Exaggerated Cardiac Contractile Response to Hypoxia in Adults Born Preterm

Gregory P Barton, Philip A Corrado, Christopher J Francois, Naomi C Chesler, Marlowe W Eldridge, Oliver Wieben, Kara N Goss, Gregory P Barton, Philip A Corrado, Christopher J Francois, Naomi C Chesler, Marlowe W Eldridge, Oliver Wieben, Kara N Goss

Abstract

Individuals born prematurely have smaller hearts, cardiac limitations to exercise, and increased overall cardiometabolic risk. The cardiac effects of acute hypoxia exposure as another physiologic stressor remain under explored. The purpose of this study was to determine the effects of hypoxia on ventricular function in adults born preterm. Adults born moderately to extremely preterm (≤32 weeks gestation or <1500 g, N = 32) and born at term (N = 18) underwent cardiac magnetic resonance imaging under normoxic (21% O2) and hypoxic (12% O2) conditions to assess cardiovascular function. In normoxia, cardiac function parameters were similar between groups. During hypoxia, the right ventricular (RV) contractile response was significantly greater in participants born premature, demonstrated by greater increases in RV ejection fraction (EF) (p = 0.002), ventricular-vascular coupling (VVC) (p = 0.004), and strain (p < 0.0001) measures compared to term-born participants, respectively. Left ventricular contractile reserve was similar to term-born participants. Adults born preterm exhibit an exaggerated contractile response to acute hypoxia, particularly in the RV. This suggests that adults born preterm may have contractile reserve, despite the lack of volume reserve identified in previous exercise studies. However, this exaggerated and hyper-adapted response may also increase their risk for late RV failure.

Keywords: cardiac function; contractile response; hypoxia; prematurity.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic showing participant flow through the study.
Figure 2
Figure 2
Right ventricular (RV) functional response is exaggerated in adults born preterm. There are significant decreases in (a) RV end-diastolic (EDVI) (p = 0.01) and (b) end-systolic volume index (ESVI) (p ≤ 0.0001) in preterm individuals, while term born-individuals do not see any decreases in RV EDVI or ESVI. Interestingly, individuals born preterm exhibit a robust contractile response to hypoxia as observed by dramatic increases in (c) RV ejection fraction (EF) (p = 0.009) and (d) RV ventricular—vascular coupling (VVC) (p = 0.01), while no changes were observed in term-born individuals. Data represent mean ± SD. * p < 0.05, ** p < 0.01, **** p < 0.0001.
Figure 3
Figure 3
Left ventricular (LV) response to hypoxia. There was a main effect of hypoxia and birth status for all LV variables. Namely, there was a 3% and 8% reduction in (a) LV EDVI from normoxia to hypoxia in term and preterm participants, respectively (p = 0.03). Acute hypoxia resulted in a 10% and 18% reduction in (b) LV ESVI in term and preterm, respectively (p = 0.03). There were similar relative changes in (c) LVEF from normoxia to hypoxia between term (5%) and preterm (8%) participants. LV ventricular vascular coupling (VVC) (d) improved in both groups as demonstrated by an increase in preterm (28%) and term-born (15%) participants, although this did not reach statistical significance (p = 0.14). Data represent mean ± SD. * p < 0.05, ** p < 0.01, **** p < 0.0001, n.s. = not significant (p > 0.05).
Figure 4
Figure 4
Biventricular function stratified by preterm with or without a history of bronchopulmonary dysplasia (BPD). There are significant decreases in (a–c) right ventricular (RV) end-diastolic index (EDVI) (p = 0.029) and end-systolic volume index (ESVI) (p = 0.0005) in preterm individuals with or without a diagnosis of BPD, while term born-individuals do not see any decreases in RV EDVI or ESVI. Interestingly, individuals born preterm with or without BPD exhibit a robust contractile response to hypoxia as observed by dramatic increases in RV ejection fraction (EF) (p = 0.026), while no changes were observed in term-born individuals. There was a main effect of hypoxia for all LV variables (d–f). The LV functional responses between groups were quantitatively different, although not statistically significant. Namely, there was a 3%, 6%, and 11% reduction in LV EDVI from normoxia to hypoxia in term, preterm, and preterm with BPD, respectively. Acute hypoxia resulted in a 10%, 18%, and 18% reduction in LV ESVI in term, preterm, and preterm with BPD, respectively. There were similar relative changes in LVEF from normoxia to hypoxia in all three groups (range 6–8% increase). In order to determine if there were differences between those with and without a history of BPD, we utilized an unpaired t-test and found no differences (p > 0.05) for all of the RV and LV measures. Data represent mean ± SD. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, n.s. = not significant (p > 0.05).
Figure 5
Figure 5
Hypoxic mediated changes in the (a,b) pulmonary artery (PA) and (c,d) aorta (Ao) by 2D phase contrast (PC) imaging. Individuals born preterm exhibit increased PA mean velocity during hypoxia, while there is a subtle reduction in PA mean velocity in term-born participants (p = 0.03). The increased PA mean velocity observed in preterm participants is likely a result of the increased RV contractile response to hypoxia. Overall, individuals born preterm display reduced baseline PA relative area change (RAC) which suggests a stiffer PA compared to term-born participants. There is a subtle reduction to PA relative area change (RAC) during hypoxia in term and preterm participants, suggesting increased PA stiffening. Overall, there were no significant changes in Ao mean velocity or RAC. Data represent mean ± SD. * p < 0.05, ** p < 0.01, n.s. = not significant (p > 0.05).

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