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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 N-Cadherin ↓N-Cadherin 3 weeks Neuregulin growth factors Embryology, 5-8 weeks Vascular endothelial growth factor Angiopoietin-1 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 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 Kaneda et al, Circ 2005 Ritter et al, Mayo Clin Proc 1997 Jenni R et al, Heart 2001 Cross section Azan stain, fibrosis Kaneda et al, Circ 2005 Van Gieson elastin stain Ritter et al, Mayo Clin Proc 1997 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 dysfunction Thallium Hamamichi Y et al, Int J Cardiovas Imag 2001 CMR- increased T2 signal 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 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 1/8412/98 • 34 adults with noncompaction Oechslin et al, JACC 2000 Oechslin et al, JACC 2000 Weiford et al, Circ 2004 Imaging for diagnosis Chow C et al, Circ 2007 Diagnosis- Echocardiography I 0.92+0.07 • X/Y ≤ 0.5 • Apex at end-diastole ▫ Subcostal ▫ Apical 4Ch Chin TK et al, Circ 1990 0.59+0.05 0.20±0.04 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 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 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 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 ▫ 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