Thanks for the kind words. As far as my experience goes, I am actually the author of the FeedWordPress plugin (I also use it daily on about a half dozen personal projects).
I do not personally run any sites with as many as 300 sources, although I've consulted with some users who do run sites that large. In general it is possible to run FWP with this many sources, but, especially if they are very active, it does take some careful fine-tuning, especially around the update scheduling process.
I would recommend turning on the Guid Index setting that you found in the Performance section. The setting is fully reversible if for any reason you need to remove it. (When you click the button to create the index, it is then replaced by a button in the same place that allows you to remove the index. If need be, the index can also be removed through a single simply MySQL command issued directly to your database server.)
What the setting does is to create a MySQL index on the guid column in the wp_posts table. Essentially, this means that when WordPress sends a request to your database to search for post records that match the guid (a unique identifier URI which is assigned to every post at the time it is created, and which never changes even if you change all of the post content), these searches will be performed more quickly, because MySQL will have already compiled some information ahead of time that helps it rapidly find any record that matches a given guid. Because FeedWordPress uses the guid field in order to determine whether or not a post from one of your feeds has already been syndicated into your blog, it frequently needs to issue these searches. For a large installation like yours, creating the index should help provide a significant performance boost. The index purely has to do with how MySQL searches through the database records; it will not add, eliminate, or modify any information in your database.
I don't know how well this explains; the technical details of the indexing are pretty closely tied to the technical ins and outs of SQL-based relational databases. But the main thing I'd want to stress is that the option is very easy to try out, should have no side effects on the kind of data you see, and can be easily removed if you decide that you need to turn it off.