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. 2020 Dec 28;3(5):574-584.
doi: 10.1016/j.cjco.2020.12.017. eCollection 2021 May.

Preterm Birth With Neonatal Interventions Accelerates Collagen Deposition in the Left Ventricle of Lambs Without Affecting Cardiomyocyte Development

Bianca Lê  1 , Mar Janna Dahl  2 , Kurt H Albertine  2 , Megan R Sutherland  1 , Mary Jane Black  1
Affiliations

Preterm Birth With Neonatal Interventions Accelerates Collagen Deposition in the Left Ventricle of Lambs Without Affecting Cardiomyocyte Development

Bianca Lê et al. CJC Open. .

Abstract
in English, French

Background: Adults born preterm (< 37 weeks' gestation) exhibit altered cardiac growth and are susceptible to cardiac dysfunction. Sheep studies have shown that moderate preterm birth results in maladaptive structural remodelling of the cardiac ventricles. The aim of this study was to examine ventricular structure in lambs born at a greater severity of preterm birth and ventilated postnatally.

Methods: Former-preterm lambs delivered at 128 days' gestation, and mechanically ventilated for a week after birth, were compared with unventilated lambs born at term (150 days' gestation), at 2 months (term: n = 10, former-preterm: n = 8), and 5 months (term: n = 9, former-preterm: n = 8) term-equivalent age. The right ventricle and left ventricle plus septum were analysed using immunohistochemistry, histology, and stereology.

Results: Cardiomyocyte number, cross-sectional area, proliferation, and apoptosis were not affected by preterm birth or age. Left ventricle plus septum interstitial collagen levels increased with age (P = 0.0015) and were exacerbated by preterm birth (P = 0.0006; 2 months term: 0.57% ± 0.07%, former-preterm: 1.44% ± 0.18%; 5 months term: 1.37% ± 0.25%, former-preterm: 2.15% ± 0.31%). Right ventricle interstitial collagen levels increased with age (P = 0.012) but were not affected by preterm birth.

Conclusion: This study is the first to explore the effect of preterm birth combined with modern neonatal interventions on the ventricular myocardium in lambs. There was no adverse impact on cardiomyocyte growth in early postnatal life. Of concern, however, there was increased collagen deposition in the preterm hearts, which has the potential to induce cardiac dysfunction, especially if it becomes exaggerated with ageing.

Introduction: Les adultes nés avant terme (< 37 semaines de grossesse) montrent une altération de la croissance cardiaque et sont exposés à une dysfonction cardiaque. Les études sur les moutons ont montré que la prématurité modérée entraîne un remodelage structurel inadapté des ventricules du cœur. L’objectif de la présente étude était d’examiner la structure ventriculaire des agneaux grands prématurés et oxygénés après la naissance.

Méthodes: Les agneaux anciens prématurés nés après 128 jours de gestation et sous respirateur durant une semaine ont été comparés aux agneaux nés à terme qui n’avaient pas été sous respirateur (150 jours de gestation) à l’âge du terme, soit deux mois (à terme : n = 10, anciens prématurés : n = 8) et cinq mois (à terme : n = 9, anciens prématurés : n = 8). Le ventricule droit et le ventricule gauche plus le septum ont été analysés par immunohistochimie, histologie et stéréologie.

Résultats: Le nombre de cardiomyocytes, la surface en coupe transversale, la prolifération et l’apoptose n’étaient pas affectés par la naissance prématurée ou l’âge. Les concentrations interstitielles en collagène du ventricule gauche plus le septum augmentaient avec l’âge (P = 0,0015) et étaient exacerbées par la naissance prématurée (P = 0,0006; âge du terme, deux mois : [à terme : 0,57 % ± 0,07 %, anciens prématurés : 1,44 % ± 0,18 % ]; âge du terme, cinq mois : [à terme : 1,37 % ± 0,25 %, anciens prématurés : 2,15 % ± 0,31 %]). Les concentrations interstitielles en collagène du ventricule droit augmentaient avec l’âge (P = 0,012), mais n’étaient pas affectées par la naissance avant terme.

Conclusion: Il s’agit de la première étude qui porte sur la combinaison des effets de la naissance avant terme aux interventions néonatales modernes sur le myocarde ventriculaire des agneaux. Aucune conséquence sur la croissance des cardiomyocytes dans la phase précoce de la vie postnatale n’a été observée. Toutefois, le dépôt accru de collagène dans le cœur des prématurés est préoccupant puisqu’il a le potentiel d’induire une dysfonction cardiaque, particulièrement s’il s’exacerbe avec le vieillissement.

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Figures

Figure 1
Figure 1
Representative photomicrographs of sections of myocardium from the left ventricles of both former-preterm lambs at (A) 2-month TEA and (B) 5-month TEA, and term lambs at (C) 2-month TEA and (D) 5-month TEA, which are absent of proliferating cardiomyocytes positive for Ki-67 antibody (brown). (E) The left ventricle from a foetal sheep heart at 100 days’ gestation was used as a positive control. Sections were counterstained with haematoxylin (purple). Scale bars = 200 μm. TEA, term-equivalent age.
Figure 2
Figure 2
Representative photomicrographs of myocardium from the left ventricles of both former-preterm lambs at (A) 2-month TEA and (B) 5-month TEA, and term lambs at (C) 2-month TEA and (D) 5-month TEA, showing negligible levels of apoptotic cardiomyocyte nuclei (green) as assessed by the TUNEL assay. (E) Rat breast tumour sections were used as a positive control. Sections were counterstained with DAPI (blue). Scale bars = 200 μm. DAPI, 4,6-diamidino-2-phenylindole hydrochloride; TEA, term-equivalent age; TUNEL, terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling.
Figure 3
Figure 3
The total number of cardiomyocytes in the (A) left ventricle plus septum and (B) right ventricle of lambs born at term (150 days’ gestation; black) or preterm (128 days’ gestation; white) at 2- and 5-month term-equivalent age. Analysis by 2-way analysis of variance, with the factors preterm birth (P), postnatal age (A), and their interaction (P∗A). Data are shown as mean ± standard error of the mean. n = 8-10/group.
Figure 4
Figure 4
Cross-sectional area of cardiomyocytes in the (A) left ventricle plus septum and (B) right ventricle of lambs born at term (150 days’ gestation; black) or preterm (128 days’ gestation; white) at 2- or 5-month term-equivalent age. Analysis by 2-way analysis of variance, with the factors preterm birth (P), postnatal age (A), and their interaction (P∗A). Data are shown as mean ± standard error of the mean. n = 8-10/group.
Figure 5
Figure 5
The percentage of interstitial collagen in the (A) left ventricle plus septum and (B) right ventricle of lambs born at term (150 days’ gestation) or preterm (128 days’ gestation) at 2- or 5-month term-equivalent age. Analysis by 2-way analysis of variance, with the factors preterm birth (P), postnatal age (A), and their interaction (P∗A). Data are shown as mean ± standard error of the mean. Representative photomicrographs of left ventricular myocardium stained with picrosirius red (collagen shown in red, and myocardium in yellow) from term-born lambs at (C) 2- and (E) 5-month, and former-preterm lambs at (D) 2- and (F) 5-month term-equivalent age. Scale bars = 200 μm. n = 8-10/group.
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