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

**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 detailed family history may warrant referral to a cardiovascular genetics service. A detailed family history is a powerful tool and can help establish a diagnosis and initiate comprehensive care in a timely fashion [154-158]. There are significant barriers to the optimal use of family history information, primarily a lack of awareness on the family's part and considerable time restrictions on the health care professional's part. Studies have shown that a majority of people do not know their family history and do not appreciate its relevance in medical management, and consequently the potential impact of family history information is diminished [159]. In an effort to increase family history awareness, tools have been developed and are available to the general public to generate and maintain a detailed family history. For example, the Health and Human Services Family History Initiative has designed a publicly available, web-based program providing a means to generate and maintain a detailed family history [160]. Genetics has transformed the use of family history information and has led to the reemergence of the detailed genetic family history. Detailed family history information is necessary for the optimal use of genetic screening and testing and this translates to the essential need of genetic coun‐ selors embedded in cardiology clinics.

challenge the existing regulatory landscape and directly impact application in the clinic [166]. For example, the meaning of a negative test often will not be clear, in addition to the ambiguity variants of unknown significance present. Despite the passage of the Genetic Information Nondiscrimination Act (GINA), a law that protects the public from insurance companies using genetic information for underwriting purposes, there are increasing concerns about privacy issues. Public education, including physician awareness, will be critical to facilitate the anticipated clinical uses of genetic information. Genetic testing will play an increasing role in the clinical management of BAV and CAVD patients. Ultimately, genotype definition may be able to identify those patients with BAV that are at risk (or not at risk) of developing CAVD or other associated problems, impacting clinical management decisions. As more is learned about the genetic basis of BAV and CAVD, the yield of clinical genetic testing will be sufficient to warrant routine diagnostic testing. As the genotypes associated with BAV and CAVD are defined, there will be a need to expand Consensus Guidelines for BAV to include full consid‐ eration of genetic information, especially overlapping silent and/or latent disease processes. Clinical applications of genetic variant panels will potentially include refined diagnosis, risk stratification (early intervention, timing of surgery), pharmacogenomics (which drug, what

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**The clinical implications of genotype definition: examples.** Because CAVD remains essen‐ tially a surgical problem, early clinical impact may be realized first in surgical considerations. For example, the pulmonary artery dimension is increased in BAV patients [167,168], consis‐ tent with previously reported histopathologic abnormalities in the pulmonary artery of BAV patients [169]. This may be clinically relevant in BAV patients who require aortic valve replacement and may be candidates for the Ross procedure (autologous pulmonary valve placed in the aortic position). Some patients with apparently isolated CAVD undergoing surgical repair may be at risk for subsequently developing TAA, a not uncommon scenario that may be predicted by genotyping. McKellar et al recently described aorta complications in 1,286 aortic valve replacement patients with a median 12 year follow up, and reported that 10% demonstrate progressive aortic enlargement and only a minority of these lead to dissection or require further surgery [170]. However, in those patients, prophylactic replacement of the aorta would be warranted and would fundamentally change the overall approach to this group of patients. In addition, stratifying by genotype CAVD patients into those with and those without aorta abnormalities potentially informs type of surgical approach as well [171,172]. The ability to identify those patients at risk before the first surgery may substantially impact clinical decision-making, including for example a selective approach to combined valve and

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 morphol‐ ogy 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

dose, risk of adverse effects), and screening strategies for relatives.

aorta replacement.

**Genetic testing is anticipated for BAV and CAVD.** As the etiology of BAV is defined and the complex genetics of CAVD is elucidated, a variety of variants associated with BAV and CAVD will be identified, including variants associated with etiology as well as variants associated with specific types of subsequent risk. All variants pertaining to CAVD will have to be organized based on utility. Once a significant proportion of cases can be diagnosed using genetic testing, clinical testing may be warranted. Presently, there are no CLIA (Clinical Laboratory Improvement Amendments) approved tests for the diagnosis or stratification of BAV or CAVD. NOTCH1 screening is of too little yield to justify testing (<2%), but may be included in larger panels of tests at a future time. Presently, there is no diagnostic utility for genetic testing for BAV or CAVD, but given the rate of discovery and the various technological advances being made, it would appear that this will occur in the near term. It is imperative that cardiologists understand the indications and limitations of clinical genetic testing [161,162]. However, genetic testing is being used for various clinical management reasons, and several of these uses have cardiovascular applications. For example, sequence variants in CYP2C9 and VKORC1 are associated with an increased bleeding risk and drug resistance, respectively, in patients taking warfarin [163,164]. Because CAVD patients often require valve replacement, and mechanical prostheses require anticoagulation, this particular example may be directly useful for CAVD patients. Ultimately, diagnostic panels of genetic variants that identify cause, and may provide insight regarding natural history, and additional management panels that identify disease-specific risks may inform clinical decision-making. Taken together, panels of genetic variants may be used in a manner similar to newborn screening, becoming an important part of the working information for every patient.

**The opportunities and challenges of genotype definition in the clinic.** Genotype definition will empower individuals and families to further control their health, extending the paradigm shift that occurred when the medical field embraced preventive medicine [165]. Increasing genetic information in the clinic creates new opportunities to improve cardiovascular health. However, this development also creates new challenges, including ethical and legal issues that challenge the existing regulatory landscape and directly impact application in the clinic [166]. For example, the meaning of a negative test often will not be clear, in addition to the ambiguity variants of unknown significance present. Despite the passage of the Genetic Information Nondiscrimination Act (GINA), a law that protects the public from insurance companies using genetic information for underwriting purposes, there are increasing concerns about privacy issues. Public education, including physician awareness, will be critical to facilitate the anticipated clinical uses of genetic information. Genetic testing will play an increasing role in the clinical management of BAV and CAVD patients. Ultimately, genotype definition may be able to identify those patients with BAV that are at risk (or not at risk) of developing CAVD or other associated problems, impacting clinical management decisions. As more is learned about the genetic basis of BAV and CAVD, the yield of clinical genetic testing will be sufficient to warrant routine diagnostic testing. As the genotypes associated with BAV and CAVD are defined, there will be a need to expand Consensus Guidelines for BAV to include full consid‐ eration of genetic information, especially overlapping silent and/or latent disease processes. Clinical applications of genetic variant panels will potentially include refined diagnosis, risk stratification (early intervention, timing of surgery), pharmacogenomics (which drug, what dose, risk of adverse effects), and screening strategies for relatives.

detailed family history may warrant referral to a cardiovascular genetics service. A detailed family history is a powerful tool and can help establish a diagnosis and initiate comprehensive care in a timely fashion [154-158]. There are significant barriers to the optimal use of family history information, primarily a lack of awareness on the family's part and considerable time restrictions on the health care professional's part. Studies have shown that a majority of people do not know their family history and do not appreciate its relevance in medical management, and consequently the potential impact of family history information is diminished [159]. In an effort to increase family history awareness, tools have been developed and are available to the general public to generate and maintain a detailed family history. For example, the Health and Human Services Family History Initiative has designed a publicly available, web-based program providing a means to generate and maintain a detailed family history [160]. Genetics has transformed the use of family history information and has led to the reemergence of the detailed genetic family history. Detailed family history information is necessary for the optimal use of genetic screening and testing and this translates to the essential need of genetic coun‐

**Genetic testing is anticipated for BAV and CAVD.** As the etiology of BAV is defined and the complex genetics of CAVD is elucidated, a variety of variants associated with BAV and CAVD will be identified, including variants associated with etiology as well as variants associated with specific types of subsequent risk. All variants pertaining to CAVD will have to be organized based on utility. Once a significant proportion of cases can be diagnosed using genetic testing, clinical testing may be warranted. Presently, there are no CLIA (Clinical Laboratory Improvement Amendments) approved tests for the diagnosis or stratification of BAV or CAVD. NOTCH1 screening is of too little yield to justify testing (<2%), but may be included in larger panels of tests at a future time. Presently, there is no diagnostic utility for genetic testing for BAV or CAVD, but given the rate of discovery and the various technological advances being made, it would appear that this will occur in the near term. It is imperative that cardiologists understand the indications and limitations of clinical genetic testing [161,162]. However, genetic testing is being used for various clinical management reasons, and several of these uses have cardiovascular applications. For example, sequence variants in CYP2C9 and VKORC1 are associated with an increased bleeding risk and drug resistance, respectively, in patients taking warfarin [163,164]. Because CAVD patients often require valve replacement, and mechanical prostheses require anticoagulation, this particular example may be directly useful for CAVD patients. Ultimately, diagnostic panels of genetic variants that identify cause, and may provide insight regarding natural history, and additional management panels that identify disease-specific risks may inform clinical decision-making. Taken together, panels of genetic variants may be used in a manner similar to newborn screening, becoming

**The opportunities and challenges of genotype definition in the clinic.** Genotype definition will empower individuals and families to further control their health, extending the paradigm shift that occurred when the medical field embraced preventive medicine [165]. Increasing genetic information in the clinic creates new opportunities to improve cardiovascular health. However, this development also creates new challenges, including ethical and legal issues that

selors embedded in cardiology clinics.

186 Calcific Aortic Valve Disease

an important part of the working information for every patient.

**The clinical implications of genotype definition: examples.** Because CAVD remains essen‐ tially a surgical problem, early clinical impact may be realized first in surgical considerations. For example, the pulmonary artery dimension is increased in BAV patients [167,168], consis‐ tent with previously reported histopathologic abnormalities in the pulmonary artery of BAV patients [169]. This may be clinically relevant in BAV patients who require aortic valve replacement and may be candidates for the Ross procedure (autologous pulmonary valve placed in the aortic position). Some patients with apparently isolated CAVD undergoing surgical repair may be at risk for subsequently developing TAA, a not uncommon scenario that may be predicted by genotyping. McKellar et al recently described aorta complications in 1,286 aortic valve replacement patients with a median 12 year follow up, and reported that 10% demonstrate progressive aortic enlargement and only a minority of these lead to dissection or require further surgery [170]. However, in those patients, prophylactic replacement of the aorta would be warranted and would fundamentally change the overall approach to this group of patients. In addition, stratifying by genotype CAVD patients into those with and those without aorta abnormalities potentially informs type of surgical approach as well [171,172]. The ability to identify those patients at risk before the first surgery may substantially impact clinical decision-making, including for example a selective approach to combined valve and aorta replacement.

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 morphol‐ ogy 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 surveil‐ lance 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.

tics--2011 update: A report from the American Heart Association. Circulation

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189

[4] Roberts WC. The congenitally bicuspid aortic valve. A study of 85 autopsy cases. Am

[5] Fernandes SM, Sanders SP, Khairy P, Jenkins KJ, Gauvreau K, Lang P, Simonds H, Colan SD. Morphology of bicuspid aortic valve in children and adolescents. J Am

[6] Hinton RB. Bicuspid aortic valve and thoracic aortic aneurysm: three patient popula‐ tions, two disease phenotypes, and one shared genotype. Cardiol Res Pract

[8] Otto CM. Valvular aortic stenosis: disease severity and timing of intervention. J Am

[9] Schoen FJ. Evolving concepts of cardiac valve dynamics: the continuum of develop‐ ment, functional structure, pathobiology, and tissue engineering. Circulation

[10] Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O'Brien KD. Characterization of the early lesion of 'degenerative' valvular aortic stenosis. Histological and immuno‐

[11] Thubrikar MJ, Aouad J, Nolan SP. Patterns of calcific deposits in operatively excised stenotic or purely regurgitant aortic valves and their relation to mechanical stress.

[12] Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: a population-based study. Lancet

[13] Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O'Gara PT, O'Rourke RA, Otto CM, Shah PM, Shane‐ wise JS. Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American Col‐ lege of Cardiology/American Heart Association Task Force on Practice Guidelines.

[14] Rajamannan NM, Gersh B, Bonow RO. Calcific aortic stenosis: from bench to the bed‐

[15] Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis,

with or without associated aortic regurgitation. Circulation 2005;111:920-925.

side--emerging clinical and cellular concepts. Heart 2003;89:801-805.

[7] Ward C. Clinical significance of the bicuspid aortic valve. Heart 2000;83:81-85.

2011;123:e18-e209.

2012;2012:926975.

2008;118:1864-1880.

2006;368:1005-1011.

J Cardiol 1970;26:72-83.

Coll Cardiol 2004;44:1648-1651.

Coll Cardiol 2006;47:2141-2151.

Am J Cardiol 1986;58:304-308.

Circulation 2008;118:e523-661.

histochemical studies. Circulation 1994;90:844-853.

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 innova‐ tive approaches to studying the genetic basis of CAVD will be needed to realize this goal.
