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. Author manuscript; available in PMC: 2022 Apr 30.
Published in final edited form as: Circ Res. 2021 Apr 29;128(9):1344–1370. doi: 10.1161/CIRCRESAHA.121.318011

Table 1. Risk factors linked to valve deterioration and disease.

Per risk factor, in-vivo, in-vitro, and human observations are presented from various studies.

Risk Factor How it could cause CAVD In-Vivo In-Vitro Human
Genetic MutationsNotch1, LPA gene, PALMD, TEX41

  • -Valve malformation in development could lead to abnormal biomechanics.

  • -NOTCH1 mutations cause developmental defects in the aortic valve, de-repression of the composition of calcium leads to AVD23.

  • -LPA, PAMLD and TEX41 variants associated with valve defects lead to malformation23,24.

  • -In mice, Notch1 repressed Runx2 activity, a transcriptional regulator of osteoblast cell fate15.

  • -In VIC, endothelial NO stimulus plays a role in downstream Notch1 signaling leading to anti- calcific effects25.

  • -Genome wide association study (GWAS) of two families with genetic histories of valve disease revealed Notch1 mutations in family members affected15.

  • -Multi-ethnic study found variation in the LPA locus is associated with AVD and calcification24.

  • -GWAS identified PALMD and TEX41 variants ↑ risk of CAVD by 20–28% and 15%, respectively, per copy of allele23.
Smoking

  • -Mechanism unclear26.

 Potential area for further study. Potential area for further study. Strong association between Degenerative Aortic Valve Disease in a study of 756 healthy male workers26.
Hypertension (HTN) /Increased Valve Resistance

  • -Altered shear profiles on endothelium.

  • -Altered cyclic strain magnitude/profile.

  • -Changes in local stiffness sensed by cells.

  • -Stage I/II HTN associated with Aortic Valve Calcium (AVC)27.

  • -Ex-vivo models of porcine valves showed nodule formation on the aortic side under 15% stretch HTN conditions in OGM media with TGF- β128.

 Potential area for further study.

  • -HTN group ↑ progression of stenosis. Angiostatin converting enzyme inhibitors (ACEIs) group ↓ progression, patients on angiotensin receptor blockers (ARBs) ↑ progression than ACEIs but ↓ than patients with HTN27.Patients <65 with ↑ systolic and pulse pressure were prevalent in AVC29

.
Hyperlipidemia

  • -Infiltration of ApoB containing lipoproteins is a key initiator of an inflammatory response promoting atherosclerosis30.

  • -Local ROS causes lipids to oxidize, which ↑ inflammation, prevents phagocytosis, and can be calcium nucleation sites31,32.

  • -In SMC-specific PTEN deletion mice, AKT upregulated Runx2 which promoted VSMC calcification31.

  • -WT, LDLR−/−, LDLR−/− Apob100, ApoE−/− mice +/− High fat diet. >50% ↓ in valve diameter, ↑ systolic pressure, left ventricular hylertrphy32.

  • -Oxidized cholesterol stimulates calcification in VICs33.

  • -ApoB (LDL, triglyceride rich remnants of VLDL, IDL, chylomicron remnants, and Lp(a) are present in all atherogenic lipoproteins24.
Diabetes/Hyperglycemia

  • -Atherosclerosis causes ↓ NO and ↑ ROS due to insulin levels34.

  • -Recent studies have associated high glucose with inflammation and pro-calcific gene expression in VIC/VEC model35,36.

 Potential area for further study.

  • -VIC actively remodeled when in hydrogels, ↑ expression of ECM proteins and MMPs. Exposure to TGF- β1 led to upregulation of BMP-2/4, SMAD, Runx2 and ↑ calcium deposition35.

  • -L-arginine transport ↑ hCAT-1 activity leading to accumulation of ROS, which ↓ NO34..
Infection 16,37,17,38,17,38

  • -Rheumatic fever (RF) driven by an autoimmune response leading to valve damage, if untreated16.

  • -Periodontal bacterial infection37.

  • -Upon ligand binding, TLR dimerization activates pro-inflammatory molecules through the activation of NF-κB37.

 Potential area for further study.

  • -If untreated RF can cause cardiac inflammation, eventually leading to Acute RF, leading to valve damage16.
Sex

  • -Male valves calcify where female valves fibrose. Many known disease pathways exclusive to each sex38.

 Potential area for further study. Potential area for further study.

  • -Higher fibrosis scores observed in AS valves in the female sex. In male sex, calcification correlated with fibrosis. BAVs and TAVs can be correlated to calcific aortic stenosis. Post-operatively, remodeling of the left ventricle more prominent in females. Females displayed a 50% ↓rate of stroke, coronary bypass surgery, and 31% ↓ total mortality rate in a 4 year follow up period38.
Kidney Disease Abnormal phosphate, calcium, and vitamin D levels, which ↑ formation of calcific deposits39. Potential area for further study. Potential area for further study.

  • - ↑ progression in patients with end stage kidney disease compared to the general population. Mineral imbalances such as Ca and Vitamin D could ↑ bone formation39.
Age The valve thickens and stiffens with increasing age40. Potential area for further study. Potential area for further study.

  • -The fibrosa thickened with age, collagen ↑ in the valve layers, especially in the fibrosa/ ventricularis layers40.