TY - JOUR
T1 - Early- to mid-gestational testosterone excess leads to adverse cardiac outcomes in postpartum sheep
AU - Alkhatib, Bashar
AU - Ciarelli, Joseph
AU - Ghnenis, Adel
AU - Pallas, Brooke
AU - Olivier, Nicholas
AU - Padmanabhan, Vasantha
AU - Vyas, Arpita Kalla
N1 - Publisher Copyright:
Copyright © 2024 the American Physiological Society.
PY - 2024/8
Y1 - 2024/8
N2 - Cardiovascular dysfunctions complicate 10–20% of pregnancies, increasing the risk for postpartum mortality. Various gestational insults, including preeclampsia are reported to be associated with adverse maternal cardiovascular outcomes. One such insult, gestational hyperandrogenism increases the risk for preeclampsia and other gestational morbidities but its impact on postpartum maternal health is not well known. We hypothesize that gestational hyperandrogenism such as testosterone (T) excess will adversely impact the maternal heart in the postpartum period. Pregnant ewes were injected with T propionate from day 30 to day 90 of gestation (term 147 days). Three months postpartum, echocardiograms, plasma cytokine profiles, cardiac morphometric, and molecular analysis were conducted [control (C) n ¼ 6, T-treated (T) n ¼ 7 number of animals]. Data were analyzed by two-tailed Student’s t test and Cohen’s effect size (d) analysis. There was a nonsignificant large magnitude decrease in cardiac output (7.64 ± 1.27 L/min vs. 10.19 ± 1.40, P ¼ 0.22, d ¼ 0.81) and fractional shortening in the T ewes compared with C (35.83 ± 2.33% vs. 41.50 ± 2.84, P ¼ 0.15, d ¼ 0.89). T treatment significantly increased 1) left ventricle (LV) weight-to-body weight ratio (2.82 ± 0.14 g/kg vs. 2.46 ± 0.08) and LV thickness (14.56 ± 0.52 mm vs. 12.50 ± 0.75), 2) proinflammatory marker [tumor necrosis factor-alpha (TNF-a)] in LV (1.66 ± 0.35 vs. 1.06 ± 0.18), 3) LV collagen (Masson’s Trichrome stain: 3.38 ± 0.35 vs. 1.49 ± 0.15 and Picrosirius red stain: 5.50 ± 0.32 vs. 3.01 ± 0.23), 4) markers of LV apoptosis, including TUNEL (8.3 ± 1.1 vs. 0.9 ± 0.18), bcl-2-associated X protein (Bax) þ -to-b-cell lymphoma 2 (Bcl2) þ ratio (0.68 ± 0.30 vs. 0.13 ± 0.02), and cleaved caspase 3 (15.4 ± 1.7 vs. 4.4 ± 0.38). These findings suggest that gestational testosterone excess adversely programs the maternal LV, leading to adverse structural and functional consequences in the postpartum period. NEW & NOTEWORTHY Using a sheep model of human translational relevance, this study provides evidence that excess gestational testosterone exposure such as that seen in hyperandrogenic disorders adversely impacts postpartum maternal hearts.
AB - Cardiovascular dysfunctions complicate 10–20% of pregnancies, increasing the risk for postpartum mortality. Various gestational insults, including preeclampsia are reported to be associated with adverse maternal cardiovascular outcomes. One such insult, gestational hyperandrogenism increases the risk for preeclampsia and other gestational morbidities but its impact on postpartum maternal health is not well known. We hypothesize that gestational hyperandrogenism such as testosterone (T) excess will adversely impact the maternal heart in the postpartum period. Pregnant ewes were injected with T propionate from day 30 to day 90 of gestation (term 147 days). Three months postpartum, echocardiograms, plasma cytokine profiles, cardiac morphometric, and molecular analysis were conducted [control (C) n ¼ 6, T-treated (T) n ¼ 7 number of animals]. Data were analyzed by two-tailed Student’s t test and Cohen’s effect size (d) analysis. There was a nonsignificant large magnitude decrease in cardiac output (7.64 ± 1.27 L/min vs. 10.19 ± 1.40, P ¼ 0.22, d ¼ 0.81) and fractional shortening in the T ewes compared with C (35.83 ± 2.33% vs. 41.50 ± 2.84, P ¼ 0.15, d ¼ 0.89). T treatment significantly increased 1) left ventricle (LV) weight-to-body weight ratio (2.82 ± 0.14 g/kg vs. 2.46 ± 0.08) and LV thickness (14.56 ± 0.52 mm vs. 12.50 ± 0.75), 2) proinflammatory marker [tumor necrosis factor-alpha (TNF-a)] in LV (1.66 ± 0.35 vs. 1.06 ± 0.18), 3) LV collagen (Masson’s Trichrome stain: 3.38 ± 0.35 vs. 1.49 ± 0.15 and Picrosirius red stain: 5.50 ± 0.32 vs. 3.01 ± 0.23), 4) markers of LV apoptosis, including TUNEL (8.3 ± 1.1 vs. 0.9 ± 0.18), bcl-2-associated X protein (Bax) þ -to-b-cell lymphoma 2 (Bcl2) þ ratio (0.68 ± 0.30 vs. 0.13 ± 0.02), and cleaved caspase 3 (15.4 ± 1.7 vs. 4.4 ± 0.38). These findings suggest that gestational testosterone excess adversely programs the maternal LV, leading to adverse structural and functional consequences in the postpartum period. NEW & NOTEWORTHY Using a sheep model of human translational relevance, this study provides evidence that excess gestational testosterone exposure such as that seen in hyperandrogenic disorders adversely impacts postpartum maternal hearts.
KW - cardiovascular
KW - hyperandrogenism
KW - maternal
KW - ovine
KW - postpartum
UR - http://www.scopus.com/inward/record.url?scp=85198919948&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00763.2023
DO - 10.1152/ajpheart.00763.2023
M3 - Article
C2 - 38819385
AN - SCOPUS:85198919948
SN - 0363-6135
VL - 327
SP - H315-H330
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 2
ER -