Cardiomyopathy in Fabry s disease

Transcription

1 Cardiomyopathy in Fabry s disease Herzinsuffizienzlunch Basel, Christiane Gruner Kardiologie, UniversitätsSpital Zürich

2 Content Background / epidemiology Differential diagnosis Clinical presentations / manifestations Treatment Devices Fabry-specific treatment (ERT, Chaperone)

3 Fabry: lysosomal storage disease Prevalence 1: alpha-galaktosidase

4 Fabry: lysosomal storage disease Yogasundaram et al, Can J Cardiol 2017;33:

5 Fabry: classic later onset CLASSIC Activity alpha-galactosidases very low/inexistent Clinical presentation in childhood / adolsecence Acroparesthesia, angiokeratoma, hypohidrosis, GI symptoms, cornea verticillata Later in disease course cardiac manifestations, renal failure, cerebrovascular events LATER ONSET Residual activity alpha-galactosidases present Age of presentation >30 70 years Cardiac, renal or cerebrovascular manifestations

6 Inheritance: X-chromosomal recessive

7 Inheritance: X-chromosomal recessive

8 Case 1 72 years old male Normal kidney and liver function Negative family history Case 2 Case 3 38 years old male Proteinuria Mother, 1 brother, 1 sister affected 18 years old female Normal kidney and liver function Elevated CK levels Negative family history

9 CMR - Case 1 CMR - Case 2 CMR - Case 3 * * * * * * *

10 Case 1 Case 2 Case 3 MYH7 c.1988g>a GAL c.902g>a PRKAG2 c.1026g>t HCM FABRY PRKAG2 CARDIO- MYOPATHY

11 ANTERO-SEPTAL ANTERIOR +20% SEPTAL INFERIOR LATERAL -20% POSTERIOR HCM ATHLETE AMYLOID FABRY LVNCMP

12 Differential Diagnosis LVH HCM (1:500): DIFFERENTIAL DIAGNOSIS Hypertensiveheart disease Athlete s heart Metabolic disorders Fabry disease Danon disease Glycogen storage diseases PRKAG2 cardiomyopathy Mucopolysaccharidosis Oxalosis Mitochondrial cytopathies Hypothyroidism Obesity Syndromaldisorders Friedreich s ataxia Noonan syndrome LEOPARD syndrome Infiltrative disorders Amyloidosis Hemochromatosis Sarcoidosis

13 Elliott P et al, Heart 2011;23: Monserrat L et al, JACC 2007;50(25): Maron SM et al, Am J of Med 2018;131:200e e8 Linthorst GE et al, J Med Genet 2010;47: Diagnosis CMP Genetic testing Clinical findings Family history CMP Past medical history Prevalence of patients with Fabry disease in cohorts with diagnosis of hypertrophic cardiomyopathy 0.5-1% Lab results ECG Imaging: Echo CMR Prevalence of patients with Fabry disease in cohorts with unexplained LVH 4%

14 Red Flags in LVH Family history (family tree, X-linked, no maleto-male transmission) Various organs involved (physical exam, lab work) ECG: PQ interval, conduction abnormalities, extent of LVH Echo: speckle tracking pattern CMR: evidence of storage disease, LGE pattern, T1 mapping

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18 Testing for Fabry Who?: Patients with unexplained LVH (males age >30, females age >40) How?: males: enzyme activity (leucocytes, heparin blood), females always genetics

19 Cardiac manifestations Left ventricular hypertrophy, right ventricular hypertrophy Diastolic dysfunction Microvascular dysfunction Valvular manifestations Aortic dilatation Arrhythmias

20 Patel V et al, Heart 2015;101: Epidemiology MACE Fabry Cohort The Heart Hospital, n = 207, mean FU 7.1 years Heart failure (NYHA III) 21 / 10% Atrial fibrillation 13 / 6% Bradycardia / Pacemaker 13 / 6% Cardiac death (5 SCD / 2 HF) 7 / 3%

21 ECG /Arrhythmias short PQ conduction abnormalities atrial fibrillation ventricular tachycardia/vf

22 Management Arrhythmias Screening at least yearly ECG and Holter-ECG BRADYARRHYTHMIAS Pacing indications following 2013 ESC recommendations for cardiac pacing and CRT EP study may be considered for further of evaluation conduction abnormalities ATRIAL FIBRILLATION Oral anticoagulation (VKA) Restoration sinus rhythm No amiodarone Brignole et al, EHJ 2013;34: Wanner C et al, Mol Genet Metabol 2018;124:

23 Ventricular Arrhythmias N = 73 prior to ERT CMR at baseline: 48 patients fibrosis (1.8% of LVM), 25 patients without fibrosis Mean FU 4.8 years 57 patients were started on ERT according to guidelines

24 Baseline (n = 16) No ERT FU (n = 16) Baseline (n = 57) ERT FU (n = 56) LV mass (g/m2) 59 ± ± ± ± 30 Septal wall thickness (mm) 8.0 ± ± ± ± 3.7 Ejection fraction (%) 60 ± 6 59 ± 8 64 ± 9 63 ± 9 Fibrosis (% LV mass) 0.5 ± ± ± ± 2.6 No Fibrosis (n = 25) Fibrosis (n = 48) LV mass (g/m2) 70 ± ± 36 Septal wall thickness (mm) 9.4 ± ± 4.0 Ejection fraction (%) 62 ± 7 64 ± 9 Fibrosis (% LV mass) ± 1.8 Malignant ventricular arrhythmias 0 13 (27%) Sudden cardiac death 0 5 (10%) Krämer J et al, Am J Cardiol 2014;114:

25 Event free rate No fibrosis p = Fibrosis Follow-up in years ERT does not prevent progress of fibrosis annual increase of fibrosis in patients with ventricular arrhythmias was 0.9% compared to 0.2% in patients without ventricular arrhythmias Krämer J et al, Am J Cardiol 2014;114:

26 Indications for primary prophylactic Defibrillator Wanner C et al, Mol Genet Metabol 2018;124:

27 Indications for primary prophylactic defibrillator Extensive LVH Nonsustained VTs Syncope (arrhythmogenic) Myocardial fibrosis PM AICD?

28 Fabry-specific treatment: ERT 0.2mg/kg body weight every other 1mg/kg body weight every other

29 N = 387; 248 agalsidase alfa, 139 agalsidase beta Beta-group: more classical forms, more kidney disease FU time: alfa-group 5.2 years, beta-group 3.8 years No difference with regards to clinical events Beta-group: trend to reduction in LV mass Alfa-group: fewer patients had immunologic response (antibodies)

30 Beck et al, Mol Genet and Metabol Reports 2015;21-27 Krämer J et al, Am J Cardiol 2014;114: Treatment success CARDIAC CONSIDERATIONS No effect on fibrosis Preservation of disease status on ERT start EARLY TREATMENT

31 Chaperone therapy: Migalastat

32 Wu et al, Human Mutation 2011;32:

33 Assessment of patients with LVH: red flags! Low threshold for Fabry testing in patients with LVH Regular follow-up: ECG, Holter, exercise test, echo, CMR (3-5 years) Risk assessment, loop recorder Early treatment