Cardiac Outcomes After Perinatal Sertraline Exposure in Mice

Abstract

Selective serotonin reuptake inhibitors are prescribed to 6–10% of pregnant women in the United States. Using an intrauterine plus neonatal exposure model to represent exposure throughout human pregnancy, we hypothesized sertraline exposure would impact intracardiac serotonin signaling and lead to small left heart syndrome in the absence of maternal psychopathology. C57BL/6 adult female mice received sertraline (5 mg/kg/d IP) or saline throughout pregnancy to time of delivery. Pups maintained exposure on postnatal days 1–14 to encompass the developmental window analogous to human gestation. Sertraline-exposed mice had increased cardiac hydroxyproline content, decreased 5-HT2B receptor mRNA levels, and increased 5-HT2A receptor and serotonin transporter mRNA levels on postnatal day 21 (p<0.05). These changes were associated with diminished exercise capacity at 6 weeks (p<0.05) and decreased adult shortening fraction and stroke volume at 5 months of age. Isolated cardiomyocytes from neonatal sertraline-exposed mice had significantly decreased proliferation, cross-sectional area and phosphorylation of Akt (p<0.05 versus neonatal control mice). Perinatal sertraline exposure alters neonatal cardiac development and produces long standing changes in adult cardiac function and exercise capacity. Further studies are needed to assess if similar findings are present in the growing population that has been exposed to SSRIs during development.

A Prospective Study Evaluating the Effects of SSRI Exposure on Cardiac Size and Function in Newborns

“…Thus, the smaller LV lengths in the SSRI-exposed infants did not render a functional or physiological difference in the left ventricle at least in the otherwise healthy newborns. While the possible mechanisms for these findings are unclear, our preclinical work and that of others suggest SSRIs decrease cardiomyocyte proliferation [10, 22]. The impact of heart size at birth is currently not well studied.…”

“…Preclinical studies are instrumental in understanding the potential mechanisms of how SSRIs influence cardiac development while eliminating confounding variables. While no cardiac malformations have been observed in our preclinical models, we have demonstrated that sertraline exposure decreases the proliferation and cross-sectional area of neonatal cardiomyocytes and increases neonatal cardiac fibrosis, resulting in significant reductions in cardiac size and function [10]. Based on these data, we hypothesized that human infants exposed to in utero SSRIs would have reduced ventricular size and cardiac function shortly after birth.…”

Effect of Low and High Doses of Two Selective Serotonin Reuptake Inhibitors on Pregnancy Outcomes and Neonatal Mortality

“…Fetal growth restriction (unrelated to SSRI exposure) leads to several fetal adaptations to restricted nutrient availability including morphological heart changes, increased cardiac workload, and cardiac function issues resembling dilated cardiomyopathy [14]. Interestingly, rodents exposed to SSRI perinatally have altered cardiac morphology [43,46] and dilated cardiomyopathy [23]. Because both drugs promote comparable neonatal mortality and increase serotonin concentrations in the maternal side of the placenta altering placental homeostasis [18,47] but have distinct placental transfer (70% fluoxetine [23] vs. 25% sertraline [24]), placental insufficiency is likely to be the underlying mechanism of SSRI-related pup mortality rather than a direct toxic effect of SSRI on fetal development.…”

Neonatal Growth Restriction Slows Cardiomyocyte Development and Reduces Adult Heart Size

“…In accordance with Institutional Animal Care and Use Committee protocol, neonatal mice were decapitated, and adult mice were exposed to 100% carbon dioxide with bilateral thoracotomy performed after 1 min of apnea. The heart was dissected and then perfused using a modified Langendorff preparation (Haskell et al, ). The aorta was cannulated and the coronary arteries were perfused with a series of oxygenated 39°C solutions including 10 min with Tyrode solution (no calcium added), 10 min with Tyrode solution containing collagenase (160 U/ml, Worthington Type II) and protease (0.78 U/ml, Sigma, Type XIV).…”

“…Hearts were bluntly dissected and processed for hematoxylin‐eosin staining and Masson's trichrome staining, as previously described (Haskell et al, ). Alternatively, transverse sections were incubated in 1.5N HCl at 37°C for 15 min followed by two rinses in 0.1 M borate buffer for antigen retrieval.…”