Cardiac magnetic resonance imaging and spectroscopy in patients with long-chain fatty acid β-oxidation deficiency

Adrianus J. Bakermans PhD1*, Suzan J.G. Knottnerus MD2, Jeannette C. Bleeker MD2,3, Aart J. Nederveen PhD1, Riekelt H. Houtkooper PhD2, Sacha Ferdinandusse PhD2, Mirjam Langeveld MD PhD4, Gustav J. Strijkers PhD5, Frits A. Wijburg MD PhD6, Ronald J.A. Wanders PhD2, S. Matthijs Boekholdt MD PhD7, and Gepke Visser MD PhD3.

1Radiology and Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 3Metabolic Diseases, Wilhelmina Children’s Hospital, UMC Utrecht, Utrecht, The Netherlands;

4Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 5Biomedical Engineering and Physics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 6Pediatrics, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 7Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

*E: a.j.bakermans@amc.uva.nl – T: 0031 20 566 47 91

  1. Cardiomyopathy can be a severe complication in patients with inborn errors of long-chain fatty acid β-oxidation (lcFAO), particularly during episodes of metabolic derangement. It has not been established yet whether functional or structural myocardial abnormalities, if any, are present from birth or develop later in life. Studies of mouse models of lcFAO deficiency [1, 2] and autopsies of patients [3] suggest that myocardial lipid accumulation and diffuse fibrosis contribute to the etiology of cardiomyopathy. In this observational case-control study, we used magnetic resonance imaging (MRI) and spectroscopy (MRS) to characterize the heart of adult patients with lcFAO deficiency.Thirteen lcFAO-deficient patients (1 female LCHADD; 4 male CPT2D; 8 VLCADD, 2 females/6 males) and thirteen age-, gender-, and BMI-matched control subjects were examined using a 3 Tesla MR system. The protocol included cinematographic MRI for the quantification of left-ventricular (LV) volumes and myocardial mass, MR tagging to assess LV torsion and strain, T1 relaxometry for the assessment of diffuse myocardial fibrosis, and proton MRS for the quantification of myocardial lipid content.LV torsion was higher in lcFAO patients compared to matched controls, whereas circumferential strain was not different. In CPT2D and VLCADD patients, LV mass was 19% higher compared to matched controls. In one female VLCADD patient, this was accompanied by a low LV ejection fraction (41%) and an elevation of the myocardial T1 relaxation time constant, indicative of diffuse fibrosis. In other patients, LV ejection fraction and other LV volumetric parameters were essentially similar to those in control subjects. Myocardial lipid content was similar in patients and controls.We found no in vivo evidence of overt lipid accumulation in the hearts of adult lcFAO-deficient patients in this cross-sectional study. The higher LV torsion observed in lcFAO patients suggests a subtle imbalance between subendocardial and subepicardial cardiomyocyte contractile function, which has also been reported to occur in normal aging [4]. Mild LV hypertrophy was present in the CPT2D and VLCADD patients. Cardiac MRI and MRS during metabolic derangement may shed light on the role of lipid accumulation and diffuse fibrosis in the development of cardiomyopathy in lcFAO-deficient patients.[1] Kurtz DM, et al. Proc Natl Acad Sci U S A 1998;95:15592-7[2] Bakermans AJ, et al. Circ Cardiovasc Imaging 2011;4:558-65[3] Bleeker JC, et al. Pediatr Dev Pathol 2017;20:269-76 [4] Hollingsworth KG, et al. Am J Physiol Heart Circ Physiol 2012;302:H885-92