35mm film is of such quality now that enlargements aren't really an issue -- keeping in mind sharpness, developer and ISO speed, etc.

Depth of field is relative with different sized negatives too -- f/8 in 35mm will have a greater zone in focus than f/8 in MF.

I think if you can get sharp negatives handheld on a big camera like a C220 then a 645 system will at least be the same.

Things like ergonomics are entirely up to you - my personal take is 35mm cameras are simpler and therefore faster, but it really boils down to whatever you get used to. A Pentax 645 in your hands for a year or three will be like second nature.