Cardiac Fabry Disease With Late Gadolinium Enhancement Is a Chronic Inflammatory Cardiomyopathy

Nordin, Sabrina; Kozor, Rebecca; Bulluck, Heerajnarain; Castelletti, Silvia; Rosmini, Stefania; Abdel‐Gadir, Amna; Baig, Shanat; Mehta, Atul; Hughes, D.A.; Moon, James

doi:10.1016/j.jacc.2016.07.741

Cited by 91 publications

(65 citation statements)

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“…Conversely, the importance of CMR in detecting myocardial inflammation in FDCM has been raised recently 23. Our report correlating CMR findings with histology and immunological profile confirms this observation, particularly for patients with MWT >15 mm, and adds a new topic for recently published guidelines on hypertrophic cardiomyopathy 24…”

Section: Discussionsupporting

confidence: 82%

Immune‐Mediated Myocarditis in Fabry Disease Cardiomyopathy

Frustaci

Verardo

Grande

et al. 2018

JAHA

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BackgroundGlycosphingolipid accumulation in Fabry cells generates a proinflammatory response that may influence disease evolution and responsiveness to enzyme replacement therapy. This study evaluated incidence, mechanism, and impact of myocarditis in Fabry disease cardiomyopathy (FDCM).Methods and ResultsMyocarditis, defined as CD3+ T lymphocytes >7/mm2 associated with necrosis of glycolipid‐laden myocardiocytes, was retrospectively evaluated in endomyocardial biopsies from 78 patients with FDCM: 13 with maximal wall thickness (MWT) <11 mm (group 1), 17 with MWT 11 to 15 mm (group 2), 30 with MWT 16 to 20 mm (group 3), and 18 with MWT >20 mm (group 4). Myocarditis was investigated by polymerase chain reaction for cardiotropic viruses, by serum antiheart and antimyosin antibodies, and by cardiac magnetic resonance. Myocarditis was recognized at histology in 48 of 78 patients with FDCM (38% of group 1, 41% of group 2, 66% of group 3, and 72% of group 4). Myocarditis was characterized by positive antiheart and antimyosin antibodies and negative polymerase chain reaction for viral genomes. CD3+ cells/mm2 correlated with myocyte necrosis, antimyosin autoantibody titer, and MWT (P<0.001,r=0.79; P<0.001, r=0.84; P<0.001, r=0.61, respectively). Cardiac magnetic resonance showed myocardial edema in 24 of 78 patients (31%): 0% of group 1, 23% of group 2, 37% of group 3, and 50% of group 4.ConclusionsMyocarditis is detectable at histology in up to 56% of patients with FDCM. It is immune mediated and correlates with disease severity. It can be disclosed by antiheart/antimyosin autoantibodies and in the advanced phase by cardiac magnetic resonance. It may contribute to progression of FDCM and resistance to enzyme replacement therapy.

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Section: Discussionsupporting

confidence: 82%

Immune‐Mediated Myocarditis in Fabry Disease Cardiomyopathy

Frustaci

Verardo

Grande

et al. 2018

JAHA

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“…Recent data suggest that in this area, in contrast to LGE from other origin, there is an increased native T1 and T2 even in the absence of wall thinning, with the T2 elevation corresponding to elevated levels of blood troponin. This suggests that the lesions on LGE may reflect chronic, active inflammation [119]. This important finding may be a critical link of underlying mutation to a final fibrotic phenotype and may point to a pathway common to other non-ischemic LGE findings and disease development.…”

Section: Clinical Applications: Current Statementioning

confidence: 99%

Clinical recommendations for cardiovascular magnetic resonance mapping of T1, T2, T2* and extracellular volume: A consensus statement by the Society for Cardiovascular Magnetic Resonance (SCMR) endorsed by the European Association for Cardiovascular Imaging (EACVI)

Messroghli

Moon

Ferreira

et al. 2016

Journal of Cardiovascular Magnetic Resonance

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Parametric mapping techniques provide a non-invasive tool for quantifying tissue alterations in myocardial disease in those eligible for cardiovascular magnetic resonance (CMR). Parametric mapping with CMR now permits the routine spatial visualization and quantification of changes in myocardial composition based on changes in T1, T2, and T2*(star) relaxation times and extracellular volume (ECV). These changes include specific disease pathways related to mainly intracellular disturbances of the cardiomyocyte (e.g., iron overload, or glycosphingolipid accumulation in Anderson-Fabry disease); extracellular disturbances in the myocardial interstitium (e.g., myocardial fibrosis or cardiac amyloidosis from accumulation of collagen or amyloid proteins, respectively); or both (myocardial edema with increased intracellular and/or extracellular water). Parametric mapping promises improvements in patient care through advances in quantitative diagnostics, inter- and intra-patient comparability, and relatedly improvements in treatment. There is a multitude of technical approaches and potential applications. This document provides a summary of the existing evidence for the clinical value of parametric mapping in the heart as of mid 2017, and gives recommendations for practical use in different clinical scenarios for scientists, clinicians, and CMR manufacturers.

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“…Native T1 is low in FD, representing sphingolipid accumulation21 22 in 85% of FD with LVH, and in up to 59% of LVH-negative patients, suggesting storage occurs early before the establishment of hypertrophy 21 23. When LGE is present without thinning, this has been shown to be associated with T2 elevation and hs-TnT release suggesting an inflammatory process 19. Thus, the order and processes of phenotype development are being pieced together.…”

Section: Discussionmentioning

confidence: 99%

Global longitudinal strain, myocardial storage and hypertrophy in Fabry disease

Vijapurapu

Nordin

Baig

et al. 2018

Heart

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IntroductionDetecting early cardiac involvement in Fabry disease (FD) is important because therapy may alter disease progression. Cardiovascular magnetic resonance (CMR) can detect T1 lowering, representing myocardial sphingolipid storage. In many diseases, early mechanical dysfunction may be detected by abnormal global longitudinal strain (GLS). We explored the relationship of early mechanical dysfunction and sphingolipid deposition in FD.MethodsAn observational study of 221 FD and 77 healthy volunteers (HVs) who underwent CMR (LV volumes, mass, native T1, GLS, late gadolinium enhancement), ECG and blood biomarkers, as part of the prospective multicentre Fabry400 study.ResultsAll FD had normal LV ejection fraction (EF 73%±8%). Mean indexed LV mass (LVMi) was 89±39 g/m2 in FD and 55.6±10 g/m2 in HV. 102 (46%) FD participants had left ventricular hypertrophy (LVH). There was a negative correlation between GLS and native T1 in FD patients (r=−0.515, p<0.001). In FD patients without LVH (early disease), as native T1 reduced there was impairment in GLS (r=−0.285, p<0.002). In the total FD cohort, ECG abnormalities were associated with a significant impairment in GLS compared with those without ECG abnormalities (abnormal: −16.7±3.5 vs normal: −20.2±2.4, p<0.001).ConclusionsGLS in FD correlates with an increase in LVMi, storage and the presence of ECG abnormalities. In LVH-negative FD (early disease), impairment in GLS is associated with a reduction in native T1, suggesting that mechanical dysfunction occurs before evidence of sphingolipid deposition (low T1).Trial registration number NCT03199001; Results.

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Cardiac Fabry Disease With Late Gadolinium Enhancement Is a Chronic Inflammatory Cardiomyopathy

Cited by 91 publications

References 5 publications

Immune‐Mediated Myocarditis in Fabry Disease Cardiomyopathy

Immune‐Mediated Myocarditis in Fabry Disease Cardiomyopathy

Clinical recommendations for cardiovascular magnetic resonance mapping of T1, T2, T2* and extracellular volume: A consensus statement by the Society for Cardiovascular Magnetic Resonance (SCMR) endorsed by the European Association for Cardiovascular Imaging (EACVI)

Global longitudinal strain, myocardial storage and hypertrophy in Fabry disease

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