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Research

 

Our research focuses on understanding the causes of sudden cardiac death in children and their families 

Heritable Arrhythmias

 

         Arrhythmias are electrical abnormalities of the heart that can cause the heart to beat inappropriately or in an uncontrolled manner.  Some of these arrhythmias are caused by genetic mutations in the DNA which cause defective proteins called ion channels to be made.  These arrhythmias are called “channelopathies” and can be passed down in families.  Many of these channelopathies can be life-threatening, and predispose susceptible family members to sudden cardiac arrest 
 
          While arrhythmias of the heart are not uncommon, heritable arrhythmias are rarer and include diseases such as long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, and idiopathic ventricular fibrillation.  All of these diseases carry a risk of sudden cardiac death, thus making an accurate diagnosis and medical management critically important.   Heritable arrhythmias are the most common cause of sudden death in children and young adults when the autopsy does not identify any abnormalities. 

          We have active research projects centered around identifying new genes that cause heritable arrhythmias and may present with unexplained sudden death – specifically, long and short QT syndromes.  Partnering with families who have inherited disease, but a negative clinical genetic test, we conduct expansive exome or genome sequencing to identify potentially new mutations which may explain their diseases.  We utilize patient-derived stem cells and genetically engineered mouse models to determine the electrical changes these identified mutations may produce in the heart with an eye towards correcting these abnormalities with existing, or new, therapies.

Cardiomyopathies

 

          Cardiomyopathies are diseases of the heart muscle itself.  As with heritable arrhythmias, cardiomyopathies are caused by genetic mutations in the DNA, which cause dysfunctional proteins produced in the heart which can prevent the heart from squeezing or relaxing normally.   Like channelopathies, cardiomyopathies can be passed in families and can result in a risk of sudden cardiac death.  The most common cause of death in young athletes, and one of the most common findings at autopsy when a child or young adult suddenly dies unexpectedly, cardiomyopathies come in many varieties.  These include  hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, left ventricular non-compaction, dilated cardiomyopathy, and restrictive cardiomyopathy.

          We have active research projects focused on identifying new genes that cause early childhood-onset, cardiomyopathy.  Partnering with families who have inherited diseases such as early heart failure or arrhythmia cardiomyopathy, but a negative clinical genetic test, we conduct expansive exome or genome sequencing to identify potentially new mutations.  We then utilize patient-derived stem cells and genetically engineered mouse models to determine the molecular and cellular changes these identified mutations may produce in the heart with a goal of correcting these abnormalities with existing, or new, therapies.

Unexplained Sudden Deaths

          The sudden cardiac death of an otherwise healthy child can devastate families and entire communities. These deaths often represent the fringe of clinical medicine where routine cardiac evaluations can be completely normal. Answers to diagnosis, risk stratification, and individualized life-saving interventions require functional genomics, cardiovascular physiology, biophysics, and molecular physiology. When these tools are leveraged in an inter-disciplinary fashion, we believe they hold the promise to diagnosing and treating some of the most challenging cardiovascular diseases of our time.  Sudden deaths such as these including diseases such as SIDS (sudden infant death syndrome)  sudden unexplained death syndrome, and sudden arrhythmic death syndrome. 

        We have on-going research projects with collaborators across Duke, medical examiners/pathologists, and the state of North Carolina to identify what role the heart may be playing in these tragic unexplained deaths.  We also coordinate these efforts with our clinic to ensure that other family members who are left behind following the death undergo a thorough risk evaluation to determine whether they too may be at risk.

Malformations of the Heart

          Structural abnormalities of the heart are one of the most common birth defects and impact about 1% of the population.  These abnormalities can take many forms, such as chambers of the heart not forming correctly (like hypoplastic left heart syndrome or tricuspid atresia), valves of the heart not forming correctly or leaking, holes in the heart (like atrial or ventricular septal defects), alterations in the position or orientation of the major blood vessels, and many other abnormalities.  While these abnormalities are relatively common, some of these diseases are likely to run in families, putting a family at risk of having other children with a malformation of the heart.

          We have research projects exploring how malformations of the hearts can be passed in families, yet there is no clear genetic reason that has been identified for many families.  We utilize expansive whole exome and whole genome genetic sequencing to identify these markers of heart disease risk and to explore the mechanisms of disease development and potentially prevention.

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