Rob credits the negative reaction to 4E being because it changed both the rules and the setting, saying that it might have been better received if the setting stayed the same while the rules changed.
I suspect he's ... not entirely wrong there. Mostly, but not entirely.
It's worth remembering that Grand History of the Realms actually preceded the 4e core books by a short time, and this was where some of the more boneheaded changes to FR lore first got released to a largely-unimpressed reception. Tyr killing Helm, just to choose one example.
For me as a customer (just as one data point, of course), this made the job one step harder for the 4e team. GHotR (and the FR 4e leaks that started to trickle out after it) was basically a huge red flag being waved around with alarms blaring 'this book is garbage and these people REALLY don't know what they are doing!' Losing my trust on something like that made it harder for me to trust WotC over 4e, and indeed, in the end I never played it.
This is not to say the ONLY reason i disliked 4e was the setting changes. I had plenty of other objections, from monsters being shallow and boring to an over-focus on the battlemap rather than the world, to the ridiculously broken and badly-thought-out maths in things like the early iterations of skill challenges. I think Heinsoo is perhaps making a few excuses here. But the setting stuff meant the ruleset came into bat with one strike already recorded (apologies for the bad sports metaphor, I'm Australian and we don't do baseball here...).
(I do feel sorry for the GHotR guy, from time to time. He was a complete FR lore nerd, one of the incredibly dedicated ones, and GHotR was his labor of fannish love for many years, and it finally got officially noticed and published, then the misfiring WotC brains trust of the time decided to populate the last chapter with some of the worst dross you could imagine, and ruthlessly blow up the setting he clearly loved. Must have been a rough experience for him)