P124Initiation of relaxation is delayed in fetal ventricular myocytes from rabbits suffering intrauterine growth restriction and worsens postnatally

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Abstract

Purpose

Intrauterine growth restriction (IUGR) is associated with cardiovascular remodelling and dysfunction persisting into adulthood, resulting in dilated and less efficient hearts. However, the underlying molecular mechanisms remain to be elucidated. Here we test the hypothesis that unbalanced calcium (Ca2+) homeostasis is a key contributor to cardiac fetal programming.

Methods

IUGR was induced in 6 pregnant New Zealand rabbits by a surgical standard protocol. Puppies were assigned to: i) fetal (30 days of gestation) or ii) young adult (70 days postnatally) groups. Fetal myocardial performance was assessed by echocardiography on day 30 of gestation. Ventricular myocytes were isolated by a multistep enzymatic digestion of myocardial fragments of the fetal heart, or by enzymatic Langendorff perfusion of the adult heart. Then, intracellular Ca2+ concentration was monitored with the calcium indicator fluo-3 and the responses to electrical field stimulation at different pacing rates were recorded and analyzed.

Results

Fetal echocardiography showed that ductus venosus, aortic isthmus pulsatility index and isovolumetric relaxation time were increased in IUGR hearts (p < 0.01). When subjected to rapid pacing, fetal IUGR cardiomyocytes also needed more time in order to reach 10% relaxation of the peak calcium transient (RT10) 0.121 ± 0.104s vs. 0.068 ± 0.079s in control (p < 0.05). The increased RT10 under IUGR persisted postnatally (0.141 ± 0.015s vs. 0.115 ± 0.016s in control, p=0.01) and was accompanied by an increased RT50 (0.529 ± 0.05s vs. 0.435 ± 0.055s in control, p < 0.001).

Conclusion

IUGR induces a permanent impairment in the initial relaxation phase that could be interpreted as a delayed onset of relaxation. Importantly, this phenomenon worsens postnatally as evidenced by an overall slowing of the relaxation process. This, suggests that IUGR-induced impairment of Ca2+ removal from the cytosol may contribute to the development of inefficient hearts with diastolic dysfunction, observed in both fetal humans and rabbits suffering IUGR, and thus provide an explaination for some cardiomyopathies with origin in the fetal life.

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