Abstract
Hypoxia plays a role in many diseases and can have a wide range of effects on cardiac metabolism depending on the extent of the hypoxic insult. Noninvasive imaging methods could shed valuable light on the metabolic effects of hypoxia on the heart in vivo. Hyperpolarized carbon‐13 magnetic resonance spectroscopy (HP 13C MRS) in particular is an exciting technique for imaging metabolism that could provide such information.The aim of our work was, therefore, to establish whether hyperpolarized 13C MRS can be used to assess the in vivo heart's metabolism of pyruvate in response to systemic acute and chronic hypoxic exposure.Groups of healthy male Wistar rats were exposed to either acute (30 minutes), 1 week or 3 weeks of hypoxia. In vivo MRS of hyperpolarized [1‐13C] pyruvate was carried out along with assessments of physiological parameters and ejection fraction. Hematocrit was elevated after 1 week and 3 weeks of hypoxia.30 minutes of hypoxia resulted in a significant reduction in pyruvate dehydrogenase (PDH) flux, whereas 1 or 3 weeks of hypoxia resulted in a PDH flux that was not different to normoxic animals. Conversion of hyperpolarized [1‐13C] pyruvate into [1‐13C] lactate was elevated following acute hypoxia, suggestive of enhanced anaerobic glycolysis. Elevated HP pyruvate to lactate conversion was also seen at the one week timepoint, in concert with an increase in lactate dehydrogenase (LDH) expression. Following three weeks of hypoxic exposure, cardiac metabolism of pyruvate was comparable with that observed in normoxia.We have successfully visualized the effects of systemic hypoxia on cardiac metabolism of pyruvate using hyperpolarized 13C MRS, with differences observed following 30 minutes and 1 week of hypoxia. This demonstrates the potential of in vivo hyperpolarized 13C MRS data for assessing the cardiometabolic effects of hypoxia in disease.
Highlights
Oxygenation of tissue is key to survival and maintenance of organ health
Heart rate was significantly elevated in 1 week hypoxic animals compared with 30 minutes of hypoxia (p = 0.04). 1 week of hypoxia caused a significant increase in hematocrit compared with normoxia (49.3 ± 0.6% and 43 ± 2%, respectively), and further, hematocrit in three week hypoxic animals was significantly increased compared with one week and normoxic values (58 ± 2%) (Figure 2E); this demonstrates systemic adaptation to hypoxia over time
Following 30 minutes of hypoxia, animals demonstrated a significant reduction in pyruvate dehydrogenase (PDH) flux (50%) compared with normoxic animals (0.009 ± 0.003 s−1 and 0.017 ± 0.007 s−1, respectively; Figure 3A)
Summary
Oxygenation of tissue is key to survival and maintenance of organ health. The heart has the potential to be exposed to a spectrum of hypoxic insults, ranging from mild and transient, to prolonged and severe. The metabolic effects of acute hypoxia are well documented, and notably involve increased glycolytic flux and transient lactate acidosis.[1,2] Prolonged and severe hypoxia requires reprogramming of cardiac metabolism; the heart downregulates oxygen‐consuming processes and upregulates glycolysis in an attempt to maximize ATP production under oxygen‐restricted conditions.[3,4,5] The effects of chronic hypoxia are observed in response to high altitude,[6] or as a factor in many pathological conditions; examples include chronic obstructive pulmonary disease,[7] complications in pregnancy,[8] sleep apnoea,[9] myocardial infarction (the peri‐infarct region)[10] and heart failure.[11] Much of this existing literature relies on ex vivo assessment of the metabolic changes that occur. Further research will clarify their clinical potential in the field of cardiac imaging
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