Left ventricular structural and functional changes in Friedreich ataxia – Relationship with body size, sex, age and genetic severity

Abstract

IntroductionAlthough a concentric pattern of left ventricular (LV) geometry appears to be common in Friedreich ataxia (FRDA), there is no accepted method for diagnosing LV abnormalities in FRDA, sex and body size have often not been taken into consideration, and it has not been clear whether children and adults should be classified using the same criteria. The aim of this study was to better define the LV geometric changes in FRDA with respect to sex, body size and subject age, and to investigate the relationship of LV changes with genetic severity, as assessed by GAA repeat length within the shorter allele of the FXN gene (GAA1).MethodsEchocardiography was performed in 216 subjects (68 children, 148 adults), measurements were made at end-diastole of LV internal diameter (LVEDID), septal wall thickness (SWT), LV length (LVEDL) and LV volume (LVEDV), and calculations were made of relative wall thickness (RWT), LV mass and LV ejection fraction (LVEF).ResultsThe most common LV abnormalities in both adults and children with FRDA were increases in RWT and age-normalized RWT. In adults with a normal LVEF, all LV variables other than RWT were larger in males independent of body surface area (BSA), and all LV variables other than SWT and RWT were positively correlated with BSA. After adjustment for sex and BSA, GAA1 was a positive correlate of SWT and RWT (but not of LV mass), and was an inverse correlate of LVEDID, LVEDL and LVEDV. In children with a normal LVEF, SWT, LV mass and LVEDL were larger in males than females after adjusting for BSA, and in combination with sex, BSA was a positive correlate of all the LV variables except SWT and RWT. In children there were no correlations of GAA1 with any of the LV variables.ConclusionIn FRDA, increases in RWT and age-normalized RWT are the most frequent LV structural abnormalities, sex and body size are important determinants of most other LV structural variables in both children and adults, and increased genetic severity is associated with a smaller left ventricle and increased LV wall thickness in adults, but not associated with LV size or wall thickness in children.

Targeted next-generation sequencing for genetic variants of left ventricular mass status among community-based adults in Taiwan

“…This finding seems in line with a previous study describing the FXN gene, which was associated with structural and functional left ventricular changes ( Peverill et al, 2019 ). For example, an increased FXN severity was associated with a smaller left ventricle and increased left ventricle wall thickness in adults but was not associated with left ventricle size or wall thickness in children ( Peverill et al, 2019 ). However, the CASQ2 , COL5A1 , and FXN genes have been reported separately and have not been linked together.…”

Myocardial and Arrhythmic Spectrum of Neuromuscular Disorders in Children

“…In other words, in children with major triplet repeats an initiallack of genotype phenotype correlation might be seen. However, with progressive age this correlation does emerge (i.e., more severe phenotype with more triplet repeats) [ 18 ].…”

Cardiovascular Research in Friedreich Ataxia

“…Using standard of care protocols, echocardiography has identified preliminary markers that are associated with poor outcomes in retrospective studies (see Table 2 ). 16 , 22 , 26 , 39 , 45 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 In a recent study examining longitudinal strain of the LV in 140 adults with FRDA (median age 34 years), 14 subjects died over 7.4 years (10% mortality rate). 49 By univariate analysis, multiple factors were associated with death including longitudinal strain, age of onset, left ventricular ejection fraction (LVEF), GAA repeat length, and LV mass.…”

“…FRDA CMR showed extracellular volume increased and cardiomyocyte size was larger than that of control subjects. Peverill, et al 54 2019 CS 216 11-46 68 children and 148 adults with FRDA. Increased LV wall thickness and smaller LV cavity associated with increased genetic severity in adults, but not in children.…”

“… 71 Relative wall thickness and longitudinal strain have also been defined in FRDA and may be useful in future studies of outcome in FRDA, but, as noted, do not predict outcome in multivariate analysis. 49 , 54 Other approaches, such as LVM indexed to either body surface area or height (eg, m 2.7 ), 72 have been predictive of outcome in hypertensive cardiomyopathy, but again these metrics have not been consistently applied or explored in FRDA. Based on data from Pousset et al, 45 LVMI may be a predictive metric in FRDA and normative values for LVMI are available for both adults and children.…”