**4. National Heart Lung and Blood Institute's research agenda for CAVD**

**New research agenda emphasizes genetics and development.** Recently, the National Heart Lung and Blood Institute Aortic Stenosis Working Group defined a comprehensive research agenda for CAVD [25]. There are nine research priorities outlined in the statement that are summarized in Table 1. These priorities emphasize the identification of genetic factors that inform etiology, risk, and pharmacologic response, pointing to the clinical impact of these efforts being new diagnostic tests, biomarkers that may improve surveillance, and panels that may inform response to specific drugs. In addition, there is an emphasis on identifying genotype-phenotype relationships focusing on BAV. Improved understanding of valve biology, especially as it pertains to genetic predispositions for CAVD, is critical and will facilitate the identification of specific mechanisms involved in disease initiation and progres‐ sion. The identification of molecular developmental processes and animal models of CAVD in vivo are needed to establish early pathogenesis and the effectiveness of new pharmacologic treatments for disease. In addition, genetic information will be increasingly important in the assessment of clinical studies that aim to refine clinical risk factors and identify new diagnostic and risk stratification tests.

**There is an increasing need for networks and biorepositories.** The current paradigm in translational human genetics research involves discovery (the identification of sequence variation associated with disease), mechanistic investigation (definition of pathogenesis), and finally development of new clinical approaches (application). Findings from human genetic studies are being taken into the laboratory where increasingly sophisticated animal models are providing the basis to define pathogenesis in a variety of diseases. The elucidation of pathogenesis subsequently results in the development of new diagnostic and therapeutic strategies, which can then be taken back to the patient. Taken together, this is referred to as the "bedside to bench to bedside" approach to disease and has led to numerous initiatives aiming to realize "translational" research goals, e.g., the NHLBI's Bench to Bassinet Program supporting excellence in pediatric cardiovascular translational research (http://www.bench‐ tobassinet.com), including CVMs such as BAV. Given the incidence of BAV and the sample size required to use new genetic discovery tools, it is necessary to combine cohorts. Genetic information is also impacting the understanding of pharmacology as it relates to drug indications and drug responses further facilitating improved care. Taken together, genetic information provides an impetus to shift the focus of medicine from treatment of end stage

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disease to strategies emphasizing primary prevention and early intervention.

Association.

**clinical care**

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 specifi‐ cally 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 Environ‐ mental 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

**5. Comprehensive counseling and genetic testing increasingly impact**

**A detailed family history remains a powerful tool and genetic testing will advance its impact.** A detailed family history refers to questioning multiple individuals within a family and requires specific demographic information (e.g., age at disease onset) and documentation of disease and other pertinent health issues by medical record review [153]. The results of a

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.

**Table 1.** Current NHLBI Research Agenda for CAVD. Reproduced from [25].

**There is an increasing need for networks and biorepositories.** The current paradigm in translational human genetics research involves discovery (the identification of sequence variation associated with disease), mechanistic investigation (definition of pathogenesis), and finally development of new clinical approaches (application). Findings from human genetic studies are being taken into the laboratory where increasingly sophisticated animal models are providing the basis to define pathogenesis in a variety of diseases. The elucidation of pathogenesis subsequently results in the development of new diagnostic and therapeutic strategies, which can then be taken back to the patient. Taken together, this is referred to as the "bedside to bench to bedside" approach to disease and has led to numerous initiatives aiming to realize "translational" research goals, e.g., the NHLBI's Bench to Bassinet Program supporting excellence in pediatric cardiovascular translational research (http://www.bench‐ tobassinet.com), including CVMs such as BAV. Given the incidence of BAV and the sample size required to use new genetic discovery tools, it is necessary to combine cohorts. Genetic information is also impacting the understanding of pharmacology as it relates to drug indications and drug responses further facilitating improved care. Taken together, genetic information provides an impetus to shift the focus of medicine from treatment of end stage disease to strategies emphasizing primary prevention and early intervention.

agenda for CAVD [25]. There are nine research priorities outlined in the statement that are summarized in Table 1. These priorities emphasize the identification of genetic factors that inform etiology, risk, and pharmacologic response, pointing to the clinical impact of these efforts being new diagnostic tests, biomarkers that may improve surveillance, and panels that may inform response to specific drugs. In addition, there is an emphasis on identifying genotype-phenotype relationships focusing on BAV. Improved understanding of valve biology, especially as it pertains to genetic predispositions for CAVD, is critical and will facilitate the identification of specific mechanisms involved in disease initiation and progres‐ sion. The identification of molecular developmental processes and animal models of CAVD in vivo are needed to establish early pathogenesis and the effectiveness of new pharmacologic treatments for disease. In addition, genetic information will be increasingly important in the assessment of clinical studies that aim to refine clinical risk factors and identify new diagnostic

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

2. Develop high-resolution and high-sensitivity imaging modalities that can identify early and subclinical CAVD,

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

5. Develop and validate suitable multi-scale in vitro, ex vivo, and animal models. Improved models are needed that

6. Identify the relationship between calcification of the AV and bone and the reciprocal regulation of these

7. Encourage, promote, or establish tissue banks that make valve tissue from surgery, pathology, and autopsy

8. Conduct clinical studies specific to CAVD to determine the feasibility of earlier pharmacological intervention in

9. Determine the risk factors and optimal timing of surgical valve replacement in view of the current state of the

unsuitable or unneeded for transplantation, with and without CAVD, available for research.

and risk stratification tests.

184 Calcific Aortic Valve Disease

severity of AS is a risk factor for surgical AV replacement.

mineralization, and micro-scale mechanotransduction

and macro-scale hemodynamics.

aortic AV sclerosis versus stenosis.

data defining the biological mechanisms of CAVD.

processes.

including molecular imaging and other innovative imaging approaches.

realistically duplicate the conditions in which human CAVD develops.

**Table 1.** Current NHLBI Research Agenda for CAVD. Reproduced from [25].

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 specifi‐ cally 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 Environ‐ mental 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.
