Mark Hamilton formerly Clinical Research Fellow West of Scotland Clinical Genetics Service markhamilton1nhsnet Scottish management guidelines for myotonic dystrophy wwwsmnscotnhsuk ID: 931580
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Slide1
Myotonic
dystrophy:
Cardiac phenotype, risk stratification and management
Mark Hamilton,
(formerly) Clinical
Research Fellow
West of Scotland Clinical Genetics Service
markhamilton1@nhs.net
Slide2Scottish management guidelines for myotonic dystrophy
www.smn.scot.nhs.uk
Ayrshire
Victor Chong,
Crosshouse HospitalBordersPaul Neary, Borders General Hospital Dumfries & GallowayGraeme Tait, Dumfries and Galloway Royal Infirmary FifeMark Francis, Victoria HospitalForth ValleyCatherine Labinjoh, Forth Valley Royal Hospital
Greater
Glasgow & Clyde
David
Murdoch,
Caroline Coats, Iain Findlay, Queen Elizabeth University Hospital
Highland
Stephen
Cross,
Raigmore
Hospital
Lanarkshire
Andrew
Docherty, Wishaw General Hospital
Brian
O’Rourke
Hairmyres
Hospital
Lothian
Martin
Denvir
, Royal Infirmary of Edinburgh
Alan
Japp
, Royal Infirmary of Edinburgh
Tayside
Anna
Maria Choy,
Ninewells
Hospital
Slide3Overview
Molecular mechanisms in myotonic dystrophy
Not just a muscle disease!
Cardiac phenotype
B
radyarrhythmia
Cardiomyopathy
Ventricular
dysrhythmias
Potential care standards
Slide4Myotonic
dystrophy type 1:
Quick facts
Commonest inherited muscle disease in
adults
1 in
8,000
Complex
, multi-system
condition
“Probably
the most variable disorder known in medicine”
DMPK
General population n. 5 to 37
Premutation
n. 38 to 49
Pathogenic n. 50 to > 1,000
CTG(n)
Slide5Type 1
(DM1)
Type 2
“proximal
myotonic myopthy”ProMMPrevalence1 in 8,000Geographical variation (generally rarer)InheritanceAD with anticipationAD; variable, butanticipation not seenMutationCTG expansion in DMPKCCTG expansion in ZNF9Age at onsetAny age possibleGenerally 3rd – 4th decadeJuvenile/congenital forms?Yes
No
Pattern of weakness
Distal
to proximal
Predominantly proximal
Muscle pain
+
++
Subtypes of myotonic dystrophy
Slide6What goes wrong in myotonic dystrophy?
Slide7What goes wrong in myotonic dystrophy?
DNA
mRNA
Slide8What goes wrong in myotonic dystrophy?
DNA
mRNA
Slide9What goes wrong in myotonic dystrophy?
DNA
mRNA
protein
Slide10What goes wrong in
myotonic dystrophy?
DNA
(CTG)n
Expanded RNA
Slide11What goes wrong in
myotonic dystrophy?
DNA
(CTG)n
Expanded RNA
Slide12What goes wrong in
myotonic dystrophy?
DNA
(CTG)n
Expanded RNA
Slide13What goes wrong in
myotonic dystrophy?
DNA
(CTG)n
Expanded RNA
Splicing factors
Slide14What goes wrong in
myotonic dystrophy?
DNA
(CTG)n
Expanded RNA
Dysregulation of alternative splicing affecting many genes
Slide15Gourdon
et al
. 2017
Dysregulation of alternative splicing
Slide16Myotonic
dystrophy is a multisystem disorder
Slide17D
ysregulated splicing in heart
SCN5A
Cardiac troponin T2 (
TNNT2
)
Dystrophin
(
DMD
)
SERCA1
Cardiac ryanodine receptor (
RYR2
)
Insulin receptor
Slide18Dysregulated splicing in heart
SCN5A
Cardiac troponin T2 (
TNNT2
)
Dystrophin
(
DMD
)
SERCA1
Cardiac ryanodine receptor (
RYR2
)
Insulin receptor
Slide191. Conducting system disease
Endomyocardial
biopsy
Samanta
et al
.
2016
Age 40: PR = 178ms, QRS = 102ms
Age 47: PR = 197ms, QRS = 126ms
Age 50: PR = 200ms, QRS = 166ms
Lau
et al
. 2015
Slide20Slide21High risk criteria
Groh criteria
(Groh
et al
. NEJM 2008)
406 adults, mean f/u 5.7 years, 81 deaths (27 sudden)
PR > 240
ms
, QRS > 120
ms
, 2
o
or 3
o heart blockRR of sudden death 3.30 (p = 0.02)Atrial tachyarrhythmia
RR of sudden death = 5.18 (p < 0.001)
‘Ballantyne criterion’
(see also Wahbi et al
. 2017)Positive family history of severe conducting system disease or sudden death
Slide22The case for pacing
1,388 patients over median 10 year follow-up
(
Wahbi
et al
. 2017)
8/17 arrhythmic deaths
were potentially
PPM treatable (5 x
asystole
, 1 x 3
o
AV block, 2 x EMD)143
(> 10
%) had major conduction defects (99 x 3
o AV block, 32 x 2o AV block, 12 x sinus node dysfunction)
Electrophysiology in 100
consecutive patients (Laurent
et al. 2011)
49 given PPM for HV ≥ 70ms
46 met Groh criteria (32 of whom
got pacemakers)Only one sudden death in ~ 6 years. A “6-fold reduction”
Slide23Invasive vs. non-invasive strategy
Retrospective study of 486 patients with PR > 200ms QRS >100
ms.
Median f/u 7.4 years
(
Wahbi
et al
. 2012)
Invasive: Systematic
EPS, PPM if
HV > 70
ms
(n.341)
Non-invasive: No EPS, or only in severe abnormality on 12-lead ECG (n.145)
Invasive strategy associated with reduced sudden death (3%
vs 11%, HR 0.28)
Slide242. Heart muscle involvement
Prevalence of clinically significant LVSD ~15%
1
cMRI
studies suggest structural abnormalities in as much as 44%
2
LVSD
LV dilatation
LV hypertrophy
Myocardial fibrosis
8%
have
cTnI
> population
99th
centile3Significant LV dysfunction may be present without high-risk ECG criteria
3
1Lau et al. 2015; 2Hermans et al. 2012; 3Hamilton et al
. 2017
Slide25Management of LVSD in myotonic dystrophy
No RCT data (to my knowledge)
Myotonic Dystrophy Foundation (MDF) consensus care recommendations (2018) suggest simply follow generic ACCF/AHA guidelines for management of heart failure
But (presumably) extreme caution needed with beta-blockers?
Slide263. Ventricular dysrhythmias
Why?
Myocardial fibrosis
LVSD
Mis
-splicing of
e.g.
SCN5A
1
Bradycardia induced
How common?
Non-sustained VTA in ~ 4%
(meta-analysis n. 886)
2
VT inducible in 18% (n.83)
3Incidence of sustained VTA 2.3% over ~ 10 years (n.1,388)4
Plus 9 sudden deaths due to proven sustained VTA (17 cause unknown, 8 due to asystole, HB or EMD)3
1Wahbi 2013; 2Petri 2012; 3Lazarus 1999; 4
Wahbi 2017
Slide27Risk factors for VTA and sudden death
(
Wahbi
et al. 2017)
Outcome
Risk factors
Overall survival
Age; male sex
; atrial fibrillation (AF);
syncope
;
heart rate
; PR and QRS intervals;
1st degree AV block
; left BBB, right BBB, and LVEF <50%
Sudden
death
Age;
family history of SD; non-sustained VT; AF; PR and QRS intervals; 1st degree AV block; left BBB
Sustained VTA
Coronary artery disease; AF; non-sustained VTA; QRS interval; left and right BBB; LVEF <50%
Major conduction defects
Age; male sex; AF; LVEF <50%;
anyconduction defect on the ECG
No disease-specific guideline for ICD implantation
Authors suggest history of VTA, severe LVSD, type 1
Brugada
ECG should prompt consideration
Slide28ICDs are a complex issue
9/23
(
39%
) complication rate in one series
(
Sochala
et al
. 2017)
Inappropriate shocks
Lead dysfunction
Infection
Some patients may be more vulnerable to psychological sequelae
Slide29Bob Ballantyne
n. ~220
Helen Gregory
n. ~50
Catherine
McWilliam
and Kirsten Patterson
n. ~ 30
DM1 Management Clinics
Yvonne Robb
n. ~90 to 110
Slide30Key documents
Brand new
Myotonic Dystrophy Foundation (MDF)
2018
Feingold
et al
. 2017
2017
Slide31All
patients with
a diagnosis of myotonic dystrophy should
have annual ECG and symptomatic review at
leastAll patients with ECG abnormality, or palpitations or syncope should be referred to cardiologist24 HolterMDF recommends 3 to 5 yearly if abnormal ECG (more frequent if clinically indicated)AHA guideline suggests 2 to 4 yearly for all EchoMDF
recommends at diagnosis then 3 to 5
yearly
(
more
frequent if clinically
indicated)
AHA
guideline suggests 2 to 4 yearly for
all
Consensus approach to management
Slide32Treatment of LVSD
According to American Heart Association Guidelines for Management of Heart Failure?
ICD placement
ACC/AHA
Guideline for Device-based
therapy
Patients
with devices should
remain under formal cardiology review
(i.e. pacemaker checks alone are not adequate
)
Is
there a role for invasive electrophysiology?
Consensus approach to management
Slide33Cardiac phenotype in myotonic dystrophy is complex
Proactive screening and early intervention for conducting system disease is life-saving
Optimal strategy for ICD
implantation not
fully elucidated
Severe LVSD, non-sustained VT,
Brugada
-like
ECG
Scottish DM1 cohort represent an excellent opportunity for audit, research and service-improvement work
Summary
Slide34The Scottish Myotonic Dystrophy Consortium
Cheryl Longman
Douglas Wilcox
Alison Wilcox
Richard PettyYvonne RobbMark HamiltonAnne-Marie TaylorMaria Elena FarrugiaHelen GregoryAlexis DuncanCatherine McWilliamJohn DeanBob BallantyneLorna MacLeishMonika RahmanAnne McKeownKirsten PattersonSarah CummingDarren G. MoncktonProgramme Manager: Hugh KennedyProgramme Support Officer: Laura Craig