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Every otherwise fatal hit will add 2 more, replacing other types of hearts if necessary, and deal 40 damage to all enemies in the room.
Once Isaac has no non-broken hearts left, he dies. Extra lives will apply at this point.
The effect does not save Isaac from fatal Devil deals.
However, by placing a Bomb, taking an otherwise lethal Devil deal, then dying from said bomb during the pickup animation, the Devil item can be taken at the cost of some broken hearts.
Interactions
Damocles: Heartbreak does not protect Isaac from Damocles.
Found Soul: The ghost gains 2 extra hits per floor, and every hit they take will damage all enemies in a room as well.
Guppy's Collar: Guppy's collar has a chance to respawn Isaac with an extra half soul heart on death, even if Isaac has already reached 12 broken hearts.
Keeper: Keeper will gain 1 broken heart instead of 3. Taking fatal damage will only grant Keeper 1 broken heart.
Plan C / Suicide King: Heartbreak does not protect Isaac from these effects.
Tainted Keeper: Tainted Keeper will gain 1 broken heart instead of 3. Taking any damage will kill him.
The Lost / Tainted Lost: The Lost has full benefit of the item. This lets him survive 4 extra hits, each hit adding 1 damage, and the 5th is fatal.
The Lost / Tainted Lost + Magic Skin / VI - The Lovers?: No broken hearts are added by the item/card, thus having no effect on Heartbreak.
Tainted Eden: The starting broken hearts are removed when Heartbreak is rerolled; however, any broken hearts gained from lethal damage will persist.
Tainted Isaac: The starting broken hearts are removed when Heartbreak is dropped; however, any broken hearts gained from lethal damage will persist.
Tainted Jacob: This effect will save Tainted Jacob while he is in his Lost form, adding two broken hearts to his regular health.