J Mol Cell Cardiol
23, 765-767 (1991)
EDITORIAL,
What
Constitutes
the CakiumParadox?
The Calcium Paradox, as originally described by Zimmerman and Hiilsmann (Zimmerman and Hiilsmann, 1966), referred to the sudden loss of electrical and mechanical activity, release of myoglobin into the perfusate and cellular destruction occurring upon readmission of calcium to isolated perfused hearts following a period of calcium depletion. The original descriptions of the ultrastructure (Muir, 1967) showed that calcium-free perfusion caused separation of cells at intercalated disc junctions. It was subsequently shown that tissue following the paradox had accumulated massive amounts of calcium. There has been a recent revival of interest in the Calcium Paradox, with debate (Bhojani and Chapman, 1990; Ruigrok, 1990) over the importance of sodium loading and calcium influxes in the pathogenesis of injury and whether or not a Calcium Paradox occurs in isolated myocytes. The debate appears to be centered about a confusion over the definitions between cellular damage due to calcium overload and that due to the Calcium Paradox. To clarify the situation there is a need for a consistent definition of what constitutes a Calcium Paradox. This editorial will adopt the view that a differentiation between the two pathological processes of Calcium Overload Injury and the Calcium Paradox would be useful in clarifying the relations between the two types of injury. The Calcium Paradox can be conceptually divided into three discrete stages. The first stage centers around the events occurring during the period of calcium depletion which set the stage for subsequent events. The second stage involves the events occurring immediately following calcium repletion and the third stage, the events that occur following cellular contracture and membrane damage. In the first stage, during the calcium-free period, two independent events occur - a weakening of 0022-2828/91/060765
+ 03 803.00/O
COMMENT
intercalated disc junctions with mechanical uncoupling of cells and changes in the electrolyte balance of the cells which predispose the cell to an influx of calcium and contracture upon return of extracellular calcium. In the second stage, immediately after calcium readmission, there is an influx of calcium but this may only be of sufficient magnitude to trigger a normal contraction or mild contracture of the cells. Upon cellular contracture, the intercalated discs separate with tearing of sarcolemmal membranes. Interestingly, despite massive contracture mechanical tracings of developed force record only a small single blip from hearts. This confirms that the cells have become mechanically uncoupled. The third stage occurs following sarcolemmal membrane damage and consists of a secondary massive calcium influx, hypercontracture of cells with formation of single, centrally located contraction bands, efflux of myoglobin from cells and an accumulation of calcium by mitochondria. The events in stages two and three are rapid and fully developed within seconds or minutes. In the first stage of injury, the first event is development of intercalated disc lesions upon extracellular calcium depletion. The adhesive material connecting cells at adherens disc junctions is a calcium-dependent calhedrin (A-CAM) protein (Volk and Geiger, 1986). Calcium depletion allows the fascia and macula adherens junctions to separate. For disc lesions to develop, calcium must be kept below 50~~ for a period of time. Any event that delays extraction of calcium from the discs would be expected to attenuate development of the paradox. These include low perfusion rates, hypothermia, or electrolyte changes which delay calcium efflux from cells. The second event of the first stage of injury sets the stage for calcium entry and is less 01991
Academic
Press
LimIted
766
R. A. Altschuld
dependent on a critically low (
23, 765-767 (1991)
EDITORIAL,
What
Constitutes
the CakiumParadox?
The Calcium Paradox, as originally described by Zimmerman and Hiilsmann (Zimmerman and Hiilsmann, 1966), referred to the sudden loss of electrical and mechanical activity, release of myoglobin into the perfusate and cellular destruction occurring upon readmission of calcium to isolated perfused hearts following a period of calcium depletion. The original descriptions of the ultrastructure (Muir, 1967) showed that calcium-free perfusion caused separation of cells at intercalated disc junctions. It was subsequently shown that tissue following the paradox had accumulated massive amounts of calcium. There has been a recent revival of interest in the Calcium Paradox, with debate (Bhojani and Chapman, 1990; Ruigrok, 1990) over the importance of sodium loading and calcium influxes in the pathogenesis of injury and whether or not a Calcium Paradox occurs in isolated myocytes. The debate appears to be centered about a confusion over the definitions between cellular damage due to calcium overload and that due to the Calcium Paradox. To clarify the situation there is a need for a consistent definition of what constitutes a Calcium Paradox. This editorial will adopt the view that a differentiation between the two pathological processes of Calcium Overload Injury and the Calcium Paradox would be useful in clarifying the relations between the two types of injury. The Calcium Paradox can be conceptually divided into three discrete stages. The first stage centers around the events occurring during the period of calcium depletion which set the stage for subsequent events. The second stage involves the events occurring immediately following calcium repletion and the third stage, the events that occur following cellular contracture and membrane damage. In the first stage, during the calcium-free period, two independent events occur - a weakening of 0022-2828/91/060765
+ 03 803.00/O
COMMENT
intercalated disc junctions with mechanical uncoupling of cells and changes in the electrolyte balance of the cells which predispose the cell to an influx of calcium and contracture upon return of extracellular calcium. In the second stage, immediately after calcium readmission, there is an influx of calcium but this may only be of sufficient magnitude to trigger a normal contraction or mild contracture of the cells. Upon cellular contracture, the intercalated discs separate with tearing of sarcolemmal membranes. Interestingly, despite massive contracture mechanical tracings of developed force record only a small single blip from hearts. This confirms that the cells have become mechanically uncoupled. The third stage occurs following sarcolemmal membrane damage and consists of a secondary massive calcium influx, hypercontracture of cells with formation of single, centrally located contraction bands, efflux of myoglobin from cells and an accumulation of calcium by mitochondria. The events in stages two and three are rapid and fully developed within seconds or minutes. In the first stage of injury, the first event is development of intercalated disc lesions upon extracellular calcium depletion. The adhesive material connecting cells at adherens disc junctions is a calcium-dependent calhedrin (A-CAM) protein (Volk and Geiger, 1986). Calcium depletion allows the fascia and macula adherens junctions to separate. For disc lesions to develop, calcium must be kept below 50~~ for a period of time. Any event that delays extraction of calcium from the discs would be expected to attenuate development of the paradox. These include low perfusion rates, hypothermia, or electrolyte changes which delay calcium efflux from cells. The second event of the first stage of injury sets the stage for calcium entry and is less 01991
Academic
Press
LimIted
766
R. A. Altschuld
dependent on a critically low (
