Registry of Unexplained Cardiac Arrest
Registry of Unexplained Cardiac Arrest
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.
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.
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