Clinical presentation and diagnosis

The macroscopic hallmark of the lesion is the appearance of prominent trabeculations in the luminal surface of the ventricle, with deep recesses between the trabeculations that extend into the ventricular wall, but which do not communicate with the coronary circulation (Fig. 1). Histologically, the findings are non-specific, ranging from normal myocardium to acquired fibrotic changes superimposed on the background of normal myocardium.¹

Figure 1. (A) Left ventricular non-compaction in the context of a ventricular septal defect (VSD) in an adult. Note the deep trabeculations extending throughout the left ventricle (AO; aorta, MV; mitral valve). (B) parasternal long axis transthoracic echocardiograph of an adult patient with isolated non-compaction of the left ventricle at end diastole, showing predominantly apical trabeculations (arrowed). (C) short axis transthoracic echocardiograph at the midcavity level showing grossly thickened trabeculated myocardium (arrowed) in a different patient.

Non-compaction can occur in association with numerous congenital cardiac malformations, including atrial and ventricular septal defects, aortic stenosis, and aortic coarctation. When no other congenital lesion is present, the lesion is said to be isolated. A male predominance has been suggested, but this has not been confirmed in recent studies.² Until quite recently, isolated ventricular non-compaction was thought to be extremely rare in adults. Its true prevalence remains uncertain, with published figures varying between 0.05 and 0.24%.¹ It is almost certain that greater awareness of the disease, and continuing improvements in diagnostic techniques, have increased the frequency of the diagnosis.

Presentation with symptoms of cardiac failure and arrhythmia is described at all ages. Familial occurrence, with X-linked and autosomal dominant inheritance, is also reported.^{3, 4} In many instances non-compaction, when seen in children, is associated with neuromuscular abnormalities and facial dysmorphism.⁵

Several papers have suggested that afflicted patients have poor left ventricular function, with a high incidence of ventricular arrhythmias and systemic thromboembolism.^6–8 Recent studies, nonetheless, report a much lower incidence of death, stroke, or documented sustained ventricular arrhythmia, probably reflecting the increased identification of pre-clinical or mild cases.^{9, 10}

The echocardiographic criterions for diagnosis have been discussed elsewhere.^10–12 The simplest criterion for diagnosis is that the distance from the epicardial surface to the peak of trabeculations is double, or more, of the distance from the surface of the epicardium to the trough of ventricular trabeculations.¹¹ Other more complex echocardiographic methods have been proposed.¹² A role for echocardiographic contrast to increase the sensitivity of diagnosis has been suggested.¹² Cardiac magnetic resonance imaging has also been reported to be a sensitive tool for diagnosis of ventricular non-compaction,¹³ but formal diagnostic criterions have not yet been formulated. Furthermore, discrepancies have been reported between magnetic resonance and echocardiographic appearances of the same heart.¹⁴ This emphasises that the diagnosis of non-compaction of the ventricles on morphological grounds is sometimes problematic. Advances in imaging technology, coupled with a deeper understanding of the biology of normal and abnormal ventricular trabeculation, may be helpful in this regard in the future.

Normal development of the left ventricle

The most cogent model of ventricular development is the “ballooning” model, in which the future apical components of both ventricles are considered to grow outwards from the outer curve of the looped tubular heart.¹⁵ Trabeculations in the embryonic heart are first evident from day 9.5 in the mouse, and at the end of the fourth gestational week of the human (Carnegie Stage 12),¹⁶ when endocardium evaginates through the cardiac jelly to contact the adjacent myocardium. It is postulated that this process initiates the formation of myocardial trabeculations, which at this stage are finger-like projections of myocardium protruding into the ventricular lumen, when seen in section,¹⁵ although the overall arrangement of the trabeculations may be more accurately described as “sponge-like”.¹⁷ It has been argued that this trabeculation allows oxygen to diffuse rapidly to the growing myocardium in the absence of coronary arteries. Indeed, the process of compaction, whereby these large embryonic trabeculations are remodelled, is coincident with development of the coronary arteries.¹⁷ Rather than being a process of resorption, compaction may be a function of changes in ventricular size and shape, leaving a reduced inner layer of trabeculations, with the compacted layer then forming the ventricular walls and conduction system.¹⁷ In hearts with non-compaction, there is an increase in the trabeculated relative to the compact layer of the ventricular walls. It is possible that this represents defective embryonic development of the ventricular walls, the effects of which are only clinically apparent many years later.

There is circumstantial evidence supporting this hypothesis. During development, Connexins 40 and 43, molecules which are integral components of the embryonic and mature conduction systems,¹⁸ are highly enriched in the non-compact as compared to the compact layer.¹⁵ Later, these molecules are found in the mature conduction system, and in the compact ventricular layer, implicating the embryonic non-compact ventricular layer as a source of the cells that form the definitive conduction system during ventricular compaction. It is of note that, as mentioned earlier, a high incidence of cardiac arrhythmias has been reported in patients with non-compaction.

Defects in the coronary microcirculation have also been reported with ventricular non-compaction,^{7, 19} suggesting that the vascularisation of the abnormal myocardium is affected. This abnormal coronary microcirculation may not be confined to obviously non-compacted ventricular segments.²⁰ Given the evidence of abnormal cardiac conduction and myocardial perfusion in this condition, it is very likely that isolated ventricular non-compaction represents a failure of normal ventricular development.

Control of ventricular development

The genetic factors controlling the early development of the ventricle are not fully understood. The fact that non-compaction does not represent a catastrophic defect in ventricular formation suggests that the developmental defect may affect the later maturation process of the ventricle, rather its initial specification. It is possible to identify several processes involved in development of the ventricular myocardium which could, in theory, lead to non-compaction if disrupted.

The growth patterns of individual embryonic cardiomyocytes have been studied in chick by marking cells with replication-defective LacZ-encoding virus,²¹ revealing a complex pattern of growth, whereby an individual myocyte gives rise to a cone-shaped clone of progeny myocytes reaching into the trabeculated layer, with the outer layers of cardiomyocytes exhibiting the highest rates of cell division. This fits with a model whereby the epicardium acts as a source of proliferative paracrine signalling to myocytes, which proliferate inwards. Retinoic acid and erythropoietin have been implicated as secreted epicardial factors controlling mitosis of the ventricular myocytes,^{22, 23} acting through their upregulation of fibroblast growth factor signalling.²⁴ Furthermore, experimental studies have shown that the cardiac-specific null mice for retinoic acid RXRalpha receptor exhibit dilated and thin ventricles.²⁵ Fibroblast growth factor, retinoic acid, and erythropoietin have not yet been implicated as genes involved in human cardiomyopathic disease, perhaps reflecting that disruption of these signalling molecules, which participate in many embryonic processes, is incompatible with a viable embryo.

Current knowledge of transcription factors controlling the early development of the ventricle is incomplete, and a full review is beyond the scope of this article. The reader is directed to several excellent recent reviews.^26–30 Mutations in several genes encoding transcription factors, nonetheless, have been shown to disrupt left ventricular formation, albeit that no single transcription factor null allele has been shown to prevent left ventricular function in isolation. This could be explained by the existence of large nuclear “transcription complexes”, made up of several transcription factors, which may participate in multiple stages of ventricular development, both the initial phase of “specification”, and the later “morphogenetic” phase of modelling. The hypothesis that transcription factors participate at multiple points in cardiac development is now supported by a wealth of experimental evidence.

The homeobox factor Nkx2.5, the first candidate for a “master regulator” of cardiac development, was isolated after searching for homologues of the Drosophila gene tinman. This gene, when deleted, results in absence of the dorsal vessel, the equivalent of the heart in the fly.^{31, 32} Nkx2.5 has been shown to associate physically with the T-box factors Tbx5³³ and Tbx20,³⁴ and GATA4,³⁵ to modulate expression of a large set of downstream genes. Nkx2.5 is a key node in the transcriptional network controlling specification of the cardiomyocytes and development of the chambers. To date, 26 mutations in Nkx2.5 causing human disease have been isolated.³⁶ Polymorphisms in the human Nkx2.5 gene have been associated with congenital cardiac malformations, as well as conduction defects.^{28, 37} As yet, no mutation in this gene has been associated with a human cardiomyopathy. Experimental evidence now suggests that Nkx2.5 could, in theory, also be a candidate gene for human cardiomyopathy. The Nkx2.5 null mouse is non-viable, and arrests early in development with an unlooped and hypoplastic heart, reflecting a role for the gene in early cardiac development.^{38, 39} Using a cardiac muscle-restricted null mouse circumvents the multiple developmental roles of Nkx2.5.⁴⁰ This late-stage cardiomyocyte Nkx2.5-null mouse exhibits heart block, and increased ventricular trabeculations. Interestingly, these defects were found to be progressive as the animal aged. In this respect, the model proposed by the authors was failure of recruitment of cells to the conduction system during embryogenesis, and overgrowth of cardiomyocytes throughout embryonic and adult life. Thus, Nkx2.5, or interacting/downstream factors, may be candidates for disease-causing genes in isolated ventricular non-compaction.

The importance of the action of secreted signalling molecules on the developing ventricles is also now being recognised. Bone Morphogenetic Protein 10 (BMP10) is unique among the large and widely expressed transforming growth factor beta family of secreted signalling molecules in that expression is restricted to the trabeculations of the wild-type ventricle.⁴¹ Deletion of BMP10 in transgenic mice results in intrauterine death, with decreased proliferation of ventricular cardiomyocytes and abnormal trabeculation,⁴² as does cardiac-restricted deletion of the receptor ALK3.⁴³ Significantly, the cardiomyocyte-restricted Nkx2.5 null mouse mentioned above exhibits raised levels of BMP10. Furthermore, driving ectopic BMP10 expression in the heart was found to result in hypertrabeculation.⁴⁰

A secreted antagonist of type 1 receptors of transforming growth factor β/bone morphogenetic protein, FK506 binding protein 12, has been implicated in cardiac hypertrophy.^{44, 45} The null mutant mouse for FK506 binding protein 12 exhibits large ventricular trabeculations, increased mitosis of myocytes, and upregulated expression of BMP10.⁴² Human mutations in FK506 binding protein 12 have been sought in human pedigrees exhibiting isolated ventricular non-compaction, but as yet none have been found.⁴⁶

None of these cardiac transcription factors or signalling molecules have yet been implicated as a gene for non-compaction in the human, although mutations in Nkx2.5 and Tbx5 have been associated with other human cardiac phenotypes.^{37, 40, 47} Genotyping of human pedigrees exhibiting isolated ventricular non-compaction for factors such as Nkx2.5 and BMP10 is awaited.

The molecular basis of isolated ventricular non-compaction in humans

While most human disease alleles for non-compaction remain unknown, the disease has been noted to be a genetically heterogeneous condition.⁴⁸ Several genetic locuses have been found to associate with ventricular non-compaction in affected pedigrees. An example is the gene G4,5 mapping to Xq28, which encodes tafazzin, and which may be the disease allele for the Barth syndrome, an X-linked syndrome affecting skeletal and cardiac muscle.^49–52 Deletion of a segment of chromosome 5q has also been reported to result in ventricular non-compaction,⁵³ and most recently, a gene mapped to 11p15 has been implicated in non-compaction.⁴ Additionally, ventricular non-compaction has been described as part of a number of congenital syndromes.¹

In a minority of human pedigrees, mutations have been found in genes encoding cytoskeletal components, such as tafazzin, or dystrophin,⁷ contractile proteins such as cypher/ZASP,⁵⁴ and nuclear envelope proteins such as emerin, or lamin A/C.⁵⁵ It is unclear as to why these mutations should cause the phenotype for non-compaction as opposed to dilated cardiomyopathy. It is possible that disruption of a putative signalling pathway involving Nkx2.5 and/or BMP10 and cytoskeletal proteins, leads to subtle alterations in ventricular morphology, and results in non-compaction.

A key question is whether adults presenting with isolated ventricular non-compaction have developed the phenotype in adulthood, or whether a sub-clinical abnormality has been present from birth. Children with hypertrabeculated left ventricular myocardium have been identified during screening of pedigrees, but it is not yet determined whether all of these individuals will go on to develop the phenotype for ventricular non-compaction. Experimental work outlined above gives at least a theoretical basis for a molecular defect that causes development of a progressive phenotype in adulthood. Another important question is whether the lesion in human ventricular non-compaction is progressive, as in these mouse models. It has been suggested that, in ventricular non-compaction presenting during childhood, the lesion is detectable at birth, and ventricular remodelling delays clinical presentation by several years.⁹ Whether this is true for disease presenting for the first time during adulthood is an open question. Interestingly, “acquired” non-compaction lesions not detected during fetal ultrasonography have been reported,⁵⁰ implying either that non-compaction could develop postnatally, or that early detection of abnormal ventricular morphology was at that time imperfect. More recently, successful detection of the non-compaction phenotype during fetal life has been reported.⁵⁶

Transgenic mouse technology is now at the point where it is possible to limit misexpression of control molecules to a given temporo-spatial point in cardiac development, thereby facilitating experiments that can examine subtle defects in cardiac development that may result in non-compaction in man. The future identification of human genes responsible for ventricular non-compaction will also shed light on the molecular basis of the disease.

Challenges for the future

The emergence of non-compaction as a new diagnosis in clinical cardiology is presenting clinicians with many diagnostic and therapeutic dilemmas. For example, data from the families of patients with isolated ventricular non-compaction, showing that isolated ventricular non-compaction can occur with or without dilated and hypertrophic cardiomyopathy in the same family suggest that, at least in some instances, isolated ventricular non-compaction is a marker of an underlying disease process rather than its primary cause.⁷ Perhaps an even greater problem is the identification of increasing numbers of patients with prominent trabeculations not fulfilling the published criterions for isolated ventricular non-compaction. Do such individuals have normal hearts, or could they be a preclinical manifestation, or forme fruste, of the more extreme phenotype? Some unconfirmed reports have also suggested that the phenotype for isolated ventricular non-compaction may appear during adult life in patients with myotonic dystrophy, or as a transient phenomenon during myocarditis. At present, it would seem more appropriate to label such cases as “hypertrabeculation”, rather than non-compaction, although without serial echocardiographic data it may be impossible to distinguish the two.

Conclusion

Our understanding of the development of the left ventricle is increasing. Experimental studies provide a theoretical basis for understanding non-compaction as seen in the human, and suggest a model in which subtle perturbations in embryonic ventriculogenesis result in a phenotype that does not become evident clinically until adulthood. Sequential and high resolution screening of cardiac morphology in affected pedigrees from newborn ages onwards is now possible, and will enable the testing of this hypothesis.