Current NHLBI Research Agenda for CAVD. Reproduced from [25].
1. The clinical taxonomy: Malformation vs. disease
2. The genetic basis of BAV and CAVD
3. The molecular taxonomy: Genes, pathways, and proteins
The classic connective tissue disorders, Marfan and Ehlers-Danlos syndromes, caused by mutations in the FIBRILLIN-1 and COLLAGEN Type 3 genes respectively, are well-known to effect the aortic valve. While there is clearly reduced penetrance for BAV in these groups, there is a significantly increased incidence for BAV in both conditions of 10-30% [71,72]. Additional genetic syndromes that affect the connective tissue include Williams syndrome and osteogenesis imperfecta, caused by mutations in the ELASTIN and COLLAGEN Type 1 genes respectively, which also have an increased incidence of valve malformation and disease [73,74]. In addition, there are a number of genetic syndromes that are associated with BAV, often in the context of complex CVM. These include aneuploidies such as deletion 4p, deletion 10p, deletion 11q (Jacobsen syndrome), trisomy 18 (Edwards syndrome), deletion 20p12 (Alagille syndrome), as well as other genetic syndromes, including Adams-Oliver syndrome and Kabuki syndrome [75,76]. Trisomy 18 is a particularly interesting entity that is associated with polyvalvular disease, an unusual type of valve disease that is characterized by malformation, including BAV, and dysplasia of the valves, a poorly understood process that does not have a clear association with CAVD but challenges the malformation-disease distinction [77]. In addition, BAV is often one of multiple CVMs in the same individual and the patterns of co-occurrence can inform cause [78]. Taken together, there is a multitude of ways that valve tissue can be affected, and a molecular understanding of these conditions will inform CAVD.
During valve remodeling, the VICs regulate expression and organization of the valve ECM [127,128]. Additional ECM remodeling enzymes such as matrix metalloproteases (MMPs) and cathepsins also are expressed during valve maturation [128,129]. VICs from developing valves are highly synthetic, and extensive remodeling is required to achieve the mature organization [127,130]. In normal adult valves, the VICs are largely quiescent with little or no cell proliferation and maintain baseline levels of ECM gene expression necessary for valve homeostasis [103]. ECM enzyme dysregulation is established in the valve disease literature [131-135]. The elastin insufficient mouse demonstrates cartilage-like nodules in the valve annulus reminiscent of calcific nodules [119,136]. MMP misexpression malformation and more disease, suggesting malformation processes are due in part to remodeling defects and malformation and disease processes are shared [136]. Similar nodules are seen in the aortic valve annulus of the Adamts9 null mouse [137], confirming the importance of ECM remodeling enzymes. Elastolysis and associated elastic fiber fragments have been implicated as a trigger for myofibroblast mediated calcification [138,139]. Loss of balance between elastases and elastase inhibitors has been identified as one fundamental cause of elastolysis [140]. Interestingly, previous studies have shown that different elastic fiber fragments have different biologic functions, for example, some fragments induce calcification while others are chemo-attractants for endothelial cells [141,142].
CAVD is characterized by VIC activation, which in turn results in increased ECM and increased remodeling enzyme gene expression [103,127,128], and hemodynamic factors may activate VICs and therefore contribute to pathology. VIC activation is apparent by induction of myofibroblast markers, such as vimentin, smooth muscle actin, and embryonic non-muscle myosin heavy chain [129]. Some VICs have been shown to be dynamic and play an active role in ECM maintenance, as well as potentially regeneration and repair, and these VICs are progenitor cells with smooth muscle like properties [101,102,103,123,146,147]. Recently, two studies have demonstrated the complex interaction between developmental programs that predispose tissue to disease and shear stresses that trigger inflammation [148,149], providing examples of how these factors when combined may cause AVD. Research efforts are beginning to reconcile developmental and biomechanical considerations in an effort to more closely examine CAVD in vivo. A better understanding of hemodynamic-induced cell-matrix perturbations may inform the search for durable valve bioprostheses [150].
4. National Heart Lung and Blood Institute’s research agenda for CAVD
1. Identify genetic, anatomic, and clinical risk factors for the distinct phases of initiation and progression of CAVD to identify individuals at higher risk, to determine interactions between risk factors, and to determine whether the severity of AS is a risk factor for surgical AV replacement. |
2. Develop high-resolution and high-sensitivity imaging modalities that can identify early and subclinical CAVD, including molecular imaging and other innovative imaging approaches. |
3. Understand the pathogenesis and pathophysiology of BAV, especially to establish correlations between phenotype and genotype, and to clarify the key features of this disease process that potentiate calcification. |
4. Understand the basic valve biology (e.g., early events, mechanisms, and regulatory effects) of CAVD, including signaling pathways and the roles of valve interstitial and endothelial cells and the autocrine and paracrine signaling between them, the extracellular matrix and matrix stiffness, the role of age-related changes in both valve cells and extracellular matrix, the interacting mechanisms of cardiovascular calcification and physiological bone mineralization, and micro-scale mechanotransduction and macro-scale hemodynamics. |
5. Develop and validate suitable multi-scale in vitro, ex vivo, and animal models. Improved models are needed that realistically duplicate the conditions in which human CAVD develops. |
6. Identify the relationship between calcification of the AV and bone and the reciprocal regulation of these processes. |
7. Encourage, promote, or establish tissue banks that make valve tissue from surgery, pathology, and autopsy unsuitable or unneeded for transplantation, with and without CAVD, available for research. |
8. Conduct clinical studies specific to CAVD to determine the feasibility of earlier pharmacological intervention in aortic AV sclerosis versus stenosis. |
9. Determine the risk factors and optimal timing of surgical valve replacement in view of the current state of the data defining the biological mechanisms of CAVD. |
Given some of the specific research priorities, for example the need to immortalize valve interstitial cell (VIC) lines, it will be important both to design biorepositories that are specifically built for cardiovascular disease needs and to organize virtual biobanks that can leverage combined resources from multiple centers. In effect, this will maximize translational impact and return on investment. The organization of biorepositories has advanced considerably in recent years, and significant strides have been made by international groups to coordinate resources. For example, the mission of the International Society for Biological and Environmental Repositories (ISBER) is to address technical, legal, ethical and managerial issues relevant to the governance of wide ranging biorepositories (http://www.isber.org) [151]. Several institutions have initiated biorepositories that include blood and tissue from CAVD patients. Virtual repositories, or multiple repositories that coordinate efforts to leverage sample size considerations, are becoming operational and the current funding climate is accelerating development of special rules to optimize tissue utility [152]. Funding bodies at the government and foundation levels need to recognize valve disease as a significant public health problem and establish valve specific funding opportunities. Further, valve biology and CAVD specific symposia are needed at large conferences, such as the American Heart Association.
5. Comprehensive counseling and genetic testing increasingly impact clinical care
Genotype phenotype information will have important implications for clinical surveillance. For example, current recommendations for functional BAV patients include screening echocardiograms every 5 years for all first-degree relatives [13]. Recently it was shown that surveillance may be modified by morphology such that pediatric patients with RN morphology are screened every 2 years because they are at higher risk of developing new AVD, while individuals with RL BAV could be monitored less aggressively in early childhood as the risk of having AVD at this time is relatively low [26]. Family members of BAV patients may be at risk for TAA or other cardiovascular disease (even if they don’t have BAV), underscoring the importance of thoughtful monitoring. Since CAVD is a latent phenotype, continued surveillance is required. Since some individuals with BAV have progressive CAVD and others never develop disease, there is reason to think that genetic insights will clarify this phenomenon. Overall, refined screening strategies promise to provide opportunities for improved care.
Ultimately, genetic information will inform the identification of new pharmacologic based therapies for CAVD [173]. Genetics research in CAVD will lead to further basic research in animal models that can define the early pathogenesis and natural history of disease and therefore identify new therapeutic targets. This paradigm will have increasing significance as bioinformatics approaches overcome the challenges of extraordinary amounts of data. There has been considerable interest in applying CAD treatment paradigms to valve disease. However, while statin therapy showed early in vitro evidence of a potentially beneficial effect, a large clinical trial demonstrated that statin therapy does not positively impact either aortic valve disease progression or the need for surgery [174]. Recently, a strategy to use pediatric valve disease patients as a means to identify early genetic aspects of CAVD has been advanced because this population provides insight into the disease process that is not confounded by the common comorbidities of adulthood, such as CAD and HTN [127,175]. Increasingly, developmental paradigms will inform the search for etiology, new treatments and better bioprostheses. New therapies are likely to emerge from molecular biology fields, and innovative approaches to studying the genetic basis of CAVD will be needed to realize this goal.
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