Well I think that Karen is really close to winning this, for many reasons.
Karen plays maybe in his best surface ( of course indoors are one too), but he has won ATP-title on outdoor hard. He has of course a powerful service, and really strong groundstrokes. I think he should have easy jobs with his service games in these conditions if he keeps his "head". He has already beaten Big John in their only meeting in RG 2017, and we all know what tough nut Isner is in GS-stage in every surface.
Well I dont think that the US players play as good here cross the boarder than they play at home in US. I mean especially Big John. I recall he dont have that good record from here in Canadien Masters in past years. Also I was seeing little bit bad play from him @Atlanta his favourite tournament, where he lost some sets and gave his service games easily away few times. Also he lost to someone like Rubin in next tournament @ Washington and that seemed really poor, although I didnt see his match. Here he won Herbert, BUT very close 1st set and Herbert is really limited player to me what comes to return. Still John won only 50% of his 2nd serves, and to me that is not a good number. I mean surely Karen can put lot more pressure to John on return, cause he is so much better overall player than Herbert.
I think this could well be very close 3 setter with breakers, or than Karen can pull this off!