Cardiac follow-up in patients with hereditary muscular diseases

Transcription

1 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

2 Diseases. Dystrofia myotonica Emery Dreifuss & Limb girdle Duchenne & Becker

3 Muscular dystrophies Duchenne, Becker, limbgirdle 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

4 Dystrofia myotonica (DM)

5 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 ( CTG repetitions) in chromosome 19 form mutant transcripts that lead to abnormal splicing. DM 2 (less fequent and adult onset ) CCTGrepititions in the CNBP/ZNF9 gene (Zinc finger protein 9 gene) in chromosome 3. The number of repetitions indicates the severity of the disease

6 Dystrofia myotonica (DM) Heart 2011 Mc Nally et al.

7 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.

8 Cardiological manifestations are seen in both DM1 and DM2. DM1 has more often a progressive cardiac phenotype EHJ Lund et al. Pathophysiology cardiac manifestations DM EHJ Elliott; 2014 EHJ Lund et al.

9 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 International J of Cardiology Petri et al.

10 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 International J of Cardiology Lau et al International J of Cardiology Petri et al.

11 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. Petri et al. Int J Cardiol 2012 AV-block (PR interval <240ms), QRS>120, and atrial arrhythmias have been shown as predictors for sudden cardac death in DM1(Groh criteria) Petri et al. Int J Cardiol 2012, Groh et al. NEJM 2008 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.

12 CMR Depressed LV function and fibrosis.

13 Flow chart for follow-up of asymptomatic patients with DM 2015 International J of Cardiology Lau et al.

14 Myotonic dystrophy Summary Patients with DM are prone to cardiac events. Heart failure is treated according to current guidelines Cardiac syncope indicates implantation of pacemaker/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 International J of Cardiology Petri et al EHJ Elliott 2014 EHJ Lund et al

15 Emery Dreifuss & Limb Girdle muscular dystrophy

16 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 og Type 2I (reported 29-62%) Gen LMNA -autosomal dominant (majority of EDMD) -recessiv (very rare) Emerin X-linked, less common cardiomyopathy LMNA -autosomal dominant Fukutin-gene (type 2I) ß-sarcoglycan-gene (type 2E) Prevalence 1 : more frequent Groh et al. Arrhythmias in the muscular dystrophies, Heart Rhythm 2012

17 Limb Girdle type 2(C-F) are caused by mutations in the subunits of the dystrophin associated sarcoglycan complex. Emerin mutations cause X-linked EDMD. Cardimyopathy is less common Limb Girdle type 2I. Mutation in fukutin gene FKRP. An enzyme involved in glycosylaton of α-dystroglycan allowing it to bind to the extracellular Mutation in Lamin matrix. A/C: Autosomal dominant EDMD, and Limb girdle type 1B. Severe cardiac phenotype.

18 Lamin A/C (LMNA) mutation 5 8 % of familial DCM LMNA in Norway: 6.4% of probands Tested for familal DCM (Hasselberg et al EHJ 2018) OUS 96 LMNA mutation positive probands (31%) and familymembers (69%) have been diagnosed at the Department of Medical Genetics, OUS form We follow up 66 LMNA mutation-positive patients and familymembers at our outpatientclinic at Rikshospitalet.

19 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 genetic basis of Emery Dreifuss muscular dystrophy Botto et al. Cardiovascular Ultrasound 2010

20 The Lamin - protein Lamina A network of filaments on the inside of the nuclear membrane Features: Structural. Essential for the size, shape and mechanical integrity of the cellular nucelus Regulates protiein synthesis via DNA transcription factors, and aid transport of m-rna from the nucleus into cytosol Mitosis. Disorganization and reorganization of the cellular nucleus during mitosis.

21 Clinical Phenotypes Cardiomyopathy Emery Dreifuss and limb-girdle muscular dystrophy Charcot Marie-Tooth disease Familial partial lipodystrophy Hutchinson-Gilford Progeria syndrom +++ Emery Dreifuss muskeldystrofi Hutchinson-Gilford Progeria syndrom

22 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)

23 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

24 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 cardiac death. The risk for sudden cardiac death was as high in patients with neuromuscular phenotype as those with obvious cardiac phenotype. VT occur before myocardial dysfunction The patients do not meet criteria for primary prophylactic ICD which is when EF < 35%. J Mol Med 2005 Pasotti et al. JACC 2008 Objectives of our research at OUS: Find risk markers for life-threatening arrhythmias in LMNA positive individuals.

25 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): (63%)probands and 15 familymembers Muscular dystrophy : 11/41 (27%). 5 with limb girdle, 4 with Emery Dreifuss, 2 with unclassified 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.

26 Myocardial function in interventricular septum - was reduced relative to the rest of the left ventricle. - correlated with PR interval. Europace 2014; 16(4):

27 CMR(n=12) Myocardial fibrosis was found exclusively in the interventricular septum and only in patients with VT. PR interval was prologned in patients with fibrosis in the septum. PR interval (ms) Septal fibrosis 320±66 No fibrosis 175±42 p=0.001 Fibrosis in the septum may be the cause of increased PR interval and VT. Lamin A/C mutation-positive patient admitted to OUS after aborted cardiac arrest /VF. PR interval was 310 ms and fibrosis was found in the septum (arrow) at CMR.

28 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

29 Hasselberg et al. EJH 2018

30 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 dispersion can 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.

31 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

32 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.

33 Duchennes and Becker muscular dystrophy Guillaume Benjamin Amand Duchenne

34 Genetics - Duchenne

35 Genetics- Becker

36 Female mutationcarriers: Usually asymptomatic, but may have mild skeletal muscle symptoms 10% have isolated cardiomyopathy. Prevalence : -Duchenne, 1:3500 boys -Becker, 1: boys Neuromuscul Disord 2003; 13:

37 Patophysiology Circ Cardiovasc Imaging. 2011:4:67-76

38 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 All who surivive the first 30 years develop cardiomyopathy. Becker % have cardiomyopathy. Int J Cardiol, 26 (3) (1990), pp Curr Opin Cardiol, 12 (3) (1997), pp Am Heart J, 155 (6) (2008), pp Am J Cardiol, 110 (1) (2012), pp

39 Duchenne and Becker muscular dystrophy Dystrofin gene X-linked, recessive only boys Abnormal dystrophin-glycoprotein complex that leads to myofibril necrosis and fat infiltration in both skeletal and heart muscle. Duchenne (1/3500 males): Almost complete lack of dystrofin: Early onset of disease Becker (1/ males): Lower degree of dystrophin deficiency. Later onset of disease DCM common and arrhytmias occur after onset of myocardial dysfunction. Some families display cardiomyopathy without skeletal muscle manifestations. Respiratory failure with increasing skeletal muscle affection. Respirator common. Median survival 35 years. Duchenne: Sudden cardiac death most often occur in severely diseased with both respiratory and cardiac failure. Respiratory failure and long-term prognosis should be taken into account when assessing indication for ICDs.

40 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

41 Finsterer, J. & Cripe, L. (2014) Treatment of dystrophin cardiomyopathies Nat. Rev. Cardiol. doi: /nrcardio

42 Typical ECG changes

43 Arrhythmias SVT VT

44 Echocardiography

45 CMR. The classical CMR pathology: -epicardial fibrosis, especially inferolaterally. Similar to changes seen in myocarditis CMR is recommended as part of the cilincal investigation in these patients. David Verhaert et al. Circ Cardiovasc Imaging. 2011;4:67-76 Copyright American Heart Association, Inc. All rights reserved.

46 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 taken into 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 assessment with echocardiography every 5 years from age Pediatrics 2005;116: Lancet Neurol 2010;9 (2):117-89

47 Key points in Duchenne and Becker muscular dystrophy Patients with dystropinopathies require presymptomatic treatment to delay the onset and severity of cardiac involvement. Treatment of symptomatic cardiac disease follows established guidelines 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 pulmonary disease in patients with dystrophinopathies, and pulmonary function should therefore be improved trough scoliosis surgery and non invasive ventilation assist devices. Sufficient pain management to reduce chatecolaminergic stress on the heart

48 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. Team at the department for genetic heart disease: -Cardiologists -Specialized nurses Collaboration with geneticists, OUS Probabillity of developing a severe cardiac phenotype. Heart failure treatment PM and ICD are considered continously. When appropriate reffered for TX investigation.