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Activated Factor VII Levels in Patients With Angiographically Confirmed Coronary Artery Disease
Activated Factor VII Levels in Patients With Angiographically Confirmed Coronary Artery Disease June E. Eichner,
PhD,
William E. Moore, MS, MPH, Eliot Schechter, MD, Dwight W. Reynolds, James H. Morrissey, PhD, and Philip C. Comp, MD, PhD,
actor VII, the first enzyme in the clotting cascade, circulates in plasma primarily as a zymogen. A F much smaller amount, approximately 0.5% of total factor VII, circulates in the activated form (VIIa).1 Both forms contribute to factor VII coagulant activity (VIIc). In epidemiologic studies, higher levels of factor VIIc have been associated with fatal, but not nonfatal, myocardial infarctions.2,3 Less abundant, but more biologically active, factor VIIa levels may modulate the formation of larger, more occlusive thrombi if rupture of plaque in a coronary artery occurs and an acute event follows.2,4 Whereas fibrin, fibrin-related products, and mural thrombi have been associated with the progression of atherosclerosis,5 – 9 little is known about the role factor VIIa plays in coronary artery disease (CAD). Consequently, we have examined factor VIIa levels in patients undergoing diagnostic coronary angiography to see if levels correspond to the presence of coronary arterial narrowing and to the degree and extent of that narrowing. jjj The study population consists of consecutive men and women having coronary angiograms at 2 hospitals, the Veterans Affairs Medical Center and the University Hospital (Oklahoma City, Oklahoma). The study was approved by the Institutional Review Board and was conducted in accordance with institutional guidelines. The patients were recruited between November 1992 and March 1994. Patients were told of the study by cardiology fellows and signed informed consent statements if they agreed to participate. Patients were not interviewed, except to obtain informed consent. Fifty-five milliliters of blood was taken at the time of coronary angiography through the arterial sheath before administration of heparin. Although detailed socioeconomic information is not available on these patients, the 2 hospitals generally serve a more indigent population than the suburban hospitals of Oklahoma City. The patient population reflects the racial mix of Oklahoma, which is predominantly white with smaller percentFrom the Department of Biostatistics and Epidemiology, College of Public Health, Department of Medicine, College of Medicine, University of Oklahoma, Oklahoma Medical Research Foundation, and the Oklahoma City Veterans Hospital, Oklahoma City, Oklahoma. This study was supported in part by Grant HS2-025 from the Oklahoma Center for the Advancement of Science and Technology, Oklahoma City, Oklahoma; American Heart Association/Oklahoma Affiliate Grant-In-Aid, Oklahoma City, Oklahoma; and SCOR Grant P50 HL-54502, National Institutes of Health, Bethesda, Maryland. Dr. Eichner’s address is: Department of Biostatistics and Epidemiology, College of Public Health, P.O. Box 26901, Oklahoma City, Oklahoma 73190. Manuscript received October 23, 1996; revised manuscript received and accepted March 19, 1997.
ages of blacks and native Americans. Most patients underwent catheterization because of complaints of angina. Other indications included previous myocardial infarction, atypical chest pain, aortic stenosis, aortic regurgitation, and mitral regurgitation. Clinical findings and procedures in the catheterization laboratories were directed by 2 coauthors (ES or DWR). Coronary angiography was performed using standard techniques. After measurement of left ventricular and aortic pressures, selective injections were performed in the right and left coronary arteries, and cineangiograms were obtained in at least 2, approximately orthogonal, views for each vessel. Left ventriculography was performed at the end of the procedure. The severity of obstruction was estimated visually by 1 of the investigators (ES or DWR) in the view in which it was most severe. Blood was collected in dihydrate sodium citrate tubes, centrifuged, and the plasma frozen at 0807C before being assayed. The factor VIIa assay is based on the principle of replacing tissue factor with a mutant form of tissue factor that retains cofactor function toward factor VIIa but no longer supports conversion of factor VII to factor VIIa. The factor VIIa-specific assay is therefore a simple clotting test similar to factor VIIc assays, except that the mutant form of tissue factor and phospholipid vesicles replace thromboplastin.1 Fibrinogen was measured by a nephelometric method (ACL 300/, Instrumentation Laboratory, Lexington, Massachusetts) in the same laboratory that assayed factor VIIa levels. Total and high-density lipoprotein cholesterol and triglycerides were measured on ethylenediaminetetraacetic acid plasma samples at the Oklahoma Medical Research Foundation Diagnostic Service Laboratory using the Centers for Disease Control standardized protocols. Low-density lipoprotein cholesterol was calculated using the Friedewald formula if triglycerides were õ400 mg/dl.10 Lipoprotein(a) [Lp(a)] was measured by electroimmunoassay. This technique is based on the electrophoretic migration of an antigen and its specific immunoprecipitation with an antibody anti-Lp(a) obtained from Dr. Walter McConathy. The area of the rockets was measured using a digitizer (Jandel Scientific, Corte Madera, California) and then compared with the area of rockets with a known concentration of Lp(a). Thirty-five specimens using this method were correlated with the enzyme-linked immunoabsorbent assay (ELISA) (Terumo Corporation, Elkton, Maryland). The correlation coefficient between the 2 methods was 0.94. Electroimmunoassay values were consistently higher than ELISA values.
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Tables I and II provide descriptive information about the white study population, which is broken ¢50% 5% to 45% up into 3 categories based on the 0 Stenosis Stenosis Stenosis maximal stenosis reported in 5% inVariable (n Å 48) p Value (n Å 445) (n Å 84) crements during coronary arteriogAge (yr) 51 { 10 57 { 10 60 { 10 õ0.0001 raphy. Those with no stenoses have 2 Body mass index (kg/m ) 29 { 6 27 { 5 28 { 5 0.39 normal coronary arteries. For white LDL cholesterol (mg/dl)* 130 { 40 144 { 49 155 { 49 0.001 males, the overall trends follow the HDL cholesterol (mg/dl) 33 { 10 34 { 13 31 { 8 0.02 expected pattern with regard to athTriglycerides (mg/dl) Means 123 { 69 151 { 81 204 { 157 õ0.0001 erosclerosis. Age, low-density liMedians 111 141 166 õ0.0001† poprotein cholesterol, triglycerides, Lipoprotein(a) (mg/dl) Lp(a), and fibrinogen are highest on Means 19 { 20 30 { 32 35 { 36 0.008 average in patients with some steMedians 10 21 21 0.007† Fibrinogen (mg/dl) nosis. This pattern is generally simMeans 303 { 78 356 { 98 359 { 126 0.01 ilar in female patients, although Medians 297 336 333 0.008† not always statistically significant, Factor VIIa (ng/ml) probably due to smaller sample Means 2.5 { 1.6 2.3 { 1.2 2.4 { 1.3 0.39 sizes. Factor VIIa showed no staMedians 2.0 1.9 2.2 0.28† tistically significant differences *Sample size for ¢50% Å 423 (due to noncalculable low-density lipoprotein cholesterol from elevated among categories of disease severtriglycerides). ity in the univariate analysis using Kruskal-Wallis analysis of variance. Values are expressed as mean { SD. both parametric and nonparametric HDL Å high-density lipoprotein; LDL Å low-density lipoprotein. statistics (Tables I and II), nor did it show any differences between smokers and nonsmokers or diabetics and nondiabetics for either men TABLE II Descriptive Statistics on Consecutive White Female Patients Undergoing Coronary Angiography or women. jjj ¢50% 5% to 45% Factor VIIc has been implicated 0 Stenosis Stenosis Stenosis Variable (n Å 44) p Value (n Å 58) (n Å 23) as a risk factor for CAD, but because it appears to be induced by a Age (yr) 52 { 9 53 { 10 57 { 10 0.02 high fat diet and is increased in hyBody mass index (kg/m2) 32 { 9 30 { 6 30 { 6 0.63 LDL cholesterol (mg/dl)* 152 { 44 199 { 71 161 { 50 0.004 perlipidemia type IIb and IV, its acHDL cholesterol (mg/dl) 37 { 11 36 { 13 35 { 11 0.73 tual relationship to disease is unTriglycerides (mg/dl) clear.11,12 Factor VIIa levels show Means 199 { 164 247 { 270 232 { 161 0.53 † little or no correlation with triglycMedians 159 165 192 0.33 Lipoprotein(a) [mg/dl] eride levels.13 Circulating factor Means 24 { 30 18 { 18 47 { 52 0.004 VIIa may serve a priming function Medians 5 5 13 0.02† to trigger the clotting cascade, and Fibrinogen (mg/dl) therefore, its distribution in those at Means 325 { 109 338 { 68 407 { 130 0.001 risk for coronary events could poMedians 291 326 383 0.002† Factor VIIa (ng/ml) tentially provide useful information. Means 2.7 { 1.4 2.7 { 1.6 2.6 { 1.6 0.97 However, despite considerable Medians 2.8 2.4 2.5 0.87 searching that ran the risk of errors *Sample sizes respectively: 41, 21, 52 (due to noncalculable low-density lipoprotein cholesterol from from multiple comparisons, there elevated triglycerides). were no factor VIIa associations Kruskal-Wallis analysis of variance. with either extent of disease or risk Values are expressed as mean { SD. factors, such as smoking or diabeAbbreviations as in Table I. tes. Factor VIIa levels were not higher in those with multivessel disExcluded from the primary analyses were patients ease (¢50% stenosis in 0, 1, 2, and 3 vessels, Kruswho had a reported myocardial infarction within 30 kal-Wallis analysis of variance, p Å 0.11 for men days before the catheterization procedure (n Å 78), and p Å 0.83 for women). A logistic regression non-white racial groups (n Å 89), and patients with model, adjusting for age and fibrinogen, showed no heart transplants (n Å 3). Statistical tests to examine association between factor VIIa and the presence of the differences in central tendencies (mean, median) advanced atheroscerotic disease (¢75% stenosis, p between patients with different degrees of stenosis Å 0.60 for the male model and p Å 0.63 for the included parametric and nonparametric (Kruskal- female model). Wallis) analysis of variance. Several logistic regresOther investigators have examined activated factor sion models were used to determine the best predic- VII in relation to myocardial infarction, carotid intimators of atherosclerosis. media thickness, and angiographically determined vesTABLE I Descriptive Statistics on Consecutive White Male Patients Undergoing Coronary Angiography
†
†
218
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JULY 15, 1997
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sel disease. Carvalho de Sousa et al14 reported elevated factor VII activation in patients with acute myocardial infarctions and unstable angina pectoris compared with controls. In contrast, raised factor VIIa levels were not observed among young postinfarction patients or with increased intima-media thickness measured by highresolution quantitative ultrasonography.15,16 In an angiographic study, Suzuki et al17 found an increase in factor VII mass that was not attributed to an increase in activated factor VII in double- and triple-vessel disease subgroups compared with the 1-vessel disease subgroup and controls. The present study provides no evidence that factor VIIa levels correlate with the degree or severity of coronary arterial narrowing. Plasma factor VIIa levels ranged from 0.4 to 8.4 ng/ml in previously studied patients with known atherosclerotic heart disease, and ranged from 0.3 to 9.3 ng/ml in white men and 0.3 to 8.9 ng/ml in white women from this clinical population.1 Plasma factor VII clotting activity and factor VIIa do not correlate closely. For a given factor VII level, factor VIIa levels may display threefold variation.1 This suggests that measuring factor VIIa may offer advantages over factor VII clotting activity in predicting fatal myocardial infarctions. Currently, we are following this cohort of patients for fatal and nonfatal myocardial infarctions and clinical interventions.
1. Morrissey JH, Macik BG, Neuenschwander PF, Comp PC. Quantification of
activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 1993;81:734–744. 2. Ruddock V, Meade TW. Factor VII activity and ischaemic heart disease: Fatal and non-fatal events. Q J Med 1994;87:403–406.
3. Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993;342:1076–1079. 4. Miller GJ, Wilkes HC, Meade TW, Bauer KA, Barzegar S, Rosenberg RD. Haemostatic changes that constitute the hypercoagulable state [letter]. Lancet 1991;338:1079. 5. Woolf N. Thrombosis and atherosclerosis. In: Bloom AL, Thomas DP, eds. Haemostasis and Thrombosis. New York: Churchill Livingstone, 1981. 6. Broadhurst P, Kelleher C, Hughes L, Imeson JD, Raftery EB. Fibrinogen, factor VII clotting activity and coronary artery disease severity. Atherosclerosis 1990;85:169–173. 7. Fuster V, Badimon JJ, Badimon L. Clinical-pathological correlations of coronary disease progression and regression. Circulation 1992;86(suppl III):III-1– III-11. 8. Folsom AR, Wu KK, Shahar E, Davis CE, for the Atherosclerosis Risk in Communities (ARIC) Study Investigators. Association of hemostatic variables with prevalent cardiovascular disease and asymptomatic carotid artery atherosclerosis. Arterioscler Thromb 1993;13:1829–1836. 9. Eichner JE, Moore WE, McKee PA, Schechter E, Reynolds DW, Qi H, Comp PC. Fibrinogen levels in women having coronary angiography. Am J Cardiol 1996;78:15–18. 10. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499–502. 11. Brace LD, Gittler-Buffa C, Miller GJ, Cole TG, Schmeisser D, Prewitt TE, Bowen PE. Factor VII coagulant activity and cholesterol changes in premenopausal women consuming a long-term cholesterol-lowering diet. Arterioscler Thromb 1994;14:1284–1289. 12. Zitoun D, Bara L, Basdevant A, Samama MM. Levels of factor VIIc associated with decreased tissue factor pathway inhibitor and increased plasminogen activator inhibitor-1 in dyslipidemias. Arterioscler Thromb Vasc Biol 1996;16:77–81. 13. Negri M, Arigliano PL, Talamini G, Carlini S, Manzato F, Bonadonna G. Levels of plasma factor VII and factor VII activated forms as a function of plasma triglyceride levels. Atherosclerosis 1993;99:55–61. 14. Carvalho de Sousa J, Azevedo J, Soria C, Barros F, Ribeiro C, Parreira F, Caen JP. Factor VII hyperactivity in acute myocardial thrombosis: a relation to the coagulation activation. Thromb Res 1988;51:165–173. 15. Moor E, Silveira A, van’t Hooft F, Suontaka AM, Ericsson P, Bomba¨ck M, Hamsten A. Coagulation factor VII mass and activity in young men with myocardial infarction at a young age: role of plasma lipoproteins and factor VII genotype. Arterioscler Thromb 1995;15:655–664. 16. Sosef MN, Bosch JG, van Oostayen J, Visser T, Reiber JHC, Rosendaal FR. Relation of plasma coagulation factor VII and fibrinogen to carotid artery intima-media thickness. Thromb Haemost 1994;72:250–254. 17. Suzuki T, Yamauchi K, Matsushita T, Furumichi T, Furui H, Tsuzuki J, Saito H. Elevation of factor VII activity and mass in coronary artery disease of varying severity. Clin Cardiol 1991;14:731–736.
Risk Factors for the Development of Slow Flow During Rotational Coronary Atherectomy Samin K. Sharma, MD, George Dangas, MD, Roxana Mehran, MD, Srinivas Duvvuri, MD, Annapoorna Kini, MD, Thomas P. Cocke, MD, Venu Kakarala, MD, Adam M. Cohen, MD, Jonathan D. Marmur, MD,and John A. Ambrose, MD uring rotational atherectomy (RA) (Rotablator), D coronary atherosclerotic plaque is largely pulverized into microdebris by the cutting action of the abrasive burr.1,2 The interaction of the debris with the distal microvasculature is not completely understood. In certain cases, the microdebris might be either too large to penetrate through the distal microFrom the Cardiovascular Institute, Mount Sinai Medical Center, New York, New York. This study was presented in part at the Eighth Transcatheter Cardiovascular Therapeutics Symposium, Washington, DC, February 1996, and at the XVIII Congress of the European Society of Cardiology, Birmingham, United Kingdom, August 1996. Dr. Sharma’s address is: Cardiac Catheterization Laboratory, Cardiovascular Institute, Box 1030, Mount Sinai Medical Center, New York, New York 10029. Manuscript received October 28, 1996; revised manuscript received and accepted March 13, 1997.
circulation or too abundant to be readily absorbed (possibly by monocytes). Both might potentially lead to slow flow, which is defined as absent or decreased distal runoff without obvious proximal obstruction, or distal filling defects in the epicardial arteries.3 – 6 Slow flow may lead to serious hemodynamic instability due to significant segmental left ventricular dyssynergy and is thought to be related to embolization of atheromatous debris to the distal microvasculature and associated vasospasm.7,8 We investigated the angiographic and clinical correlates of slow flow during RA. jjj We analyzed the data of 225 consecutive Rotablator cases performed at the Mount Sinai Hospital (August 1994 to August 1995). The decision to per-
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PhD,
William E. Moore, MS, MPH, Eliot Schechter, MD, Dwight W. Reynolds, James H. Morrissey, PhD, and Philip C. Comp, MD, PhD,
actor VII, the first enzyme in the clotting cascade, circulates in plasma primarily as a zymogen. A F much smaller amount, approximately 0.5% of total factor VII, circulates in the activated form (VIIa).1 Both forms contribute to factor VII coagulant activity (VIIc). In epidemiologic studies, higher levels of factor VIIc have been associated with fatal, but not nonfatal, myocardial infarctions.2,3 Less abundant, but more biologically active, factor VIIa levels may modulate the formation of larger, more occlusive thrombi if rupture of plaque in a coronary artery occurs and an acute event follows.2,4 Whereas fibrin, fibrin-related products, and mural thrombi have been associated with the progression of atherosclerosis,5 – 9 little is known about the role factor VIIa plays in coronary artery disease (CAD). Consequently, we have examined factor VIIa levels in patients undergoing diagnostic coronary angiography to see if levels correspond to the presence of coronary arterial narrowing and to the degree and extent of that narrowing. jjj The study population consists of consecutive men and women having coronary angiograms at 2 hospitals, the Veterans Affairs Medical Center and the University Hospital (Oklahoma City, Oklahoma). The study was approved by the Institutional Review Board and was conducted in accordance with institutional guidelines. The patients were recruited between November 1992 and March 1994. Patients were told of the study by cardiology fellows and signed informed consent statements if they agreed to participate. Patients were not interviewed, except to obtain informed consent. Fifty-five milliliters of blood was taken at the time of coronary angiography through the arterial sheath before administration of heparin. Although detailed socioeconomic information is not available on these patients, the 2 hospitals generally serve a more indigent population than the suburban hospitals of Oklahoma City. The patient population reflects the racial mix of Oklahoma, which is predominantly white with smaller percentFrom the Department of Biostatistics and Epidemiology, College of Public Health, Department of Medicine, College of Medicine, University of Oklahoma, Oklahoma Medical Research Foundation, and the Oklahoma City Veterans Hospital, Oklahoma City, Oklahoma. This study was supported in part by Grant HS2-025 from the Oklahoma Center for the Advancement of Science and Technology, Oklahoma City, Oklahoma; American Heart Association/Oklahoma Affiliate Grant-In-Aid, Oklahoma City, Oklahoma; and SCOR Grant P50 HL-54502, National Institutes of Health, Bethesda, Maryland. Dr. Eichner’s address is: Department of Biostatistics and Epidemiology, College of Public Health, P.O. Box 26901, Oklahoma City, Oklahoma 73190. Manuscript received October 23, 1996; revised manuscript received and accepted March 19, 1997.
ages of blacks and native Americans. Most patients underwent catheterization because of complaints of angina. Other indications included previous myocardial infarction, atypical chest pain, aortic stenosis, aortic regurgitation, and mitral regurgitation. Clinical findings and procedures in the catheterization laboratories were directed by 2 coauthors (ES or DWR). Coronary angiography was performed using standard techniques. After measurement of left ventricular and aortic pressures, selective injections were performed in the right and left coronary arteries, and cineangiograms were obtained in at least 2, approximately orthogonal, views for each vessel. Left ventriculography was performed at the end of the procedure. The severity of obstruction was estimated visually by 1 of the investigators (ES or DWR) in the view in which it was most severe. Blood was collected in dihydrate sodium citrate tubes, centrifuged, and the plasma frozen at 0807C before being assayed. The factor VIIa assay is based on the principle of replacing tissue factor with a mutant form of tissue factor that retains cofactor function toward factor VIIa but no longer supports conversion of factor VII to factor VIIa. The factor VIIa-specific assay is therefore a simple clotting test similar to factor VIIc assays, except that the mutant form of tissue factor and phospholipid vesicles replace thromboplastin.1 Fibrinogen was measured by a nephelometric method (ACL 300/, Instrumentation Laboratory, Lexington, Massachusetts) in the same laboratory that assayed factor VIIa levels. Total and high-density lipoprotein cholesterol and triglycerides were measured on ethylenediaminetetraacetic acid plasma samples at the Oklahoma Medical Research Foundation Diagnostic Service Laboratory using the Centers for Disease Control standardized protocols. Low-density lipoprotein cholesterol was calculated using the Friedewald formula if triglycerides were õ400 mg/dl.10 Lipoprotein(a) [Lp(a)] was measured by electroimmunoassay. This technique is based on the electrophoretic migration of an antigen and its specific immunoprecipitation with an antibody anti-Lp(a) obtained from Dr. Walter McConathy. The area of the rockets was measured using a digitizer (Jandel Scientific, Corte Madera, California) and then compared with the area of rockets with a known concentration of Lp(a). Thirty-five specimens using this method were correlated with the enzyme-linked immunoabsorbent assay (ELISA) (Terumo Corporation, Elkton, Maryland). The correlation coefficient between the 2 methods was 0.94. Electroimmunoassay values were consistently higher than ELISA values.
Q1997 by Excerpta Medica, Inc.
0002-9149/97/$17.00 PII S0002-9149(97)00324-X
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/ 2w26 5157 Mp
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Tables I and II provide descriptive information about the white study population, which is broken ¢50% 5% to 45% up into 3 categories based on the 0 Stenosis Stenosis Stenosis maximal stenosis reported in 5% inVariable (n Å 48) p Value (n Å 445) (n Å 84) crements during coronary arteriogAge (yr) 51 { 10 57 { 10 60 { 10 õ0.0001 raphy. Those with no stenoses have 2 Body mass index (kg/m ) 29 { 6 27 { 5 28 { 5 0.39 normal coronary arteries. For white LDL cholesterol (mg/dl)* 130 { 40 144 { 49 155 { 49 0.001 males, the overall trends follow the HDL cholesterol (mg/dl) 33 { 10 34 { 13 31 { 8 0.02 expected pattern with regard to athTriglycerides (mg/dl) Means 123 { 69 151 { 81 204 { 157 õ0.0001 erosclerosis. Age, low-density liMedians 111 141 166 õ0.0001† poprotein cholesterol, triglycerides, Lipoprotein(a) (mg/dl) Lp(a), and fibrinogen are highest on Means 19 { 20 30 { 32 35 { 36 0.008 average in patients with some steMedians 10 21 21 0.007† Fibrinogen (mg/dl) nosis. This pattern is generally simMeans 303 { 78 356 { 98 359 { 126 0.01 ilar in female patients, although Medians 297 336 333 0.008† not always statistically significant, Factor VIIa (ng/ml) probably due to smaller sample Means 2.5 { 1.6 2.3 { 1.2 2.4 { 1.3 0.39 sizes. Factor VIIa showed no staMedians 2.0 1.9 2.2 0.28† tistically significant differences *Sample size for ¢50% Å 423 (due to noncalculable low-density lipoprotein cholesterol from elevated among categories of disease severtriglycerides). ity in the univariate analysis using Kruskal-Wallis analysis of variance. Values are expressed as mean { SD. both parametric and nonparametric HDL Å high-density lipoprotein; LDL Å low-density lipoprotein. statistics (Tables I and II), nor did it show any differences between smokers and nonsmokers or diabetics and nondiabetics for either men TABLE II Descriptive Statistics on Consecutive White Female Patients Undergoing Coronary Angiography or women. jjj ¢50% 5% to 45% Factor VIIc has been implicated 0 Stenosis Stenosis Stenosis Variable (n Å 44) p Value (n Å 58) (n Å 23) as a risk factor for CAD, but because it appears to be induced by a Age (yr) 52 { 9 53 { 10 57 { 10 0.02 high fat diet and is increased in hyBody mass index (kg/m2) 32 { 9 30 { 6 30 { 6 0.63 LDL cholesterol (mg/dl)* 152 { 44 199 { 71 161 { 50 0.004 perlipidemia type IIb and IV, its acHDL cholesterol (mg/dl) 37 { 11 36 { 13 35 { 11 0.73 tual relationship to disease is unTriglycerides (mg/dl) clear.11,12 Factor VIIa levels show Means 199 { 164 247 { 270 232 { 161 0.53 † little or no correlation with triglycMedians 159 165 192 0.33 Lipoprotein(a) [mg/dl] eride levels.13 Circulating factor Means 24 { 30 18 { 18 47 { 52 0.004 VIIa may serve a priming function Medians 5 5 13 0.02† to trigger the clotting cascade, and Fibrinogen (mg/dl) therefore, its distribution in those at Means 325 { 109 338 { 68 407 { 130 0.001 risk for coronary events could poMedians 291 326 383 0.002† Factor VIIa (ng/ml) tentially provide useful information. Means 2.7 { 1.4 2.7 { 1.6 2.6 { 1.6 0.97 However, despite considerable Medians 2.8 2.4 2.5 0.87 searching that ran the risk of errors *Sample sizes respectively: 41, 21, 52 (due to noncalculable low-density lipoprotein cholesterol from from multiple comparisons, there elevated triglycerides). were no factor VIIa associations Kruskal-Wallis analysis of variance. with either extent of disease or risk Values are expressed as mean { SD. factors, such as smoking or diabeAbbreviations as in Table I. tes. Factor VIIa levels were not higher in those with multivessel disExcluded from the primary analyses were patients ease (¢50% stenosis in 0, 1, 2, and 3 vessels, Kruswho had a reported myocardial infarction within 30 kal-Wallis analysis of variance, p Å 0.11 for men days before the catheterization procedure (n Å 78), and p Å 0.83 for women). A logistic regression non-white racial groups (n Å 89), and patients with model, adjusting for age and fibrinogen, showed no heart transplants (n Å 3). Statistical tests to examine association between factor VIIa and the presence of the differences in central tendencies (mean, median) advanced atheroscerotic disease (¢75% stenosis, p between patients with different degrees of stenosis Å 0.60 for the male model and p Å 0.63 for the included parametric and nonparametric (Kruskal- female model). Wallis) analysis of variance. Several logistic regresOther investigators have examined activated factor sion models were used to determine the best predic- VII in relation to myocardial infarction, carotid intimators of atherosclerosis. media thickness, and angiographically determined vesTABLE I Descriptive Statistics on Consecutive White Male Patients Undergoing Coronary Angiography
†
†
218
THE AMERICAN JOURNAL OF CARDIOLOGYT
/ 2w26 5157 Mp
218
VOL. 80
Tuesday Jun 10 10:53 PM
JULY 15, 1997
EL–AJC (v. 80, no. 2 ’97)
5157
sel disease. Carvalho de Sousa et al14 reported elevated factor VII activation in patients with acute myocardial infarctions and unstable angina pectoris compared with controls. In contrast, raised factor VIIa levels were not observed among young postinfarction patients or with increased intima-media thickness measured by highresolution quantitative ultrasonography.15,16 In an angiographic study, Suzuki et al17 found an increase in factor VII mass that was not attributed to an increase in activated factor VII in double- and triple-vessel disease subgroups compared with the 1-vessel disease subgroup and controls. The present study provides no evidence that factor VIIa levels correlate with the degree or severity of coronary arterial narrowing. Plasma factor VIIa levels ranged from 0.4 to 8.4 ng/ml in previously studied patients with known atherosclerotic heart disease, and ranged from 0.3 to 9.3 ng/ml in white men and 0.3 to 8.9 ng/ml in white women from this clinical population.1 Plasma factor VII clotting activity and factor VIIa do not correlate closely. For a given factor VII level, factor VIIa levels may display threefold variation.1 This suggests that measuring factor VIIa may offer advantages over factor VII clotting activity in predicting fatal myocardial infarctions. Currently, we are following this cohort of patients for fatal and nonfatal myocardial infarctions and clinical interventions.
1. Morrissey JH, Macik BG, Neuenschwander PF, Comp PC. Quantification of
activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 1993;81:734–744. 2. Ruddock V, Meade TW. Factor VII activity and ischaemic heart disease: Fatal and non-fatal events. Q J Med 1994;87:403–406.
3. Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993;342:1076–1079. 4. Miller GJ, Wilkes HC, Meade TW, Bauer KA, Barzegar S, Rosenberg RD. Haemostatic changes that constitute the hypercoagulable state [letter]. Lancet 1991;338:1079. 5. Woolf N. Thrombosis and atherosclerosis. In: Bloom AL, Thomas DP, eds. Haemostasis and Thrombosis. New York: Churchill Livingstone, 1981. 6. Broadhurst P, Kelleher C, Hughes L, Imeson JD, Raftery EB. Fibrinogen, factor VII clotting activity and coronary artery disease severity. Atherosclerosis 1990;85:169–173. 7. Fuster V, Badimon JJ, Badimon L. Clinical-pathological correlations of coronary disease progression and regression. Circulation 1992;86(suppl III):III-1– III-11. 8. Folsom AR, Wu KK, Shahar E, Davis CE, for the Atherosclerosis Risk in Communities (ARIC) Study Investigators. Association of hemostatic variables with prevalent cardiovascular disease and asymptomatic carotid artery atherosclerosis. Arterioscler Thromb 1993;13:1829–1836. 9. Eichner JE, Moore WE, McKee PA, Schechter E, Reynolds DW, Qi H, Comp PC. Fibrinogen levels in women having coronary angiography. Am J Cardiol 1996;78:15–18. 10. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499–502. 11. Brace LD, Gittler-Buffa C, Miller GJ, Cole TG, Schmeisser D, Prewitt TE, Bowen PE. Factor VII coagulant activity and cholesterol changes in premenopausal women consuming a long-term cholesterol-lowering diet. Arterioscler Thromb 1994;14:1284–1289. 12. Zitoun D, Bara L, Basdevant A, Samama MM. Levels of factor VIIc associated with decreased tissue factor pathway inhibitor and increased plasminogen activator inhibitor-1 in dyslipidemias. Arterioscler Thromb Vasc Biol 1996;16:77–81. 13. Negri M, Arigliano PL, Talamini G, Carlini S, Manzato F, Bonadonna G. Levels of plasma factor VII and factor VII activated forms as a function of plasma triglyceride levels. Atherosclerosis 1993;99:55–61. 14. Carvalho de Sousa J, Azevedo J, Soria C, Barros F, Ribeiro C, Parreira F, Caen JP. Factor VII hyperactivity in acute myocardial thrombosis: a relation to the coagulation activation. Thromb Res 1988;51:165–173. 15. Moor E, Silveira A, van’t Hooft F, Suontaka AM, Ericsson P, Bomba¨ck M, Hamsten A. Coagulation factor VII mass and activity in young men with myocardial infarction at a young age: role of plasma lipoproteins and factor VII genotype. Arterioscler Thromb 1995;15:655–664. 16. Sosef MN, Bosch JG, van Oostayen J, Visser T, Reiber JHC, Rosendaal FR. Relation of plasma coagulation factor VII and fibrinogen to carotid artery intima-media thickness. Thromb Haemost 1994;72:250–254. 17. Suzuki T, Yamauchi K, Matsushita T, Furumichi T, Furui H, Tsuzuki J, Saito H. Elevation of factor VII activity and mass in coronary artery disease of varying severity. Clin Cardiol 1991;14:731–736.
Risk Factors for the Development of Slow Flow During Rotational Coronary Atherectomy Samin K. Sharma, MD, George Dangas, MD, Roxana Mehran, MD, Srinivas Duvvuri, MD, Annapoorna Kini, MD, Thomas P. Cocke, MD, Venu Kakarala, MD, Adam M. Cohen, MD, Jonathan D. Marmur, MD,and John A. Ambrose, MD uring rotational atherectomy (RA) (Rotablator), D coronary atherosclerotic plaque is largely pulverized into microdebris by the cutting action of the abrasive burr.1,2 The interaction of the debris with the distal microvasculature is not completely understood. In certain cases, the microdebris might be either too large to penetrate through the distal microFrom the Cardiovascular Institute, Mount Sinai Medical Center, New York, New York. This study was presented in part at the Eighth Transcatheter Cardiovascular Therapeutics Symposium, Washington, DC, February 1996, and at the XVIII Congress of the European Society of Cardiology, Birmingham, United Kingdom, August 1996. Dr. Sharma’s address is: Cardiac Catheterization Laboratory, Cardiovascular Institute, Box 1030, Mount Sinai Medical Center, New York, New York 10029. Manuscript received October 28, 1996; revised manuscript received and accepted March 13, 1997.
circulation or too abundant to be readily absorbed (possibly by monocytes). Both might potentially lead to slow flow, which is defined as absent or decreased distal runoff without obvious proximal obstruction, or distal filling defects in the epicardial arteries.3 – 6 Slow flow may lead to serious hemodynamic instability due to significant segmental left ventricular dyssynergy and is thought to be related to embolization of atheromatous debris to the distal microvasculature and associated vasospasm.7,8 We investigated the angiographic and clinical correlates of slow flow during RA. jjj We analyzed the data of 225 consecutive Rotablator cases performed at the Mount Sinai Hospital (August 1994 to August 1995). The decision to per-
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