Human adaptation to hypoxia in critical illness

The syndrome of critical illness is a complex physiological stressor that can be triggered by diverse pathologies. It is widely believed that organ dysfunction and death result from bioenergetic failure caused by inadequate cellular oxygen supply. Teleologically, life has evolved to survive in the face of stressors by undergoing a suite of adaptive changes. Adaptation not only comprises alterations in systemic physiology but also involves molecular reprogramming within cells. The concept of cellular adaptation in critically ill patients is a matter of contention in part because medical interventions mask underlying physiology, creating the artificial construct of “chronic critical illness,” without which death would be imminent. Thus far, the intensive care armamentarium has not targeted cellular metabolism to preserve a temporary equilibrium but instead attempts to normalize global oxygen and substrate delivery. Here, we review adaptations to hypoxia that have been demonstrated in cellular models and in human conditions associated with hypoxia, including the hypobaric hypoxia of high altitude, the intrauterine low-oxygen environment, and adult myocardial hibernation. Common features include upregulation of glycolytic ATP production, enhancement of respiratory efficiency, downregulation of mitochondrial density, and suppression of energy-consuming processes. We argue that these innate cellular adaptations to hypoxia represent potential avenues for intervention that have thus far remained untapped by intensive care medicine.

Myocardial hibernation: molecular mechanisms, clinical significance and diagnostic methods

Myocardial hibernation is a persistent inhibition of contractility of the viable myocardium of the left ventricle, resulting from its hypoperfusion. The most important manifestation of hibernation is the preservation of the viability of the myocardial tissue. This phenomenon is based on three main mechanisms: 1) myocardial metabolic adaptation, manifested by enhanced glucose uptake; 2) activation of the cardiomyocyte death gene program; 3) programmed cell death, i. e. autophagy and apoptosis of cardiomyocytes. Methods for diagnosing viable myocardium include dobutamine stress echocardiography, single photon emission computed tomography of the myocardium, positron emission tomography, magnetic resonance imaging and electromechanical mapping. In the clinical aspect, the presence and volume of viable myocardium are taken into account when addressing the issue of revascularization in patients with one- and two-vessel coronary artery disease without involvement of the anterior descending artery, as well as in patients with a significant decrease in the global myocardial contractile function, when surgery can lead to an increase in the left ventricular ejection fraction.

Abstract 18884: Proteomic Profiling Reveals Reduction in Electron Transport Chain Proteins in the Hearts of Hibernating Arctic Ground Squirrels Compared with Rats after Surgical Ischemia and Reperfusion: A Convergence of Mammalian Cardio-protective Strategies

Introduction: Mammalian hibernation is a natural molecular adaptation to extreme environmental conditions with important applications for perioperative organ protection. We conducted an integrated proteomic analysis to identify species and season-specific correlates of the cardioprotective phenotype. Methods: Quantitative 2D-LC/LC-MS/MS was used in the myocardium of summer active arctic ground squirrels (AGS), winter hibernating AGS, and rats subjected to deep hypothermic cardiac arrest and reperfusion. Results: Hibernating AGS display robust cardioprotection in our model of I/R compared with rats using both biomarker (Fig 1) and echocardiographic assessment of cardiac injury. Proteomic analysis revealed significant reduction in subunits of all five electron transport chain (ETC) complexes in hibernating AGS compared with rats, only complex 5 showed increased expression of some subunits after I/R.Fig 2 Conclusions: Proteomic profiling revealed dichotomy in the cardioprotective adaptations employed by hibernating AGS and rat. The proteomic profile of hibernating AGS resembles that of myocardial hibernation in other mammals, with significant downregulation of mitochondrial ETC complexes. However, unlike myocardial hibernation in non-hibernators, AGS demonstrated downregulation of glycolytic and other myocardial energetic pathways with the exception of fatty acid oxidation. Sirtuin 3 - a key regulator of mitochondrial bioenergetics - was robustly upregulated in AGS, suggesting that preventing hyperacetylation of key metabolic enzymes may be a cardioprotective strategy employed by hibernators.