Table 1.
Basic science and clinical studies demonstrating the association between oxidative stress and aortic stenosis.
| First Author [Ref] | Year | Study Type | Key Findings |
|---|---|---|---|
| Arsenault BJ 34 | 2014 | Cohort study (n=17,553) | Patients with Lp(a) levels in the top tertile had a higher risk of AS The genetic variant rs10455872, which is associated with higher levels of Lp(a), is also associated with increased risk of AS |
| Bosse K 50 | 2013 | In vitro - porcine VICs | Nitric oxide prevents spontaneous calcification of porcine VICs Endothelial-derived NO signalling increases the expression of the NOTCH1 target gene |
| Bouchareb R 48 | 2015 | In vitro - human VICs | Autotaxin is transported in the aortic valve by Lp(a) and promotes inflammation and mineralisation of the valve |
| Capoulade R 27 | 2015 | Cohort study (n=220) | Elevated Lp(a) and OxPL levels are associated with faster AS progression and the need for aortic valve replacement |
| Choi B 46 | 2017 | In vitro - human VICs | NO depletion in human VICs activates the NF-kB pathway, which promotes DPP-4 expression and subsequently induces osteogenic differentiation via reducing IGF-1 signalling |
| Côté C 35 | 2008 | Ex vivo - human aortic valve tissue | Increased levels of circulating oxLDLs are associated with worse fibrocalcific remodelling of valvular tissue in AS |
| Demir B 6 | 2012 | Cohort study (n=64) | There is a positive correlation between serum uric acid levels and AS severity Uric acid accelerates the formation of oxLDLs and may decrease NO levels |
| Hofmanis J 29 | 2019 | Case control study (n=102) | AS severity is negatively correlated with levels of HDL cholesterol; higher MPO levels are negatively correlated with levels of HDL cholesterol as well MPO causes HDL cholesterol dysfunction via oxidation, reducing its protective effects |
| Kamstrup PR 36 | 2013 | Cohort study (n=77,680) | Elevated Lp(a) levels and genotypes that increase plasma Lp(a) levels are associated with an increased risk of AS |
| Langsted A 77 | 2016 | Cohort study (n=103,083) | PCSK9 loss-of-function mutation have lower levels of Lp(a) and reduced risk of AS |
| Li F 37 | 2015 | In vitro - porcine VICs | oxLDLs induce VIC osteogenesis via activation of the receptor for advanced glycation end products (RAGE) |
| Liu H 57 | 2020 | In vitro - human VICs | NADPH oxidase 2 is significantly increased in human calcific aortic valves |
| Matilla L 67 | 2019 | In vitro - human VICs | Soluble ST2 disrupts mitochondrial fusion and oxidative phosphorylation capacity, as well as activates the osteogenic NF-kB pathway Soluble ST2 levels are positively correlated with oxidative stress and inflammation |
| Mercier N 64 | 2020 | In vitro - human VICs | SSAO levels were positively correlated with increasing calcification SSAO inhibition decreased VIC calcification |
| Miller JD 16 | 2008 | In vitro - superoxide and superoxide dismutase levels were measured in human aortic valves | Superoxide and hydrogen peroxide levels were increased in calcified regions of the aortic valve Superoxide dismutase activity and expression were reduced in calcified regions of the aortic valve |
| Mohty D 38 | 2008 | Ex vivo - human aortic valve tissue | Valves with higher oxLDL content had higher levels of inflammatory cells, TNF-α and tissue remodelling |
| Nsaibia MJ 49 | 2016 | Case-control study (n=300) | Lp(a) and oxPL levels were associated with higher autotaxin activity; patients with higher autotaxin and Lp(a) and oxPL levels had an increased risk of AS |
| Peña-Silva RA 62 | 2009 | Ex vivo - human heart valves incubated with serotonin | Superoxide levels were increased after incubation with serotonin Inhibitors of flavin-oxidases or monoamine oxidase prevented the serotonin-induced increase in superoxide levels |
| Perrot N 78 | 2020 | Ex vivo - human heart valves | PCSK9 expression was higher in valve tissue from patients with calcific AS compared to control patients PCSK9 levels were increased in human VICs incubated in an osteogenic medium, and a PCSK9 neutralising |
| In vitro - human VICs incubated in an osteogenic medium | antibody significantly reduced calcium accumulation | ||
| Yu B 45 | 2017 | In vitro - human VICs incubated in an osteogenic medium containing Lp(a) and OxPLs | Prolonged incubation of the VICs with Lp(a) significantly increased calcium deposition Calcium deposition was further augmented when VICs were incubated with both Lp(a) and OxPLs |
| Yu B 39 | 2018 | In vitro - human VICs incubated in an osteogenic medium containing Lp(a) and OxPLs | Incubation of VICs with Lp(a) significantly increased ROS formation |
| Zeng Q 40 | 2014 | In vitro - human VICs incubated incubated in an osteogenic medium | VICs incubated with oxLDLs had higher expression of the BMP-2 pathway and NOTCH1 signalling, with resultant increase in osteogenesis |
| Zheng KH 41 | 2019 | Cohort study (n=145) | Patients with Lp(a) and OxPL levels in the top tertile had greater progression of valvular CT calcium score, faster haemodynamic progression on echocardiography, increased risk of aortic valve replacement and death |
AS = aortic stenosis; DPP-4 = dipeptidyl peptidase-4; HDL = high density lipoproteins; IGF-1 = insulin-like growth factor 1; Lp(a) = lipoprotein(a); MPO = myeloperoxidase; NADPH = nicotinamide adenine dinucleotide phosphate; NF-kB = nuclear factor kappa light chain enhancer of activated B cells; NO = nitric oxide; oxLDL = oxidesed low density lipoproteins; oxPL = oxidised phospholipids; PCSK9 = proprotein convertase subtilisin/kexin type 9; ROS = reactive oxygen species; SSAO = semicarbazide-sensitive amine oxidase; ST2 = interleukin 1 receptor-like 1; TNF-α = tumour necrosis factor-alpha; VIC = valvular interstitial cells.