Documentation of slow coronary flow by the TIMI frame count in patients with coronary ectasia

In summary, our findings suggest that tHcy, together with age and gender, is a strong predictor of the severity of CAD. Thus, tHcy is an independent cardiovascular marker that should be assessed in the evaluation of a patient’s cardiovascular risk profile. 1. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995;274:1049–1057. 2. Seshadri N, Robinson K. Homocysteine, B vitamins, and coronary artery disease. Med Clin North Am 2000;84:215–237. 3. Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med 1998;49:31–62. 4. Tsai JC, Perrella MA, Yoshizumi M, Hsieh CM, Haber E, Schlegel R, Lee ME. Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proc Natl Acad Sci USA 1994;91:6369–6373. 5. Tang L, Mamotte CD, Van Bockxmeer FM, Taylor RR. The effect of homocysteine on DNA synthesis in cultured human vascular smooth muscle. Atherosclerosis 1998;136:169–173. 6. Tawakol A, Omland T, Gerhard M, Wu JT, Creager MA. Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation 1997;95:1119–1121. 7. Rodgers GM, Kane WH. Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 1986;77:1909– 1916. 8. Rodgers GM, Conn MT. Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells. Blood 1990;75:895– 901. 9. Hajjar KA, Mauri L, Jacovina AT, Zhong F, Mirza UA, Padovan JC, Chait BT. Tissue plasminogen activator binding to the annexin II tail domain. Direct modulation by homocysteine. J Biol Chem 1998;273:9987–9993. 10. Fryer RH, Wilson BD, Gubler DB, Fitzgerald LA, Rodgers GM. Homocys-

teine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arterioscler Thromb 1993;13:1327–1333. 11. Alfthan G, Pekkanen J, Jauhiainen M, Pitkaniemi J, Karvonen M, Tuomilehto J, Salonen JT, Ehnholm C. Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis 1994;106:9–19. 12. Chasan-Taber L, Selhub J, Rosenberg IH, Malinow MR, Terry P, Tishler PV, Willett W, Hennekens CH, Stampfer MJ. A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. J Am Coll Nutr 1996;15:136–143. 13. Evans RW, Shaten BJ, Hempel JD, Cutler JA, Kuller LH. Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscler Thromb Vasc Biol 1997;17:1947–1953. 14. Folsom AR, Nieto FJ, McGovern PG, Tsai MY, Malinow MR, Eckfeldt JH, Hess DL, Davis CE. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 1998;98:204–210. 15. Ubbink JB, Hayward Vermaak WJ, Bissbort S. Rapid high-performance liquid chromatographic assay for total homocysteine levels in human serum. J Chromatogr 1991;565:441–446. 16. Egerton W, Silberberg J, Crooks R, Ray C, Xie L, Dudman N. Serial measures of plasma homocyst(e)ine after acute myocardial infarction. Am J Cardiol 1996;77:759–761. 17. Tokgozoglu SL, Alikasifoglu M, Unsal I, Atalar E, Aytemir K, Ozer N, Ovunc K, Usal O, Kes S, Tuncbilek E. Methylene tetrahydrofolate reductase genotype and the risk and extent of coronary artery disease in a population with low plasma folate. Heart 1999;81:518–522. 18. von Eckardstein A, Malinow MR, Upson B, Heinrich J, Schulte H, Schonfeld R, Kohler E, Assmann G. Effects of age, lipoproteins, and hemostatic parameters on the role of homocyst(e)inemia as a cardiovascular risk factor in men. Arterioscler Thromb 1994;14:460–464. 19. Verhoef P, Kok FJ, Kruyssen DA, Schouten EG, Witteman JC, Grobbee DE, Ueland PM, Refsum H. Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis. Arterioscler Thromb Vasc Biol 1997;17:989–995. 20. Chao CL, Tsai HH, Lee CM, Hsu SM, Kao JT, Chien KL, Sung FC, Lee YT. The graded effect of hyperhomocysteinemia on the severity and extent of coronary atherosclerosis. Atherosclerosis 1999;147:379–386.

Documentation of Slow Coronary Flow by the TIMI Frame Count in Patients With Coronary Ectasia Manolis C. Papadakis, MD, Athanassios Manginas, MD, Panayotis Cotileas, MD, Vassilios Demopoulos, MD, Vassilios Voudris, MD, Gregory Pavlides, MD, Stefanos G. Foussas, MD, and Dennis V. Cokkinos, MD

C

oronary artery ectasia (CAE) is characterized by segmental or diffuse dilation of the coronary arteries to ⬎1.5 the diameter of the adjacent segments of the same artery or of different arteries; it has been found in about 5% of coronary arteriograms.1 It coexists in about 80% of cases with obstructive coronary disease.1,2 CAE has been considered to be present with slow coronary flow; however, the only study in which coronary flow velocity was actually measured, even if indirectly, was published in 1978 when Swanton et al3 measured the coronary sinus flow in 2 patients with ectasia. In a recent study, Kruger et al4 found “stigmata” of impaired blood flow, such as “slow flow,” “stasis,” and “milking phenomenon” by subjective evaluation. In Kawasaki’s syndrome, which presents with localized coronary aneurysms, Hamaoka From the 1st Cardiology Department, Onassis Cardiac Surgery Center, Athens; 401st General Army Hospital, Athens; and Tzanio State Hospital, Pireus, Greece. Dr. Manginas’ address is: Onassis Cardiac Surgery Center, 356 Sygrou Avenue, Kallithea, Athens, Greece, 17674. E-mail: [email protected]. Manuscript received May 21, 2001; revised manuscript received and accepted July 2, 2001.

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and coworkers5 measured coronary flow velocity with the Flowire (Endosonics Corporation, California) and found coronary sinus flow to be significantly decreased inside the aneurysm but normal in the adjacent normal segments. In 1996, Gibson et al6 introduced the Thrombolysis In Myocardial Infarction (TIMI) frame count method for measuring coronary flow velocity from coronary arteriograms. This measurement has been significantly correlated with flow velocity measured with the Flowire by several investigators during baseline conditions or hyperemia.7,8 We applied this technique to measurement of the coronary flow velocity in patients with CAE, either coexisting with obstructive coronary artery disease or alone. We retrospectively studied the coronary arteriograms of 173 patients divided into 4 groups: 42 patients with isolated CAE, without co-existing stenotic lesions of ⬎50% (mean age 58.9 ⫾ 11.4 years) (group A); 45 patients with CAE coexisting with significant stenoses (⬎70%) (mean age 61.3 ⫾ 8.2 years) (group B); 56 patients with ⬎70% stenoses but without occlusion or ectasia (mean age 61.4 ⫾ 9.3 years) (group C); and 30 control patients without significant (⬎50% 0002-9149/01/$–see front matter PII S0002-9149(01)01984-1

FIGURE 1. Angiograms of the right coronary artery from a patient with coronary ectasia (a-c) illustrating three representative cine frames and reaching a TIMI frame count of 30. Below (d-f) representative frames from a patient without coronary stenoses or ectasia reaching a TIMI frame count of 18.

TABLE 1 TIMI Frame Count Measurements in Patients With Coronary Artery Ectasia (CAE) (group A), CAE and Significant Stenoses (group B), Isolated Significant Stenoses Without CAE (group C), and Controls (group D), In the Left Anterior Descending, Left Circumflex, and Right Coronary Arteries TIMI Frame Count

Group A n ⫽ 42 Group B n ⫽ 45 Group C n ⫽ 56 Group D n ⫽ 30

Left Anterior Descending*

Left Circumflex

Right Coronary

28.2 ⫾ 10.6 n ⫽ 14 26.2 ⫾ 12.3 n ⫽ 11 20.2 ⫾ 8.9† n ⫽ 30 20.2 ⫾ 1.1† n ⫽ 30

31.6 ⫾ 11 n ⫽ 27 35 ⫾ 7.5 n ⫽ 13 20 ⫾ 9‡ n ⫽ 25 19.6 ⫾ 2.1‡ n ⫽ 30

27.1 ⫾ 11.9 n ⫽ 39 35.9 ⫾ 17.8㛳 n ⫽ 28 21.5 ⫾ 9.8§ n ⫽ 10 20.3 ⫾ 2.1§ n ⫽ 30

*The corrected TIMI frame count is shown for the left anterior descending artery. † p ⬍0.01 versus group A and group B; ‡p ⬍0.001 versus group A and group B; §p ⬍0.01 versus group B; 㛳p ⫽ 0.015 versus group A.

diameter stenoses) obstructive coronary artery disease (mean age 59.0 ⫾ 9.3 years) (group D). The arteries involved and TIMI flow characteristics are listed in Table 1. We found that, using the TIMI frame count method, patients with CAE in the left anterior descending and left circumflex arteries had significantly lower flow velocity than both patients with significant stenoses and control patients; there were no significant differences among these groups. Patients with ectasia coexisting with obstructive disease had the slowest flow in their right coronary arteries. In left anterior

descending and left circumflex arteries with ectasia, however, the presence of stenoses did not further impair flow velocity (Figure 1). The natural course of patients with CAE has been studied by numerous investigators. Most agree that when obstructive disease coexists with ectasia, the prognosis is not different from that of coronary disease alone.1,9,10 The course of patients with isolated ectasia is less well defined. During long-term followup,11 the course is not as benign as that during shorter interval studies.2 The increased incidence of angina and the higher than expected incidence of myocardial infarction may be attributed to the slow coronary flow. We believe that our study is the first to document, in a large number of patients, that CAE is associated with diminished coronary flow velocity. However, even this finding cannot give any insight as to the optimal pharmacologic therapy these patients should receive. Further prospective studies are needed to elucidate the optimal therapeutic approach for patients with this form of atherosclerotic coronary disease. In conclusion, we demonstrated, using the TIMI frame count method, that patients with coronary ectasia have lower coronary flow velocity than both patients with obstructive coronary artery disease and control patients. 1. Swaye PS, Fisher LD, Litwin P, Vignola PA, Judkins MP, Kemp HG, Mudd

GJ, Gosselin AJ. Aneurysmal coronary artery disease. Circulation 1983;67:134– 138. 2. Demopoulos V, Olympios C, Fakiolas C, Pissimissis E, Economides N, Adamopoulou E, Foussas S, Cokkinos DV. The natural history of aneurysmal coronary artery disease. Heart 1997;78:136–141. 3. Swanton RH, Thomas MC, Coltart DJ, Jenkins BS, Webb Peploe MM,

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Williams BT. Coronary artery ectasia—a variant of occlusive arteriosclerosis. Br Heart J 1978;40:393–400. 4. Kruger D, Stierle U, Herrmann G, Simon R, Sheikhzadeh A. Exercise-induced myocardial ischemia in isolated coronary artery ectasias and aneurysms (“dilated coronaropathy”). J Am Coll Cardiol 1999;34:1461–1470. 5. Hamaoka K, Onouchi Z, Kamiya Y, Sakata K. Evaluation of coronary flow velocity dynamics and flow reserve in patients with Kawasaki disease by means of a Doppler guide wire. J Am Coll Cardiol 1998;31:833–840. 6. Gibson CM, Cannon CP, Daley WL, Dodge JT, Alexander B, Marble SJ, Mc Cabe CH, Raymond L, Fortin T, Poole WK, Braunwald E. The TIMI frame count, a quantitative method of assessing coronary artery flow. Circulation 1996;93:879–888. 7. Kern MJ, Moore JA, Aguirre FV, Bach RG, Caracciolo EA, Wolfoi T, Khoury AF, Mechem C, Donohue TJ. Determination of angiographic (TIMI grade) blood

flow by intracoronary Doppler flow velocity during acute myocardial infaction. Circulation 1996;94:1545–1552. 8. Manginas A, Gatzov P, Chasikidis C, Voudris V, Pavlides G, Cokkinos DV. Estimation of coronary flow reserve using the Thrombolysis In Myocardial Infarction (TIMI) frame count method. Am J Cardiol 1999;83:1562–1565. 9. Markis JE, Joffe CD, Cohn PF, Feen DJ, Hermann MV, Corlin R. Clinical significance of coronary arterial ectasia. Am J Cardiol 1976;37:217–222. 10. Farto-e-Abreu P, Mesquita A, Silva JA, Seabra-Gomes R. Coronary artery ectasia: clinical and angiographic characteristics and prognosis. Rev Port Cardiol 1993;12:305–310. 11. Demopoulos V, Dalampiras P, Sifaki M, Olympios C, Foussas S, Cokkinos DV. Isolated coronary artery ectasia does not have a benign long-term prognosis. J Am Coll Cardiol 1999;33(Suppl A):363A (Abstr).

Intravascular Ultrasound Assessment of the Mechanism of Lumen Enlargement During Cutting Balloon Angioplasty Treatment of In-Stent Restenosis Javed M. Ahmed, MRCP, Gary S. Mintz, MD, Marco Castagna, MD, Neil J. Weissman, MD, Augusto D. Pichard, MD, Lowell F. Satler, MD, and Kenneth M. Kent, MD, PhD ecause of its ability to directly visualize coronary arteries in vivo, intravascular ultrasound (IVUS) B has been used to study the mechanism of lumen enlargement with most angioplasty devices whether during the treatment of de novo stenosis1–7 or during the treatment of in-stent restenosis.8 –10 One of these new devices is the cutting balloon, a novel coronary dilation catheter with 3 to 4 microtomes mounted longitudinally on the surface of the balloon. Recently, it has gained favor for the treatment of in-stent restenosis.11,12 The present study uses sequential IVUS imaging before and after cutting balloon angioplasty to determine the mechanism of lumen enlargement during cutting balloon treatment of in-stent restenosis. •••

The study population included 10 patients who had a first episode of in-stent restenosis in a nonostial, native artery lesion that was previously treated with only a single stent. There were 6 men and 4 women (mean age 62 ⫾ 13 years). Lesion location was the left anterior descending artery in 3 patients, the left circumflex artery in 4, and the right coronary artery in 3 patients. Preintervention IVUS was performed (see the following). The cutting balloon (Interventional Technologies, Irvine, California) was then used as previously described with either single or multiple inflations at a maximum inflation pressure of 10 atm.11–15 Afterwards, IVUS imaging was repeated before any addiFrom the Intravascular Ultrasound Imaging and Cardiac Catheterization Laboratories, 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, Washington Hospital Center, 110 Irving St NW, Suite 4B-1, Washington, DC 20010. E-mail: [email protected]. Manuscript received April 17, 2001; revised manuscript received and accepted June 5, 2001.

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tional adjunct percutaneous transluminal coronary angioplasty (PTCA) or stent implantation. All IVUS studies were performed after administration of 200 ␮g of nitroglycerin using a commercially available scanner (Boston Scientific Corporation/Cardiovascular Imaging Systems, Fremont, California). Imaging and image analysis were performed according to standard protocols.1–10 The imaging sequence was acquired using motorized transducer pullback at a speed of 0.5 mm/s. Images were stored on a 0.5-in high-resolution tape for offline analysis. Using computerized planimetry (TapeMeasure, Indec Systems, Mountain View, California) intrastent and 5-mm-long proximal and distal reference segment measurements were made every 1 mm and then averaged. Cross-sectional area (CSA) measurements before and after cutting balloon angioplasty included: (1) proximal and distal reference segment external elastic membrane, lumen, and plaque ⫹ media (external elastic membrane area minus plaque area), and (2) intrastent external elastic membrane, stent, peristent plaque ⫹ media (external elastic membrane minus lumen), lumen, and in-stent intimal hyperplasia (stent minus lumen). A computer-based, automated edge-detection algorithm (CMS, MEDIS, Leiden, The Netherlands) was used to analyze cine angiograms. Using the outer diameter of the contrast-filled catheter as the calibration standard, reference and intrastent minimal lumen diameters (worst view) were measured before and after cutting balloon angioplasty according to previously published protocols.16 Statistical analysis was performed using Statview 4.5 (SAS Institute, Cary, North Carolina). Continuous variables are presented as mean ⫾ 1 SD and compared using paired or unpaired Student’s t test. A p value ⬍0.05 was considered significant. Quantitative angiographic measurements before 0002-9149/01/$–see front matter PII S0002-9149(01)01985-3