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

Abstract

Aims: Cardiomyopathy produces significant mortality in patients with Friedreich ataxia (FA), a genetic disorder that produces 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 performed. 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/m², respectively, indicating preserved systolic function and absence of significant hypertrophy. Myocardial 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 = 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 = 0.64, P < 0.001). Peripheral platelet iron measurement showed no distinction between patients and controls (5.4 ± 8.5 × 10⁻⁷ vs. 5.5 ± 2.9 × 10⁻⁷ ng/platelet, P = 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.

Figure 1

Southern blot analysis shows no GAA expansion in a normal control (lane 1), 160 and 500 repeats in an affected control (lane 2), and ∼733 and 1200 repeats in Friedreich ataxia patient 28 (lane 3).

Figure 2

Size of the GAA expansion on the smaller allele (minGAA) vs. relative wall thickness (RWT) in patients shows increased concentric remodelling with increased pathologic GAA expansion (r = 0.64, P < 0.001).

Figure 3

Cardiac magnetic resonance end-diastolic images of the left ventricle (LV) in cross-section (A and D), stress perfusion (B and E), and rest perfusion (C and F) are shown from two 33-year-old patients with Friedreich ataxia. The first (A–C) has concentric remodelling (RWT 0.46) and impaired myocardial perfusion reserve (B, arrows; MPRI 0.7) compared with the second (D–F) who has normal RWT (0.38) and normal perfusion reserve (MPRI 1.1). RWT, relative wall thickness; MPRI, myocardial perfusion reserve index.

Figure 4

Late gadolinium enhancement images demonstrate mid-myocardial fibrosis at the inferior RV–LV junction in one Friedreich ataxia patient (left, arrow) compared with the similar acquisition in a late gadolinium enhancement-negative Friedreich ataxia patient (right).

Figure 5

Linear regression of endocardial to epicardial myocardial perfusion reserve index (MPRI) vs. number of metabolic syndrome factors (0 through 5) demonstrates worse perfusion reserve with increased number of met-S risk factors.

Figure 6

Frataxin deficiency affects insulin production as well as skeletal lipogenesis, both potentially contributing to metabolic syndrome that may itself affect capillary density. In conjunction with a possible direct effect on endothelial cells (EC), these effects may act synergistically to limit myocardial perfusion reserve.