Calcification and extracellular matrix dysregulation in human postmortem and surgical aortic valves

Abstract

ObjectivesCalcific aortic valve disease (CAVD) is a progressive disease ranging from aortic valve (AoV) sclerosis to AoV stenosis (AS), characterised by severe calcification with impaired leaflet function. Due to the lack of early symptoms, the pathological progression towards valve dysfunction is poorly understood. The early patterns of AoV calcification and altered extracellular matrix (ECM) organisation were analysed in individuals postmortem without clinical AS compared with clinical AS.MethodsHistological patterns of calcification and ECM organisation in postmortem AoV leaflets without clinical AS obtained from a tissue repository and surgical specimens obtained from individuals with clinical AS were compared with in vivo imaging prior to transcatheter AoV implantation.ResultsAoV calcification was detected in all samples from individuals >50 years old, with severity increasing with age, independent of known CAVD risk factors. Two distinct types of calcification were identified: ‘Intrinsic’, primarily found at the leaflet hinge of postmortem leaflets, accompanied by abnormal collagen and proteoglycan deposition; and ‘Nodular’, extending from the middle to the tip regions in more severely affected postmortem leaflets and surgical specimens, associated with increased elastin fragmentation and loss of elastin integrity. Even in the absence of increased thickening, abnormalities in ECM composition were observed in postmortem leaflets without clinical AS and worsen in clinical AS.ConclusionsTwo distinct phenotypes of AoV calcification are apparent. While the ‘nodular’ form is recognised on in vivo imaging and is present with CAVD and valve dysfunction, it is unclear if the ‘intrinsic’ form is pathological or detected on in vivo imaging.

Identification of key genes in calcific aortic valve disease by integrated bioinformatics analysis

“…[ 26 – 28 ] In addition, ECM organization is one of the hallmarks of CAVD which have been reported previously. [ 29 , 30 ] CAV is characterized by fibrotic thickening of the valve leaflets, inflammation, neoangiogenesis, calcification, and the presence of other ectopic mesenchymal tissues, especially in the fibrosa layer. [ 31 ]…”

Heartbeat: sex differences in patient-reported outcomes with atrial fibrillation

“…' An understanding of the cellular and molecular mechanisms of calcific aortic stenosis (AS) might allow targeted medical therapy to prevent disease initiation and progression. Gomez-Stallons and colleagues 3 compared histological patterns of aortic valve leaflet calcification in patients with and Heart November 2019 Vol 105 No 21 Heartbeat Figure 3 (1) Robust in vivo screening combined with radiotracers or near-infrared fluorescent calcium tracer to track the progression of calcific aortic valve disease in high-risk populations (hypertension, diabetes, hyperlipidaemia, bicuspid aortic valve) for early intervention and screening should be performed in parallel with (2) next-generation 'omics' techniques that enable collection and study of the entire genome, miRNAome, transcriptome, proteome and secretome. 3The massive amount of data generated by this multi-omics approach is increasingly being analysed with the aid of artificial intelligence, where machine learning algorithms are employed to identify the most promising drug targets.…”

Proteoglycan 4 is Increased in Human Calcified Aortic Valves and Enhances Valvular Interstitial Cell Calcification

“…Proteoglycans are negatively charged molecules capable of promoting lipid retention [10] as well as transforming growth factor beta (TGF-β) retention [11], a cytokine known to promote VIC trans-differentiation [12]. Observational studies have revealed that regions with moderate calcification exhibit an expansion of the proteoglycan content towards the fibrosa layer of the valve [13] and that these proteoglycans tend to accumulate in the surroundings of calcified nodules [14]. Importantly, these observations have been confirmed with proteomics, revealing that fibrotic parts of the valve present higher levels of proteoglycans [15], specifically proteoglycan 4 (PRG4).…”