CAVD and Shear Stress
Although atherosclerotic coronary artery disease and CAVD share common features, they do have differences in rheology. This difference may provide at least a partial explanation for the differences in pathophysiology and response to therapy. 76–80 CAVD is characterised by pulsatile shear stress on the ventricular side and low and reciprocating shear stress on the aortic side, 81 whereas the coronary artery is exposed to sustained laminar blood flow under normal circumstances. 82 As stenosis progresses, wall shear stress across the aortic valve dramatically increases. 76 Ahamed and colleagues have demonstrated that in vitro shear stress can activate latent transforming growth factor (TGF)- β 1, 82 a critical pro-fibrotic growth factor that can induce fibrosis and calcification. 83 They also showed that active TGF- β 1 could be eluted from thrombi formed in response to vascular injury in the carotid artery of mice where partial occlusion may have led to high local shear stress. 82 Subsequently, Albro et al. independently confirmed that shear stress can activate latent TGF- β 1 in synovial fluid. 83 These data raise the possibility of an association between the activation of circulating latent TGF- β 1 under high shear stress and the development of CAVD. Because platelets contribute ~45 % of the baseline circulating TGF- β 1 level 84 and have 40–100 times more latent TGF- β 1 than any other cells, 85 it is possible that shear stress has two separate effects – inducing release of latent TGF- β 1 from platelets and activating the released latent TGF- β 1. This mechanism may contribute to the progression of CAVD, because aortic valve narrowing increases shear stress resulting in greater release of platelet TGF- β 1 and TGF- β 1 activation. This in turn may lead to progressive valve narrowing and fibrosis, and thus even greater shear stress.
Calcifying valves initially have macrophage and T-cell infiltrates as a result of endothelial injury. 74 Bone morphogenetic protein (BMP)-2 and BMP-4 are then expressed by myofibroblasts and preosteoblasts adjacent to these lymphocytic infiltrates. 74 Furthermore, cardiac valves express markers of osteoblastic differentiation, including core-binding factor alpha 1 and osteocalcin. 26 These valves also calcify in a manner similar to osteogenesis, with lamellar bone evident in the majority of pathological specimens examined. 85 Congenitally bicuspid aortic valves uniformly show signs of calcification by the time individuals reach age 30, 86 which may, in part, be attributable to the particular mechanical stressors to which these valves are subjected. 87 Recently, the molecular mechanism underlying bicuspid aortic valve calcification was solved. Mutations in the transcriptional regulator NOTCH1 resulted in aortic valve anomalies and severe calcification, owing to impaired repression of the osteoblast stimulator runt-related transcription factor 2 (RUNX2). 88
Recent evidence suggests that CAVD is the result of an active inflammatory process affecting the valve and leading to osteoblastic transformation with bone formation of VICs by activation of the receptor activator of nuclear factor- κ B (RANK). 89
Regulatory Pathways
There is increasing evidence that regulatory pathways that control heart valve development also are active with valve pathogenesis later in life. CAVD includes the activation of VICs in addition to increased expression of transcription factors that regulate the earliest events of valvulogenesis in the developing embryo. 90 In addition to valve developmental pathways, regulatory proteins that promote the development of cartilage and bone lineages also are active in diseased valves. 91 Thus, knowledge of the molecular regulatory pathways that control valve development will likely be informative in determining the molecular mechanisms of valve pathogenesis.
Aetiology
CAVD has multifactorial aetiology. Many factors are centered on an inflammatory process affecting the valve and leading to calcification, 74,85 including deposition of LDLs, 44,45 osteoblastic transformation with bone formation of valvular interstitial cells, connective tissue synthesis and tissue remodelling. On a microscopic level, the aortic leaflets contain disorganised collagen fibres, chronic inflammatory cells, extracellular bone matrix proteins, lipidic proteins and bone minerals. 5 Calcification of the valve occurs following trans-differentiation of the VICs through a myofibroblast stage and into osteoblast cells. 71,92
Half of adults undergoing aortic valve replacement have a bicuspid aortic valve associated, and nearly all of them will need to have a new valve inserted. 93 Shear stress occurring with each cardiac systole is greater in a bicuspid valve than in a tri leaflet structure and these valves calcify earlier. 93
Interestingly, the expression of RANK ligand (RANKL) by osteoblast cells will be actively involved in the activation and differentiation of osteoclast cells. 89 RANKL levels normally rise with age and can predict cardiovascular events in humans, while osteoprotegerin (a physiological inhibitor of RANK) deficit can lead to vascular calcification in animal models. 94,95 This study highlights an in vitro model to assess the mechanisms of aortic valve calcification.95