Echocardiography Conference Connie Tsao Jan 21, 2009 LV Noncompaction Echocardiography Conference Connie Tsao Jan 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 weeks Anterolateral mesoderm N-Cadherin Epithelium ↓N-Cadherin Endocardium Myocardium Fuse into single beating heart tube Trabeculations free wall, lower v septum. Exchange diffusion. Thought provide contractile force Cardiac Tube 3 weeks Neuregulin growth factors Trabeculations

Embryology, 5-8 weeks Compaction Endocardium Sub-epicardial space Vascular endothelial growth factor Angiopoietin-1 Sub-epicardial space Microvessels  coronary circulation 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 circulation Lauer RM et al, NEJM 1964 Dusek J et al, Arch Pathol 1975

Ebstein Anomaly and Noncompaction Diastolic noncomp/comp ratios 3.3-3.5. LVEF 60%, RVEF 57%. 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 Charcot Marie Tooth: Hereditary motor sensory neuropathy, defect in myelin gene Nail-patella: autosomal dominant; hypoplastic/no patella, dystrophic nails, and dysplasia of elbows and iliac horns +/- Renal involvement

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 8 pts referred to UCLA , mean 8.9 yrs

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 Mayo: 82% males, Oechslin: 74%,

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 Kaneda et al, Circ 2005 Ritter et al, Mayo Clin Proc 1997 Jenni R et al, Heart 2001

Cross section Azan stain, fibrosis Van Gieson elastin stain Kaneda et al, Circ 2005 Ritter et al, Mayo Clin Proc 1997

Clinical Features Heart failure Arrhythmia Thromboembolism Dyspnea Chest pain Arrhythmia Atrial fibrillation Ventricular tachycardia Thromboembolism CVA/TIA Pulmonary embolism

Heart Failure Restrictive hemodynamics on catheterization 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 dysfunction Thallium CMR- increased T2 signal Hamamichi Y et al, Int J Cardiovas Imag 2001 Ichida F et al, JACC 1999

PET Jenni R et al, JACC 2002 Jenni R et al, Heart 2001

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 36 yo M w/ recurrent VT, echo w/ noncomp, ICD, fired several x, transplt 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 1990 Ritter M et al., Mayo Clin Proc 1997 Oechslin E 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

Apical, inferior, lateral Oechslin et al, JACC 2000

Weiford et al, Circ 2004

Imaging for diagnosis

Outpouching LV close to apex, hypertrabec appearance Chow C et al, Circ 2007

Diagnosis- Echocardiography I 0.92+0.07 0.59+0.05 0.20±0.04 X/Y ≤ 0.5 Apex at end-diastole Subcostal Apical 4Ch 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 34 pts, compared w/ similar groups Jenni R et al, Heart 2001

Noncompacted/ Compacted Ratio Mean±SD Noncompacted/ Compacted Ratio Range 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 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

4Ch of IVNC hearts. None of patients hearts w/ DCM showed path features of IVNC 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 Boyd et al looked at LV trabed at autopsy in 474 normal hearts. 68% prominent trabec but only 4% did count exceed 3, none >5. 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 Similar clinical characteristics between groups Some DCM had perfused recesses and 2 layered structure, but no wall thickening, no hypertrabec or meshwork 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 Ichida et al used Chin’s criteria. Ritter didn’t use # criteria. IVNC similar findings to apical HCM, DCM, ARVC, endocardial fibroelastosis, cardiac mets

Routine 2D TTE With Definity Chow et al, Circ 2007

JACC 2005 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)

Methods 17 segment model Noncompacted segment 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 Healthy volunteers: 91% subjects w/ IVNC in apex, 78% mid, 21% base. Most common ant. Similar in other groups

CMR criteria NC/C ratio >2.3 in diastole Sensitivity 86% Specificity 99% PPV 75% NPV 99%

Followed for 44±40 months; 18 alive (53%) 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 Mean f/u 46 mos; median 32, range 6-179 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 CV events: hospitalization for CHF, thromboembolism, sustained arrhtyhmias, syncope, ICD interventions, heart transplantation, CV death

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