Silviu Itescu The Legend, page-408

Yeah look that's fair enough, and that is the most reasonable explanation I've heard around here thus far.

I honestly appreciate the well thought out response!

I guess my issues with that are the following:

1) The effect on LVESV (that you've referred to) was not replicated in MSBs study

2) Current understanding of heart failure does not involve the local inflammatory response being significant enough to cause down stream systemic inflammatory effects (for example, someone with rheumatoid arthritis, inflammatory bowel disease, etc have much more systemic inflammation, if you go by inflammatory markers in the blood. Would localised injection of MSCs also decrease their risk of stroke? You'd expect it to, if you are right).

If systemic inflammation was such a risk to stroke, anti-inflammatories would be theorised to have an effect on it (steroids, NSAIDS, TBFa inhibitors, etc). Aspirin does, but not because of the inflammatory effects.

3) Systemic injection of MSCs do get directed to the lungs. But that's fine for aGVHD, doesn't seem to factor into that mechanism. Wouldn't that be better as an arterial infusion?

So sure, your mechanism could potentially explain. If the risk of stroke in heart failure was due to some liberation of systemic factors that we currently don't appreciate in our current understanding (could be the case) then this could be a good treatment for that.

But I'm skeptical. Because as you've pointed out, previous studies have shown a significant effect on LVESV as well with these treatments, and this failed to replicate that.

So either this is blowing our understanding of heart failure out of the water, or it's merely a byproduct of statistical monkey business that can come about from any study looking at a number of predetermined secondary endpoints.

I hope it's the first! But I know where my money is for now.