Impaired myocardial perfusion reserve and fibrosis in Friedreich ataxia: a mitochondrial cardiomyopathy with metabolic syndrome

Cardiomyopathy produces significant mortality in patients with Friedreich ataxia (FA), a genetic disorder that pro- duces intra-mitochondrial iron accumulation. We sought to test the hypothesis that abnormal myocardial perfusion reserve and fibrosis represent early manifestations of cardiomyopathy. Methods and results Twenty-six patients with genetically proven FA ages 36+ 12 years without cardiomyopathy and eight controls underwent cardiac magnetic resonance with adenosine. Precontrast imaging for myocardial iron estimation was per- formed. Myocardial perfusion reserve index (MPRI) was quantified using the normalized upslope of myocardial enhancement during vasodilator stress vs. rest. Left ventricular (LV) mass and volumes were computed from short-axis cine images. Serologies included lipids, and platelets were isolated for iron quantification using inductively coupled plasma mass spectrometry. Left ventricular ejection fraction and mass averaged 64.1+ 8.3% and 62.7+ 16.7 g/m 2 , respectively, indicating preserved systolic function and absence of significant hypertrophy. Myocar- dial perfusion reserve index quantification revealed significantly lower endocardial-to-epicardial perfusion reserve in patients vs. controls (0.80+ 0.18 vs. 1.22+ 0.36, P ¼ 0.01). Lower MPRI was predicted by increased number of metabolic syndrome (met-S) features (P , 0.01). Worse concentric remodelling occurred with increased GAA repeat length (r ¼ 0.64, P , 0.001). Peripheral platelet iron measurement showed no distinction between patients and controls (5.4+ 8.5 × 10 27 vs. 5.5+ 2.9 × 10 27 ng/platelet, P ¼ 0.88), nor did myocardial T2* measures. Conclusions Patients with FA have abnormal myocardial perfusion reserve that parallels met-S severity. Impaired perfusion reserve and fibrosis occur in the absence of significant hypertrophy and prior to clinical heart failure, providing potential therapeutic targets for stage B cardiomyopathy in FA and related myocardial diseases.