Center for Cardiovascular and Pulmonary Research
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Research Beat
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Research Study: Genetics of Left Ventricular Outflow Tract Malformations
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In The News
Knowledge of Heart Disease’s Genetic Nature Doesn’t Guarantee Awareness of Available Genetic Testing
Although parents may understand that their child’s heart condition is inherited this doesn’t ensure that they are also aware of genetic testing that could identify the genetic cause of their child’s disease. These are the findings of a Nationwide Children’s Hospital study that looked at the genetic heart condition, HCM.
Hypertrophic cardiomyopathy (HCM) is a genetic condition in which the heart muscle becomes thick, forcing the heart to work harder to pump blood. HCM is considered to be idiopathic when no other cause can be determined. Idiopathic HCM patients can experience symptoms ranging from fainting to heart failure or may not experience any symptoms; the condition can be diagnosed anytime from infancy to old age.
First-Degree Relatives are Also at Risk
“HCM is a frightening diagnosis for most patients due to the risk of sudden cardiac death,” said Timothy Hoffman, MD, medical director of the Heart Transplant and Heart Failure Program at Nationwide Children’s. ”It can also be frightening for siblings, parents and children since its genetic nature puts all first-degree relatives at a 50 percent chance of also carrying the disease-causing mutation.” Regular cardiovascular examinations are recommended for all first-degree relatives, but genetic testing is the only available method to determine specifically which relatives carry the mutation.
Genetic Testing is Recommended for HCM but Isn't Common Practice
Although genetic testing has been recommended for individuals with HCM since 2006, it has not yet been incorporated into routine practice across the United States. “There is a complete lack of literature on patient or parent interest in and attitudes toward genetic testing for HCM,” said Genetic Counselor Sara Fitzgerald-Butt, MS, CGC, one of the study authors.
Fewer than 1/3 of Parents Aware of Available HCM Genetic Testing
To gauge parents’ perception of HCM and related genetic testing, researchers conducted telephone interviews with adult caregiver of HCM patients seen at Nationwide Children’s between 2004 and 2007. More than three-fourths of participants agreed that their child’s HCM was inherited; however, less than one-third were aware that HCM genetic testing is available. Once made aware of the availability of HCM genetic testing, 62 percent said they would consider the testing for themselves or their child.
“It’s important to identify factors that influence whether or not children receive genetic testing in multi-factorial diseases like HCM, especially since genetic test results not only affect the child’s diagnosis but can lead to identification of asymptomatic mutation carriers within their immediate family,” said Dr. Hoffman.
In this study, parental age, education level and awareness that HCM is inherited were the best predictors of interest in HCM genetic testing. “This study provides health care providers with a framework to understand caregivers’ knowledge and views of genetic testing, which can be used to improve clinical care for pediatric HCM patients,” said Fitzgerald-Butt.
Fitzgerald-Butt SM, Byrne L, Gerhardt CA, Vannatta K, Hoffman TM, McBride KL. Parental Knowledge and Attitudes toward Hypertrophic Cardiomyopathy Genetic Testing. Pediatr Cardiol. 2009 Dec 1. [Epub ahead of print]
Children’s Hospitals May Be Best for Adult Congenital Heart Patients
Despite being treated at a hospital designed for pediatric care, adult patients with congenital heart disease fare as well as kids at Nationwide Children’s. These are the findings from a study appearing in the International Journal of Cardiology that provides more data to the discussion as to where adult patients with childhood heart complications belong.
Adults with congenital heart disease comprise one of the fastest growing populations within cardiology; 90 percent of all infants born with a congenital heart defect are expected to survive into adulthood. Yet for many reasons, most of the patients are lost to care after adolescence and present to cardiology care during a health crisis, requiring cardiac procedures and hospitalization. Should adult congenital heart disease patients be admitted to an adult hospital where there is typically little or no experience with congenital heart disease anatomy, physiology, diagnostic tests and invasive procedures? Or should they go to a pediatric hospital where there is expertise in congenital heart disease and the performance and interpretation of diagnostic and invasive studies, but have facilities geared to children with typically no adult services and anxiety among staff caring for adult patients?
Adults Receive Equally Exceptional Care at Nationwide Children's
Faculty at Nationwide Children’s studied the outcomes of 782 adult patients (ranging from 18 to 80 years of age) who received cardiac surgery or another condition-related procedure at Nationwide Children’s between 2002 and 2007. These patient outcomes were then compared with measures for children receiving cardiac care at the same institution since there currently aren’t alternative benchmarks or standardized quality measures to compare with adult congenital heart outcomes.
Results showed that there were no significant differences in outcomes between the age groups. Throughout the examined period, only 4 of the 782 patients were transferred to an adult institution, one who elected to be transferred for dialysis. Nationwide Children’s experienced a lower mortality and complication rate than other institutions. This study is the first to show that a free-standing pediatric hospital with an onsite multidisciplinary adult congenital heart disease service can achieve high survival rates and quality of life with an adult patient population.
Nationwide Children's Unique Care Model
Our program demonstrates a unique model for care of the adult congenital heart disease patient,” said Curt Daniels, MD, director of the Adolescent and Adult Congenital Heart Disease Program and one of the study authors. “A multidisciplinary discussion of each case assures a balanced consideration of risks and benefits and promotes patient-focused decision making.
These findings suggest that future models of adult congenital heart disease care that incorporate multidisciplinary programs within a pediatric hospital should be considered to care for this growing, unique and complex population.
Crumb SR, et al. Quality outcomes of ACHD patients undergoing cardiovascular procedures and hospital admissions in a free-standing children's hospital. Int J Cardiol. 2009 Aug 7. [Epub ahead of print]
Common Molecular Mechanism Linked to Three Separate Heart Defects
Three separate heart defects share a common defect at the molecular level, according to a study by members of the Center for Molecular and Human Genetics.
Aortic valve stenosis (AVS), coarctation of the aorta (COA), and hypoplastic left heart syndrome (HLHS) are three cardiac defects that involve the heart’s left ventricular outflow tract (LVOT). All three are serious defects, particularly HLHS, which still causes death in up to 40 percent of infants born with the condition, despite aggressive surgical intervention. Presumably, these defects are caused by a developmental mechanism involving the inner lining of the heart. Yet until now, a molecular similarity between the three defects had not been identified.
“Clinicians traditionally thought of these heart defects as separate entities,” said Kim McBride, MD, principal investigator in the Center for Molecular and Human Genetics and lead author of this study. “More recent views have grouped them together based on findings from cardiac developmental biology, observations of clustering in families, and our own previous work on inheritance analysis.”
In this study, researchers hypothesized that mutations in the NOTCH1 gene may be implicated in AVS, COA and HLHS. Notch is a signaling pathway involved in multiple developmental processes, and mutations of the NOTCH1 gene have been identified in a condition called bicuspid aortic valve, which is more common in families with LVOT malformations.
Ninety-one patients with LVOT malformations had their DNA screened for mutations in NOTCH1 and were compared to 216 ethnically matched samples without LVOT malformations. Results showed that NOTCH1 gene mutations are present in AVS, COA and HLHS. A detailed functional assessment using a cell based system showed two specific mutations reduce signaling through the Notch signaling pathway.
The molecular mechanisms by which these mutations affect Notch signaling are, as yet, unclear. Still, this study suggests that the levels of Notch signaling play a vital role during cardiovascular development, and relatively minor changes may promote LVOT defects. These findings also emphasize the hereditary nature of these defects and explain why they co-occur within families.
“This is the first time a common molecular event has been elucidated for AVS, COA, and HLHS. This supports our previous idea that these defects may share a common developmental pathogenesis,” said Dr. McBride. “Further, we have evidence the developing endocardium and endothelium may play a role in the causation of these defects. We can now focus our research to better understand what goes wrong during development. Identifying a specific gene also now holds hope for eventually providing better risk counseling for families.”
McBride KL, Riley MF, Zender GA, Fitzgerald-Butt SM, Towbin JA, Belmont JW, Cole SE. NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling. Hum Mol Genet. 2008 Jun 30. [Epub ahead of print]
