Myocardial hibernation and “embalmment”

EDITORIALS

Myocardial hibernation and "embalmment" Tali T. Bashour, MD, and Dean T. Mason, MD. San Francisco, Calif.

The recognition that myocardial tissue can "hibernate" in response to profound ischemia and later partially or fully resumes its function, represents a major advance in the understanding of the pathophysiology of ischemic heart disease. This entails far-reaching investigational and therapeutic implications. 1-3 In a recent comprehensive editorial review, Rahimtoola 4 addressed the current concepts of the hibernation phenomenon and its prevelance in different ischemic syndromes. He correctly pointed out that many of the underlying biologic processes remain to a large extent unknown. Furthermore, the timing and extent of the functional recovery that follows reestablishment of coronary perfusion are only partially understood. Much remains to be learned, especially concerning the biochemical disturbance and ultrastructural histopathology. Certain concepts not previously discussed in the context of hibernation may represent extensions of the same basic phenomenon, and will be addressed in the following discussion. Acute and chronic adaptation to ischemia. The relationship between silent or painless ischemia and myocardial dysfunction is indeed intriguing. The concept of the ischemic cascade suggests that pain is a late manifestation of ischemia. Myocardial diastolic function is first affected, followed by systolic dysfunction and then by ST segment shift before pain is experienced.5 This sequence is supported by clinical observations during exercise-induced ischemia, especially that affecting a large area of the left ventricle such as is the case in left main coronary artery disease. Dyspnea and atrial gallop are commonly observed as early manifestations, followed by hypotension and ST segment depression. Pulmonary edema or serious ventricular arrhythmia may even occur before the onset of pain. Defense mechanisms may be acutely enlisted in an attempt to arrest the progresFrom the Western Heart Institute, St. Mary's Hospital & Medical Center; and University of California San Francisco. Received for publication Oct. 20,1989; accepted Nov. 14, 1989. Reprint requests: Tali T. Bashour, MD, Western Heart Institute, St. Mary's Hospital and Medical Center, 450 Stanyan St., San Francisco, CA 94117. 4/1/18037

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sion of ischemia before the onset of chest pain. In the presence of rich collateral supply, ST segment depression and even myocardial dysfunction may also be averted. Hibernation, on the other hand, represents an extreme regulatory mechanism in response to chronic and profound ischemia, whereby the meager supply of coronary flow is exclusively used to maintain survival and structural integrity. The mechanisms responsible for hibernation are probably distinctly different from those involved in acute adaptation. It is logical to assume that depression of kinetic function would result in impressive preservation of energy, thereby allowing the utilization of the critically reduced coronary flow for the sole purpose of maintaining enough tissue nutrition to permit survival. In chemical terms, a viable muscle should contain at least small amounts of inorganic phosphorus compounds and should manifest a normal or increased glucose metabolic activity. The detection in vivo of adenosine triphosphate (ATP) and phosphocreatine (PC) is still not practically achievable. However, magnetic resonance spectroscopy techniques hold promise in this area. Myocardial uptake of glucose, on the other hand, can now be detected by positron emission tomography (PET). Despite cessation of mechanical function, the presence of ATP and the increased uptake of glucose indicate a viable hibernating myocardium. Distinguishing this condition from similarly nonfunctioning but irreversibly damaged myocardium has obvious significance in planning interventional revascularization. Prolonged and permanent hibernation-- "myocardial embalmment." The elapsed time between reperfusion

and functional recovery is probably dependent upon the amount of available inorganic phosphorus compounds and the rate at which they can be replenished. Therefore the recovery of markedly depleted segments is expected to be significantly delayed. Histologic integrity is likely to be required before any chance of recovery is to be expected. The function of areas with fibrotic scarring or massive edematous degeneration and a total lack of inorganic phosphorus compounds is probably permanently lost. This chemical variability may account for the clinical ob-

Volume 119 Number 3, Part 1

Myocardial hibernation and embalmment

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Table I. Conditions of myocardial tissue and their corresponding characteristics

State of the myocardium

Ultrastructural anatomy

Coronary flow

Mechanical function

Normal Ischemic

N N

N ~

N ~

N N

N N or mildly

N Excellent

Stunned

N

"Embalmed"

?

Critically

Absent

?

Mildly J~ Markedly ~ Absent

Very good

?N

~ or absent Absent

?

Hibernating

Recently restored Markedly

Absent

Absent

Absent

Dead

Abnormal

Glucose uptake

?

ATP and PC content

Absent

Recovery potential

Fair to good Very poor; Future ? Absent

N, Normal; ~, reduced; ?, increased; ?, unknown; ATP, adenosine triphosphate; PC, phosphocreatine.

servation t h a t dysfunction is frequently but not always reversible. 6 Nonfibrotic myocardial segments with apparently normal histology but an irrevocably damaged energy system may then undergo an "embalming" process that leaves them in permanent hibernation. This may account for the discrepancy between Q wave distribution and the larger extent of dysfunction as demonstrated by PET studies, 7 as well as for the nonuniform response of hibernating segments to a nitroglycerin test or to revascularization procedures. 6 Caution should be exercised, however, before the diagnosis of irreversible hibernation can be made with certainty, since very late recovery after restoration of coronary blood flow may still take place, s Gradual recovery can also be observed in animal experiments. 9 On the other hand, recovery of segments that presumably still contain appreciable amounts of ATP can occur promptly, as observed by intraoperative transesophageal echocardiographic studies. 1~Hibernating myocardium may then recovery rapidly after restoration of flow or may remain "stunned" for a variable period of time that can extend to 1 year and probably even longer. Thus the condition represents an overlap between hibernation and stunning. In the former, flow is by definition critically reduced, while in the latter effective flow has been restored. For unknown reasons, the myocardium is unable in these cases to deploy the now available substrate in order to overcome its total inactivity. Ultrastructural changes, or a defect in enzymatic mechanisms, will have to be presumed. Whether the myocardium will remain permanently "embalmed" or may potentially respond to a yet undefined "Prince Charming" is at present a mere speculation, or a scientific fantasy. The state of myocardial tissue then varies in a spectrum that extends from normalcy to complete ablation (Table I). Each stage is distinguishable by certain anatomic and

functional characteristics, as well as by its recovery potentials. Can hibernation

occur with normal coronary

arteries?

Myocardial dysfunction with normal coronary arteries may result from toxic, inflammatory, or infiltrative causes, or as a result of prolonged volume or pressure ouverloads. These mechanisms are involved in what is commonly referred to as secondary cardiomyopathy. Left venricular ejection fraction is frequently reduced in cases of advanced aortic stenosis or aortic regurgitation. In many cases, an improvement of systolic function can be observed long after surgical correction of valvular dysfunction. It is reasonable to speculate that at least some myocardial segments were hibernating, presumably in an attempt to limit the increase in oxygen consumption and restore the balance between the demand for coronary flow and the available supply. Such hibernation may be viewed as similar in nature to ischemic hibernation, albeit it is due in this case to relative ischemia of the markedly enlarged or hypertrophic cardiac muscle. In conclusion, the points raised in this discussion are merely speculative. They may, however, help call attention to the fact that our knowledge of the processes involved in myocardial hibernation is still in the embryonic stage. Our means of predicting the potential for and the extent of the myocardium's recovery are quite limited. Future investigations should concentrate on two areas: the ultrastructural anatomy of normally-appearing noncontracting myocardium and its ongoing perfusion and metabolic correlations. REFERENCES

1. Rahimtoola SH. A perspective on the three large multicenter randomized clinical trials of coronary bypass surgery for chronic stable angina. Circulation 1985;72:V-123. 2. Bashour TT. Of myocardial life, hibernation and death. AM HEART J 1986;112:427.

March 1990

Bashour and Mason 3. Braunwald E, Rutherford JD. Reversible ischemic left ventricular dysfunction: evidence for the "hibernating myocardiurn." J Am Coll Cardiol 1986;8:1467. 4. Rahimtoola SH. The hibernating myocardium. AM HEARTJ 1989;117:211. 5. Hauser AM, Vellappillil G, Ramos RG, Gordon S, Timis GC. Sequence of mechanical, electrocardiographic and clinical effects of repeated coronary artery occlusion in human beings: echocardiographic observations during coronary angioplasty. J Am Coll Cardiol 1985;5:193. 6. Rahimtoola SH, Grunkemeier GL, Teply JF, Lambert LE, Thomas DR, Suen FY, Starr A. Changes in coronary bypass surgery leading to improved survival. JAMA 1981;246-1912. 7. Brunken, R, Tillisch J, Schwaiger M, Child JS, Marshall R, Mandelkern M, Phelps ME, Schellbert HR. Regional perfusion, glucose metabolism, and wall motion in patients with chronic electrocardiographic Q wave infarctions: evidence for

American Heart Journal

persistence of viable tissue in some infarct regions by positron em{ssion tomography. Circulation 1986;73:951. 8. Mintz LJ, Ingels NB Jr, Daughters GIII, Stinson EB, Alderman EL. Sequential studies of left ventricular function and wall motion after coronary bypass surgery. Am J Cardiol 1980;45:210. 9. Matsuzaki M, Gallagher KP, Kemper WS, White F, Ross J Jr. Sustained regional dysfunction produced by prolonged coronary stenosis: gradual recovery after reperfusion. Circulation 1983;68:170. 10. Topol EJ, Weiss JL, Guzman PA, Dorsey-Lima S, Blanck TJJ, Humphrey LS, Baumgartner WA, Flaherty JT, Reitz BA. Immediate improvement of dysfunctional myocardial segments after coronary revascularization: detection by intraoperative transesophageal echocardiography. J Am Coll Cardiol 1984;4:1123.

Appraisal of false positive results in nuclear cardiac imaging Abdulmassih S. Iskandrian, MD, and Jaekyeong Heo, MD. Philadelphia, Pa.

Exercise thallium-201 myocardial imaging and r e s t / exercise radionuclide angiography have proved to be Very valuable in the m a n a g e m e n t of patients with ischemic h e a r t disease. 1 T h e increasing use of t o m e graphic techniques and the future use of t e c h n e t i u m b o u n d myocardial perfusion agents will u n d o u b t e d l y provide additional advantages. False positive results (patients with n o r m a l or no significant coronary art e r y disease by angiography b u t who have abnormal test results) are not u n c o m m o n with b o t h techniques and are reasons for concern and frustration, as t h e y i n t r o d u c e an e l e m e n t of anxiety to the patients and decrease the confidence of physicians in the use of these techniques. W h a t are the causes of false positive results? T h e s e m a y be grouped into three categories.

1. Problems in interpretation: Either underestimation of the coronary arteriographic findings or overestimation of the imaging findings. Examples of From the Philadelphia Heart Institute, Presbyterian Medical Center of Philadelphia. Received for publication Sept. 7, 1989; accepted Oct. 13, 1989. Reprint requests: A.S. Iskandrian, MD, Philadelphia Heart Institute, Presbyterian Medical Center of Philadelphia, 39th and Market Streets, Philadelphia, PA 19104. 4/1/18036 708

u n d e r e s t i m a t i o n of arteriographic findings include flush occlusion of a branch; u n d e r e s t i m a t i o n of the degree of p e r c e n t diameter stenosis due to overlap, eccentricity, poor films, i m p r o p e r views, inexperience, or the unreliability of p e r c e n t diameter stenosis to predict the h e m o d y n a m i c significance of coron a r y obstruction. 1 Examples of overestimation of imaging findings include poor films, inexperience, failure to recognize normal variance such as valve planes, a t t e n u a t i o n artifacts, or the heavy reliance on a u t o m a t e d techniques in imaging interpretation. Causes of artifacts on thallium-201 single p h o t o n emission c o m p u t e d t o m o g r a p h y ( S P E C T ) imaging have recently been reviewed by D e P u e y and Garcia 2 and include breast attenuation, lateral chest wall fat, diaphragmatic attenuation, overlying visceral activity, myocardial hot spots, apical variations, p a t i e n t motion, oblique axis and "bulls-eye" reconstruction errors, center of rotation errors, and camera field nonuniformity. Causes of false positive results with rest/exercise radionuclide angiography include p a t i e n t motion, selection of the region of interest, background subtraction, subjective n a t u r e of i n t e r p r e t i n g wall motion abnormality, and o t h e r nontechnical factors such as low level of exercise, high resting ejection fraction (hy-