LV NoncompactionEchocardiography Conference

Connie TsaoJan 21, 2009

Terms•Left ventricular noncompaction in

association with congenital abnormalities•Isolated left ventricular noncompaction

▫Left ventricular hypertrabeculation▫Persistent myocardial sinusoids▫Spongy myocardium

Outline• Definitions• Embryology• Pathophysiology• Associations with other disease • Isolated LV noncompaction• Epidemiology• Genetics• Pathology• Clinical Features• Diagnosis

▫ Echocardiography▫ Cardiovascular magnetic resonance

• Prognosis• Management

Definition• Congenital heart

disease• Myocardial wall

distortion▫ Prominent trabeculae▫ Deep intertrabecular

recesses• Continuity between

LV cavity and recesses

• Primary cardiomyopathy in 2006 World Heath Organization classification

Ritter M et al, Mayo Clin Proc 1997

Early Embryology, <5 weeksAnterolateral

mesoderm

Epithelium

Endocardium Myocardium

N-Cadherin

Cardiac Tube

Trabeculations

Neuregulin growth factors

3 weeks

↓N-Cadherin

Embryology, 5-8 weeksEndocardium

Sub-epicardial space

Microvessels coronary

circulation

Vascular endothelial growth factorAngiopoietin-1

Compaction• Base apex

• Epi- endocardium• Intratrabecular

recesses myocardial capillaries

Srivastava D, Nature 2000; and RP, Nature Rev Genetics 2002

Pathogenesis of Noncompaction•Arrest of endomyocardial morphogenesis•Potential pathological processes

preventing regression of sinusoids (Weiford et

al, Circ 2004):▫Pressure overload▫Ischemia

•Not proven

History •First described in association with other

congenital abnormalities▫Obstruction of LVOT/RVOT

Pulmonary atresia with intact ventricular septum

▫Complex cyanotic congenital heart disease▫Anomalous coronary arteries

•Intertrabecular recesses communicate with ventricular cavity and coronary circulationLauer RM et al, NEJM 1964Dusek J et al, Arch Pathol 1975

Ebstein Anomaly and Noncompaction

Bagur RH, et al. Circ 2008

… in association with other disease• Neuromuscular disorders• Metabolic disease• Genetic syndromes

▫Barth syndrome X-linked, dilated CMP, neutropenia, skeletal myopathy,

mitochondrial abnormalities, lactic acidosis G4.5 gene in Xq28: encodes tafazzins proteins:

acyltransferase functions in mitochondria, expressed in heart/muscle cells

▫Charcot-Marie-Tooth▫Nail-patella

Similar phenotypes•Dilated cardiomyopathy•HCM•Restrictive cardiomyopathy•Left-dominant arrhythmogenic

cardiomyopathy▫42 patients with unexplained IL TWI,

arrhythmia of LV origin, and/or LDAC or familial myocardial fibrosis

▫5 patients fulfilled echocardiographic criteria for LVNC

Sen-Chowdhry S et al., JACC 2008

1st Report of Isolated Noncompaction

Epidemiology of Isolated LV Noncompaction•Children Adults, elderly•0.05% (Ritter M et al, Mayo Clin Proc 1997)

▫37,555 echocardiograms 17 cases▫Prominent, excessive trabeculations

•0.014% (Oechslin EN et al, JACC 2000)▫242,857 echocardiograms 34 cases▫Noncompacted/compacted ≥ 2:1

•Men >> women

Genetics• Sporadic or familial• Familial in 18-50% (Oechslin et al, JACC 2000, Chin et al,

Circ 1990, Xing et al, Mol Genet Metab 2006)• Autosomal dominant with incomplete penetrance >

X-linked or autosomal recessive• G4.5 gene of Xq28 region (Bleyl SB et al, Am J Med Genet

1997): taffazin• α-dystrobrevin gene (Ichida F et al, Circ 2001)

▫Links cytoskeleton of myocytes to extracellular matrix• LIM domain binding protein 3/ZASP• Sarcomere genes: β myosin heavy chain (MYH7), α

cardiac actin (ACTC), cardiac troponin T (TNNT2) (Klaassen S et al., Circ 2008)

Pathology

Ritter et al, Mayo Clin Proc 1997Jenni R et al, Heart 2001

Kaneda et al, Circ 2005

Cross sectionAzan stain, fibrosis Van Gieson elastin stain

Ritter et al, Mayo Clin Proc 1997

Kaneda et al, Circ 2005

Clinical Features•Heart failure

▫Dyspnea▫Chest pain

•Arrhythmia▫Atrial fibrillation▫Ventricular tachycardia

•Thromboembolism▫CVA/TIA▫Pulmonary embolism

Heart FailureDiastolic Systolic• Restrictive hemodynamics

on catheterization• Initial presentation as

restrictive cardiomyopathy• Pathophysiology

▫ Abnormal relaxation▫ Decreased compliance

due to volume of trabeculations

• No significant epicardial coronary disease

• Subendocardial hypoperfusion

• chronic microvascular ischemia

Ichida F et al, JACC 1999; Sen-Chowdhry et al, Curr Opin Card 2008

Microvascular dysfunctionThallium CMR- increased T2 signal

Hamamichi Y et al, Int J Cardiovas Imag 2001

Ichida F et al, JACC 1999

PET

Jenni R et al, Heart 2001

Jenni R et al, JACC 2002

Electrophysiology• Atrial fibrillation• Ventricular tachycardia

ECG:• Left or right axis deviation• PR prolongation• Left ventricular hypertrophy• LBBB, RBBB, IVCD• Repolarization abnormalities• In pediatric population:

▫ Sinus bradycardia▫ WPW

Duru F et al, J Cardiovasc Electrophysiol 2000

LVH, T-wave abnormalities

McCrohon, J. A. et al. Circulation 2002;106:e22-e23

Thromboembolism• Stroke• TIA• Pulmonary embolus• Mesenteric infarction• Reported 21-38% • Etiology

▫ Stasis of blood in deep recesses/trabeculations

▫ Atrial fibrillation

Chin TK et al, Circ 1990Ritter M et al., Mayo Clin Proc 1997Oechslin E et al, JACC 2000

Oechslin et al, JACC 2000

Clinical Manifestations• Largest

comprehensive study in adults to date

• Review of all echocardiograms 1/84-12/98

• 34 adults with noncompaction

Oechslin et al, JACC 2000

Weiford et al, Circ 2004

Imaging for diagnosis

Chow C et al, Circ 2007

Diagnosis- Echocardiography I

• X/Y ≤ 0.5• Apex at end-diastole

▫ Subcostal▫ Apical 4Ch

0.59+0.05 0.20±0.040.92+0.07

Chin TK et al, Circ 1990

Diagnosis- Echocardiography II• Compacted and

noncompacted layers of ventricular wall▫ Thickened endocardial

layer▫ Prominent trabeculations▫ Deep recesses▫ Ratio noncompacted to

compacted >2:1▫ End-systole

• Trabecular meshwork in apex or midventricular segments of inferior and lateral wall Jenni R et al, Heart

2001

Noncompacted/ Compacted Ratio Mean±SD

Noncompacted/ Compacted RatioRange

Noncompaction (n=34)

3.5±0.8 2.3-5

Dilated CMP (n=10)

0.8±0.4 0.4-2.0

Hypertensive heart dz (n=9)

1.1±0.5 0.4-2.0

• All p <0.001 vs. noncompaction group • Autopsy validation in 7 of 34 noncompaction patients• Autopsy validation in all dilated cardiomyopathy patients

Jenni R et al, Heart 2001

Jenni R et al, Heart 2001

Jenni R et al, Heart 2001

Weiford et al, Circ 2004 Ichida F et al, JACC 1999

Diagnosis- Echocardiography III•>3 trabeculations protruding from LV wall

▫Apical to papillary muscles▫On single image plane

•Intertrabecular spaces in continuity with ventricular cavity▫Visualized on color doppler

Stollberger C et al, Am J Cardiol 2002

Validation of Jenni criteria•Blinded retrospective review of records

comparing patients with:▫LVNC (n=19)▫Dilated cardiomyopathy (n=31)▫Hypertensive heart disease (n=22)▫Chronic severe valvular disease (n=86)

Mitral regurgitation (n=22) Aortic regurgitation (n=20) Aortic stenosis (bi- and tri-leaflet valves,

n=44)Frischknecht B et al, J Am Soc Echocardiogr 2005

Frischknecht B et al, J Am Soc Echocardiogr 2005

Frischknecht B et al, J Am Soc Echocardiogr 2005

Accuracy of Combined Echocardiographic criteria• 199 patients referred to heart failure clinic• Compared with 60 normal controls• Evaluated all 3 echo criteria• 47 patients (24%) fulfilled any echo criteria

▫Chin et al, 19%▫Jenni et al, 15%▫Stollberger et al, 13%▫Combined: 7% fulfilled all 3 criteria

• 5 controls (8%) fulfilled echo criteria▫4 controls African-American

• Current criteria too sensitive?Kohli S et al, EHJ 2008

An underdiagnosed disease?•27 pediatric patients with noncompaction

(Ichida F et al, JACC 1999)▫Diagnosis missed in 89% patients▫Alternative diagnoses: dilated cardiomyopathy,

apical hypertrophic cardiomyopathy, restrictive cardiomyopathy, myocarditis

• 17 adults identified with noncompaction of 37,555 echos screened (Ritter M et al., Mayo Clin Proc 1997)▫Onset of symptoms to diagnosis: 3.5±5.7 years

Routine 2D TTE With Definity

Chow et al, Circ 2007

•7 patients with clinical noncompaction by echo or CMR (5M, 14-46 years)▫At least 1 of following: similar appearance in 1st

degree relatives, assoc neuromuscular d/o, thromboembolic disease, regional WMA

•Comparison to: Healthy volunteers (n=45), athletes (n=25), HCM (n=39), dilated CMP (n=14), Hypertensive heart dz (n=17), AS (n=30)

JACC 2005

Methods•17 segment model

▫Excluded true apex as thinner wall•Noncompacted segment

▫2 myocardial layers with different tissue compaction

▫Segment of most pronounced trabeculations

•Ratio of noncompacted to compacted myocardium in diastole measured

• Healthy volunteers: 91% subjects w/ NC in apex, 78% mid, 21% base. • Most common anterior• Similar distribution in other groups

• Noncompaction patients significantly greater # segments involved (10±3) than all other groups

CMR criteria• NC/C ratio >2.3 in

diastole▫Sensitivity 86%▫Specificity 99%▫PPV 75%▫NPV 99%

Oechslin et al, JACC 2000

Weiford et al, Circ 2004

Not so poor prognosis?•45 patients referred for cardiomyopathy

▫28M, 17F▫37±17 yrs (13-83)▫Majority in NYHA Class I-II CHF (64%)▫20% NSVT, no sustained arrhythmias▫Medical rx:

60% anticoagulation for EF <25% or thromboembolism 90% ACE-I 47% beta blockers

▫At 46 month followup, 97% mean survival from death or transplantation

Murphy RT et al, EHJ 2005

• 65 pts with suspected noncompaction• 74% symptom-based referral, 26% asymptomatic• Followed for mean 46 ± 44 mos (6-193 mos)• Non-symptom group more benign characteristics

▫Younger, fewer ECG abnormalities, greater LVEF, lower left atrial size

• No difference in extent of noncompaction• No major CV events in asymptomatic group• 31% symptomatic group CV death, transplantation• Independent predictors of CV death, transplantation:

▫NYHA III-IV, ventricular arrhythmias, LA size

Management• Screening 1st degree family members• Treatment of heart failure

▫Medical rx: Improved LVEF, decreased LVM in infant rx with

carvedilol (Toyono M et al, Heart 2001)

▫Consideration of biventricular PPM/ICD• Screening for arrhythmias

▫Consideration of ICD• Anticoagulation

▫Atrial fibrillation and/or LVEF <40%• Heart transplantation

Conclusions•Rare congenital heart disease thought to result

from an arrest in early cardiac embryogenesis▫Genetic and sporadic forms

•Clinical manifestations:▫Heart failure▫Arrhythmias▫Thromboembolism

•Diagnosis by echocardiography or CMR▫Advances in imaging increased recognition

•Variable prognosis, likely long natural history•Treatment based on clinical manifestations