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Bristol Heart Institute, Bristol Royal Infirmary, Bristol, BS2 8HW, United Kingdom
(Email: paulmodi{at}doctors.org.uk).
We read with interest the article by O'Brien and colleagues [1]. Many techniques of pediatric myocardial protection have been extrapolated from adult hearts, but due to the structural, functional and metabolic differences between immature and mature myocardium, this strategy does not stand up to scientific rigor. Cardioplegia should be tailored to the immature heart in the context of differences in age, cyanotic status, and pressure/volume overload, because all these variables influence the susceptibility to ischemia-reperfusion injury [2]. In fact, this is exactly why this area is so difficult to study in a clinical context.
Nonphysiologic increases in tissue calcium (Ca2+) during ischemia or reperfusion are inevitably associated with tissue injury, and the neonatal heart may be more susceptible to calcium-mediated injury because its sarcoplasmic reticulum is not fully developed and trans-sarcolemmal calcium influx therefore plays a greater role; mitochondrial calcium uptake is also greater and the calcium sensitivity of cardiac myofilaments is markedly different. This explains why immature hearts are more sensitive to calcium channel blockers compared with adult hearts and why ischemic injury in the newborn heart can be modified with an L-type Ca2+ channel antagonist and is affected by changes in extracellular Ca2+ concentration [3]. These various factors influencing ionic homeostasis and excitation-contraction coupling vary with developmental stage, further confounding clinical studies like this one with a wide range of ages.
The use of animal models of the clinically relevant stresses that pediatric hearts are subjected to, such as hypoxia, is vital for investigating pediatric cardioplegic strategies. In an intact neonatal pig model (age 5 to 18 days), good myocardial protection was achieved in nonhypoxic hearts subjected to short ischemic intervals independent of cardioplegia Ca2+ concentration; however, in hypoxically stressed hearts, hypocalcemic cardioplegic solutions were superior [4]. Interestingly, pediatric cardioplegia was superior even in acyanotic hearts in this study, perhaps indicating the significant metabolic stress of volume and pressure loading to which these hearts are subjected.
Magnesium (Mg2+) modulates intracellular Ca2+ levels by inhibiting trans-sarcolemmal Ca2+ entry, as well as displacing Ca2+ from binding sites on the cell membrane. Postischemic Ca2+ entry is further limited because Mg2+ and lidocaine both prevent Na+ influx, the latter by blocking Na+ channels. Sodium accumulation during ischemia is detrimental because it is exchanged for Ca2+ during reperfusion due to reverse Na+-Ca2+ exchange. In the same neonatal pig model, Mg2+ enrichment of hypocalcemic cardioplegic solutions provided complete functional recovery in hearts subjected to severe stress (hypoxia and ischemia) rather than hypoxia alone [5].
The authors are to be congratulated for attempting to take us from bench to bedside and for providing a plausible explanation for differences in injury. The scale of the difference in troponin T release is surprising and emphasizes the importance of tailoring the cardioplegia to the myocardium. The fact that this did not translate into a meaningful clinical difference is not surprising and simply highlights the sensitivity of using troponin levels as a marker of myocardial injury.
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