© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
The Calcium Paradox
Much of the present knowledge of the heart's physiology is derived from experiments with isolated perfused hearts. Usually based on the technique of Langendorff. It was, and largely still is, a logic defying problem that the survival of an isolated heart in a perfusion apparatus is only possible for a very limited time. In the early sixties I was working in the laboratory of Professor Durrer in the Wilhelmina Gasthuis in Amsterdam and decided to try to solve that problem. A close friend of mine, W.C. Hülsmann, was willing to help with his extensive knowledge of biochemistry and we started to try different substrates in the perfusion fluid. We never succeeded in prolonging the survival of the isolated heart but were confronted with many new findings. One of the first things we discovered was that sodium acetoacetate inhibited the contractile performance of the heart in such a way that a full electromechanical dissociation could be induced. We thus had rediscovered something that G.R. Mines had already published about in 1913 [1] and A.K.M. Noyons in 1908 [2]: the electromechanical dissociation.
In our research we soon found the central role of the calcium ion in the coupling of electrical and mechanical activity. We also discovered that after longer periods of calcium-free perfusion it was impossible to re-introduce calcium into the perfusion without extensive, impressive and irreversible damage to the heart muscle cells. The Calcium Paradox was discovered.
The finding that other agents, able to bind or chelate calcium ions could also invoke the calcium paradox added urgency to our work. At that time citrate was used to induce cardioplegia during cardiac surgery. We showed that the electronmicroscopic changes in "stone heart" (a dreaded and lethal complication of heart surgery) was identical to the changes observed in the calcium paradox. We also feared that the increase in citrate at cellular level as caused by ischemia could also be instrumental in the reperfusion damage of infarcted areas. We theorized about the crush syndrome, about isolated kidneys and about the damage seen in fat-emboli and pulmonary embolism. In short we saw many problems that could be related to calcium and membrane integrity.
Although a staggering amount of work has been done about reperfusion damage and organ preservation and even the name "Oxygen Paradox" has become a common term, I feel that a lot of work still has to be done.
A while ago there was a symposium called "25 years of Calcium Paradox" where a distinguished Japanese researcher asked me if I was family of the Zimmerman that discovered the Calcium Paradox? When I explained that it was me, myself and I, he responded very politely that he was surprised because he was sure that I should be dead by now....
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- Mines G.R. On functional analysis by the action of electrolytes. J. Physiol. (1913) 46:188.
[Free Full Text] - Noyons A.K.M. About the independence of the electrocardiogram with regard to the form-cardiogram. Proc. Roy. Acad. Amsterdam. (1908) 11:273.
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