Letter by Peverill Regarding Article, “The Heart in Friedreich Ataxia: Definition of Cardiomyopathy, Disease Severity, and Correlation With Neurological Symptoms”

Abstract

In Friedreich ataxia (FA), cardiac disease is the major cause of premature mortality 1 and a common cause of symptoms, yet our understanding of the nature of the myocardial involvement in FA remains incomplete. Weidemann et al 2 are therefore to be congratulated for their report on comprehensive cardiac data acquired from a large cohort of FA subjects. The main aim of the study was the development of criteria for staging of the cardiomyopathy in FA; however, there are assumptions underlying the analysis that merit further consideration.One assumption of Weidemann et al is that an increase in left ventricular (LV) mass is the main cardiac feature in FA. 2 This then led to investigation of the univariate correlates of cardiac magnetic resonance-determined LV mass and the conclusion that echocardiographic interventricular septal thickness at end-diastole provides a reliable method to detect LV hypertrophy in FA. However, the reported correlation coefficient of 0.49 for interventricular septal thickness at end-diastole with LV mass indicates only a modest relationship for a predictive variable, and using only interventricular septal thickness at end-diastole to predict LV mass does not take into consideration a possible independent contribution of LV end-diastolic diameter, which had a similar correlation coefficient with LV mass on univariate analysis (rϭ0.46). Moreover, concomitant consideration of LV end-diastolic diameter may be of particular importance in FA, where increased wall thickness is commonly associated with decreased LV end-diastolic diameter. 3 Such a pattern of LV remodeling results in increased relative wall thickness, and thus an abnormal left ventricle, but LV mass can remain within the normal range. 3 Using interventricular septal thickness at end-diastole without also considering LV end-diastolic diameter has led to a potential anomaly in the staging system, where the mean relative wall thickness in the group, defined as having no cardiomyopathy, is at the upper limit of the normal range. This suggests that a proportion of this group who were classified as normal had increased relative wall thickness and may therefore have had FA myocardial involvement. 2 GAA repeat length on the shorter allele of the FXN gene (GAA1) is a predictor of age at symptom onset, has been a predictor of cardiac involvement in FA in a number of previous studies, 3,4 and is possibly of most importance is a predictor of earlier mortality. 1 It is therefore an important consideration that no relation of GAA1 with the proposed FA cardiomyopathy staging system was evident.Mortality can occur in childhood in FA, and the mean age of death is in the mid 30s, 1 indicating that age may also need to be a consideration in the classification of cardiomyopathy in FA subjects aged 8 to 70 years. It could be argued that subjects who died prematurely of a cardiac cause had severe cardiac disease, yet those subjects clearly could not be part of the analysis. Indeed, one interpretation of previous reports of an inverse relation between L...

Cardiovascular Research in Friedreich Ataxia

“…Any meaningful “staging” or predictive tools for outcome must include the young. Otherwise, cross-sectional studies are biased and not useful (see Peverill letter 137 ). Earlier diagnosis is certain to generate a better understanding of the natural history of the heart in this disease, as well as identifying fundamental mechanisms of Fe-S cluster assembly and regulation.…”

Clinical Insights Into Heritable Cardiomyopathies

“…The cardiac phenotype is manifested by arrhythmias and HCM. Heart failure remains the leading cause of death in this population ( Kipps et al, 2009 ; Peverill, 2012 ; Weidemann et al, 2012 ).…”

Genetics of Cardiomyopathy

“…The cardiac phenotype is manifested by arrhythmias and HCM. Heart failure remains the leading cause of death in this population [77,78]. HCM is seen in approximately two-thirds of patients with Friedreich's ataxia, and one-third of those cases develop during childhood [79].…”