Clin. Cardiol. 14, 20-24 (1991)

Limitations of Coronary Angiography : An Underestimated Problem? D. KATR~TSIS, M . D . , M.WEBB-PEPLOE. M.D., F . R . C . P . Department of Cardiology, St. Thomas's Hospital, London, England

Summary: Angiographic imaging suffers from many limitations which may distort the diagnostic information obtained from coronary arteriograms. Radiographic features limiting precise coronary stenosis measurement are caused by the x-ray source, the image intensifier, and the chemical properties of the cinefilm. Biologic variations are introduced by fluctuations in angiographic contrast concentration and flow- or contrast-dependent coronary dilation. Random errors are also introduced by the selection of the radiographic projection and frame to be analyzed and the digitization of cineangiograms. These limitations and their significance in distorting quantitative information obtained from coronary angiograms are discussed in this review.

Key words: coronary angiography , coronary stenosis quantitation, limitations of

Introduction Because of the limitations inherent in simple visual interpretation of coronary angiograms, several methods enabling a more precise and objective quantitation of the luminal dimensions have been developed. Simple measurement with calipers, optic scale devices and digital calipers, computer-assisted manual edge t r a ~ i n g , ~ videodensitometric e ~ a l u a t i o n ,and ~ . ~edge detection com-

Address for reprints:

Dr. D. Katritsis Department of Cardiological Sciences St. George's Hospital Medical School Cranmer Terrace London SW17 ORE, England Received: July 10, 1990 Accepted: August 16, 1990

puter programs for quantitation of either digitized cine or digitally acquired angiograrns,"-l0 have all been tried with considerable success. All these techniques can reduce subjectivity and interobserver variability and are now considered essential in our effort to properly quantitate coronary artery stenoses. 1 1 . 1 2 However sophisticated these methods are, they all derive their basic information from angiographic images, thus suffering from all the limitations inherent in this image modality. These limitations and their importance in distorting information obtained from coronary arteriography are discussed in this review.

Radiographic Factors Limiting Precise Stenosis Measurement X-ray travels in such a straight line and is so predictably attenuated in transit through various substances that it has become the standard for precise definition of structural detail in many fields. Indeed, in its industrial application, x-ray detects fatigue cracks a few microns wide in metals. Unfortunately, this degree of precision cannot be achieved with clinical arteriography. Distortions Caused by the X-Ray Source

The photodensity or logarithmic intensity profile of a vessel along a scan line traversing it would appear as illustrated in Figure l . It is clear that the edges of the vessel are not sharply demarcated, but demonstrate a penumbra (edge gradient) or border zone of less radiodensity between the more radiodense central lumen of the artery and the radiolucent area external to the artery.l3.I4This edge unsharpness or penumbra zone is mainly due to two radiographic effects: the progressive decrease in contrast media-depth as the lumen edge is approached from the lumen center (subject unsharpness), and the finite size of the source (focal spot) of the x-ray beams in the imaging system. The large amounts of heat generated in x-ray production prevents the source from being made very small (ideally a point). The larger the focal spot, the more x-

D. Katritsia and M. M. Webb-Peploc: Limitations of coronary angiography

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FIG I Examplc of scan photodcnsitornetry profile of the edge of a contrast-tilled vessel set in a variable density background. Density niay vary as a result of sampling error. background irregularities, or the opacified vessel. The vessel edge may be defined as ( I ) E, thc point at which density first rises above local variations, (2) S, the point of greatest slope in the edge gradient, (3) F, the point at which the theoretical edge function best correlates with the observcd density profile. [Modified from Brown ef ul., Progr Curdiovu.sc Dis 28, 403 (1986), Ref. 13, with kind permission.]

ray sources there are and as a result the larger the size of the penumbra at the edge of the projected image. In addition, Compton scattering and off-focus radiation as well as kilovoltage, vessel size, and contrast medium concentration may affect radiographic contrast and, therefore, may potentially affect the size and shape of edge gradient.I4 Consequently, the edge point must be defined as some function of varying density in the edge profile: either where the image density first arises above the local background (outer border method), or where the rate of change of image density is greatest (first derivative method), or where the theoretical edge density function most closely corresponds with the observed density profile. In Gould’s laboratory, for example, a satisfactory overall correlation between predicted (from their pressure-flow equation) versus measured pressure gradients was obtained only when the arterial border was drawn by visual estimate in the center of this penumbral zone. I 6 Normally, with relatively round cross-section, the border zone constitutes 1015 74 of a coronary artery 3 mm in diameter. l 6 However, at stenoses, particularly as eccentricity increases, this zone may become relatively large. Several other radiographic factors can limit precise stenosis measurement. Other image distortions caused by the x-ray source are beam hardening and quantum mottle, I 3 , l 4 As the beam passes through an object, the x-rays of lower energy are attenuated, thus the mean photon energy of the unattenuated x-rays increases; in other words, the beam hardens. The random statistical variation of low levels of transmitted gamma radiation (i.e., photons) results in focal irregularities in image contrast called quantum mottle (and recognized as graininess in the final image), which may obscure the vessel borders. Increasing the exposure

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increases the number of x-ray photons absorbed, thus decreasing statistical fluctuations in x-ray energy and reducing quantum mottle. In any case, edge resolution is a function of radiation energy, to which there are practical safety limits. The large number of images, up to 4,000, obtained during the 15-30 minutes of a typical coronary angiographic procedure, severely restricts the energy per image available. This limited energy per image determines, on one hand, the flux of x-ray photons to the image intensifier and therefore the noise in the image, and on the other hand, the average kilovolt (kV) level at which the x-rays can be generated and, therefore, among other factors, the contrast detail in the image (Fig. I).’’ Distortion Caused by the Image Intensifier Phenomena such as veiling glare, vignetting, and piticushion distortion are introduced by the image intensifier. l 3 Pincushion distortion results from the convex curvature of the input phosphor vacuum tube and the nonuniform focusing of the electron beam and causes deterioration of images located peripherally in the angiographic film. This can result in a 5 4 % error in direct scaled dimensional estimate^.^ The same effects cause veiling glare (nonuniform brightness) and vignetting (higher brightness in the center than at the edge of the output screen). Other Radiographic Causes of Distortion Divergence of the x-ray beam results in distortion of the image due to selective magnification of objects that are closer to the x-ray source. This results in an error approximating 1.5%of the estimate per centimeter separating the scaling object and the measured object along the x-ray beam axis.I3 The difference in attenuation coefficient between iodinated contrast medium and biologic tissues is not great, so that the usual local variations in background tissue density may alter the apparent location of the opacified lumen edge.13 When the image is recorded on film, the exposure must be such that the image of interest is formed in the linear range of the film characteristic c ~ r v e ,otherwise ~ . ~ ~ the vessel edge may be “burned away” o r “whited out.” This is because the cinefilm exposure-density relation is overall nonlinear, exhibiting an S-shaped transfer function known as the Hurter-Driffield c ~ r v e . ~ . ~ ~ Finally, variations in camera speed, film quality, and film development parameters can affect the ultimate quality of the image.

Limitations Caused by Biologic Variations The angiographic image and the quantitative measurements derived from it are influenced by many biologic

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Clin. Cardiol. Vol. 14, January 1991

variables. One of the most important causes of these tluctuations is the variation in contrast medium concentration,20which is reduced during diastole due to increased blood flow. Border-detecting errors due to incomplete contrast mixture have been particularly encountered with large diameter bypass grafts. 2 1 In addition, pulsatile pressure may contribute to the periodicity of arterial measurements. In canine normal coronary arteries, a 5% variation in diameter of a 3-4 mm epicardial segment has been noted angiographically.20 Substantial tlow-dependent coronary dilatation has been recently shown in humans as even though this response is impaired in the presence of a t h e r o ~ c l e r o s i s . ~ ~ In a recent report,Iy proximal left anterior descending (LAD) diameters, exposed to increased flow, were increased by 6.5% in normal arteries and by 4.6%in coronary artery disease, as measured by a previously validated border-detection method. In another flow-mediated dilation was observed in angiographically normal LAD segments but was markedly impaired in atherosclerotic vessels, probably due to impaired endothelial vasodilator function. 24 Furthermore, the vasodilating effect of the dye and the injection of the contrast per se can be associated with an increase in lumen diameter of up to 5 % .2o During the latter part of all injections, contrast medium filling of myocardial capillaries and small adjacent side branches may cause spurious changes in quantitative measurements. Atherosclerotic coronary arteries, in particular, have a rich network of vasa vasorumZswhich, when filled during a late phase of contrast medium injection, can slightly change the shape of the edge gradient. Furthermore, the use of ionic contrast media has been shown to exert potent dose- and time-dependent vasomotor effects. 26 Adverse effects of conventional contrast media are related to the single-valence cations, such as sodium and meglumine, to an imbalance in the ratio of sodium to calcium ions, to the high osmolality of the solutions, and to their hyperviscosity . Hyperosmolality may cause massive shifting of tissue water into the capillaries and increase the intravascular volume.27Furthermore, intracoronary injection of those media produce direct myocardial depression, followed by adrenergically mediated reflexes. 28 Thus nonionic, isosmotic dye, which can prevent these effects,2y may, theoretically at least, improve the diagnostic accuracy of such methods. It remains to be seen whether early concerns about the increased thrombogenicity of these agents prove to be unduly exaggerated as has been recently shown. 30 Variations in the coronary vasomotor tone are also important when angiography is employed for the assessment of medical interventions and should, ideally, be controlled during such assessment. 27 Finally, motion blurring can result from the movements of coronary arteries which may occasionally achieve a velocity of up to 27 cmls for a short period during the cardiac cycle.31

Limitations Caused by the Selection of the Radiographic Projection and Frame to be Analyzed Even when a vessel segment is well-filled with contrast medium, free of overlapping branches, and intersected by the x-ray beam perpendicular to its centerline, underestimation of the lesion severity can occur because of an inadequate radiographic view. The most common problem is that the cross-sections of many atherosclerotic coronary artery lumens deviate from circular symmetry. Irregular appearing stenoses have been observed with increased frequency both in clinical coronary a n g i ~ g r a m sand ~ ~ by coronary a n g i o ~ c o p yand ~ ~ intracoronary ultrasound imaging.34 Spears et al. l 3 analyzed the potential error incurred when extrapolating lumen cross-sectional area from the apparent diameters in different radiographic projections of an elliptical cross-section. They found that when the ratio of the true major/minor axis is greater than two, one cannot predict within 95% confidence limits that the error in estimating cross-sectional area from two arbitrarily oriented perpendicular views will be less than 20%. As the degree of ellipticity increases or as the angle between the views becomes less than 90°, the maximum potential error likewise increases. The necessity of two perpendicular views for precise coronary quantitation cannot be overstated. However, the probability of overestimating cross-sectional area of a highly elliptical lumen is much greater than that of underestimating the area.20 Spears and Sandor20have therefore suggested that it might be clinically prudent to use the smallest of the diameters noted in estimating percent area stenosis, rather than averaging diameters from multiple views. Another problem is that a thin, sheltlike lesion, may not be appreciated until it is viewed within a few degrees of its profile projection. Virmani et al. 35 described a group of patients succumbing to sudden death who were found to have ostial ridges or shelves which partially obstructed either the right or left coronary arteries. Since these ridges were more likely to occur when a coronary artery arose at an acute angle from the aortic root, it is apparent that these thin shelves cannot be visualized when the proximal segment of the coronary artery is viewed perpendicular to the direction of the x-ray beam. Furthermore, the amount of x-ray absorption is very much dependent on the angiographic projection used, so that the energy per image ideally should be made dependent on the specific absorption in a selected projection in order to achieve the optimum kilovolt levels. The effects of random frame selection relative to the cardiac cycle phase is not important for border-detection measurements, provided that the selected frames are close to the true end-diastolic frame.3hReiber et al. 36 studied 38 angiograms in the end-diastolic frame, the three immediately preceding frames, and the three following frames. No significant differences were noted in the mean difference and the standard deviations of the differences

D . Katritsis and M . M . Webb-Peploc: Limitations of coronary angiography

(variabilities) in the stenotic diameter, percent diameter stenosis. and area of atherosclerotic plaque obtained in the various frames with respect to the end-diastolic frame. Unfortunately, densitometric findings were not discussed in this study.

Variations Secondary to Digitization of Cineangiograms The application of computer-assisted border-detecting algorithms requires information in digital format. Thus cineangiograms are digitized usually into a 5 12 x 5 12 matrix with eight bits (256 grey levels) brightness resolution. This necessary procedure can, however, introduce errors even under ideal conditions. Variability in diameter measurements as a result of digitizing system noise has been reported to be approximately 1 % ,*O but when the diameter of this vessel segment was determined over many consecutive cineframes, a variability of approximately 4 % was noted despite ideal exposure conditions.*O This problem can be overcome by the direct acquisition of radiographic data on digital format.

Future Directions and Conclusion Today, coronary angiography is considered the definitive procedure for determining the presence of ischemic heart disease and subjective or automated interpretation of coronary angiograms the accepted method for the assessment of its severity in everyday clinical practice. Quantifying severity of coronary artery stenosis is critical to clinical decision making, and the development of sophisticated, computer-assisted quantitative techniques has greatly improved our diagnostic accuracy. However, the enthusiasm for these advanced techniques has led to overestimation of their potential, and sometimes overlooks the important limitations of the angiographic procedure. Indeed, many sources of error exist and limit the precision of information derived from coronary angiograms. Such limitations are caused by radiographic factors inherent in our present equipment, biological variations, technical problems with the handling of image data, and random errors in selecting projections and frames for analysis. Despite the impressive progress of coronary angiography the last two decades, cinefilm techniques have not really advanced, except for new film products with faster emulsions and better quality films.4’ Video imaging has recently made rapid progress and may play an important role in the handling and processing of’ image data. Developments such as the application of plumbicon imaging tubes,4i which provide optimal fast imaging with low lag (image smearing of rapidly moving objects), pulsed progressive f l ~ o r o s c o p yallowing ~~ the reduction of radiation to both the doctor and the patient,

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and a recent technique allowing acquisition of video data using 525-line video systems while displaying the image on a 1,023 line video monitor38are promising examples. Digital subtraction angiographic (DSA) techniques have demonstrated significant promise in coronary disease assessment. In our laboratory, DSA is routinely used for performing percutaneous transluminal coronary angioplasty (PTCA), and has greatly facilitated the procedure and the quantitation of the result^.^^.^^ However, it cannot as yet fully replace film-based coronary imaging, since further refinements in the hardware and software of the existing equipment and advances in archival systems are required. Future efforts should be oriented not only toward improved methods of quantitating coronary stenoses using the existing technical background, but also in standardizing our acquisition methods and perfecting the present equipment for radiographic imaging.

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