Isaac's Heart

Effects

Isaac's body becomes immune to all damage.
A heart familiar appears and closely follows Isaac. If the heart is hurt, Isaac is hurt.
(Added in Repentance) The heart tries to position itself in the opposite direction of where Isaac is shooting.
(Added in Repentance) The heart charges up as Isaac fires. At full charge, upon releasing the fire button, it knocks back nearby enemies and tears, creates a small puddle of red creep on the ground, and releases blood shots in 8 directions that deal 8 damage.
(Added in Repentance) Enemies that come in contact with Isaac take 2x Isaac's current damage per tick or 4x Isaac's damage per second.
(Removed in Repentance) Most enemies now target the heart instead of Isaac. Eyes and other similar enemies, however, will still target Isaac.

(Added in Repentance) Sacrifice Rooms can't be used.
(Removed in Repentance) Blood Donation Machines and Devil Beggars can be used for free.
- During (Added in Afterbirth)(The Guardian) The Guardian challenge, Devil Beggars and Blood Donation Machines deal damage to Isaac.
Spikes (including Curse Room doors and Spiked Chests) do no damage. The door to (Mausoleum) Mausoleum does cause damage.
Picking up a non-orbital familiar will cause either Isaac's Heart or the other familiar to be layered over the other's sprite. This is due to the heart not taking up the spot that the other familiar follows in.
Co-op babies gain the immunity effect without spawning additional hearts.
(Removed in Afterbirth) Enemy Brimstone shots (such as from The Bloat) will not do any damage to the heart.
The tracking lasers from Hush and light pillars from Isaac (Boss) do not damage the heart.

(Added in Afterbirth) Box of Friends: Box of Friends does not duplicate the heart, making it safe to use.
(Removed in Repentance) Breath of Life: Isaac can be infinitely invulnerable, as invincibility carries out to the heart without hurting the player. Note that the item needs to be activated for longer than one second for the invulnerability to kick in, however.
(Added in Afterbirth †)(Duct Tape) Duct Tape: Makes dodging significantly easier.
E. Coli: Isaac can turn enemies into poop without taking damage.
Gnawed Leaf: Invincibility carries over to the heart.
Holy Mantle: The shield effect carries over to the heart.
(Removed in Repentance) IV Bag: Can be used without taking damage, resulting in an infinite amount of coins.
Kamikaze!: As long as the heart is away from the blast radius, no damage is taken. The character must be at high enough speed for this.
(Removed in Repentance) Razor Blade: Isaac cannot take damage from the Razor Blade, allowing for infinite uses of the item.
(Added in Afterbirth † / Removed in Repentance) Sacrificial Altar: Can remove the Isaac's Heart familiar while the item remains, making Isaac invulnerable.
- (Added in Repentance) Sacrificial Altar now doesn't remove Isaac's Heart.
(Added in Afterbirth) Serpent's Kiss: Isaac can poison enemies by contact without taking damage, allowing for free black hearts.

(Added in Afterbirth †)(Baby-Bender) Baby-Bender: The heart's tears do not gain homing.
(Added in Repentance) BFFS!: Fires additional shots in random directions, and leaves larger puddles of creep.
Dry Baby / (Added in Afterbirth) Farting Baby: If you have picked up either of the babies into the first familiar spot before Isaac's Heart, they will block enemy shots before they can hit the heart. Enemies touching the heart can still do damage, and picking up the babies after the heart will cause the heart's hitbox to be checked first against shots.
(Added in Repentance)(Gigante Bean) Gigante Bean: Increases the knockback amount and radius of the heart when fully charged. Highly useful.
(Added in Afterbirth †) King Baby: The Heart will follow King Baby. This makes it much harder to avoid damage, but also makes other synergies like Kamikaze! much easier to use.
(Added in Repentance) A Pound of Flesh: Consumables can no longer be picked up in Shops.
Sharp Plug: Sharp Plug can no longer be used.
The Soul: Isaac's body repels projectiles, but Isaac's Heart doesn't.
(Added in Repentance) (Tainted Forgotten) Tainted Forgotten: Not recommended. The heart follows Tainted Forgotten. Tainted Soul does not deal collision damage and can still be hurt by enemies. The heart will still damage Tainted Forgotten if hit by an enemy, effectively giving it two hitboxes.