Abstract
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Introduction: Acute high altitude diseases (AHAD) seriously endanger the health and life safety. Calorie restriction (CR) programs may enhance myocardial resistance to hypoxia damage and protect cardiac function through metabolic reprogramming. It can rapidly improve hypoxia tolerance and prevent AHAD, which has great application and development prospects. However, the lack of reliable quantitative criteria and protocols to evaluate the effectiveness of metabolic transformation and hypoxia tolerance improvement severely restricts its development and promotion. 18F-FDG PET/CT, which continuously visualizes and accurately quantifies myocardial glucose uptake levels, can predict the improvement of hypoxic tolerance due to myocardial metabolic reprogramming under different nutritional and conditions. The aim of this study was to establish and validate a molecular imaging prediction scheme for quantitative predicting and monitoring acute hypoxia tolerance, and to analyze the metabolic transformation process and related mechanisms based on metabolomics. It is expected to promote the clinical transformation process of hypoxic tolerance enhancement scheme based on metabolic optimization.
Methods: Male SD rats were randomly divided into normal diet, fasting and ketogenic diet with different altitude. The self-developed low-pressure chamber system was used to simulate the high altitude environment of 7620 m, and 24h survival rate of rats was observed. PET/CT was used to observe and quantitatively calculate the myocardial 18F-FDG uptake level in each group. Serum samples of rats were collected for detection of blood glucose, blood ketone, and non-esterified fatty acid (NEFA) concentrations. The changes of myocardial metabolic pattern were analyzed by targeted metabolomics/lipidomics analysis and the western blotting of myocardial metabolic related proteins in 72h fasting and 14 days ketogenic diet rats. HE staining and transmission electron microscopy were used to observe changes in myocardial fiber and mitochondrial morphology.
Results: Fasting and ketogenic diet pretreatment significantly increased the survival rate of rats exposed to 7620m for 24h, from 12.2% to 88.6% and 75.0%, respectively. The myocardial 18F-FDG uptake level of fasting and ketogenic diet rats was significantly decreased and the change of SUV ratio were highly correlated with the 24h survival rate (P<0.01, R2=0.8956 and 0.7722). The blood glucose level decreased, the blood ketone and NEAF levels increased. PLS-DA analysis showed that the myocardial metabolic pattern changed significantly after 72h fasting and 14d ketogenic diet. The levels of 22 energy metabolism-related indicators and 34 long-/medium-chain fatty acids were significantly up-regulated (17; 20) or down-regulated (5; 14). WB showed a significant increase in AMPK activity of fasting rats (P<0.01). Fasting significantly inhibited the expression of HIF-1α (P<0.05), while ketogenic diet significantly up-regulated it (P<0.01). The expression of PGC1, GLUT1 and GLUT4 were significantly up-regulated in both. HE and TEM results showed that the myocardium with normal diet was seriously damaged after hypoxia. All these damages in 72h fasting rats was significantly reduced. In addition, significant up-regulation of autophagy was observed in the fasting rats. LVEF% and LVFS% were significantly decreased after 7620m acute hypoxia and the reduction of 72h fasting rats was significantly lower (P<0.01). Metabolic imaging predicted a bias of less than 10% in the improvement of hypoxia tolerance and the quantitative results were not significantly affected by different dynamic imaging times and glucose intervention.
Conclusions: The quantitative indexes of myocardial 18F-FDG uptake metabolism imaging and the regression formula can visualize and accurately predict the hypoxia tolerance. The mechanism may through protecting myocardial tissue and cardiac function by optimizing energy metabolism and enhancing myocardial autophagy.
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