- Email: [email protected]
three-vessel coronary artery disease by coronary angiography
FIGURE 1. Change in vessel size (delta EEM) as a function of plaque accumulation (delta plaque 1 media) in the lesion site compared with the reference segment in current or past smokers (left) and nonsmokers (right).
In conclusion, based on our IVUS observations in patients with coronary artery disease, patients with current or previous smoking history have similar reference and lesion site arterial size, plaque burden, lumen dimension, attenuated compensatory vascular remodeling response, and less lesion site calcium as nonsmokers. 1. Ockene IS, Miller NH. Cigarette smoking, cardiovascular disease, and stroke. Circulation 1997;96:3243–3247. 2. Anderson KM, Wilson PW, Odell PM, Kannel WD. An updated coronary risk profile: a statement for health professionals. Circulation 1991;83:356 –362. 3. Hasdai D, Garratt KN, Grill DE, Lerman A, Holmes DR. Effect of smoking on the long-term outcome after successful percutaneous coronary revascularization. N Engl J Med 1997;336:755–761. 4. Shinton R, Beevers G. Meta-analysis of relation between cigarette smoking and stroke. Br Med J 1989;298:789 –794. 5. Grines CL, Topol EJ, O’Neill WW, George BS, Kereiakes D, Phillips HR, Leimberger JD, Woodlief LH, Califf RM. Effect of cigarette smoking on outcome after thrombolytic therapy for myocardial infarction. Circulation 1995;91:298 – 303. 6. Hasdai D, Rihal CS, Lerman A, Grill D, Holmes DR. Smokers undergoing
percutaneous coronary revascularization present with fewer narrowings in the target coronary artery. Am J Cardiol 1997;80:1212–1214. 7. Fitzgerald GA, Oates JA, Nowak J. Cigarette smoking and hemostatic function. Am Heart J 1988;115:267–271. 8. Martin JL, Wilson JR, Ferraro N, Laskey WK, Kleaveland JP, Hirshfeld JW. Acute coronary vasoconstrictive effects of cigarette smoking in coronary heart disease. Am J Cardiol 1984;54:56 – 60. 9. Barry J, Mead K, Nabel EG, Rocco MB, Campell S, Fenton T, Mudge GH, Selwyn AP. Effect of smoking on the activity of ischemic heart disease. JAMA 1989;261:398 – 402. 10. Hong MK, Mintz GS, Popma JJ, Kent KM, Pichard AD, Satler LF, Leon MB. Limitation of angiography for analyzing coronary atherosclerosis progression or regression. Ann Intern Med 1994;121:348 –354. 11. Weissman NJ, Chari R, Mendelsohn FO, Breall JA, Tanguay JF, Diver DJ, Gersh BJ. Patient and plaque characteristics associated with coronary artery remodeling: an intravascular ultrasound analysis (abstr). J Am Coll Cardiol 1997(suppl);29:124A. 12. Tauth J, Pinnow E, Sullebarger T, Basta L, Gursoy S, Lindsay J, Matar F. Predictors of coronary arterial remodeling patterns in patients with myocardial ischemia. Am J Cardiol 1997;80:1352–1355. 13. Schmermund A, Baumgart D, Gorge G, Seibel R, Gronemeyer D, Haude M, Rumberger J, Erbel R. Coronary artery calcium in acute coronary syndromes. Circulation 1997;96:1461–1469. 14. Rasheed Q, Nair R, Sheehan H, Hodgson JMB. Correlation of intracoronary ultrasound plaque characteristics in atherosclerotic coronary disease patients with clinical variables. Am J Cardiol 1994;73:753–758.
Predictors of Outcome of Medically Treated Patients With Left Main/Three-Vessel Coronary Artery Disease by Coronary Angiography Aman M. Amanullah,
MD, PhD,
Jaekyeong Heo, MD, Elmo Acio, and Ami E. Iskandrian, MD
M
yocardial perfusion single-photon emission computed tomography (SPECT) with exercise or pharmacologic stress has significant prognostic implications and has been shown to provide incremental prognostic value over that provided by clinical, historic, and stress information for the prediction of adverse outcome.1–5 This was demonstrated in patients with known or suspected coronary artery disease (CAD). Patients with left main and/or 3-vessel CAD
From the Department of Medicine, Division of Cardiology, MCP Hahnemann School of Medicine, Philadelphia, Pennsylvania. Dr. Iskandrian’s address is: Division of Cardiology, Mail Stop 471, Broad and Vine Street, Philadelphia, Pennsylvania 19102. E-mail: [email protected]. Manuscript received June 12, 1998; revised manuscript received and accepted August 24, 1998.
MD,
Jagat Narula,
MD,
are at increased risk of future cardiac events6 – 8; however, it is possible that there is a subset of such patients who are at low risk if treated medically. To date, little is known regarding the prognostic value of SPECT in these high-risk patients. This study was designed to examine the predictors of outcome of medically treated patients with left main and/or 3-vessel CAD using stress SPECT thallium-201 imaging. •••
The study population consisted of patients who had documented left main and/or 3-vessel CAD noted on angiography and had undergone exercise or adenosine pharmacologic stress thallium-201 SPECT within 3 months. These data were collected between January 1987 and March 1993. Patients with a history of BRIEF REPORTS
445
minutes. At the end of the third minute of infusion, 3 mCi of thallium-201 was injected intravenously. Medical Treatment Revascularization Leads V1, V5, and aVF were moni(n 5 186) (n 5 210) tored continuously, and a 12-lead Men/women 136/50 179/31* electrocardiogram and blood presAge (yr) 64 6 9 64 6 10 sure were monitored at each minute Diabetes mellitus 50 (27%) 39 (19%) of adenosine infusion. SPECT imSystemic hypertension 100 (54%) 118 (56%) ages were obtained 5 minutes and 4 Peak exercise heart rate (beats/min) 125 6 21 125 6 25 Positive electrocardiographic response 62 (33%) 95 (45%)* hours after thallium injection. Exercise duration (min) 6.8 6 2.6 6.2 6 3.1* Myocardial perfusion SPECT METs achieved 6.9 6 2.9 6.8 6 2.6 was performed using our previously Transient left ventricular dilation 76 (41%) 85 (40%) † described protocol.5,10 Three shortIncreased lung thallium-201 uptake 70 (38%) 116 (55%) axis slices at the apical, mid, and Multivessel perfusion abnormality 129 (69%) 154 (73%) Perfusion defect .15% of left ventricle 135 (73%) 160 (76%) basal levels were selected; each was SPECT score 3.9 6 1.7 4.0 6 1.8 divided into 6 segments. The apical perfusion pattern was assessed in 2 *p ,0.05; †p ,0.01. segments at the midventricular level tomogram of the vertical long-axis plane, yielding a total of 20 segments TABLE II Demographics, Stress Test Characteristics, and SPECT Results of the Study Population per patient. A perfusion abnormality in the initial image that demonstrated No Hard Events Hard Events complete or partial redistribution on (n 5 134) (n 5 52) the delayed image involving 25% of Men/women 101/33 35/17 the segment was considered a reversAge (yr) 64 6 9 64 6 10 ible abnormality. A perfusion abnorDiabetes mellitus 33 (25%) 17 (33%) Systemic hypertension 74 (55%) 26 (50%) mality that remained unchanged in Peak exercise heart rate (beats/min) 127 6 20 120 6 22 the delayed image was considered a Positive electrocardiographic response 42 (31%) 20 (38%) fixed abnormality. Perfusion defects Exercise duration (min) 7.1 6 2.7 6.3 6 2.3* in .1 vascular territory were considMETs achieved 7.2 6 2.9 6.0 6 2.8* ered a multivessel thallium abnorTransient left ventricular dilation 54 (40%) 22 (44%) Increased lung thallium-201 uptake 44 (33%) 26 (50%)* mality. Polar maps were used to Multivessel perfusion abnormality 86 (64%) 43 (83%)* quantitate the size of the perfusion Perfusion defect .15% of left ventricle 90 (67%) 45 (87%)* abnormality by comparing each pa† SPECT score 3.7 6 1.8 4.4 6 1.6 tient’s profile with a gender-matched *p ,0.05; †p ,0.01. normal profile. An abnormality was defined if the data points were 2.5 SD below the mean normal limit. previous myocardial infarction, recent unstable an- The extent of perfusion abnormality was quantitated gina, or coronary revascularization were not included visually as the number of segments with an abnormal in this study. All patients were followed-up by perfusion pattern. Regions of interest were placed scripted telephone interview by persons blinded to the over the myocardium and the left lung, and count patients’ test results. Events were defined as cardiac densities were derived from the initial postexercise images to derive the lung/heart ratio. A ratio ,50% is death or nonfatal myocardial infarction. Symptom-limited treadmill exercise testing was considered normal in our laboratory. The initial and performed in 127 patients using the Bruce protocol. 4-hour images were assessed subjectively for the presExercise end points were excessive fatigue, dyspnea, ence of left ventricular dilation. Each patient was dizziness or angina pectoris of at least moderate de- assigned a SPECT score (0 to 7) based on the size of gree, hypotension, ST-segment depression $3 mm, or perfusion defect (0 5 no perfusion defect; 1 5 ,10% significant arrhythmia. At peak exercise, 3 mCi of [of left ventricle] perfusion defect; 2 5 ,20% perfuthallium-201 was injected intravenously, and the pa- sion defect; 3 5 ,30% perfusion defect; 4 5 $30% tients continued to exercise for an additional 1 minute. perfusion defect), presence of multivessel scan abnorImages were obtained 5 to 10 minutes after termina- mality (0 5 absent; 1 5 present), transient left ventricular cavity dilation during stress (0 5 absent; 1 5 tion of exercise and 4 hours later. Adenosine myocardial perfusion study was per- present), or increased lung/heart ratio (0 5 absent; formed in 59 patients using our previously described 1 5 present). A patient was considered to be at low method.9 In brief, patients were instructed not to con- risk if the SPECT score was #1, at intermediate risk sume coffee or caffeine-containing products for 24 if the score was 2 to 4, and at high risk if the score was hours before the test. After baseline electrocardio- 5 to 7. All coronary angiograms were performed using the gram, heart rate, and blood pressure measurements were obtained, adenosine was infused at a rate of 140 Judkins methods and were analyzed by 2 observers mg/kg/min with an infusion pump and continued for 6 who were unaware of the clinical or scintigraphic TABLE I Demographics, Stress Test Characteristics, and SPECT Results of the Medically Treated and Revascularized Groups
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,0.05). Also, the left ventricular ejection fraction was lower in the former group (50 6 19 vs 59 6 15; p 5 0.05). Among SPECT variables, univariate predictors of events included a large perfusion defect (87% vs 67%; p ,0.05), multivessel scan abnormality (83% vs 64%; p ,0.05), increased lung thallium uptake (50% vs 33%; p ,0.05), and the SPECT score (4.4 6 1.6 vs 3.7 6 1.8; p ,0.01). The results of multivariable Cox proportional-hazards analysis revealed the SPECT score as the only independent predictor of outcome (chi-square 5 6; p 5 0.02). Kaplan-Meier survival curves of patients with high, intermediate, and low risk based on SPECT scores are shown in Figure 1. The cardiac event rate at 30 months was 30% in the high-risk FIGURE 1. Kaplan-Meier curves showing cardiac event-free survival of low-, intermedigroup (SPECT score 5 to 7; n 5 ate-, and high-risk patients based on SPECT score. p 5 0.01 between high- and low-risk 86 patients), 19% in the mediumsubgroups. or intermediate-risk group (SPECT score 2 to 4; n 5 58 patients), and 7% in the low-risk group (SPECT data. Significant CAD was defined as .50% diameter score 0 to 1; n 5 42 patients) (relative risk 5 4.6, 95% narrowing of a major epicardial coronary artery or 1 of confidence interval 5 1.2 to 5.8; p 5 0.01). its major branches. ••• All values are expressed as mean 6 SD. ComparThe present study assessed the predictors of outisons between groups of continuous variables were come in patients with left main and/or 3-vessel CAD. made using paired and unpaired Student’s t test. Com- The results show that, even in these angiographically parisons of proportions were computed using a chi- high-risk patients, SPECT is useful in predicting outsquare statistic. p ,0.05 was considered statistically come. There was a 4.6-fold difference in event-free significant. We performed multivariable Cox propor- survival between low- and high-risk subsets based on tional-hazards analysis to determine the most power- SPECT scores. In addition, among clinical, stress, and ful predictors of cardiac events. Kaplan-Meier actuar- nuclear variables, the SPECT score was the only inial analyses were performed to illustrate the time- dependent predictor of outcome. dependent cumulative probabilities of cardiac eventfree survival in low-, intermediate-, and high-risk Previous studies demonstrated that patients subgroups. with left main/3-vessel CAD and left ventricular Of a total of 396 patients with left main and/or dysfunction benefit from coronary revasculariza3-vessel CAD noted by coronary angiography, 210 tion,6 – 8 and many patients in our initial population (53%) underwent coronary revascularization within 3 underwent coronary revascularization. It should months after SPECT study. The remaining 186 pa- be noted that the mean ejection fraction was nortients were treated medically. Table I shows the base- mal in our medically treated group, and, although line clinical characteristics and stress and nuclear vari- the overall cardiac event rate in these medically ables of the revascularized and medically treated treated patients was high, stress SPECT was useful groups. In the medically treated group, significant left in identifying a relatively low-risk subset who had main disease was present in 22 patients, 3-vessel CAD an annual event rate of 2.8%. These patients conin 160, and a combination of left main and 3-vessel stituted 23% of the total population of medically CAD in 4. During a mean follow-up of 36 6 26 treated patients. It is possible that submaximal months, there were 52 hard cardiac events (nonfatal exercise (in those who underwent exercise testing) myocardial infarction 5 27; cardiac death 5 25). The may have underestimated the extent of ischemia. baseline clinical characteristics of the patients who The low-risk group in this study had a higher event experienced cardiac events and those who did not rate than in other studies but the definition of low have events were similar (Table II). The patients who risk is different, as normal SPECT was unusual in experienced events had a lower exercise duration the current series. In contrast, patients with a high(6.3 6 2.3 vs 7.1 6 2.7 minutes; p ,0.05) and a lower risk SPECT had a significantly worse outcome, exercise capacity (6.0 6 2.8 vs 7.2 6 2.9 METs; p with a 4.6-fold higher event rate. BRIEF REPORTS
447
1. Zaret BL, Wackers FJ. Nuclear cardiology. N Engl J Med 1993;329:775–783. 2. Brown KA. Prognostic value of thallium-201 myocardial perfusion imaging: a
diagnostic tool comes of age. Circulation 1991;83:363–381. 3. Staniloff HM, Forrester JS, Berman DS, Swan HJC. Prediction of death, myocardial infarction, and worsening chest pain using thallium scintigraphy and exercise electrocardiography. J Nucl Med 1986;27:1842–1848. 4. Ladenheim ML, Pollock BH, Rozanski A, Berman DS, Staniloff HM, Forrester JS, Diamond GA. Extent and severity of myocardial hypoperfusion as predictors of prognosis in patients with suspected coronary artery disease. J Am Coll Cardiol 1986;7:464 – 471. 5. Iskandrian AE, Chae SC, Heo J, Stanberry CD, Wasserieben V, Cave V. Independent and incremental prognostic value of exercise single-photon emission computed tomographic (SPECT) thallium imaging in coronary artery disease. J Am Coll Cardiol 1993;22:665– 670. 6. CASS Principal Investigators and Their Associates. Coronary Artery Surgery
Study (CASS): a randomized trial of coronary artery bypass surgery survival data. Circulation 1983;68:939 –950. 7. Takaro T, Hultgren HN, Lipton MJ, Detre KM, Participants in the VA Study Group. The VA Cooperative Randomized Study of Surgery for Coronary Arterial Occlusive Disease: II. Subgroup with significant left main lesions. Circulation 1976;54(suppl III):III-107–III-117. 8. European Coronary Surgery Study Group. Long-term results of prospective randomized study of coronary artery bypass surgery in stable angina pectoris. Lancet 1982;2:1173–1180. 9. Aksut SV, Pancholy S, Cassel D, Cave V, Heo J, Iskandrian AS. Results of adenosine single photon emission computed tomography thallium-201 imaging in hemodynamic nonresponders. Am Heart J 1995;130:67–70. 10. Iskandrian AS, Heo J, Askenase A, Segal BL, Helfant RH. Thallium imaging with single photon emission computed tomography. Am Heart J 1987;114:852– 865.
Circadian Rhythm of Acute Pulmonary Edema Ilan Kitzis, MD, David Zeltser, MD, MHA, Michael Kassirer, MD, Ilana Itzcowich, MD, Yona Weissman, BA, Shlomo Laniado, MD, Gad Keren, MD, and Sami Viskin, MD ircadian periodicity has been demonstrated for various cardiovascular syndromes, including sudC den death and acute myocardial infarction (AMI) or ischemia.1–3 Most of these events occur early in the morning and, to a lesser degree, late in the evening. We assessed the circadian pattern of the onset of acute cardiogenic pulmonary edema. •••
The study was conducted in a university-affiliated metropolitan hospital. The emergency department treats an average of 250 to 300 patients/day. We reviewed the hospital records of patients discharged between January 1990 and December 1995 with the diagnosis of acute cardiogenic pulmonary edema. Patients were included in the study if the admitting diagnosis of pulmonary edema was not changed after in-hospital evaluation. The diagnosis of pulmonary edema was based on the presence of all the following criteria: (1) dyspnea of acute onset as the main complaint, (2) rales heard over both lungs, and (3) appropriate treatment for pulmonary edema administered in the emergency room or in the ambulance. Chest x-ray films consistent with the diagnosis of pulmonary edema were required for inclusion, whereas invasive recordings of intracardiac pressures were not. Because the circadian variation of AMI is known,2 we excluded patients in whom pulmonary edema was an early complication of an acute infarction. Accordingly, patients were excluded if (1) chest pain was the main complaint, (2) pulmonary edema was due to cardiogenic shock, (3) the electrocardiogram showed new ST-segment elevation, new Q waves, or new left bundle branch block, or (4) elevated levels of cardiac enzymes suggested AMI. Patients with end-stage renal failure and patients with severe chronic heart failFrom the Department of Cardiology, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Dr. Viskin’s address is: Department of Cardiology, Tel Aviv Sourasky Medical Center, Weizman 6 Street, Tel Aviv 64239, Israel. E-mail: [email protected]. Manuscript received July 16, 1998; revised manuscript received and accepted August 21, 1998.
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ure (functional class III to IV) who were admitted because of exacerbation of chronic symptoms also were excluded. The time of onset of pulmonary edema was estimated from the time of arrival to the emergency room, the time of calling an ambulance, and the time of the ambulance’s arrival to the patient’s home. The distribution of the number of pulmonary edema episodes occurring in 4-hour intervals was tested for differences among the 6 periods using the chi-square test for goodness of fit. If this test showed significant differences, the 4-hour period with the highest frequency was tested to evaluate its difference from the average of the other 5 periods combined. The excess incidence of pulmonary edema also was expressed as a ratio of the frequency of pulmonary edema in the 4-hour intervals compared with the average of frequencies in the other 5 time intervals. The same analysis was performed for 6-hour intervals. Because multiple testing was performed within a table, all differences were analyzed using a critical value for a chi-square test with 3 and 5 degrees of freedom. A p value ,0.05 was considered significant. A total of 460 hospitalizations for acute pulmonary edema was evaluated (Table I). There were 212 patients (ages 76.5 6 9 years, range 45 to 97). All patients had coronary disease and most had an old myocardial infarction. Mean left ventricular ejection fraction was 0.35 6 0.16 (range 0.13 to 0.80). A low ejection fraction (,0.4) was present in .60% of patients, and 2 or 3 vessel coronary artery disease existed in 75% of patients who underwent catheterization. The average number of admissions per patient was 2. The frequency of onset of acute pulmonary edema, as determined from the time of arrival to the emergency room, was significantly increased from 8:00 A.M. to 12:00 P.M. and from 6:00 P.M. to midnight (Figure 1). There was a trough in the admission frequency (only 8.5% of all admissions) during the afternoon period (from midday to 4:00 P.M.). Using 4-hour blocks, both the morning peak (8:00 A.M. to FEBRUARY 1, 1999
In conclusion, based on our IVUS observations in patients with coronary artery disease, patients with current or previous smoking history have similar reference and lesion site arterial size, plaque burden, lumen dimension, attenuated compensatory vascular remodeling response, and less lesion site calcium as nonsmokers. 1. Ockene IS, Miller NH. Cigarette smoking, cardiovascular disease, and stroke. Circulation 1997;96:3243–3247. 2. Anderson KM, Wilson PW, Odell PM, Kannel WD. An updated coronary risk profile: a statement for health professionals. Circulation 1991;83:356 –362. 3. Hasdai D, Garratt KN, Grill DE, Lerman A, Holmes DR. Effect of smoking on the long-term outcome after successful percutaneous coronary revascularization. N Engl J Med 1997;336:755–761. 4. Shinton R, Beevers G. Meta-analysis of relation between cigarette smoking and stroke. Br Med J 1989;298:789 –794. 5. Grines CL, Topol EJ, O’Neill WW, George BS, Kereiakes D, Phillips HR, Leimberger JD, Woodlief LH, Califf RM. Effect of cigarette smoking on outcome after thrombolytic therapy for myocardial infarction. Circulation 1995;91:298 – 303. 6. Hasdai D, Rihal CS, Lerman A, Grill D, Holmes DR. Smokers undergoing
percutaneous coronary revascularization present with fewer narrowings in the target coronary artery. Am J Cardiol 1997;80:1212–1214. 7. Fitzgerald GA, Oates JA, Nowak J. Cigarette smoking and hemostatic function. Am Heart J 1988;115:267–271. 8. Martin JL, Wilson JR, Ferraro N, Laskey WK, Kleaveland JP, Hirshfeld JW. Acute coronary vasoconstrictive effects of cigarette smoking in coronary heart disease. Am J Cardiol 1984;54:56 – 60. 9. Barry J, Mead K, Nabel EG, Rocco MB, Campell S, Fenton T, Mudge GH, Selwyn AP. Effect of smoking on the activity of ischemic heart disease. JAMA 1989;261:398 – 402. 10. Hong MK, Mintz GS, Popma JJ, Kent KM, Pichard AD, Satler LF, Leon MB. Limitation of angiography for analyzing coronary atherosclerosis progression or regression. Ann Intern Med 1994;121:348 –354. 11. Weissman NJ, Chari R, Mendelsohn FO, Breall JA, Tanguay JF, Diver DJ, Gersh BJ. Patient and plaque characteristics associated with coronary artery remodeling: an intravascular ultrasound analysis (abstr). J Am Coll Cardiol 1997(suppl);29:124A. 12. Tauth J, Pinnow E, Sullebarger T, Basta L, Gursoy S, Lindsay J, Matar F. Predictors of coronary arterial remodeling patterns in patients with myocardial ischemia. Am J Cardiol 1997;80:1352–1355. 13. Schmermund A, Baumgart D, Gorge G, Seibel R, Gronemeyer D, Haude M, Rumberger J, Erbel R. Coronary artery calcium in acute coronary syndromes. Circulation 1997;96:1461–1469. 14. Rasheed Q, Nair R, Sheehan H, Hodgson JMB. Correlation of intracoronary ultrasound plaque characteristics in atherosclerotic coronary disease patients with clinical variables. Am J Cardiol 1994;73:753–758.
Predictors of Outcome of Medically Treated Patients With Left Main/Three-Vessel Coronary Artery Disease by Coronary Angiography Aman M. Amanullah,
MD, PhD,
Jaekyeong Heo, MD, Elmo Acio, and Ami E. Iskandrian, MD
M
yocardial perfusion single-photon emission computed tomography (SPECT) with exercise or pharmacologic stress has significant prognostic implications and has been shown to provide incremental prognostic value over that provided by clinical, historic, and stress information for the prediction of adverse outcome.1–5 This was demonstrated in patients with known or suspected coronary artery disease (CAD). Patients with left main and/or 3-vessel CAD
From the Department of Medicine, Division of Cardiology, MCP Hahnemann School of Medicine, Philadelphia, Pennsylvania. Dr. Iskandrian’s address is: Division of Cardiology, Mail Stop 471, Broad and Vine Street, Philadelphia, Pennsylvania 19102. E-mail: [email protected]. Manuscript received June 12, 1998; revised manuscript received and accepted August 24, 1998.
MD,
Jagat Narula,
MD,
are at increased risk of future cardiac events6 – 8; however, it is possible that there is a subset of such patients who are at low risk if treated medically. To date, little is known regarding the prognostic value of SPECT in these high-risk patients. This study was designed to examine the predictors of outcome of medically treated patients with left main and/or 3-vessel CAD using stress SPECT thallium-201 imaging. •••
The study population consisted of patients who had documented left main and/or 3-vessel CAD noted on angiography and had undergone exercise or adenosine pharmacologic stress thallium-201 SPECT within 3 months. These data were collected between January 1987 and March 1993. Patients with a history of BRIEF REPORTS
445
minutes. At the end of the third minute of infusion, 3 mCi of thallium-201 was injected intravenously. Medical Treatment Revascularization Leads V1, V5, and aVF were moni(n 5 186) (n 5 210) tored continuously, and a 12-lead Men/women 136/50 179/31* electrocardiogram and blood presAge (yr) 64 6 9 64 6 10 sure were monitored at each minute Diabetes mellitus 50 (27%) 39 (19%) of adenosine infusion. SPECT imSystemic hypertension 100 (54%) 118 (56%) ages were obtained 5 minutes and 4 Peak exercise heart rate (beats/min) 125 6 21 125 6 25 Positive electrocardiographic response 62 (33%) 95 (45%)* hours after thallium injection. Exercise duration (min) 6.8 6 2.6 6.2 6 3.1* Myocardial perfusion SPECT METs achieved 6.9 6 2.9 6.8 6 2.6 was performed using our previously Transient left ventricular dilation 76 (41%) 85 (40%) † described protocol.5,10 Three shortIncreased lung thallium-201 uptake 70 (38%) 116 (55%) axis slices at the apical, mid, and Multivessel perfusion abnormality 129 (69%) 154 (73%) Perfusion defect .15% of left ventricle 135 (73%) 160 (76%) basal levels were selected; each was SPECT score 3.9 6 1.7 4.0 6 1.8 divided into 6 segments. The apical perfusion pattern was assessed in 2 *p ,0.05; †p ,0.01. segments at the midventricular level tomogram of the vertical long-axis plane, yielding a total of 20 segments TABLE II Demographics, Stress Test Characteristics, and SPECT Results of the Study Population per patient. A perfusion abnormality in the initial image that demonstrated No Hard Events Hard Events complete or partial redistribution on (n 5 134) (n 5 52) the delayed image involving 25% of Men/women 101/33 35/17 the segment was considered a reversAge (yr) 64 6 9 64 6 10 ible abnormality. A perfusion abnorDiabetes mellitus 33 (25%) 17 (33%) Systemic hypertension 74 (55%) 26 (50%) mality that remained unchanged in Peak exercise heart rate (beats/min) 127 6 20 120 6 22 the delayed image was considered a Positive electrocardiographic response 42 (31%) 20 (38%) fixed abnormality. Perfusion defects Exercise duration (min) 7.1 6 2.7 6.3 6 2.3* in .1 vascular territory were considMETs achieved 7.2 6 2.9 6.0 6 2.8* ered a multivessel thallium abnorTransient left ventricular dilation 54 (40%) 22 (44%) Increased lung thallium-201 uptake 44 (33%) 26 (50%)* mality. Polar maps were used to Multivessel perfusion abnormality 86 (64%) 43 (83%)* quantitate the size of the perfusion Perfusion defect .15% of left ventricle 90 (67%) 45 (87%)* abnormality by comparing each pa† SPECT score 3.7 6 1.8 4.4 6 1.6 tient’s profile with a gender-matched *p ,0.05; †p ,0.01. normal profile. An abnormality was defined if the data points were 2.5 SD below the mean normal limit. previous myocardial infarction, recent unstable an- The extent of perfusion abnormality was quantitated gina, or coronary revascularization were not included visually as the number of segments with an abnormal in this study. All patients were followed-up by perfusion pattern. Regions of interest were placed scripted telephone interview by persons blinded to the over the myocardium and the left lung, and count patients’ test results. Events were defined as cardiac densities were derived from the initial postexercise images to derive the lung/heart ratio. A ratio ,50% is death or nonfatal myocardial infarction. Symptom-limited treadmill exercise testing was considered normal in our laboratory. The initial and performed in 127 patients using the Bruce protocol. 4-hour images were assessed subjectively for the presExercise end points were excessive fatigue, dyspnea, ence of left ventricular dilation. Each patient was dizziness or angina pectoris of at least moderate de- assigned a SPECT score (0 to 7) based on the size of gree, hypotension, ST-segment depression $3 mm, or perfusion defect (0 5 no perfusion defect; 1 5 ,10% significant arrhythmia. At peak exercise, 3 mCi of [of left ventricle] perfusion defect; 2 5 ,20% perfuthallium-201 was injected intravenously, and the pa- sion defect; 3 5 ,30% perfusion defect; 4 5 $30% tients continued to exercise for an additional 1 minute. perfusion defect), presence of multivessel scan abnorImages were obtained 5 to 10 minutes after termina- mality (0 5 absent; 1 5 present), transient left ventricular cavity dilation during stress (0 5 absent; 1 5 tion of exercise and 4 hours later. Adenosine myocardial perfusion study was per- present), or increased lung/heart ratio (0 5 absent; formed in 59 patients using our previously described 1 5 present). A patient was considered to be at low method.9 In brief, patients were instructed not to con- risk if the SPECT score was #1, at intermediate risk sume coffee or caffeine-containing products for 24 if the score was 2 to 4, and at high risk if the score was hours before the test. After baseline electrocardio- 5 to 7. All coronary angiograms were performed using the gram, heart rate, and blood pressure measurements were obtained, adenosine was infused at a rate of 140 Judkins methods and were analyzed by 2 observers mg/kg/min with an infusion pump and continued for 6 who were unaware of the clinical or scintigraphic TABLE I Demographics, Stress Test Characteristics, and SPECT Results of the Medically Treated and Revascularized Groups
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,0.05). Also, the left ventricular ejection fraction was lower in the former group (50 6 19 vs 59 6 15; p 5 0.05). Among SPECT variables, univariate predictors of events included a large perfusion defect (87% vs 67%; p ,0.05), multivessel scan abnormality (83% vs 64%; p ,0.05), increased lung thallium uptake (50% vs 33%; p ,0.05), and the SPECT score (4.4 6 1.6 vs 3.7 6 1.8; p ,0.01). The results of multivariable Cox proportional-hazards analysis revealed the SPECT score as the only independent predictor of outcome (chi-square 5 6; p 5 0.02). Kaplan-Meier survival curves of patients with high, intermediate, and low risk based on SPECT scores are shown in Figure 1. The cardiac event rate at 30 months was 30% in the high-risk FIGURE 1. Kaplan-Meier curves showing cardiac event-free survival of low-, intermedigroup (SPECT score 5 to 7; n 5 ate-, and high-risk patients based on SPECT score. p 5 0.01 between high- and low-risk 86 patients), 19% in the mediumsubgroups. or intermediate-risk group (SPECT score 2 to 4; n 5 58 patients), and 7% in the low-risk group (SPECT data. Significant CAD was defined as .50% diameter score 0 to 1; n 5 42 patients) (relative risk 5 4.6, 95% narrowing of a major epicardial coronary artery or 1 of confidence interval 5 1.2 to 5.8; p 5 0.01). its major branches. ••• All values are expressed as mean 6 SD. ComparThe present study assessed the predictors of outisons between groups of continuous variables were come in patients with left main and/or 3-vessel CAD. made using paired and unpaired Student’s t test. Com- The results show that, even in these angiographically parisons of proportions were computed using a chi- high-risk patients, SPECT is useful in predicting outsquare statistic. p ,0.05 was considered statistically come. There was a 4.6-fold difference in event-free significant. We performed multivariable Cox propor- survival between low- and high-risk subsets based on tional-hazards analysis to determine the most power- SPECT scores. In addition, among clinical, stress, and ful predictors of cardiac events. Kaplan-Meier actuar- nuclear variables, the SPECT score was the only inial analyses were performed to illustrate the time- dependent predictor of outcome. dependent cumulative probabilities of cardiac eventfree survival in low-, intermediate-, and high-risk Previous studies demonstrated that patients subgroups. with left main/3-vessel CAD and left ventricular Of a total of 396 patients with left main and/or dysfunction benefit from coronary revasculariza3-vessel CAD noted by coronary angiography, 210 tion,6 – 8 and many patients in our initial population (53%) underwent coronary revascularization within 3 underwent coronary revascularization. It should months after SPECT study. The remaining 186 pa- be noted that the mean ejection fraction was nortients were treated medically. Table I shows the base- mal in our medically treated group, and, although line clinical characteristics and stress and nuclear vari- the overall cardiac event rate in these medically ables of the revascularized and medically treated treated patients was high, stress SPECT was useful groups. In the medically treated group, significant left in identifying a relatively low-risk subset who had main disease was present in 22 patients, 3-vessel CAD an annual event rate of 2.8%. These patients conin 160, and a combination of left main and 3-vessel stituted 23% of the total population of medically CAD in 4. During a mean follow-up of 36 6 26 treated patients. It is possible that submaximal months, there were 52 hard cardiac events (nonfatal exercise (in those who underwent exercise testing) myocardial infarction 5 27; cardiac death 5 25). The may have underestimated the extent of ischemia. baseline clinical characteristics of the patients who The low-risk group in this study had a higher event experienced cardiac events and those who did not rate than in other studies but the definition of low have events were similar (Table II). The patients who risk is different, as normal SPECT was unusual in experienced events had a lower exercise duration the current series. In contrast, patients with a high(6.3 6 2.3 vs 7.1 6 2.7 minutes; p ,0.05) and a lower risk SPECT had a significantly worse outcome, exercise capacity (6.0 6 2.8 vs 7.2 6 2.9 METs; p with a 4.6-fold higher event rate. BRIEF REPORTS
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1. Zaret BL, Wackers FJ. Nuclear cardiology. N Engl J Med 1993;329:775–783. 2. Brown KA. Prognostic value of thallium-201 myocardial perfusion imaging: a
diagnostic tool comes of age. Circulation 1991;83:363–381. 3. Staniloff HM, Forrester JS, Berman DS, Swan HJC. Prediction of death, myocardial infarction, and worsening chest pain using thallium scintigraphy and exercise electrocardiography. J Nucl Med 1986;27:1842–1848. 4. Ladenheim ML, Pollock BH, Rozanski A, Berman DS, Staniloff HM, Forrester JS, Diamond GA. Extent and severity of myocardial hypoperfusion as predictors of prognosis in patients with suspected coronary artery disease. J Am Coll Cardiol 1986;7:464 – 471. 5. Iskandrian AE, Chae SC, Heo J, Stanberry CD, Wasserieben V, Cave V. Independent and incremental prognostic value of exercise single-photon emission computed tomographic (SPECT) thallium imaging in coronary artery disease. J Am Coll Cardiol 1993;22:665– 670. 6. CASS Principal Investigators and Their Associates. Coronary Artery Surgery
Study (CASS): a randomized trial of coronary artery bypass surgery survival data. Circulation 1983;68:939 –950. 7. Takaro T, Hultgren HN, Lipton MJ, Detre KM, Participants in the VA Study Group. The VA Cooperative Randomized Study of Surgery for Coronary Arterial Occlusive Disease: II. Subgroup with significant left main lesions. Circulation 1976;54(suppl III):III-107–III-117. 8. European Coronary Surgery Study Group. Long-term results of prospective randomized study of coronary artery bypass surgery in stable angina pectoris. Lancet 1982;2:1173–1180. 9. Aksut SV, Pancholy S, Cassel D, Cave V, Heo J, Iskandrian AS. Results of adenosine single photon emission computed tomography thallium-201 imaging in hemodynamic nonresponders. Am Heart J 1995;130:67–70. 10. Iskandrian AS, Heo J, Askenase A, Segal BL, Helfant RH. Thallium imaging with single photon emission computed tomography. Am Heart J 1987;114:852– 865.
Circadian Rhythm of Acute Pulmonary Edema Ilan Kitzis, MD, David Zeltser, MD, MHA, Michael Kassirer, MD, Ilana Itzcowich, MD, Yona Weissman, BA, Shlomo Laniado, MD, Gad Keren, MD, and Sami Viskin, MD ircadian periodicity has been demonstrated for various cardiovascular syndromes, including sudC den death and acute myocardial infarction (AMI) or ischemia.1–3 Most of these events occur early in the morning and, to a lesser degree, late in the evening. We assessed the circadian pattern of the onset of acute cardiogenic pulmonary edema. •••
The study was conducted in a university-affiliated metropolitan hospital. The emergency department treats an average of 250 to 300 patients/day. We reviewed the hospital records of patients discharged between January 1990 and December 1995 with the diagnosis of acute cardiogenic pulmonary edema. Patients were included in the study if the admitting diagnosis of pulmonary edema was not changed after in-hospital evaluation. The diagnosis of pulmonary edema was based on the presence of all the following criteria: (1) dyspnea of acute onset as the main complaint, (2) rales heard over both lungs, and (3) appropriate treatment for pulmonary edema administered in the emergency room or in the ambulance. Chest x-ray films consistent with the diagnosis of pulmonary edema were required for inclusion, whereas invasive recordings of intracardiac pressures were not. Because the circadian variation of AMI is known,2 we excluded patients in whom pulmonary edema was an early complication of an acute infarction. Accordingly, patients were excluded if (1) chest pain was the main complaint, (2) pulmonary edema was due to cardiogenic shock, (3) the electrocardiogram showed new ST-segment elevation, new Q waves, or new left bundle branch block, or (4) elevated levels of cardiac enzymes suggested AMI. Patients with end-stage renal failure and patients with severe chronic heart failFrom the Department of Cardiology, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Dr. Viskin’s address is: Department of Cardiology, Tel Aviv Sourasky Medical Center, Weizman 6 Street, Tel Aviv 64239, Israel. E-mail: [email protected]. Manuscript received July 16, 1998; revised manuscript received and accepted August 21, 1998.
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ure (functional class III to IV) who were admitted because of exacerbation of chronic symptoms also were excluded. The time of onset of pulmonary edema was estimated from the time of arrival to the emergency room, the time of calling an ambulance, and the time of the ambulance’s arrival to the patient’s home. The distribution of the number of pulmonary edema episodes occurring in 4-hour intervals was tested for differences among the 6 periods using the chi-square test for goodness of fit. If this test showed significant differences, the 4-hour period with the highest frequency was tested to evaluate its difference from the average of the other 5 periods combined. The excess incidence of pulmonary edema also was expressed as a ratio of the frequency of pulmonary edema in the 4-hour intervals compared with the average of frequencies in the other 5 time intervals. The same analysis was performed for 6-hour intervals. Because multiple testing was performed within a table, all differences were analyzed using a critical value for a chi-square test with 3 and 5 degrees of freedom. A p value ,0.05 was considered significant. A total of 460 hospitalizations for acute pulmonary edema was evaluated (Table I). There were 212 patients (ages 76.5 6 9 years, range 45 to 97). All patients had coronary disease and most had an old myocardial infarction. Mean left ventricular ejection fraction was 0.35 6 0.16 (range 0.13 to 0.80). A low ejection fraction (,0.4) was present in .60% of patients, and 2 or 3 vessel coronary artery disease existed in 75% of patients who underwent catheterization. The average number of admissions per patient was 2. The frequency of onset of acute pulmonary edema, as determined from the time of arrival to the emergency room, was significantly increased from 8:00 A.M. to 12:00 P.M. and from 6:00 P.M. to midnight (Figure 1). There was a trough in the admission frequency (only 8.5% of all admissions) during the afternoon period (from midday to 4:00 P.M.). Using 4-hour blocks, both the morning peak (8:00 A.M. to FEBRUARY 1, 1999