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Ματθαίος Β. Διδάγγελος
Επιστ. Συνεργάτης
Α’ Καρδιολογική Κλινική Α.Π.Θ.
Π.Γ.Ν.Θ. ΑΧΕΠΑ
Disclosures
• None
Muscular Dystrophies
• Group of muscle diseases
– progressive skeletal muscle weakness
– hamper locomotion
• Prevalence
– 19.8-25.1 per 100,000
• General characteristics:
– inherited disorders caused by gene mutations
– defects in muscle proteins
– death of muscle cells and tissue
Theadom A, et al. Prevalence of muscular dystrophies: a systematic literature review. Neuroepidemiology. 2014;43(3-4):259-68.
Muscular Dystrophies with Gene Locations and Products
Disease
X-linked recessive muscular
dystrophies
Gene Locus
Gene Product
Duchenne muscular dystrophy
Xp21
Dystrophin
Becker muscular dystrophy
Xp21
EDMD
Autosomal dominant LGMD
LGMD1A
LGMD1B
LGMD1C
LGMD1D
LGMD1E
Autosomal recessive LGMD
LGMD2A
LGMD2B
LGMD2C
LGMD2D
LGMD2E
LGMD2F
LGMD2G
LGMD2H
LGMD2I
LGMD2J
MDCs
MDC1A "classic" MDC
MDC1B
MDC1C
MDC1D
FMDC
Muscle-eye-brain disease
Walker-Warburg syndrome
Other MDCs
MDC with rigid spine myopathy
Bethlem autosomal dominant myopathy
Ullrich myopathy
Intermediate filament myopathy
Desmin
aB-Crystallin
Epidermolysis bullosa and muscular
dystrophy
Xq28
Emerin
5q22-5q31
1q11-21
3p25
7q
7q
Myotilin
Lamin A and C
Caveolin-3
Unknown
Unknown
15q15
2p13
13q12
17q12-q21
4q12
5q33-q34
17q11-q12
9q3-q34
19q13.3
2q24.3
Calpain-3
Dysferlin
y-Sarcoglycan
a-Sarcoglycan
p-Sarcoglycan
S-Sarcoglycan
Telethonin
TRIM32
Fukutin-related protein
Titin
6q22
12q13
19q13.3
9q31-q33
1p32-p34
?
a2-Laminin (merosin)
a7-Integrin
Fukutin-related protein
LARGE
Fukutin
POMGnT
POMGnT
1q35-36
21q22
2q37
Selenoprotein N
Collagen VIa1, a2
Collagen VIa3
2
11q21-23
Desmin
Desmin, aB-Crystallin
8q24-qter
Plectin
80%
Dystrophin
Allelic Disorders
Isolated cardiomyopathy, Becker
muscular dystrophy
Isolated cardiomyopathy, Duchenne
muscular dystrophy
LGMD1B
Myofibrillar myopathy
Autosomal dominant EDMD
MDC1C, FMDC
LGMD2I
Dystrophin and the dystrophin-associated
glycoprotein complex (DAGC)
1. Darras BT, et al.Dystrophinopathies. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1119/
2. Juan-Mateu J, et al. DMD Mutations in 576 Dystrophinopathy Families: A Step Forward in Genotype-Phenotype Correlations. PLoS One. 2015 Aug 18;10(8):e0135189.
Dystrophinopathies
Dystrophin gene
Largest known
human gene
2.22Mb
79 exons
8 promoters
Xp21
X-linked recessive
1. Darras BT, et al.Dystrophinopathies. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1119/
2. Juan-Mateu J, et al. DMD Mutations in 576 Dystrophinopathy Families: A Step Forward in Genotype-Phenotype Correlations. PLoS One. 2015 Aug 18;10(8):e0135189.
Dystrophinopathies
1. Darras BT, et al.Dystrophinopathies. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1119/
2. Juan-Mateu J, et al. DMD Mutations in 576 Dystrophinopathy Families: A Step Forward in Genotype-Phenotype Correlations. PLoS One. 2015 Aug 18;10(8):e0135189.
Pathogenesis
Inheritance
Incidence
Prevalence
DMD
1:3,500
6:100,000
BMD
1:18,450
2,4:100,000
1. Darras BT, et al.Dystrophinopathies. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1119/
2. Juan-Mateu J, et al. DMD Mutations in 576 Dystrophinopathy Families: A Step Forward in Genotype-Phenotype Correlations. PLoS One. 2015 Aug 18;10(8):e0135189.
Clinical characteristics
1. Darras BT, et al.Dystrophinopathies. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1119/
2. Juan-Mateu J, et al. DMD Mutations in 576 Dystrophinopathy Families: A Step Forward in Genotype-Phenotype Correlations. PLoS One. 2015 Aug 18;10(8):e0135189.
Clinical characteristics
DMD
•
•
•
•
Progressive symmetric muscle
weakness (proximal greater than
distal) often with calf hypertrophy
Symptoms present < 5years old
Wheelchair dependency < 13
years old
Death at 20-30 years old
BMD
•
•
•
•
•
•
•
Progressive symmetric
muscle weakness and atrophy
(proximal greater than distal)
often with calf hypertrophy
Weakness of quadriceps
femoris may be the only sign
Activity-induced cramping
(present in some individuals)
Flexion contractures of the
elbows (if present, late in the
course)
Wheelchair dependency (if
present, ≥ 16 years old)
Preservation of neck flexor
muscle strength (differentiates
BMD from DMD)
Death at 60 years old
DMD-DCM
•
•
•
Dilated cardiomyopathy with
congestive heart failure, with
males typically presenting
between ages 20-40 years
and females presenting later
in life
Usually no clinical evidence of
skeletal muscle disease; may
be classified as "subclinical"
BMD
Rapid progression to death in
several years in males and
slower progression over a
decade or more in females
1. Darras BT, et al.Dystrophinopathies. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1119/
2. Juan-Mateu J, et al. DMD Mutations in 576 Dystrophinopathy Families: A Step Forward in Genotype-Phenotype Correlations. PLoS One. 2015 Aug 18;10(8):e0135189.
Cardiomyopathy development
Darras BT, et al.Dystrophinopathies. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1119/
Juan-Mateu J, et al. DMD Mutations in 576 Dystrophinopathy Families: A Step Forward in Genotype-Phenotype Correlations. PLoS One. 2015 Aug 18;10(8):e0135189.
Kaspar RW, et al. Current understanding and management of dilated cardiomyopathy in Duchenne and Becker muscular dystrophy. J Am Acad Nurse Pract. 2009
May;21(5):241-9.
Cardiomyopathy
• Subclinical or clinical cardiac involvement:
– 90% of individuals with DMD/BMD
• Cardiac involvement as cause of death
– 20% in DMD
– 50% in BMD
Darras BT, et al.Dystrophinopathies. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1119/
Juan-Mateu J, et al. DMD Mutations in 576 Dystrophinopathy Families: A Step Forward in Genotype-Phenotype Correlations. PLoS One. 2015 Aug 18;10(8):e0135189.
Cardiomyopathy in DMD
•
Incidence:
–
–
–
30% by 14 years
50% by 18 years
~100% > 18 years
•
Initial decline in LV systolic function
•
Clinically overt heart failure may be delayed or absent due to relative
physical inactivity
•
Neither the age of onset nor the severity of cardiomyopathy is correlated
with the type of mutation
Mavrogeni S, et al. Cardiac involvement in Duchenne and Becker muscular dystrophy. World J Cardiol. 2015 Jul 26;7(7):410-4. doi: 10.4330/wjc.v7.i7.410.
Cardiomyopathy in BMD
• Early RV dysfunction – Later LV impairment
• Myocardial damage progression due to strenuous muscle exercise
 pressure or volume overload  mechanical stress harmful for
dystrophin-deficient myocardial cells
• High heart transplantation rate 5 years after diagnosis
• No correlation with the severity of skeletal muscle manifestations or
the deleted exons
Mavrogeni S, et al. Cardiac involvement in Duchenne and Becker muscular dystrophy. World J Cardiol. 2015 Jul 26;7(7):410-4. doi: 10.4330/wjc.v7.i7.410.
Melacini P, et al. Cardiac involvement in Becker muscular dystrophy. J Am Coll Cardiol. 1993 Dec;22(7):1927-34.
Melacini P, et al. Myocardial involvement is very frequent among patients affected with subclinical Becker's muscular dystrophy. Circulation. 1996 Dec 15;94(12):3168-75.
Steare SE, et al. Subclinical cardiomyopathy in Becker muscular dystrophy. Br Heart J. 1992 Sep;68(3):304-8.
Cardiomyopathy in female carriers
•
Hypertrophy, arrhythmias, dilated cardiomyopathy, severe heart failure
necessitating heart transplantation
•
Clinically overt cardiac disease:
–
–
15-55% in carriers < 16 years
45-90% in carriers > 16 years
•
ECG abnormalities: 47%
•
Subclinical cardiac disease
–
–
Exercise to unmask LV systolic dysfunction
cMRI to detect myocardial fibrosis
Mavrogeni S, et al. Cardiac involvement in Duchenne and Becker muscular dystrophy. World J Cardiol. 2015 Jul 26;7(7):410-4. doi: 10.4330/wjc.v7.i7.410.
Florian A, et al. Cardiac involvement in female Duchenne and Becker muscular dystrophy carriers in comparison to their first-degree male relatives: a comparative cardiovascular
magnetic resonance study. Eur Heart J Cardiovasc Imaging. 2015 Jun 25. pii: jev161.
Politano L, et al. Development of cardiomyopathy in female carriers of Duchenne and Becker muscular dystrophies. JAMA. 1996 May 1;275(17):1335-8.
Diagnosis
Kaspar RW, et al. Current understanding and management of dilated cardiomyopathy in Duchenne and Becker muscular dystrophy. J Am Acad Nurse Pract. 2009
May;21(5):241-9.
Biochemistry analyses
• Elevated:
–
–
–
–
–
CPK
CK-MB
cTnI
BNP
NT-proBNP
Matsumura T, et al. Cardiac troponin I for accurate evaluation of cardiac status in myopathic patients. Brain Dev. 2007 Sep;29(8):496-501.
Schade van Westrum S, et al. Brain natriuretic peptide is not predictive of dilated cardiomyopathy in Becker and Duchenne muscular dystrophy patients and carriers. BMC
Neurol. 2013 Jul 16;13:88.
ECG abnormalities
•
ECG / Holter ECG:
–
–
DMD: Abnormal 90%
BMD: Abnormal 75%
•
May precede the onset of cardiac
dysfunction
•
Arrythmias usually occur after the
development of the dilated cardiomyopathy
•
Routine monitoring of ECGs may detect
early cardiomyopathy even if left ventricular
function is still preserved
Bouhouch R, et al. Management of cardiac involvement in neuromuscular diseases: review. Open Cardiovasc Med J. 2008;2:93-6.
James J, et al. Electrocardiographic abnormalities in very young Duchenne muscular dystrophy patients precede the onset of cardiac dysfunction. Neuromuscul Disord. 2011
Jul;21(7):462-7.
Mavrogeni S, et al. Cardiac involvement in Duchenne and Becker muscular dystrophy. World J Cardiol. 2015 Jul 26;7(7):410-4. doi: 10.4330/wjc.v7.i7.410.
Steare SE, et al. Subclinical cardiomyopathy in Becker muscular dystrophy. Br Heart J. 1992 Sep;68(3):304-8.
Santos MA, et al. Duchenne muscular dystrophy: electrocardiographic analysis of 131 patients. Arq Bras Cardiol 2010; 94:620-624.
Petri H, et al. Progression of cardiac involvement in patients with limb-girdle type 2 and Becker muscular dystrophies: a 9-year follow-up study. Int J Cardiol 2015; 182:403-411.
Kaspar RW, et al. Current understanding and management of dilated cardiomyopathy in Duchenne and Becker muscular dystrophy. J Am Acad Nurse Pract. 2009
May;21(5):241-9.
Echocardiography
•
Normal (at initial stages)
•
Valvular insufficiencies
•
Mild to severe myocardial thickening
(at initial stages)
•
Systolic ventricular dyssynchrony
(particularly if EF < 35%)
•
LV dilatation
•
Myocardial strain imaging
–
•
Reduced systolic function (regional
wall motion abnormalities or global
hypokinesia)
•
decreased peak systolic strain of the posterior
wall
Transmural strain profile (TMSP)
–
detect subclinical LV dysfunction
Fayssoil A, et al. Cardiac asynchrony in Duchenne muscular dystrophy. J Clin Monit Comput 2013; 27: 587-589.
Yamamoto T, et al. Utility of transmural myocardial strain profile for prediction of early left ventricular dysfunction in patients with Duchenne muscular
dystrophy. Am J Cardiol 2013; 111: 902-907.
Mori K, et al. Myocardial strain imaging for early detection of cardiac involvement in patients with Duchenne’s progressive muscular dystrophy. Echocardiography 2007; 24: 598-608.
Finsterer J, Cripe L. Treatment of dystrophin cardiomyopathies. Nat Rev Cardiol. 2014 Mar;11(3):168-79.
Su JA, et al. Left Ventricular Tonic Contraction as a Novel Biomarker of Cardiomyopathy in Duchenne Muscular Dystrophy. Pediatr Cardiol. 2015 Dec 29.
Myocardial strain
↓ peak systolic strain of the
posterior wall despite normal
standard echo findings
1.
2.
3.
4.
Fayssoil A, et al. Cardiac asynchrony in Duchenne muscular dystrophy. J Clin Monit Comput 2013; 27: 587-589.
Yamamoto T, et al. Utility of transmural myocardial strain profile for prediction of early left ventricular dysfunction in patients with Duchenne muscular
dystrophy. Am J Cardiol 2013; 111: 902-907.
Mori K, et al. Myocardial strain imaging for early detection of cardiac involvement in patients with Duchenne’s progressive muscular dystrophy. Echocardiography 2007; 24:
598-608.
Transmural strain
profile (TMSP)
LVPW motion abnormality
↓EF
1.
2.
3.
4.
Fayssoil A, et al. Cardiac asynchrony in Duchenne muscular dystrophy. J Clin Monit Comput 2013; 27: 587-589.
Yamamoto T, et al. Utility of transmural myocardial strain profile for prediction of early left ventricular dysfunction in patients with Duchenne muscular
dystrophy. Am J Cardiol 2013; 111: 902-907.
Mori K, et al. Myocardial strain imaging for early detection of cardiac involvement in patients with Duchenne’s progressive muscular dystrophy. Echocardiography 2007; 24:
598-608.
cMRI
•
Late gadolinium enhancement (LGE)
•
Presence of subepicardial fibrosis in the inferolateral wall (similar to that observed in
viral myocarditis)
•
Advantages:
–
–
–
•
Myocardial fibrosis observed even if the echo evaluation remains normal  early sensitive
index to start cardioprotective treatment
Screening tool to detect patients at high risk for ventricular arrhythmias, more advanced
disease, adverse LV remodelling and death
LVEF≤ 45% and “transmural” pattern of myocardial fibrosis independently predict the
occurrence of adverse cardiac events
Dyssynchrony
–
–
mechanical associated with normal QRS complex and extensive lateral fibrosis
unlikely that CRT beneficial
Mavrogeni S, et al. Cardiovascular magnetic resonance imaging evaluation of two families with Becker muscular dystrophy. Neuromuscul Disord 2010; 20: 717-719.
Hor KN, et al. Presence of mechanical dyssynchrony in Duchenne muscular dystrophy. J Cardiovasc Magn Reson. 2011 Feb 2;13:12.
LGE enhancement regions
DMD patients
Female DMD carriers
Hor KN, et al. Prevalence and distribution of late gadolinium enhancement in a large population of patients with Duchenne muscular dystrophy: effect of age and left ventricular systolic
function. J Cardiovasc Magn Reson. 2013 Dec 21;15:107.
Sub-epicardial
LGE type
Mid-myocardial
Sub-epicardial
Mavrogeni S, et al. Cardiovascular magnetic resonance imaging evaluation of two families with Becker muscular dystrophy. Neuromuscul Disord 2010; 20: 717-719.
Giglio V, et al. Patterns of late gadolinium enhancement in Duchenne muscular dystrophy carriers. J Cardiovasc Magn Reson. 2014 Jul 9;16:45. doi: 10.1186/1532-429X-16-45.
Extracellular
volume fraction –
cMRI:
detection of early
‘diffuse’ myocardial
fibrosis that cannot
be depicted by
conventional LGE
Florian A, et al. Myocardial fibrosis imaging based on T1-mapping and extracellular volume fraction (ECV) measurement in muscular dystrophy patients: diagnostic value
compared with conventional late gadolinium enhancement (LGE) imaging. Eur Heart J Cardiovasc Imaging. 2014 Sep;15(9):1004-12.
Myocardial strain - cMRI
Abnormalities are prevalent despite normal EF
Hor KN, et al. Circumferential strain analysis identifies strata of cardiomyopathy in Duchenne muscular dystrophy: a cardiac magnetic resonance tagging study. J Am Coll
Cardiol. 2009 Apr 7;53(14):1204-10.
Other investigations
•
Thallium scintigraphy
–
•
SPECT:
–
–
•
Th-201: Nonreversible myocardial perfusion defects in the
anterior, inferoposterior and apical walls
I-123: hyperactivity of the myocardial sympathetic nervous
system
PET:
–
•
reduced perfusion in the anterolateral, septal and apical LV
walls even in the subclinical stage
globally poor perfusion
Endomyocardial biopsy (no characteristic histological
features)
–
–
–
–
hypertrophy of the myocardiocytes
endocardial or interstitial fibrosis
cytoplasmic lipofuscinosis, focal lymphocytic infiltration, huge,
pleomorphic, bizarre myonuclei of variable size, shape and
staining
focal necrosis
Cardiomyopathy Treatment
•
Initiation in early preclinical stages
•
Optimal management of scoliosis,
noninvasive positive pressure ventilation,
pain therapy
•
ACEi/ ARBs
•
B-blockers
•
Molecular therapies
– Experimental but promising
•
Mineralocorticoid receptor antagonists
(eplerenone)
•
Pacemakers/ ICDs/CRT/CRT-D:
– on the basis of guidelines used for
nonischemic cardiomyopathies
•
Corticosteroids: ambiguous
•
Symptomatic heart failure + arrythmias
– follow well-established guidelines for
the general treatment of cardiac
disease
Finsterer J, et al. Treatment of dystrophin cardiomyopathies. Nat Rev Cardiol. 2014 Mar;11(3):168-79.
Groh WJ. Arrhythmias in the muscular dystrophies. Heart Rhythm. 2012 Nov;9(11):1890-5.
McNally EM, et al. Contemporary cardiac issues in Duchenne muscular dystrophy. Working Group of the National Heart, Lung, and Blood Institute in collaboration with Parent Project Muscular
Dystrophy. Circulation. 2015 May 5;131(18):1590-8.
Politano L, Nigro G. Treatment of dystrophinopathic cardiomyopathy: review of the literature and personal results. Acta Myol. 2012 May;31(1):24-30.
Prognosis
Connuck DM, et al. Pediatric Cardiomyopathy Registry Study Group. Am Heart J. 2008 Jun;155(6):998-1005.
Prognosis
Correlated:
•
•
•
LV systolic dysfunction in echo
Fibrosis in cMRI
SPECT: Th201 uptake in septum
Not correlated:
•
•
•
ECG
Ventricular arrythmias
Late potentials
LGE(+)
LGE(-)
Corrado G, et al. Prognostic value of electrocardiograms, ventricular late potentials, ventricular arrhythmias, and left ventricular systolic dysfunction in patients with Duchenne muscular
dystrophy. Am J Cardiol. 2002 Apr 1;89(7):838-41.
Menon SC, et al. Predictive value of myocardial delayed enhancement in Duchenne muscular dystrophy. Pediatr Cardiol. 2014 Oct;35(7):1279-85.
Naruse H, et al. The relationship between clinical stage, prognosis and myocardial damage in patients with Duchenne-type muscular dystrophy: five-year follow-up study. Ann
Nucl Med. 2004 May;18(3):203-8.
RECOMMENDATIONS
2005
American Academy of Pediatrics Section on Cardiology and Cardiac Surgery. Cardiovascular health supervision for individuals affected by Duchenne or Becker muscular
dystrophy. Pediatrics. 2005 Dec;116(6):1569-73.
RECOMMENDATIONS
2010
2015
McNally EM, et al. Contemporary cardiac issues in Duchenne muscular dystrophy. Working Group of the National Heart, Lung, and Blood Institute in collaboration with Parent
Project Muscular Dystrophy. Circulation. 2015 May 5;131(18):1590-8.
• should begin after confirmation of the diagnosis.
1. Cardiac care of the patient
with DMD or BMD
2. Complete cardiac
evaluation
•
•
•
•
•
3. Typical signs and symptoms
of cardiac dysfunction may not
be present secondary to the
patient’s musculoskeletal
limitations.
•Weight loss, cough, nausea and vomiting, orthopnea, and increased
fatigue with a decreased ability to tolerate the daily regimen may
represent cardiac impairment and should be investigated.
•Development of dilated cardiomyopathy usually precedes the
development of heart-failure symptoms by years and must be
identified at its earliest onset.
4.Signs and symptoms of
cardiac dysfunction should
be treated
history
physical examination
ECG
TTE
MUGA or cMRI in limited echocardiographic windows
• Diuretics
• ACEi
• ARBs
• Mineralocorticoid receptor antagonists
5. Abnormalities of cardiac
rhythm should be promptly
investigated and treated.
6. Respiratory abnormalities
contribute to the
cardiovascular morbidity and
mortality of the disease.
7. Individuals undergoing
treatment with
glucocorticoids
8. Complete cardiac
evaluation should be
undertaken before scoliosis
surgery or other major
surgical procedures.
• Periodic Holter monitoring should be considered for patients
with demonstrated cardiac dysfunction.
• Concurrent evaluation and treatment of respiratory
abnormalities are recommended.Concurrent evaluation and
treatment of respiratory abnormalities are recommended.
• increased cardiac surveillance with specific monitoring for
weight gain and hypertension.
• Consideration should be given to cardiac stress testing (such as
a dobutamine stress echocardiogram) if abnormalities of
cardiac function are present during resting evaluation. Medical
therapy should be optimized before surgery, and the risks and
benefits of the procedure should be discussed in detail with the
patient and the family.
• in patients with severe cardiac dysfunction to
prevent systemic thromboembolic events.
10. Anticoagulation therapy
• actively involved in the care of patients with DMD or
BMD in an intensive care setting.
11. Experienced clinicians
• optimized to the special needs of patients with DMD
or BMD.
12. Nutritional status
RECOMMENDATIONS SPECIFIC FOR CARDIAC
CARE IN PATIENTS WITH DMD
Complete cardiac evaluation at diagnosis or at 6 years old and
at least biennially until 10 years.
Yearly complete cardiac evaluations should begin at
approximately 10 years of age or at the onset of cardiac signs
and symptoms.
Abnormalities of ventricular function on non-invasive cardiac
imaging studies warrant increased surveillance (at least every 6
months) and should prompt initiation of pharmacological
therapy, irrespective of the age at which they are detected.
The usefulness of an internal cardiac defibrillator has not been
established and needs further research.
RECOMMENDATIONS SPECIFIC FOR CARDIAC
CARE IN PATIENTS WITH BMD
Complete cardiac evaluations should begin at
approximately 10 years of age or at the onset of
signs and symptoms.
Evaluations should continue at least biennially.
RECOMMENDATIONS FOR CARDIAC CARE IN
CARRIERS OF DMD OR BMD
Carriers of DMD or BMD should be made aware of the risk of developing
cardiomyopathy and educated about the signs and symptoms of heart
failure.
Patients should undergo initial complete cardiac evaluation in late
adolescence or early adulthood or at the onset of cardiac signs and
symptoms, if these signs or symptoms appear earlier.
Carriers should be screened with a complete cardiac evaluation at a
minimum of every 5 years starting at 25 to 30 years of age.
Treatment of cardiac disease is similar to that outlined for boys with DMD
or BMD.
Conclusions
Cardiomyopat
hy: frequent,
progressive,
major cause of
death
Regular
cardiac reevaluation
DMD - BMD:
X-linked
dystrophin
genetic
disorders
Early
treatment
initiation:
ACEi, bblockers
Efforts to
recognize
subclinical
cardiac
involvement:
ECG, echo,
cMRI