Female offspring from obese mothers exhibit cardiac dysfunction that is exacerbated by multiple pregnancies

Pregnancy is a natural physiological stressor to the maternal cardiovascular (CV) system requiring increases in cardiac output and blood volume to support efficient nutrient and oxygen delivery to the developing fetus. Obesity adds to this stress on the CV system and the proportion of women of reproductive age who are obese has steadily increased worldwide, further increasing CV risk in the mothers and in their offspring. In the present study, we examined if female offspring from obese mothers exhibit diastolic dysfunction and if this underlying dysfunction is exacerbated when offspring undergo multiple pregnancies (MP). Female offspring from lean Sprague-Dawley rats fed a normal diet (ND-Offs, n=15) and offspring from high fat diet-fed obese mothers (HFD-Offs, n=13) were maintained on a normal diet after weaning. Starting at 9 weeks of age, 5 female offspring from each group were mated with ND-Offs sires for five consecutive pregnancies. Then, body weight and body composition were measured, and cardiac function was assessed by left ventricle catheterization (Millar catheter). Mitochondrial function was assessed in isolated cardiac fibers using Oroboros Oxygraphy-2k. Age-matched virgin female HFD-Offs (n=8) exhibited signs of diastolic dysfunction compared to virgin ND-Offs (n=10), as indicated by reduced -dP/dt (-10,966±861 vs. -14,884±971 mmHg/sec, p=0.0096) and prolonged isovolumetric relaxation time (Tau, 5.7±0.1 vs. 4.9±0.1, p=0.0002). After 5 pregnancies, MP-HFD-Offs exhibited slightly greater body weight (371±9 vs. 342±13 g) with 25% more fat mass (35±4 vs. 28±3 g), and larger hearts (1,506±41 vs. 1,325±42 mg, p=0.0150) with more collagen deposition compared to MP-ND-Offs. MP-HFD-Offs also exhibited reduced maximal rate of left ventricular pressure rise (+dP/dt: 8,911±563 vs. 12,370±515 mmHg/sec, p=0.0019), and worse diastolic function (-dP/dt: -8,624±1011 vs. -11,612±67 mmHg/sec, p=0.0278 and Tau: 9.0±1.1 vs. 5.9±0.1, p=0.0045) measured at weaning day of the 5 th pregnancy. We also found reduced cardiac mitochondrial pyruvate-supported respiration rate in MP-HFD-Offs when pyruvate was supplied in combination with malate, glutamate and succinate, supporting electron flux via mitochondrial complexes I and II, whereas no differences between groups were observed for palmitoyl-supported respiration. Our results suggest that female offspring from obese mothers exhibit diastolic dysfunction, which is exacerbated by MP, even when the offspring consume a healthy diet and remain lean. 1R01HL163076, NIDDK 1R01DK121411, NIGMS P30GM104357 and U54GM115428 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.