Clinical Investigation
The Subclinical Cardiomyopathy of Friedreich's Ataxia in a Pediatric Population

https://doi.org/10.1016/j.cardfail.2017.09.012Get rights and content

Highlights

Abstract

Background

Identification of a subclinical cardiomyopathy in pediatric patients with Friedreich's ataxia (FA) has not been well-described.

Methods

We performed echocardiography (Echo), cardiac magnetic resonance imaging (cMRI), and neurologic assessment in a cross-sectional analysis of 48 genetically confirmed FA subjects aged 9–17 years with moderate neurologic impairment but without a cardiovascular history. Echo- and cMRI-determined left ventricular mass were indexed (LVMI) to height in grams/m2.7. LV remodeling was categorized as concentric remodeling (CR), concentric hypertrophy (CH), or eccentric hypertrophy based upon Echo- determined relative LV wall thickness.

Results

Echo LVMI exceeded age-based normal values in 85% of subjects, and cMRI-determined LVMI correlated with depression of both diastolic and systolic tissue Doppler velocity (E′: r = –0.65, P < .001, S′: r = –0.46, P < .001) as well as increased early diastolic Doppler flow velocity/tissue velocity ratio (r = 0.55, P < .001), a marker of elevated LV filling pressure. Similar associations were found with echo-determined LV mass. Evidence of depressed LV relaxation and increased LV stiffness were observed in 88% and 71%, of subjects, respectively, despite a normal LV ejection fraction in almost all cases (mean = 60% + 7%). CR and CH were present in 40% and 44% of the study group, respectively, although significant depressions of E′ and S′ were observed only in subjects with CH (P < .005).

Conclusions

A subclinical hypertrophic cardiomyopathy is common in pediatric FA patients and CH is associated with both diastolic and systolic dysfunction.

Section snippets

Study Population

The study population consisted of subjects with clinically and genetically confirmed FA presenting to the National Institutes of Health Clinical Center (Bethesda, Maryland) for participation in a randomized, double-blind, placebo-controlled, dose-ranging trial to assess the effects of the antioxidant, idebenone, on levels of oxidative stress markers and neurological function (NCT00229632). A prespecified cardiac substudy was approved within the main trial by the Institutional Review Board of

Results

The study population (Table 1) consisted of 48 subjects (23 females/25 males) with a mean age of 13 ± 2 years (range 9–17). The mean age at the time of diagnosis was 8 ± 3 years with a mean disease duration of 2 ± 2 years. Average neurological function was moderately depressed (mean FARS 51 ± 17) but ranged from mild to severe impairment (FARS 16–80). All subjects were in normal sinus rhythm at the time of the study and had a normal cardiac examination; none had clinical signs, symptoms, or a

Prevalence of Cardiomyopathic Features

There are few reliable data documenting prevalence of FA cardiomyopathy in an exclusively pediatric population because almost all prior reports include populations of mixed age. Older patients may, through survival selection, either represent a population with less severe disease28 or have experienced progressive LV systolic dysfunction, wall thinning, and LV dilatation over time.5, 29, 30, 31, 32 Thus, prevalence of cardiomyopathic signs in heterogenous age groups may also be confounded by

Conclusions

We document a high prevalence of LV remodeling and associated metrics of LV dysfunction in a homogeneous pediatric population with FA. These results require validation in larger FA populations, and future trials should incorporate serial assessment and clinical follow-up to evaluate the clinical value of these biomarkers as predictors of outcome and indicators for early intervention.

Disclosures

Dr. Plehn is currently employed by and owns stock in Covance, Inc, a commercial drug development company and a division of the Laboratory Corporation of America. Dr. Di Prospero is currently employed by and owns stock in Johnson and Johnson, LLC.

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    Funding: This work was entirely funded by intramural support from the National Institutes of Health with outsourcing of echocardiographic analysis to the Medstar Research Institute.

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