Augusto, JB

Baig, S

Geberhiwot, T

Hodson, J

Hughes, DA

Kotecha, D

Kozor, R

Lewis, N

Moon, JC

Nordin, S

Price, AM

Steeds, RP

Vijapurapu, R

Wheeldon, N

English

UCL Discovery

iMAIL J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 3 , N O . 8 , 2 0 2 0A U G U S T 2 0 2 0 : 1 8 3 8 – 6 01850Longitudinal Assessment ofCardiac Involvement in Fabry DiseaseUsing Cardiovascular MagneticResonance ImagingFabry disease (FD) is an X-linked lysosomal storagedisorder resulting in accumulation of sphingolipids inthe heart, which leads to progressive left ventricularhypertrophy (LVH), fibrosis, and premature death (1).Although previous studies have tracked changes inmass using echocardiography (2), cardiovascularmagnetic resonance (CMR) is the gold standard forreproducible measurement of mass and offers insightinto the relationship between sphingolipid deposi-tion, LVH, and fibrosis in FD over time, using T1 andT2 mapping, as well as late gadolinium enhancement(LGE). (3) The aim of this study was to define LVchanges in FD over time and to consider use ofenzyme replacement therapy (ERT).This was a multicenter longitudinal study usingCMR in 100 patients with FD (gene positive; 44%men; mean age 44  14 years). Local clinical gover-nance and ethical approval was obtained (NRESLondon 14/LO/1948, UHB clinical governance:RRK6621). Participants underwent 1.5-T CMR(Avanto, Siemens Healthcare, Erlangen, Germany)using a standard protocol that quantified LV mass andtissue characterization with T1 [Modified Look-LockerInversion recovery sequence, 3(3)3(3)5 samplingscheme] and T2 mapping pre-contrast and inversionrecovery imaging for LGE post-contrast. T1 maps wereFIGURE 1 Change in Absolute LV Mass and Native T1 Over Time, Split by Sex and ERT StatusAbsolute LV Mass (g)Years from Baseline1001502002503000 2 4 6 8Female - No ERTFemale - ERTMale - No ERTMale - ERTANative T1 - Global Mid LV (ms)Years from Baseline8008509009501,0000 2 4 6 8Female - No ERTFemale - ERTMale - No ERTMale - ERTB(A) Change in left ventricular (LV) mass. Gradient per year: men: no enzyme replacement therapy (ERT) þ1.9% versus ERT þ2.5%; women: no ERT þ1.1% versusERT þ0.9%; p < 0.05. No significant differences comparing no ERT versus ERT. (B) Change in T1 time. Gradient per year: men: no ERT 7.6 ms vs. ERT 2.4 ms;women: no ERT 8.3 ms vs. ERT þ6.2 ms; p < 0.05. A significant difference was present comparing no ERT versus ERT in women only (p < 0.001).J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 3 , N O . 8 , 2 0 2 0 iMAILA U G U S T 2 0 2 0 : 1 8 3 8 – 6 01851analyzed using semi-automated segmentation at themid-LV cavity, with a 20:20 percentage offset and anaverage of all segments taken (following artefactualsegment exclusion), which gave global T1 mapping.LGE was quantified using a threshold of 6 SDs abovethe mean signal intensity of the referencemyocardium.The median duration of follow-up was 37 months(interquartile range [IQR]: 20 to 60 months), with amedian of 2 follow-up visits per patient (range 2 to 6).Fifty percent of patients were on ERT at baseline (37on agalsidase-alpha and 13 on agalsidase-beta). Atbaseline, men had higher indexed LV mass (LVMi)and maximum wall thickness (MWT) compared withwomen (median LVMi: 111.8 g/m2 [IQR: 85.4 to 149.2g/m2] vs. 62.7 g/m2 [IQR: 56.7 to 82.5 g/m2]; MWT:16 mm [IQR: 12 to 18 mm] vs. 10 mm [IQR: 9 to 12 mm];p < 0.001 for both). Thirty-one patients (33%) hadLGE at baseline (men: 49% vs. women: 21%;p ¼ 0.008), with a similar mass of LGE seen (men 8.5 g[IQR: 3.2 to 19.6 g] vs. women: 7.4 g [IQR: 1.4 to 15.2g]; p ¼ 0.359).There was an increase in absolute LVM over time(n ¼ 100), with a gradient of 2.4% (95% confidenceinterval [CI]: 1.8% to 3.1%) per year in men (p < 0.001)and 1.0% (95% CI: 0.3 to 1.7%) per year in women(p ¼ 0.005). Native T1 decreased over time in men(3.4 ms per year; 95% CI: 6.4 to 0.4; p ¼ 0.029),but no significant change was observed in women(p ¼ 0.831). Mass of LGE increased by 36.6% (95% CI:14.0% to 63.7%) per year in men (p < 0.001) and by12.0% (95% CI: 2.0% to 23.0%) per year in women(p ¼ 0.011). There were no changes in the proportionsof male and female patients with chronic kidneydisease, ischemic heart disease, or hypertension overthe study period.Five patients received ERT during follow-up andwere excluded from subgroup analysis by ERT status(Figure 1). ERT usage differed by sex, with 32 of 41(78%) men on ERT compared with 18 of 54 (33%)women (p < 0.001). The increase in LVM over timeremained significant despite the use of ERT in bothmen (ERT: 2.5% per year; 95% CI: 1.9% to 3.0%;p < 0.001; no ERT: 1.9% per year; 95% CI: 0.3% to3.6%; p ¼ 0.020) and women (ERT: 0.9% per year;95% CI: 0.1% to 1.8%; p ¼ 0.025; no ERT: 1.1% peryear; 95% CI: 0.3% to 1.9%; p ¼ 0.005). T1 decreasedover time in men not on ERT (7.6 ms per year; 95%CI: 12.6 to 2.5; p ¼ 0.003), although there was atendency to a smaller reduction on ERT (2.4 ms;95% CI: 4.6 to 0.1; p ¼ 0.039; between groups:p ¼ 0.064). However, in women, T1 decreased overtime in those not on ERT (8.3 ms per year; 95% CI:12.6 to 3.9; p < 0.001) but increased in the ERTgroup (þ6.2 ms per year; 95% CI: 2.0 to 10.4;p ¼ 0.004; between groups: p < 0.001).This longitudinal CMR study was consistent with asex-specific myocardial response in FD. Men hadmore advanced cardiac involvement at baseline andprogressed at a greater rate than women, despite useiMAIL J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 3 , N O . 8 , 2 0 2 0A U G U S T 2 0 2 0 : 1 8 3 8 – 6 01852of disease-modifying therapy. During this study,these changes were less clear in women, and theimpact of ERT was more pronounced. Although LVmass increased in women on ERT, T1 time increased,which could be consistent with either a sex-dependent response to therapy or a difference inmyocardial response to storage. Limitations includedthe small sample size and lack of established prog-nostic T1 data, which made the relevance andimportance of this parameter in disease progressionunclear.Ravi Vijapurapu, MBChBShanat Baig, MBBSSabrina Nordin, MBBSJoão B. Augusto, MDAnna M. Price, MBChBNigel Wheeldon, MDNigel Lewis, PhDRebecca Kozor, PhDDipak Kotecha, PhDJames Hodson, BScDerralynn A. Hughes, PhDJames C. Moon, MDTarekegn Geberhiwot, MDRichard P. Steeds, MD**Department of CardiologyMindlesohn WayQueen Elizabeth HospitalEdgbastonBirmingham B15 2THUnited KingdomE-mail: rick.steeds@uhb.nhs.ukhttps://doi.org/10.1016/j.jcmg.2020.03.004© 2020 The Authors. Published by Elsevier on behalf of the American College ofCardiology Foundation. This is an open access article under the CC BY license(http://creativecommons.org/licenses/by/4.0/Please note: Facilities used in this study were supported by a block grant fromthe British Heart Foundation to the Institute of Cardiovascular Sciences, Uni-versity of Birmingham. The Fabry400 study was funded by a grant fromSanofi-Genzyme. Dr. Vijapurapu has received a travel grant from Amicus; andhas received honoraria from Takeda. Dr. Nordin has received speaker fees fromShire. Dr. Kozor has received honoraria from Sanofi. Dr. Kotecha has received aresearch grant from Menarini; has received advisory board and speaker feesfrom Bayer and Atricure; and has performed collaborative research withServier, Bayer, Novartis, AstraZeneca, and GlaxoSmithKline. Dr. Hughes hasbeen a consultant and has received honoraria from Takeda, Sanofi, andAmicus. Dr. Geberhiwot has been a consultant and has received an unre-stricted research grant from Sanofi-Genzyme and Takeda. Dr. Steeds has beena consultant for Freeline Therapeutics; has received research grants fromSanofi-Genzyme and Takeda; and lecture fees from Amicus. All other authorshave reported that they have no relationships relevant to the contents of thispaper to disclose.The authors attest they are in compliance with human studies committees andanimal welfare regulations of the authors’ institutions and Food and DrugAdministration guidelines, including patient consent where appropriate. Formore information, visit the JACC: Cardiovascular Imaging author instructionspage.RE F E RENCE S1. Baig S, Vijapurapu R, Alharbi F, et al. Diagnosis and treatment of the car-diovascular consequences of Fabry disease. QJM 2019;112:3–9.2. Kampmann C, Linhart A, Baehner F, et al. Onset and progression of theAnderson-Fabry disease related cardiomyopathy. Int J Cardiol 2008;130:367–73.3. Nordin S, Kozor R, Medina-Menacho K, et al. Proposed stages of myocardialphenotype development in Fabry disease. J Am Coll Cardiol Img 2019;12:1673–83.

Longitudinal Assessment of Cardiac Involvement in Fabry Disease Using Cardiovascular Magnetic Resonance Imaging

https://discovery.ucl.ac.uk/10106867/7/Bicho%20Augusto_1-s2.0-S1936878X20302448-main_extracted.pdf

Longitudinal Assessment of Cardiac Involvement in Fabry Disease Using Cardiovascular Magnetic Resonance Imaging

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