How would the mechanics of the controller make a difference? If you put it in your left hand, it's no longer RT to attack, it's LT. The only thing that might bother me is the weapon being on a different side of the screen.
It probably wouldn't take long to get used to, but you'd be pushing the opposite trigger to attack and vice versa to block and as you said, it might be a little visually confusing at first. I could do it actually with some practice and probably not a lot of it. I guess I was just remembering back to when I tried to switch the control mechanics on the controller in shooters. So, you'd walk with the opposite stick, but then if you have to jump over an obstacle for example, you'd have to move your thumb off the stick over to the face buttons to jump. In essence, you stop walking, ceasing forward momentum, and jump in place instead of forward. However, that is obviously a different issue and doesn't really apply, so I could actually get away with playing a lefty character pretty easily, and it seems I'll be able to.