© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Morphological changes of heart muscle caused by successive perfusion with calcium-free and calcium-containing solutions (calcium paradox)
Emeritus Professor of Biochemistry, Erasmus University, Rotterdam, The Netherlands
KEYWORDS Calcium (cellular); Histo(patho)logy; Ischemia; Reperfusion
The phenomenon ‘calcium paradox’ has been found by Zimmerman and myself in 1966 [1]. At that time I was interested in the effects of fatty acids and ketone bodies as energy sources for the beating heart, after studies on isolated heart mitochondria. Fortunately, I heard from Zimmerman of his work on isolated rat hearts, perfused according to the Langendorff technique. I prepared an isotonic, neutral, solution of sodium acetylacetate to be added to the glucose-containing Ringer salt-solution used. Due to a misunderstanding, the mixing of the two solutions did not take place. Instead, after perfusion of the heart with the Ringer solution, brief perfusion with the aqueous sodium acetylacetate took place. The result was unexpected as the heart stopped beating immediately while its electrical activity continued, known as electro-mechanical dissociation [2]. Prolonged preperfusion with the 0.15 M aqueous acetylacetate, however, led to irreversible arrest of the heart in systole after resuming perfusion with the Ringer solution, while the reddish color of the heart disappeared and the effluent became brownish–red, due to the loss of myoglobin from the heart. Morphological studies of the heart showed hypercontracted cardiomyocytes alternated with ‘empty’ cardiomyocyten along the sarcomeres [3].
In summary, the ‘calcium paradox phenomenon’ is the result of a technical error as Ca2+-free perfusion, after a few minutes, followed by Ca2+-containing perfusion, results in Ca2+ overload of cells and therefore to hypercontraction. Decalcification of plasmalemma results in increase of motional freedom of phospholipids and leakage upon recalcification, resulting in loss of soluble cell constituents [4]. This paper mentions that cooling or addition of amphipathic (membranophilic) compounds, such as local anaesthetics, tranquilizers (or other positively charged amphipathic compounds such as acylcarnitines) may protect against imminent Ca2+ overload and cell damage [5]. Conclusion: the ‘calcium paradox’ has been a warning clinical use of Ca2+-free perfusion in cardiac surgery, as return to Ca2+-containing media causes tissue destruction.
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- Zimmerman A.N.E., Hülsmann W.C. Paradoxal influence of calcium ions on the permeability of the cell membranes of the isolated rat heart. Nature (1966) 211(49):646–647.[CrossRef][Medline]
- Zimmerman ANE, Meyler FL, Hülsmann WC. The inhibitory effect of acetoacetate on myocardial contraction. Lancet 1962;757–758.
- Zimmerman A.N.E., Daems W., Hülsmann W.C., et al. Morphological changes of heart muscle caused by successive perfusion with calcium-free and calcium-containing solutions (calcium paradox). Cardiovasc Res (1967) 1:201–209.
[Abstract/Free Full Text] - Hülsmann W.C. On the mechanism of the calcium paradox ‘the release of hydrolytic enzymes’. Eur Heart J (1983) 4:57–61.
[Abstract/Free Full Text] - Hülsmann W.C., Dubelaar M.L., Lamers J.M., Maccari F. Protection by acylcarnitines and phenylmethylsulfonyl–fluoride of rat hearts subjected to ischemia and reperfusion. Biochim Biophys Acta (1985) 847:62–66.[Medline]
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