Characterizing Friedreich’s Ataxia Cardiomyopathy with Serial Cardiac MRIs

Background: Friedreich’s ataxia (FA) is a hereditary neuromuscular disorder in which cardiac involvement is the leading cause of death. However, the natural history of FA-associated cardiomyopathy (FAC) is poorly understood. This study aims to characterize the temporal evolution of cardiac MRI (CMR) manifestations of FAC and correlate them with clinical status.

Methods: This is a retrospective single-center study of patients with FA. Records of all subjects with FA with at least one CMR were reviewed. CMR data included left ventricle (LV) ejection fraction (EF), segmental late gadolinium enhancement (LGE), and LV wall thickness. Linear mixed-effects models were used to assess association of LGE status and time from symptom onset with CMR findings.

Results: Fifteen patients (mean age 22.7 years, SD 7.6) and 37 CMRs were evaluated with an average span of 12.4 years from symptom onset to the most recent CMR. There were no deaths at the time of data collection. Six (40%) patients had qualitative evidence of LGE on CMR, most notable in the inferolateral and anterolateral segments of the LV base, mid-portion, and apex. Subjects who were LGE negative remained so over the observation period. Those with LGE were on average older at the time of CMR than those without LGE (24.7 versus 21.3 years). There was an increase in LGE by an average of 0.5 segments per year (-0.9 to 1.4, ICC 0.88). There was no association between presence of LGE and use of a wheelchair (OR 1.4, p >0.99), bulbar dysfunction (OR 4.0, p=0.31), or cardiac symptoms (OR 1.3, p >0.99). All patients with LGE had neuropathy. Two (13%) subjects had no symptoms of neuropathy; they did not have LGE but did have evidence of LV hypertrophy. In a mixed model analysis, presence of LGE and time from symptom onset showed some evidence of association with a decline in LVEF (βLGE= -4.88 (-20.11, 11.7), βtime from symptoms= -0.76 (-1.71, 0.35), βinteraction= 0.06 (-1.24, 1.37)).

Qualitative LV thickness was most notable in the anteroseptal and inferoseptal segments of the LV base, mid-portion, and apex. Maximum LV thickness did not correlate with time from symptom onset or presence of LGE. However, there was a slight positive trend in maximum LV thickness for those without LGE and a slight negative trend for those with LGE (βLGE= 4.4 (-0.69, 9.57), βtime from symptoms= 0.17 (-0.18, 0.51), βinteraction= -0.38 (-0.84, 0.06)).

When comparing the use of CMR to echocardiography, there was a strong linear correlation with regards to LVEF (R= 0.56, p=0.013). However, LVEF on CMR was on average 3.6% lower compared to echocardiography done at a similar timepoint (±1.96 SD= -18, 10.8).

Conclusion: CMR can serve as a valuable tool in FA for detecting early and serial changes in LGE, LVEF, and wall thickness. LGE is not universal in these patients and may be associated with a decline in LVEF. Association of CMR biomarkers with prognosis, therapeutic candidacy, and outcomes should be explored with larger, multi-center studies.

Mean left ventricle (LV) thickness (A) and late gadolinium enhancement (LGE) presence (B) by myocardial segments.

Observed (top) and model predicted (bottom) left ventricle ejection fraction (LVEF) over time and by presence of late gadolinium enhancement (LGE). The presence of LGE and time from symptom onset showed some evidence of association with a decline in LVEF (βLGE= -4.88 (-20.11, 11.7), βtime from symptoms= -0.76 (-1.71, 0.35), βinteraction= 0.06 (-1.24, 1.37), ICC 0.48, Marginal R2 0.32, Conditional R2 0.65).

Observed (top) and model predicted (bottom) progression of maximum left ventricle (LV) thickness over time by presence of late gadolinium enhancement (LGE). Progression of LV thickness was variable and not related to time from symptom onset or the presence of LGE. However, a slight positive trend in maximum LV thickness for those without LGE (gray) and a slight negative trend for those with LGE (black) was noted (βLGE= 4.4 (-0.69, 9.57), βtime from symptoms= 0.17 (-0.18, 0.51), βinteraction= -0.38 (-0.84, 0.06), ICC 0.39, marginal R2 0.11, conditional R2 0.46).