Abstract Body: Background: The heart adapts to pregnancy at transcriptional, metabolic, morphologic, and functional levels, ensuring that demands of both the mother and developing child are adequately met. How extra-cardiac signals coordinate cardiac adaptation to pregnancy is poorly understood. For various maternal tissues, including mammary glands, adipose and pancreatic β-cells, lactogenic hormones act via the prolactin receptor (PRLR) to orchestrate tissue adaptation during pregnancy.

Objective: To determine whether cardiomyocyte prolactin signaling is required for cardiac adaptation to pregnancy.

Approach: Timed pregnancies were performed in cardiomyocyte-specific PRLR knockout (cmPRLR-KO) and littermate control (CON) female mice at 9 weeks of age. Systolic and diastolic function were assessed by echocardiography at gestation day 16. Immediately following echocardiography, hearts were isolated for gravimetric, histologic, and molecular analyses. In a subset of studies, the impact of multiple (3) sequential pregnancies was investigated in cmPRLR-KO and CON mice. In all experiments, non-pregnant age-matched female mice were assessed in an identical manner.

Results: As anticipated, a single pregnancy increased biventricular weight (+17%; p<0.001), cardiomyocyte size (+64%; p<0.001), left ventricular (LV) area (+8%; p=0.045), and cardiac output (+16%; p=0.032) in CON mice. In contrast, pregnancy-induced alterations in these parameters were either abolished or significantly (p<0.05) attenuated in cmPRLR-KO mice. Given impaired cardiac adaptation of cmPRLR-KO mice to a single pregnancy, we hypothesized that this may lead to maladaptation following multiple pregnancies. Consistent with this premise, 3 sequential pregnancies resulted in cardiomyopathy in cmPRLR-KO mice (but not in CON mice), characterized by reduced LV ejection fraction (-45%; p<0.001), increased LV volume (+196%; p<0.001), increased cardiomyocyte size (+69%; p=0.001), and induction of adverse cardiac remodeling markers (e.g., +266% nppa mRNA; p=0.002).

Conclusions: Cardiomyocyte prolactin signaling is essential for adaptation of the heart to pregnancy. Loss of cardiomyocyte prolactin signaling precipitates cardiomyopathy following multiple pregnancies.