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