumps are the first physiologic response upon initial exposure to hypobaric hypoxia. Hemoglobin is the balancing energy-saving time-evolving equilibrating factor. The increased hemoglobin at high altitude reduces the percentage of dissolved oxygen in the arterial oxygen content with respect to sea level. At high altitude, the acid-base balance must be adequately interpreted using the high altitude Van-Slyke correction factors. Pulse-oximetry measurements during breath-holding at high altitude allow for the evaluation of high altitude diseases. The Tolerance to Hypoxia Formula shows that, paradoxically, the higher the altitude the more tolerance to hypoxia. All organisms adapt physiologically and optimally to a high-altitude environment to survive. Reduction of pulmonary hypertension in HAPE through oxygen administration results in a favorable outcome.

The tolerance to hypoxia is defined by a time-sensitive response of the gene regulatory network in sea urchin embryos

Deoxygenation, the reduction of oxygen level in the oceans induced by global warming and anthropogenic disturbances, is a major threat to marine life. This change in oxygen level could be especially harmful to marine embryos that utilize endogenous hypoxia and redox gradients as morphogens during normal development. Here we show that the tolerance to hypoxic conditions changes between different developmental stages of the sea urchin embryo, possibly due to the structure of the gene regulatory networks (GRNs). We demonstrate that during normal development, bone morphogenetic protein (BMP) pathway restricts the activity of the vascular endothelial growth factor (VEGF) pathway to two lateral domains and by that controls proper skeletal patterning. Hypoxia applied during early development strongly perturbs the activity of Nodal and BMP pathways that affect VEGF pathway, dorsal-ventral (DV) and skeletogenic patterning. These pathways are largely unaffected by hypoxia applied after DV-axis formation. We propose that the use of redox and hypoxia as morphogens makes the sea urchin embryo highly sensitive to environmental hypoxia during early development, but the GRN structure provides higher tolerance to hypoxia at later stages.

Pneumolysis and “silent hypoxemia” in COVID-19

COVID-19 severe lung compromised patients often evolve to life-threatening hypoxia. The mechanisms involved are not fully understood. Their understanding is crucial to improve the outcomes. Initially, past-experience lead to the implementation of standardized protocols assuming this disease would be the same as SARS-CoV. Impulsive use of ventilators in extreme cases ended up in over 88% fatality. We compare medical and physiological high altitude acute and chronic hypoxia experience with COVID-19 hypoxemia. A pathophysiological analysis is performed based on literature review and histopathological findings. Application of the Tolerance to Hypoxia formula = Hemoglobin/PaCO2 +3.01 to COVID-19, enlightens its critical hypoxemia. Pneumolysis is defined as progressive alveolar-capillary destruction resulting from the CoV-2 attack to pneumocytes. The adequate interpretation of the histopathological lung biopsy photomicrographs reveals these alterations. The three theoretical pathophysiological stages of progressive hypoxemia (silent hypoxemia, gasping, and death zone) are described. At high altitude, normal low oxygen saturation (SpO2) levels (with intact lung tissue and adequate acid-base status) could be considered silent hypoxemia. At sea level, in COVID-19, the silent hypoxemia starting at SpO2 =< 90% (comparable to a normal SPO2 {88-92%} at 3,500m) suddenly evolves to critical hypoxemia. This, as a consequence of progressive pneumolysis + inflammation + overexpressed immunity + HAPE-type edema resulting in pulmonary shunting. The proposed treatment is based on the improvement of the Tolerance to Hypoxia (Hemoglobin factor), inflammation reduction, antibiotics, rehydration & anticoagulation if required. Understanding the pathophysiology of COVID-19 may assist in this disease's management.

Laminin‐221 Enhances Therapeutic Effects of Human‐Induced Pluripotent Stem Cell–Derived 3‐Dimensional Engineered Cardiac Tissue Transplantation in a Rat Ischemic Cardiomyopathy Model

Background Extracellular matrix, especially laminin‐221, may play crucial roles in viability and survival of human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPS‐CMs) after in vivo transplant. Then, we hypothesized laminin‐221 may have an adjuvant effect on therapeutic efficacy by enhancing cell viability and survival after transplantation of 3‐dimensional engineered cardiac tissue (ECT) to a rat model of myocardial infarction. Methods and Results In vitro study indicates the impacts of laminin‐221 on hiPS‐CMs were analyzed on the basis of mechanical function, mitochondrial function, and tolerance to hypoxia. We constructed 3‐dimensional ECT containing hiPS‐CMs and fibrin gel conjugated with laminin‐221. Heart function and in vivo behavior were assessed after engraftment of 3‐dimensional ECT (laminin‐conjugated ECT, n=10; ECT, n=10; control, n=10) in a rat model of myocardial infarction. In vitro assessment indicated that laminin‐221 improves systolic velocity, diastolic velocity, and maximum capacity of oxidative metabolism of hiPS‐CMs. Cell viability and lactate dehydrogenase production revealed that laminin‐221 improved tolerance to hypoxia. Furthermore, analysis of mRNA expression revealed that antiapoptotic genes were upregulated in the laminin group under hypoxic conditions. Left ventricular ejection fraction of the laminin‐conjugated ECT group was significantly better than that of other groups 4 weeks after transplantation. Laminin‐conjugated ECT transplantation was associated with significant improvements in expression levels of rat vascular endothelial growth factor. In early assessments, cell survival was also improved in laminin‐conjugated ECTs compared with ECT transplantation without laminin‐221. Conclusions In vitro laminin‐221 enhanced mechanical and metabolic function of hiPS‐CMs and improved the therapeutic impact of 3‐dimensional ECT in a rat ischemic cardiomyopathy model. These findings suggest that adjuvant laminin‐221 may provide a clinical benefit to hiPS‐CM constructs.

The tolerance to hypoxia is defined by a time-sensitive response of the gene regulatory network in sea urchin embryos

Deoxygenation, the reduction of oxygen level in the oceans induced by global warming and anthropogenic disturbances, is a major threat to marine life. This change in oxygen level could be especially harmful to marine embryos that utilize endogenous hypoxia and redox gradients as morphogens during normal development. Here we show that the tolerance to hypoxic conditions changes between different developmental stages of the sea urchin embryo, due to the structure of the gene regulatory networks (GRNs). We demonstrate that during normal development, bone morphogenetic protein (BMP) pathway restricts the activity of the vascular endothelial growth factor (VEGF) pathway to two lateral domains and by that controls proper skeletal patterning. Hypoxia applied during early development strongly perturbs the activity of Nodal and BMP pathways that affect VEGF pathway, dorsal-ventral (DV) and skeletogenic patterning. These pathways are largely unaffected by hypoxia applied after DV axis formation. We propose that the use of redox and hypoxia as morphogens makes the sea urchin embryo highly sensitive to environmental hypoxia during early development, but the GRN structure provides higher tolerance to hypoxia at later stages.Summary statementThe use of hypoxia and redox gradients as morphogens makes sea urchin early development sensitive to environmental hypoxia. This sensitivity decreases later, due to the structure of the gene regulatory network.

Hypoxia-tolerant vascular endothelial growth factor-A (VEGF-A) and the genetic variations of VEGFA in Sherpa highlanders

Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, partly by one of the adaptation mechanisms promoting increases of microcirculatory blood flow and capillary density at high altitude for restoring oxygen supply to tissues. Hypoxia stimulates vascular endothelial growth factor (VEGF), which is an important signaling protein involved in hypoxia-stimulated vasculogenesis and angiogenesis. Our present study included 51 Sherpas dwelling in Namche Bazaar village (3440 m) and 76 non-Sherpa lowlanders residing in Kathmandu (1300 m) in Nepal. In these participants, we measured plasma VEGF-A concentrations and genotyped five single-nucleotide polymorphisms (SNPs) of VEGFA: rs699947, rs8333061, rs1570360, and rs2010963 in the 5′-untranslated region (5′-UTR); and rs3025039 in the 3′-UTR. The average circulating VEGF-A level in Sherpas did not respond to hypoxia at the high altitude in 3440 m, remaining equivalent to the level in non-Sherpa lowlanders at low altitude. Allele discriminations for the analyzed SNPs revealed significant genetic divergences of rs699947, rs8333061, and rs2010963 in Sherpa highlanders compared with non-Sherpa lowlanders, East Asians, South Asians, and the global population; however, consistency with the indigenous Tibetan highlanders from the Tibet Plateau. On the other hand, the SNP rs3025039 in the 3′-UTR presented constant preserved genetic variation among global populations. Our findings indicated that the physiological sea-level VEGF-A concentration in Sherpa highlanders at high altitude was probably linked with the significant variations of VEGFA in Sherpas that regulate the gene expression in a manner of tolerance to hypoxia through production of the optimal biological level of VEGF-A at high altitudes. Precise angiogenesis at high altitude contributes to the adaptive levels of capillary density and microcirculation, providing efficient and effective diffusion of oxygen to tissues and representing human adaptation to high-altitude hypoxia environment.Author summarySherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, partly by one of the adaptation mechanisms promoting increases of microcirculatory blood flow and capillary density at high altitude for restoring oxygen supply to tissues. Vascular endothelial growth factor (VEGF) is mainly stimulated by hypoxia, and is an important signaling protein involved in hypoxia-stimulated vasculogenesis and angiogenesis. Interestingly, we found that the circulating VEGF-A level in Sherpa highlanders did not respond to hypoxia at high altitude. Furthermore, allele discrimination of the single nucleotide polymorphisms (SNPs) of VEGFA revealed significant divergences of rs699947, rs8333061, and rs2010963 within the VEGFA regulation region in Sherpa highlanders compared to the non-Sherpa lowlanders, East Asians, South Asians, and the global population; however, consistency with Tibetan highlanders from the Tibet Plateau. We propose that the hypoxia-tolerant circulating VEGF-A level in Sherpa highlanders is linked with the genetic variations of VEGFA, contributing to human adaptation to high-altitude hypoxic environments.