Ventricle-Specific Metabolic Differences in the Newborn Piglet Myocardium In Vivo and During Arrested Global Ischemia

Abstract

Ventricular dysfunction is reported greater in the left (LV) versus right ventricle (RV) in infants following surgically induced ischemia. Ventricle-specific differences in baseline metabolism may alter response to ischemia thus affecting postischemic functional recovery. This study identifies ventricle-specific metabolic differences in the newborn (piglet) heart at baseline (working) and during ischemia (arrested). Baseline LV citrate synthase (CS) and hydroxyacyl-CoA dehydrogenase (HAD) activities were 15% and 18% lower (p Ͻ 0.02), whereas creatine kinase (CK) and phosphofructokinase (PFK) activities were 40% and 23% higher (p Ͻ 0.04) than the RV. Baseline LV glycogen reserves were also 55% higher (p ϭ 0.004). By 15 min of ischemia, LV ATP was 20% lower (p Ͻ 0.05), lactate was 51% higher (p ϭ 0.001), and hydrogen ions (H ϩ ) were 43% higher (p ϭ 0.03) compared with the RV. These differences persisted for the entire ischemic period (p Ͻ 0.02). After 45 min of ischemia, the LV used 58% less (p Ͻ 0.05) glycogen than the RV. These findings demonstrate that the enhanced glycolytic capacity of the newborn LV was accompanied by greater anaerobic end-product accumulation and lower energy levels during ischemia. This profile may offer one explanation for greater LV-dysfunction relative to the RV in children following ischemia. C linical studies continue to report persistent postoperative dysfunction in the left ventricle (LV) of children even after successful repair of pathology affecting the right ventricle (RV) (1,2). Experimental studies in the newborn heart suggest a lower tolerance of the LV to ischemia, as LV recovery of function following ischemia is far worse than that seen in the RV (3). Whether these findings are a result of ventricle-specific differences in postnatal myocardial metabolic maturation is currently unknown.During postnatal cardiac maturation, the LV undergoes rapid "physiologic" hypertrophy relative to the RV in response to postnatal changes in systemic and pulmonary circulation (4). Morphologic studies using newborn animals have reported a lower capillary density in the LV relative to the RV as noted by greater LV myocyte-to-capillary ratios and intercapillary distances (5). Lower tissue perfusion capacity in the face of increased postnatal ventricular workloads and rapid ventricular growth in the newborn LV may result in underperfusion. Whether this has detrimental effects on metabolic capacity and response to ischemia is unknown.During postnatal cardiac maturation, there is a shift in energy substrate reliance where the use of fatty acids dramatically increases and that of glucose decreases (6 -9). Central to this transition is an early decrease in the activity of key enzymes involved in the glycolytic pathway and an increase in the enzymes responsible for fatty acid and oxidative metabolism (8,9). Interestingly, studies have shown that adult hearts adapt to chronic increases in ventricular workloads by shifting energy substrate reliance away from fatty acid and oxidative pathways b...

Age- and Chamber-Specific Differences in Oxidative Stress After Ischemic Injury

“…Although our study demonstrates similarities between adults and newborn rabbits for SOD, most published studies show important species-dependent changes. In pigs, for example, SOD and catalase increase during the first few weeks of life before stabilizing [32], whereas rats generally demonstrate an age-dependent decrease in antioxidant levels [35]. In addition, we found that in newborns, the right ventricle had significantly decreased SOD activity compared with the left ventricle.…”

“…For example, previous studies demonstrated that during IR injury in newborn pigs, the left ventricle had significantly less ATP than the right ventricle as well as increased hydrogen ion formation [32, 48]. Although there were no data to determine whether this was the cause of diminished function, it does outline that the right and left ventricles experience different responses to the same injury.…”

Superior cardiac function via anaplerotic pyruvate in the immature swine heart after cardiopulmonary bypass and reperfusion

“…Studies in neonatal animal models have suggested that enhanced myocardial reliance on carbohydrate metabolism plays an important role in determining postischemic dysfunction (3,29). The neonatal heart demonstrates a shift in substrate metabolism from predominantly carbohydrate to fatty acid oxidation within the first 1-2 wk after birth (2,4,18).…”

Sex Differences in Newborn Myocardial Metabolism and Response to Ischemia

“…Interestingly, this study demonstrated that despite greater and more rapid accumulation of anaerobic end-products, the newborn female myocardium had a greater ability to undergo glycogenolysis dur-ing ischemia suggesting the presence of sex-specific differences in glycolytic enzyme sensitivity to anaerobic endproducts in the newborn myocardium. In addition, previous work demonstrated that in newborns, the left ventricle despite having higher glycogen levels than the right ventricle had greater anaerobic end-product accumulation and lower energy levels during ischemia (25). The current work suggests this ischemic profile is exacerbated in females, putting them at even greater risk.…”

“…Previous work demonstrated that in newborns, compared with the right ventricle, the left ventricle had enhanced glycolytic capacity which resulted in greater anaerobic endproduct accumulation and lower energy levels during ischemia (25). This study is the first to investigate and characterize sex-specific differences in baseline and ischemic metabolism in this high-risk ventricle of the newborn.…”