title: Impaired myocardial development resulting in neonatal cardiac hypoplasia alters postnatal growth and stress response in the heart.
abstract: OBJECTIVE
  Foetal growth has been proposed to influence cardiovascular health in adulthood, a process referred to as foetal programming. Indeed, intrauterine growth restriction in animal models alters heart size and cardiomyocyte number in the perinatal period, yet the consequences for the adult or challenged heart are largely unknown. The aim of this study was to elucidate postnatal myocardial growth pattern, left ventricular function, and stress response in the adult heart after neonatal cardiac hypoplasia in mice.
  
  
  RESULTS
  Utilizing a new mouse model of impaired cardiac development leading to fully functional but hypoplastic hearts at birth, we show that myocardial mass is normalized until early adulthood by accelerated physiological cardiomyocyte hypertrophy. Compensatory hypertrophy, however, cannot be maintained upon ageing, resulting in reduced organ size without maladaptive myocardial remodelling. Angiotensin II stress revealed aberrant cardiomyocyte growth kinetics in adult hearts after neonatal hypoplasia compared with normally developed controls, characterized by reversible overshooting hypertrophy. This exaggerated growth mainly depends on STAT3, whose inhibition during angiotensin II treatment reduces left ventricular mass in both groups but causes contractile dysfunction in developmentally impaired hearts only. Whereas JAK/STAT3 inhibition reduces cardiomyocyte cross-sectional area in the latter, it prevents fibrosis in control hearts, indicating fundamentally different mechanisms of action.
  
  
  CONCLUSIONS
  Impaired prenatal development leading to neonatal cardiac hypoplasia alters postnatal cardiac growth and stress response in vivo, thereby linking foetal programming to organ size control in the heart.
authors: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin 13125, Germany drenckhahn@mdc-berlin.de.
authors: Jörg-Detlef
authors: JD
authors: Drenckhahn
authors: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin 13125, Germany.
authors: Jette
authors: J
authors: Strasen
authors: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin 13125, Germany.
authors: Kirsten
authors: K
authors: Heinecke
authors: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin 13125, Germany.
authors: Patrick
authors: P
authors: Langner
authors: Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia.
authors: Kom Voy
authors: KV
authors: Yin
authors: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin 13125, Germany.
authors: Friederike
authors: F
authors: Skole
authors: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin 13125, Germany.
authors: Maria
authors: M
authors: Hennig
authors: Experimental and Clinical Research Center, Charité Medical Faculty, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors: Bastian
authors: B
authors: Spallek
authors: Experimental and Clinical Research Center, Charité Medical Faculty, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors: Robert
authors: R
authors: Fischer
authors: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin 13125, Germany Charité Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Kardiologie, Berlin, Germany.
authors: Florian
authors: F
authors: Blaschke
authors: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin 13125, Germany.
authors: Arnd
authors: A
authors: Heuser
authors: Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia Department of Pediatrics, University of Washington, Seattle, USA Center of Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, USA.
authors: Timothy C
authors: TC
authors: Cox
authors: Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia.
authors: Mary Jane
authors: MJ
authors: Black
authors: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin 13125, Germany.
authors: Ludwig
authors: L
authors: Thierfelder
mesh_terms: D000375:Aging / Q000502:physiology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development*; D047108:Embryonic Development / Q000502:physiology*; D005260:Female; D047109:Fetal Development / Q000502:physiology*; D006321:Heart / Q000187:drug effects / Q000196:embryology* / Q000503:physiopathology*; D006984:Hypertrophy; D008190:Lyases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009929:Organ Size / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000804:Angiotensin II; D008190:Lyases; C031581:cytochrome C synthetase
keywords: Cardiac growth; Fetal programming; Hypertrophy