Differences in the determinants of right ventricular and regional left ventricular long-axis dysfunction in Friedreich ataxia

Abstract

BackgroundFriedreich ataxia (FRDA) is an autosomal recessive neurodegenerative condition which also has effects on the heart. In 96% of affected individuals FRDA is due to homozygosity of a GAA repeat expansion in intron 1 of the frataxin (FXN) gene. The number of GAA repeats have been shown to relate to disease severity in FRDA, this thought to be via an inverse relationship of GAA repeat number and cellular frataxin levels. We investigated the effects of FRDA on regional long axis function of the left and right ventricles, and also the relationship of long axis systolic (s`) and early diastolic (e`) peak velocities with GAA repeat number on the shorter (GAA1) and longer FXN alleles (GAA2).MethodsThe study group of 78 adult subjects (age 32±9 years) with FRDA and normal left ventricular (LV) ejection fraction were compared to 54 healthy control subjects of similar age, sex and body size. Tissue Doppler imaging (TDI) signals were recorded at the mitral annulus for measurement of s`and e`of the septal, lateral, anterior and inferior walls and at the tricuspid annulus for measurement of right ventricular (RV) s`and e`.ResultsAll the regional LV s`and e`, and both RV s`and RV e`, were lower in individuals with FRDA compared to controls (p<0.001 for all). On multivariate analysis, which included LV septal wall thickness (SWT), RV s`and RV e`were both inversely correlated with GAA1 (β = -0.32 & -0.33, respectively, p = 0.01), but not with GAA2, whereas anterior and lateral s`were both inversely correlated with GAA2 (β = -0.25 and β = -0.28, p = 0.02) but not with GAA1. Increasing SWT was the most consistent LV structural correlate of lower s`and e`, whereas age was a consistent inverse correlate of e`but not of s`.ConclusionThere are generalized abnormalities of both LV regional and RV long axis function in FRDA, but there are also regional differences in the association of this dysfunction with the smaller and larger GAA repeats in the FXN gene.

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

“…Comparison of LV echocardiographic findings in adult subjects with FRDA with age and sex-matched control subjects has been reported previously in subgroups of the current cohort who were part of studies which investigated LV and right ventricular long-axis function [7, 11]. Findings from these studies in the subjects with FRDA included increases in LV wall thickness, LV mass index and RWT, and a decrease in LVEDID compared to control subjects.…”

“…Cardiac disease is a frequent accompaniment of FRDA and not only can lead to arrhythmias and cardiac failure, but has been reported to be the most common cause of death [2, 3]. LV structural changes in FRDA have been documented in a number of studies, with increase in LV wall thickness and reduction in LV chamber size being commonly reported abnormalities [4–11]. It is also well recognized that some subjects with FRDA develop a reduced LV ejection fraction and increased LV size, and there is some evidence to suggest that this follows a progression from an earlier stage in which there was increased wall thickness [12].…”

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.…”

Myocardial ischaemia reperfusion injury and cardioprotection in the presence of sensory neuropathy: Therapeutic options

“…FRDA caused by an autosomal recessive mutation, which leads to a GAA repeat expansion in intron 1 in the gene of the mitochondrial protein frataxin (Durr et al, 1996). FRDA also involves cardiac disturbances such as increased LV wall thickness, reduced chamber size and finally hypertrophic cardiomyopathy leading to heart failure with preserved ejection fraction (HFpEF; Peverill, Donelan, Corben, & Delatycki, 2018). Impaired myocardial perfusion in an FRDA patient was described to be the result of microvascular abnormality without epicardial coronary artery disease (Raman, Dickerson, & Al-Dahhak, 2008).…”