Table 2:

Molecular, Cellular, and Structural Changes per Class⁵ of Aortic Insufficiency (AI), and Implications For Future Therapy

AI Class	I	II	III
Current Surgical Approach(es)	Valve sparing root remodeling/replacement	Prolapse repair Surgical valve replacement	Leaflet repair Surgical valve replacement
Molecular Involvement	Biglycan24 Decorin16,24,37 Lrp124,37,45 Osteopontin16 TGF-β24,37	5-HT2 Receptors44	5-HT40 AngII41 Biglycan19,24 BMP and BMP-232–35 Krox2046,47 Lp(a)38,72,73 Osteopontin16 pRb48 TNF-α20,30–32
Cellular Involvement		VIC activation44	VIC activation Osteoblast differentiation16,19,24,32–35 Myofibroblast-like differentiation29 VEC inactivation55,56,61 VEC transformation60,61
Valve Extracellular Matrix Involvement		ECM disorganization due to VIC activation44	ECM disorganization30,46–48
Larger Pathways Implicated	LDL	5-HT44	CAVD67–71 LDL67,69–71 5-HT40
Remodeling Location(s) and Mechanisms	Root dilation and surrounding valve structure	Cusp prolapse/coaptation	Cusp calcification and thickening
Proposed Future Treatment*	Valve sparing root remodeling/replacement	5-HT antagonists80,81 TAVR	5-HT antagonists80,81 ACE inhibitors45, 78,79 TAVR

5-HT-Serotonin

AngII-Angiotensin II

BMP-Bone Morphogenic Protein

CAVD -Calcific Aortic Valve Disease

ECM-Extracellular Matrix

LDL-Low Density Lipoprotein

Lp(a)- Lipoprotein (a)

Lrp1-Low Density Lipoprotein Receptor-Related Protein 1

pRb-Retinoblastoma Protein Tumor Suppressor

TGF-β-Transforming Growth Factor Beta

TNF-α-Tumor Necrosis Factor Alpha

VEC-Valve Endothelial Cell

VIC-Valve Interstitial Cell

^*Further Research Necessary