585
EDITORIALS
Myocardial stunning Among the many emotive phrases lately introduced to describe the reaction of the myocardium to ischaemia and reperfusion,l stunning seems one of the best; implicit in this notion is the development of a reversible mechanical defect, so that full recovery of function is delayed yet eventually achieved.22 Braunwald and Kloner33 in 1982 first drew clinicians’ attention to stunning, describing it as "a brief bout of ischaemia that may stun the heart, but not kill it". The favoured mechanism at that time was that resynthesis of adenosine triphosphate (ATP) was delayed because the nucleotide precursors were washed out during the reperfusion period. However, Braunwald and Kloner3wisely concluded that other abnormalities, including those of calcium flux, should be sought. Recent reviews emphasise that myocardial stunning is only part of the spectrum of reperfusion injury which comprises arrhythmias, stunning, microvascular injury, and accelerated cell necrosis.4,5 Reperfusion arrhythmias, although probably of no great relevance when reperfusion is achieved by coronary thrombolysis, can be life-threatening during post-cardioplegic reperfusion after open-heart surgery. The two main factors concerned with the genesis of experimental reperfusion arrhythmias are the formation of oxygen-derived free radicals6 and intracellular cytosolic calcium overload.Most, but not all,8 studies with free-radical scavengers have shown an antiarrhythmic effect. Moreover, comparison of the effect of reperfusion with the reintroduction of molecular oxygen shows that free radicals cannot be the only cause of reperfusion arrhythmias.9 Consequently it has been proposed that cytosolic calcium overload and free-radical formation might act as cofactors in the genesis of such arrhythmias41o Very similar proposals have been
made for myocardial stunning,for which there have also been many studies with free-radical scavengers, by no means all giving positive results.4 Preliminary evidence shows that free radicals enhance cytosolic calcium levels by damaging the sarcoplasmic reticulum, thereby enhancing calcium release.ll Having thus identified calcium as likely to be the ultimate culprit in the mechanism of stunning and having firmly shed the ATP deficiency theory en route,12,13 we must ask how calcium-induced damage comes about. Here the data of Kusuoka et a114 are impressive. These researchers measured calcium oscillations directly by nuclear magnetic resonance techniques in isolated perfused rat hearts and found enhanced not decreased calcium transients in stunned hearts. Nevertheless, as Marbanls notes, "these observations point to a problem at the level of the myofilaments but provide no indication as to why their responsiveness to calcium is reduced in the stunned heart". A logical conclusion of the calcium theory is that measures that reduce the entry of calcium or the accumulation of calcium in the immediate post-ischaemic period should protect against stunning. One such procedure could be the administration of calcium antagonists at the time of
reperfusion.11,11 Excess cytosolic calcium, with its excess recycling in and out of the sarcoplasmic reticulum, is energy requiring. Thus, Bavaria’s18 suggestion of considerable oxygen wastage in post-ischaemic hearts that had been infused with catecholamines, a procedure that should increase cytosolic calcium, makes good sense. However, if such oxygen wastage were fundamental to the cause of stunning the addition of oxygen-requiring positive inotropic agents would not lessen the process. 13 Once stunning has occurred, the myocardium is hypocontractile, so should respond to positive inotropic interventions-eg, increased external calcium or catecholamine oc-adrenergic stimulation.19 At this stage a calcium antagonist would probably be harmful, or at least not protective. Yet surprisingly Przyklenk et al20 found that minute doses of nifedipine administered by the intracoronary route alleviated stunning in the dog heart 30 minutes after reperfusion, at a time when it would seem logical to give a positive and not a negative inotropic agent. A possible explanation is that the calcium antagonist is acting on some extramyocardial factor-eg, generation of free radicals in endothelial cells.21 Does stunning occur in man? Indirect evidence is strong,2but direct evidence is still short of proof.22 Stunning seems to occur after percutaneous transluminal coronary angioplasty,23 effort angina,24 unstable angina,25 thrombolytic reperfusion,26 and cardiac surgery22,27 Although there are also negative studies, Bolli et al,2Z in their review of the evidence, argue convincingly in favour of the clinical relevance of myocardial stunning. Scientific proof will require
586
simultaneous
measurement of regional myocardial and function to differentiate between perfusion stunning and sustained silent ischaemia. The main candidates for clinical testing against stunning are the calcium antagonists and free-radical scavengers. The angiotensin-converting-enzyme inhibitors may also exert some inhibitory effect on stunning.28 The next step will be to compare the effects of these three types of agents on stunning in large animals before selecting the best candidate to try in man.
1. Poole-Wilson PA. Reperfusion damage in heart muscle: still unexplained but with new clinical relevance. Clin Physiol 1987; 7: 439-53. 2. Bolli R. Mechanism of myocardial "stunning". Circulation 1990; 82: 723-38.
3. Braunwald E, Kloner RA. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation 1982; 66: 1146-49. 4. Opie LH. Reperfusion injury and its pharmacological modification. Circulation 1989; 80: 1049-62. 5. Hearse DJ. Ischemia, reperfusion, and the determinants of tissue injury. Cardiovasc Drugs Ther 1990; 4: 767-76. 6. Bernier M, Hearse DJ, Manning AS. Reperfusion-induced arrhythmias and oxygen-derived free radicals. Studies with "anti-free radical" interventions and a free radical-generating system in the isolated perfused rat heart. Circ Res 1986; 58: 331-40. 7. Opie LH, Coetzee WA. Role of calcium ions in reperfusion arrhythmias. Relevance to pharmacological intervention. Cardiovasc Drugs Ther 1988; 2: 623-36. 8. Coetzee WA, Owen P, Dennis SC, Saman S, Opie LH. Reperfusion damage: free radicals mediate delayed membrane changes rather than early ventricular arrhythmias. Cardiovasc Res 1990; 24: 156-64. 9. Yamada M, Hearse DJ, Curtis MJ. Reperfusion and readmission of oxygen. Pathophysiological relevance of oxygen-derived free radicals to arrhythmogenesis. Circ Res 1990; 67: 1211-24. 10. Hearse DJ, Tosaki A. Free radicals and calcium: simultaneous interacting triggers as determinants of vulnerability to reperfusion-induced arrhythmias in the rat heart. J Mol Cell Cardiol 1988; 20: 213-23. 11. Cumming DVE, Holmberg SRM, Kusama Y, et al. Effects of reactive oxygen species on the structure and function of the calcium-release channel from isolated sheep cardiac sarcoplasmic reticulum. J Physiol 1990; 420: 88. 12. Taegtmeyer H, Roberts AFC, Raine AEG. Energy metabolism in reperfused heart muscle: metabolic correlates to return of function.
JACC 1985; 6: 864-70. 13. Ambrosio G, Jacobus WE, Bergman CA. Preserved high-energy phosphate metabolic reserve in globally "stunned" hearts despite reduction of basal ATP content and contractility. J Mol Cell Cardiol 19: 953-64. 14. Kusuoka H, Koretsune Y, Chacko VP, et al. Excitation-contraction coupling in postischemic myocardium. Does failure of activator Ca2 + transients underlie stunning? Circ Res 1990; 66: 1268-76. 15. Marban E. Myocardial stunning and hibernation. The physiology behind the colloquialisms. Circulation 1991; 83: 681-88. 16. Przyklenk K, Kloner RA. Effect of verapamil on postischemic "stunned" myocardium: importance of the timing of treatment. JACC 1988; 11: 614-23. 17. Du Toit E, Owen P, Opie LH. Attenuated reperfusion stunning with a calcium channel antagonist or internal calcium blocker in the isolated perfused rat heart. J Mol Cell Cardiol 1990; 22 (suppl III): S58 (abstr). 18. Bavaria JE, Furukawa S, Kreiner G, et al. Myocardial oxygen utilization after reversible global ischemia. J Thorac Cardiovasc Surg 1990; 100: 210-20. 19. Mercier JC, Lando U, Kanmatsuse K, et al. Divergent effects of inotropic stimulation on the ischemic and severely depressed reperfused myocardium. Circulation 1982; 66: 397-400. 20. Przyklenk K, Ghafari GB, Eitzman DT, Kloner RA. Nifedipine administered after reperfusion ablates systolic contractile dysfunction of postischemic "stunned" myocardium. JACC 1989; 13: 1176-83. 21. Mak IT, Boehme P, Weglicki WB. Protection against free radical injury in endothelial cells by calcium blockers—correlation with antioxidant activity and glutathione levels. Circulation 1990; 82 (suppl III): 264
1987;
(abstr). R, Hartley CT, Rabinovitz RS. Clinical relevance of myocardial "stunning". Cardiovasc Drugs Ther (in press). 23. Wijns W, Serruys PW, Slager CJ, et al. Effect of coronary occlusion during percutaneous transluminal angioplasty in humans on left 22. Bolli
24. 25.
26.
27.
28.
ventricular chamber stiffness and regional diastolic pressure-radius relations. JACC 1986; 7: 455-63. Kloner RA, Allen J, Zheng Y, Ruiz C. Myocardial stunning following exercise treadmill testing in man. JACC 1990; 15: 203 (abstr). Nixon JV, Brown CN, Smitherman TC. Identification of transient and persistent segmental wall motion abnormalities in patients with unstable angina by two-dimensional echocardiography. Circulation 1982; 7: 1497-503. Schmidt WG, Sheehan FH, von Essen R, et al. Evolution of left ventricular function after intracoronary thrombolysis for acute myocardial infarction. Am J Cardiol 1989; 63: 497-502. Ferrari R, Alfieri O, Curello S, et al. Occurrence of oxidative stress during reperfusion of the human heart. Circulation 1990; 81: 201-11. Przyklenk K, Kloner RA. Angiotensin converting enzyme inhibitors enhance contractile function of "stunned" myocardium by different mechanisms of action. Circulation 1990; 82 (suppl III): 264 (abstr).
Recurrent brief
depression and anxiety
In the past ten years there have been many apparent advances in the classification of psychiatric disorder. In particular, the numerically largest group, sometimes collectively described as "non-psychotic", have been subjected to much tighter diagnostic scrutiny than ever before. The key to the new classification is provided by operational criteriathese are well-defined characteristics that can be recorded consistently and, when they occur in sufficient numbers, cross the threshold for the diagnosis in question. By use of such criteria the most prevalent psychiatric conditions, anxiety and depression, have been separated into adjustment
disorders, generalised anxiety disorder, panic disorder, major depressive episode, and dysthymic disorder.1 Ideally each operational criterion should not be shared or overlap with others from different diagnoses. Thus, in the game of diagnostic ’Monopoly’, players accumulate houses of operational criteria until they have sufficient to purchase diagnostic hotels, which remain on the same site till sold. This exercise has stimulated considerable research and has convinced many sceptics that neurotic disorder can be classified satisfactorily on the basis of primary symptoms without any need to invoke theoretical constructs. However, there is a less attractive aspect to the making of these new diagnoses. The minimum duration of symptoms necessary before making a diagnosis varies between the extremes of panic disorder, in which one panic attack can be sufficient to trigger off the diagnostic requirements for the disorder if it is followed by persistent fear of having others, and dysthymic disorder, in which depressive symptoms have to be present for most of the previous two-year period. These temporal elements have not been subjected to the same scrutiny as have the individual symptoms. The reasoning behind the time limits imposed on different diagnoses is far from clear. The diagnosis of major depressive episode requires depressive symptoms to have been present for two weeks, but for its anxiety equivalent, generalised anxiety disorder, symptoms have to have been present
EDITORIALS
Myocardial stunning Among the many emotive phrases lately introduced to describe the reaction of the myocardium to ischaemia and reperfusion,l stunning seems one of the best; implicit in this notion is the development of a reversible mechanical defect, so that full recovery of function is delayed yet eventually achieved.22 Braunwald and Kloner33 in 1982 first drew clinicians’ attention to stunning, describing it as "a brief bout of ischaemia that may stun the heart, but not kill it". The favoured mechanism at that time was that resynthesis of adenosine triphosphate (ATP) was delayed because the nucleotide precursors were washed out during the reperfusion period. However, Braunwald and Kloner3wisely concluded that other abnormalities, including those of calcium flux, should be sought. Recent reviews emphasise that myocardial stunning is only part of the spectrum of reperfusion injury which comprises arrhythmias, stunning, microvascular injury, and accelerated cell necrosis.4,5 Reperfusion arrhythmias, although probably of no great relevance when reperfusion is achieved by coronary thrombolysis, can be life-threatening during post-cardioplegic reperfusion after open-heart surgery. The two main factors concerned with the genesis of experimental reperfusion arrhythmias are the formation of oxygen-derived free radicals6 and intracellular cytosolic calcium overload.Most, but not all,8 studies with free-radical scavengers have shown an antiarrhythmic effect. Moreover, comparison of the effect of reperfusion with the reintroduction of molecular oxygen shows that free radicals cannot be the only cause of reperfusion arrhythmias.9 Consequently it has been proposed that cytosolic calcium overload and free-radical formation might act as cofactors in the genesis of such arrhythmias41o Very similar proposals have been
made for myocardial stunning,for which there have also been many studies with free-radical scavengers, by no means all giving positive results.4 Preliminary evidence shows that free radicals enhance cytosolic calcium levels by damaging the sarcoplasmic reticulum, thereby enhancing calcium release.ll Having thus identified calcium as likely to be the ultimate culprit in the mechanism of stunning and having firmly shed the ATP deficiency theory en route,12,13 we must ask how calcium-induced damage comes about. Here the data of Kusuoka et a114 are impressive. These researchers measured calcium oscillations directly by nuclear magnetic resonance techniques in isolated perfused rat hearts and found enhanced not decreased calcium transients in stunned hearts. Nevertheless, as Marbanls notes, "these observations point to a problem at the level of the myofilaments but provide no indication as to why their responsiveness to calcium is reduced in the stunned heart". A logical conclusion of the calcium theory is that measures that reduce the entry of calcium or the accumulation of calcium in the immediate post-ischaemic period should protect against stunning. One such procedure could be the administration of calcium antagonists at the time of
reperfusion.11,11 Excess cytosolic calcium, with its excess recycling in and out of the sarcoplasmic reticulum, is energy requiring. Thus, Bavaria’s18 suggestion of considerable oxygen wastage in post-ischaemic hearts that had been infused with catecholamines, a procedure that should increase cytosolic calcium, makes good sense. However, if such oxygen wastage were fundamental to the cause of stunning the addition of oxygen-requiring positive inotropic agents would not lessen the process. 13 Once stunning has occurred, the myocardium is hypocontractile, so should respond to positive inotropic interventions-eg, increased external calcium or catecholamine oc-adrenergic stimulation.19 At this stage a calcium antagonist would probably be harmful, or at least not protective. Yet surprisingly Przyklenk et al20 found that minute doses of nifedipine administered by the intracoronary route alleviated stunning in the dog heart 30 minutes after reperfusion, at a time when it would seem logical to give a positive and not a negative inotropic agent. A possible explanation is that the calcium antagonist is acting on some extramyocardial factor-eg, generation of free radicals in endothelial cells.21 Does stunning occur in man? Indirect evidence is strong,2but direct evidence is still short of proof.22 Stunning seems to occur after percutaneous transluminal coronary angioplasty,23 effort angina,24 unstable angina,25 thrombolytic reperfusion,26 and cardiac surgery22,27 Although there are also negative studies, Bolli et al,2Z in their review of the evidence, argue convincingly in favour of the clinical relevance of myocardial stunning. Scientific proof will require
586
simultaneous
measurement of regional myocardial and function to differentiate between perfusion stunning and sustained silent ischaemia. The main candidates for clinical testing against stunning are the calcium antagonists and free-radical scavengers. The angiotensin-converting-enzyme inhibitors may also exert some inhibitory effect on stunning.28 The next step will be to compare the effects of these three types of agents on stunning in large animals before selecting the best candidate to try in man.
1. Poole-Wilson PA. Reperfusion damage in heart muscle: still unexplained but with new clinical relevance. Clin Physiol 1987; 7: 439-53. 2. Bolli R. Mechanism of myocardial "stunning". Circulation 1990; 82: 723-38.
3. Braunwald E, Kloner RA. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation 1982; 66: 1146-49. 4. Opie LH. Reperfusion injury and its pharmacological modification. Circulation 1989; 80: 1049-62. 5. Hearse DJ. Ischemia, reperfusion, and the determinants of tissue injury. Cardiovasc Drugs Ther 1990; 4: 767-76. 6. Bernier M, Hearse DJ, Manning AS. Reperfusion-induced arrhythmias and oxygen-derived free radicals. Studies with "anti-free radical" interventions and a free radical-generating system in the isolated perfused rat heart. Circ Res 1986; 58: 331-40. 7. Opie LH, Coetzee WA. Role of calcium ions in reperfusion arrhythmias. Relevance to pharmacological intervention. Cardiovasc Drugs Ther 1988; 2: 623-36. 8. Coetzee WA, Owen P, Dennis SC, Saman S, Opie LH. Reperfusion damage: free radicals mediate delayed membrane changes rather than early ventricular arrhythmias. Cardiovasc Res 1990; 24: 156-64. 9. Yamada M, Hearse DJ, Curtis MJ. Reperfusion and readmission of oxygen. Pathophysiological relevance of oxygen-derived free radicals to arrhythmogenesis. Circ Res 1990; 67: 1211-24. 10. Hearse DJ, Tosaki A. Free radicals and calcium: simultaneous interacting triggers as determinants of vulnerability to reperfusion-induced arrhythmias in the rat heart. J Mol Cell Cardiol 1988; 20: 213-23. 11. Cumming DVE, Holmberg SRM, Kusama Y, et al. Effects of reactive oxygen species on the structure and function of the calcium-release channel from isolated sheep cardiac sarcoplasmic reticulum. J Physiol 1990; 420: 88. 12. Taegtmeyer H, Roberts AFC, Raine AEG. Energy metabolism in reperfused heart muscle: metabolic correlates to return of function.
JACC 1985; 6: 864-70. 13. Ambrosio G, Jacobus WE, Bergman CA. Preserved high-energy phosphate metabolic reserve in globally "stunned" hearts despite reduction of basal ATP content and contractility. J Mol Cell Cardiol 19: 953-64. 14. Kusuoka H, Koretsune Y, Chacko VP, et al. Excitation-contraction coupling in postischemic myocardium. Does failure of activator Ca2 + transients underlie stunning? Circ Res 1990; 66: 1268-76. 15. Marban E. Myocardial stunning and hibernation. The physiology behind the colloquialisms. Circulation 1991; 83: 681-88. 16. Przyklenk K, Kloner RA. Effect of verapamil on postischemic "stunned" myocardium: importance of the timing of treatment. JACC 1988; 11: 614-23. 17. Du Toit E, Owen P, Opie LH. Attenuated reperfusion stunning with a calcium channel antagonist or internal calcium blocker in the isolated perfused rat heart. J Mol Cell Cardiol 1990; 22 (suppl III): S58 (abstr). 18. Bavaria JE, Furukawa S, Kreiner G, et al. Myocardial oxygen utilization after reversible global ischemia. J Thorac Cardiovasc Surg 1990; 100: 210-20. 19. Mercier JC, Lando U, Kanmatsuse K, et al. Divergent effects of inotropic stimulation on the ischemic and severely depressed reperfused myocardium. Circulation 1982; 66: 397-400. 20. Przyklenk K, Ghafari GB, Eitzman DT, Kloner RA. Nifedipine administered after reperfusion ablates systolic contractile dysfunction of postischemic "stunned" myocardium. JACC 1989; 13: 1176-83. 21. Mak IT, Boehme P, Weglicki WB. Protection against free radical injury in endothelial cells by calcium blockers—correlation with antioxidant activity and glutathione levels. Circulation 1990; 82 (suppl III): 264
1987;
(abstr). R, Hartley CT, Rabinovitz RS. Clinical relevance of myocardial "stunning". Cardiovasc Drugs Ther (in press). 23. Wijns W, Serruys PW, Slager CJ, et al. Effect of coronary occlusion during percutaneous transluminal angioplasty in humans on left 22. Bolli
24. 25.
26.
27.
28.
ventricular chamber stiffness and regional diastolic pressure-radius relations. JACC 1986; 7: 455-63. Kloner RA, Allen J, Zheng Y, Ruiz C. Myocardial stunning following exercise treadmill testing in man. JACC 1990; 15: 203 (abstr). Nixon JV, Brown CN, Smitherman TC. Identification of transient and persistent segmental wall motion abnormalities in patients with unstable angina by two-dimensional echocardiography. Circulation 1982; 7: 1497-503. Schmidt WG, Sheehan FH, von Essen R, et al. Evolution of left ventricular function after intracoronary thrombolysis for acute myocardial infarction. Am J Cardiol 1989; 63: 497-502. Ferrari R, Alfieri O, Curello S, et al. Occurrence of oxidative stress during reperfusion of the human heart. Circulation 1990; 81: 201-11. Przyklenk K, Kloner RA. Angiotensin converting enzyme inhibitors enhance contractile function of "stunned" myocardium by different mechanisms of action. Circulation 1990; 82 (suppl III): 264 (abstr).
Recurrent brief
depression and anxiety
In the past ten years there have been many apparent advances in the classification of psychiatric disorder. In particular, the numerically largest group, sometimes collectively described as "non-psychotic", have been subjected to much tighter diagnostic scrutiny than ever before. The key to the new classification is provided by operational criteriathese are well-defined characteristics that can be recorded consistently and, when they occur in sufficient numbers, cross the threshold for the diagnosis in question. By use of such criteria the most prevalent psychiatric conditions, anxiety and depression, have been separated into adjustment
disorders, generalised anxiety disorder, panic disorder, major depressive episode, and dysthymic disorder.1 Ideally each operational criterion should not be shared or overlap with others from different diagnoses. Thus, in the game of diagnostic ’Monopoly’, players accumulate houses of operational criteria until they have sufficient to purchase diagnostic hotels, which remain on the same site till sold. This exercise has stimulated considerable research and has convinced many sceptics that neurotic disorder can be classified satisfactorily on the basis of primary symptoms without any need to invoke theoretical constructs. However, there is a less attractive aspect to the making of these new diagnoses. The minimum duration of symptoms necessary before making a diagnosis varies between the extremes of panic disorder, in which one panic attack can be sufficient to trigger off the diagnostic requirements for the disorder if it is followed by persistent fear of having others, and dysthymic disorder, in which depressive symptoms have to be present for most of the previous two-year period. These temporal elements have not been subjected to the same scrutiny as have the individual symptoms. The reasoning behind the time limits imposed on different diagnoses is far from clear. The diagnosis of major depressive episode requires depressive symptoms to have been present for two weeks, but for its anxiety equivalent, generalised anxiety disorder, symptoms have to have been present
