Br J: first published as 10.1136/hrt.48.3.265 on 1 September 1982. Downloaded from BrHeartJ7 1982; 48: 265-71

Coronary narrowing without irreversible myocardial damage or development of collaterals Assessment of "critical" stenosis in a human model

ERLING FALK From the Institute ofPathology, Randers Centralsygehus, Denmark

SUMMARY Postinfarction cardiac rupture is the result of thrombotic occlusion of a functional end artery with no previous myocardial damage in the perfusion area of the occluded artery. The pre-existing atherosclerotic stenosis at the site of thrombosis is thus "non-critical" in relation to the development of collateral vessels and/or irreversible myocardial damage. Eleven cases of posiinfarction cardiac rupture were studie by microscopy of cross-sections of the thrombosed segments. At the site of the thrombosis, pre-existing atherosclerosis had narrowed the lumen to 11% or less of its normal cross-sectional area. Maximal pre-existing narrowing of the proximal left anterior descending artery was found in a case with 97% stenosis (histologically measured cross-sectional area reduction) and an estimated residual lumen of 0*71 mm2. The pre- stenotic luminal area which is usually considered angiographically as "normal" was in all cases shown histologically to be severely narrowed by a diffuse intimal thickening. It is concluded that organic coronary stenosis must be far greater than 75% to be responsible for copyright. the development of collateral vessels and/or irreversible myocardial damage.

Coronary artery stenosis that limits flow below ously been shown that a uniform patho-anatomical basal demands is usually considered critical. In substrate exists in postinfarction cardiac rupture, con-

human disease, however, the term "critical stenosis" sisting of an acute coronary occlusion with a recent http://heart.bmj.com/ is poorly defined, especially as no consistent relation myocardial infarct which is transmural and totally has been documented between symptoms of unprotected by scar or collateral vessels.6 Conse- ischaemic heart disease and the extent and severity of quently, in these we find acute occlusions of coronary narrowing.I-3 In addition, a severe stenotic functional end , and the pre-existing organic lesion may be bypassed and adequately compensated stenosis at the site of thrombosis can thus be consi- by collateral vessels, which make evaluation of the dered "non-critical" in relation to the development of ischaemic significance of the stenosis, per se, impos- collateral vessels and/or irreversible myocardial dam-

sible. In animal studies, however, a critical level of age. on September 26, 2021 by guest. Protected stenosis has been identified. Isolated proximal coro- This paper presents a quantitative assessment ofthe nary stenosis has to reduce the luminal cross-sectional pre-existing luminal narrowing in acutely thrombosed area by about 95% before resting myocardial flow fails coronary arteries from 11 patients with postinfarction to meet the demand.45 At that degree of acute obs- cardiac rupture. truction, the peripheral vascular bed is maximally dilated and further narrowing will cause myocardial Subjects and methods ischaemia at rest. At necropsy we are occasionally provided with a Nine consecutive necropsy patients with heart rup- human model which is comparable with the experi- ture from Randers Hospital and two cases referred mental, isolated coronary stenosis. Thus it has previ- from another hospital in the same period (1 February 1980 to 30 June 1981) form the basis for this study. The study was supported by a grant from Hjerteforeningen (The Danish Heart After the heart was weighed the coronary arteries Foundation). were gently flushed via the aorta with 100 ml 4% for- Accepted for publication 13 April 1982 maldehyde solution and then a barium gelatine 265 Br Heart J: first published as 10.1136/hrt.48.3.265 on 1 September 1982. Downloaded from 266 Falk medium at 40°C was injected under a pressure of 150 cent to the rupture. mmHg maintained for 15 minutes. The medium was hardened by cooling and angiograms were taken in TISSUE SHRINKAGE different projections. The heart was fixed for two To calculate the shrinkage that occurs when an artery weeks in a 4% formaldehyde solution, decalcified for is processed for microscopy the following experiment three weeks in EDTA (ethylenediaminetetraacetic was performed. Unfixed segments of injected arteries acid), and then stored for at least one week in forma- were dissected free from the hearts, placed directly on lin. The main coronary arteries and those of their radiographic film, and x-rayed. X-rays were repeated branches thicker than 1 mm were cross-sectioned at 3 after fixation, dehydration, clearing, and embedding mm intervals. Each segment, angiographically shown in paraffin. During this procedure and at the final to be stenosed or occluded, was processed for micros- microscopical examination of the histological sections copy. All thrombosed segments were cross-sectioned it was observed that the shrinkage of the radio-opaque at 200 ,um intervals and the point of maximal luminal medium was equal to or a little more pronounced than reduction resulting from old atherosclerotic plaques the shrinkage of the artery lumen. The segments was identified. The ventricular portion of the heart where the shrinkage of the x-ray medium equalled the was cut into 1 cm thick slices parallel to the atrioven- luminal shrinkage were selected for measurements. tricular groove, photographed, and x-rayed, with each The luminal diameters were measured on the radio- slice placed directly on the film. Several histological graphs and the luminal area shrinkage resulting from sections were prepared from the perfusion area of tissue processing was calculated. One-hundred and each coronary artery and from the myocardium adja- fifty measurements were done on 15 different vascular segments.

Table 1 Clinical data in 11 patients with postinfarction cardiac rupture Case No. Age (y) Sex Survival* (d) Preinfarction cardiac symptomst 1 82 F 1 None 2 69 M < 1 Unstable angina 3 69 M 3 None copyright. 4 80 M < 1 None 5 71 F

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Fig. 1 Case 2 iUustrating hozw severe a stenosis can be without collatral development orevidence ofirreversible myocardial damage in theform ofscar. (A) Postmortem angiogram in the anteroposteior view showing total occlusion oftheproximal left anterior descending artery (thick arrow) without collateral distalfiUing ofthe vessel (original natural size). (B) Radiograph ofa transverse myocardial slice showing no collateral vascularfiUing in the peifsion area ofthe left anteior descending artery (original natural size). (C) Photograph ofthe same myocardial slice showing rupture ofthe anterior left ventriciar wall. Microscopy showed anteroseptal infarction less than I day old; no myocardialfibrosis was present (original natural size). (D) Histological sectionfrom angiographic "normal" segment (thin arrow in A) showing diffiuse intimal thickening with the lumen 64%obliterated (original magiufication x 8). (E) Histological section showing occluding thrombus at the site ofmaximal atherosclerotic narrowing (thick arrow in A). This degree ofold stenosis (91% cross-sectional area reduction) has not caused collateral development orproduced irreversible myocardial damage in theform offibrosis. In this case a histological area stenosis of91% corresponds to an angiographic area stenosis of82% (original magnification x 8). Br Heart J: first published as 10.1136/hrt.48.3.265 on 1 September 1982. Downloaded from IA Falk

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BC.C Fig. 2 Correlation ofangiographic andpathologicalfindings (case 5). (A) Angiogram shoing total occlusion ofleft anteior descendingartery (thick arrow) withpoor coUateral distalfiUing ofthe vessel (original natural size). (B) Histological section ofthe left antmor descending arteryjust after the bifurcation ofthe kft main artery (thtn arrow) where the vessel angiographically appears "normal" with a wide lumen. Nevertheless, the luminal narrwing resuingfronm diffuse atherosclerotic intmalthiening is 71%at that point. That is the reason why the real stenosis is consistently derestimated angiographicaly (original magnpication x 14). (C) Histological sectionfrom the left antenordescending artery at the site ofmaximalstenosis resukingfrom old atheroscleroticplaques (thick arrow); the residual lumen is occluded by a recent thromnbus. The histological area stenosis of98%corresponds in this case to an angiographic area stenosis of95% (original magnification x 14). Br Heart J: first published as 10.1136/hrt.48.3.265 on 1 September 1982. Downloaded from Coronary arteiy narrowing, myocardial damage, and collaterals 269

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- 'Adpppp _~II ppp- Fig. 3 Shrinkage oftissue and contrast mediwn caused byprocessing for nicroscopy. (A) Radiograph ofan ufixed vascular segment placed directly on the x-rayfilm. (B) The same segment afterfixation and decalcj1ication. (C) The same segment after dehydration, clearing, and paraffin ittilration. That the shrinkage ofthe contrast mediun equals the luninal shrinkage is shown by radiographs ofcorresponding cross-sections and by microscopy ofthefinal histological sections (D). The total shnnkage (A to C) results in a reduction ofthe hwninal area to approximate two thirds ofthe originalarea ofthe unprocessed vessel. ((A), (B), and (C) original magnfication x 2 5; (D) original magnfication x 11)). PERFUSION AREA Recent thrombi superimposed on atherosclerotic The relative amount of ventricular myocardium sup- plaques were found in all patients, and the site of plied by the three large coronary arteries varies myocardial rupture corresponded with the point of according to the anatomy of the coronary artery tree. arterial occlusion. At the site of the thrombus, all

The perfusion areas of the coronary arteries were patients had histological stenosis of more than 89% copyright. identified from the angiograms, and the percentage of caused by old atherosclerotic plaques. Apart from ventricular myocardium supplied by each artery was cases 8 and 9, the angiograms disclosed no collateral determined according to the results of Kalbfleisch and vessels bypassing the thrombotic occlusions (Fig. 1 Hort.7 The perfusion area of the first diagonal branch and 2) and careful microscopical examination of the was considered as large as that of the left anterior myocardium showed no fibrosis in the perfusion area descending artery distal to the first diagonal branch.8 of the thrombosed artery. Cases 8 and 9 had ruptured ventricular aneurysms. The prestenotic segments http://heart.bmj.com/ DEFINITIONS which, on angiograms, are usually considered as Histological stenosis: the ratio between the cross- "normal" were in all cases severely narrowed because sectional area of the residual lumen and the assumed of diffuse intimal thickening (confluent atherosclero- original cross-sectional luminal area of the vessel at tic lesions) (Fig. 1 and 2). Formalin fixation did not the point under consideration (the area encircled by cause any significant tissue shrinkage (no difference the internal elastic membrane). All cross-sectional between vessels dissected free and vessels in situ) but areas are calculated from measurements of maximal the subsequent tissue processing resulted in a reduc- and minimal diameters assuming an elliptical cross- tion of the luminal area to approximate two-thirds of on September 26, 2021 by guest. Protected section (measured by projection microscopy using a the original area of the unfixed vessel (median: 65%, Reichert Lanometer). range: 50% to 74%) (Fig. 3). Angiographic stenosis: the ratio between the stenotic luminal area and the greatest prestenotic luminal area Discussion (which angiographically would be judged as "nor- mal"). As the vessels in question are thrombosed and Necropsy studies have shown that the infarction size thus not visualised on the angiograms, the two areas is usually smaller than the perfusion area of the ob- had to be determined by microscopy of the histologi- structed vessel'0-12 and even cases of total coronary cal sections. occlusion with no myocardial damage have been reported. "l 13 The ability of collateral vessels to pro- Results tect jeopardised myocardium is thus obvious. There- fore, to evaluate the ischaemic significance of organic Clinical and pathological findings are summarised in stenoses, one has to identify stenotic lesions not Table 1 and 2. bypassed by collateral vessels. But as many functional Br Heart J: first published as 10.1136/hrt.48.3.265 on 1 September 1982. Downloaded from 270 Falk collateral vessels are below the resolution of modem which often corresponds to a histological area reduc- cineangiographic equipment,'4 in vivo determination tion of 75%.' 18 The result is that the angiographer of the human "critical stenosis" may be unreliable. compares stenotic segment with adjacent "normal The degree of coronary artery narrowing causing looking" but, nevertheless, narrowed segment, and irreversible myocardial damage is thus poorly defined the real degree of stenosis is thus consistently under- clinically. In fatal heart disease, however, the nec- estimated. To overcome this problem in ropsy occasionally discloses postinfarction cardiac angiographic-histological correlative studies, it is rupture, and in these cases the existence of significant necessary to measure the stenotic residual lumen pre- collateral vessels can be excluded in the light of func- cisely and then to calculate the true size of the lumen. tional considerations, not merely because of inability The clinician has to compensate for dimensional to detect such vessels angiographically. errors caused by angiographic magnification while the Thus, using a refined injection and dissection tech- pathologist has to correct for postmortem alterations nique, Wessler et al.6 have shown that postinfarction and tissue shrinkage secondary to processing for mic- cardiac rupture is the result of thrombotic occlusion roscopy. Our histological procedures resulted in an ofa functional end artery with no evidence ofprevious area reduction to two-thirds of the area of the unpro- myocardial damage (fibrosis) in the perfusion area of cessed vessel. This figure is in general agreement with the thrombosed artery. The reliability of their techni- the results obtained by measurements of volume que m showing collateral vessels in human hearts changes of whole organs and tissue specimens fixed in without coronary artery disease has been ques- formalin and processed for embedding in tioned's 16 but their method has been reliable in paraffin.21 22 hearts with coronary occlusions. 'S The present study McMahon et al.23 have measured angiographically was not undertaken to clear up the pathogenesis of the minimum cross-sectional lumen area in patients postinfarction cardiac rupture, but our results are in with unstable angina and proximal single vessel dis- agreement with the results of Wessler et al. Cases 8 ease without collateral vessels and found it 0.6 mm2 and 9 are unusual cases of late myocardial rupture (92% cross-sectional area reduction). Our cases 1, 6, (ruptured aneurysms four and 10 weeks after the and 8 show proximal stenoses with a residual lumen of

acute infarction) and the angiographically visible col- the same magnitude (0-71, 0*71, and 0 77 mm2). As copyright. all lateral vessels have probably developed secondarily to stenoses in our cases are "non-critical", the present the thrombotic occlusions. study fully confirms the observation of McMahon The aim ofour study was to determine the maximal et al. that a very severe coronary stenosis can be toler- degree of old organic obstruction in the thrombosed ated in a functional end artery without irreversible coronary artery in cases of postinfarction cardiac rup- myocardial damage in the perfusion area of the ob- ture. These stenoses have not yet reached a degree structed vessel. Stenotic coronary lesions with less that causes collateral development and/or irreversible than 900/o angiographic diameter reduction canhttp://heart.bmj.com/ myocardial damage. undoubtedly produce myocardial ischaemia and angi- Many pathologists consider an histological area nal pain during exercise, but from a haemodynamic stenosis of 75% as significant.''7 18 This study, how- point of view they are of moderate degree only, since ever, shows that a pure organic stenosis far greater they are practically never accompanied by angiog- than 75% may be well tolerated. Thus, stenoses grea- raphically visible collateral circulation. 14 24 The pres- ter than 95% were observed without evidence of ent pathological study confirms clinical observations irreversible myocardial damage in the corresponding that an organic stenosis has to be very severe to be

perfusion area. held responsible for development of collateral vessels. on September 26, 2021 by guest. Protected Minor degrees of organic obstruction may of course be clinically significant in causing myocardial The author thanks Drs Jens Vilhelm Thorborg and ischaemia and angina during exercise and, if vasocon- Jens Sand Kristensen for their help. striction (spasm) is superimposed, even at rest.'920 Histological stenosis is not comparable with angio- graphic stenosis. The pathologist compares the References residual lumen with the presumed original lumen the elastic 1 Roberts WC. The coronary arteries in fatal coronary (area encircled by internal membrane) events. In: Chung EK, ed. Controversy in cardiology. New while the clinician compares the most narrowed seg- York, Heidelberg, Berlin: Springer-Verlag, 1976: 1-22. ment with the adjacent "normal" arterial segment as 2 Proudfit WL, Shirey EK, Sones FM Jr. Distribution of depicted on the angiogram. The adjacent "normal" arterial lesions demonstrated by selective cinecoronary segment, however, is never normal, as the coronary arteriography. Circulation 1967; 36: 54-62. arteries in ischaemic heart disease in addition to focal 3 Rafflenbeul W, Urthaler F, Lichtlen P, James TN. stenotic lesions have diffuse intimal thickening'8 Quantitative difference in "critical" stenosis between Br Heart J: first published as 10.1136/hrt.48.3.265 on 1 September 1982. Downloaded from Coronary artery narrowing, myocardial damage, and collaterals 271 right and left coronary artery in man. Circulation 1980; 15 Rodriguez FL, Robbins SL. Postmortem angiographic 62: 1188-96. studies on the coronary arterial circulation. Am HeartJ 4 Gould KL, Lipscomb K, Hamilton GW. Physiologic 1%5; 70: 348-64. basis for assessing critical coronary stenosis. Am J Car- 16 Cohen MV. The functional value of coronary collaterals diol 1974; 33: 87-94. in myocardial and therapeutic approach to 5 Gregg DE, Dedynek JL. Compensatory changes in the enhance collateral flow. Am Heart J 1978; 95: 396-404. heart during progressive coronary artery stenosis. In: 17 Davies MJ, Woolf N, Robertson WB. Pathology ofacute Maseri A, Klassen GA, Lesch M, eds. Prmary and secon- with particular reference to occlu- dary angina pectoris. New York: Grune & Stratton, 1978: sive coronary thrombi. Br Heart J 1976; 38: 659-64. 3-11. 18 Amett EN, Isner JM, Redwood DR, et al. Coronary 6 Wessler S, Zoll PM, Schlesinger MJ. The pathogenesis artery narrowing in coronary heart disease: comparison of spontaneous cardiac rupture. Circulation 1952; 6: of cineangiographic and necropsy findings. Ann Inten 334-51. Med 1979; 91: 350-6. 7 Kalbfleisch H, Hort W. Quantitative study on the size of 19 Maseri A. Pathogenetic mechanisms of angina pectoris: coronary artery supplying areas postmortem. Am HeartJ expanding views. Br Heart J 1980; 43: 648-60. 1977; 94: 183-8. 20 MacAlpin RN. Relation of coronary arterial spasm to 8 Hori M, Inoue M, Ohgitani N, et al. Site and severity of sites of organic stenosis. Am J Cardiol 1980; 46: 143-53. coronary narrowing and infarct size in man. Br Heart J 21 Baker JR. Principles ofbiological microtechnique. London: 1980; 44: 271-9. Methuen, 1958: 75-86. 9 Mallory GK, White PD, Salcedo-Salgar J. The speed of 22 Bahr GF, Bloom G, Friberg U. Volume changes of tis- healing of myocardial infarction. Am Heart J 1939; 18: sues in physiological fluids during fixation in osmium 647-71. tetroxide or formaldehyde and during subsequent treat- 10 Jones AM. The functional role of intercoronary anasto- ment. Exp Cel Res 1957; 12: 342-55. moses. Acta Cardiol (Brux) 1965; 11, suppl: 130-44. 23 McMahon MM, Brown BG, Cukingnan R, et al. Quan- 11 Baroldi G. Functional morphology of the anastomotic titative coronary angiography: measurement of the "crit- circulation in human cardiac pathology. In: Bajusz E, ical" stenosis in patients with unstable angina and Jasmin G, eds. Methods and achievements in experimental single-vessel disease without collaterals. Circulation 1979; pathology. vol. 5. Functional morphology of the heart. 60: 106-13. Basel: Karger, 1971: 438-73. 24 Levin DC, Kauff M, Baltaxe HA. Coronary collateral

12 Lee JT, Ideker RE, Reimer KA. Myocardial infarct size circulation. AJR 1973; 119: 463-73. copyright. and location in relation to the coronary vascular bed at risk in man. Circulation 1981; 64: 526-34. 13 Blumgart HL, Schlesinger MJ, Zoll PM. Angina pec- toris, coronary failure and acute myocardial infarction. jAMA 1941; 116: 91-7. Requests for reprints to Dr Erling Falk, Institute of 14 Gensini, GG, Bruto da Costa BC. The coronary collateral circulation in living man. Am J Cardiol 1%9; 24: 393- Pathology, Aalborg sygehus, Nord, DK-9000 Aal- 400. borg, Denmark. http://heart.bmj.com/ on September 26, 2021 by guest. Protected