Did everything we attempt to improve end in
success? Alas, no. One thing I don’t particularly like about the ORd’s calcium handling is the fact that
the release from the sarcoplasmic reticulum (SR) depends directly on the L-type
calcium current. The release should ideally depend, among other things, on the
calcium concentration adjacent to the sarcoplasmic reticulum. Beyond the
phenomenological nature of the dependence of release on L-type calcium current,
this for example also prevents the possibility of the cells manifesting delayed
afterdepolarisations in a physiological way [1].
Basically
after finishing the ToR-ORd model as it is now, Dr. Alfonso Bueno-Orovio has
suggested that calcium-dependent SR release would be a really nice thing to
have, with which I heartily agreed, and we started working on it together. I
really needed a break at the time, but then again, we thought that if it was
achievable to change the SR release without breaking many other properties, it
would be silly not to try it. There aren’t so many models of calcium-dependent
SR release, so we experimented with several formulations. Unfortunately, with
regards to what phenotypes the model could show, none worked as well as the
existing formulation. It was often impossible to get reasonable alternans [2],
and in some cases the rate dependence of calcium cycling seemed to become
rather exaggerated (huge increases in SR loading with increased pacing rate etc. [3]).
Anyway, we tried many different things together with Alfonso – first it didn’t
look promising, but we were in such a situation many times before, and there
were many things on the TODO list to check and explore if they couldn’t remedy
the issues. Except one day, the list became empty – we explored what we could,
perturbed all the parameters, tried various formulations. We looked at each
other one day and almost in unison agreed we’d give up. I suspect the issues we met are probably
linked not just to the SR release, but to other elements of calcium handling in
the existing model: SERCA pumps, CaMKII, SR diffusion, calcium buffering, maybe
the cell compartmentalization, and potentially also the L-type calcium current.
I think these parts of the model are in some form implicitly adjusted to work
nicely with the L-type-calcium-current-dependent SR release, and when we want
to change the SR release, the other components might have to change as well.
Doing such changes would be another major project in itself, and we felt it was
out of scope of our existing work. The issue with model development is that you
know how long it takes only when you finish – there is no guarantee that hard
and meticulous work alone will give you success. For such reasons, we drew a
line and agreed we’d keep ToR-ORd as it is.
It is an
interesting philosophical question on how much to prefer the set of phenotypes
that a model manifests consistent with literature, versus accurate mechanisms.
I generally lean towards the mechanisms - whenever there was a situation in
ToR-ORd development, where I thought “well, this is a bit off mechanism, but
seems to work fine for now”, it always came back to kick me and it had to be
reworked more thoroughly. On the other hand, there has to be some balance, and
it is hard to persuade others that a new model is really worthwhile
when it seems, at the first sight, to behave worse than previous ones. People
are busy and the first sight may be the last one they give. My first intuitive
reaction to such thinking is “but you don’t want to have a good behavior with
the wrong mechanism”, but then I’m afraid that models are models, and for most
mechanism there (if not all), one can go deep enough to find some flaw. Rather
than to go for the wild goose chase of trying to fix everything, it may be
perhaps more reasonable to be well-aware of the model’s limitations and take
them into account when interpreting model simulations. This is by the way
another reason why I’m so much in favor of deep model analysis that goes to the
low-level of the models workings, as only then it’s possible to assess how
plausible the model prediction is. A newly discovered ionic current/flux is
incorporated in a model and it induces a particular behavior? Great, but why
exactly? Computer simulations (as is often stated in article introductions)
allow perfect observability and control over the model, so why not to use that?
[1] It is
possible to come up with some form of explicit store-overload mechanism
depending on the SR loading. However, this then may not be very sensitive to
established important factors in formation of delayed afterdepolarisations that
rely on elevation of calcium adjacent to the SR, such as SR leak etc.
[2] Couldn’t we be happy with a model without alternans? We
probably could – however, unlike some other prearrhythmic behaviours which are
relatively sparse and usually require disease or drug block to manifest,
alternans appears to be achievable relatively consistently even in healthy
hearts.
Even if there are exceptions (which can be also due to laboratory protocols),
capability of alternans formation still seems to be relatively general property
of myocyte calcium cycling and losing it raises a flag that something is not
ideal.
[3] At the same
time, many properties were not broken and in most regards, the model was
absolutely fine, giving us hope and even a bit of belief that the ToR-ORd model is
generally sensible.
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