Cardiomyopathies. Andre Keren, MD

Transcription

1 Cardiomyopathies Andre Keren, MD

2 Cardiomyopathies Heart muscle disease of unknown etiology

3 Elliott P et al. Eur Heart J 2008;29:

4 Definition of Cardiomyopathies Elliott P et al. Eur Heart J 2008;29:

5 Original Classifiacation DCM ARVC RCM HCM Modified from Roberts W, Human Path, 1975

6 Elliott P et al. Eur Heart J 2008;29:

7 Elliott P et Elliott al. Eur P et Heart al. Eur J 2008;29: Heart J 2008;29:

8 Cardiomyopathies Dilated CM (DCM) Hypertrophic CM (HCM) Restrictive CM (RCM) Arrhythmogenic RV dysplasia (ARVD)

9 PATHOLOGY OF CM Nonspecific degenerative changes: DCM, (RCM) Myocardial dissaray: HCM Fatty degeneration/ myocard replacement: ARVD

10 (ryanodine) Seidman GS& Seidman C, Cell 2001:104:557

11 Mode of Inheritance of Cardiomyopathies A=AD, B=AR, C=X linked, D=? Charron P. Eur Heart J 2010;31:

12 Dilated CM DCM

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16 Genetics Virus DNA Mutation Altered gene product T-Cell activation?autoantibodies?cytokines Autoimmunity Myocardial Dysfunction Myocarditis Viral persistence DILATED CARDIOMYOPATHY Adapted from Mestroni et al BHJ 1997;72:S35

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18 Meta-analysis of Clinical Characteristics of 299 Carriers of LMNA Gene Mutations * * *Same proportion of SD in neuromuscular type (43%) as in the isolated cardiac type (50%) van Berlo JH, Pinto YM et al. J Mol Med 2005;83:79-83

19 THERAPY OF DCM Similar to therapy of heart failure - Medical (drugs) - Interventions: pacing for AV block biventricular pacing (CRT) Implantable Defibrillator (ICD) - Surgery: - Heart transplantation

20 Restrictive CM

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23 Cardiac Amyloid

24 Familial HCM with Troponin T mutation DR, 54 y/o, Mother DH, 30 y/o, Daughter, DB, 17 y/o, son

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26 Arrhythmogenic Right Ventricular Cardiomyopathy Dx- structural, functional and electrophysiologic abnormalities, secondary to fibrofatty replacement of RV±LV myocytes

27 ARVC (ARVD) Fibrofatty replacement of RV myocardium 20% of SD in young, in North Italy Familial in >30% of pts - autosomal dominant (clasical ARVC) - autosomal recessive (Naxos disease) Molecular mechanism: - apoptosis due to defective cellular junction and/or Ca homeostasis

28 HISTOLOGY OF ARVD Figure 2. Endomyocardial biopsy of RV from an affected family member; hematoxylin-eosin stain; magnification x400. Replacement of myocytes with fatty and fibrous tissue is classic for ARVD. Ahmad F, RobertsR, et al. Circulation 1998;98:2791

29 Courtesy Corrado D

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31 ARVD: NAXOS DISEASE Figure 1. A, WH as a feature of Naxos disease (non-african ancestry). B and C, Palmar and plantar keratoderma. Note clear demarcation at border with dorsal skin. D, Histopathological preparation of palmar skin biopsy. Severe hyperkeratosis without epidermolysis. Coonar AS et al. Circulation 1998;97:2049

32 Venetian ship on its way to the Holyland

33 T inversion in V1-3 RV Involvement T inversion diffuse RV+LV involvement Epsilon waves

34 Healthy black Athlete Pt with ARVC Corrado D, European Heart J 2010;31:

35 Circulation 2010;121:

36 Hypertrophic CM HCM

37 AO HCM SEPTUM LV

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40 HOCM (Hypertrophic obstructive CM) AO SEPTUM LV

41 HOCM: ASH & SAM (25% of HCM cases 70% post Exercise) MR SAM SAM: Systolic Anterior Motion (of MV)

42 DIAGNOSIS Symptoms: Dyspnea, Chest pain, Syncope Examination: HOCM ECG: LVH ECHO: Most useful Dx tool Holter: Arrhythmias Ex test: BP response Catheterisation: R/O associated CAD

43 DIAGNOSIS Examination: HOCM ECG: LVH ECHO: Most useful Dx tool Holter: Arrhythmias, Non-sustained VT Ex test: BP response (Pathological Decrease) Catheterisation: R/O associated CAD

44 Bisferiens LVOT Physical findings in HOCM 4 triple MR

45 Gradient increase CONTRACTILITY INCREASE PERIPH.RESIST DECREASE VOLUME DECREASE

46 Gradient increase CONTRACTILITY INCREASE PERIPH.RESIST DECREASE VOLUME DECREASE digoxin

47 Gradient increase CONTRACTILITY INCREASE PERIPH.RESIST DECREASE VOLUME DECREASE digoxin nitrates

48 Gradient increase CONTRACTILITY INCREASE PERIPH.RESIST DECREASE VOLUME DECREASE digoxin nitrates diuretics

49 Other maneuvers in HCM

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51 Courtesy

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54 Fig. 1. Diagrammatic representation of the molecular structure of the sarcomere showing the thick (myosin) and thin (actin) filaments and the location of the proteins myosin heavy chain, myosin light chains, myosin binding protein-c, -tropomyosin, troponin T and troponin I that are mutated in HCM. Spirito P, Seidman CE, McKenna WJ, Maron BJ. NEJM 1997;336:775

55 Major Mutations in HCM: their relation to sudden death Beta myosin heavy chain (35%): typical features, both malignant and benign types Myosin binding protein C (15%): late appearance, usually benign Troponin T (15%): mild hypertrophy, malignant

56 Survival in HCM: Genotype Troponin T vs ß-MHC Watkins H et al.1995; 332:1058

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58 THERAPY OF HCM 1. ALL: - Arrhythmias (antiarrhythmics: Amiodarone) - Ischemia (small vessels - Verapamil) - Prevention of bacterial endocarditis (Antibiotics)

59 THERAPY OF HCM 1. ALL: - Arrhythmias (antiarrhythmics: Amiodarone) - Ischemia (small vessels - Verapamil) - Prevention of bacterial endocarditis (Antibiotics) 2. Thearapy of gradient

60 THERAPY OF OBSTRUCTION IN HOCM FOR SYMPTOMATIC RELIEF - Drugs: beta blockers, verapamil Avoid: digoxin, nitrates, diuretics - Interventions: pacemaker DDD alcohol septal ablation -Surgery: myomectomy

61 Nishimura RA. NEJM 2004;350:1320-7

62 A. Keren NEJM 347:1307,2002

63 Septal Ablation in HOCM Acute Hemodynamic Result LV (200 mmhg) AO (200 mmhg) LV LV (200 mmhg) AO (200 mmhg) LV Ao Ao

64 THERAPY OF HCM 1. ALL: - Arrhythmias (antiarrhythmics: Amiodarone) - Ischemia (small vessels - Verapamil) - Prevention of bacterial endocarditis (Antibiotics) 2. Thearapy of gradient 3.PREVENTION OF SUDDEN DEATH RISK STRATIFICATION & ICD

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66 Risk Stratification for Sudden Death in HCM Sudden cardiac death in HCM - Rare (0.5-1%/year), but devastating event for the family, community - ICD prevents SD but is associated with significant long term morbidity - only a minority of pts at risk of SD - what are the criteria for defining pts at risk of SD?

67 Risk of sudden death HCM is the major cause of SD in young & in athletes

68 Asymptomatic 35-Year-old Man. Received ICD prophylactically because of Fam Hx of SD related to HCM and marked IVS thickness (31 mm). The ECG was obtained 4 years &8 months after ICD implantation. The data were recorded at 1:20 a.m. while the patient was asleep. After 4 beats of SR, VT starts, 200 b/min (Panel A). The ICD senses VT and charges (Panel B). The VT deteriorates into VF (Panel C). The ICD discharges appropriately (a 20-J shock denoted by the bar, Panel D) and restores SR. Adapted from Maron et al. 30 Spirito P, Maron BJ, et al. NEJM 2000; 342:1778

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70 Maron BJ, McKenna WJ et al. European Heart J 2003;24:

71 Youth Genotype Family History NYHA III/IV Exercise capacity Syncope Severe LVH Large gradient Diastolic dysfunction Abn Exercise BP Ischaemia Atrial fibrillation Non-sustained VT Inducible VT/VF Fractionation Risk Factors in HCM Family History Syncope Exercise BP NSVT LVH

72 1.0 More Risk Factors Lower is the Survival Cumulative Survival Log Rank for Trend p= N= Log Rank p< Follow-up (months) Elliott PM et al. Lancet 2001;357:

73 Risk factors for Sudden Death in HCM Ressuscitated sudden death Family history of sudden death Syncopes Decrease in BP during exercise Nonsustained VT LVH > 3.0 cm Malignant mutation (like troponint) LVOT Gradient (minor)

74 ACC/ESC Consensus 2003

75 Strongest Risk Factors: Cardiac arrest/sustained VT RISK STRATIFICATION Multiple familial SD Recurrent syncope Multiple-repetitive NSVT Massive LVH (>3cm) Abnormal blood press. on EX. Malignant genotype Highest (>2) ICD Gradient (minor) Intermediate (1) Lowest (0)

76 Prognosis in different beta myosin heavy chain mutations

77 Limited Role of Genetic Testing in risk Stratification of HCM Keren A et al, Nature Clin Pract Cardiovasc Med 2008;5:

78 The Risk/Benefit Ratio of ICD Implantation Preservation of Life Inappropriate Shocks Lead Complications (25%;5%/y) Infection Thrombosis Recalls Courtesy of Barry Maron

79 Complications Inappropriate shocks in 25%* Infection 3.8% Hemorrhage/thrombus 1.6% Lead problems 6.7% ICD malfunction at time of VF in 1patient who died *similar in primary /secondary Maron JB et al. JAMA 2007;298:

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81 The End of Consensus About the Consensus Document

82 Maron JB et al. JAMA 2007;298:

83 Rate of Appropriate Shocks (100 person-yr) % of appropriate shocks Courtesy of Maron BJ Overall p= No. Risk Factors for Primary Prevention Maron, BJ et. al. JAMA 2007;298:405

84 Who Should receive an ICD in HCM?

85 Euroscore principle 2012 ACCF/AHA Guideline 2011 ACC/ESC Consensus Document (2003)

86 Gersh BJ, Maron BJ et al. Circulation Dec 13; 124(24):

87 ADDITIONAL Possible (2003) / Potential (2011)* Risk Factors for SD ACC/ESC 2003; ACCF/AHA 2011 Original Atrial fibrillation Myocardial ischemia LVOT obstruction Intense physical act High risk mutation Additional Young age Gadolinium late enhancement Burned out phase LV apical aneurysm * Risk modifiers

88 A P VS D B Maron MS et. al. Circulation 2008; 118:1541 Figure 1. P D C VS P D LA D E F * * * * * *

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90 Prognostic Value of Late Gadolinium Enhancement Green JJ et al. JACC Cardiovasc Iamging 2012

91 Euroscore principle 2012 ACCF/AHA Guideline 2011 ACC/ESC Consensus Document (2003)

92 ICD IN PRIMARY PREVENTION OF SCD Appropriate Shock Rate is 4.6%/year O Mahony C, Heart 2012;98:

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94 1664 pts>16 ys

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99 Summary of Current Recommendations O RISK FACTOR - REASSURE > 2 RISK FACTORS - ICD 1 RISK FACTOR - ACCF/AHA: - ICD reasonable (FHSCD/LVH/Syncope) - ICD can be useful (NSVT or ABPR + Risk Modifier present) 1 RISK FACTOR - ESC - New guideline Integrated assessment

100 When a thing ceases to be a matter of controversy it ceases to be a matter of interest William Hazlitt

101 Thank you