Cardiomyopathy in Fabry’sdisease

Herzinsuffizienzlunch Basel, 11.09.2018

Christiane GrunerKardiologie, UniversitätsSpital Zürich

Content

• Background / epidemiology• Differential diagnosis• Clinical presentations / manifestations• Treatment

• Devices• Fabry-specific treatment (ERT, Chaperone)

Fabry: lysosomal storage disease

alpha-Galaktosidase

Prevalence 1:40’000

Fabry: lysosomal storage disease

Yogasundaram et al, Can J Cardiol 2017;33:883-897

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

Inheritance: X-chromosomal recessive

Inheritance: X-chromosomal recessive

Case 2 Case 3Case 1• 72 years old male• Normal kidney and

liver function• Negative family

history

• 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

CMR - Case 2 CMR - Case 3CMR - Case 1

** * **

**

Case 1 Case 2 Case 3

MYH7 c.1988G>A GAL c.902G>A PRKAG2 c.1026G>T

HCM FABRYPRKAG2 CARDIO-

MYOPATHY

ANTERO-SEPTAL

-20%

+20%

SEPTAL

ANTERIOR

INFERIOR

POSTERIOR

LATERAL

HCM ATHLETE

LVNCMPFABRYAMYLOID

Differential Diagnosis LVHHCM (1:500): DIFFERENTIAL DIAGNOSIS

Hypertensive heart diseaseAthlete’s heartMetabolic disorders Syndromal disorders

Fabry disease Friedreich’s ataxiaDanon diseaseGlycogen storage diseases

Noonan syndromeLEOPARD syndrome

PRKAG2 cardiomyopathy Infiltrative disordersMucopolysaccharidosis AmyloidosisOxalosis HemochromatosisMitochondrial cytopathies SarcoidosisHypothyroidismObesity

Diagnosis CMP

CMP

Past medical history

ECG

Imaging:EchoCMR

Lab results

Genetic testing

Clinical findings

Family history

Elliott P et al, Heart 2011;23:1957-60Monserrat L et al, JACC 2007;50(25):2399-403

Maron SM et al, Am J of Med 2018;131:200e200-200e8Linthorst GE et al, J Med Genet 2010;47:217-222

Prevalence of patients with Fabry disease in cohorts

with diagnosis of hypertrophic

cardiomyopathy0.5-1%

Prevalence of patients with Fabry disease in cohorts with unexplained LVH

4%

Red Flags in LVH

• Family history (family tree, X-linked, no male-to-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

Testing for Fabry

• Who?: Patients with unexplained LVH (males age >30, females age >40)

• How?: males: enzyme activity (leucocytes, heparin blood), females always genetics

Cardiac manifestations

• Left ventricular hypertrophy, right ventricular hypertrophy

• Diastolic dysfunction• Microvascular

dysfunction• Valvular manifestations• Aortic dilatation• Arrhythmias

Fabry Cohort The Heart Hospital, n = 207, mean FU 7.1 yearsHeart failure (NYHA III) 21 / 10%Atrial fibrillation 13 / 6%Bradycardia / Pacemaker 13 / 6%Cardiac death (5 SCD / 2 HF) 7 / 3%

Epidemiology MACE

Patel V et al, Heart 2015;101:961-966

ECG /Arrhythmias

short PQ

conduction abnormalities

atrial fibrillation

ventricular tachycardia/VF

Management Arrhythmias

• Screening at least yearly ECG and Holter-ECG

Brignole et al, EHJ 2013;34:2281-2239Wanner C et al, Mol Genet Metabol 2018;124:189-203

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

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

Krämer J et al, Am J Cardiol 2014;114:895-900

No ERT ERTBaseline (n = 16)

FU (n = 16) Baseline(n = 57)

FU (n = 56)

LV mass (g/m2) 59 ± 11 61 ± 14 92 ± 33 90 ± 30Septal wall thickness (mm)

8.0 ± 1.6 8.6 ± 1.9 12.2 ± 3.7 12.3 ± 3.7

Ejection fraction (%) 60 ± 6 59 ± 8 64 ± 9 63 ± 9Fibrosis (% LV mass) 0.5 ± 0.8 0.7 ± 1.0 1.4 ± 1.9 2.5 ± 2.6

No Fibrosis (n = 25) Fibrosis (n = 48)LV mass (g/m2) 70 ± 16 93 ± 36Septal wall thickness (mm) 9.4 ± 2.4 12.2 ± 4.0Ejection fraction (%) 62 ± 7 64 ± 9Fibrosis (% LV mass) 0 1.8 ± 1.8Malignant ventricular arrhythmias 0 13 (27%)Sudden cardiac death 0 5 (10%)

Krämer J et al, Am J Cardiol 2014;114:895-900

• 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

1.0

0.8

0.6

0.4

0.2

0.00 2 4 6 8 10

Follow-up in years

Eve

nt fr

ee r

ate

p = 0.017

No fibrosis

Fibrosis

Indications for primary prophylactic Defibrillator

Wanner C et al, Mol Genet Metabol 2018;124:189-203

Indications for primary prophylactic defibrillator

• Extensive LVH• Nonsustained VTs• Syncope (arrhythmogenic)• Myocardial fibrosis• PM AICD?

Fabry-specific treatment: ERT

0.2mg/kg body weight every

other

1mg/kg body weight every

other

• 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)

Treatment success

Beck et al, Mol Genet and Metabol Reports 2015;21-27Krämer J et al, Am J Cardiol 2014;114:895-900

CARDIAC CONSIDERATIONS

• No effect on fibrosis• Preservation of disease

status on ERT start

EARLY TREATMENT

Chaperone therapy: Migalastat

Wu et al, Human Mutation 2011;32:965-977

• 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