Long term effects of fetal undernutrition on rat heart. Role of hypertension and oxidative stress

Background and aims Fetal undernutrition is a risk factor for heart disease in both genders, despite the protection of women against hypertension development. Using a rat model of maternal undernutrition ( MUN) we aimed to assess possible sex differences in the development of cardiac alterations and the implication of hypertension and cardiac oxidative stress. Methods Male and female offspring from rats fed ad libitum ( control) or with 50% of the normal daily intake during the second half of gestation ( MUN) were used. Heart weight/body weight ratio ( HW/BW), hemodynamic parameters ( anaesthetized rats) and plasma brain natriuretic peptide ( BNP, ELISA) were assessed in 21-day, 6-month and 22-month old rats. Plasma testosterone ( ELISA) and cardiac protein expression of enzymes related to reactive oxygen species synthesis ( p22 phox, xanthine-oxidase) and degradation ( catalase, Cu/Zn-SOD, Mn-SOD, Ec-SOD) were evaluated in 21-day and 6-month old rats ( Western Blot). Heart structure and function was studied at the age of 22 months ( echocardiography). Results At the age of 21 days MUN males exhibited significantly larger HW/BW and cardiac p22 phox expression while females had reduced p22 phox expression, compared to their respective sex-matched controls. At the age of 6-months, MUN males showed significantly larger blood pressure and cardiac xanthine-oxidase expression; MUN females were normotensive and had a lower cardiac expression of antioxidant enzymes, compared to their respective sex-matched controls. At the age of 22 months, both MUN males and females showed larger HW/BW and left ventricular mass and lower ejection fraction compared to sex-matched controls; only MUN males exhibited hypertension and a larger plasma BNP compared to aged male controls. Conclusions 1) During perinatal life females exposed to fetal undernutrition are protected from cardiac alterations, but in ageing they exhibit ventricular hypertrophy and functional loss, like MUN males; 2) cardiac oxidative stress might be implicated in the observed heart alterations in both sexes and 3) the severity of cardiac damage might be greater in males due to hypertension.