The calcium paradox revisited An artefact of great heuristic value

The 1967 paper by Zimmerman et al. [1] is a sequel to one published in the previous year [2] in which Ariaen Zimmerman and Willem Hulsmann had described an artefact produced on an isolated rat heart preparation. It is exceptional that an artefact receives so much attention and is not forgotten three decades later. The observation they made is that, when an isolated heart is perfused for 2 min with a Ca2+ free, otherwise normal Krebs-Henseleit buffer and then with buffer containing a physiological Ca2+ concentration, it rapidly deteriorates. Massive enzyme release occurs and the heart becomes pale due to myoglobin loss. The 1967 paper demonstrates that these changes are accompanied with dramatic alterations of myocardial ultrastructure, i.e. membrane disruption, myofibrillar hypercontracture and mitochondrial damage. The discoverers named this impressive artefact ‘calcium paradox’. Since the original description this phenomenon has fascinated hundreds of researchers, with the highest research activity in the 1980s. This brief review is an attempt to explain 33 years after the original description the main reasons for this long-lasting fascination. It is not intended to duplicate previous scientific reviews [3–6]. In the 1970s and 1980s the pathophysiological importance of calcium for the heart was in the centre of scientific awareness. The calcium paradox was soon regarded as a paradigm in this area of research as it became clear that repletion of the once Ca2+ depleted heart leads to massive Ca2+ influx into the myocardial cells, a phenomenon also observed in other situations of severe myocardial cell injury. In particular, it was a widely accepted hypothesis that the calcium paradox represents a paradigm for the pathomechanism of severe ischemia-reperfusion injury. In the words of Albrecht Fleckenstein [7]: “Certainly, with restoring the blood perfusion of the previous ischemic region, an unlimited Ca2+ …