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, as he will then have 2 broken hearts, except if you manage to have 3+ HP, with Mother's Kiss, for example.
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.
Tainted Lost can't normally obtain it, as it doesn't have the offensive item tag
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.
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.
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, as he will then have 2 broken hearts, except if you manage to have 3+ HP, with 
Mother's Kiss, for example.
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.
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.
Tainted Eve Unlocks 
The Beast Unlocks 
The Binding of Isaac: Rebirth
