© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
The new ischemic syndromes—an old phenomenon disguised with a new glossary?1
University of Brescia, Chair of Cardiology, Spedali Civili, Brescia; Salvatore Maugeri Foundation, IRCCS, Cardiovascular Pathophysiology Research Centre, Gussago, Brescia, Italy
* Correspondence address: Università degli Studi di Brescia, Cattedra di Cardiologia, c/o Spedali Civili, p.le Spedali Civili, 1, 25123 Brescia, Italy. Tel.: +39 (30) 3995-776; fax: +39 (30) 3701-078; e-mail: ferrari@master.cci.unibs.it
Received 9 September 1996;
KEYWORDS Preconditioning; Stunning; Myocardial ischemia; Myocardial infarct
The light is flickering in the room next to the hospital hemodynamic lab. Huddled behind the Tagarno monitor are half a dozen surgeons and interventional cardiologists. The group is divided, on one side there is what, nowadays, is a rather rare example of an old-fashioned thinking ‘bedside’ cardiologist. On the other side of the screen there is a line of elbowing, excited cardioscientists clutching a series of ice-coated tubes containing biopsies from the left ventricle of Mr. X.
Judging from the rather animated discussion about his coronary angiogram, Mr. X is a serious case. He is 58 years old, complains of dyspnea, has a history of several myocardial infarctions and was admitted because of prolonged chest pain. A comparison with his previous ventriculogram suggests that the anterior region of the left ventricle is chronically akinetic. The ejection fraction is severely reduced (being less than 25%), he has 3 severe stenoses in different branches of the left coronary artery and all are suitable for revascularization. As is often the case, opinions differ; the cardiologists favour revascularization, but the surgeons are reluctant.
"This is a typical case of hibernation," says the first expert. "I wouldn't go that far," says the second, "to me it's clear that there is remodelling of an old scar."
"Well, OK, maybe there's some fibrosis here but, you know, that means less than nothing. I bet I can show you a clear mismatch with PET and, if I'm right, you have got to operate on him!," the cardiologist insists. "OK, but I'll only do it when I have evidence of viability, no stunning and a positive dobutamine," the surgeon snorts.
It is at this stage that the old-fashioned bedside cardiologist wonders if he is in the right room or even in the right department: "I must be, Mr. X is my patient, but I don't know what on earth they are all talking about!"
Meanwhile the conversation continues.
"You aren't worried about the low ejection fraction, are you?," the modern cardiologist asks the surgeon. "I'm back from the AHA, where they showed the worse it is, the better the recovery." "I was in that satellite too," says another colleague, "and was amazed to hear that hibernation doesn't exist anymore. Nowadays it's all repetitive stunning progressing to chronic underperfusion without contraction, a sort of mummification with a degree of apoptosis, I'll bet that's what's going on here." "It's the apoptosis that frightens me." The surgeon slowly nods.
These words catch the attention of the cardioscientist. "Hey, what the devil does a cardiologist and a surgeon know about apoptosis?", he jumps to his feet and leaps into the conversation. "To tell the truth, I could hardly follow what you're talking about either, but I can tell you that apoptosis in the strict sense of the word cannot exist in the myocytes. In any case, in my opinion, this ventricle is preconditioned, it has adapted to chronic ischemia regardless of whether it is stunned or hibernating." "You're right," says another colleague holding up the biopsies. "Give me a couple of days and I'll tell you about expression of HSP12, mRNA for ANP, and the type of SERCA. I have no doubt we're dealing with embryonic, dedifferentiated hibernating or stunned myocytes, intermixed with areas of structural remodelling. He'll do fine with surgery—the flow is likely to be normal anyway." At this point the old cardiologist sits down and takes a big breath.
"Hibernation, stunning, preconditioning, remodelling...—my God! Is this going to be the terminology for the year 2000? I'm just back from a course on the glossary of molecular biology, but they didn't mention any of this phraseology, and what's more I'm now told that poor Mr. X has got chronic ischemia which I thought didn't exist; he has a low ejection fraction which I thought meant a bad prognosis with surgery. Despite this, these modern experts say the opposite and they want to revascularise the left ventricle even if its flow appears to be normal. I don't understand... I was sure they were going to put him on the waiting list for transplantation. I'm getting old. But I really must learn about this darn hibernation, stunning, preconditioning, remodelling, but... where? I couldn't stand another course on essential glossaries for the modern cardiologist!"
The correct diagnostic and therapeutic approach to cases like the one of Mr. X is beyond the aim of this short editorial. I do, however, share some of the perplexities of the old cardiologist. Undoubtedly, integrated detailed analyses of regional myocardial blood flow, function, metabolism and morphology in ischemic and reperfused myocardium have led to the identification of phenomena unheard of a decade ago.
Concepts such as prolonged ischemia without reperfusion inevitably resulting in necrosis, or reperfusion after a short period of ischemia resulting in an immediate recovery of function are now being challenged. New concepts have developed such as the belief that one or more brief episodes of ischemia can increase rather than reduce the myocyte's resistance to further ischemic injury. An area of necrosis is no longer considered to be just a dead part of the ventricle, it is now realised to be susceptible to structural changes leading to a vicious circle that is amenable to medical treatment.
These conditions have been named by their own ‘fathers’ as hibernation [1], stunning [2], preconditioning [3], and remodelling [4].
On one hand, such terminology is a useful shorthand that has fired the imagination of cardiologists; on the other hand, such semantics can generate confusion as the imagination develops a perspective of its own. Shahbudin Rahimtoola won himself fame in the art of communication when, adopting the Latin word for ‘winter’, hiberna, to dramatise a clinical syndrome, he popularised the term ‘hibernating myocardium’, first coined by Diamond et al. [5], to describe "a state of persistently impaired myocardial and left ventricular function at rest due to reduced coronary blood flow that can be partially or completely restored to normal if the myocardial/oxygen supply relationship is favourably altered, either by improving blood flow and/or by reducing demand" [1].
The same linguistic triumph does not apply to Guy Heyndrickx, the first to observe that "the myocardium rendered ischemic, but not irreversibly damaged, exhibits prolonged depression of regional myocardial function, long after the complete return of blood flow and resumption of a normal electrocardiographic pattern" [6]. Unfortunately, he failed to call it ‘stunned myocardium’, a prize that was claimed by Braunwald and Kloner a decade later [2]. In doing so they conferred authority and popularity to what is now one of the most common problems in clinical and experimental cardiology. What words can do...!
Both the hibernating and stunned myocardium refer to viable, though dysfunctional, myocardium which has the potential for functional improvement. With the rapid advance of skills in revascularization procedures, the ability to make distinction between reversibly and irreversibly injured myocardium becomes of paramount clinical importance. Unfortunately, the pathophysiological distinction between hibernating and stunned myocardium is as controversial as the mechanisms underlying the conditions. Irreversible damage leads to necrosis which in turn might cause ventricular bulging with deleterious consequences for the ejection of blood from the ventricle. Thanks to Marc Pfeffer, this phenomenon is now known as ‘remodelling’, a name that has focused the interest of cardiologists on the geometry of the ventricle, on the biochemistry of cell repair, on the mechanisms of cell-to-cell communication, and on the possibility of effective pharmaceutical intervention.
Keith Reimer and Robert Jennings must be proud of having used the word ‘ischemic preconditioning’ to describe a rapid adaptation to ischemic stress, based on studies in which a 40 min test episode of ischemia in dogs was preceded by four 5 min cycles of ischemia, each separated by 5 min of reperfusion. Infarct size in the ‘preconditioned’ dogs was only 25% of the size expected from a simple 40 min test episode of ischemia followed by reperfusion. They did not immediately realise the power and the hope that would emanate from the term ‘preconditioning’ but it has spawned an entire new branch of research dealing with ‘endogenous protection’ and ‘memory’ in the heart. As a result, clinicians hope that, one day, they will be able to pharmacologically precondition hearts or even persuade their patients that a little ischemia is better than nothing!
Of course, the pathophysiology, the mechanisms and the signal cascades that underlie hibernation, stunning, remodelling and ischemic preconditioning are not yet clear. Equally, their clinical relevance is not established. But everybody talks about, dreams of, studies and writes about these conditions from their own perspective.
The result? Each investigator has a model that is different from the other. Each group of patients stands on its own. There is a clear need for a common approach to study the same problem—beyond the terminology—from the same angle with different skills.
Maybe it was this need that persuaded the European Union to grant the European Society of Cardiology Working Group on Cellular Biology of the Heart a Biomed Concerted Action on the New ischemic syndromes: hibernation, stunning, remodelling and preconditioning. We have borrowed the title from Lionel Opie's Cape Town meeting in December 1995, sponsored by the Council on Molecular and Cellular Cardiology of the International Society and Federation of Cardiology.
We are delighted to start our task by publishing, in the coming issues of Cardiovascular Research, position papers on these syndromes as well as their clinical application. The series will end with an overview of the clinical implications. Our main goal will be to provide, in some way, the old and the modern cardiologist alike with an easily understood description of these entities and the questions and controversies that surround them.
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Acknowledgements |
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I wish to thank all members of the European Commission Biomed-2 Concerted Action 95-0838 (DGXII SSMA) ‘The New Ischemic Syndromes’ (C. Ceconi, J.W. de Jong, D. Garcia-Dorado, C. Guarnieri, S. Haunsø, D.J. Hearse, G. Heusch, D. Kremastinos, P. Menasché, M. Ovize, H.M. Piper, P. Poole-Wilson, T.J.C. Ruigrok, K. Schwartz, P.D. Verdouw, D. Yellon) for their useful comments and suggestions.
Support was provided by a grant for the same European Commission Biomed-2 Concerted Action mentioned above.
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Notes |
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1 On behalf of participants of the EEC Biomed Concerted Action "The New Ischaemic Syndromes".
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References |
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 Top References |
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- Rahimtoola S.H. Coronary bypass surgery for chronic angina. Circulation (1982) 65:225–241.
[Free Full Text] - Braunwald E., Kloner R.A. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation (1982) 66:1146–1149.
[Abstract/Free Full Text] - Reimer K.A., Murry C.E., Yamasawa I., Hill M.L., Jennings R.B. Four brief periods of myocardial ischemia cause no cumulative ATP loss or necrosis. Am J Physiol (1986) 251:H1306–H1315.[Web of Science][Medline]
- Pfeffer M.A., Lamas G.A., Vaughan D.E., Parisi A.F., Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med (1988) 319:80–86.[Abstract]
- Diamond G.A., Forrester J.S., deLuz P.L., Wyatt H.L., Swan L.J.C. Post-extrasystolic potentiation of ischemic myocardium by atrial stimulation. Am Heart J (1978) 95:204–210.[CrossRef][Web of Science][Medline]
- Heyndrickx G.R., Millard R.W., McRitchie R.J., Maroko P.R., Vatner S.F. Regional myocardial functional and electrophysiological alterations after brief coronary artery occlusion in conscious dogs. J Clin Invest (1975) 56:978–985.[Web of Science][Medline]
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