Every otherwise fatal hit will add 2 more, replacing other types of hearts if necessary, and activates The Necronomicon's effect, dealing 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.
Notes
At the maximum of 11 broken hearts, Isaac gains a total of +2.75 damage.
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.
Synergies
A Missing Page / Missing Page 2: Deals an additional +40 damage when Isaac dies. Effects stack together and with multiple copies.
Found Soul: The ghost gains 2 extra hits per floor, and every hit they take will damage all enemies in a room as well.
Interactions
Damocles: Heartbreak does not protect Isaac from Damocles.
Keeper: Keeper will gain 1 broken heart instead of 3. Taking fatal damage will only grant Keeper 1 broken heart.
Magdalene + Birthright: Can hold up to 17 broken hearts, totaling +4.25 damage instead.
Plan C / Suicide King: Heartbreak does not protect Isaac from these effects.
Tainted Eden / Tainted Isaac: The starting broken hearts are removed when Heartbreak is rerolled/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 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.
Mother's Kiss can mitigate this as it gives Tainted Keeper an extra coin heart.
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.
The Necronomicon's effect, dealing 40 damage to all enemies in the room.
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.
A Missing Page / 
Missing Page 2: Deals an additional +40 damage when Isaac dies. Effects stack together and with multiple copies.
Found Soul: The ghost gains 2 extra hits per floor, and every hit they take will damage all enemies in a room as well.
Damocles: Heartbreak does not protect Isaac from Damocles.
Keeper: Keeper will gain 1 broken heart instead of 3. Taking fatal damage will only grant Keeper 1 broken heart.
Magdalene + 
Birthright: Can hold up to 17 broken hearts, totaling +4.25 damage instead.
Plan C / 
Suicide King: Heartbreak does not protect Isaac from these effects.
Tainted Eden / 
Tainted Isaac: The starting broken hearts are removed when Heartbreak is rerolled/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 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.
Mother's Kiss can mitigate this as it gives Tainted Keeper an extra coin heart.
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 Eve Unlocks 
The Beast Unlocks 
The Binding of Isaac: Rebirth
