Your options are single click (thrust), and held click (pound)
Your upgrades and gameplan are tied to these interactions. Do not engage in either if a heart is about to pop (thrust has more "active frames") and DO be actively doing something with reversed hearts, when you unlock them.
Other than that, experiment and have fun!
Hearts clearly seem to scale the further along you are in a run, certain monster hearts feeling absolutely egregious by loop 2 and the game as a whole being nigh impossible by four.
Sustain or big bonk is a necessity for every build because of it, and outside of some fine-tuning I sadly don't think there's much to be said about damage taken