Excessive Trabeculation of the Left Ventricle

Petersen, Steffen E.; Jensen, Bjarke; Aung, Nay; Friedrich, Matthias G.; McMahon, Colin J.; Mohiddin, Saidi A; Pignatelli, Ricardo H.; Ricci, Fabrizio; Anderson, Robert H.; Bluemke, David A.

doi:10.1016/j.jcmg.2022.12.026

Cited by 48 publications

(78 citation statements)

References 142 publications

(185 reference statements)

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“…NKX2-5, NOTCH1 , and GATA4 , have high confidence for non-syndromic CHD, atrial septal defect ( NKX2-5, GATA4 ), aortic valve stenosis and tetralogy of fallot ( NOTCH1 ). NKX2-5 when suppressed causes excessive trabeculation in models 10 and it is identified in carriers with LVNC alongside DCM or conduction disease 31 . GATA6 is a transcription factor with a role during heart development and has been linked to several congenital heart disease phenotypes previously 32 and HAND1 has moderate evidence for congenital heart disease 33 .…”

Section: Resultsmentioning

confidence: 99%

Genetic and phenotypic architecture of human myocardial trabeculation

McGurk,

Qiao,

Zheng

et al. 2024

Preprint

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Cardiac trabeculae form a network of muscular strands that line the inner surfaces of the heart. Their development depends on multiscale morphogenetic processes and, while highly conserved across vertebrate evolution, their role in the pathophysiology of the mature heart is not fully understood. We report variant associations across the allele frequency spectrum for trabecular morphology in 47,803 participants of the UK Biobank using fractal dimension analysis of cardiac imaging. We identified an association between trabeculation and rare variants in 56 genes that regulate myocardial contractility and ventricular development. Genome-wide association studies identified 68 novel loci in pathways that regulate sarcomeric function, differentiation of the conduction system, and cell fate determination. We found that trabeculation-associated variants were modifiers of cardiomyopathy phenotypes with opposing effects in hypertrophic and dilated cardiomyopathy. Together, these data provide insights into mechanisms that regulate trabecular development and plasticity, and identify a potential role in modifying monogenic disease expression.

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Section: Resultsmentioning

confidence: 99%

Genetic and phenotypic architecture of human myocardial trabeculation

McGurk,

Qiao,

Zheng

et al. 2024

Preprint

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“…The developmental transition from the highly trabeculated wall to one dominated by compact myocardium has mostly been investigated in a biomedical context to give perspectives to so‐called noncompaction (Freedom et al, 2005; MacGrogan et al, 2018; Sedmera et al, 2000; Shi et al, 2023; Wilsbacher & McNally, 2016). Since noncompaction presupposes compaction, the increasing interest in noncompaction (Finsterer et al, 2017; Hussein et al, 2015; Towbin & Johnson, 2022) has likely led to a misattributed and exaggerated importance to compaction (D'Silva & Jensen, 2020; Faber, D'Silva, et al, 2021; Henderson & Anderson, 2009; Petersen et al, 2023). In biology, shape change is often driven by differential growth rates (Gould, 1966), and this is also the case for the pig, as we show here, and in human, mice, and chicken (Faber et al, 2022), and even in animals with an almost “smooth” RV ventricular wall such as shrews (Chang et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…At tissue level, myocardium of the trabecular and compact layer is not different with regard to density of sarcomeres, vasculature, and mitochondria and the cardiomyocytes of the two layers do not differ in strength (Faber et al, 2022). There is then a growing concern that the importance of compaction has been much exaggerated (Anderson et al, 2017; Faber, D'Silva, et al, 2021; Petersen et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Trabeculations of the porcine and human cardiac ventricles are different in number but similar in total volume

Jensen,

Salvatori,

Schouten

et al. 2024

Clinical Anatomy

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An intricate meshwork of trabeculations lines the luminal side of cardiac ventricles. Compaction, a developmental process, is thought to reduce trabeculations by adding them to the neighboring compact wall which is then enlarged. When pig, a plausible cardiac donor for xenotransplantation, is compared to human, the ventricular walls appear to have fewer trabeculations. We hypothesized the trabecular volume is proportionally smaller in pig than in human. Macroscopically, we observed in 16 pig hearts that the ventricular walls harbor few but large trabeculations. Close inspection revealed a high number of tiny trabeculations, a few hundred, within the recesses of the large trabeculations. While tiny, these were still larger than embryonic trabeculations and even when considering their number, the total tally of trabeculations in pig was much fewer than in human. Volumetrics based on high‐resolution MRI of additional six pig hearts compared to six human hearts, revealed the left ventricles were not significantly differently trabeculated (21.5 versus 22.8%, respectively), and the porcine right ventricles were only slightly less trabeculated (42.1 vs 49.3%, respectively). We then analyzed volumetrically 10 pig embryonic hearts from gestational day 14–35. The trabecular and compact layer always grew, as did the intertrabecular recesses, in contrast to what compaction predicts. The proportions of the trabecular and compact layers changed substantially, nonetheless, due to differences in their growth rate rather than compaction. In conclusion, processes that affect the trabecular morphology do not necessarily affect the proportion of trabecular‐to‐compact myocardium and they are then distinct from compaction.

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“…While a reduction in the number of trabeculations and intertrabecular recesses is consistent with compaction, the development of the papillary muscle exemplifies that the same morphometric readout is equally consistent with the coalescence of trabeculations within the trabecular layer. Extensive coalescence of trabeculations within the trabecular layer may occur in pig since the proportional volumes of the trabecular layers are similar between pig and human, while the porcine walls have fewer trabeculations (Jensen et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

The changing morphology of the ventricular walls of mouse and human with increasing gestation

Jensen,

Chang,

Bamforth

et al. 2024

Journal of Anatomy

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That the highly trabeculated ventricular walls of the developing embryos transform to the arrangement during the fetal stages, when the mural architecture is dominated by the thickness of the compact myocardium, has been explained by the coalescence of trabeculations, often erroneously described as ‘compaction’. Recent data, however, support differential rates of growth of the trabecular and compact layers as the major driver of change. Here, these processes were assessed quantitatively and visualized in standardized views. We used a larger dataset than has previously been available of mouse hearts, covering the period from embryonic day 10.5 to postnatal day 3, supported by images from human hearts. The volume of the trabecular layer increased throughout development, in contrast to what would be expected had there been ‘compaction’. During the transition from embryonic to fetal life, the rapid growth of the compact layer diminished the proportion of trabeculations. Similarly, great expansion of the central cavity reduced the proportion of the total cavity made up of intertrabecular recesses. Illustrations of the hearts with the median value of left ventricular trabeculation confirm a pronounced growth of the compact wall, with prominence of the central cavity. This corresponds, in morphological terms, to a reduction in the extent of the trabecular layer. Similar observations were made in the human hearts. We conclude that it is a period of comparatively slow growth of the trabecular layer, rather than so‐called compaction, that is the major determinant of the changing morphology of the ventricular walls of both mouse and human hearts.

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Excessive Trabeculation of the Left Ventricle

Cited by 48 publications

References 142 publications

Genetic and phenotypic architecture of human myocardial trabeculation

Genetic and phenotypic architecture of human myocardial trabeculation

Trabeculations of the porcine and human cardiac ventricles are different in number but similar in total volume

The changing morphology of the ventricular walls of mouse and human with increasing gestation

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