Family trees could predict risk of death in inherited arrhythmias

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Eline Nannenberg, Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands, and colleagues have found that the Family Tree Mortality Ratio (FTMR) method can identify the age ranges that carry the greatest risk of death from an inherited arrhythmia syndrome.

In their study, published in Circulation: Cardiovascular Genetics, Nannenberg et al reported that a number of “pressing questions” remain unanswered about the risk of sudden cardiac death in patients with inherited arrhythmias. They wrote: “Should all asymptomatic carriers of a disease-causing mutation be treated? If so, at which age should treatment be started and from what age onward can treatment be safely withheld in asymptomatic patients? What are the optimal genetic and cardiologic screening strategies?”


Using the FTMR method, they developed large family trees of families with six different mutations: long QT syndrome (LQTS) 1, LQTS 2, LQTS 3, SCN5A-overlap syndrome (LQTS3, Brugada syndrome/conduction disease), RYR2 gene-related catecholaminergic polymorhphic ventricular tachycardia (CPVT), and the Brugada syndrome. Nannenberg et al said: “This method allows us to study the mortality in times when the disease was not known and therapy was not available, and thus provide information on the natural course of the disease.”


The overall standardised mortality ratio (SMR) in the LQTS 1 family tree was 1.5 and there was significant, severe excess mortality in the one to 19 years old age range category (SMR 3; 95% confidence interval 1.7–5). However when Nannenberg et al examined smaller age ranges in this family tree, they found that only the age range one to nine years was associated with significant excess mortality (SMR 2.9; 95% CI 1.5–5.1). In the 10–19 years age range, the SMR was high (SMR 3.4; 95% CI 0.7–9.9) but not to a significant extent. The investigators also identified significant excess mortality in specific age ranges in the other inherited arrhythmias examined.


For example, in the SCN5A-overlap syndrome family tree, severe excess mortality was seen after the age of 10 (SMR 9.8 in 10–14 category; 95% CI 4.2–19.2) and peaked between 20 and 39 years (SMR 3.8; 95% CI 2.5–5.7) with no excess mortality observed in people older than 60 years.


Nannenberg et al wrote that their data might help to guide treatment and genetic and cardiological screening strategies in families with an inherited arrhythmia syndrome. They added: “Our best example, because of its large size [10,510 person-years], is the family with the SCN5A-overlap syndrome. Based on the increased overall SMR and the mortality per age category, cardiological and genetic screening of the first degree family members of SCN5Aa-overlap syndrome mutation carriers is justified from the age of five years until the age of 60.”


They added implantation of a pacemaker or an implantable cardioverter defibrillator in patients who are found to have this syndrome can be “postponed well after the age of five years and is not needed after the age of 60 in asymptomatic patients not treated before.”


Nannenberg told Cardiac Rhythm News: “We need to be careful about drawing conclusions for families with arrhythmias caused by different mutations, more research is needed to see if mutations can be grouped based on their pathophysiological mechanism before our results can be generalised to other families.”

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