The calcium paradox.

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