Developmental determinants of cardiac sensitivity to hypoxia

Abstract

Cardiac sensitivity to oxygen deprivation changes significantly during ontogenetic development. However, the mechanisms for the higher tolerance of the immature heart, possibilities of protection, and the potential impact of perinatal hypoxia on cardiac tolerance to oxygen deprivation in adults have not yet been satisfactorily clarified. The hypoxic tolerance of an isolated rat heart showed a triphasic pattern: significant decrease from postnatal day 1 to 7, followed by increase to the weaning period, and final decline to adulthood. We have observed significant ontogenetic changes in mitochondrial oxidative phosphorylation and mitochondrial membrane potential, as well as in the role of the mitochondrial permeability transition pores in myocardial injury. These results support the hypothesis that cardiac mitochondria are deeply involved in the regulation of cardiac tolerance to oxygen deprivation during ontogenetic development. Ischemic preconditioning failed to increase tolerance to oxygen deprivation in the highly tolerant hearts of newborn rats. Chronic hypoxic exposure during early development may cause in-utero or neonatal programming of several genes that can change the susceptibility of the adult heart to ischemia-reperfusion injury; this effect is sex dependent. These results would have important clinical implications, since cardiac sensitivity in adult patients may be significantly affected by perinatal hypoxia in a sex-dependent manner.

Ischemia/Reperfusion

“…However, intervention initiated within 12 h has beneficial effects (471). The sensitivity of neonatal hearts to I/R depends on age, with the immature myocardium being highly susceptible to ischemia (849), whereas enhanced tolerance is seen shortly thereafter (401, 563, 611, 642, 849). …”

Consecutive Isoproterenol and Adenosine Treatment Confers Marked Protection against Reperfusion Injury in Adult but Not in Immature Heart: A Role for Glycogen

“…What is not known is whether this intervention can protect the immature heart. This issue is further complicated by the fact that unlike adult heart, the vulnerability of postnatal hearts to I/R changes during development and follows a triphasic pattern in rats with 1 and 14–21 days old being most resistant to I/R injury [ 12 , 13 , 14 , 15 ]. Clinical research has also shown developmentally-related differences in cardiac vulnerability to cardiac I/R in patients undergoing open heart surgery [ 16 , 17 ].…”

Normoxic and Hyperoxic Cardiopulmonary Bypass in Congenital Heart Disease

“…All of these processes accommodate the shift from a hypoxic in utero environ to a normoxic ex utero one. However, the precise mechanisms behind this varying resistance to oxygen deprivation in neonatal myocardium have still not been clearly defined [ 47 , 48 ].…”

“…Cyanosis, chronic hypoxia, remains the most common preoperative physiological stress in paediatric cardiac patients [ 1 , 49 ] as well as the single largest cause of mortality [ 47 , 48 ]. In the clinical setting, it seems as though patients with cyanotic congenital heart defects have severely diminished myocardial protection [ 1 ], as well as persistently impaired ventricular function following corrective surgery and a higher rate of morbidity and mortality compared to nonhypoxaemic patients [ 50 – 52 ].…”