Permanent Cardiac Sarcomere Changes in a Rabbit Model of Intrauterine Growth Restriction

Abstract

BackgroundIntrauterine growth restriction (IUGR) induces fetal cardiac remodelling and dysfunction, which persists postnatally and may explain the link between low birth weight and increased cardiovascular mortality in adulthood. However, the cellular and molecular bases for these changes are still not well understood. We tested the hypothesis that IUGR is associated with structural and functional gene expression changes in the fetal sarcomere cytoarchitecture, which remain present in adulthood.Methods and ResultsIUGR was induced in New Zealand pregnant rabbits by selective ligation of the utero-placental vessels. Fetal echocardiography demonstrated more globular hearts and signs of cardiac dysfunction in IUGR. Second harmonic generation microscopy (SHGM) showed shorter sarcomere length and shorter A-band and thick-thin filament interaction lengths, that were already present in utero and persisted at 70 postnatal days (adulthood). Sarcomeric M-band (GO: 0031430) functional term was over-represented in IUGR fetal hearts.ConclusionThe results suggest that IUGR induces cardiac dysfunction and permanent changes on the sarcomere.

Cardiovascular Remodeling and Dysfunction Across a Range of Growth Restriction Severity in Small for Gestational Age Infants – Implications for Fetal Programming –

“…We speculate that chronic hypoxia in utero resulted in longitudinal dysfunction because decreased longitudinal movement is mediated by subendocardial and subepicardial fibers, which are highly sensitive to hypoxia. 21 The observed significant increase in heart rate in the severe SGA group that was associated with decreased LS may represent a compensatory mechanism that preserves LV output. Crispi et al have presented similar findings in children (average age, 5 years) with a history of IUGR.…”

“…7 An experimental study using an IUGR rabbit model has shown that chronic hypoxia in utero results in sarcomere shortening. 21 Those authors speculated that the shortened sarcomere might change the titin isoform, because titin is a large protein that determines sarcomere length. Interestingly, cardiac samples from human IUGR fetus autopsies have also demonstrated shorter sarcomeres.…”

Models of Intrauterine growth restriction and fetal programming in rabbits

“…There were also changes in the heart and kidneys in rabbit kits in response to surgical ligature of uteroplacental vessels. In particular, reduced uteroplacental blood flow decreased fetal heart weight and caused systolic and diastolic dysfunction (Schipke et al, ) in association with an increase in myocardial wall thickness, left ventricular hypovascularisation and hypertrophy, altered expression of metabolic genes, and disorganized cardiomyocyte ultrastructure (reduced sarcomere length and mitochondrial density; Gonzalez‐Tendero et al, ; Guitart‐Mampel et al, ; Gumus et al, ; Schipke et al, ; Torre et al, ). Utero‐placental insufficiency also reduced kidney weight, decreased renal glomeruli number and lead to glomerular capillary congestion and oxidative stress in developing rabbits kits (Bassan et al, ; Figueroa et al, ).…”

Oxidative damage and nitric oxide synthase induction by surgical uteroplacental circulation restriction in the rabbit fetal heart

“…Previously, using the same animal model, Gratacós described that fetal echocardiography showed a more globular cardiac shape, with a lower right sphericity index but similar wall thickness, in UCR subjects compared with that in controls. Furthermore, the control and UCR groups showed similar ejection fractions, although the UCR group had lower mitral annular peak velocities (S′), suggesting cardiac dysfunction . Using our model of IUGR, we found a similar wall thickness in UCR rabbits as in controls, but we did not test mitral annular peak velocities.…”

“…Furthermore, the control and UCR groups showed similar ejection fractions, although the UCR group had lower mitral annular peak velocities (S 0 ), suggesting cardiac dysfunction. 16 Using our model of IUGR, we found a similar wall thickness in UCR rabbits as in controls, but we did not test mitral annular peak velocities.…”