Integrative Multi-Omics Analysis in Calcific Aortic Valve Disease Reveals a Link to the Formation of Amyloid-Like Deposits

Abstract

Calcific aortic valve disease (CAVD) is the most prevalent valvular heart disease in the developed world, yet no pharmacological therapy exists. Here, we hypothesize that the integration of multiple omic data represents an approach towards unveiling novel molecular networks in CAVD. Databases were searched for CAVD omic studies. Differentially expressed molecules from calcified and control samples were retrieved, identifying 32 micro RNAs (miRNA), 596 mRNAs and 80 proteins. Over-representation pathway analysis revealed platelet degranulation and complement/coagulation cascade as dysregulated pathways. Multi-omics integration of overlapping proteome/transcriptome molecules, with the miRNAs, identified a CAVD protein–protein interaction network containing seven seed genes (apolipoprotein A1 (APOA1), hemoglobin subunit β (HBB), transferrin (TF), α-2-macroglobulin (A2M), transforming growth factor β-induced protein (TGFBI), serpin family A member 1 (SERPINA1), lipopolysaccharide binding protein (LBP), inter-α-trypsin inhibitor heavy chain 3 (ITIH3) and immunoglobulin κ constant (IGKC)), four input miRNAs (miR-335-5p, miR-3663-3p, miR-21-5p, miR-93-5p) and two connector genes (amyloid beta precursor protein (APP) and transthyretin (TTR)). In a metabolite–gene–disease network, Alzheimer’s disease exhibited the highest degree of betweenness. To further strengthen the associations based on the multi-omics approach, we validated the presence of APP and TTR in calcified valves from CAVD patients by immunohistochemistry. Our study suggests a novel molecular CAVD network potentially linked to the formation of amyloid-like structures. Further investigations on the associated mechanisms and therapeutic potential of targeting amyloid-like deposits in CAVD may offer significant health benefits.

Transthyretin: From Structural Stability to Osteoarticular and Cardiovascular Diseases

“…These observations indicate that physiological fibrinolysis in vivo is interconnected with the formation of TTR amyloid [ 190 ]. Since plasmin activation occurs in vivo at sites of injury (i.e., on vascular and arterial walls or vascular basement membrane), an intersection between TTR amyloid formation and the fibrinolytic system corresponds to previous observations concerning CAVD [ 155 ]. Additionally, cleavage-induced formation of TTR amyloid may lead to local microcalcification in situ due to the binding of Ca 2+ by destabilized TTR molecules [ 47 , 108 ].…”

“…The molecular mechanisms of CAVD are similar to those characteristic for pathogenesis of atherosclerosis [ 171 ]. Complex analysis of the transcriptome, proteome, and miRNA datasets differentially expressed in CAVD allowed the creation of a three-dimensional multilayered model of the disease [ 155 ]. The 3D network of interactions of seven input genes, four input miRNAs, and two connectors indicated that two amyloid-forming proteins, amyloid β precursor protein (APP) and TTR, play central roles in the processes underlying CAVD [ 155 ].…”

“…Therefore, the network indicated a connection between cardiovascular and amyloid diseases. Amyloid depositions of APP were localized to the fibrocalcific region of the aortic valve using immunohistochemistry, and TTR deposits were detected in both calcified valves and the fibrocalcific region of the aortic valve in CAVD patients [ 155 ]. Analysis revealed the importance of the crosstalk of the coagulation/complement cascade pathway with platelets in etiology of the disease [ 155 ].…”

“…Amyloid depositions of APP were localized to the fibrocalcific region of the aortic valve using immunohistochemistry, and TTR deposits were detected in both calcified valves and the fibrocalcific region of the aortic valve in CAVD patients [ 155 ]. Analysis revealed the importance of the crosstalk of the coagulation/complement cascade pathway with platelets in etiology of the disease [ 155 ]. Increased risk of thromboembolism observed in CA [ 172 ] is in good agreement with these observations.…”

Panomics: New Databases for Advancing Cardiology

“…Methylomic, metabolomic, and proteomic data were combined to form a multi-layered network whereby the omic data sources were matched with sources of healthy and calcified aortic valves. The novel networks in this study found associations between amyloid deposits on aortic valves in Alzheimer's patients and highlighted associated genes to the valve spongiosa layer, which has previously not been central to calcific aortic valvular disease research (100). Network methods, specifically deep neural networks, attracted the public eye after Google DeepMind's AlphaFold 2 model predicted protein folded structures using only the amino-acid sequence with near-identical performance as gold standard experimental methods, such as cryo-electron microscopy (101,102).…”