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Correspondence  |   May 2013
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Author Affiliations & Notes
  • Mansoureh Eghbali, Ph.D.
    David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California. meghbali@ucla.edu
  • (Accepted for publication January 29, 2013.)
    (Accepted for publication January 29, 2013.)×
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Correspondence   |   May 2013
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Anesthesiology 05 2013, Vol.118, 1238-1240. doi:10.1097/ALN.0b013e31828baec5
Anesthesiology 05 2013, Vol.118, 1238-1240. doi:10.1097/ALN.0b013e31828baec5
We thank Drs. Reiss and Podgoreanu for highlighting our recent findings1–4  on intralipid and raising all these important questions about the mechanisms underlying the cardioprotective action of one of the most promising agents.
In the acute cardioprotective action of intralipid as in ischemia–reperfusion injury2  and bupivacaine overdose,3  inhibition of mitochondrial permeability transition pore (mPTP) opening seems to be one of the key mechanisms. We found that inhibition of mPTP by intralipid is due to increased phosphorylation of glycogen synthase kinase 3 beta1  and/or decreased pH by improving mitochondrial electron transport chain function through fatty acid oxidation pathway.3  The fact that cyclosporine-A, which inhibits the opening of the mPTP as efficiently as intralipid, is not able to reduce the infarct size and improve the heart function as intralipid,1  may suggest that inhibition of mPTP opening, although necessary, certainly is not the only mechanism underlying intralipid-induced cardioprotection. However, it is important to note that the effect of cyclosporine-A on the mPTP is not selective, because cyclosporine-A can also inhibit the phosphatase calcineurin activity.5  This interaction of cyclosporine-A with phosphatase calcineurin is independent of its action on mPTP.5  However, it is possible that the effect of cyclosporine-A on calcineurin may limit the cyclosporine-A–induced cardioprotection. Therefore, to clarify whether there is a correlation between the degree of functional and tissue protection with inhibition of mPTP opening, intralipid must be compared with a nonimmunosuppressive cyclosporine-A analog, which lacks the ability to inhibit calcineurin such as N-methyl-4-isoleucine cyclosporin 811.6 
We agree with Drs. Riess and Podgoreanu that it is important to identify which component of intralipid is exerting this cardioprotective effect. Despite several attempts from our group, we have not been able to make the individual compounds lipid soluble. We will however proceed to examine the relative contributions of each subcomponent of intralipid on the cardiac functional recovery and infarct size after ischemia in the acute setting and in the chronic setting as in pulmonary hypertension. We believe that elucidating the cardioprotective effects of each of the components of intralipid may also shed light on possible different mechanisms of action in vivo versus ex vivo because in vivo intralipid is metabolized. We recently elucidated the involvement of opioid receptors in mediating the cardioprotective action of intralipid; as in the presence of opioid receptor antagonists, intralipid failed to rescue bupivacaine-induced cardiac arrest.7  Future studies are needed to identify which component(s) of intralipid is(are) in fact interacting with the opioid receptor and whether this interaction is direct or indirect.
The cardiac ischemia–reperfusion injury coincides with significant metabolic abnormalities. Numerous studies have suggested that high circulating levels of free fatty acid during cardiac ischemia may increase myocardial damage.8–12  However, other studies have shown that improving the capacity of fatty acid oxidation at reperfusion may improve the cardiac mechanical performance.13–15  Non-glucose substrates have also been shown to play an important role in maintaining energy expenditure during catecholamine stimulation after myocardial stunning.16  All these findings suggest that pathophysiologic mechanism of ischemia–reperfusion is at least partially related to deficient turnover of energy substrates, more specifically free fatty acid. It is reasonable therefore to speculate intralipid may shift the metabolism from glucose to fatty acid at reperfusion and consequently lead to more myocardial energy production. In fact, in the context of bupivacaine overdose, the rescue action of intralipid was completely abolished in the presence of an inhibitor of β-oxidation.3  Facilitating β-oxidation in the postischemic heart through the addition of carnitine has also proven to be beneficial to myocardial recovery.17,18 
Modulation of membrane lipid composition and formation of caveolae on the sarcolemma could be one of the other possible mechanisms of protection as suggested by Dr. Patel’s group.19  Improving membrane fluidity by intralipid might also contribute to reducing the myocardial injury. Intralipid may help the myocardium after an ischemic episode to better tolerate calcium overload and excessive production of reactive oxygen species in the first few minutes of reperfusion as seen in ischemic postconditioning and in controlled reperfusion as shown in Ovize’s laboratory.20 
The rescue action of intralipid in the chronic setting observed in pulmonary hypertension, on the other hand, could be mediated by its genomic effect through transcription factors leading to stimulation of angiogenesis, suppression of inflammation, fibrosis, and hypertrophy, in both lung and right ventricle.4 
Our findings, as have been highlighted by Drs. Riess and Podgoreanu, raise the intriguing possibility that intralipid could serve as a promising cardioprotective agent not only for resuscitation of the local anesthetic cardiotoxicity but also for treatment of acute myocardial infarction and pulmonary hypertension. Our exciting work certainly calls for further investigation in unraveling other possible mechanisms involved in both the acute and chronic rescue action of intralipid.
Jingyuan Li, Ph.D., Jean C. Bopassa, Ph.D., Siamak Rahman, M.D., Mansoureh Eghbali, Ph.D.* *David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California. meghbali@ucla.edu
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