- Email: [email protected]
Determinants of angiographically silent stenoses in patients with coronary artery disease
using IVUS; therefore, the true frequency of multiple plaque ruptures and their impact on patient outcomes remains unknown. The diagnosis of thrombus by IVUS is presumptive. Multiple plaque ruptures are often angiographically silent (especially when present in the same artery), occur in larger arteries with more diffuse disease (longer lesions and more positive remodeling), and are more often associated with thrombus formation. 1. Davies MJ, Thomas A. Thrombosis and acute coronary-artery lesions in
sudden cardiac ischemic death. N Engl J Med 1984;310:1137–1140. 2. Farb A, Burke AP, Tang AL, Liang TY, Mannan P, Smialek J, Virmani R.
Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation 1996;93:1354 –1363. 3. Moriuchi M, Saito S, Takaiwa Y, Honye J, Fukui T, Horiuchi K, Takayama T, Yajima J, Shimizu T, Chiku M, Komaki K, Tanigawa N, Ozawa Y, Kanmatsuse K. Assessment of plaque rupture by intravascular ultrasound. Heart Vessels 1997; Suppl 12:178 –181. 4. Nagai T, Luo H, Atar S, Lepor NE, Fishbein MC, Siegel RJ. Intravascular ultrasound imaging of ruptured atherosclerotic plaques in coronary arteries. Am J Cardiol 1999;83:135–137. 5. von Birgelen C, Klinkhart W, Mintz GS, Papatheodorou A, Herrmann J, Baumgart D, Haude M, Wieneke H, Ge J, Erbel R. Plaque distribution and vascular remodeling of ruptured and nonruptured coronary plaques in the same vessel: an intravascular ultrasound study in vivo. J Am Coll Cardiol 2001;37: 1864 –1870. 6. Rioufol G, Finet G, Ginon I, Andre-Fouet X, Rossi R, Vialle E, Desjoyaux E, Convert G, Huret JF, Tabib A. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study. Circulation 2002;106:804 –808. 7. Lansky AJ, Popma JJ. Qualitative and quantitative angiography. In: Topol EJ,
ed. Textbook of Interventional Cardiology. Philadelphia: W. B. Saunders, 1999: 725–747. 8. Ambrose JA, Winters SL, Arora RR, Eng A, Riccio A, Gorlin R, Fuster V. Angiographic evolution of coronary artery morphology in unstable angina. J Am Coll Cardiol 1986;7:472–478. 9. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, Pinto FJ, Rosenfield K, Siegel RJ, Tuzcu EM, Yock PG. ACC Clinical Expert Consensus Document on standards for the acquisition, measurement and reporting of intravascular ultrasound studies: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents (Committee to Develop a Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies [IVUS]). J Am Coll Cardiol 2001;37:1478 –1492. 10. Chemarin-Alibelli MJ, Pieraggi MT, Elbaz M, Carrie D, Fourcade J, Puel J, Tobis J. Identification of coronary thrombus after myocardial infarction by intracoronary ultrasound compared with histology of tissues sampled by atherectomy. Am J Cardiol 1996;77:344 –349. 11. Kearney P, Erbel R, Rupprecht HJ, Ge J, Koch L, Voigtlander T, Stahr P, Gorge G, Meyer J. Differences in the morphology of unstable and stable coronary lesions and their impact on the mechanisms of angioplasty. An in vivo study with intravascular ultrasound. Eur Heart J 1996;17:721–730. 12. Levin DC, Fallon JT. Significance of the angiographic morphology of localized coronary stenoses: histopathologic correlations. Circulation 1982;66: 316 –320. 13. Asakura M, Ueda Y, Yamaguchi O, Adachi T, Hirayama A, Hori M, Kodama K. Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction: an angioscopic study. J Am Coll Cardiol 2001;37:1284 –1288. 14. Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfesh M, O’Neill WW. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2000;343:915–922. 15. Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes. Circulation 2000;101:598 –603. 16. Yamagishi M, Terashima M, Awano K, Kijima M, Nakatani S, Daikoku S, Ito K, Yasumura Y, Miyatake K. Morphology of vulnerable coronary plaque: insights from follow-up of patients examined by intravascular ultrasound before an acute coronary syndrome. J Am Coll Cardiol 2000;35:106 –111. 17. Nakamura M, Nishikawa H, Mukai S, Setsuda M, Nakajima K, Tamada H, Suzuki H, Ohnishi T, Kakuta Y, Nakano T, Yeung AC. Impact of coronary artery remodeling on clinical presentation of coronary artery disease: an intravascular ultrasound study. J Am Coll Cardiol 2001;37:63–69.
Determinants of Angiographically Silent Stenoses in Patients With Coronary Artery Disease Akiko Maehara, MD, Gary S. Mintz, MD, Anh B. Bui, MD, Marco T. Castagna, MD, Augusto D. Pichard, MD, Lowell F. Satler, MD, Ron Waksman, MD, William O. Suddath, MD, Kenneth M. Kent, MD, PhD, and Neil J. Weissman, MD pproximately 20% of all patients who undergo coronary angiography for suspected coronary A heart disease have normal angiograms or only mild disease (angiographic diameter stenosis [DS] ⬍50%).1 Although the long-term prognosis is better for patients with normal angiograms or mild disease than those with critical stenoses, almost half of the patients with normal angiograms or mild disease continue to have anginal chest pain.1–3 Explanations for continued symptoms have included coronary artery spasm, syndrome X, noncoronary etiologies, and stenoses that are significant but angiographically unrecFrom the Cardiovascular Research Institute, Washington Hospital Center, Washington, DC; and the Cardiovascular Research Foundation, New York, New York. Dr. Weissman’s address is: Cardiovascular Research Institute, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010. E-mail: [email protected]. Manuscript received December 5, 2002; revised manuscript received and accepted February 20, 2003. ©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 June 1, 2003
ognized.4 – 6 This report examines the frequency and predictors of angiographically occult lesions in an interventional patient population. •••
We evaluated the clinical, angiographic, and intravascular ultrasound (IVUS) findings of 436 arteries in 404 consecutive patients who underwent planned percutaneous coronary intervention (PCI) to determine the frequency of angiographically occult lesions. All lesions with an IVUS minimum lumen cross-sectional area (CSA) ⬍4 mm2 in a native artery with a mean reference lumen CSA ⬎7 mm2 (those equivalent to a 3-mm angiographic reference lumen diameter) were identified; quantitative angiography was used to separate lesions into those with a DS ⬍50% versus those with a DS ⱖ50%. Left main lesions and previously stented lesions were excluded. Patient demographics were confirmed by hospital chart review. Coronary risk factors included diabetes 0002-9149/03/$–see front matter doi:10.1016/S0002-9149(03)00324-2
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TABLE 1 Clinical Characteristics of 404 Patients Age (yrs) Men/women Unstable angina pectoris Acute or recent myocardial infarction* Stable angina pectoris No symptoms Systemic hypertension Diabetes mellitus Hypercholesterolemia† Current smoker Previous percutaneous intervention Previous bypass surgery Previous myocardial infarction Left ventricular ejection fraction ⱕ30% Multivessel coronary disease‡
63 ⫾ 11 292/112 229 (57%) 96 (24%) 38 (9%) 41 (10%) 262 (65%) 87 (22%) 233 (58%) 77 (19%) 99 (25%) 44 (11%) 80 (20%) 22 (5%) 173 (43%)
*Duration between onset of myocardial infarction and treatment was 7 ⫾ 8 days. † Hypercholesterolemia defined as the need for medical treatment or ⬎240 mg/dl. ‡ Multivessel disease considered as an angiographic diameter stenosis ⬎50% in ⱖ2 epicardial vessels.
FIGURE 1. A histogram of a normal distribution of angiographic DS in the present population of 500 lesions with an IVUS minimum lumen area <4.0 mm2 is shown. Shadowed areas indicate the lesions with an angiographic DS <50%.
mellitus (diet-controlled, oral agent, and insulin-treated), hypertension (medically treated only), hypercholesterolemia (medically treated or a measured serum cholesterol ⬎240 mg/dl), and being a current smoker. Unstable angina was defined as new onset severe angina, accelerated angina, or angina at rest. Recent myocardial infarction occurred less than 6 weeks before the study. Previous myocardial infarction, coronary artery bypass grafting, PCIs, and left ventricular function were identified. All angiograms were analyzed using an automated edge-detection algorithm (CAAS II; Pie Medical, Maas1336 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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tricht, The Netherlands) by an independent angiographic core laboratory (ABB) that was blinded to the IVUS findings except for information regarding lesion location. With the outer diameter of the contrast-filled catheter used for calibration, minimum lumen diameter in diastole was measured from multiple projections acquired after the administration of intracoronary nitroglycerin; results from the “worst” view were recorded. Reference diameter was the average of user-defined 5-mm-long angiographically normal segments proximal and distal to the lesion, but between any major side branches. The DS was calculated as reference diameter minus minimum lumen diameter times 100 divided by reference lumen diameter. The target lesion location was designated as ostial, proximal, mid, or distal. An ostial lesion began within 3 mm of a major coronary artery ostium. Lesion length was measured as the distance from the proximal shoulder to the distal shoulder in the projection with the least amount of foreshortening. An angiographically occult lesion was defined as DS ⬍50%. All IVUS studies were performed before any intervention and after the intracoronary administration of nitroglycerin 200 g using a commercially available IVUS system (Boston Scientific Corp./SciMed, Maple Grove, Minnesota). The IVUS catheter was advanced distally and retrograde imaging was performed back to the aorto-ostial junction at an automatic pullback speed of 0.5 mm/s. The lesion site was the image slice with the smallest lumen CSA. The reference segments were the most normal looking cross sections within 10 mm proximal and distal to the lesion but before any side branch. Multiple lesions in the same artery had ⬎5- mm-long reference segments between them; if not, they were considered to be part of 1 long lesion. Using planimetry software (TapeMeasure; INDEC Systems Inc., Capitola, California), lesion and reference segments were analyzed as: external elastic membrane (EEM) CSA (millimeters squared); lumen CSA (millimeters squared); plaque and media ( P&M ⫽ EEM ⫺ lumen ) CSA (millimeters squared); plaque burden percentage (P&M CSA ⫻ 100 ⫼ by EEM CSA); minimum and maximum lumen diameters (millimeters); lumen ratio (minimum lumen diameter ⫼ maximum lumen diameter); minimum and maximum P&M thickness (millimeters); and eccentricity index (maximum P&M thickness ⫼ minimum P&M thickness). Lesion length (millimeters) was calculated as the length between the proximal and distal reference sites. The remodeling index was calculated as the lesion divided by the mean reference EEM CSA. The area stenosis was calculated as mean reference lumen CSA minus minimum lumen CSA divided by mean reference lumen CSA. Calcium was identified as an echo brighter than the adventitia with acoustic shadowing. The maximum arc of calcium (degrees) within the lesion was measured with an electronic protractor centered on the lumen. Also, calcium length (millimeters) within the lesion was measured. Statistical analysis was performed using SAS software (SAS Institute, Cary, North Carolina). ContinJUNE 1, 2003
patients with diabetes mellitus or in patients with stable angina or no symptoms. Also lesions with an angiographic DS ⬍50% tended to be more frequent in women and in patients with hypertension. Table 3 lists the univariate IVUS predictors of a lesion with an angiographic DS ⬍50%. These lesions were in smaller arteries (smaller reference EEM and lumen CSA), had larger lumens with a more elliptical shape (smaller lumen ratio), had less plaque burden, and had shorter lengths. Plaque characteristics such as calcium and eccentricity were not important. Stenoses with an angiographic DS ⬍50% were found more often in patients with multiple lesions in a same artery and in the right coronary artery (52%) than those found in the left anterior descending (31%) or left circumflex artery (17%). The relation between the IVUS minimum lumen CSA and an angiographic FIGURE 2. This right coronary artery had 3 lesions (A, C, and E) with an IVUS miniDS ⬎50% is shown in Figure 3. mum lumen CSA <4.0 mm2. Only the distal lesion (E) had an angiographic DS >50%. The variables entered into a multivariate logistic regression model to determine the independent predictors uous variables are presented as mean ⫾ 1 SD, and of a lesion with an angiographic DS ⬍50% were: (1) categoric variables are presented as frequencies. patient demographics (age, gender, diabetes mellitus, The relation between 2 continuous variables was hypertension, hypercholesterolemia, current smoker, evaluated using simple regression analysis. Multi- symptoms of myocardial infarction or unstable angina variate logistic regression analysis was used to de- versus stable angina or no symptoms, left ventricular termine the independent predictors of an angio- ejection fraction ⱕ30%); (2) lesion demographics (mulgraphic DS ⬍50%. All univariate predictors (p tiple vessel disease; restenotic versus de novo lesion; ⱕ0.25) were entered into the multivariate model, ostial, proximal, mid, or distal lesion location; right verand stepwise selection was used to determine inde- sus left coronary artery location; multiple lesions in a same artery); (3) quantitative angiographic measurependent predictors. Overall, there were 500 lesions with an IVUS ments (reference diameter and lesion length); (4) IVUS minimum lumen CSA ⬍4.0 mm2 in 436 arteries of lesion measurements (EEM CSA, lumen CSA, plaque 404 patients. Patient demographics are listed in Table burden, minimum and maximum lumen diameters, lu1. Lesion location was left anterior descending in 168, men ratio, minimum and maximum P&M thickness, left circumflex in 120, and right coronary in 212. In plaque eccentricity, lesion length, arcs and length of addition, 37 lesions were ostial, 239 were proximal, calcium); and (5) IVUS mean reference measurements 166 were mid-vessel, and 58 were distal. Fifty-six (EEM CSA, lumen CSA, plaque burden). The independent predictors of angiographically occult stenoses were lesions (11%) were restenotic. Figure 1 shows the frequency distribution of the multiple stenoses in a same artery, right coronary artery angiographic DS in these 500 lesions; 28% (140 of location, a larger lesion maximum lumen diameter, a 500) had an angiographic DS ⬍50%. The correlation smaller lesion plaque burden, and a smaller reference between the angiographic and IVUS minimum lumen lumen CSA (Table 4). diameter was r ⫽ 0.391 (p ⬍0.0001); the correlation ••• between the angiographic DS and the IVUS area stenosis was r ⫽ 0.494 (p ⬍0.0001). Figure 2 demonThe main findings of the present investigation strates an example of a patient with multiple lesions in were that (1) 28% of stenoses with an IVUS minithe right coronary artery; each have an IVUS mini- mum lumen area <4.0 mm2 had an angiographic DS mum lumen area ⬍4.0 mm2, and only the distal lesion <50% and (2) that there were distinct predictors of these stenoses (multiple lesions in the same artery, had an angiographic DS ⱖ50%. Table 2 lists the univariate clinical and angiographic right coronary artery location, a larger maximum predictors of a lesion with an angiographic DS ⬍50%. lumen diameter, smaller reference lumen area and These lesions were shorter and found more frequently in lesion plaque burden, and diabetes). BRIEF REPORTS
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TABLE 2 Univariate Angiographic Findings and Clinical Demographics Predictive of an Angiographic Diameter Stenosis (DS) ⬍50%
Diabetes mellitus Systemic hypertension Unstable angina or myocardial infarction Women Coronary angiography DS (%) Minimum lumen diameter (mm) Reference diameter (mm) Lesion length (mm)
DS ⬍50% (n ⫽ 140)
DS ⱖ50% (n ⫽ 360)
29% 73% 75% 30%
20% 65% 83% 23%
39 1.8 3.0 11.2
⫾ ⫾ ⫾ ⫾
48 0.3 0.6 4.3
67 1.0 3.1 13.0
⫾ ⫾ ⫾ ⫾
Odds Ratio (95% CI) 1.7 1.5 0.6 1.4
11 0.4 0.6 5.5
(1.1–2.6) (0.9–2.2) (0.4–1.0) (0.9–2.2)
— — 0.82 (0.59–1.15)/1 mm 0.92 (0.88–0.97)/1 mm
p Value 0.03 0.1 0.05 0.12 — — 0.25 0.0006
CI ⫽ confidential interval.
TABLE 3 Univariate Intravascular Ultrasound (IVUS) Predictors of an Angiographic Diameter Stenosis (DS) ⬍50% DS ⬍50% (n ⫽ 140) Mean reference EEM CSA (mm2) Lumen CSA (mm2) Plaque burden (%) Lesion EEM CSA (mm2) Lumen CSA (mm2) Minimum lumen diameter (mm) Maximum lumen diameter (mm) Lumen ratio Plaque burden (%) Eccentricity index Maximum calcium arc (°) Calcium length (mm) Lesion length (mm) Remodeling index Multiple lesions in same artery (%) Right coronary artery (%)
DS ⱖ50% (n ⫽ 360)
15.4 ⫾ 3.1 9.3 ⫾ 1.7 39 ⫾ 9 14.5 2.7 1.6 2.1 0.78 80 7.7 106 6.5 11.0 0.96
16.3 ⫾ 4.1 9.7 ⫾ 2.1 39 ⫾ 9
⫾ 3.9 ⫾ 0.7 ⫾ 0.3 ⫾ 0.4 ⫾ 0.11 ⫾6 ⫾ 11.2 ⫾ 98 ⫾ 6.1 ⫾ 7.0 ⫾ 0.19 41 52
15.7 2.1 1.4 1.8 0.82 86 6.7 116 7.4 13.3 0.98
⫾ 4.7 ⫾ 0.7 ⫾ 0.2 ⫾ 0.4 ⫾ 0.09 ⫾6 ⫾ 12.0 ⫾ 96 ⫾ 7.0 ⫾ 8.6 ⫾ 0.23 18 35
Odds Ratio (95% CI)
p Value
0.94 (0.89–1.0)/1 mm2 0.89 (0.80–0.99)/1 mm2 0.98 (0.79–1.22)/10%
0.03 0.03 0.86
0.94 3.0 13.9 9.6 1.57 4.8 1.00 0.99 0.98 0.96 0.94 3.9 1.7
(0.90–0.99)/1 mm2 (2.3–4.0)/1 mm2 (6.1–31.3)/1 mm (5.4–17.0)/1 mm (1.29–1.91)/0.1 (3.3–7.0)/10% (0.99–1.02)/0.1 (0.99–1.00)/1° (0.95–1.01)/1 mm (0.93–0.99)/1 mm (0.86–1.04)/0.1 (2.1–5.1) (1.1–2.5)
0.02 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 0.45 0.29 0.16 0.004 0.2 ⬍0.0001 0.009
Abbreviation as in Table 2.
TABLE 4 Independent Predictors of an Angiographic Diameter Stenosis (DS) ⬍50% Odds Ratio (95% CI) Multiple lesions in same artery Right coronary artery Lesion maximum lumen diameter Lesion plaque burden Mean reference lumen CSA Diabetes mellitus
2.7 (1.6–4.7) 1.7 (1.1–3.0) 9.5 (3.9–23.0)/1 mm 0.44 (0.27–0.73)/10% 0.75 (0.65–0.87)/1 mm2 1.6 (0.91–2.85)
p Value 0.0003 0.03 ⬍0.0001 0.0001 0.0002 0.1
Abbreviation as in Table 2.
FIGURE 3. Diagram of the frequency of lesions with an angiographic DS more or <50% as a function of IVUS minimum lumen CSA is shown. Lesions with an angiographic DS >50% had larger minimum lumen CSAs. However, even some lesions with relatively small IVUS minimum lumen CSAs had an angiographic DS <50%.
1. Kemp HG, Kronmal RA, Vlietstra RE, Frye RL. Seven year survival of
patients with normal or near normal coronary arteriograms: a CASS registry study. J Am Coll Cardiol 1986;7:479 –483. 2. Proudfit WL, Bruschke VG, Sones FM Jr. Clinical course of patients with
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normal or slightly or moderately abnormal coronary arteriograms: 10-year follow-up of 521 patients. Circulation 1980;62:712–717. 3. Foussas SG, Adamopoulou EN, Kafaltis NA, Fakiolas C, Olympios C, Pisimissis E, Siogas K, Pappas S, Cokkinos DV, Sideris D. Clinical characteristics and follow-up of patients with chest pain and normal coronary arteries. Angiology 1998;49:349 –354. 4. Bertrand ME, LaBlanche JM, Tilmant PY, Thieuleux FA, Delforge MR, Carre AG, Asseman P, Berzin B, Libersa C, Laurent JM. Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography. Circulation 1982;65:1299 –1306. 5. Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA. Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. J Am Coll Cardiol 1995;25:807–814. 6. Thomas AC, Davies MJ, Dilly S, Dilly N, Franc F. Potential errors in the estimation of coronary arterial stenosis from clinical arteriography with reference to the shape of the coronary arterial lumen. Br Heart J 1986;55:129 –139.
JUNE 1, 2003
sudden cardiac ischemic death. N Engl J Med 1984;310:1137–1140. 2. Farb A, Burke AP, Tang AL, Liang TY, Mannan P, Smialek J, Virmani R.
Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation 1996;93:1354 –1363. 3. Moriuchi M, Saito S, Takaiwa Y, Honye J, Fukui T, Horiuchi K, Takayama T, Yajima J, Shimizu T, Chiku M, Komaki K, Tanigawa N, Ozawa Y, Kanmatsuse K. Assessment of plaque rupture by intravascular ultrasound. Heart Vessels 1997; Suppl 12:178 –181. 4. Nagai T, Luo H, Atar S, Lepor NE, Fishbein MC, Siegel RJ. Intravascular ultrasound imaging of ruptured atherosclerotic plaques in coronary arteries. Am J Cardiol 1999;83:135–137. 5. von Birgelen C, Klinkhart W, Mintz GS, Papatheodorou A, Herrmann J, Baumgart D, Haude M, Wieneke H, Ge J, Erbel R. Plaque distribution and vascular remodeling of ruptured and nonruptured coronary plaques in the same vessel: an intravascular ultrasound study in vivo. J Am Coll Cardiol 2001;37: 1864 –1870. 6. Rioufol G, Finet G, Ginon I, Andre-Fouet X, Rossi R, Vialle E, Desjoyaux E, Convert G, Huret JF, Tabib A. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study. Circulation 2002;106:804 –808. 7. Lansky AJ, Popma JJ. Qualitative and quantitative angiography. In: Topol EJ,
ed. Textbook of Interventional Cardiology. Philadelphia: W. B. Saunders, 1999: 725–747. 8. Ambrose JA, Winters SL, Arora RR, Eng A, Riccio A, Gorlin R, Fuster V. Angiographic evolution of coronary artery morphology in unstable angina. J Am Coll Cardiol 1986;7:472–478. 9. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, Pinto FJ, Rosenfield K, Siegel RJ, Tuzcu EM, Yock PG. ACC Clinical Expert Consensus Document on standards for the acquisition, measurement and reporting of intravascular ultrasound studies: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents (Committee to Develop a Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies [IVUS]). J Am Coll Cardiol 2001;37:1478 –1492. 10. Chemarin-Alibelli MJ, Pieraggi MT, Elbaz M, Carrie D, Fourcade J, Puel J, Tobis J. Identification of coronary thrombus after myocardial infarction by intracoronary ultrasound compared with histology of tissues sampled by atherectomy. Am J Cardiol 1996;77:344 –349. 11. Kearney P, Erbel R, Rupprecht HJ, Ge J, Koch L, Voigtlander T, Stahr P, Gorge G, Meyer J. Differences in the morphology of unstable and stable coronary lesions and their impact on the mechanisms of angioplasty. An in vivo study with intravascular ultrasound. Eur Heart J 1996;17:721–730. 12. Levin DC, Fallon JT. Significance of the angiographic morphology of localized coronary stenoses: histopathologic correlations. Circulation 1982;66: 316 –320. 13. Asakura M, Ueda Y, Yamaguchi O, Adachi T, Hirayama A, Hori M, Kodama K. Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction: an angioscopic study. J Am Coll Cardiol 2001;37:1284 –1288. 14. Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfesh M, O’Neill WW. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2000;343:915–922. 15. Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes. Circulation 2000;101:598 –603. 16. Yamagishi M, Terashima M, Awano K, Kijima M, Nakatani S, Daikoku S, Ito K, Yasumura Y, Miyatake K. Morphology of vulnerable coronary plaque: insights from follow-up of patients examined by intravascular ultrasound before an acute coronary syndrome. J Am Coll Cardiol 2000;35:106 –111. 17. Nakamura M, Nishikawa H, Mukai S, Setsuda M, Nakajima K, Tamada H, Suzuki H, Ohnishi T, Kakuta Y, Nakano T, Yeung AC. Impact of coronary artery remodeling on clinical presentation of coronary artery disease: an intravascular ultrasound study. J Am Coll Cardiol 2001;37:63–69.
Determinants of Angiographically Silent Stenoses in Patients With Coronary Artery Disease Akiko Maehara, MD, Gary S. Mintz, MD, Anh B. Bui, MD, Marco T. Castagna, MD, Augusto D. Pichard, MD, Lowell F. Satler, MD, Ron Waksman, MD, William O. Suddath, MD, Kenneth M. Kent, MD, PhD, and Neil J. Weissman, MD pproximately 20% of all patients who undergo coronary angiography for suspected coronary A heart disease have normal angiograms or only mild disease (angiographic diameter stenosis [DS] ⬍50%).1 Although the long-term prognosis is better for patients with normal angiograms or mild disease than those with critical stenoses, almost half of the patients with normal angiograms or mild disease continue to have anginal chest pain.1–3 Explanations for continued symptoms have included coronary artery spasm, syndrome X, noncoronary etiologies, and stenoses that are significant but angiographically unrecFrom the Cardiovascular Research Institute, Washington Hospital Center, Washington, DC; and the Cardiovascular Research Foundation, New York, New York. Dr. Weissman’s address is: Cardiovascular Research Institute, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010. E-mail: [email protected]. Manuscript received December 5, 2002; revised manuscript received and accepted February 20, 2003. ©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 June 1, 2003
ognized.4 – 6 This report examines the frequency and predictors of angiographically occult lesions in an interventional patient population. •••
We evaluated the clinical, angiographic, and intravascular ultrasound (IVUS) findings of 436 arteries in 404 consecutive patients who underwent planned percutaneous coronary intervention (PCI) to determine the frequency of angiographically occult lesions. All lesions with an IVUS minimum lumen cross-sectional area (CSA) ⬍4 mm2 in a native artery with a mean reference lumen CSA ⬎7 mm2 (those equivalent to a 3-mm angiographic reference lumen diameter) were identified; quantitative angiography was used to separate lesions into those with a DS ⬍50% versus those with a DS ⱖ50%. Left main lesions and previously stented lesions were excluded. Patient demographics were confirmed by hospital chart review. Coronary risk factors included diabetes 0002-9149/03/$–see front matter doi:10.1016/S0002-9149(03)00324-2
1335
TABLE 1 Clinical Characteristics of 404 Patients Age (yrs) Men/women Unstable angina pectoris Acute or recent myocardial infarction* Stable angina pectoris No symptoms Systemic hypertension Diabetes mellitus Hypercholesterolemia† Current smoker Previous percutaneous intervention Previous bypass surgery Previous myocardial infarction Left ventricular ejection fraction ⱕ30% Multivessel coronary disease‡
63 ⫾ 11 292/112 229 (57%) 96 (24%) 38 (9%) 41 (10%) 262 (65%) 87 (22%) 233 (58%) 77 (19%) 99 (25%) 44 (11%) 80 (20%) 22 (5%) 173 (43%)
*Duration between onset of myocardial infarction and treatment was 7 ⫾ 8 days. † Hypercholesterolemia defined as the need for medical treatment or ⬎240 mg/dl. ‡ Multivessel disease considered as an angiographic diameter stenosis ⬎50% in ⱖ2 epicardial vessels.
FIGURE 1. A histogram of a normal distribution of angiographic DS in the present population of 500 lesions with an IVUS minimum lumen area <4.0 mm2 is shown. Shadowed areas indicate the lesions with an angiographic DS <50%.
mellitus (diet-controlled, oral agent, and insulin-treated), hypertension (medically treated only), hypercholesterolemia (medically treated or a measured serum cholesterol ⬎240 mg/dl), and being a current smoker. Unstable angina was defined as new onset severe angina, accelerated angina, or angina at rest. Recent myocardial infarction occurred less than 6 weeks before the study. Previous myocardial infarction, coronary artery bypass grafting, PCIs, and left ventricular function were identified. All angiograms were analyzed using an automated edge-detection algorithm (CAAS II; Pie Medical, Maas1336 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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tricht, The Netherlands) by an independent angiographic core laboratory (ABB) that was blinded to the IVUS findings except for information regarding lesion location. With the outer diameter of the contrast-filled catheter used for calibration, minimum lumen diameter in diastole was measured from multiple projections acquired after the administration of intracoronary nitroglycerin; results from the “worst” view were recorded. Reference diameter was the average of user-defined 5-mm-long angiographically normal segments proximal and distal to the lesion, but between any major side branches. The DS was calculated as reference diameter minus minimum lumen diameter times 100 divided by reference lumen diameter. The target lesion location was designated as ostial, proximal, mid, or distal. An ostial lesion began within 3 mm of a major coronary artery ostium. Lesion length was measured as the distance from the proximal shoulder to the distal shoulder in the projection with the least amount of foreshortening. An angiographically occult lesion was defined as DS ⬍50%. All IVUS studies were performed before any intervention and after the intracoronary administration of nitroglycerin 200 g using a commercially available IVUS system (Boston Scientific Corp./SciMed, Maple Grove, Minnesota). The IVUS catheter was advanced distally and retrograde imaging was performed back to the aorto-ostial junction at an automatic pullback speed of 0.5 mm/s. The lesion site was the image slice with the smallest lumen CSA. The reference segments were the most normal looking cross sections within 10 mm proximal and distal to the lesion but before any side branch. Multiple lesions in the same artery had ⬎5- mm-long reference segments between them; if not, they were considered to be part of 1 long lesion. Using planimetry software (TapeMeasure; INDEC Systems Inc., Capitola, California), lesion and reference segments were analyzed as: external elastic membrane (EEM) CSA (millimeters squared); lumen CSA (millimeters squared); plaque and media ( P&M ⫽ EEM ⫺ lumen ) CSA (millimeters squared); plaque burden percentage (P&M CSA ⫻ 100 ⫼ by EEM CSA); minimum and maximum lumen diameters (millimeters); lumen ratio (minimum lumen diameter ⫼ maximum lumen diameter); minimum and maximum P&M thickness (millimeters); and eccentricity index (maximum P&M thickness ⫼ minimum P&M thickness). Lesion length (millimeters) was calculated as the length between the proximal and distal reference sites. The remodeling index was calculated as the lesion divided by the mean reference EEM CSA. The area stenosis was calculated as mean reference lumen CSA minus minimum lumen CSA divided by mean reference lumen CSA. Calcium was identified as an echo brighter than the adventitia with acoustic shadowing. The maximum arc of calcium (degrees) within the lesion was measured with an electronic protractor centered on the lumen. Also, calcium length (millimeters) within the lesion was measured. Statistical analysis was performed using SAS software (SAS Institute, Cary, North Carolina). ContinJUNE 1, 2003
patients with diabetes mellitus or in patients with stable angina or no symptoms. Also lesions with an angiographic DS ⬍50% tended to be more frequent in women and in patients with hypertension. Table 3 lists the univariate IVUS predictors of a lesion with an angiographic DS ⬍50%. These lesions were in smaller arteries (smaller reference EEM and lumen CSA), had larger lumens with a more elliptical shape (smaller lumen ratio), had less plaque burden, and had shorter lengths. Plaque characteristics such as calcium and eccentricity were not important. Stenoses with an angiographic DS ⬍50% were found more often in patients with multiple lesions in a same artery and in the right coronary artery (52%) than those found in the left anterior descending (31%) or left circumflex artery (17%). The relation between the IVUS minimum lumen CSA and an angiographic FIGURE 2. This right coronary artery had 3 lesions (A, C, and E) with an IVUS miniDS ⬎50% is shown in Figure 3. mum lumen CSA <4.0 mm2. Only the distal lesion (E) had an angiographic DS >50%. The variables entered into a multivariate logistic regression model to determine the independent predictors uous variables are presented as mean ⫾ 1 SD, and of a lesion with an angiographic DS ⬍50% were: (1) categoric variables are presented as frequencies. patient demographics (age, gender, diabetes mellitus, The relation between 2 continuous variables was hypertension, hypercholesterolemia, current smoker, evaluated using simple regression analysis. Multi- symptoms of myocardial infarction or unstable angina variate logistic regression analysis was used to de- versus stable angina or no symptoms, left ventricular termine the independent predictors of an angio- ejection fraction ⱕ30%); (2) lesion demographics (mulgraphic DS ⬍50%. All univariate predictors (p tiple vessel disease; restenotic versus de novo lesion; ⱕ0.25) were entered into the multivariate model, ostial, proximal, mid, or distal lesion location; right verand stepwise selection was used to determine inde- sus left coronary artery location; multiple lesions in a same artery); (3) quantitative angiographic measurependent predictors. Overall, there were 500 lesions with an IVUS ments (reference diameter and lesion length); (4) IVUS minimum lumen CSA ⬍4.0 mm2 in 436 arteries of lesion measurements (EEM CSA, lumen CSA, plaque 404 patients. Patient demographics are listed in Table burden, minimum and maximum lumen diameters, lu1. Lesion location was left anterior descending in 168, men ratio, minimum and maximum P&M thickness, left circumflex in 120, and right coronary in 212. In plaque eccentricity, lesion length, arcs and length of addition, 37 lesions were ostial, 239 were proximal, calcium); and (5) IVUS mean reference measurements 166 were mid-vessel, and 58 were distal. Fifty-six (EEM CSA, lumen CSA, plaque burden). The independent predictors of angiographically occult stenoses were lesions (11%) were restenotic. Figure 1 shows the frequency distribution of the multiple stenoses in a same artery, right coronary artery angiographic DS in these 500 lesions; 28% (140 of location, a larger lesion maximum lumen diameter, a 500) had an angiographic DS ⬍50%. The correlation smaller lesion plaque burden, and a smaller reference between the angiographic and IVUS minimum lumen lumen CSA (Table 4). diameter was r ⫽ 0.391 (p ⬍0.0001); the correlation ••• between the angiographic DS and the IVUS area stenosis was r ⫽ 0.494 (p ⬍0.0001). Figure 2 demonThe main findings of the present investigation strates an example of a patient with multiple lesions in were that (1) 28% of stenoses with an IVUS minithe right coronary artery; each have an IVUS mini- mum lumen area <4.0 mm2 had an angiographic DS mum lumen area ⬍4.0 mm2, and only the distal lesion <50% and (2) that there were distinct predictors of these stenoses (multiple lesions in the same artery, had an angiographic DS ⱖ50%. Table 2 lists the univariate clinical and angiographic right coronary artery location, a larger maximum predictors of a lesion with an angiographic DS ⬍50%. lumen diameter, smaller reference lumen area and These lesions were shorter and found more frequently in lesion plaque burden, and diabetes). BRIEF REPORTS
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TABLE 2 Univariate Angiographic Findings and Clinical Demographics Predictive of an Angiographic Diameter Stenosis (DS) ⬍50%
Diabetes mellitus Systemic hypertension Unstable angina or myocardial infarction Women Coronary angiography DS (%) Minimum lumen diameter (mm) Reference diameter (mm) Lesion length (mm)
DS ⬍50% (n ⫽ 140)
DS ⱖ50% (n ⫽ 360)
29% 73% 75% 30%
20% 65% 83% 23%
39 1.8 3.0 11.2
⫾ ⫾ ⫾ ⫾
48 0.3 0.6 4.3
67 1.0 3.1 13.0
⫾ ⫾ ⫾ ⫾
Odds Ratio (95% CI) 1.7 1.5 0.6 1.4
11 0.4 0.6 5.5
(1.1–2.6) (0.9–2.2) (0.4–1.0) (0.9–2.2)
— — 0.82 (0.59–1.15)/1 mm 0.92 (0.88–0.97)/1 mm
p Value 0.03 0.1 0.05 0.12 — — 0.25 0.0006
CI ⫽ confidential interval.
TABLE 3 Univariate Intravascular Ultrasound (IVUS) Predictors of an Angiographic Diameter Stenosis (DS) ⬍50% DS ⬍50% (n ⫽ 140) Mean reference EEM CSA (mm2) Lumen CSA (mm2) Plaque burden (%) Lesion EEM CSA (mm2) Lumen CSA (mm2) Minimum lumen diameter (mm) Maximum lumen diameter (mm) Lumen ratio Plaque burden (%) Eccentricity index Maximum calcium arc (°) Calcium length (mm) Lesion length (mm) Remodeling index Multiple lesions in same artery (%) Right coronary artery (%)
DS ⱖ50% (n ⫽ 360)
15.4 ⫾ 3.1 9.3 ⫾ 1.7 39 ⫾ 9 14.5 2.7 1.6 2.1 0.78 80 7.7 106 6.5 11.0 0.96
16.3 ⫾ 4.1 9.7 ⫾ 2.1 39 ⫾ 9
⫾ 3.9 ⫾ 0.7 ⫾ 0.3 ⫾ 0.4 ⫾ 0.11 ⫾6 ⫾ 11.2 ⫾ 98 ⫾ 6.1 ⫾ 7.0 ⫾ 0.19 41 52
15.7 2.1 1.4 1.8 0.82 86 6.7 116 7.4 13.3 0.98
⫾ 4.7 ⫾ 0.7 ⫾ 0.2 ⫾ 0.4 ⫾ 0.09 ⫾6 ⫾ 12.0 ⫾ 96 ⫾ 7.0 ⫾ 8.6 ⫾ 0.23 18 35
Odds Ratio (95% CI)
p Value
0.94 (0.89–1.0)/1 mm2 0.89 (0.80–0.99)/1 mm2 0.98 (0.79–1.22)/10%
0.03 0.03 0.86
0.94 3.0 13.9 9.6 1.57 4.8 1.00 0.99 0.98 0.96 0.94 3.9 1.7
(0.90–0.99)/1 mm2 (2.3–4.0)/1 mm2 (6.1–31.3)/1 mm (5.4–17.0)/1 mm (1.29–1.91)/0.1 (3.3–7.0)/10% (0.99–1.02)/0.1 (0.99–1.00)/1° (0.95–1.01)/1 mm (0.93–0.99)/1 mm (0.86–1.04)/0.1 (2.1–5.1) (1.1–2.5)
0.02 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 0.45 0.29 0.16 0.004 0.2 ⬍0.0001 0.009
Abbreviation as in Table 2.
TABLE 4 Independent Predictors of an Angiographic Diameter Stenosis (DS) ⬍50% Odds Ratio (95% CI) Multiple lesions in same artery Right coronary artery Lesion maximum lumen diameter Lesion plaque burden Mean reference lumen CSA Diabetes mellitus
2.7 (1.6–4.7) 1.7 (1.1–3.0) 9.5 (3.9–23.0)/1 mm 0.44 (0.27–0.73)/10% 0.75 (0.65–0.87)/1 mm2 1.6 (0.91–2.85)
p Value 0.0003 0.03 ⬍0.0001 0.0001 0.0002 0.1
Abbreviation as in Table 2.
FIGURE 3. Diagram of the frequency of lesions with an angiographic DS more or <50% as a function of IVUS minimum lumen CSA is shown. Lesions with an angiographic DS >50% had larger minimum lumen CSAs. However, even some lesions with relatively small IVUS minimum lumen CSAs had an angiographic DS <50%.
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