Translation of research discoveries to clinical care in arrhythmogenic right ventricular cardiomyopathy in Newfoundland and Labrador: Lessons for health policy in genetic disease

Abstract

Arrhythmogenic right ventricular cardiomyopathy, a lethal autosomal dominant cause of sudden cardiac death in young people, is prevalent in Newfoundland and Labrador (genetic subtype ARVD5). In the absence of implantable cardioverter defibrillator treatment, death rates are extremely high. Research into arrhythmogenic right ventricular cardiomyopathy (ARVD5) began in the 1980s and the causative gene and mutation were discovered in 2008. The decades of research highlighted major issues associated with the ethical management of genetic information and the translation of research findings to clinical care. We describe these issues and the strategies used in managing them. Effective knowledge transfer of the research information has resulted in systematic clinical and genetic screening coupled with genetic counseling and treatment for at-risk family members. Improved survival for patients has been one clear result of this strategy. Optimal care of families where individuals are at-high risk of inheriting a disease with high morbidity and mortality requires the full integration of both genetic research and clinical genetics programs. Although yet to be fully effected in our setting, our discussion highlights both the ethical necessity as well as some practical barriers in realizing this outcome. Genet Med 2009:11(12):859 -865.

“Awakening to” a new meaning of being at-risk for arrhythmogenic right ventricular cardiomyopathy: a grounded theory study

“…The function of the TMEM43 gene is not entirely understood; however, it is thought to be part of the adipogenic pathway regulated by PPARy. A dysregulation in this pathway leads to the replacement of the myocardium with fibro-fatty material on the ventricle wall that decreases the cardiac myocytes' ability to function properly, predisposing individuals to fatal ventricular arrhythmias (Hodgkinson et al 2009;Marcus et al 1982;Merner et al 2008). Management of ARVC includes the insertion of an implantable cardioverter defibrillator, pharmaceutical interventions, restricted physical activity (Gollob et al 2011) and, in severe cases, a heart transplant.…”

“…ARVC5 is a fully penetrant autosomal dominant heart disease in NL that results in a sudden cardiac death chiefly in young males (Hodgkinson et al 2009). The gene for ARVC is located on 3p25 and is the result of a missense mutation in TMEM43 p.S358L found in cardiac tissue (Merner et al 2008).…”

Long-Term Clinical Outcome of Arrhythmogenic Right Ventricular Cardiomyopathy in Individuals With a p.S358L Mutation in TMEM43 Following Implantable Cardioverter Defibrillator Therapy

“…From 1998 onward, all ICD treatment decisions for NL residents were made by one electrophysiologist (Dr Connors), and the majority of ICDs (72%) were provided between 2000 and 2009 following (1) cascade screening of relatives and (2) genetic results obtained initially using a research-generated disease-associated haplotype 24 and later direct mutation analysis. 7 The ICD was recommended immediately in mutation (or haplotype)-positive postpubertal males and following any abnormal cardiac clinical test in females (ventricular ectopy, poor R wave progression [PRWP], prolonged QRS, documented dilatation of the left or right ventricle, or reduced ejection fraction).…”

Returning Results: Let's Be Honest!

“…Although his death could have been prevented, he died at a very young age (Pullman and Hodgkinson, 2006). This study raises some important questions, not only about the ethical duty to return results within a research setting (Samuels et al, 2008;Hodgkinson et al, 2009) but also about participants' right to refuse results and researchers' responsibility to respect or override that choice. The researchers in Pullman's and Hodgkinson's study discussed the need for policies that do not offer the option of refusing disclosure of life-saving results.…”