Left ventricular non-compaction: have we reached the limits of conventional imaging?

This editorial refers to ‘A systematic review and meta-analysis of the prevalence of left ventricular non-compaction in adults’†, by S.B. Ross et al., on page 1428. The classical approach to clinical diagnosis involves the elucidation of symptoms and signs followed by targeted laboratory or instrumental investigations that confirm or refute the suspicion of disease.1 Left ventricular non-compaction (LVNC) is an entity defined entirely by the appearance of prominent left ventricular trabeculae and deep intertrabecular recesses on cardiac imaging2 that is thought to represent an abnormality of myocardial development. So-called ‘hypertrabeculation’ of the left ventricle is described as an isolated phenomenon in normal hearts and in association with cardiomyopathy (dilated, hypertrophic, and restrictive) and congenital heart disease.3 Clinical manifestations and the age at symptom onset vary greatly and depend on the associated cardiac abnormalities. Reported complications include systemic thrombo-embolism, ventricular arrhythmias, sudden cardiac death, and progressive heart failure.4 In common with most myocardial disorders, LVNC is often a heritable trait; for example, in children, LVNC is associated with Barth syndrome, a rare X-linked multisystem disorder caused by mutations in the G4.5 gene that encodes the tafazzin family of peptides.5 More commonly, LVNC is caused by genes implicated in classical cardiomyopathies such as sarcomeric (ACTC1, MYH7, MYBPC3, TNNT2, and TPM1), desmosomal (DSP and PKP2), nuclear envelope protein (LMNA), and z-disk (LDB3), as well as genes implicated in muscular dystrophy, and mitochondrial and io channel disorders.6 Reported mutations in the MIB1 gene, which is responsible for the death-associated protein kinase (DAPK)-interacting protein, suggest a role of the Notch signalling pathway, which is involved in trabecular maturation.6 The diagnosis of LVNC requires demonstration of large and/or numerous ventricular trabeculae, a normal or thin compacted myocardial layer, and the presence of deep intertrabecular recesses that communicate with the left ventricular cavity. However, in spite of the efforts of numerous investigators, there is still no consensus on the imaging criteria for LVNC. Most studies have used a ratio between non-compacted and compacted myocardial layers, but methods (e.g. measurement in systole or diastole) and cut-off values for normality vary.7 , 8 The reliance on a simple ratio also means that an increased thickness of the non-compacted layer (as may occur in physiological or pathological hypertrophy) or a decreased thickness of the compacted layer (e.g. as a consequence of myocardial scarring) can result in an erroneous diagnosis of LVNC, even in healthy individuals. In this issue of the European Heart Journal, Barratt Ross and colleagues perform a systematic review and meta-analysis of studies reporting LVNC prevalence in adults;9 a total of 59 papers that allowed calculation of the LVNC prevalence among 67 distinct cohorts were analysed. Two-thirds of cohorts were comprised of patients with cardiac disease, and the rest were population-representative volunteers, healthy controls, athletes, and non-cardiac patients. There were 36 studies that used echocardiography, 26 that utilized cardiac magnetic resonance (CMR), and one that used multidetector computed tomography. As expected, the prevalence of LVNC varied depending on the imaging modality, diagnostic criteria, and study cohort. CMR appeared more sensitive, with a total prevalence of 14.79% compared with 1.28% for echocardiography. Irrespective of the imaging modality, athletes had the highest prevalence (27.29% using CMR and 3.16% using echocardiography) followed by healthy controls (15.03% using CMR and 1.05% using echocardiography) and lastly cardiac patients (9.76% using CMR and 0.90% using echocardiography). In addition, CMR reported LVNC in 36.21% and echocardiography in 2.21% of non-cardiac cohorts. Overall, across all cohorts, the prevalence of LVNC reported using CMR was 12-fold higher compared with echocardiography. Although most studies were of moderate or high risk of bias, there was modest variability between their quality in comparison with the heterogeneity observed in determining the prevalence of LVNC between the imaging modality and type of cohort. The most striking result from this study is the high prevalence of a supposedly abnormal phenomenon in normal healthy people or in individuals with non-cardiac disease. The lessons are that extreme caution should be employed when appending the label LVNC to an individual, particularly when they are well, and have no family history of cardiac disease or other signs consistent with a myocardial abnormality. This is particularly true in situations where physiological remodelling of the ventricle results in prominent ventricular trabeculae such as, for example, athletic training and pregnancy. Evidence also suggests that normal ethnic variation in ventricular morphology can result in misdiagnosis.10 Current evidence suggests that LVNC is a real entity and at the extreme it is not difficult to recognize (Figure 1). However, our inability to accurately define normal patterns of ventricular trabeculation makes it unlikely that more studies using the same approach to quantification will assist in resolving a genuine disorder of cardiac embryogenesis from normal variation. Instead, new approaches to quantification and multiparametric models that consider other morphological, genetic, and clinical variables would seem to offer more promise. Whatever the approach, our human inclination to rely solely on visual pattern recognition and our enthusiasm for new technologies should be tempered by a more holistic and integrated approach to disease definition.11 Cardiac magnetic resonance imaging scans of two different individuals with similar LVNC features are presented. The top three rows are four-chamber, two-chamber, and short-axis cine images, respectively. The bottom row are short axis late gadolinium enhancement (LGE) images. (A) A 46-year-old gentleman of African origin was worked up for minor palpitations that he was experiencing. There is no family history of sudden cardiac death or cardiomyopathy. He was considered to have LVNC on his cardiac imaging, but his electrocardiogram and 24 h Holter monitoring were unremarkable. He has been followed up for 9 years, without any adverse outcomes or disease progression. (B) A 26-year-old man was assessed as part of family screening. He reports shortness of breath on exertion (NYHA class II) and he has a family history of dilated cardiomyopathy with conduction disease in both his father and brother. He himself, has tri-fascicular block with prolonged PR interval, right bundle branch block, and left anterior fascicular block. On his cardiac imaging, significant non-compaction in both ventricles, mild to moderate LV systolic dysfunction, and significant LGE was observed. An extensive cardiomyopathy gene panel has been negative. Conflit of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.