Noncompaction cardiomyopathy is characterized by the presence of extensive trabeculations, which could lead to heart failure and malignant arrhythmias. How trabeculations resolve to form compact myocardium is poorly understood. Elucidation of this process is critical to understanding the pathophysiology of noncompaction disease. Here we use genetic lineage tracing to mark the Nppa+ or Hey2+ cardiomyocytes as trabecular and compact components of the ventricular wall. We find that Nppa+ and Hey2+ cardiomyocytes, respectively, from the endocardial and epicardial zones of the ventricular wall postnatally. Interposed between these two postnatal layers is a hybrid zone, which is composed of cells derived from both the Nppa+ and Hey2+ populations. Inhibition of the fetal Hey2+ cell contribution to the hybrid zone results in persistence of excessive trabeculations in postnatal heart. Our findings indicate that the expansion of Hey2+ fetal compact component, and its contribution to the hybrid myocardial zone, are essential for normal formation of the ventricular walls.Fetal trabecular muscles in the heart undergo a poorly described morphogenetic process that results into a solidified compact myocardium after birth. Tian et al. show that cardiomyocytes in the fetal compact layer also contribute to this process, forming a hybrid myocardial zone that is composed of cells derived from both trabecular and compact layers.

Cardiology Department Zhongshan Hospital Fudan University Shanghai 200032 China

Cardiovascular and Metabolic Diseases Innovative Medicines and Early Clinical Development Biotech Unit AstraZeneca Mölndal 43183 Sweden

Department of Cardiology Children's Hospital Boston 300 Longwood Avenue Boston Massachusetts 02115 USA

Department of Cardiology The 1st Affiliated Hospital School of Medicine Zhejiang University 79 Qingchun Road Hangzhou Zhejiang 310003 China

Department of Cardiovascular Medicine Southern Medical University Affiliated Fengxian Hospital Shanghai 201499 China

Department of Neurosurgery Huashan Hospital State Key Laboratory of Medical Neurobiology Institutes of Brain Science and Shanghai Medical College Fudan University Shanghai 200032 China

Department of Pharmacology School of Basic Medical Sciences Tianjin Medical University Tianjin 300070 China

Division of Cardiovascular Medicine Department of Medicine Stanford Cardiovascular Institute Stanford University School of Medicine Stanford Caliornia 94305 USA

Harvard Stem Cell Institute Harvard University Cambridge Massachusetts 02138 USA

Institute of Anatomy 1st Faculty of Medicine Charles University; Institute of Physiology The Czech Academy of Sciences Prague 12800 Czech Republic

Institute of Genetic Medicine Newcastle University Newcastle upon Tyne NE1 7RU UK

Key Laboratory of Nutrition and Metabolism Institute for Nutritional Sciences Shanghai Institutes for Biological Sciences Chinese Academy of Sciences University of Chinese Academy of Sciences Shanghai 200031 China

Key Laboratory of Regenerative Medicine of Ministry of Education Institute of Aging and Regenerative Medicine Jinan University Guangzhou 510632 China

School of Life Science and Technology Shanghai Tech University Shanghai 201210 China

State Key Laboratory of Cardiovascular Disease Fuwai Hospital National Center for Cardiovascular Disease Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100037 China

State Key Laboratory of Genetic Engineering School of Life Sciences Fudan University Shanghai 200433 China

The State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences University of Chinese Academy of Sciences Shanghai 200031 China

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Nat Rev Cardiol. 2017 Aug 16;14(9):504. doi: 10.1038/nrcardio.2017.125. PubMed

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