1. OBJECTIVES 1.Review the background and clinical presentation of left ventricular noncompaction (LVNC). 2.Explore the imaging of LVNC, with emphasis on magnetic resonance imaging (MRI) features and diagnostic criteria. 3.Examine the role of MRI in prognosis of LVNC, and in evaluation of its complications. OBJECTIVES 1.Review the background and clinical presentation of left ventricular noncompaction (LVNC). 2.Explore the imaging of LVNC, with emphasis on magnetic resonance imaging (MRI) features and diagnostic criteria. 3.Examine the role of MRI in prognosis of LVNC, and in evaluation of its complications. References: 1.Weisz, Sara H., et al. "Left ventricular non compaction in children." Congenital Heart Disease 5.5 (2010): 384-397. 2.Chin, Thomas K., et al. "Isolated noncompaction of left ventricular myocardium. A study of eight cases." Circulation 82.2 (1990): 507-513. 3.Bhatia, Nisha L., et al. "Isolated noncompaction of the left ventricular myocardium in adults: a systematic overview." Journal of Cardiac Failure 17.9 (2011): 771-778. 4.Oechslin, Erwin, and Rolf Jenni. "Left ventricular non-compaction revisited: a distinct phenotype with genetic heterogeneity?." European Heart Journal (2011): ehq508. 5.Paterick, Timothy E., and A. Jamil Tajik. "Left ventricular noncompaction." Circulation Journal 76 (2012). 6.Thuny, Franck, et al. "Assessment of left ventricular non-compaction in adults: side-by-side comparison of cardiac magnetic resonance imaging with echocardiography." Archives of Cardiovascular Diseases 103.3 (2010): 150-159. 7.Niemann, Markus, Stefan Störk, and Frank Weidemann. "Left Ventricular Noncompaction Cardiomyopathy An Overdiagnosed Disease." Circulation 126.16 (2012): e240-e243. 8.Petersen, Steffen E., et al. "Left ventricular non-compaction insights from cardiovascular magnetic resonance imaging." Journal of the American College of Cardiology 46.1 (2005): 101-105. 9.Dodd, Jonathan D., et al. "Quantification of left ventricular noncompaction and trabecular delayed hyperenhancement with cardiac MRI: correlation with clinical severity." American Journal of Roentgenology 189.4 (2007): 974-980. 10.Udeoji, Dioma U., et al. "Left ventricular noncompaction cardiomyopathy: updated review." Therapeutic Advances in Cardiovascular Disease 7.5 (2013): 260-273.J 11.Jenni, Rolf, Erwin N. Oechslin, and Bernd van der Loo. "Isolated ventricular non-compaction of the myocardium in adults." Heart 93.1 (2007): 11-15. 12.Bagur, R. H., Lederlin, M., Montaudon, M., Latrabe, V., Corneloup, O., Iriart, X., & Laurent, F. (2008). Ebstein anomaly associated with left ventricular noncompaction. Circulation, 118(16), e662- e664. BACKGROUND LVNC is a rare and incompletely understood disease with an often nonspecific presentation. It is thought to be secondary to arrest in the normal myocardial compaction, which occurs during weeks 5-8 of embryogenesis, as the delivery of oxygen to the myocardium evolves from bathing of blood into the spongy cardiac sinusoids to the compaction of tissue and development of perfusion by coronary arteries. 1,2 LVNC is characterized by persistence of the embryogenic left ventricular wall trabeculae communicating with the ventricular cavity. Up to one-third of the cases of LVNC have a familial link, however the linkage and penetrance are both hetrogenous. 3 There is a suspected shared etiology between LVNC and other cardiomyopathies, suggested by similar mutations in sarcomere protein genes. The transmission is non-uniform, and both X-linked and autosomal dominant inheritance patterns have been identified. 4 The diagnosis of LVNC is complicated by overlap with other cardiomyopathies and acute cardiac disease manifesting as transient noncompaction, as well its nonspecific clinical presentation. The diagnosis of LVNC thus first-most relies on excluding other diagnosis and is then assisted by imaging. BACKGROUND LVNC is a rare and incompletely understood disease with an often nonspecific presentation. It is thought to be secondary to arrest in the normal myocardial compaction, which occurs during weeks 5-8 of embryogenesis, as the delivery of oxygen to the myocardium evolves from bathing of blood into the spongy cardiac sinusoids to the compaction of tissue and development of perfusion by coronary arteries. 1,2 LVNC is characterized by persistence of the embryogenic left ventricular wall trabeculae communicating with the ventricular cavity. Up to one-third of the cases of LVNC have a familial link, however the linkage and penetrance are both hetrogenous. 3 There is a suspected shared etiology between LVNC and other cardiomyopathies, suggested by similar mutations in sarcomere protein genes. The transmission is non-uniform, and both X-linked and autosomal dominant inheritance patterns have been identified. 4 The diagnosis of LVNC is complicated by overlap with other cardiomyopathies and acute cardiac disease manifesting as transient noncompaction, as well its nonspecific clinical presentation. The diagnosis of LVNC thus first-most relies on excluding other diagnosis and is then assisted by imaging. 32 year-old female who presented to ED after failed treatment for diagnosis of chronic bronchitis by her PCP. Patient was in CHF at presentation with reduced ejection fraction (EF) on echocardiogram and an apical thrombus (not shown). MR showed apicolateral C:NC ratio was 3:1, compatible with LVNC, with LVEF of 26%. Patient is medically managed for NYHA Class III CHF, and the LV thrombus resolved post warfarin anticoagulation. 14 year-old male with arrhythmias and long QT syndrome. MR was compatible with LVNC (ratio 3.5:1). Prominent RV trabeculations raised the possibility of RV involvement as well. LVEF was normal. 15 year-old male (above) with exertional chest pain, family history of sudden cardiac death, and MR compatible with LVNC (ratio 2.5:1). The patient’s brother suffered sudden cardiac death (at age 7, post mortem testing was notable for a Myn-7 variant). LVEF was mildly decreased at 51%. Patient was treated with a beta-blocker, empiric aspirin 81 mg daily, and ICD placement. Fig. 1: In a review of fifteen patients with an MRI diagnosis of LVNC (ages 9 – 67, with mean age of 35 years, 11 males and 4 female), we found the majority of patients presented with a clinical history of arrhythmias. Several patients also presented for MRI after echocardiogram with a family history of cardiomyopathy (most commonly hypertrophic cardiomyopathy), with or without sudden cardiac death. The initial clinical presentation of heart failure was in patients with markedly decreased left ventricular ejection fraction (LVEF), 19-26% when quantified on MRI. Most other patients had milder decreased LVEF on quantitative analysis. 25 year-old with premature ventricular contractures and Ebstein’s anomaly (EA). MR was compatible with LVNC (12/17 segments, ratio 4:1) with LVEF of 37%, and possible RV involvement, as suggested by prominent RV trabeculations. Patient also had apically displaced septal leaflet of the tricuspid valve (arrow) with tricuspid regurgitation in keeping with EA. Left ventricular myocardial anomalies have been reported in up to 39% of EA patients. 12 Patient was treated with a beta blocker, an ACE inhibitor, and empiric low-dose aspirin. 58 year-old male (left) with paroxysmal ventricular tachycardia and LVNC (ratio 2.5:1) with normal LVEF of 59%. MRI images also show an atrial septal aneurysm (arrow) without flow jet to indicate a defect. Presence of other concomitant cardiac abnormalities is not uncommon in LVNC, especially in children. 1,5 CLINICAL PRESENTATION The clinical presentation of LVNC is variable and can vary from asymptomatic to severe cardiac dysfunction. Symptoms may include arrhythmias, cardiac failure, cardiac embolism, and sudden death. The most common clinical presentation is heart failure. 3 Variable ECG abnormalities have been reported in LVNC, including ventricular arrhythmias and AV or complete heart block. Presentation with embolic phenomena is rare but may include stroke, bowel ischemia, and pulmonary thromboembolism. The diagnosis if further complicated by possible undulating course of clinical presentation which has been reported in children and young adults. 3 The variable and nonspecific symptomatology may lead to missed or delayed diagnosis. 5 CLINICAL PRESENTATION The clinical presentation of LVNC is variable and can vary from asymptomatic to severe cardiac dysfunction. Symptoms may include arrhythmias, cardiac failure, cardiac embolism, and sudden death. The most common clinical presentation is heart failure. 3 Variable ECG abnormalities have been reported in LVNC, including ventricular arrhythmias and AV or complete heart block. Presentation with embolic phenomena is rare but may include stroke, bowel ischemia, and pulmonary thromboembolism. The diagnosis if further complicated by possible undulating course of clinical presentation which has been reported in children and young adults. 3 The variable and nonspecific symptomatology may lead to missed or delayed diagnosis. 5 IMAGING OF LVNC Imaging of LVNC has strongly relied historically on echocardiogram. However, due to its superior soft tissue contrast and better visualization of the apical and lateral segments of the left ventricle, cardiac MRI has become an adjunct and is used to confirm LVNC. 6 Several diagnostic criteria for imaging diagnosis have been reported with variable sensitivity and specificity. As the specificity of all modalities is imperfect, the first tenant of making the diagnosis of LVNC should be the exclusion of other cardiomyopathies to avoid over-diagnosis. 7 IMAGING OF LVNC Imaging of LVNC has strongly relied historically on echocardiogram. However, due to its superior soft tissue contrast and better visualization of the apical and lateral segments of the left ventricle, cardiac MRI has become an adjunct and is used to confirm LVNC. 6 Several diagnostic criteria for imaging diagnosis have been reported with variable sensitivity and specificity. As the specificity of all modalities is imperfect, the first tenant of making the diagnosis of LVNC should be the exclusion of other cardiomyopathies to avoid over-diagnosis. 7 MRI CRITERIA FOR DIAGNOSIS OF LVNC Diagnosis of LVNC by MRI is also complicated by the normal variability in left ventricular trabeculations which can lead to over diagnosis. This is especially seen at the left ventricular apex (reported in up to 91% of healthy persons). 7,8 Qualitatively, patients with LVNC should have significantly more involved segments (utilizing the American Heart Association 17 segment model) when compared to healthy volunteers or patients with other cardiomyopathies. 8 Several quantitative criteria exist for the diagnosis of LVNC based on echocardiogram (Jenni, Chin and Stöllberger, Belanger, Gebhard), with Jenni et. al examining the left ventricle at end systole. 4,7 Fewer criteria for MRI diagnosis have been described, most notably by Peterson and Jacquier, proposing diagnostic criteria measurements at end diastole. 6 Nearly all studies investigating magnetic resonance (MR) and echocardiogram for the diagnosis of LVNC emphasize the absence of other underlying cardiomyopathy and stress the two-layer appearance in greater than normal distribution. Often, there is suggestion of co-existing right ventricular non compaction (RVNC). However to date, there are no studied quantitative criteria for RVNC. It may be suggested in concomitance if suspected on imaging. 9 MR cine sequences allow for assessment of cardiac function. Thus, MR allows for quantification and observation over time of the most common complication of LVNC, which is heart failure. MR also allows for evaluation of chamber volume, assessment for thrombus formation, and evaluation for other structural anomalies. MRI for LVNC should be performed with gadolinium to access for trabecular and delayed myocardial enhancement (DME). 6 DME may be seen in both non-compacted and compacted segments, indicating fibrosis and scarring. DME can extend to morphologically normal segments, and hypo- perfusion has been reported on perfusion imaging. 8,9 MRI CRITERIA FOR DIAGNOSIS OF LVNC Diagnosis of LVNC by MRI is also complicated by the normal variability in left ventricular trabeculations which can lead to over diagnosis. This is especially seen at the left ventricular apex (reported in up to 91% of healthy persons). 7,8 Qualitatively, patients with LVNC should have significantly more involved segments (utilizing the American Heart Association 17 segment model) when compared to healthy volunteers or patients with other cardiomyopathies. 8 Several quantitative criteria exist for the diagnosis of LVNC based on echocardiogram (Jenni, Chin and Stöllberger, Belanger, Gebhard), with Jenni et. al examining the left ventricle at end systole. 4,7 Fewer criteria for MRI diagnosis have been described, most notably by Peterson and Jacquier, proposing diagnostic criteria measurements at end diastole. 6 Nearly all studies investigating magnetic resonance (MR) and echocardiogram for the diagnosis of LVNC emphasize the absence of other underlying cardiomyopathy and stress the two-layer appearance in greater than normal distribution. Often, there is suggestion of co-existing right ventricular non compaction (RVNC). However to date, there are no studied quantitative criteria for RVNC. It may be suggested in concomitance if suspected on imaging. 9 MR cine sequences allow for assessment of cardiac function. Thus, MR allows for quantification and observation over time of the most common complication of LVNC, which is heart failure. MR also allows for evaluation of chamber volume, assessment for thrombus formation, and evaluation for other structural anomalies. MRI for LVNC should be performed with gadolinium to access for trabecular and delayed myocardial enhancement (DME). 6 DME may be seen in both non-compacted and compacted segments, indicating fibrosis and scarring. DME can extend to morphologically normal segments, and hypo- perfusion has been reported on perfusion imaging. 8,9 LV Cavity Trabeculations Recesses Compacted myocardium Non-compacted myocardium MRI CASES OF LVNC Fig. 2: There are greater than normal number of trabeculations with deep intervening recesses in LVNC. Quantitative measurement may be obtained on MRI in end-diastole by measuring the non-compacted layer and dividing it by the measurement of the compacted layer. A ratio of >2.3 has high diagnostic accuracy for distinguishing LVNC from trabeculations observed in healthy, dilated, or hypertrophied hearts. PROGNOSIS AND TREATMENT LVNC has variable clinical progression. Imaging features such as degree of non-compaction have poor correlation with quantitative LV systolic dysfunction. 9 DME and enhancement of the trabeculae have been suggested to be more prevalent in rapidly progressive cases of heart failure. 9 The morbidity of LVNC is high secondary to limitation by heart failure, arrhythmias, and embolism. Therapeutic goals are directed towards improving cardiac function and managing clinical symptoms. 10,11 Due to the deep trabecular recesses and decreased contractibility there is a propensity for formation of blood clots. Low dose prophylactic anticoagulation is often implemented but there is no current consensus on prophylactic anticoagulation therapy. 11 PROGNOSIS AND TREATMENT LVNC has variable clinical progression. Imaging features such as degree of non-compaction have poor correlation with quantitative LV systolic dysfunction. 9 DME and enhancement of the trabeculae have been suggested to be more prevalent in rapidly progressive cases of heart failure. 9 The morbidity of LVNC is high secondary to limitation by heart failure, arrhythmias, and embolism. Therapeutic goals are directed towards improving cardiac function and managing clinical symptoms. 10,11 Due to the deep trabecular recesses and decreased contractibility there is a propensity for formation of blood clots. Low dose prophylactic anticoagulation is often implemented but there is no current consensus on prophylactic anticoagulation therapy. 11