Cardiac follow-up in patients with hereditary muscular diseases

Tromsø 7. september 2018

Eystein Theodor Ek Skjølsvik, MD

Professor Kristina H. Haugaa, MD, PhD

Unit for genetic cardiac diseases, OUS Rikshospitalet

Diseases.

• Dystrofia myotonica

• Emery Dreifuss & Limb girdle

• Duchenne & Becker

Muscular dystrophies

Duchenne, Becker, limb-girdle type 2C-2F og 2I

• Depressed left ventricular(LV) function

- ”Dilated Cardiomyopathy” (DCM) – is the primary cardiac manifestation.

– Risk for arrythmia and conduction disturbances are proportional to LV dysfunction

Dystrofia myotonica, Emery Dreifuss og limb-girdle type 1B

• Atrioventricular(AV) block, supraventricular and ventricular arrythmias are often the primary cardiac manifestation, irrespective of left ventricular function.

– DCM often develop secondary

Dystrofia myotonica (DM)

Dystrofia myotonica (DM)• DM the most common genetic muscular dystrophy in

adults

• Incidence 1:8000 (DM1) and 1:20000 (DM2)

• autosomal- dominant inheritance

• 2 types:

• DM 1. Extensions of repetitive trinucleotide sequences (CTG) in the DMPK gene (50-1000 CTG repetitions) in chromosome 19 form mutant transcripts that lead to abnormal splicing.

• DM 2 (less fequent and ”adult onset”) 75 – 11.000 CCTG-repititions in the CNBP/ZNF9 gene (Zinc finger protein 9 gene) in chromosome 3.

• The number of repetitions indicates the severity of the disease

Dystrofia myotonica (DM)

Heart 2011 Mc Nally et al.

• DM 1 symptoms occur in the 2nd to 4th decade with typical myotonia, slowly progressive myopahty and manifestations from multiple organs:Can affect:

• cardiovasculary system• respiratory system• endocrine system• CNS• gastrointestinal system• sight; cataracts• genitourinary system

• The phenotypic variability provides a wide range of clinical manifestations

International J of Cardiology 2014 Lau et al.

• Cardiological manifestations are seen in both DM1 and DM2.

• DM1 has more often a progressive cardiac phenotype.2014 EHJ Lund et al.

2014 EHJ Elliott; 2014 EHJ Lund et al.

Pathophysiology cardiac manifestationsDM1.

Cardiac manifestations:• Cardiac fibrosis and fatty infiltration• AV block grade 1 (25%)• AV block grade 2 (6%)• QTc > 440 ms (10-20%)• ORS > 120ms (20%)• Frequent VES (15%)• atrial and ventricular arrhythmia (< 10%)• Left bundle branch block (3 - 6%)• Right bundle branch block (4 - 6%)

2015 International J of Cardiology Lau et al.2014 International J of Cardiology Petri et al.

Cardiac manifestations:• LV hypertrophy (20%)• LV dilatation (20%)• LV dysfunction (14%)

• LV systolic dysfunction is associated with increased age, number of CTG repititions, PR interval > 200ms og QRS > 120 ms• 9.2 år follow-up data showed

• that heart failure was associated with 4 times higher risk of all cause mortality • 6 times increased risk of cardiac death in patients with DM.

2015 International J of Cardiology Lau et al.2014 International J of Cardiology Petri et al.

• Venticular arrhythmias and sudden cardiac death

– 1/3 of deaths in DM1 are cardiac deaths.

– Sudden cardiac death is 3 times more frequent than in the normal population.

– AV-block (PR interval <240ms), QRS>120, and atrial arrhythmias have been shown as predictors for sudden cardac death in DM1(Groh criteria)

• Generally, arrythmias and conduction disorders increase with decreasing muscle strength.– However, the relationship between cardac and skeletal muscle

affection is not 100%.

– Several studies have shown that cardiomyopathy may be present despite minimal skeletal muscle affection.

Petri et al. Int J Cardiol 2012

Petri et al. Int J Cardiol 2012, Groh et al. NEJM 2008

CMRDepressed LV function and fibrosis.

Flow chart for follow-up of asymptomatic patients with DM

2015 International J of Cardiology Lau et al.

Myotonic dystrophy–Summary

•Patients with DM are prone to cardiac events.• Heart failure is treated according to current guidelines• Cardiac syncope indicates implantation ofpacemaker/ICD• ICD indication is assessed continously due to increased risk of ventricular arrhythmias and sudden cardac death

2015 International J of Cardiology Lau et al.2014 International J of Cardiology Petri et al.2014 EHJ Elliott2014 EHJ Lund et al

Emery Dreifuss & Limb Girdle

muscular dystrophy

Emery Dreifuss Limb girdle, type 1B

Limb girdle, type 2

Muscle weakness Childhood-adolecence Most often in adults Child-adulthood/ in the 40s

Contractures Common Less common

Cardiomyopathy >90% >90% ? Type 2E ogType 2I (reported 29-62%)

Gen •LMNA-autosomal dominant (majority of EDMD) -recessiv (very rare)•Emerin – X-linked, less commoncardiomyopathy

•LMNA -autosomal dominant

•Fukutin-gene (type 2I)•ß-sarcoglycan-gene (type 2E)

Prevalence 1 : 100 000 ”more frequent”

Groh et al. Arrhythmias in the muscular dystrophies, Heart Rhythm 2012

Limb Girdle type 2(C-F) are causedby mutations in the subunits ofthe dystrophinassociatedsarcoglycancomplex.

Emerinmutationscause X-linkedEDMD. Cardimyopathyis less common

Limb Girdletype 2I. Mutation in fukutin gene FKRP. An enzyme involved in glycosylaton of α-Dystroglycanallowing it to bind to theextracellularmatrix.

Mutation in Lamin A/C: Autosomal dominant EDMD, and Limbgirdle type 1B. Severe cardiacphenotype.

5 – 8 % of familial DCM

LMNA in Norway: 6.4% of probands

Tested for familal DCM (Hasselberg et al EHJ 2018)

Lamin A/C (LMNA) mutation

OUS

• 96 LMNA mutation positive probands (31%) and familymembers (69%) have been diagnosed at theDepartment of Medical Genetics, OUS form 2003-2015.

• We follow up 66 LMNA mutation-positive patients and familymembers at our outpatientclinic at Rikshospitalet.

The Lamin A/C gene = LMNA

• Chromosome 1, long arm: q21.2-q21.3

• Consists of 12 exons

• Lamin A and lamin C are formed by alternate splicing in exon 10

• Mutations

– The first mutation was reported in 1999 under search for the geneticbasis of Emery Dreifuss muscular dystrophy

Botto et al. Cardiovascular Ultrasound 2010

The Lamin - protein

• ”Lamina”

– A network of filaments on the insideof the nuclear membrane

• Features:

– Structural. Essential for the size, shapeand mechanical integrity of thecellular nucelus

– Regulates protiein synthesis via DNA transcription factors, and aid transport of m-RNA from the nucleus intocytosol

– Mitosis. Disorganization and reorganization of the cellular nucleusduring mitosis.

Clinical Phenotypes

• Cardiomyopathy

• Emery Dreifuss and limb-girdle musculardystrophy

• Charcot Marie-Tooth disease

• Familial partial lipodystrophy

• Hutchinson-Gilford Progeria syndrom

+++

http://geneticsf.labanca.net/?attachment_id=353

Emery Dreifuss muskeldystrofi

Hutchinson-Gilford Progeria syndrom

Cardiomyopathy

• Supraventricular arrhythmia

-< 30 years of age

-Atrial fibrillation

-Atrial flutter

-SVT

• Atrioventricular block

-< 30 years of age

-Progressive

-50% receive a pacemaker (lifetime risk)

• Ventricular arrhythmia

– VES

– Non sustained VT

– VT / VF and sudden cardiac death

• Dilated cardiomyopathy(DCM)

– Often develop secondary to AV-block and arrhythmia.

– CRT-D

– Cardiac transplantation

Lamin A/C mutation =”a malignant disease”

• Penetrance of cardimyopathy 100% at 60 years of age

Ventricular arrhythmia – COMMON

• Meta-analysis of 299 mutation carriers:

– 46 % of deaths were due to sudden cardiacdeath.

– The risk for sudden cardiac death was as high in patients with neuromuscular phenotype as thosewith obvious cardiac phenotype.

J Mol Med 2005

• VT occur before myocardial dysfunction

The patients do not meet criteria for primaryprophylactic ICD which is when EF < 35%.

• Objectives of our research at OUS: Find risk markers for life-threatening arrhythmias in LMNA positive individuals.

Pasotti et al. JACC 2008

Study 1

Risk prediction of ventricular arrhythmias and myocardial function in Lamin A/C mutation positive subjects

Nina E. Hasselberg, Thor Edvardsen, Helle Petri, Knut . Berge, Trond. Leren,

Henning Bundgaard, Kristina H. Haugaa

Europace 2014; 16(4): 563-71

• 26 (63%)probands and 15 familymembers

• Muscular dystrophy : 11/41 (27%).

• 5 with limb girdle, 4 with Emery Dreifuss, 2 withunclassified muscle dystrophy.

• Cardiac penetrance: 36/41 (88%)

• 21/41(51%) with documented VT

• Markers for VT

• Prolonged PR interval (p<0.001) and AV block

• DCM was not a marker for VT

• DCM andVT were as frequent among those with and without phenotypic muscle dystrophy.

Myocardial function in interventricular septum

- was reduced relative to the rest of the left ventricle.

- correlated with PR interval.

Europace 2014; 16(4): 563-71

CMR(n=12)

Myocardial fibrosis was found exclusively in the interventricular septum and only in patients with VT.

PR interval was prologned in patients withfibrosis in the septum.

Fibrosis in the septum may be the cause ofincreased PR interval and VT.

Lamin A/C mutation-positive patient admitted to OUS after abortedcardiac arrest /VF. PR interval was 310 ms and fibrosis was found in the septum (arrow) at CMR.

PR interval(ms)

Septal fibrosis 320±66

No fibrosis 175±42

p=0.001

Mechanical Dispersion by Strain Echocardiography: A Predictor of Ventricular Arrhythmias in Subjects With Lamin A/C Mutations

Kristina H. Haugaa, Nina E. Hasselberg, Thor Edvardsen

JACC Cardiovasc Imaging, 2014, Epub ahead of print

• 11/33 (33%) with documented VT.

• Mecahanical dispersion measured by strain analysis at echocardiography:

– Is a measure of how sychronously the left ventricle contracts

– Was a strong risk marker for VT

Hasselberg et al. EJH 2018

Clinical implications for Lamin A/C patients

PR interval as risk marker

-Measurement of PR interval is a simple, inexpensive and easily accessible tool for predicting VT

-Is evaluated in all lamin A/C genotype positive patients, irrespective of cardiac or neuromuscular phenotype

- Echocardiography with strain analysis and calculation of mechanical dispersioncan further contriubute to risk assessment

ICD implantation

-Should be considered at an earlier stage than whats

told in current guidelines (EF<35%).

-ICD-implantation is considered already when the patient

has and indication for conventional pacemaker due to

AV-block.

Evaluation and follow-up

• Genetic testing should be performed in patients with phenotypical muscular dystrophy.

• Important when LMNA-mutation is detected:

– No correlation between severity of muscular dystrophy and risk of heart failure.

– Cardiac penetrance and phenotypic expression vary between family members with identical genotype

• In the case of detected LMNA mutation, the patient must be reffered to a cardiologist, preferably at the department of cardiology Rikshospitalet.

• Frequent regular follow up consultations are indicated (every 6-12 months):

– ECG and Holter monitoring

– Echocardiography

– CMR

Treatment – LMNA mutation

• AV-block, arrhythmia and cardiac failure-are treated according to current guidelines.

• Low treshold for ICD implant when AV-block, ventricular arrhythmia, or DCM

• Cardiac transplantation is common in patients with terminal heart failure (<65 years).

• Studies have shown that highly competitive sports increase the risk of VT. Therefore we recommend that LMNA mutation-positive patients avoid competitive sports.

• Family members are offered genetic counseling and genetic testing.

Duchennes and Becker muscular dystrophy

Guillaume Benjamin Amand Duchenne

Genetics - Duchenne

Genetics- Becker

Prevalence :-Duchenne, 1:3500 boys-Becker, 1: 30 000 boys

Neuromuscul Disord 2003; 13: 166 – 72.

Female mutationcarriers:Usually asymptomatic, but mayhave mild skeletal musclesymptoms 10% have isolatedcardiomyopathy.

Patophysiology

Circ Cardiovasc Imaging. 2011:4:67-76

Cardiomyopathy in Duchenne and Becker muscular dystrophy.

• Incidence of cardiac affection is age dependent– 25 % at 6 years of age

– 59% at 10 years of age

• Median age for debut of cardiomyopathy is about 14-15

• All who surivive the first 30 years develop cardiomyopathy.

• Becker 50-70 % have cardiomyopathy.

Int J Cardiol, 26 (3) (1990), pp. 271–277Curr Opin Cardiol, 12 (3) (1997), pp. 329–343Am Heart J, 155 (6) (2008), pp. 998–1005Am J Cardiol, 110 (1) (2012), pp. 98–102

Duchenne and Becker muscular dystrophy• Dystrofin gene

• X-linked, recessive only boys

• Abnormal dystrophin-glycoprotein complex that leads to myofibril necrosisand fat infiltration in both skeletal and heart muscle.

• Duchenne (1/3500 males): Almost complete lack of dystrofin: Early onset ofdisease

• Becker (1/30 000 males): Lower degree of dystrophin deficiency. Later onsetof disease

• DCM common and arrhytmias occur after onset of myocardial dysfunction.

• Some families display cardiomyopathy without skeletal musclemanifestations.

• Respiratory failure with increasing skeletal muscle affection. Respirator common. Median survival 35 years.

• Duchenne: Sudden cardiac death most often occur in severely diseased withboth respiratory and cardiac failure.

• Respiratory failure and long-term prognosis should be taken into accountwhen assessing indication for ICDs.

• Due to reduced physical performance, the classic heart failure symptoms have late onset.

• The slow developing myopathies often have more severe cardiomyopathy (Becker)

Circ Cardiovasc Imaging. 2011:4:67-76

Finsterer, J. & Cripe, L. (2014) Treatment of dystrophin cardiomyopathiesNat. Rev. Cardiol. doi:10.1038/nrcardio.2013.213

Typical ECG changes

Arrhythmias

SVT VT

Echocardiography

.

David Verhaert et al. Circ Cardiovasc Imaging.

2011;4:67-76

Copyright © American Heart Association, Inc. All rights reserved.

CMR

The classical CMR pathology:-epicardial fibrosis, especially inferolaterally. Similar to changes seen in myocarditis

CMR is recommended as part of the cilincalinvestigation in these patients.

Treatment: • Cardiac failure, conduction disturbances and arrhythmias are

treated with medication and PM/ICD according to guidelines.

• ICD implantation prolong life but:

– Respiratory failure and long-term prognosis should be takeninto account when assessing ICD indication.

Follow up:• ECG, holter-monitoring, and echocardiography from 6 years of

age and every second year up to 8 years. Then annually from 10 years of age. 1

• Female carriers are recommended cardiological assessmentwith echocardiography every 5 years from age 16. 2

1Pediatrics 2005;116:1569-732Lancet Neurol 2010;9 (2):117-89

Key points in Duchenne and Becker muscular dystrophy• Patients with dystropinopathies require presymptomatic

treatment to delay the onset and severity of cardiacinvolvement.

• Treatment of symptomatic cardiac disease follows establishedguidelines on treatment of heartfailure both with devices and drugs.

• Non pharmacological treatment regimes are PM, ICD, CRT, LVAD and heart transplantation in some patients.

• A strong association exists between cardiac and pulmonarydisease in patients with dystrophinopathies, and pulmonaryfunction should therefore be improved trough scoliosis surgeryand non invasive ventilation assist devices.

• Sufficient pain management to reduce chatecolaminergic stress on the heart

Summary : Muscular dystrophy-patients at the department of cardiology, OUS Rikshospitalet

• Consultation and counselling

• ECG, 24h-rhythm registration

• Exercise-ecg/ergospirometry

• Echocardiography

• CMR

• every 6 months – every 2 years ? Frequency depends on

– Age, symptoms and clinical findings.

– Probabillity of developing a severe cardiac phenotype.

• Heart failure treatment

• PM and ICD are considered continously.

• When appropriate reffered for TX investigation.

”Team” at the department for genetic heart disease:-Cardiologists-Specialized nursesCollaboration with geneticists, OUS