1. Echocardiography Conference Connie Tsao Jan 21, 2009
LV Noncompaction
Echocardiography Conference
Connie Tsao
Jan 21, 2009

2. Terms
Left ventricular noncompaction in association with congenital abnormalities
Isolated left ventricular noncompaction
Left ventricular hypertrabeculation
Persistent myocardial sinusoids
Spongy myocardium

3. Outline Definitions Embryology Pathophysiology
Associations with other disease
Isolated LV noncompaction
Epidemiology
Genetics
Pathology
Clinical Features
Diagnosis
Echocardiography
Cardiovascular magnetic resonance
Prognosis
Management

4. 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

5. 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

6. 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

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

8. Pathogenesis of Noncompaction
Arrest of endomyocardial morphogenesis
Potential pathological processes preventing regression of sinusoids (Weiford et al, Circ 2004):
Pressure overload
Ischemia
Not proven

9. 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

10. Ebstein Anomaly and Noncompaction
Diastolic noncomp/comp ratios LVEF 60%, RVEF 57%.
Bagur RH, et al. Circ 2008

11. … 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

12. 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

13. 1st Report of Isolated Noncompaction
8 pts referred to UCLA , mean 8.9 yrs

15. 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%,

16. 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)

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

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

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

20. 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

21. Microvascular dysfunction
Thallium
CMR- increased T2 signal
Hamamichi Y et al, Int J Cardiovas Imag 2001
Ichida F et al, JACC 1999

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

23. 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

24. LVH, T-wave abnormalities
McCrohon, J. A. et al. Circulation 2002;106:e22-e23

25. 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

26. 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

27. Apical, inferior, lateral
Oechslin et al, JACC 2000

28. Weiford et al, Circ 2004

29. Imaging for diagnosis

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

31. Diagnosis- Echocardiography I
0.20±0.04
X/Y ≤ 0.5
Apex at end-diastole
Subcostal
Apical 4Ch
Chin TK et al, Circ 1990

32. 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

33. 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
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

34. 4Ch of IVNC hearts. None of patients hearts w/ DCM showed path features of IVNC
Jenni R et al, Heart 2001

35. Jenni R et al, Heart 2001

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

37. 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

38. 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

39. 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

40. Frischknecht B et al, J Am Soc Echocardiogr 2005

41. 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

42. 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

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

44. JACC 2005
7 patients with clinical noncompaction by echo or CMR (5M, 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)

45. 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

46. 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

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

52. Followed for 44±40 months; 18 alive (53%)
Oechslin et al, JACC 2000

53. Weiford et al, Circ 2004

54. 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

55. 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

56. 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

57. 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