Top

Published in:

01-10-2019 | Cardiomyopathy | Riley Symposium

Defects in Trabecular Development Contribute to Left Ventricular Noncompaction

Authors: Caroline Choquet, Robert G. Kelly, Lucile Miquerol

Published in: Pediatric Cardiology | Issue 7/2019

Abstract

Left ventricular noncompaction (LVNC) is a genetically heterogeneous disorder the etiology of which is still debated. During fetal development, trabecular cardiomyocytes contribute extensively to the working myocardium and the ventricular conduction system. The impact of developmental defects in trabecular myocardium in the etiology of LVNC has been debated. Recently we generated new mouse models of LVNC by the conditional deletion of the key cardiac transcription factor encoding gene Nkx2-5 in trabecular myocardium at critical steps of trabecular development. These conditional mutant mice recapitulate pathological features similar to those observed in LVNC patients, including a hypertrabeculated left ventricle with deep endocardial recesses, subendocardial fibrosis, conduction defects, strain defects, and progressive heart failure. After discussing recent findings describing the respective contribution of trabecular and compact myocardium during ventricular morphogenesis, this review will focus on new data reflecting the link between trabecular development and LVNC.

Towbin JA, Lorts A, Jefferies JL (2015) Left ventricular non-compaction cardiomyopathy. Lancet 386:813–825. https://doi.org/10.1016/S0140-6736(14)61282-4 CrossRefPubMed

Anderson RH, Jensen B, Mohun TJ et al (2017) Key questions relating to left ventricular noncompaction cardiomyopathy: is the emperor still wearing any clothes? Can J Cardiol 33:747–757. https://doi.org/10.1016/j.cjca.2017.01.017 CrossRefPubMed

Samsa LA, Yang B, Liu J (2014) Embryonic cardiac chamber maturation: trabeculation, conduction and cardiomyocyte proliferation. Am J Med Genet C 1:20. https://doi.org/10.1002/ajmg.c.31366.Embryonic CrossRef

Zhang W, Chen H, Qu X et al (2013) Molecular mechanism of ventricular trabeculation/compaction and the pathogenesis of the left ventricular noncompaction cardiomyopathy (LVNC). Am J Med Genet Part C 163:144–156. https://doi.org/10.1002/ajmg.c.31369 CrossRef

Miquerol L, Moreno-Rascon N, Beyer S et al (2010) Biphasic development of the mammalian ventricular conduction system. Circ Res 107:153–161. https://doi.org/10.1161/CIRCRESAHA.110.218156 CrossRefPubMed

Beyer S, Kelly RG, Miquerol L (2011) Inducible Cx40-Cre expression in the cardiac conduction system and arterial endothelial cells. Genesis 49:83–91. https://doi.org/10.1002/dvg.20687 CrossRefPubMed

Choquet C, Nguyen THM, Sicard P et al (2018) Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy. PLoS Geent 14:e1007502CrossRef

Challice CE, Viragh S (1974) The architectural development of the early mammalian heart. Tissue Cell 6:447–462. https://doi.org/10.1016/0040-8166(74)90037-8 CrossRefPubMed

Thomas PS, Sedmera D (1996) Trabeculation in the embryonic heart. Comp Gen Pharmacol 18:607

10.

Sedmera D, Pexieder T, Vuillemin M et al (2000) Developmental patterning of the myocardium. Anat Rec 258:319–337. https://doi.org/10.1002/(SICI)1097-0185(20000401)258:4%3c319:AID-AR1%3e3.0.CO;2-O CrossRefPubMed

11.

Sankova B, Benes J, Krejci E et al (2012) The effect of connexin40 deficiency on ventricular conduction system function during development. Cardiovasc Res 95:469–479. https://doi.org/10.1093/cvr/cvs210 CrossRefPubMed

12.

Cherian AV, Fukuda R, Augustine SM et al (2016) N-cadherin relocalization during cardiac trabeculation. Proc Natl Acad Sci USA 113:7569–7574. https://doi.org/10.1073/pnas.1606385113 CrossRefPubMed

13.

Staudt DW, Liu J, Thorn KS et al (2014) High-resolution imaging of cardiomyocyte behavior reveals two distinct steps in ventricular trabeculation. Development 141:585–593. https://doi.org/10.1242/dev.098632 CrossRefPubMedPubMedCentral

14.

Han P, Bloomekatz J, Ren J et al (2016) Coordinating cardiomyocyte interactions to direct ventricular chamber morphogenesis. Nature 534:700–704. https://doi.org/10.1038/nature18310 CrossRefPubMedPubMedCentral

15.

Peshkovsky C, Totong R, Yelon D (2011) Dependence of cardiac trabeculation on neuregulin signaling and blood flow in zebrafish. Dev Dyn 240:446–456. https://doi.org/10.1002/dvdy.22526 CrossRefPubMed

16.

Li J, Miao L, Shieh D et al (2016) Single-cell lineage tracing reveals that oriented cell division contributes to trabecular morphogenesis and regional specification. Cell Rep 15:158–170. https://doi.org/10.1016/j.celrep.2016.03.012 CrossRefPubMedPubMedCentral

17.

del Monte-Nieto G, Ramialison M, Adam AAS et al (2018) Control of cardiac jelly dynamics by NOTCH1 and NRG1 defines the building plan for trabeculation. Nature 557:439–445. https://doi.org/10.1038/s41586-018-0110-6 CrossRefPubMed

18.

Grego-bessa J, Luna-zurita L, Monte G et al (2007) Notch Signalling is essential for ventricular development. Dev Cell 12:415–429. https://doi.org/10.1016/j.devcel.2006.12.011.Notch CrossRefPubMedPubMedCentral

19.

Stankunas K, Hang CT, Tsun Z et al (2009) Endocardial Brg1 represses ADAMTS1 to maintain the microenvironment for myocardial morphogenesis. Dev Cell 14:298–311. https://doi.org/10.1016/j.devcel.2007.11.018.Endocardial CrossRef

20.

Cheng G, Litchenberg WH, Cole GJ et al (1999) Development of the cardiac conduction system involves recruitment within a multipotent cardiomyogenic lineage. Development 126:5041–5049. https://doi.org/10.1038/nature09714 CrossRefPubMed

21.

Meilhac SM, Kelly RG, Rocancourt D et al (2003) A retrospective clonal analysis of the myocardium reveals two phases of clonal growth in the developing mouse heart. Development 130:3877–3889. https://doi.org/10.1242/dev.00580 CrossRefPubMed

22.

Bossie A, Ph D, Greenspan A et al (2004) BMP-10 is essential for maintaining cardiac growth during murine cardiogenesis. Development 16:21–30. https://doi.org/10.1097/JGP.0b013e31813546f2.Placebo-Controlled CrossRef

23.

Kim K-H, Rosen A, Hussein SMI et al (2016) Irx3 is required for postnatal maturation of the mouse ventricular conduction system. Sci Rep 6:19197. https://doi.org/10.1038/srep19197 CrossRefPubMedPubMedCentral

24.

Tian X, Li Y, He L et al (2017) Identification of a hybrid myocardial zone in the mammalian heart after birth. Nat Commun 8:87. https://doi.org/10.1038/s41467-017-00118-1 CrossRefPubMedPubMedCentral

25.

Shekhar A, Li X, Liu F-Y et al (2016) Transcription factor ETV1 is essential for rapid conduction in the heart. J Clin Invest 1:11. https://doi.org/10.1172/JCI87968.Introduction CrossRef

26.

Li Y, Tian X, Zhao H et al (2018) Genetic targeting of Purkinje fibres by Sema3a- CreERT2. Sci Rep 8:1–9. https://doi.org/10.1038/s41598-018-20829-9 CrossRef

27.

Zhang W, Chen H, Wang Y et al (2011) Tbx20 transcription factor is a downstream mediator for bone morphogenetic protein-10 in regulating cardiac ventricular wall development and function. J Biol Chem 286:36820–36829. https://doi.org/10.1074/jbc.M111.279679 CrossRefPubMedPubMedCentral

28.

Li G, Xu A, Sim S et al (2016) Transcriptomic profiling maps anatomically patterned subpopulations among single embryonic cardiac cells. Dev Cell 39:491–507. https://doi.org/10.1016/j.devcel.2016.10.014 CrossRefPubMedPubMedCentral

29.

Foglia MJ, Poss KD (2016) Building and re-building the heart by cardiomyocyte proliferation. Development 143:729–740. https://doi.org/10.1242/dev.132910 CrossRefPubMedPubMedCentral

30.

Jensen B, Wang T, Christoffels VM, Moorman AFM (2013) Evolution and development of the building plan of the vertebrate heart. Biochim Biophys Acta - Mol Cell Res 1833:783–794. https://doi.org/10.1016/j.bbamcr.2012.10.004 CrossRef

31.

Sánchez-Iranzo H, Galardi-Castilla M, Minguillón C et al (2018) Tbx5a lineage tracing shows cardiomyocyte plasticity during zebrafish heart regeneration. Nat Commun. https://doi.org/10.1038/s41467-017-02650-6 CrossRefPubMedPubMedCentral

32.

Wu B, Zhang Z, Lui W et al (2012) Endocardial cells form the coronary arteries by angiogenesis through myocardial-endocardial VEGF signaling. Cell 151:1083–1096. https://doi.org/10.1016/j.cell.2012.10.023.Endocardial CrossRefPubMedPubMedCentral

33.

Tian X, Hu T, Zhang H et al (2014) De Novo formation of a distinct coronary vascular population in neonatal heart. Science 49:1841–1850. https://doi.org/10.1016/j.jacc.2007.01.076.White CrossRef

34.

Miquerol L, Thireau J, Bideaux P et al (2015) Endothelial plasticity drives arterial remodeling within the endocardium after myocardial infarction. Circ Res 116:1765–1771. https://doi.org/10.1161/CIRCRESAHA.116.306476 CrossRefPubMed

35.

Miquerol L, Kelly RG (2012) Organogenesis of the vertebrate heart. Wiley Interdiscip Rev Dev Biol 2:17–29. https://doi.org/10.1002/wdev.68 CrossRefPubMed

36.

Rhee S, Chung JI, King DA et al (2018) Endothelial deletion of Ino80 disrupts coronary angiogenesis and causes congenital heart disease. Nat Commun. https://doi.org/10.1038/s41467-017-02796-3 CrossRefPubMedPubMedCentral

37.

Sereti KI, Nguyen NB, Kamran P et al (2018) Analysis of cardiomyocyte clonal expansion during mouse heart development and injury. Nat Commun. https://doi.org/10.1038/s41467-018-02891-z CrossRefPubMedPubMedCentral

38.

Zhang S, Kim K, Rosen A, et al. (2011) Iroquois homeobox gene 3 establishes fast conduction in the cardiac His-Purkinje network Irx3 deficient mice viable. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1106911108 CrossRefPubMed

39.

Ikeda U, Minamisawa M, Koyama J (2015) Isolated left ventricular non-compaction cardiomyopathy in adults. J Cardiol 65:91–97. https://doi.org/10.1016/j.jjcc.2014.10.005 CrossRefPubMed

40.

Roberts WC, Karia SJ, Ko JM et al (2011) Examination of isolated ventricular noncompaction (hypertrabeculation) as a distinct entity in adults. Am J Cardiol 108:747–752. https://doi.org/10.1016/j.amjcard.2011.04.027 CrossRefPubMed

41.

Costa MW, Guo G, Wolstein O et al (2014) Functional characterization of a novel mutation in NKX2-5 associated with congenital heart disease and adult-onset cardiomyopathy. Circ Cardiovasc Genet 6:1–21. https://doi.org/10.1161/CIRCGENETICS.113.000057.Functional CrossRef

42.

Ashraf H, Pradhan L, Chang EI et al (2014) A mouse model of human congenital heart disease high incidence of diverse cardiac anomalies and ventricular noncompaction produced by heterozygous Nkx2-5 homeodomain missense mutation. Circ Cardiovasc Genet 7:423–433. https://doi.org/10.1161/CIRCGENETICS.113.000281 CrossRefPubMedPubMedCentral

43.

Gittenberger-de Adriana C, Groot Hoppenbrouwers T, Miquerol L et al (2016) 14-3-3epsilon controls multiple developmental processes in the mouse heart. Dev Dyn 245:1107–1123CrossRef

44.

Choquet C, Marcadet L, Beyer S et al (2016) Segregation of central ventricular conduction system lineages in early SMA+ cardiomyocytes occurs prior to heart tube formation. J Cardiovasc Dev Dis 3:2. https://doi.org/10.3390/jcdd3010002 CrossRefPubMedCentral

45.

Bressan M, Liu G, Mikawa T (2013) Early mesodermal cues assign avian cardiac pacemaker fate potential in a tertiary heart field. Science 340:744–748. https://doi.org/10.1126/science.1232877 CrossRefPubMedPubMedCentral

46.

Finsterer J, Stöllberger C, Towbin JA (2017) Left ventricular noncompaction cardiomyopathy: cardiac, neuromuscular, and genetic factors. Nat Rev Cardiol 14:224–237. https://doi.org/10.1038/nrcardio.2016.207 CrossRefPubMed

47.

Klaassen S, Probst S, Oechslin E et al (2008) Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation 117:2893–2901. https://doi.org/10.1161/CIRCULATIONAHA.107.746164 CrossRefPubMed

48.

Freedom RM, Yoo SJ, Perrin D et al (2005) The morphological spectrum of ventricular noncompaction. Cardiol. Young 15:345–364CrossRefPubMed

49.

Chen H, Zhang W, Sun X et al (2013) Fkbp1a controls ventricular myocardium trabeculation and compaction by regulating endocardial Notch1 activity. Development 140:1946–1957. https://doi.org/10.1242/dev.089920 CrossRefPubMedPubMedCentral

50.

Luxán G, Casanova JC, Martínez-Poveda B et al (2013) Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy. Nat Med 19:193–201. https://doi.org/10.1038/nm.3046 CrossRefPubMed

51.

Zhao C, Guo H, Li J et al (2014) Numb family proteins are essential for cardiac morphogenesis and progenitor differentiation. Development 141:281–295. https://doi.org/10.1242/dev.093690 CrossRefPubMedPubMedCentral

52.

Pashmforoush M, Lu JT, Chen H et al (2004) Nkx2-5 pathways and congenital heart disease: loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block. Cell 117:373–386. https://doi.org/10.1016/S0092-8674(04)00405-2 CrossRefPubMed

53.

Liu Y, Chen H, Shou W (2018) Potential common pathogenic pathways for the left ventricular noncompaction cardiomyopathy (LVNC). Pediatr Cardiol 39:1099–1106. https://doi.org/10.1007/s00246-018-1882-z CrossRefPubMedPubMedCentral

54.

Li D, Hallett MA, Zhu W et al (2011) Dishevelled-associated activator of morphogenesis 1 (Daam1) is required for heart morphogenesis. Development 138:303–315. https://doi.org/10.1242/dev.055566 CrossRefPubMedPubMedCentral

55.

Jensen B, van der Wal AC, Moorman AFM, Christoffels VM (2017) Excessive trabeculations in noncompaction do not have the embryonic identity. Int J Cardiol 227:325–330. https://doi.org/10.1016/j.ijcard.2016.11.089 CrossRefPubMed

56.

Jay PY, Harris BS, Maguire CT et al (2004) Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system. J Clin Invest 113:1130–1137. https://doi.org/10.1172/JCI200419846 CrossRefPubMedPubMedCentral

57.

Meysen S, Marger L, Hewett KW et al (2007) Nkx2.5 cell-autonomous gene function is required for the postnatal formation of the peripheral ventricular conduction system. Dev Biol 303:740–753. https://doi.org/10.1016/j.ydbio.2006.12.044 CrossRefPubMed

58.

Palomino Doza J, Salguero-Bodes R, de la Parte M, Arribas-Ynsaurriaga F (2018) Association Between Mutations in the NKX2.5 Homeobox, Atrial Septal Defects, Ventricular Noncompaction and Sudden Cardiac Death. Rev Española Cardiol 71:53–55. https://doi.org/10.1016/j.rec.2017.02.032 CrossRef

59.

D’Amato G, Luxán G, del Monte-Nieto G et al (2015) Sequential Notch activation regulates ventricular chamber development. Nat Cell Biol 18:7–20. https://doi.org/10.1038/ncb3280 CrossRefPubMedPubMedCentral

Title: Defects in Trabecular Development Contribute to Left Ventricular Noncompaction
Authors: Caroline Choquet
Robert G. Kelly
Lucile Miquerol
Publication date: 01-10-2019
Publisher: Springer US
Keyword: Cardiomyopathy
Published in: Pediatric Cardiology / Issue 7/2019
Print ISSN: 0172-0643
Electronic ISSN: 1432-1971
DOI: https://doi.org/10.1007/s00246-019-02161-9

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Defects in Trabecular Development Contribute to Left Ventricular Noncompaction

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 7/2019

Sex-Specific Differences in Ventricular Dimensions in Repaired Tetralogy of Fallot: A Retrospective Study

Exercise Capacity in Asymptomatic Adult Patients Treated for Coarctation of the Aorta

Adverse Perioperative Events in Children with Complex Congenital Heart Disease Undergoing Operative Scoliosis Repair in the Contemporary Era

Phases and Mechanisms of Embryonic Cardiomyocyte Proliferation and Ventricular Wall Morphogenesis

Insights into Arch Vessel Development in the Bovine Aortic Arch

Talin and Kindlin as Integrin-Activating Proteins: Focus on the Heart

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page