* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download 1 - Livemedia
Survey
Document related concepts
Heart failure wikipedia , lookup
Remote ischemic conditioning wikipedia , lookup
Echocardiography wikipedia , lookup
Cardiothoracic surgery wikipedia , lookup
Cardiac surgery wikipedia , lookup
Electrocardiography wikipedia , lookup
Coronary artery disease wikipedia , lookup
Cardiac contractility modulation wikipedia , lookup
Management of acute coronary syndrome wikipedia , lookup
Hypertrophic cardiomyopathy wikipedia , lookup
Cardiac arrest wikipedia , lookup
Arrhythmogenic right ventricular dysplasia wikipedia , lookup
Transcript
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