Rethinking Left Ventricular Noncompaction and Excessive Left Ventricular Trabeculation: Development, Genetics, and a Proposed Conceptual Framework

Figures

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  Figure 1. Formation of the ventricular wall: from arrest of compaction to differential growth. (A) Two models of ventricular wall growth. In the classical model, trabeculae coalesce from the epicardial toward the endocardial side during late gestation to form the compact layer, so that the absolute amount of the trabecular layer must fall. Systematic morphometry of the human heart has not documented such a decrease [6]. In the current model, both the trabecular and the compact layer continue to grow, and the compact layer grows faster, so that the ratio between them declines with time; this differential growth describes the human and mouse ventricular wall [6,8]. Trabecular and compact-wall cardiomyocytes generate equivalent force and show no essential difference in contractile or mitochondria-related protein content, which is inconsistent with the interpretation of trabeculae as a persistent fetal-type myocardium [7,19]. The drawings are schematic and are not to scale. (B) Absolute trajectories of the two layers and the corresponding noncompacted-to-compacted (N/C) ratio. In fetal-onset LVNC, the N/C ratio increases over time and exceeds two throughout the perinatal period, a change not…

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  Figure 2. Molecular and cellular pathways of ventricular wall growth and the routes leading to excessive trabeculation. (A) The pathways that control trabeculation and growth of the compact layer: endocardial–myocardial signaling, transcriptional regulation, extracellular matrix and chromatin regulation, cell cycle, polarity and cell mechanics, and coordination with the coronary vasculature. (B) The six routes by which these pathways are perturbed—five genetic and one acquired, load-dependent—which act in parallel rather than in sequence and converge on the same morphology. The individual pathways, the genes assigned to each route and the supporting evidence are described in Section 3 and Section 4 and in Table 1 and are not repeated here. Unless otherwise indicated, the mechanisms shown derive from mouse, zebrafish or in vitro systems. ECM, extracellular matrix; LVNC, left ventricular noncompaction.

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  Figure 3. Assignment of the clinical pathophysiologic context of excessive left ventricular trabeculation. Assignment proceeds from two judgements: first, whether an overt cardiomyopathy-level functional or electrophysiological abnormality is present that is not sufficiently explained by another cardiac disease or by pathological hemodynamic loading; and second, whether a pre-existing cardiac disease or pathological hemodynamic loading capable of explaining the findings is present. Physiological loading, such as pregnancy or athletic training, is not treated as pathological loading at this step. The operational definitions of these judgements, the three resulting Categories, the risk modifiers within Category 3 and the recommended evaluation for each phenotypic group are given in Section 7.1 and Section 7.2 and in Table 2 and are not repeated here. In the systolic-dysfunction node, the pediatric threshold is not yet defined (Section 7.1). It is not claimed that Category 1 has been established as a disease entity. CMR, cardiac magnetic resonance; LVNC, left ventricular noncompaction; P/LP, pathogenic or likely pathogenic.