Long-term impact of postnatal nutritional programming on cardiac sensitivity to ischemia-reperfusion injury in vivo and on glucose metabolism
Authors: Rigal E , Greco C G , Josse M J , Rochette L R , Guenancia C G , Vergely C V 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): Fondation de France

Introduction
Nutritional environment during intra uterine and postnatal period has a major impact on health and disease in adulthood. The early programming of cardiometabolic risk through a postnatal overfeeding in rodents leads to a permanent increase in body weight, associated with alteration of left ventricular contractility, higher cardiac sensitivty to ischemic or chemo-toxic stresses and alterations of glucose métabolism in adulthood. However, these data have mainly obtained in young rodents and less is known for older animals.

Purpose
Our aim was to evaluate the impact of postnatal overfeeding (PNOF) on cardiac function, on cardiac sensitivity to ischemia-reperfusion (I-R) injury in vivo, on glucose metabolism and on metabolic profile of pericardial adipose tissue (PAT) in young (4 months), adult (6 months) and old (12 months) male mice.

Methods
PNOF was induced by the reduction of litter size of C57/BL6 mice immediately after birth: normally-fed group (NF) was composed of 9 male pups/mother and overfed group (PNOF) of 3 pups/mother. Echocardiography and blood sugar tests (glucose tolerance and insulin resistance) were performed at all ages. An in vivo ischemia-reperfusion injury was induced by the ligation of the left anterior descending coronary artery for 45 minutes followed by 24 h of reperfusion. PAT was harvested and weighted, in order to investigate by rt-qPCR its inflammatory status. All experiments were performed in 4-, 6- and 12-months aged mice.

Results
PNOF induced an early and permanent increase in body weight in PNOF group, independently of mice’s age (+23% at 24 days of life, +14% at 4 months, +23% at 6 and 12 months, compared to NF group). Echocardiographic measurements showed an alteration of left ventricular ejection fraction in mice aged from 4 months up to 12 months (-11 % on average, compared to NF groups). PNOF mice presented glucose intolerance and insulin resistance from 4 to 12 months of age. Moreover, PNOF mice had a higher PAT mass indexed to body weight with increased inflammatory status and decreased activin A mRNA expression at 6 and 12 months. Finally, PNOF induced a significant increase of infarct size at 4 months (+37%, p&lt;0.01, n=8), 6 months (+32%, p&lt;0.05, n=9) and 12 months (+38%, p&lt;0,05, n=9) after cardiac surgery.

Conclusion
Nutritional programming through short-term PNOF induced an early and permanent overweight, an increase in pericardial fat mass with a greater inflammatory status, associated with alterations of glucose metabolism, alteration of systolic function and a higher sensitivity to ischemia reperfusion injury induced in vivo. The cellular mechanisms of these pathological modifications induced by PNOF need further exploration but could involve alterations in cardiomyocyte pathways and/or modification of global inflammatory status. Therefore, the PNOF mice model corresponds to a relevant experimental model of programmed metabolic syndrome as we known in humans.