Sex Differences in Newborn Myocardial Metabolism and Response to Ischemia

Abstract

ABSTRACT:In children with congenital heart disease, female sex has been linked to greater in-hospital mortality associated with low cardiac output, yet the reasons for this are unclear. Therefore, we examined whether newborn sex differences in the heart's metabolic response to ischemia exist. Left ventricular (LV) in vivo and ischemic biopsies of newborn male and female piglets were compared. Tissue ATP, creatine phosphate (CP), glycogen, anaerobic end-products lactate and hydrogen ion (H ϩ ), and key regulatory enzymes were measured. Compared with males, newborn females displayed 14% lower ATP, 22% lower CP, and 32% lower glycogen reserves (p Ͻ 0.05) at baseline. During ischemia, newborn females accumulated 17% greater lactate and 40% greater H ϩ accumulation (p Ͻ 0.02), which was associated with earlier cessation of glycolysis and lower ischemic ATP levels (p Ͻ 0.02) compared with males. Newborn females demonstrated a greater ability to use their glycogen reserves, resulting in significantly lower (p Ͻ 0.003) glycogen levels throughout the ischemic period. Thus, newborn females are at a metabolic disadvantage because they exhibited lower energy levels and greater tissue lactic acidosis, both linked to an increase susceptibility to ischemic injury and impair myocardial function on reperfusion. (Pediatr Res 70: 148-152, 2011)

Age‐Dependent Sex Effects on Outcomes After Pediatric Cardiac Surgery

“…This age‐dependent sex disparity appears to exist only in infants with higher‐risk procedures typically associated with exposure to significant ischemia‐reperfusion. The particular vulnerability of girls in this group of operations may be related to the metabolic disadvantage of female newborn hearts because of lower baseline high‐energy phosphates (ATP and creatine phosphate) and lower myocardial glycogen reserves compared with boys, as documented in animal studies . This may lead to increased susceptibility to ischemic injury and impaired myocardial function after reperfusion.…”

“…There are wide biological differences between males and females that may affect myocardial remodeling, response to myocardial stress or ischemia‐reperfusion injury, inflammatory response after exposure to CPB, propensity for arrhythmias, and pulmonary or systemic vascular tone, all of which potentially affect outcomes after cardiac operations . Sex‐related differences in incidence and outcomes have been documented for ischemic heart disease, stroke, heart failure, valve disease, and pulmonary hypertension .…”

“…There are wide biological differences between males and females that may affect myocardial remodeling, response to myocardial stress or ischemia-reperfusion injury, inflammatory response after exposure to CPB, propensity for arrhythmias, and pulmonary or systemic vascular tone, all of which potentially affect outcomes after cardiac operations. 12,23 Sex-related differences in incidence and outcomes have been documented for ischemic heart disease, stroke, heart failure, valve disease, and pulmonary hypertension. [24][25][26][27] In relation to CHD, sexrelated differences in incidence have been reported for several lesions such as transposition of the great arteries and left-sided obstructive lesions (more common in males) and atrial septal defects and Ebstein's anomaly (more common in females).…”

“…For example, weight at surgery has been shown to affect outcomes, and the age‐ and sex‐adjusted weight can differ significantly between boys and girls. In addition, recent animal data suggest a significant metabolic disadvantage of the female neonatal heart, making it vulnerable to ischemia and reperfusion injury . Looking for interactions with known risk factors affecting surgical outcomes for CHD may explain some of the discrepancies with previous studies.…”

“…In addition, recent animal data suggest a significant metabolic disadvantage of the female neonatal heart, making it vulnerable to ischemia and reperfusion injury. 12 Looking for interactions with known risk factors affecting surgical outcomes for CHD may explain some of the discrepancies with previous studies. Some of these interactions (age 9 complexity of operation) were suggested by Marelli et al 11 but never tested.…”