Patient case: 36-year-old female with Brugada syndrome; genetic feature: SCN5A

Clinical trial: Registry of Unexplained Cardiac Arrest

Summary: The CASPER will collect systematic clinical assessments of patients and families within the multicenter Canadian Inherited Heart Rhythm Research Network. Unexplained Cardiac Arrest patients and family members will undergo standardized testing for evidence of primary electrical disease and latent cardiomyopathy along with clinical genetics screening of affected individuals based on an evident or unmasked phenotype.

Detailed description: Arrhythmias caused by congenital or acquired abnormalities of cardiac K+ or Na+ channels are increasingly recognized as a cause of syncope and sudden death. Cardiac arrest in the absence of overt structural heart disease was previously considered idiopathic ventricular fibrillation (IVF). The list of causes of "unexplained" cardiac arrest (UCA) now encompasses K+ related abnormalities (Long and Short QT, Andersen's), Na+ related (Long QT3, Brugada), Ca++ related (Catecholaminergic Polymorphic Ventricular Tachycardia-CPVT), and latent cardiomyopathy. These underlying causes of cardiac arrest are overtly familial in 30-60% of cases. Clinical detection of the underlying phenotype is crucial to direct appropriate treatment, genetic testing and screening of family members.
  Phenotype recognition of the range of these rare genetic conditions includes non-invasive and invasive testing to demonstrate the hallmarks of each individual condition, and exclude common causes such as ischemic or idiopathic forms of cardiomyopathy. The outcomes from this type of testing have not been assessed in a systematic fashion in patients with UCA or their family members. Phenotype-genotype correlation is necessary to develop optimal diagnostic testing in probands and screening techniques in their family members, which will result in disease-specific therapy. Genetic testing of patients with an overt phenotype demonstrates a potentially causative mutation in 50-75% of LQTS patients, and 20% of Brugada's Syndrome patients. Despite recognized mutations with phenotypic expression models, 30-80% of patients will have negative gene screening despite overt or latent clinical disease.
  The proposed project is evaluating a systematic approach to clinical assessment and genetic screening of patients and families with UCA and suspected inherited arrhythmias involving:
  1. A multicenter registry of UCA patients, their family members and referred patients with familial sudden death undergoing standardized testing for evidence of primary electrical disease (PED). The single center pilot experience at the applicant's institution has proven feasibility, and has been accepted for publication in Circulation, indicating novelty. Ten centers across Canada have agreed to participate. The target is to enroll 1500 UCA probands, 1st degree family members. 1st degree relatives of autopsy negative unexplained sudden death victims.
  2. Long term cardiac monitoring for (3 years) in select high-risk patients with an injectable cardiac monitor to detect potential substrate and/ore triggers for sudden death.
  3. DNA/plasma collection and biobanking for stratified whole exome sequencing.

Eligibility: Inclusion Criteria:
  -  Cardiac arrest requiring cardioversion or defibrillation.
  -  Syncope with documented polymorphic ventricular tachycardia felt to be responsible for the index event.
  -  First degree relative of an index case of UCA undergoing clinical testing.
  -  First degree relative of a family member with UCA or sudden death before age 35 with a negative autopsy for cause of death, presumed arrhythmic.
  -  First degree relative of a family member with UCA or sudden death with objective evidence of primary electrical disease, such as a diagnostic electrocardiogram (ECG), exercise test, drug infusion, or genetic testing.
  Exclusion Criteria:
  -  Coronary artery disease (stenosis > 50%)
  -  Reduced left ventricular function (left ventricular ejection fraction [LVEF] < 50%)
  -  Event managed without an implantable cardioverter defibrillator [ICD] (for follow-up portion)
  -  Unwilling or unable to provide clinical follow-up (for follow-up portion)
  -  Comorbidity making survival of > 1 year unlikely
  -  Persistent resting QTc > 460 msec for males and 480 msec for females
  -  Reversible cause of cardiac arrest such as marked hypokalemia (< 2.8 mmol/l) or drug overdose sufficient in gravity without other cause to explain the cardiac arrest
  -  Hemodynamically stable sustained monomorphic ventricular tachycardia with a QRS morphology consistent with recognized forms of idiopathic ventricular tachycardia (outflow tract or apical septal)
  -  Brugada's sign with e2 mm ST elevation in V1 and/or V2
  -  Unwilling or unable to provide consent

Relevance to patient case: not relevant