Tissue Inhibitor of Metalloproteinase 4 (Timp4) Deletion in Mice Impacts Maternal Cardiac Function during Pregnancy and Postpartum.

Reversible physiological cardiac hypertrophy of the maternal heart occurs during pregnancy and involves extracellular matrix (ECM) remodeling. Previous mouse studies revealed that changes in ECM molecules accompany functional changes in the left ventricle (LV) during late pregnancy and postpartum. In this study, we aimed to determine the effect of global Timp4 deletion in female mice on LV functional parameters and ECM molecules during the cardiac remodeling that occurs during pregnancy and the first postpartum month. Heart weights normalized to tibia lengths were increased in Timp4 knockout (Timp4 KO) females compared to wildtypes. Serial echocardiography was performed on pregnancy days (eds) 10, 12, 18 and postpartum days (ppds) 2, 7, 14, 21, and 28 and revealed that both wildtype and Timp4 KO mice increased end systolic and end diastolic volumes (ESV, EDV) by mid to late pregnancy compared to virgins, with EDV changes persisting through the postpartum period. Compared to wildtypes, Timp4 KO mice exhibited lower ESV in virgins and on most pregnancy and postpartum days, whereas EDV was lower at pregnancy days 12 and 18 and ppd28. Ejection fraction was higher in Timp4 KO mice for almost all days, compared to wildtypes. High molecular weight forms of COL1A1 and COL3A1 proteins in LV were elevated in Timp4 KO virgins, and COL1A1 was higher at ed18 and ppd2 compared to wildtypes. Timp4 KO mice during late pregnancy and on most postpartum days were able to maintain stroke volume similar to wildtype mice through increased ejection fraction.