Maternal nutrient restriction during pregnancy and lactation leads to impaired right ventricular function in young adult baboons

Abstract

Key points: Maternal nutrient restriction induces intrauterine growth restriction (IUGR) and leads to heightened cardiovascular risks later in life. We report right ventricular (RV) filling and ejection abnormalities in IUGR young adult baboons using cardiac magnetic resonance imaging. Both functional and morphological indicators of poor RV function were seen, many of which were similar to effects of ageing, but also with a few key differences. We observed more pronounced RV changes compared to our previous report of the left ventricle, suggesting there is likely to be a component of isolated RV abnormality in addition to expected haemodynamic sequelae from left ventricular dysfunction. In particular, our findings raise the suspicion of pulmonary hypertension after IUGR. This study establishes that IUGR also leads to impairment of the right ventricle in addition to the left ventricle classically studied.

Abstract: Maternal nutrient restriction induces intrauterine growth restriction (IUGR), increasing later life chronic disease including cardiovascular dysfunction. Our left ventricular (LV) CMRI studies in IUGR baboons (8 M, 8 F, 5.7 years - human equivalent approximately 25 years), control offspring (8 M, 8 F, 5.6 years), and normal elderly (OLD) baboons (6 M, 6 F, mean 15.9 years) revealed long-term LV abnormalities in IUGR offspring. Although it is known that right ventricular (RV) function is dependent on LV health, the IUGR right ventricle remains poorly studied. We examined the right ventricle with cardiac magnetic resonance imaging in the same cohorts. We observed decreased ejection fraction (49 ± 2 vs. 33 ± 3%, P < 0.001), cardiac index (2.73 ± 0.27 vs. 1.89 ± 0.20 l min^-1 m^-2 , P < 0.05), early filling rate/body surface area (BSA) (109.2 ± 7.8 vs. 44.6 ± 7.3 ml s^-1 m^-2 , P < 0.001), wall thickening (61 ± 3 vs. 44 ± 5%, P < 0.05), and longitudinal shortening (26 ± 3 vs. 15 ± 2%, P < 0.01) in IUGR animals with increased chamber volumes. Many, but not all, of these changes share similarities to normal older animals. Our findings suggest IUGR-induced pulmonary hypertension should be further investigated and that atrial volume, pulmonic outflow and interventricular septal motion may provide valuable insights into IUGR cardiovascular physiology. Overall, our findings reaffirm that gestational and neonatal challenges can result in long-term programming of poor offspring cardiovascular health. To our knowledge, this is the first study reporting IUGR-induced programmed adult RV dysfunction in an experimental primate model.

Keywords: baboon; cardiac MRI; developmental programming; intrauterine growth restriction (IUGR); maternal nutrient restriction; nonhuman primates; right ventricle.

Figure 1. Analysis of CMRI data

For CMRI, short axis images of the ventricles were obtained en bloc in a phase‐specific manner. A, a sample raw image. B and C, semi‐automatic application of endocardial RV contour (B) is performed to produce a working RV model for quantification of measurements (C). Wall thickness measurement is taken from visually selected representative positions of the right ventricle free wall (bar, B). Also shown are the LV tracings previously reported (B). [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2. RV ejection and filling rates in CTL, OLD and IUGR baboons

A, decreased RV‐EF is seen in both OLD (P < 0.05) and IUGR groups (P < 0.001) compared to CTL. B, this decrease in ejection fraction is reflected in normalized cardiac output where decreased values are again seen in both OLD (P < 0.01) and IUGR (P < 0.05). C and D, both eFR (C) and overall filling rate (D) are decreased in OLD (eFR/BSA P < 0.001, FR/BSA P < 0.01) and IUGR (eFR/BSA P < 0.001, FR/BSA P < 0.05). No sex difference or group‐sex interaction was seen in these four measurements. One outlier was removed from male OLD group in C; two outliers were removed from female CTL group in D. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3. Changes of RV morphology

A, RV longitudinal shortening is decreased in OLD (P < 0.05) and IUGR (P < 0.005) compared to CTL. B, similarly, RV‐WTF is decreased in both OLD (P < 0.05) and IUGR (P < 0.05) compared to CTL. C and D, RV remodelling occurs in OLD, with both RV sphericity indices decreased at both end‐systole (C) and end‐diastole (D). In contrast, there is pseudo‐normalization of the IUGR sphericity indices secondary to both increased chamber volume and decreased longitudinal shortening. No sex difference or group–sex interaction was seen in these four measurements. One outlier was removed from the male OLD group in both C and D. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 4. Correlation analyses of RV ejection and filling rates

A, a positive correlation is seen between RV‐EF and birth weight (R = 0.59, P < 0.001) with group stratification. Individually, the correlation is not significant (CTL P = 0.16, IUGR P = 0.10). B, similarly, a positive correlation is identified between RV‐eFR and birth weight (R = 0.59, P < 0.001). Individually, the correlation is not significant (CTL P = 0.15, IUGR P = 0.15). C, RV‐EF correlates strongly with LV‐EF (R = 0.80, P < 0.001), seen individually per group (CTL P < 0.05, OLD P < 0.05, IUGR P < 0.01). D, RV ejection and filling functions are highly correlated (R = 0.76, P < 0.001), seen individually per group (CTL P < 0.01, OLD P < 0.01, IUGR P = 0.001). [Color figure can be viewed at wileyonlinelibrary.com]

Figure 5. RV longitudinal shortening and wall thickening are associated with RV ejection fraction

A, RV‐EF is significantly correlated with RV‐LSF (R = 0.73, P < 0.001). This correlation is seen individually within groups (CTL P = 0.03, OLD P = 0.02, IUGR P = 0.0003) without between‐group differences (P = 0.43). B, RV‐EF also correlates with RV‐WTF (R = 0.75, P < 0.001). This correlation is seen individually within groups (CTL P = 0.01, OLD P = 0.002, IUGR P = 0.005) without between‐group differences (P = 0.38). [Color figure can be viewed at wileyonlinelibrary.com]