title: Tafazzin knockdown in mice leads to a developmental cardiomyopathy with early diastolic dysfunction preceding myocardial noncompaction.
abstract: BACKGROUND
  Barth syndrome is a rare, multisystem disorder caused by mutations in tafazzin that lead to cardiolipin deficiency and mitochondrial abnormalities. Patients most commonly develop an early-onset cardiomyopathy in infancy or fetal life.
  
  
  RESULTS
  Knockdown of tafazzin (TAZKD) in a mouse model was induced from the start of gestation via a doxycycline-inducible shRNA transgenic approach. All liveborn TAZKD mice died within the neonatal period, and in vivo echocardiography revealed prenatal loss of TAZKD embryos at E12.5-14.5. TAZKD E13.5 embryos and newborn mice demonstrated significant tafazzin knockdown, and mass spectrometry analysis of hearts revealed abnormal cardiolipin profiles typical of Barth syndrome. Electron microscopy of TAZKD hearts demonstrated ultrastructural abnormalities in mitochondria at both E13.5 and newborn stages. Newborn TAZKD mice exhibited a significant reduction in total mitochondrial area, smaller size of individual mitochondria, reduced cristae density, and disruption of the normal parallel orientation between mitochondria and sarcomeres. Echocardiography of E13.5 and newborn TAZKD mice showed good systolic function, but early diastolic dysfunction was evident from an abnormal flow pattern in the dorsal aorta. Strikingly, histology of E13.5 and newborn TAZKD hearts showed myocardial thinning, hypertrabeculation and noncompaction, and defective ventricular septation. Altered cellular proliferation occurring within a narrow developmental window accompanied the myocardial hypertrabeculation-noncompaction.
  
  
  CONCLUSIONS
  In this murine model, tafazzin deficiency leads to a unique developmental cardiomyopathy characterized by ventricular myocardial hypertrabeculation-noncompaction and early lethality. A central role of cardiolipin and mitochondrial functioning is strongly implicated in cardiomyocyte differentiation and myocardial patterning required for heart development. (J Am Heart Assoc. 2012;1:jah3-e000455 doi: 10.1161/JAHA.111.000455.).
authors.affiliation: Department of Pediatrics (Pediatric Cardiology), New York University School of Medicine,  New York (C.K.L.P., N.V.).
authors.forename: Colin K L
authors.initials: CK
authors.lastname: Phoon
authors.forename: Devrim
authors.initials: D
authors.lastname: Acehan
authors.forename: Michael
authors.initials: M
authors.lastname: Schlame
authors.forename: David L
authors.initials: DL
authors.lastname: Stokes
authors.forename: Irit
authors.initials: I
authors.lastname: Edelman-Novemsky
authors.forename: Dawen
authors.initials: D
authors.lastname: Yu
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Nitya
authors.initials: N
authors.lastname: Viswanathan
authors.forename: Mindong
authors.initials: M
authors.lastname: Ren
keywords: Barth syndrome; cardiolipin; mitochondrial disease; noncompaction cardiomyopathy; tafazzin