cardiomyopathies andre keren, md דר ' ישראל גוטסמן מערך הלב, הדסה...
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CardiomyopathiesAndre Keren, MD
גוטסמן' ישראל דר , כרם עין הדסה הלב מערך
Cardiomyopathies
• Cardiomyopathies: Heart muscle disease• A myocardial disorder in which the heart
muscle is structurally and functionally abnormal in the absence of:
coronary artery disease, hypertension, valvular disease and congenital heart disease
Cardiomyopathies
• Dilated CM (DCM)
• Hypertrophic CM (HCM)
• Restrictive CM (RCM)
• Arrhythmogenic RV dysplasia (ARVD)
Classification of Cardiomyopathies
Dilated RestrictiveArrhythmogenic RV dysplasia
Hypertrophic
Dilated CM(DCM)
Hypertrophic CM(HCM)
Restrictive CM(RCM)
Normal
מורחבת היפרטרופיתרסטריקטיבי
ת
חלל החדר גודל + + / - N N- /
החדר התכווצות - - + + N- /
השריר עובי N- / + + / +N
ממצאים מורפולוגיים
מורחבת היפרטרופיתרסטריקטיבי
ת
האי סיבתלב ספיקת
סיסטולית דיאסטולית דיאסטולית
המוות סיבתהעיקרית
, לב ספיקת איפתאומי מוות
פתאומי מוות, משתנה פרוגנוזה
לב ספיקת אי
קליניקה עיקרית
Pathogenesis
SarcomereBasic Unit of The Muscle
Genetics of CMP
Genes encoding: Cytoskeletal proteins – DCM:• Beta/delta-sarcoglycan• Dystrophin • desmin and lamin A/C
(intermediate filament)Sarcomeric proteins – DCM/HCM:• Actin• b-myosin heavy chain• a-tropomyosin• cardiac troponin THCM:• cardiac troponin I• titin • myosin light chains
Genetics of CMP
Genetics of CMP
Functional alterations caused by Z-disc mutations
HCM
DCM
Hypertrophic Cardiomyopathy (HCM)
Hypertrophic Cardiomyopathy (HCM)
• Most common genetic cardiovascular disease
• Prevalence 0.2% (1:500) • Autosomal dominant trait • Gene mutations of cardiac sarcomere
proteins• 18 genes and >500 individual mutations
have been identified…
Spirito P, Seidman CE, McKenna WJ, Maron BJ. NEJM 1997;336:775
Genetic Mutations in HCM
Major Mutations in HCM:Risk of 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
Non-Sarcomeric mutations that causeStorage diseases and mimic LV Hypertophy
• Anderson-Fabry disease: X-linked lysosomal storage disease ( -a galactosidase A)
• PRKAG2 mutation
Glycogen accumulation
• Danon disease: LAMP2 mutation X-linked
Massive hypertrophy,
preexitation,
malignant prognosis
Hypertrophic Cardiomyopathy (HCM)
LVHypertrophyLVOT
obstruction
HCM
SEPTUM LV
AO
LV Hypertrophy
Natural History of LV Hypertrophy
Increase in LV hypertrophy after adolescence
HCM - Histopathology
Normal
• Myocardial Disarray
• Fibrosis
Small-vessel disease: Remodeled intramural coronary arteriole with thickened media and narrowed lumen
SAMSystolic Anterior
Motion of MV
LVOT obstructionLeft Ventricular Outflow Obstruction (Dynamic)
Pathophysiology
Mitral Regurgitation
ASHAsymmetric septal
hypertrophy
Mitral valve Abnormalities
Diastolic dysfunction
Clinical Presentation
• Sudden death – ventricular tachyarrhythmias• Asymptomatic• Chest Pain• Limited functional capacity• Progressive heart failure• Embolic stroke
Symptoms• Exertional dyspnea, Exercise intolerance• Fatigue • Chest pain• Syncope
Pathophysiology • LV outflow obstruction - elevated LV
pressures and wall stress• Diastolic dysfunction - impaired LV filling due
to noncompliant and thickened wall• Myocardial ischemia from the small vessel
disease
Diagnosis
• Examination: Characteristic findings• ECG: LVH• Echo: Most useful diagnostic tool• ECG Holter: Arrhythmias• Stress test: Blood pressure response• Catheterization: rule out associated CAD
Triple
BisferiensLVOT
MR
4
Physical findings in HOCM
Maneuvers and HOCM Murmur
Murmur increase:• Valsalva maneuver• Exercise• Standing
ECG in HCM
LVH, ST-T changes, T wave inversion
• Abnormal in 90% of patients
Echocardiography in HCM
LVH, ASH, SAM, MR
Natural History of HCM
Mortality in HCMHigher in younger patients - SCD
Functional Capacity and SCD
Causes of SCD in young athletes
HCM is the major cause of SCD in young & in athletes
LV Hypertrophy and SCD
Significant increase in SCD risk if Max Wall thickness >30mm
Risk Factors:
• Cardiac arrest/sustained VT
• Multiple familial SD• Unexplained syncope• Massive LVH (>3cm)
• Multiple-repetitive NSVT• Abnormal blood pressure on
exercise
• Malignant genotype (troponinT)• End stage disease• Extensive delayed enhancement on MRI• Marked LVOT outflow obstruction (rest)
Highest(>2)
Intermediate(1)
Lowest(0)
ICD
?
Risk Stratification
11%/yr
4%/yr
Therapy
• Reduce LVOT obstruction• Alleviate elevated diastolic pressures• Reduce microvascular ischemia
Beta Blockers, Verapamil, Disopyramide
• Atrial Fibrillation
Amiodorone, Anticoagulants
• Heart Failure
HF therapy
Therapy
Interventions to reduce LVOT obstruction: • Pacemaker (DDD): Reduces obstruction
• Alcohol septal ablation• Surgical myomectomy
Nishimura RA. NEJM 2004;350:1320-7
Septal Myomectomy in HOCM
NEJM 347:1307,2002A. Keren
Septal Ablation in HOCM
Septal Ablation in HOCM Acute Hemodynamic Result
Dilated Cardiomyopathy (DCM)
Normal Heart Dilated Cardiomyopathy (DCM)
Dilated Cardiomyopathy (DCM)
Dilated Cardiomyopathy (DCM)
• Myocarditis: Viral/ Inflammatory• Idiopathic (50%)• Genetic
Dilated Cardiomyopathy (DCM)
• Sensitivity and toxins: alcohol, catecholamines, anthracyclines, irradiation
• Metabolic cardiomyopathy: endocrine abnormalities, glycogen storage disease, deficiencies (hypokalemia), and nutritional disorders
• General systemic disease: connective tissue disorders and infiltrative diseases: sarcoidosis and leukemia
• Muscular dystrophies: Duchenne, Becker-type, myotonic dystrophies
• Neuromuscular disorders: Friedreich ataxia, Noonan syndrome, lentiginosis
Dilated Cardiomyopathy (DCM)
• Peripartum• Tachycardia-mediated• Sarcoidosis
Dilated Cardiomyopathy (DCM)Familial
Genetic (~50%):• Family history• Genetic testing: low yield even in familial
DCM (20-30%)• Promising future (?) with deep sequencing
Myocarditis
Immune Response
DilatedCardiomyopathy
Virus
Genetics
Clinical Presentation
Development of symptoms and signs of heart failure• Gradual symptoms or incidental finding• Progressive symptoms for periods varying
from weeks to months with acute HF due to intercurrent illnesses
• Aggressive, life-threatening fulminant heart failure (fulminant lymphocytic myocarditis, giant cell myocarditis)
Prognosis in DCM
Average five-year mortality of ~20 percent
Prognosis in DCM
Variable survival in patients with dilated cardiomyopathy depending on underlying etiologic basis
Therapy in DCM
• Standard heart failure drug therapy Interventions: • Defibrillator• Biventricular pacingSurgery: • Heart transplantation• LV assist device
Restrictive Cardiomyopathy(RCM)
RCM - Pathophysiology
• Biatrial enlargement• Normal-sized ventricles • Marked interstitial fibrosis
• Increase ventricular wall stiffness
• abnormal diastolic function:• Myocardial fibrosis• Myocardial infiltration• Scarring of the endomyocard • Myocyte hypertrophy
• Impaired diastolic filling of the ventricle → heart failure
Restrictive Cardiomyopathies
Noninfiltrative • Idiopathic cardiomyopathy (50%)* • Familial cardiomyopathy• Hypertrophic cardiomyopathy• Scleroderma• Pseudoxanthoma elasticum• Diabetic cardiomyopathy
Infiltrative • Amyloidosis * • Sarcoidosis * • Gaucher disease• Hurler disease• Fatty infiltration
Storage Disease • Hemochromatosis• Fabry disease• Glycogen storage disease
Endomyocardial• Endomyocardial fibrosis * • Hypereosinophilic syndrome• Carcinoid heart disease• Metastatic cancers• Radiation * • Anthracycline * • Drugs causing fibrous
endocarditis - serotonin, methysergide, ergotamine, mercurial agents, busulfan
Symptoms and Signs• Fatigue, Dyspnea, Exercise intolerance• Right-sided congestive heart failure:
peripheral edema, hepatomegaly, ascites, and anasarca
• Physical examination:• elevated jugular venous pulse, • Kussmaul sign (rising JVP during inspiration)
• S3 and S4 gallops are common• apical pulse is palpable
• Signs and symptoms of systemic disease: amyloidosis, iron storage disease
DifferentiateRestrictive CMP vs Constrictive Pericarditis
• Echocardiography• Cardiac Catheterization• Endomyocardial Biopsy for pathological
diagnosis• MRI (myocard), CT (pericard)
Restrictive Physiology• Increased LV thickness and mass• Abnormal myocardium• Small LV size• Normal systolic function• Biatrial enlargement• Pericardial effusion
Mitral e’ velocities<5cm/sec
DipPlateau
Hemodynamics of Restrictive Physiology
• Elevated left- and right-sided filling pressures• “Square root” sign in ventricular pressure recordings• LV-RV EDP diff>5mmHg • Respiratory LV-RV systolic "concordance“
Prognosis in RCM
Prognosis is worse with infiltrative RCM particularly Amyloidosis
Cardiac Amyloidosis Progressive infiltrative cardiomyopathy - twisted
beta-pleated sheet fibrils - grave prognosis
• Primary - AL protein plasma cell dyscrasias
30% cardiac involvement Chemo/Bone-marrow Tx
• Secondary AA protein less myocardial infiltration
• Familial Transthyretin autosomal dominant
25% significant cardiac involvement, conduction system Neurologic or renal involvement Liver Tx
• Senile ANP or transthyretin – variable infiltration
Cardiac Amyloid
Amyloidosis
• Restrictive Cardiomyopathy• Systolic Heart Failure – progressive disease• Orthostatic Hypotension - amyloid infiltration of the
autonomic nervous system
• Conduction System Disease - Sudden cardiac death: malignant arrhythmias or conduction block
Arrhythmogenic Right Ventricular Cardiomyopathy
(ARVC)
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
• Fibrofatty replacement of RV myocardium• 20% of SCD 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 (desmosome) and/or Calcium homeostasis - reprogrammed myocyte cell biology to a fibrofatty lineage
Arrhythmogenic Right Ventricular Cardiomyopathy
Dx- structural, functional and electrophysiologic abnormalities, secondary to fibrofatty replacement of RV±LV myocytes
Pathology of ARVD
Endomyocardial biopsy of RV from an affected family member; H&E stain; magnification x400. Replacement of myocytes with fatty and fibrous tissue is classic for ARVD.
Ahmad F, Roberts R, et al. Circulation 1998;98:2791
ARVD: NAXOS DISEASE
• Skin - palmar-plantar keratosis
• Woolly hair
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