Intrauterine exposure to chronic hypoxia in the rat leads to progressive diastolic function and increased aortic stiffness from early postnatal developmental stages

Aim: We sought to explore whether fetal hypoxia exposure, an insult of placental insufficiency, is associated with left ventricular dysfunction and increased aortic stiffness at early postnatal ages. Methods: Pregnant Sprague Dawley rats were exposed to hypoxic conditions (11.5% FiO2) from embryonic day E15-21 or normoxic conditions (controls). After delivery, left ventricular function and aortic pulse wave velocity (measure of aortic stiffness) were assessed longitudinally by echocardiography from day 1 through week 8. A mixed ANOVA with repeated measures was performed to compare findings between groups across time. Myocardial hematoxylin and eosin and picro-sirius staining were performed to evaluate myocyte nuclear shape and collagen fiber characteristics, respectively. Results: Systolic function parameters transiently increased following hypoxia exposure primarily at week 2 (p <.008). In contrast, diastolic dysfunction progressed following fetal hypoxia exposure beginning weeks 1–2 with lower early inflow Doppler velocities, and less of an increase in early to late inflow velocity ratios and annular and septal E’/A’ tissue velocities compared to controls (p <.008). As further evidence of altered diastolic function, isovolumetric relaxation time was significantly shorter relative to the cardiac cycle following hypoxia exposure from week 1 onward (p <.008). Aortic stiffness was greater following hypoxia from day 1 through week 8 (p <.008, except week 4). Hypoxia exposure was also associated with altered nuclear shape at week 2 and increased collagen fiber thickness at week 4. Conclusion: Chronic fetal hypoxia is associated with progressive LV diastolic dysfunction, which corresponds with changes in nuclear shape and collagen fiber thickness, and increased aortic stiffness from early postnatal stages.