Section 3 -

Ventricular Noncompaction Glenn P. Taylor Department of Laboratory Medicine and Pathobiology University of Toronto Department of Pediatric Laboratory Medicine Hospital for Sick Children Toronto , ON

Ventricular noncompaction, also called ventricular hypertrabeculation, persistent spongy myocardium, dysplastic cardiac development and other designations, is a pathologically, diagnostically and clinically controversial entity characterized by aberration of the trabecular morphology of the heart ventricles, chiefly the left [1, 2]. The ventricular dysmorphology occurs with otherwise structurally normal heart, designated isolated ventricular noncompaction, and in the presence of significant congenital heart anomalies. Occasional reports from the early part of last century included descriptions corresponding to ventricular noncompaction, but only in the last 30 years, predominantly in the last 10, has there been detailed clinicopathologic investigation of this condition [3]. Contemporary reports generally restrict discussion to noncompaction without associated congenital heart malformations. Despite growing appreciation of ventricular noncompaction, its status as a specific entity remains uncertain, as reflected by its listing in the "unclassified cardiomyopathy" group of the 1995 WHO/ISFC classification of cardiomyopathies [4] Definition Ventricular noncompaction is characterized by excessively prominent ventricular trabeculae with deep intertrabecular recesses that do not communicate with the coronary circulation. The abnormality chiefly affects the apical and mid-ventricular portions of the left ventricle free wall, although the right ventricle may be involved as well rarely the septum. Both anatomical and echocardiographic features have been proposed, but the definitive diagnostic criteria remain debated [5, 6]. Most of the recent literature on the morphology of noncompaction concerns imaging studies, particularly echocardiography, and relates to the left ventricle. Echocardiographic findings used to diagnose isolated left ventricular noncompaction include: Multiple prominent ventricular trabeculations with deep intertrabecular recesses demonstrating continuity with the ventricular cavity by colour Doppler imaging [7]. More than three prominent trabeculae apical to the papillary muscles [2]. The above with the left ventricle demonstrating a two layered myocardium having a ratio of thickness of noncompacted-to-compacted myocardium > 1.4 [8]. A two-layered myocardium with the end systolic thickness of the noncompacted subendocardial layer more than twice the thickness of the compacted subepicardial layer [6]. A recent magnetic resonance imaging study concluded that a diastolic noncompacted-to compacted ratio > 2.3 reliably identified left ventricular noncompaction [9]. Burke and colleagues have to date reported the most detailed anatomical pathology review of ventricular noncompaction [5]. Of the 14 hearts examined, 12 were from infants, 1 from an adolescent and 1 from a young adult. One heart was an explant. Ten cases had associated, but generally minor, cardiac anomalies. Nine of the individuals presented with sudden death. Only one heart had normal weight for age, the others were up to three times heavier than expected. The hearts were selected on the basis of two key gross features: 1) poorly developed left ventricle papillary muscles and 2) in the midventricle to apex a two layered myocardium having a prominent "spongy" inner zone of irregular trabeculae and recesses and a compacted outer layer that was 50% or less of the full thickness of the ventricle. Microscopy in some cases demonstrated the endocardial-lined recesses extending to within 1 mm of the epicardium. Additional findings included endocardial fibroelastosis and subendocardial replacement fibrosis of varying extent. Right ventricle involvement, defined as a noncompacted zone greater than 75% of the thickness of the ventricle, occurred in 6 cases. Similar anatomic findings have been reported in other series, although papillary muscle abnormalities have not been generally emphasized [10]. Gross variants include hemangioma-like "spongy" myocardium and thinned myocardium with excessive luminal surface trabeculations and cords [2]. Thrombi may develop in the deep recesses and be potential sources of systemic thromboembolism. Noncompaction affects the right ventricle in less than half of cases and only rarely the interventricular septum. The differential diagnosis, both anatomically and with imaging studies, must consider enlarged trabeculae associated with ventricular hypertrophy and sometimes dilated cardiomyopathy, endomyocardial fibroelastosis, mural thrombi and prominent trabeculae (although usually less than 3), cords and false tendons often seen in normal hearts [1]. Etiology Ventricular noncompaction is most widely believed to be a failure in the normal condensation of ventricular myocardium that occurs during embryogenesis when development of the coronary circulation supersedes perfusion of the myocardium by intracavitary diffusion [1]. Additional cardiac anomalies may accompany this aberrant development, including of the coronary arteries and conotruncal derivatives. In approximately 20% of cases of Ebstein malformation of the tricuspid valve, a right ventricle myocardial developmental abnormality, the left ventricle shows noncompaction-type changes. About half of reported pediatric cases of isolated noncompaction have familial association, whereas in adults familial recurrence is reported in less than 20% of cases. There is genetic heterogeneity. Ventricular noncompaction occurs in some cases of Barth syndrome, an X-linked disorder involving Xq28. Other X-linked cases without Barth syndrome have been mapped to the same genetic region. The candidate gene is tafazzin (G4.5). Emery-Dreifuss muscular dystrophy and myotubular myopathy also map to the Xq28 region. Familial association in adults is more often autosomal dominant. Genetic abnormalities involving 18q12.1-q12.2 (alpha-dystrobrevin gene), del(5)(q35.1-35.3) (cardiac specific homeobox, CSX) and 11p15 have been identified [11]. Other syndromes associated with ventricular noncompaction include Noonan, Roifman, Melnick-Needles and Nail-Patella. About a third of the reported affected children demonstrate characteristic facial dysmorphism [12]. Stollberger and Finisterer argue that, at least for the adult population, other etiologies than aberrant embryonic development should also be considered for ventricular noncompaction, and that it may represent a morphologic endpoint of different pathogenetic mechanisms [2]. Supporting the possibility for acquired etiologies of noncompaction are serial echocardiographic observations of the development of noncompaction in apparently originally normal hearts. As well, ventricular noncompaction has been documented with aortic stenosis, pulmonary atresia with intact ventricular septum and other congenital cardiac anomalies that promote high intracavitary ventricular pressures. This suggests that the noncompaction-like appearance in these settings might instead represent hypertrophic and ischemic consequences of the hemodynamic challenge rather than a primary developmental anomaly. Epidemiology Ventricular noncompaction has been considered rare, with a reported incidence of 0.014% for isolated noncompaction in a prospective echocardiographic study of adult patients [13]. Other echocardiography studies with mixed age populations report prevalence from 0.05% to 0.24%. Two large retrospective echocardiography studies of pediatric populations similarly determined noncompaction accounts for approximately 10% of diagnosed cardiomyopathies (hypertrophic cardiomyopathy, in comparison, accounted for approximately 25% of pediatric cardiomyopathy) [8, 14]. The prevalence of ventricular noncompaction in these studies was about 0.12%. The pediatric groups show an approximate 60% male predominance, similar to the sex distribution over all age groups noted in a review of published cases [2]. Diagnosis has been made antenatally and in the aged. Clinical The major clinical consequences of isolated ventricular noncompaction are heart failure, dysrhythmias, and thromboembolic events. Decreased systolic function is reported in the majority of patients, but impaired diastolic function and restrictive-type dysfunction also occur. The cardiac rhythm disorders include ventricular arrhythmias, supraventricular tachycardias, atrial fibrillation, Wolff-Parkinson-White syndrome, complete heart block and bundle branch block. Sudden death is a well-appreciated occurrence in patients with ventricular noncompaction. In the adult population, thromboembolic events such as cerebrovascular accidents are reported to occur in approximately 20 to 40% of patients. In children, where noncompaction is more likely to be secondary than in the adult population, other cardiac malformations and syndromic manifestations contribute to the clinical concerns. Stollberger and Finisterer have stressed, at least for the adult population, the importance of neuromuscular disease such as Becker's muscular dystrophy, myotonic dystrophy and various metabolic myopathies, that affect up to 80% of patients with ventricular noncompaction. The prognosis for patients with ventricular noncompaction has been considered poor, with 50% to 60% of patients dying or undergoing cardiac transplantation within 5 to 6 years [13] A recent pediatric series reported unfavourable outcome at 3 years from diagnosis in 27% of patients [15]. Despite these studies, asymptomatic patients with ventricular noncompaction and patients demonstrating waxing and waning of symptoms are reported. Treatment for noncompaction includes management of heart failure, antiarrhythmic drugs and anticoagulation. Biventricular pacemakers and implantable defibrillators may be considered. Heart transplantation has been performed. Screening of first degree relatives for noncompaction and investigation of patients with noncompaction for neuromuscular disorders have been advocated. References Freedom RM, Yoo SJ, Perrin D, et al. The morphological spectrum of ventricular noncompaction. Cardiol Young. 2005;15:345-64. Stollberger C, Finsterer J. Left ventricular hypertrabeculation/noncompaction. J Am Soc Echocardiogr. 2004;17:91-100. Dusek J, Ostadal B, Duskova M. Postnatal persistence of spongy myocardium with embryonic blood supply. Arch Pathol. 1975;99:312-7. Richardson P, McKenna W, Bristow M, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation. 1996;93:841-2. Burke A, Mont E, Kutys R, et al. Left ventricular noncompaction: a pathological study of 14 cases. Hum Pathol. 2005;36:403-11. Jenni R, Oechslin E, Schneider J, et al. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart. 2001;86:666-71. Agmon Y, Connolly HM, Olson LJ, et al. Noncompaction of the ventricular myocardium. J Am Soc Echocardiogr. 1999;12:859-63. Pignatelli RH, McMahon CJ, Dreyer WJ, et al. Clinical characterization of left ventricular noncompaction in children: a relatively common form of cardiomyopathy. Circulation. 2003;108:2672-8. Petersen SE, Selvanayagam JB, Wiesmann F, et al. Left ventricular non-compaction: insights from cardiovascular magnetic resonance imaging. J Am Coll Cardiol. 2005;46:101-5. Ritter M, Oechslin E, Sutsch G, et al. Isolated noncompaction of the myocardium in adults. Mayo Clin Proc. 1997;72:26-31. Weiford BC, Subbarao VD, Mulhern KM. Noncompaction of the ventricular myocardium. Circulation. 2004;109:2965-71. Chin TK, Perloff JK, Williams RG, et al. Isolated noncompaction of left ventricular myocardium. A study of eight cases. Circulation. 1990;82:507-13. Oechslin EN, Attenhofer Jost CH, Rojas JR, et al. Long-term follow-up of 34 adults with isolated left ventricular noncompaction: a distinct cardiomyopathy with poor prognosis. J Am Coll Cardiol. 2000;36:493-500. Nugent AW, Daubeney PE, Chondros P, et al. The epidemiology of childhood cardiomyopathy in Australia. N Engl J Med. 2003;348:1639-46. Wald R, Veldtman G, Golding F, et al. Determinants of outcome in isolated ventricular noncompaction in childhood. Am J Cardiol. 2004;94:1581-4.