This is organized by Natural Serotypes (found in nature) and Engineered Capsids (specifically designed to improve cardiac specificity and reduce liver accumulation).

Quick Legend: Administration Routes

• IV (Intravenous): Systemic injection. The vector must circulate and cross the vascular endothelium to reach the heart muscle. High risk of sequestration in the liver.
• IC (Intracoronary): Injection via catheter directly into the coronary arteries. Provides higher local concentration to the heart than IV.
• IM (Intramyocardial): Direct injection into the heart muscle wall (via open surgery or catheter). Best for localized treatment (e.g., infarct zones).

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1. Natural AAV Serotypes

Serotype	Primary Target Cells	Preferred Route	Key Characteristics & Notes
AAV9	Cardiomyocytes (CMs)	IV / IC	The Gold Standard. • The most efficient natural serotype for the heart via systemic delivery. • Crosses the vascular endothelium efficiently to reach the myocardium. • Major Drawback: Extreme liver tropism (it is a “liver sponge”), requiring high doses to get enough vector to the heart.
AAV6	Cardiomyocytes, Fibroblasts	IM	The Direct Injector. • Very efficient when injected directly into the muscle tissue. • Less efficient than AAV9 for systemic (IV) delivery because it is cleared rapidly from the blood and targets the liver/spleen heavily.
AAV8	Cardiomyocytes	IV	The Liver Specialist. • Transduces heart muscle well, but its affinity for the liver is even stronger than AAV9. • Often used for liver-directed gene therapies; less ideal for heart unless liver-specific promoters are used to silence expression there.
AAV1	Cardiomyocytes, Skeletal Muscle	IM	Muscle Preference. • Similar to AAV6; historically used for direct muscle injections (SERCA2a trials). • Effective for local delivery but poor for systemic/pan-cardiac coverage.

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2. Engineered & Synthetic Capsids

The “Holy Grail” of cardiac AAV is finding a capsid that hits the heart but ignores the liver.

Variant	Primary Target Cells	Preferred Route	Key Characteristics & Notes
AAV2i8	Cardiomyocytes	IV	The Liver-Detargeted Mutant. • A chimera of AAV2 (capsid) with AAV8 components and specific mutations. • Drastically reduced liver tropism compared to AAV9, while maintaining high cardiac transduction efficiency. • A top choice for systemic delivery when liver toxicity is a concern.
MyoAAV	Cardiomyocytes, Skeletal Muscle	IV	The New Standard? • A newer class of engineered capsids (e.g., MyoAAV 4A) identified by the Broad Institute. • Uses RGD motifs to target integrins. • Shows superior potency in primates with significantly reduced liver accumulation compared to AAV9.
AAV-SASTG	Cardiomyocytes	IV	AAV9 Variant. • An AAV9 capsid with a specific peptide insertion (SASTG). • Enhances heart transduction efficiency over wild-type AAV9 in certain animal models.

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3. Tropism by Target Tissue

If you are designing a study, start here:

• Global Heart Delivery (Systemic): AAV9 (Standard) or AAV2i8 / MyoAAV (if liver toxicity is a major concern).
• Localized Ischemia/Infarct (Direct Injection): AAV6 or AAV1 (via Intramyocardial injection).
• Liver Avoidance: AAV2i8 (Detargeted) or use a cardiac-specific promoter (like cTnT).
• Cardiac Fibroblasts: AAV6 generally hits fibroblasts better than AAV9.

Critical Factor: The Liver Sponge Effect

In cardiac gene therapy, the heart is in constant competition with the liver.

• The Trap: When you inject AAV9 intravenously, >90% of the dose ends up in the liver, leaving only a fraction for the heart.
• The Solution:
  1. Capsid Engineering: Use AAV2i8 or MyoAAV to physically stop the virus from entering liver cells.
  2. Promoter Restriction: Use a promoter like Troponin T (cTnT) or Myosin Heavy Chain (MHC). The virus will still enter the liver, but the gene won’t turn on, preventing liver toxicity (though not the “sponge” effect).