Multiparity induces persistent myocardial structural, functional and transcriptomic remodelling in mice

Pregnancy poses unique hemodynamic and metabolic demands on the heart. Recent data suggests that a history of multiple pregnancies may be associated with a late-term increased risk of heart failure with preserved ejection fraction (HFpEF), however, the mechanistic basis is unknown. We postulated that the repetitive biological and hemodynamic impact of multiple pregnancies could cause persistent myocardial remodelling providing a substrate for subsequent HFpEF. Multiparous (MP) mice (C57Bl/6J) aged 24 months were compared to age-matched non-parous (NP) mice (n = 8) in a blinded analysis. We evaluated blood pressure, body composition, gross weight and histologic cardiac structure. Cardiac function was assessed by echocardiography together with transcriptomic analysis of the left ventricular myocardium. At 15 months post oestrous cycle disruption, MP mice continued to demonstrate a constellation of myocardial alterations including higher heart to tibial length ratio (P < 0.05), body weight (P < 0.01), and fat mass (P < 0.01) compared to NP mice. MP mice had increased isovolumetric relaxation time (P < 0.01), increased end-diastolic (P < 0.05) and systolic volumes (P < 0.005), and mildly reduced left ventricular ejection fractions (LVEF) (P < 0.005) compared to non-parous mice. This was accompanied by marked elevations in mRNA levels of cardiac markers; Myh6 (P < 0.01) and Nppa (P < 0.01). mRNA levels of Il18 (P < 0.05) and the basal extracellular matrix protein-fibronectin (P < 0.05) were also increased, with a significant increase in interstitial fibrosis (P < 0.05). Bulk RNA sequencing (RNA Seq) further revealed persistent differential expression of 128 genes with over/under-represented pathways involved in extracellular matrix (ECM) regulation and organic anion/ion transport, respectively. Multiparity alters cardiac gene profile and causes myocardial remodelling that persists into later life, providing a potential foundation for the HF phenotypes such as HFpEF. Further studies are required to investigate the nature of the interaction between pregnancy-associated remodelling and other factors known to be associated with HFpEF development.