Key Questions Relating to Left Ventricular Noncompaction Cardiomyopathy: Is the Emperor Still Wearing Any Clothes?

doi:10.1016/j.cjca.2017.01.017

Canadian Journal of Cardiology

Volume 33, Issue 6, June 2017, Pages 747-757

https://doi.org/10.1016/j.cjca.2017.01.017 Get rights and content

Abstract

The evidence is increasing that left ventricular noncompaction cardiomyopathy as it is currently defined does not represent a failure of compaction of pre-existing trabecular myocardium found during embryonic development to form the compact component of the ventricular walls. Neither is there evidence of which we are aware to favour the notion that the entity is a return to a phenotype seen in cold-blooded animals. It is also known that when seen in adults, the presence of excessive ventricular trabeculations does not portend a poor prognosis when the ejection fraction is normal, with the risks of complications such as arrhythmia and stroke being rare in this setting. It is also the case that images of “noncompaction” as provided from children or autopsy studies are quite different from the features observed clinically in asymptomatic adults with excessive trabeculation. Our review suggests that the presence of an excessively trabeculated left ventricular wall is not in itself a clinical entity. It is equally possible that the excessive trabeculation is no more than a bystander in the presence of additional lesions such as dilated cardiomyopathy, with the additional lesions being responsible for the reduced ejection fraction bringing a given patient to clinical attention. We, therefore, argue that the term “noncompaction cardiomyopathy” is misleading, because there is neither failure of compaction nor a cardiomyopathic process in most individuals that fulfill widely used diagnostic criteria.

Résumé

De plus en plus d’éléments probants tendent à montrer que l’hypertrabéculation ventriculaire gauche (aussi appelée « non-compaction ventriculaire gauche » ou « myocarde spongieux »), telle qu’elle est définie actuellement, ne correspond pas à un défaut de compaction du myocarde trabéculé au cours de l’embryogenèse, laquelle compaction permet la formation de l’élément compact des parois ventriculaires. Selon nos connaissances, aucune donnée probante ne vient non plus appuyer le concept selon lequel cette entité clinique correspondrait au retour d’un phénotype observé chez les animaux à sang froid. Nous savons également que chez les adultes dont la fraction d’éjection est normale, la présence d’une hypertrabéculation ventriculaire n’est pas associée à un pronostic défavorable et que, dans ce contexte, le risque de complications, telles qu’une arythmie ou un accident vasculaire cérébral (AVC), est faible. Les images de « non-compaction » provenant d’examens d’enfants ou d’autopsies vont dans le même sens, puisqu’elles révèlent des particularités très différentes des caractéristiques cliniques observées chez des adultes asymptomatiques présentant une hypertrabéculation. Selon les résultats de notre analyse, l’aspect hypertrabéculé de la paroi ventriculaire gauche n’est pas une entité clinique en soi. Il est également possible qu’en présence de lésions additionnelles, comme une cardiomyopathie dilatée à l’origine de la diminution de la fraction d’éjection qui a motivé la consultation clinique d’un patient donné, l’hypertrabéculation soit accidentelle. Par conséquent, nous soutenons que le terme « non-compaction ventriculaire gauche » est trompeur, car, chez la plupart des patients qui remplissent les critères diagnostiques largement utilisés, on n’observe aucun défaut de compaction ni de signes de cardiomyopathie.

Section snippets

Trabeculations in the Animal Kingdom

The formation of the trabecular layer of the ventricular walls was recently reviewed in the Canadian Journal of Cardiology.¹¹ All vertebrate animals during their embryogenesis exhibit a highly trabeculated ventricle.¹² The trabeculations within the embryonic ventricle are thin, less than 50 μm in diameter, so they are adequately supplied by diffusion from the luminal blood in which they are bathed. Because there is no coronary circulation during the early stages of embryogenesis, greater

What Is the Experimental Evidence Supporting the Notion of Compaction of Pre-existing Trabeculations?

Many of the current clinical descriptions relating to left ventricular noncompaction, as indeed was the case in one of our original essays on the topic, introduce their work by presuming that the initial trabeculations observed in the developing human heart coalesce to form the compact components of the ventricular walls. The review provided by Sedmera et al.,²⁵ which included one of the current authors, is usually cited as the basis for this presumption. The review, however, was just that. It

What Is the Evidence in Humans Supporting the Notion of Compaction of Pre-existing Trabeculations?

If compaction of pre-existing trabeculations is an important contribution to formation of the compact wall, we would predict that in the adult heart, the compact wall should be greatest in the hearts with the least trabeculations. To test this possibility, we assessed the relation of the thicknesses of the compact and trabeculated layers of the left ventricular wall from our published data set of almost 3000 individuals.¹⁰ This analysis shows that the thickness of the compacted wall is

What Is the Evidence Relating to Defects of Proliferation?

If not reflecting compaction of pre-existing trabeculations, it is certainly possible that noncompaction relates to defects of proliferation.28, 29 At the time that compaction is thought to occur, which is around the transition from the embryonic to fetal period of development, the embryo weighs no more than 3 g, with the heart itself weighing only 30 mg. This is more than 4 orders of magnitude smaller than the adult arrangement.³⁰ If noncompaction is found in an infant or adult, proliferation

What Are the Phenotypic Features of Noncompaction?

A cursory examination of the images now readily available by searching the Internet for noncompaction reveals marked anatomical heterogeneity. Much of the variability reflects the different techniques used for the purposes of diagnosis. Further problems are inherent in the use of various criteria for diagnosis, because these vary for those using echocardiography, as they do for those using the seemingly more accurate technique of magnetic resonance imaging. The most common appearance now

Noncompaction Has a Multiplicity of Anatomical Phenotypes

It is perhaps surprising that none of the images available from autopsied hearts replicate the trilaminar appearance described here. The images from autopsies typically tend to reveal the presence of hypertrophied trabeculations, often in the presence of a fibroelastotic endocardial surface layer. This produces a more obvious bilaminar arrangement. Some of the clinical images similarly show hypertrophied trabeculations rather than the lace-like configuration visible in most of the magnetic

What Then Are the Genetics of Excessive Trabeculation?

It is established that noncompaction is often associated with mitochondrial disorders.38, 39 Genetic defects are identified in some two-fifths of patients, and these defects are distributed on 20 different genes.⁴⁰ The affected genes often code for proteins that constitute part of the contractile apparatus or otherwise partake in the excitation-contraction coupling, such as the calcium handling ryanodine receptors.11, 41, 42 The same genes, however, are linked to cardiomyopathies in general.

Is There a Difference Between Children and Adults?

Another of the key questions relates to whether the condition seen in children is different from that seen in adults. In case series of children diagnosed with noncompaction, the prognosis appears to be poor,⁴⁹ with some investigators finding high mortality in individuals with low ejection fractions.⁵⁰ It is likely that those with more severe forms of excessive trabeculation present in childhood,⁴⁷ perhaps explaining the more benign adult forms. Certainly, a survivor bias may partly explain the

How Best Then Can We Describe the Condition?

Although the appearance is most frequently described as noncompaction, we submit that our discussion shows this to be less than satisfactory. The very use of the term implies that there has been some degree of failure of compaction during development. As shown earlier, there is no evidence of which we are aware to show that the initial embryonic trabeculations contribute substantially to the compact wall by a process of compaction. Extensive embryonic-like trabeculations can be expected if

How Excessive Are the Trabeculations?

The burning current question is whether the excessive nature of the trabeculations represents an abnormality in itself or is no more than an epiphenomenon. There is now much evidence accruing to favour the second alternative.³⁹ The extensive investigation of the individuals collected together in the Multi-Ethnic Study of Atherosclerosis (MESA) shows that there is a fairly normal distribution of the extent of trabeculation, forming a bell-shaped curve with a degree of rightward skewing (Fig. 5).

How Then Should We Assess Individuals With Excessive Trabeculation?

There is significant controversy regarding the appropriate diagnostic criteria for noncompaction. The current imaging techniques used for diagnosis have recently been reviewed and controversies outlined.⁵⁶ Some authors rely on a ratio of compacted to trabeculated myocardium of greater than 2 or a trabecular mass of greater than 20% of total mass.⁴ The estimation of ventricular mass made by Jacquier et al.,⁴ however, is greatly exaggerated, because they included the intertrabecular lumens as

Is There a Specific Difference Between Noncompaction and Dilated Cardiomyopathy in the Setting of Excessive Trabeculations?

Whether or not noncompaction represents a distinct cardiomyopathy is also controversial.⁴¹ A thin compacted layer is seen by some as a prerequisite for the diagnosis.1, 39, 41 In another study with age- and sex-matched adults, a maximal compacted thickness of < 8 mm was proposed as a specific marker that would allow the differentiation of the pathologic variant of excessive trabeculation and thus prevent overdiagnosis.⁵⁷ It is certainly possible that the presence of excessive trabeculations in

Conclusions

There is growing evidence to indicate the lack of any connection between the mere presence of excessive ventricular trabeculation and mortality, the risk of arrhythmias, or stroke. Specifically, there is no convincing evidence that the extent of ventricular trabeculations has incremental prognostic value in asymptomatic individuals, those with a normal ejection fraction, or even those with dilated cardiomyopathy. Noncompaction, as currently defined, is not “arrested development,” failure of the

Funding Sources

D.H.M. is employed by the Taunton & Somerset Hospital. N.A. has a Wellcome Trust Research Training fellowship. S.E.P. and F.Z. acknowledge support from the National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts.

Disclosures

The authors have no conflicts of interest to disclose.

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Cited by (87)

Myocardial perfusion in excessively trabeculated hearts: Insights from imaging and histological studies
2023, Journal of Cardiology
Citation Excerpt :
Under these circumstances, a reduction in false positive diagnoses is desirable and with regards to excessive trabeculation there is arguably a substantial scope for reduction of false positive diagnoses. Specifically, many clinicians face a challenge with how to deal with individuals who fulfill structural diagnostic criteria but who are otherwise asymptomatic and have a normal heart size, pump function, and no personal or family history of major adverse cardiovascular events (these are so-called “benign” cases, [1,2]). Consequently, in the clinic the reduction of false positive diagnosis is as much a matter of concern as the identification of true cases [1].
In gestation, the coronary circulation develops initially in the compact layer and it expands only in fetal development to the trabeculations. Conflicting data have been published as to whether the trabecular layer is hypoperfused relative to the compact wall after birth. If so, this could explain the poor pump function in patients with left ventricular excessive trabeculation, or so-called noncompaction. Here, we review direct and indirect assessments of myocardial perfusion in normal and excessively trabeculated hearts by in vivo imaging by magnetic resonance imaging (MRI), positron emission tomography (PET)/single photon emission computed tomography (SPECT), and echocardiography in addition to histology, injections of labelled microspheres in animals, and electrocardiography. In MRI, PET/SPECT, and echocardiography, flow of blood or myocardial uptake of blood-borne tracer molecules are measured. The imaged trabecular layer comprises trabeculations and blood-filled intertrabecular spaces whereas the compact layer comprises tissue only, and spatio-temporal resolution likely affects measurements of myocardial perfusion differently in the two layers. Overall, studies measuring myocardial uptake of tracers (PET/SPECT) suggest trabecular hypoperfusion. Studies measuring the quantity of blood (echocardiography and MRI) suggest trabecular hyperperfusion. These conflicting results are reconciled if the low uptake from intertrabecular spaces in PET/SPECT and the high signal from intertrabecular spaces in MRI and echocardiography are considered opposite biases. Histology on human hearts reveal a similar capillary density of trabecular and compact myocardium. Injections of labelled microspheres in animals reveal a similar perfusion of trabecular and compact myocardium. In conclusion, trabecular and compact muscle are likely equally perfused in normal hearts and most cases of excessive trabeculation.
Excessive Trabeculation of the Left Ventricle: JACC: Cardiovascular Imaging Expert Panel Paper
2023, JACC: Cardiovascular Imaging
Excessive trabeculation, often referred to as “noncompacted” myocardium, has been described at all ages, from the fetus to the adult. Current evidence for myocardial development, however, does not support the formation of compact myocardium from noncompacted myocardium, nor the arrest of this process to result in so-called noncompaction. Excessive trabeculation is frequently observed by imaging studies in healthy individuals, as well as in association with pregnancy, athletic activity, and with cardiac diseases of inherited, acquired, developmental, or congenital origins. Adults with incidentally noted excessive trabeculation frequently require no further follow-up based on trabecular pattern alone. Patients with cardiomyopathy and excessive trabeculation are managed by cardiovascular symptoms rather than the trabecular pattern. To date, the prognostic role of excessive trabeculation in adults has not been shown to be independent of other myocardial disease. In neonates and children with excessive trabeculation and normal or abnormal function, clinical caution seems warranted because of the reported association with genetic and neuromuscular disorders. This report summarizes the evidence concerning the etiology, pathophysiology, and clinical relevance of excessive trabeculation. Gaps in current knowledge of the clinical relevance of excessive trabeculation are indicated, with priorities suggested for future research and improved diagnosis in adults and children.
Equal force generation potential of trabecular and compact wall ventricular cardiomyocytes
2022, iScience
Citation Excerpt :
The trabeculated layer of the left ventricle receives much clinical attention because it potentially associates with poor pump function (Hussein et al., 2015; Kittleson et al., 2017). When the trabeculated layer thickness is expressed relative to the compact wall thickness in end diastole, the distribution of the general population exhibits a median ratio of approximately 1 with a long tail towards the excessively trabeculated (Anderson et al., 2017). The cases that make up the tail may be diagnosed as “noncompaction”, “hypertrabeculation”, or exhibiting “persistent sinusoids” even if these diagnoses are not fully overlapping and there is no consensus on the exact point along the tail at which the threshold for ‘excessive’ should be placed (D’Silva and Jensen, 2020; Finsterer et al., 2017).
Trabecular myocardium makes up most of the ventricular wall of the human embryo. A process of compaction in the fetal period presumably changes ventricular wall morphology by converting ostensibly weaker trabecular myocardium into stronger compact myocardium. Using developmental series of embryonic and fetal humans, mice and chickens, we show ventricular morphogenesis is driven by differential rates of growth of trabecular and compact layers rather than a process of compaction. In mouse, fetal cardiomyocytes are relatively weak but adult cardiomyocytes from the trabecular and compact layer show an equally large force generating capacity. In fetal and adult humans, trabecular and compact myocardium are not different in abundance of immunohistochemically detected vascular, mitochondrial and sarcomeric proteins. Similar findings are made in human excessive trabeculation, a congenital malformation. In conclusion, trabecular and compact myocardium is equally equipped for force production and their proportions are determined by differential growth rates rather than by compaction.
The morphogenesis of abnormal coronary arteries in the congenitally malformed heart
2022, Journal of Thoracic and Cardiovascular Surgery
Lack of morphometric evidence for ventricular compaction in humans
2021, Journal of Cardiology
The remodeling of the compact wall by incorporation of trabecular myocardium, referred to as compaction, receives much attention because it is thought that its failure causes left ventricular non-compaction cardiomyopathy (LVNC). Although the notion of compaction is broadly accepted, the nature and strength of the evidence supporting this process is underexposed. Here, we review the literature that quantitatively investigated the development of the ventricular wall to understand the extent of compaction in humans, mice, and chickens. We queried PubMed using several search terms, screened 1127 records, and selected 56 publications containing quantitative data on ventricular growth. For humans, only 34 studies quantified wall development. The key premise of compaction, namely a reduction of the trabecular layer, was never documented. Instead, the trabecular layer grows slower than the compact wall in later development and this changes wall architecture. There were no reports of a sudden enlargement of the compact layer (from incorporated trabeculae), be it in thickness, area, or volume. Therefore, no evidence for compaction was found. Only in chickens, a sudden increase in compact myocardial thickness layer was reported coinciding with a decrease in trabecular thickness. In mice, morphometric and lineage tracing investigations have yielded conflicting results that allow for limited compaction to occur. In conclusion, compaction in human development is not supported while rapid intrinsic growth of the compact wall is supported in all species. If compaction takes place, it likely plays a much smaller role in determining wall architecture than intrinsic growth of the compact wall.
Trabeculations of the porcine and human cardiac ventricles are different in number but similar in total volume
2024, Clinical Anatomy

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: See editorial by Oechslin and Jenni, pages 701–704 of this issue.

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ReviewKey Questions Relating to Left Ventricular Noncompaction Cardiomyopathy: Is the Emperor Still Wearing Any Clothes?

Abstract

Résumé

Section snippets

Trabeculations in the Animal Kingdom

What Is the Experimental Evidence Supporting the Notion of Compaction of Pre-existing Trabeculations?

What Is the Evidence in Humans Supporting the Notion of Compaction of Pre-existing Trabeculations?

What Is the Evidence Relating to Defects of Proliferation?

What Are the Phenotypic Features of Noncompaction?

Noncompaction Has a Multiplicity of Anatomical Phenotypes

What Then Are the Genetics of Excessive Trabeculation?

Is There a Difference Between Children and Adults?

How Best Then Can We Describe the Condition?

How Excessive Are the Trabeculations?

How Then Should We Assess Individuals With Excessive Trabeculation?

Is There a Specific Difference Between Noncompaction and Dilated Cardiomyopathy in the Setting of Excessive Trabeculations?

Conclusions

Funding Sources

Disclosures

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JACC Cardiovasc Imaging

J Cardiovasc Magn Reson

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Dev Biol

J Electrocardiol

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J Am Coll Cardiol

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J Am Coll Cardiol

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Lancet

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JACC Cardiovasc Imaging

Imaging

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J Am Soc Echocardiogr

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Neuromuscul Disord

J Card Fail

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Int J Cardiol

Review
Key Questions Relating to Left Ventricular Noncompaction Cardiomyopathy: Is the Emperor Still Wearing Any Clothes?