Severe left heart obstruction with retrograde arch flow influences fetal cerebral and placental blood flow.

OBJECTIVE: Decreased middle cerebral artery (MCA) pulsatility index (PI) is a marker of fetal brain-sparing in placental insufficiency and it is also found in fetuses with severe congenital heart disease. This study sought to explore the impact of anatomical subtypes in fetal heart disease on MCA-PI and head growth. METHODS: We retrospectively reviewed fetal echocardiograms of pregnancies complicated by fetal hypoplastic left heart syndrome (HLHS; n = 42) with and without anatomic coarctation (n = 28 and n = 10, respectively), isolated severe aortic coarctation (n = 21), D-transposition of the great arteries (TGA; n = 11) and pulmonary outflow tract obstruction without forward flow across the pulmonary valve (POTO; n = 15), comparing observations with gestational age-matched controls (n = 89). No fetus had major extracardiac pathology or aneuploidy. MCA and umbilical artery (UA) PI, the cerebral placental ratio (CPR = MCA-PI/ UA-PI) and neonatal head circumference were obtained and expressed as Z-scores. RESULTS: Lower MCA-PI, higher UA-PI and lower CPR were observed in fetal HLHS and isolated coarctation with reversed arch flow (n = 6) (P < 0.001) but not TGA, POTO or isolated coarctation with antegrade arch flow (n = 15) compared with controls. No difference was found between HLHS with anatomical coarctation and those without; however, MCA-PI correlated positively with neonatal head circumference in HLHS with reversed distal arch flow (r = 0.33, P < 0.05). CONCLUSIONS: Severe left heart obstruction with reversed aortic arch flow is associated with altered fetal cerebral blood flow, and in these conditions, MCA-PI positively correlates with head growth. Anatomical arch obstruction itself may not be a contributing factor to altered MCA flow in fetal HLHS.

Analysis of connexin43 expression under the control of a metallothionein promoter.

Transfection of C6 glioma cells with connexin43 (Cx43) cDNA under a constitutive promoter resulted in expression of Cx43 protein, an increase in functional gap junctions, and reduced growth under in vitro and in vivo conditions (D. Zhu et al., Proc. Natl. Acad. Sci. USA, 88: 1883-1887, 1991). To allow for precise temporal and quantitative control of Cx43 gene expression, the Cx43 cDNA was inserted into an expression vector [pSV2M(2)6] containing a modified metallothionein promoter. Upon transfection of this vector into C6 cells, clones were isolated that expressed increased levels of inducible Cx43 protein and dye coupling. The level of induction of Cx43 expression increased with increasing concentration of Zn2+, thus enabling the use of the same clone with different levels of gap junctions present. Although we observed no change in cell growth under in vitro conditions following exposure to Zn2+ or Cd2+, clones with inducible expression of Cx43 were characterized by reduced growth in vivo. Within tumors, the level of expression of Cx43 mRNA and protein corresponded to that seen in vitro following the addition of Zn2+. The suppression of tumor growth in vivo correlated with the level of induced Cx43 expression.