Failure of angiography to accurately depict the extent of coronary artery narrowing in three fatal cases of percutaneous transluminal coronary angioplasty

The angiographic and pathologic findings are described in three patients who died less than 24 h after failed percutaneous transluminal coronary angioplasty. In two of the three patients, coronary angiography performed before angioplasty disclosed apparently focal lesions in the left anterior descending and right coronary arteries. In these two patients quantitative angiographic analysis disclosed a minimal lumen cross-sectional area of 1.82 and 0.47 mm2, respectively, at the sites of apparently focal stenoses before angioplasty; corresponding percent lumen area narrowing measured 84% and 91%, respectively, by quantitative angiography at these two sites. In the third patient, coronary angioplasty was undertaken when the patient developed spontaneous occlusion of the right coronary artery several hours after diagnostic angiography. Retrospective quantitative angiographic analysis of the right coronary artery revealed a minimal lumen cross-sectional area of 1.14 mm2, with 85% lumen area narrowing at the site of subsequent total occlusion and angioplasty. In each of these three patients, necropsy examination disclosed that the distribution of coronary narrowing in the artery treated by angioplasty was in fact not focal; rather, in each of these three patients, the artery treated by angioplasty, as well as the extramural coronary arteries not treated by angioplasty, were severely narrowed by diffusely distributed atherosclerotic plaque. The angiographic and necropsy findings in these three patients document that coronary narrowing that remains occult by virtue of diffuse distribution may complicate evaluation of patients being considered for coronary angioplasty.

The angiographic and pathologic findings are described in three patients who died <24 h after failed percolaneuus transluminal coronary angioplasty .In two of the three patients, coronary angiography performed before angioplasty disclosed app^renlly focal lesions in the left anterior descending and right coronary arteries.In these two patients quantitative angiographic analysis disclosed a minimal lumen cross-sectional area of 1 .82and 0.47 min, respectively, at the sites of apparently focal s~cnoses before angioplasty; corresponding percent lumen area narrowing measured 84% and 91 %, respectively, by quantitative an iography at these 1500 sites.
In the third patient, coronary angioplasty was undertaken when the patient developed spontaneous occlusion of the right coronary artery several hours after diagnostic angingraph;, Retrospective quantitative angiographic analysis of the right coronary Although certain limitations of coronary angiography have been repeatedly documented by pathologic (1-9) and physiologic (10-13) studies, modifications involving instrumentation and analysis have been considered to obviate many of these previously established liabilities .Certain liabilities, however, remain unsolved, Chief among these is the pathoanatomic finding of diffuse.severe coronary artery narrowing .Diffusely diseased arteries have been demonstrated at necropsy (14)(15)(16)(17) and are recognized to constitute a pitfall of diagnostic angiogrophy (18); such diffuse, severe narrowing has less frequently been documented or even considered in patients undergoing percutaneous transluminal coronary angioplasty in whom angiographic evidence of focal narrowing represents the essential criterion for nonsurgical therapy .
The three patients described in this report document the extent to which diffuse coronary narrowing continues to artery revealed a minimal lumen cross-sectional area of 1 .14mm, with 8517 !omen area narrowing at the site of subsequent total occlusion and angioplasty.
In each of these three patients, necropsy examination disclosed that the distribution of coronary narrowing in the artery treated by angioplasty was in fact not focal ; rather, in each of these three patients, the artery treated by angioplasty, as well as the extramural coronary arteries not treated by angioplasty, were severely narrowed by diffusely distributed atherosclerotic plaque.The angiographic and necropsy findings in these three patients document that -onary narrowing that remains occult by virtue of diffuse distribution may complicate evaluation of patients being considered for coronary angioplasty .
(J Am Colf Cardiof 1992;!9:1261-70) pose a liability for angiographic analysis .including quantitalive analysis of images recorded in multiple orthogonal obliquities.In particular, these three cases illustrate the extent to which this liability may compromise attempts to perform pertutaneous coronary artery revascularization .

Methods
Clinical data.Coronary angiography and coronary angirlplasty were performed on three patients at two institutions with standard diagnostic and interventionl techniques .The clinical history was obtained retrospectively from medical records, catheterization record:; and reports of pathologic examination .
Angiographic analysis.Selective representative enddiastolic frames of coronary arteringrams were analyzed in at least two orthogonal views .Clue frames were digitally acquired onto computer memory by using a tine video camera mounted on a standard tine projector (Tagarno) .Digitally acquired images were then quantitatively analyzed with use of a previously validated commercially available edge-detection computer-assisted software program (Image-Comm) .Calibration was performed by using the known dimensions of the angiographic catheter.Standard gray scales were employed .Absolute artery dimensions (lumen diameter and cross-sectional area) were determined for sites 0035-to97rot/ss.00 of both maximal stenosis and reference segments (segments with angiographicelly normal appearance adjacent to sites of maximal stenosis) .Percent stenosis was calculated as the difference between the lumen cross-sectional area of the reference segment and the stenotic segment, divided by the lumen cross-sectional area of the reference segment .
Pathologic examination.At necropsy .the epicardial coronary arteries were excised intact and serially crosssectioned at 5-mm intervals .In Patient 3 .this procedure was performed after the coronary arteries had been selectively cannulated and perfused with 10% buffered formalin at a mean pressure of 80 mm Hg .In the remaining two cases the coronary arteries were examined without pressure perfusion fixation .Ech 5-mm section was inspected grossly for percent cross-sectional area narrowing and the presence of intracoronary thrombus .and these findings were recorded.The 5-mm sections were then prepared for light microscopic examination as described previously (19) .Briefly, each coronary artery was decalcified in a solution of 10% formic acid and fermalin if necessary, and fixed overnight in 10% buffered fetmalin .Segments were then dehydrated in graded alcohol, c' eared with xylene, impregnated with and embedded in par ffin, and sectioned into 4-µm thick sections .
Sections stained with Verhoelfs elastic tissue stain as well as sections stained with hematoxylin-eosin were prepared from each 5-mm segment .The elastic-tissue-stained sections prepared from the coronary arteries of each patient were then inspected by light microscopy .Lumen crosssectional area narrowing was calculated by positioning elastic-stained sections on the stage of a projection-light microscope.The image was then magnified 25 times onto a piece of opaque white paper and pencil tracings were made of the section's original lumen, denoted by the black-staining internal elastic membrane and the inner lumen, demarcated by the internal perimeter of the atherosclerotic plaque, Mensurements of lumen area and native arterial area were performed by on-line computer analysis with commercially available computer software and hardware (Summasketch-MacMeasure.Apple Computer) .Percent cross-sectional area narrowing was calculated by using the measured and original lumen areas .

Case Reports Patient I
A 54-year old man had a history of stable exertional angina for 8 years .One month befc-e admission, he developed a crescendo anginal pattern, with angina occurring up to 3 times/day with minimal exertion .Elective coronary angiography performed 2 weeks before admission revealed a left dominant coronary circulation, focal stenosis of the proximal left anterior descending coronary artery (Fig .I, a  and b), and no focal narrowing of the remaining vessels .
Coronary angioplasty and emergency coronary bypass surgery .The patient was readmitted for elective coronary angioplasty of the left anterior descending coronary artery .A 0.014-in .(0 .036-cm) guide wire was advanced easily beyond the proximal stenosis into the distal left anterior descending artery.However, the angioplasty catheter could not be advanced across the high grade stenosis, and ventricular tachycardia developed.The arrhythmia was treated successfully with a precordial thump and intravenous lidocaine .but hypotension required insertion of an intraaortic balloon pump .Despite these interventions, hypotension persisted in association with bradycardia refractory to atropine .Cardiopulmonary resuscitation was begun and the patient was taken to the operating room for emergency coronary artery bypass surgery .Saphenous vein bypass grafts were placed to the left anterior descending coronary artery and the left obt :ise marginal branch of the left circumflex coronary artery .Despite the use of amrinone, 1-norepinephrine (Levophed).dopamine and epinephrine, atrioventricular pacing, luteaaortic balloon counterpulsation and a left ventricular assist device, the patient could not be weaned from cardiopulmonary bypass and he died .
Necropsy .Examination of the left ventricle disclosed suhendocardial reperfusion hemorrhage, distributed circumferentially from apex to base .Serial gross examination of the excised extramural coronary arteries revealed severe diffuse coronary disease, involving nearly every segment of the left main, left anterior descending .left circumflex and right coronary arteries .Histologic examination of the coronary arteries confirmed the gross findings of severe coronary atherosclerosis distributed diffusely along the entire left anterior descending artery-with lumen cross-sectional area narrowing varying from 80 .7% to 96 .7%(Fig .2, top right ; Fig. 3) .There were no signs of extensive disruption or dissection of the plaque or underlying wall .
Quantitative angiogr1phy .Post-hoc quantitative angiographic analysis (Fib.2, top left) of the left anterior descending artery (before angioplasty) disclosed that the apparently nonstenotic reference segment measured 3 .77mm in diameter and 11 .15tom e in cross-sectional area.Quantitative analysis of the site of maximal stenosis, evaluated in the left anterior oblique projection (Fig .III), disclosed a lumen diameter of 0,75 mm, lumen cross-sectional area of 0 .44III and 93% stenosis .With use of the least foreshortened projection, in this case the lateral view (Fig .In; Fig .2, top left), the site of most severe stenosis before coronary angioplasty measured 1 .52mm in diameter and 1 .82name in lumen cross-sectional area ; percent stenosis for this site before angioplasty was 84% .

Patient 2
A 70-year old man with a 3-year history of stable angina pectoris developed a crescendo angina pattern during the 2 months before hospital admission .On the day of admission No other evidence of an acute or remote myocardial infarction was found .Histologic examination of the coronary arteries disclosed severe diffuse three-vessel coronary artery narrowing that contrasted with the angiographic findings suggesting focal obstruction .Histologic examination of the right coronary artery in particular revealed lumen crosssectional area narrowing that varied from 86 .5% to 97.7% (Fig. 2, middle right ; Fig. 4).
Quantitative angiography .Post-hoe quantitative angiographic analysis of the right coronary artery before angoplasty disclosed that the apparently noastenotic reference segment measured 2.6 mm in diameter and 5 .3mm2 in cross-sectional area.The site of most severe stenosis before coronary angioplasty measured 0.78 mm in diameter and 0 .47mm 2 in cross-sectional area; calculated percent stenosis for the site of most severe stenosis before angioplasty was 91% (Fig .2. middle left) .
Patient 3 A 37-year old man presented to another hospital after the sudden onset of substernal chest pain that had begun 6 days earlier while he was driving a truck .An electrocardiogram .eco:ded on admissjcn to the caargency room revealed only with the reactive hyperemic response .These investigators (12) concluded that the most important factor responsible for this documented discrepancy was "the usually diffuse nature of coronary atherosclerosis ."Even when the coronary segment of interest is relatively short, elimination of a truly normal baseline by submaximal narrowing constitute:, a serious liability .The left main coronary artery, for example, is the shortest of the major extramural coronary arteries ; however, when it is narrowed to an equivalent degree over its entire length, identification of left main coronary artery disease may be missed (9,35) .Beau et al .(36) demonstrated that the development of mild to moderate narrowing in the segments directly adjacent to sites of stenosis treated by coronary angioplasty may lead one to underestimate the degree of restenusis apparent upon repeat angiography .
Identification of diffuse narrowing .The angiographic and necropsy findings in the present three patients document that previous concerns regarding coronary narrowing that remains occult by virtue of diffuse distribution extend to the evaluation of patients being considered for coronary angio-plasty .The angiographic finding of focal narrowing has long been regarded as the essential criterion for coronary angto .plasty (37 .38) .Because of the limited number of patients studied at necropsy shortly after angiuplasty .the prevalence of diffuse disease masquerading as a nearly normal baseline remains undetermined.However .the present three cases suggest that such anatomy may be more common than has been previously recognized .
Algorithms developed for quantitative angiography diminish to some extent the liabilities posed by diffusely diseased vessels .Harrison et al .(Ill .for example.found that mensirement of minimal lumen diameter improved the correlation between lesion assessment by coronary angiog : raphy and reactive hyperemic response (r = 0 .731 .Beats et al .(36) showed that use of the interpolated reference diameter permitted more accurate assessment of restenosis after angioplasty .As our three cases illustrate, however, unless the absolute lumen dimensions can be interpreted to distinguish nonobstructed.diminutive arteries from arteries that are diffusely and severely narrowed • the extent of corunar: disease in patients undergoing coronary angioplasty may nevertheless be underestimated.
In the present three cases, the extent to which diagnostic angiography failed to reflect severe, diffuse coronary artery disease may have contributed to each patient's death.Not only was coronary narrowing more diffuse and more severe than anticipated in the artery selected for angioplasty .but also. the other extramural arteries were similarly affected .As a result, the ischemic burden at the time of balloon inflation was underestimated in these three patients .Had each been recognized to have diffuse three-vessel coronary artery narrowing, it is questionable-at least in the elective cases of Patients I and 2-that angioplasty would have been recommended .
How may the assessment of patients such as those described in this report be improved?:Devious investigations (39) .including those of Harrison et al .(11) and While el al .(12) cited earlier, have indicated that complementary use of physiologic tests, such as assessment of coronary do,, reserve .may serve to distinguish diffusely diseased arteries from nonobstructed vessels of lesser caliber .In certain patients being considered for coronary angioplasty .however, such as Patients I and 2 in the present report, the issue is not whether the lesions recognized by angiography are capable of causing myocardial ischemia .but rather to what extent the vessels are in fact compromised .Gould (39) previously suggested that the ideal instrument for assessment of stenosis severity should allow composite analysis of both relative and absolute percent .-.arrowing .as well as lesion length, absolute diameter of the normal artery and blood viscosity .Certain new imaging techniques .such as intravascular ultrasound (4d-43), which permit most of these measurements, may ultimately provide mole accurate definition of the diffusely diseased artery .
Potential limitations .Because pathologic examination was employed as the reference standard in this report.1269 certain limitations of this methodology must be acknowlectgcd .First. the coronary arteries from Patients I and 2 were examined at necropsy without pressure distension .Woiinsky and Glagov 1441 previously demonstrated a corresponding iacreasc in the radius of rabbit aortas examined at necropsy as intraluminal distending pressure is increased from 5 to 80 mm Hg .Second Siegel et al. (45) previously demonstrated that in nondistended vessels with moderate to severe atherosclerosis .histologic processing leads to a reduction in total arterial area without a corresponding rednclion in the area of the residual arterial lumen .Thus the former may lead to overestimation of lumen narrowing .
whereas the latter may lead to its underestimation .It is difficult to determine with certainty the extent to which each of these factors affected pathologic analyses in the present three cases .However. because the issue in the present report concerned the distribution rather than the absolute dimensions of coronary artery narrowing, the validity of the observations reported here appears to be preserved .

Figure 1 .
Figure 1.Representative frames from the cineangiograms .a, Patient I .Selective left coronary artery injection in lateral (LAT) view .b, Same patient .Cranially angutated left anterior oblique (LAO) projection.Arrows indicate the site of focal narrowing .e, Patient 2 .Selective angiographic study of the right coronary artery in a right anterior oblique projection demonstrated a tubular stenosis, d, Patient 3 .Selective right coronary artery injection in a right anterior oblique projection before acute occlusion.