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Table 2 Cardiac signs: guideline stipulations and PREDICT-FD consensus [11]

From: Do clinical guidelines facilitate or impede drivers of treatment in Fabry disease?

 

Early indicators of histological damage (heart biopsy)

Markers of early systolic/diastolic dysfunction

Elevated serum cardiac troponin

Early indicators of LVH

Late Gd+ on cMRI

Elevated serum NT-proBNP

Reduced myocardial T1 relaxation time on cMRI

Abnormal ECG

Abnormal echocardiogram

Abnormal wall motion on echocardiogram

Symptomatic cardiac disease

PREDICT-FDa [11]

 + (NR)

 + 

 + 

 + 

 + 

 + 

 + 

 + 

 + 

 + 

–

EFWGb [1]

–

–

–

Wall thickness > 12 mm with minimal/no fibrosis

All, I

–

–

–

Rhythm disturbances

All, I

–

–

–

Australia [24]

All

Allc

–

Alld

Alld

–

Allc

Allc

Alld

–

–

Canadae [21]

Confirmatory diagnosis

Grade 2 or 3 diastolic dysfunctionf

 > 2 × ULN

Wall thickness:

M, > 12 mm

F, > 11 mm

LVH Romhilt–Estes score > 5g

Left ventricular wall

 > ULN

1.5 T magnet

M, < 901 ms

F, 916 ms

Conduction/rhythm abnormalh

Diastolic filling abnormal

Left atrium > 34 mL/m2

Moderate-to-severe mitral or aortic insufficiency

Abnormal longitudinal strain gradient left ventricle

 

–

Catalonia (Spain)

–

Alli

–

Alli,j

Allk

–

Allj

Allj

Alli

Alli

–

Francel [23, 25]

Fm

–

–

–

–

Fm

–

Fm

Fm

–

–

Portugal [22]

–

 

–

LVH in adults

Cardiomyopathy in children

Myocardial fibrosis

–

–

All, arrhythmia

Adults, conduction disturbance

–

–

Dyspnea, palpitations, syncope, thoracic pain

Slovenia (FCGHSG)

Confirmatory biopsy if needed in cF and in late-onset adultsn

Diastolic dysfunction

–

Hypertrophic cardiomyopathy

Signs of fibrosis

–

–

 

Signs of fibrosis by speckle tracing

  

Switzerlando

Fp

Fq

–

Fq

–

–

Fq

Fq

–

–

–

UKr [26]

–

–

–

Wall thickness:

M, > 13 mm

F, > 12 mm

All

–

–

–

Alls

–

–

  1. Unpublished guidelines are summarized in Additional file 1: Table S1
  2. aConsensus was reached that FD-specific treatment should be initiated at diagnosis in male patients aged 16 years or older who are asymptomatic for organ involvement, in boys younger than 16 years old with early indicators of organ involvement, and in all patients with guideline indicators of organ involvement
  3. bRecommendations are based on class of evidence assigned: class I, treatment recommended or indicated; class IIA, treatment should be considered; class IIB, treatment may be considered; class III, treatment not recommended
  4. cSignificant life-threatening arrhythmia or conduction defect
  5. dLVH as evidenced by cMRI or echocardiogram data, in the absence of hypertension
  6. eTreatment initiated based two criteria. Many cardiac manifestations may be attributable to hypertension, so this must be ruled out or treated for 12 months. One additional criterion not shown in the table: abnormal base–apex circumferential strain gradient on cMRI
  7. fAmerican Society of Echocardiography and/or the presence of speckle tracking abnormalities
  8. gAdditional criteria: LVM increase of 5 g/m2/y based on three measurements over at least 12 months; LVMI ≥ 20% above normal
  9. hAtrioventricular block, short PR interval, left bundle branch block, ventricular or atrial tachyarrhythmias, sinus bradycardia in the absence of negative chronotropic drugs or other causes
  10. iEchocardiographic changes: increased LVM, systolic or diastolic dysfunction, echocardiogram with persistently altered Doppler tissue
  11. jElectrocardiographic changes; LVH; arrhythmia
  12. kAlteration in cMRI suggestive of deposit
  13. lAll male patients with a confirmed FD diagnosis should be offered ERT from age 18 years; ERT may be considered in children (6–18 years) with cardiac involvement
  14. mTreatment should be offered to women who develop cardiomyopathy; guideline does not specify how cardiomyopathy should be diagnosed, so various methods of diagnosis have been included except cMRI
  15. nAlso if necessary in asymptomatic boys with a classical mutation
  16. oERT is practically always indicated in men, even those with mild symptoms and low organ involvement, and in patients undergoing hemodialysis or with a kidney transplant
  17. pRelevant, histologically proven Gb3 deposits in kidney or heart biopsies
  18. qManifest diastolic dysfunction, LVH, arrhythmias, attributable to cardiac involvement in FD
  19. rFD-specific therapy should be considered in male patients with classical mutations at diagnosis; tabulated additional considerations apply to male and female patients with later-onset disease
  20. sLVMI above normal for age and sex by 2D echocardiogram/cMRI
  21.  + , achieved consensus in PREDICT-FD; 2D, two-dimensional; cF, female patient(s) with classical disease; cMRI, cardiac magnetic resonance imaging; ECG, electrocardiogram; EFWG, European Fabry Working Group; F, female patient(s); FCGHSG, Fabry Center, General Hospital Slovenj Gradec; FD, Fabry disease; Gb3, globotriaosylceramide; Gd+ , gadolinium enhancement; LVH, left ventricular hypertrophy; LVM, left ventricular mass; LVMI, LVM index; M, male patient(s); NR, achieved consensus but not recommended for safety reasons; NT-proBNP, N-terminal pro-natriuretic brain peptide; ULN, upper limit of normal; y, year