KristoriaBlack wrote:Hello,

I'll have free access to the full article when it gets published in the regular science journal (not the pre-publication edition) in a few weeks. If you want email me in 2 or 3 weeks to remind me and I can get it for you for free. (Or you can always email the authors for a reprint. Don't worry about the journal. Science is funded by your tax dollars. Information belongs to the people.)

I'm not sure exactly how the biology of AMS differs from that of CMS. There are people on this forum much more knowledgeable than I. You can always email the authors of the research study and ask them if their work is relevant to AMS.

My first reaction would be that they are not very similar. My limited understanding is that the problem with CMS is one of increased hematocrit: a too high concentration of red blood cells that have an overall a lower oxygen saturation.

With respect to AMS once the body is acclimatized the human is good to go. So what exactly happens molecularly and physiologically when someone acclimatizes? One of the things that happen at altitude is that the body needs to breath deeper and more frequently. This in turn causes less carbon dioxide in the body, making the blood more alkaline. This change in the pH causes the body to repress respiration. This problem is resolved upon acclimatization when the kidneys begin to excrete bicarbonate, so that a human can continue to breath deeper and faster while maintaining a steady pH in their blood.

A second thing that happens during acclimatization however is an increase in the hematocrit (the concentration of red blood cells.) This increase is very rapid and not due to the de novo production of red blood cells initially but rather to a decrease in the blood volume. (Dehydration and an increase in urine production). Since the kidneys produce EPO there is also an increase in the absolute numbers of red blood cells (not just the concentration) but this is not seem right away.

So to summarize, acclimatization involves many changes (some biochemical) and is correlated with an increased hematocrit, in this case an increase in the hematocrit is good for the climber. While CMS is also correlated with an increased hematocrit and in the context of CMS it is bad for the climber. See the problem?


On the other hand this line of reasoning might be totally wrong. One should note that a correlation does not equal causation. Has anyone actually tested whether the increase in hematocrit is good for the climber's short term adaptation to high altitude? It does not matter what is intuitive, it is only cold, hard experimental data that is to be believed. If the increase in hematocrit is so good for the acclimatization process then why are we encouraged to drink water to prevent dehydration? We know that drinking water is good for acclimatization, but would that not just decrease the hematocrit by diluting the blood? (It may just be me that doesn't get it. )

So who knows. Assuming that a HIF inhibitor would work for AMS, would a HIF inhibitor work time wise? The answer again is who knows? HIF does everything their cousin. Activation of EPO is just one of the millions of things that HIF does. Perhaps HIF is detrimental to adaptation to high altitude in other ways. (This would be counter intuitive based on what we know at present, but the human body is quite the complex machine and our knowledge of why people develop AMS is far from being complete.)

I do wonder what other genes they found. I would expect there to be differences in genes that sense carbon dioxide and pH. Its going to be interesting to see.

So that's my spiel. (Pity the sucker that some day gets stuck sharing a tent with me in the Himalayas having to wait out a storm: I can blabber on about science for weeks on end!! )


Cheers,

Christine

KristoriaBlack wrote:So to summarize, acclimatization involves many changes (some biochemical) and is correlated with an increased hematocrit, in this case an increase in the hematocrit is good for the climber. While CMS is also correlated with an increased hematocrit and in the context of CMS it is bad for the climber. See the problem?


On the other hand this line of reasoning might be totally wrong. One should note that a correlation does not equal causation. Has anyone actually tested whether the increase in hematocrit is good for the climber's short term adaptation to high altitude? It does not matter what is intuitive, it is only cold, hard experimental data that is to be believed. If the increase in hematocrit is so good for the acclimatization process then why are we encouraged to drink water to prevent dehydration? We know that drinking water is good for acclimatization, but would that not just decrease the hematocrit by diluting the blood? (It may just be me that doesn't get it. )

So who knows. Assuming that a HIF inhibitor would work for AMS, would a HIF inhibitor work time wise? The answer again is who knows?

cb294 wrote:
Commenting as a geneticist / developmental biologist (not a physiologist, so count that for what it is worth) I´d doubt that the dehydration induced increase in hematocrit is helpful in acclimatization and avoidance of AMS. If anything, reduced capillary flow should negatively affect total transport capacity.

The slow, Epo mediated increase in total erythrocytes at more or less normal density will eventually increase oxygen carrying capacity, but that takes several days to weeks (unlike the fast pH response).

So even if modulating HIF/PPARa activity could well have an affect on AMS, it would probably be by one of the ten thousand other targets of HIF, but unlikely by targetting Epo mediated erythrogenesis.

Anyway, I´d love to see is what the oxygen carrying capacity of Tibetans actually is (higher despite lower or equal hematocrit?), and even more, whether the mutations suppressing the HIF response (avoiding CMS caused by chronically increased hematocrit but sacificing some oxygen carrying capacity) are balanced by other mechanisms that upregulate oxygen transfer to the target organs. In the end you don´t really care how much oxygen you have in your blood but about the levels in your brain and muscles.

kozman18 wrote:....
I also would like to see more studies on the Tibetan population -- both genetic and with respect to oxygen carrying capacity. These studies appear to hold the key to CMS, and maybe will open some doors with respect to AMS....

cb294 wrote:

kozman18 wrote:....
I also would like to see more studies on the Tibetan population -- both genetic and with respect to oxygen carrying capacity. These studies appear to hold the key to CMS, and maybe will open some doors with respect to AMS....

Hi,

I am very sceptic as to what we can learn from adaptation to CMS with respect to treating/preventing AMS.

In a very simplified view, one could interpret CMS in genetically not adapted lowlanders as the cost of acclimatization (i.e., a side effect of successfully avoiding AMS, e.g. overproduction of red blood cells). In a way, adaptation for CMS avoidance in Tibetans might mask whatever helps the same people avoid AMS.

Might be more promising to study individual people who acutely adapt to height very well, irrespective of there CMS resistance. I don´t recall the study (maybe just an anecdotal report) exactly, but I seem to remember that height tolerance in expedition mountaineers was correlated with a REDUCED pulse and breathing response to oxygen deprivation, presumably again avoiding hyperventilation associated pH problems.

Let me check if I can find the reference for that,

Christian