- Email: [email protected]
or Peripheral Artery Disease
Prevalence of Coronary Heart Disease in Patients With Aortic Aneurysm and/or Peripheral Artery Disease Kenichi Hirose, MDa, Taishiro Chikamori, MDa,*, Satoshi Hida, MDa, Hirokazu Tanaka, MDa, Yuko Igarashi, MDa, Yoshiko Watanabe, MDb, Nobusato Koizumi, MDb, Satoshi Kawaguchi, MDb, Yukio Obitsu, MDb, Hiroshi Shigematsu, MDb, and Akira Yamashina, MDa Although the presence of coronary heart disease (CHD) was the major determinant of perioperative mortality and long-term prognosis in patients with aortic aneurysm (AA) and peripheral artery disease (PAD), the prevalence and severity of CHD in patients with individual vascular diseases was unknown. Adenosine triphosphate–loading myocardial single-photon emission computed tomography therefore was performed in 788 patients with vascular diseases of the aorta and peripheral arteries, with AA in 500, PAD localized in the lower-limb arteries in 183, and combined AA and PAD in 105. Patients with known CHD, such as those with previous myocardial infarction or revascularization procedures, were excluded. Myocardial single-photon emission computed tomography was analyzed using a 20-segment model, and summed stress scores and summed difference scores were calculated. Stress-induced myocardial ischemia was defined as a summed difference score >2. The presence of myocardial ischemia was highest in patients with combined PAD and AA (73%), followed by PAD (55%; p ⴝ 0.005), and the lowest in patients with AA (37%; p <0.0001). Summed stress score was also the highest in patients with combined PAD and AA (11.6 ⴞ 9.9), followed by PAD (7.8 ⴞ 8.8; p <0.0001), and the lowest in patients with AA (4.0 ⴞ 6.2; p <0.0001 for both). Similarly, summed difference score was the highest in patients with combined PAD and AA (6.4 ⴞ 6.1), followed by PAD (4.4 ⴞ 5.7; p ⴝ 0.001) and AA (2.3 ⴞ 4.0; p <0.0001 for both). In conclusion, the prevalence of CHD in patients with PAD was >50%, and although myocardial ischemia was observed in only 1⁄3 of patients with AA, its prevalence not only doubled, but also indicated extensive myocardial ischemia when combined with PAD. Thus, cardiac evaluation was particularly important in patients with combined AA and PAD. © 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009;103:1215–1220) Although the most important determinant of perioperative mortality and long-term prognosis in patients with vascular diseases was associated coronary heart disease (CHD),1– 4 the prevalence of CHD in patients with different vascular diseases, such as aortic aneurysm (AA) and peripheral artery disease (PAD), has not been fully elucidated. The present study evaluated the prevalence and severity of CHD using pharmacologic stress single-photon emission computed tomography (SPECT) in patients with various types of vascular diseases. Methods We studied 788 consecutive patients with AA and/or PAD undergoing diagnostic workup for CHD using stress SPECT from January 2002 to August 2007. There were 654 men and 134 women aged 71 ⫾ 9 years (range 25 to 90 years). Patients with previous myocardial infarction, angiographically documented CHD, or previous revascularization Departments of aCardiology and bVascular Surgery, Tokyo Medical University, Tokyo, Japan. Manuscript received October 15, 2008; revised manuscript received and accepted January 9, 2009. *Corresponding author: Tel: ⫹81-3-3342-6111; fax: ⫹81-3-53816652. E-mail address: [email protected] (T. Chikamori). 0002-9149/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.01.033
were excluded. Hypertension was found in 603 patients; hypercholesterolemia, in 152; and diabetes mellitus, in 153. AA was defined as a partially or totally dilated aortic wall with diameter expansion ⱖ45 mm in the ascending aorta and aortic arch, ⱖ40 mm in the descending aorta, and ⱖ30 mm in the abdominal aorta irrespective of cause.5,6 PAD was defined as both ankle– brachial pressure index ⬍0.9 and significant diameter narrowing in the iliac or femoral arteries documented angiographically.7 Carotid or subclavian artery stenosis cases were not included in this study. AA was found in 500 patients, with thoracic AA in 200, abdominal AA in 228, and chronic aortic dissection in 72, whereas PAD was observed in 183 patients, and the combination of AA and PAD was found in 105 patients (Figure 1). Ankle– brachial systolic blood pressure index was obtained for all patients clinically suspected of having PAD or with an angiogram showing peripheral arterial narrowing during evaluation of AA. The ankle– brachial pressure index was measured using a volume plethysmographic apparatus (FORM/ABI; Colin Co. Ltd., Komaki, Japan) with the patient in a supine position after resting in the same position for ⱖ5 minutes, as described previously.8 All recordings were performed while patients were using their regular medication, but not receiving intravenous drugs, at the time of the study. www.AJConline.org
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The American Journal of Cardiology (www.AJConline.org) Table 1 Clinical characteristics of 788 patients
Figure 1. Three types of vascular diseases are represented in this diagram to show a vascular disease of combined AA and PAD. Thoracic AA and chronic aortic dissection with an aortic dilatation are not shown in this schema.
Figure 2. Assignment of a myocardial segment for scoring images from SPECT. Each image from SPECT was divided into 20 segments and visually evaluated using a 5-grade scale of 0 (normal), 1 (slight decrease in uptake), 2 (moderate decrease in uptake), 3 (severe decrease in uptake), or 4 (absence of radioactive uptake).
Pharmacologic stress SPECT was performed ⱖ15 hours after cessation of cardioactive medications. For the stress, adenosine triphosphate disodium was used in all patients. We injected adenosine triphosphate disodium 0.16 mg/kg over 5 minutes, and 2 minutes before the end of infusion, thallium-201 111 MBq was injected intravenously. Image acquisition was started 10 minutes after stress application. Delayed images were obtained 4 hours later. Data were acquired using a 2-detector camera (Prism 2000XP; Picker Int., Cleveland, Ohio, or E.CAM Signature; Siemens AG, Erlangen, Germany) using a low-energy high-resolution parallel multihole collimator. Single-photon emission computed tomographic images were reconstructed from data using a data processor (Odyssey VP; Picker Int., or e.soft; Siemens AG) combined with a Butterworth filter (order 8; cutoff frequency 0.25) and a ramp filter, without attenuation or scatter correction. Each single-photon emission computed tomographic image was divided into 20 segments and visually evaluated by 2 cardiologists blinded to clinical information using a 5-grade scale (Figure 2).9 Totals of the scores for all segments during stress and at rest were designated the summed stress score and summed rest score, respectively. Summed stress score minus summed rest score defined the summed difference score. Abnormal results from SPECT were defined as summed stress score ⱖ4 and/or summed difference score ⱖ2, and stress-induced myocardial ischemia, as summed difference score ⱖ2.10 –12 Disagreements in image interpretation were resolved by consensus. Indications for coronary angiography were decided by the attending physicians based on clinical risk profiles of
Age (yrs) Men/women Coronary risk factors Hypertension Hypercholesterolemia Diabetes mellitus History of angina Ankle–brachial index (n ⫽ 428)
AA (n ⫽ 500)
PAD (n ⫽ 183)
71 ⫾ 9 400/100
70 ⫾ 9 163/20
389 (78%)* 45 (29%) 57 (11%)† 61 (12%)‡ 1.39 ⫾ 0.30‡
127 (69%)* 68 (37%) 76 (42%)† 43 (24%)‡ 0.53 ⫾ 0.15‡
AA ⫹ PAD (n ⫽ 105) 71 ⫾ 9 91/14 87 (83%)* 39 (37%) 20 (19%)† 28 (27%)‡ 0.68 ⫾ 0.19‡
Hypercholesterolemia was defined as serum total cholesterol ⱖ220 mg/dl or low-density lipoprotein cholesterol ⱖ140 mg/dl or both. Hypertension was defined as systolic blood pressure ⱖ140 mm Hg and/or diastolic blood pressure ⱖ90 mm Hg. Obesity was defined as body mass index ⱖ25 kg/m2. * p ⬍0.05, PAD versus combined PAD and AA or AA. † p ⫽ 0.001, AA versus combined PAD and AA or PAD. ‡ p ⬍0.05, combined PAD and AA versus PAD versus AA.
patients, results of noninvasive tests, and the patient’s preference. All patients who underwent coronary angiography were admitted to the Department of Cardiology, where thorough history taking, physical examination, and blood tests were performed. Multidirection coronary angiography was performed according to Judkins’ method. Degree of coronary artery stenosis was visually rated using calipers, and stenosis was deemed significant when ⱖ75% diameter narrowing was noted.13 For all patients who underwent cardiac catheterization, treatment strategy was discussed in the presence of the primary physicians, nuclear cardiologists, interventional cardiologists, and cardiovascular surgeons. Results were presented as mean ⫾ 1 SD. Student’s t test or Mann-Whitney U test was used to compare the means of continuous variables, and categorical variables were analyzed using chi-square test. Analysis of variance was performed for comparisons among ⱖ3 groups, followed by Bonferroni’s post hoc test. Univariate analysis was conducted using the logistic regression method, and stepwise multivariate analysis was conducted using the multiple logistic regression method. A p value ⬍0.05 was regarded as denoting a statistically significant difference. Computations were performed using the SPSS-PC⫹ computer program (version 11.0; SPSS Inc., Chicago, Illinois). Results Of 788 patients, only 132 (17%) had a history of angina pectoris. Age, gender, and prevalence of hypercholesterolemia were similar in patients with AA, PAD, and combined AA and PAD (Table 1). The incidence of diabetes mellitus was higher in patients with PAD than in those with AA or combined AA and PAD, whereas the prevalence of hypertension was higher in patients with AA and combined AA and PAD than those with PAD alone. Ankle– brachial index was highest in patients with AA (140 patients), followed by those with combined AA and PAD, and the lowest in patients with PAD.
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Figure 5. Numbers of patients who underwent coronary angiography (CAG) and coronary revascularization (Revasc). Half the patients in the combined group (56 patients; 54%) and 1⁄3 of the PAD group (63 patients; 34%) underwent CAG, whereas only 1/5 of the AA group (101 patients; 20%) required CAG (p ⬍0.05 using analysis of variance). The proportion of patients who underwent coronary revascularization was the highest in patients with combined AA and PAD. Figure 3. The prevalence of abnormal single-photon emission computed tomographic findings and stress-induced myocardial ischemia in patients with individual vascular diseases.
Table 2 Clinical characteristics of 220 patients who underwent coronary angiography
Age (yrs) Men/women Coronary risk factors Hypertension Hypercholesterolemia Diabetes mellitus Smoking Chronic kidney disease Obesity Angina pectoris Perfusion image Summed stress scores Summed rest scores Summed difference scores
Figure 4. Summed stress and difference scores assessed using myocardial perfusion imaging in patients with individual vascular diseases.
The presence of abnormal single-photon emission computed tomographic results was highest in patients with combined AA and PAD, followed by those with PAD, and lowest in patients with AA (Figure 3). Similarly, the prevalence of stress-induced myocardial ischemia was highest in patients with combined PAD and AA, followed by PAD, and lowest in those with AA (Figure 3). We assessed the extent and severity of stress-induced myocardial perfusion abnormalities using SPECT with a 20-segment model. Summed stress score was highest in patients with combined PAD and AA, followed by PAD, and lowest in patients with AA (11.6 ⫾ 9.9 vs 7.7 ⫾ 8.8 vs 4.0 ⫾ 6.2, respectively; p ⬍0.0001 for all comparisons; Figure 4). Also, a moderate to severe perfusion abnormality, defined as summed stress score ⱖ9,10 –12 was observed in 51% of patients with combined AA and PAD, 35% of those with PAD (p ⫽ 0.005), and 19% of those with AA (p ⬍0.0001 for both). Similarly, summed difference score was highest in patients with combined PAD and AA, fol-
AA (n ⫽ 101)
PAD (n ⫽ 63)
AA ⫹ PAD (n ⫽ 56)
70 ⫾ 9 85/16
68 ⫾ 8 57/6
71 ⫾ 9 49/7
81 (79%) 38 (37%) 13 (13%)* 50 (50%)† 57 (56%) 30 (30%) 22 (22%)
50 (79%) 32 (51%) 33 (53%)* 52 (83%)† 44 (70%)† 13 (21%) 24 (38%)
81 (79%) 38 (37%) 13 (13%)* 36 (64%) 22 (39%)† 8 (14%) 18 (32%)
9.1 ⫾ 7.6‡ 3.6 ⫾ 5.3 5.5 ⫾ 5.2‡
12.9 ⫾ 8.8‡ 5.0 ⫾ 5.3 7.9 ⫾ 6.4‡
16.1 ⫾ 9.0‡ 6.9 ⫾ 6.2 9.2 ⫾ 5.5‡
Chronic kidney disease was defined as estimated glomerular filtration rate ⬍60 ml/min/1.73 m2. * p ⬍0.05, combined PAD and AA or AA versus PAD. † p ⬍0.05, combined PAD and AA versus PAD or PAD versus AA. ‡ p ⬍0.05, combined PAD and AA or PAD versus AA.
Figure 6. Incidences of 1-, 2-, and 3-vessel disease (VD) in 220 patients who underwent coronary angiography. In patients with AA and those with PAD, 29% and 51% of patients had multivessel disease, whereas in patients with combined AA and PAD, incidences of significant coronary artery disease and multivessel disease were 82% and 66%, respectively.
lowed by those with PAD (6.4 ⫾ 6.1 vs 4.4 ⫾ 5.7; p ⫽ 0.001), and lowest in patients with AA (4.4 ⫾ 5.7 vs 2.3 ⫾ 4.0; p ⬍0.0001; Figure 4).
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Table 3 Predictors for multivessel disease using the Cox proportional hazard model Univariate Analysis
Age ⱖ65 yrs Men Hypertension Hypercholesterolemia Diabetes mellitus Smoking Obesity Chronic kidney disease ABI ⬍0.9 Combined AA and PAD SSS ⱖ9 SDS ⱖ8
Multivariate Analysis
Cox HR (95% CI)
p Value
Cox HR (95% CI)
p Value
3.0 (1.5–5.9) 2.5 (1.1–6.0) 1.2 (0.6–2.4) 2.1 (1.2–3.6) 3.0 (1.6–5.7) 2.0 (1.2–3.6) 0.8 (0.4–1.5) 0.8 (0.5–1.3) 3.3 (1.9–5.7) 3.2 (1.7–6.1) 9.2 (4.7–18.1) 4.1 (2.3–7.2)
0.002 0.03 0.61 0.008 0.001 0.01 0.53 0.36 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001
7.2 (3.0–17.4) 2.9 (1.0–8.9)
⬍0.0001 0.06
2.2 (1.1–4.4) 2.7 (1.2–6.4) 1.6 (0.7–3.3)
0.03 0.02 0.24
1.1 (0.4–2.5) 2.8 (1.0–7.6) 9.4 (3.7–24.1) 1.3 (0.6–3.1)
0.97 0.04 ⬍0.0001 0.54
ABI ⫽ ankle– brachial pressure index; CI ⫽ confidence interval; HR ⫽ hazard ratio; SSS ⫽ summed stress score; SDS ⫽ summed difference score.
Based on clinical symptoms and electrocardiographic and scintigraphic findings, coronary angiography was performed in 220 of 788 patients (28%), and subsequent coronary revascularization was undertaken in 93 patients (12%). Of 788 patients, 428 (54%) underwent surgical treatment for AA and/or PAD. The proportion of patients undergoing coronary angiography and revascularization in each group is shown in Figure 5, and clinical characteristics are listed in Table 2. Prevalences of diabetes mellitus and chronic kidney disease and the rate of cigarette smoking were highest in patients with PAD. Coronary angiography showed 1-vessel disease in 51 patients, 2-vessel disease in 60, and 3-vessel disease in 38; the remaining 71 patients had insignificant lesions. A significant correlation (r ⫽ 0.48, p ⬍0.001) was found between the summed difference score and extent of CHD, whereas 21% of patients with a summed difference score ⱖ2 had insignificant coronary lesions. Incidences of 1-, 2-, and 3-vessel disease in each group are shown in Figure 6. In patients with AA alone and those with PAD alone, 29% and 51% of patients had multivessel disease, respectively. However, in patients with combined AA and PAD, incidences of significant coronary artery disease and multivessel disease were 82% and 66%, respectively (Figure 6). In detecting multivessel disease, multiple logistic regression analysis was performed using clinical and scintigraphic variables. This showed that summed stress score ⱖ9, advanced age, combined AA and PAD, diabetes mellitus, and hypercholesterolemia were independent predictors of multivessel disease (Table 3). Discussion The present study evaluated the prevalence and extent of stress-induced myocardial ischemia assessed using myocardial perfusion imaging, an established noninvasive marker for CHD,10 –12,14,15 in 788 consecutive patients with AA, PAD, or both. Although patients with documented CHD, such as those with previous myocardial infarction or revascularization procedures, were not included in this population, the prevalence of CHD in patients with PAD was ⬎50%, higher than the 37% observed in patients with AA only. However, the prevalence of CHD almost doubled
from 37% to 73% in patients with combined AA with PAD. In addition, the extent and severity of myocardial ischemia assessed using the summed different score were highest in patients with combined PAD and AA, followed by those with PAD, and lowest in patients with AA. Furthermore, most patients with combined AA and PAD underwent coronary angiography, and multivessel disease, a high-risk subset of CHD, was found in 66% of patients. Multivariate analysis also showed that the presence of combined vascular diseases and moderate to severe perfusion abnormalities were independent predictors of multivessel disease (Table 3). Taking into consideration that the most important determinant of perioperative mortality and long-term survival in patients with vascular diseases was associated CHD,1– 4 cardiac evaluation was particularly important in patients with combined AA and PAD because of the high prevalence of extensive CHD. Many previous studies reported remarkably high incidences of CHD in patients with other vascular diseases.1,3,16–18 Using coronary angiography in patients with abdominal AA, Kaskas and Kieffer1 reported a prevalence of 43% in 794 patients, and Kioka et al16 showed an incidence of 46% in 94 patients. Quigley et al17 reported a lower incidence of 33% in 102 such patients using both angiography and thallium myocardial imaging. Results of our study showing a CHD prevalence in patients with AA of 37% were similar to the latter report of Quigley et al,17 presumably because the method applied to detect CHD was different from that used in previous reports: physiologic assessment versus anatomic evaluation.9 –11,14,15 In patients with PAD, Hertzer et al3 reported a prevalence of 57% in 381 patients, and Bhatt et al18 showed an incidence of 45% in 8,273 patients using coronary angiography. The prevalence of 55% in our study was intermediate between those observations. Although previous reports focused on the prevalence of CHD in patients with vascular diseases, the present study had an advantage owing to the availability of myocardial perfusion imaging in assessing the extent and severity of stress-induced perfusion abnormalities and myocardial ischemia. Again, the greatest extent of myocardial ischemia was observed in patients with combined AA and PAD. Evaluation for the extent and severity of perfu-
Coronary Artery Disease/CHD in Vascular Diseases
sion abnormalities is of utmost importance because coronary revascularization may improve the prognosis of patients with moderate to severe perfusion abnormalities.12,19,20 Conversely, in patients with less severe abnormalities using SPECT, intensive medical management may be appropriate.19,20 Thus, patients with combined AA and PAD may be advised to undergo myocardial SPECT to determine whether they have moderate to severe perfusion abnormalities, for which coronary angiography is considered indicated.15 Although the mentioned studies evaluated various forms of vascular diseases in different populations, our study consisted of a series of consecutive patients in a single center, facilitating comparison of the prevalence of associated CHD in patients with various vascular diseases. Furthermore, results of this study focused on the combination of AA and PAD, first reported by Ochsner and DeCamp21 in 1960. Several studies have been reported sporadically since then. Galland et al22 and Barba et al23 reported the prevalence of AA in patients with PAD as 13% to 14%, which agreed with results of our study. Sugawara et al24 reported that the most common cause of late death after successful surgery for patients with combined AA and PAD was acute myocardial infarction, with an incidence significantly higher than that observed in patients with abdominal AA alone. Although the precise etiologic mechanisms producing stenosis in peripheral arteries in patients with AA or causing dilation of the aorta in those with PAD were unknown, patients with both an aneurysm and stenosis in the aortoarterial system may be regarded as being at an advanced stage of atherosclerosis.4,25,26 The present study required not only anatomic, but also physiologic criteria for the diagnosis of PAD regardless of the presence or absence of combined AA. The ankle– brachial pressure index therefore significantly decreased in patients with PAD alone and combined vascular diseases. Considering the significant association of CHD, particularly with combined AA and PAD, one should measure both brachial and ankle blood pressure to calculate the ankle– brachial pressure index when diagnosis of AA is made. When an anatomic diagnosis of abdominal AA was made on the basis of a transverse section of computed tomographic image or ultrasound, it was often difficult to detect a stenotic lesion at the distal site of an aneurysm.27,28 Thus, measuring ankle– brachial pressure index will avoid this diagnostic pitfall in the detection of PAD in patients with an AA and also contribute to better detection of the associated CHD. The present study had several limitations common to any study relying on retrospective data collection. In particular, not all patients underwent invasive coronary angiography for the reasons mentioned. Although stress myocardial SPECT often showed false-positive findings caused by attenuation artifacts, this situation was similar among the 3 groups of patients with vascular diseases. Moreover, the extent and severity of CHD in patients with AA, PAD, and combined vascular diseases, noninvasively assessed in all patients using myocardial perfusion imaging, were consistent with those observed in selected patients using invasive coronary angiography. Thus, the significant association of combined AA and PAD with extensive CHD shown in this study seemed reasonable and needed to be kept in mind when evaluating patients with vascular diseases.
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Acknowledgment: The authors thank Prof. J. Patrick Barron, PhD (ABD), of Tokyo Medical University International Medical Communications Center for review of the English manuscript. 1. Koskas F, Kieffer E. Long-term survival after elective repair of infrarenal abdominal aortic aneurysm: results of a prospective multicentric study. Association for Academic Research in Vascular Surgery (AURC). Ann Vasc Surg 1997;11:473– 481. 2. Fleisher LA, Eagle KA, Shaffer T, Anderson GF. Perioperative- and long-term mortality rates after major vascular surgery: the relationship to preoperative testing in the Medicare population. Anesth Analg 1999;89:849 – 855. 3. Hertzer NR, Beven EG, Young JR, O’Hara PJ, Ruschhaupt WF III, Graor RA, Dewolfe VG, Maljovec LC. Coronary artery disease in peripheral vascular patients: a classification of 1000 coronary angiograms and results of surgical management. Ann Surg 1984;199:223– 233. 4. Welten GM, Schouten O, Hoeks SE, Chonchol M, Vidakovic R, van Domburg RT, Bax JJ, van Sambeek MR, Poldermans D. Long-term prognosis of patients with peripheral arterial disease: a comparison in patients with coronary artery disease. J Am Coll Cardiol 2008;51: 1588 –1596. 5. Johnston KW, Rutherford RB, Tilson MD, Shah DM, Hollier L, Stanley JC. Suggested standards for reporting on arterial aneurysms: Subcommittee on Reporting Standards for Arterial Aneurysms, Ad Hoc Committee on Reporting Standards, Society for Vascular Surgery and North American Chapter, International Society for Cardiovascular Surgery. J Vasc Surg 1991;13:452– 458. 6. Thompson RW, Geraghty PJ, Lee JK. Abdominal aortic aneurysms: basic mechanisms and clinical implications. Curr Probl Surg 2002; 39:110 –230. 7. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, Bell K, Caporusso J, Durand-Zaleski I, Komori K, et al; TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg 2007; 33(suppl 1):S1–S75. 8. Ouriel K, McDonnell AE, Metz CE, Zarins CK. Critical evaluation of stress testing in the diagnosis of peripheral vascular disease. Surgery 1982;91:686 – 693. 9. Berman DS, Hachamovitch R, Kiat H, Cohen I, Cabico JA, Wang FP, Friedman JD, Germano G, Van Train K, Diamond GA. Incremental value of prognostic testing in patients with known or suspected ischemic heart disease: a basis for optimal utilization of exercise technetium-99m sestamibi myocardial perfusion singlephoton emission computed tomography. J Am Coll Cardiol 1995; 26:639 – 647. 10. Hachamovitch R, Berman DS, Shaw LJ, Kiat H, Cohen I, Cabico JA, Friedman J, Diamond GA. Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction. Circulation 1998; 97:535–543. 11. Sharir T, Germano G, Kang X, Lewin HC, Miranda R, Cohen I, Agafitei RD, Friedman JD, Berman DS. Prediction of myocardial infarction versus cardiac death by gated myocardial perfusion SPECT: risk stratification by the amount of stress-induced ischemia and the poststress ejection fraction. J Nucl Med 2001;42:831– 837. 12. Nishimura T, Nakajima K, Kusuoka H, Yamashina A, Nishimura S. Prognostic study of risk stratification among Japanese patients with ischemic heart disease using gated myocardial perfusion SPECT: J-ACCESS Study. Eur J Nucl Med Mol Imaging 2008;35:319 –328. 13. Austen WG, Edwards JE, Frye RL, Gensini GG, Gott VL, Griffith LS, McGoon DC, Murphy ML, Roe BB. A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association. Circulation 1975;51:5– 40. 14. Brown KA. Prognostic value of thallium-201 myocardial perfusion imaging. A diagnostic tool comes of age. Circulation 1991;83:363– 381. 15. Beller GA, Zaret BL. Contributions of nuclear cardiology to diagnosis and prognosis of patients with coronary artery disease. Circulation 2000;101:1465–1478.
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16. Kioka Y, Tanabe A, Kotani Y, Yamada N, Nakahama M, Ueda T, Seitou T, Maruyama M. Review of coronary artery disease in patients with infrarenal abdominal aortic aneurysm. Circ J 2002; 66:1110 –1112. 17. Quigley FG, Clark D, Avramovic J. Cardiac assessment with thallium scanning prior to aortic aneurysm repair. Cardiovasc Surg 1999;7: 640 – 644. 18. Bhatt DL, Steg PG, Ohman EM, Hirsch AT, Ikeda Y, Mas JL, Goto S, Liau CS, Richard AJ, Röther J, Wilson PW; REACH Registry Investigators. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 2006;295:180 –189. 19. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 2003;107:2900 – 2906. 20. Shaw LJ, Berman DS, Maron DJ, Mancini J, Hayes SW, Hartigan PM, Weintraub WS, O’Rourke RA, Dada M, Spertus JA, et al. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: Results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) Trial nuclear substudy. Circulation 2008;117:1283–1291. 21. Ochsner A Jr., Decamp PT. Management of abdominal aorticoiliac aneurysms associated with occlusive arterial disease: a study of 31 operative cases. South Med J 1960;53:732–735.
22. Galland RB, Simmons MJ, Torrie EP. Prevalence of abdominal aortic aneurysm in patients with occlusive peripheral vascular disease. Br J Surg 1991;78:1259 –1260. 23. Barba A, Estallo L, Rodríguez L, Baquer M, Vega de Céniga M. Detection of abdominal aortic aneurysm in patients with peripheral artery disease. Eur J Vasc Endovasc Surg 2005;30:504 –508. 24. Sugawara Y, Takagi A, Sato O, Miyata T, Koyama H, Kimura H, Shirakawa M, Furuya T, Makuuchi M. Clinical analysis of abdominal aortic aneurysms associated with iliofemoral occlusive disease. Jpn Circ J 1997;61:14 –18. 25. Spring S, van der Loo B, Krieger E, Amann-Vesti BR, Rousson V, Koppensteiner R. Decreased wall shear stress in the common carotid artery of patients with peripheral arterial disease or abdominal aortic aneurysm: relation to blood rheology, vascular risk factors, and intimamedia thickness. J Vasc Surg 2006;43:56 – 63. 26. Kurvers HA, van der Graaf Y, Blankensteijn JD, Visseren FL, Eikelboom BC; SMART Study Group. Screening for asymptomatic internal carotid artery stenosis and aneurysm of the abdominal aorta: comparing the yield between patients with manifest atherosclerosis and patients with risk factors for atherosclerosis only. J Vasc Surg 2003;37: 1226 –1233. 27. Adachi K, Iwasawa T, Ono T. Screening for abdominal aortic aneurysms during a basic medical checkup in residents of a Japanese rural community, Surg Today 2000;30:594 –599. 28. Scott RA, Ashton HA, Kay DN. Abdominal aortic aneurysm in 4237 screened patients: prevalence, development and management over 6 years. Br J Surg 1991;78:1122–1125.
were excluded. Hypertension was found in 603 patients; hypercholesterolemia, in 152; and diabetes mellitus, in 153. AA was defined as a partially or totally dilated aortic wall with diameter expansion ⱖ45 mm in the ascending aorta and aortic arch, ⱖ40 mm in the descending aorta, and ⱖ30 mm in the abdominal aorta irrespective of cause.5,6 PAD was defined as both ankle– brachial pressure index ⬍0.9 and significant diameter narrowing in the iliac or femoral arteries documented angiographically.7 Carotid or subclavian artery stenosis cases were not included in this study. AA was found in 500 patients, with thoracic AA in 200, abdominal AA in 228, and chronic aortic dissection in 72, whereas PAD was observed in 183 patients, and the combination of AA and PAD was found in 105 patients (Figure 1). Ankle– brachial systolic blood pressure index was obtained for all patients clinically suspected of having PAD or with an angiogram showing peripheral arterial narrowing during evaluation of AA. The ankle– brachial pressure index was measured using a volume plethysmographic apparatus (FORM/ABI; Colin Co. Ltd., Komaki, Japan) with the patient in a supine position after resting in the same position for ⱖ5 minutes, as described previously.8 All recordings were performed while patients were using their regular medication, but not receiving intravenous drugs, at the time of the study. www.AJConline.org
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The American Journal of Cardiology (www.AJConline.org) Table 1 Clinical characteristics of 788 patients
Figure 1. Three types of vascular diseases are represented in this diagram to show a vascular disease of combined AA and PAD. Thoracic AA and chronic aortic dissection with an aortic dilatation are not shown in this schema.
Figure 2. Assignment of a myocardial segment for scoring images from SPECT. Each image from SPECT was divided into 20 segments and visually evaluated using a 5-grade scale of 0 (normal), 1 (slight decrease in uptake), 2 (moderate decrease in uptake), 3 (severe decrease in uptake), or 4 (absence of radioactive uptake).
Pharmacologic stress SPECT was performed ⱖ15 hours after cessation of cardioactive medications. For the stress, adenosine triphosphate disodium was used in all patients. We injected adenosine triphosphate disodium 0.16 mg/kg over 5 minutes, and 2 minutes before the end of infusion, thallium-201 111 MBq was injected intravenously. Image acquisition was started 10 minutes after stress application. Delayed images were obtained 4 hours later. Data were acquired using a 2-detector camera (Prism 2000XP; Picker Int., Cleveland, Ohio, or E.CAM Signature; Siemens AG, Erlangen, Germany) using a low-energy high-resolution parallel multihole collimator. Single-photon emission computed tomographic images were reconstructed from data using a data processor (Odyssey VP; Picker Int., or e.soft; Siemens AG) combined with a Butterworth filter (order 8; cutoff frequency 0.25) and a ramp filter, without attenuation or scatter correction. Each single-photon emission computed tomographic image was divided into 20 segments and visually evaluated by 2 cardiologists blinded to clinical information using a 5-grade scale (Figure 2).9 Totals of the scores for all segments during stress and at rest were designated the summed stress score and summed rest score, respectively. Summed stress score minus summed rest score defined the summed difference score. Abnormal results from SPECT were defined as summed stress score ⱖ4 and/or summed difference score ⱖ2, and stress-induced myocardial ischemia, as summed difference score ⱖ2.10 –12 Disagreements in image interpretation were resolved by consensus. Indications for coronary angiography were decided by the attending physicians based on clinical risk profiles of
Age (yrs) Men/women Coronary risk factors Hypertension Hypercholesterolemia Diabetes mellitus History of angina Ankle–brachial index (n ⫽ 428)
AA (n ⫽ 500)
PAD (n ⫽ 183)
71 ⫾ 9 400/100
70 ⫾ 9 163/20
389 (78%)* 45 (29%) 57 (11%)† 61 (12%)‡ 1.39 ⫾ 0.30‡
127 (69%)* 68 (37%) 76 (42%)† 43 (24%)‡ 0.53 ⫾ 0.15‡
AA ⫹ PAD (n ⫽ 105) 71 ⫾ 9 91/14 87 (83%)* 39 (37%) 20 (19%)† 28 (27%)‡ 0.68 ⫾ 0.19‡
Hypercholesterolemia was defined as serum total cholesterol ⱖ220 mg/dl or low-density lipoprotein cholesterol ⱖ140 mg/dl or both. Hypertension was defined as systolic blood pressure ⱖ140 mm Hg and/or diastolic blood pressure ⱖ90 mm Hg. Obesity was defined as body mass index ⱖ25 kg/m2. * p ⬍0.05, PAD versus combined PAD and AA or AA. † p ⫽ 0.001, AA versus combined PAD and AA or PAD. ‡ p ⬍0.05, combined PAD and AA versus PAD versus AA.
patients, results of noninvasive tests, and the patient’s preference. All patients who underwent coronary angiography were admitted to the Department of Cardiology, where thorough history taking, physical examination, and blood tests were performed. Multidirection coronary angiography was performed according to Judkins’ method. Degree of coronary artery stenosis was visually rated using calipers, and stenosis was deemed significant when ⱖ75% diameter narrowing was noted.13 For all patients who underwent cardiac catheterization, treatment strategy was discussed in the presence of the primary physicians, nuclear cardiologists, interventional cardiologists, and cardiovascular surgeons. Results were presented as mean ⫾ 1 SD. Student’s t test or Mann-Whitney U test was used to compare the means of continuous variables, and categorical variables were analyzed using chi-square test. Analysis of variance was performed for comparisons among ⱖ3 groups, followed by Bonferroni’s post hoc test. Univariate analysis was conducted using the logistic regression method, and stepwise multivariate analysis was conducted using the multiple logistic regression method. A p value ⬍0.05 was regarded as denoting a statistically significant difference. Computations were performed using the SPSS-PC⫹ computer program (version 11.0; SPSS Inc., Chicago, Illinois). Results Of 788 patients, only 132 (17%) had a history of angina pectoris. Age, gender, and prevalence of hypercholesterolemia were similar in patients with AA, PAD, and combined AA and PAD (Table 1). The incidence of diabetes mellitus was higher in patients with PAD than in those with AA or combined AA and PAD, whereas the prevalence of hypertension was higher in patients with AA and combined AA and PAD than those with PAD alone. Ankle– brachial index was highest in patients with AA (140 patients), followed by those with combined AA and PAD, and the lowest in patients with PAD.
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Figure 5. Numbers of patients who underwent coronary angiography (CAG) and coronary revascularization (Revasc). Half the patients in the combined group (56 patients; 54%) and 1⁄3 of the PAD group (63 patients; 34%) underwent CAG, whereas only 1/5 of the AA group (101 patients; 20%) required CAG (p ⬍0.05 using analysis of variance). The proportion of patients who underwent coronary revascularization was the highest in patients with combined AA and PAD. Figure 3. The prevalence of abnormal single-photon emission computed tomographic findings and stress-induced myocardial ischemia in patients with individual vascular diseases.
Table 2 Clinical characteristics of 220 patients who underwent coronary angiography
Age (yrs) Men/women Coronary risk factors Hypertension Hypercholesterolemia Diabetes mellitus Smoking Chronic kidney disease Obesity Angina pectoris Perfusion image Summed stress scores Summed rest scores Summed difference scores
Figure 4. Summed stress and difference scores assessed using myocardial perfusion imaging in patients with individual vascular diseases.
The presence of abnormal single-photon emission computed tomographic results was highest in patients with combined AA and PAD, followed by those with PAD, and lowest in patients with AA (Figure 3). Similarly, the prevalence of stress-induced myocardial ischemia was highest in patients with combined PAD and AA, followed by PAD, and lowest in those with AA (Figure 3). We assessed the extent and severity of stress-induced myocardial perfusion abnormalities using SPECT with a 20-segment model. Summed stress score was highest in patients with combined PAD and AA, followed by PAD, and lowest in patients with AA (11.6 ⫾ 9.9 vs 7.7 ⫾ 8.8 vs 4.0 ⫾ 6.2, respectively; p ⬍0.0001 for all comparisons; Figure 4). Also, a moderate to severe perfusion abnormality, defined as summed stress score ⱖ9,10 –12 was observed in 51% of patients with combined AA and PAD, 35% of those with PAD (p ⫽ 0.005), and 19% of those with AA (p ⬍0.0001 for both). Similarly, summed difference score was highest in patients with combined PAD and AA, fol-
AA (n ⫽ 101)
PAD (n ⫽ 63)
AA ⫹ PAD (n ⫽ 56)
70 ⫾ 9 85/16
68 ⫾ 8 57/6
71 ⫾ 9 49/7
81 (79%) 38 (37%) 13 (13%)* 50 (50%)† 57 (56%) 30 (30%) 22 (22%)
50 (79%) 32 (51%) 33 (53%)* 52 (83%)† 44 (70%)† 13 (21%) 24 (38%)
81 (79%) 38 (37%) 13 (13%)* 36 (64%) 22 (39%)† 8 (14%) 18 (32%)
9.1 ⫾ 7.6‡ 3.6 ⫾ 5.3 5.5 ⫾ 5.2‡
12.9 ⫾ 8.8‡ 5.0 ⫾ 5.3 7.9 ⫾ 6.4‡
16.1 ⫾ 9.0‡ 6.9 ⫾ 6.2 9.2 ⫾ 5.5‡
Chronic kidney disease was defined as estimated glomerular filtration rate ⬍60 ml/min/1.73 m2. * p ⬍0.05, combined PAD and AA or AA versus PAD. † p ⬍0.05, combined PAD and AA versus PAD or PAD versus AA. ‡ p ⬍0.05, combined PAD and AA or PAD versus AA.
Figure 6. Incidences of 1-, 2-, and 3-vessel disease (VD) in 220 patients who underwent coronary angiography. In patients with AA and those with PAD, 29% and 51% of patients had multivessel disease, whereas in patients with combined AA and PAD, incidences of significant coronary artery disease and multivessel disease were 82% and 66%, respectively.
lowed by those with PAD (6.4 ⫾ 6.1 vs 4.4 ⫾ 5.7; p ⫽ 0.001), and lowest in patients with AA (4.4 ⫾ 5.7 vs 2.3 ⫾ 4.0; p ⬍0.0001; Figure 4).
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Table 3 Predictors for multivessel disease using the Cox proportional hazard model Univariate Analysis
Age ⱖ65 yrs Men Hypertension Hypercholesterolemia Diabetes mellitus Smoking Obesity Chronic kidney disease ABI ⬍0.9 Combined AA and PAD SSS ⱖ9 SDS ⱖ8
Multivariate Analysis
Cox HR (95% CI)
p Value
Cox HR (95% CI)
p Value
3.0 (1.5–5.9) 2.5 (1.1–6.0) 1.2 (0.6–2.4) 2.1 (1.2–3.6) 3.0 (1.6–5.7) 2.0 (1.2–3.6) 0.8 (0.4–1.5) 0.8 (0.5–1.3) 3.3 (1.9–5.7) 3.2 (1.7–6.1) 9.2 (4.7–18.1) 4.1 (2.3–7.2)
0.002 0.03 0.61 0.008 0.001 0.01 0.53 0.36 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001
7.2 (3.0–17.4) 2.9 (1.0–8.9)
⬍0.0001 0.06
2.2 (1.1–4.4) 2.7 (1.2–6.4) 1.6 (0.7–3.3)
0.03 0.02 0.24
1.1 (0.4–2.5) 2.8 (1.0–7.6) 9.4 (3.7–24.1) 1.3 (0.6–3.1)
0.97 0.04 ⬍0.0001 0.54
ABI ⫽ ankle– brachial pressure index; CI ⫽ confidence interval; HR ⫽ hazard ratio; SSS ⫽ summed stress score; SDS ⫽ summed difference score.
Based on clinical symptoms and electrocardiographic and scintigraphic findings, coronary angiography was performed in 220 of 788 patients (28%), and subsequent coronary revascularization was undertaken in 93 patients (12%). Of 788 patients, 428 (54%) underwent surgical treatment for AA and/or PAD. The proportion of patients undergoing coronary angiography and revascularization in each group is shown in Figure 5, and clinical characteristics are listed in Table 2. Prevalences of diabetes mellitus and chronic kidney disease and the rate of cigarette smoking were highest in patients with PAD. Coronary angiography showed 1-vessel disease in 51 patients, 2-vessel disease in 60, and 3-vessel disease in 38; the remaining 71 patients had insignificant lesions. A significant correlation (r ⫽ 0.48, p ⬍0.001) was found between the summed difference score and extent of CHD, whereas 21% of patients with a summed difference score ⱖ2 had insignificant coronary lesions. Incidences of 1-, 2-, and 3-vessel disease in each group are shown in Figure 6. In patients with AA alone and those with PAD alone, 29% and 51% of patients had multivessel disease, respectively. However, in patients with combined AA and PAD, incidences of significant coronary artery disease and multivessel disease were 82% and 66%, respectively (Figure 6). In detecting multivessel disease, multiple logistic regression analysis was performed using clinical and scintigraphic variables. This showed that summed stress score ⱖ9, advanced age, combined AA and PAD, diabetes mellitus, and hypercholesterolemia were independent predictors of multivessel disease (Table 3). Discussion The present study evaluated the prevalence and extent of stress-induced myocardial ischemia assessed using myocardial perfusion imaging, an established noninvasive marker for CHD,10 –12,14,15 in 788 consecutive patients with AA, PAD, or both. Although patients with documented CHD, such as those with previous myocardial infarction or revascularization procedures, were not included in this population, the prevalence of CHD in patients with PAD was ⬎50%, higher than the 37% observed in patients with AA only. However, the prevalence of CHD almost doubled
from 37% to 73% in patients with combined AA with PAD. In addition, the extent and severity of myocardial ischemia assessed using the summed different score were highest in patients with combined PAD and AA, followed by those with PAD, and lowest in patients with AA. Furthermore, most patients with combined AA and PAD underwent coronary angiography, and multivessel disease, a high-risk subset of CHD, was found in 66% of patients. Multivariate analysis also showed that the presence of combined vascular diseases and moderate to severe perfusion abnormalities were independent predictors of multivessel disease (Table 3). Taking into consideration that the most important determinant of perioperative mortality and long-term survival in patients with vascular diseases was associated CHD,1– 4 cardiac evaluation was particularly important in patients with combined AA and PAD because of the high prevalence of extensive CHD. Many previous studies reported remarkably high incidences of CHD in patients with other vascular diseases.1,3,16–18 Using coronary angiography in patients with abdominal AA, Kaskas and Kieffer1 reported a prevalence of 43% in 794 patients, and Kioka et al16 showed an incidence of 46% in 94 patients. Quigley et al17 reported a lower incidence of 33% in 102 such patients using both angiography and thallium myocardial imaging. Results of our study showing a CHD prevalence in patients with AA of 37% were similar to the latter report of Quigley et al,17 presumably because the method applied to detect CHD was different from that used in previous reports: physiologic assessment versus anatomic evaluation.9 –11,14,15 In patients with PAD, Hertzer et al3 reported a prevalence of 57% in 381 patients, and Bhatt et al18 showed an incidence of 45% in 8,273 patients using coronary angiography. The prevalence of 55% in our study was intermediate between those observations. Although previous reports focused on the prevalence of CHD in patients with vascular diseases, the present study had an advantage owing to the availability of myocardial perfusion imaging in assessing the extent and severity of stress-induced perfusion abnormalities and myocardial ischemia. Again, the greatest extent of myocardial ischemia was observed in patients with combined AA and PAD. Evaluation for the extent and severity of perfu-
Coronary Artery Disease/CHD in Vascular Diseases
sion abnormalities is of utmost importance because coronary revascularization may improve the prognosis of patients with moderate to severe perfusion abnormalities.12,19,20 Conversely, in patients with less severe abnormalities using SPECT, intensive medical management may be appropriate.19,20 Thus, patients with combined AA and PAD may be advised to undergo myocardial SPECT to determine whether they have moderate to severe perfusion abnormalities, for which coronary angiography is considered indicated.15 Although the mentioned studies evaluated various forms of vascular diseases in different populations, our study consisted of a series of consecutive patients in a single center, facilitating comparison of the prevalence of associated CHD in patients with various vascular diseases. Furthermore, results of this study focused on the combination of AA and PAD, first reported by Ochsner and DeCamp21 in 1960. Several studies have been reported sporadically since then. Galland et al22 and Barba et al23 reported the prevalence of AA in patients with PAD as 13% to 14%, which agreed with results of our study. Sugawara et al24 reported that the most common cause of late death after successful surgery for patients with combined AA and PAD was acute myocardial infarction, with an incidence significantly higher than that observed in patients with abdominal AA alone. Although the precise etiologic mechanisms producing stenosis in peripheral arteries in patients with AA or causing dilation of the aorta in those with PAD were unknown, patients with both an aneurysm and stenosis in the aortoarterial system may be regarded as being at an advanced stage of atherosclerosis.4,25,26 The present study required not only anatomic, but also physiologic criteria for the diagnosis of PAD regardless of the presence or absence of combined AA. The ankle– brachial pressure index therefore significantly decreased in patients with PAD alone and combined vascular diseases. Considering the significant association of CHD, particularly with combined AA and PAD, one should measure both brachial and ankle blood pressure to calculate the ankle– brachial pressure index when diagnosis of AA is made. When an anatomic diagnosis of abdominal AA was made on the basis of a transverse section of computed tomographic image or ultrasound, it was often difficult to detect a stenotic lesion at the distal site of an aneurysm.27,28 Thus, measuring ankle– brachial pressure index will avoid this diagnostic pitfall in the detection of PAD in patients with an AA and also contribute to better detection of the associated CHD. The present study had several limitations common to any study relying on retrospective data collection. In particular, not all patients underwent invasive coronary angiography for the reasons mentioned. Although stress myocardial SPECT often showed false-positive findings caused by attenuation artifacts, this situation was similar among the 3 groups of patients with vascular diseases. Moreover, the extent and severity of CHD in patients with AA, PAD, and combined vascular diseases, noninvasively assessed in all patients using myocardial perfusion imaging, were consistent with those observed in selected patients using invasive coronary angiography. Thus, the significant association of combined AA and PAD with extensive CHD shown in this study seemed reasonable and needed to be kept in mind when evaluating patients with vascular diseases.
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