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 weeks

Endocardium

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 1997

Jenni R et al, Heart 2001

Kaneda et al, Circ 2005

Cross section

Azan 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 Failure

Diastolic 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