- Email: [email protected]
Effects of the repeated administration of adenosine and heparin on myocardial perfusion in patients with chronic stable angina pectoris
Effects of the Repeated Administration of Adenosine and Heparin on Myocardial Perfusion in Patients With Chronic Stable Angina Pectoris Hal V. Barron, MD, Maria G. Sciammarella, MD, Kathy Lenihan, Andrew D. Michaels, MD, and Elias H. Botvinick, MD
NP,
The mechanism by which ischemia stimulates angiogenesis is unknown. Adenosine is released during myocardial ischemia and may be a mediator of this process. Experimental data suggest that heparin may enhance this effect. The purpose of this open-labeled, placebocontrolled trial was to determine whether repeated intravenous administration of adenosine and heparin could mimic physiologic angiogenesis and reduce the amount of exercise-induced myocardial ischemia in patients with coronary artery disease. Subjects with chronic stable angina refractory to conventional medical therapy and not suitable for revascularization received either adenosine (140 g/kg/min for 6 minutes) and heparin (10,000 U bolus), (n ⴝ 14), or placebo, (n ⴝ 7) daily for 10 days. All patients underwent baseline and follow-up exercise testing with thallium-201 single-photon emission computed tomography myocardial perfu-
sion imaging. A semiquantitative assessment of the extent and severity of the perfusion abnormalities was calculated by 2 blinded investigators. There was no significant change in exercise duration or in the peak heart rate systolic blood pressure product associated with adenosine and heparin compared with placebo treatment. There was, however, a 9% reduction in the extent (60.6 ⴞ 4.0 vs 54.9 ⴞ 4.1, p ⴝ 0.03) and a 14% improvement in severity (41.5 ⴞ 3.2 vs 35.7 ⴞ 2.9, p ⴝ 0.01) of the myocardial perfusion abnormalities seen in patients who received adenosine and heparin compared with placebo. Thus, in this pilot study, repeated administration of adenosine and heparin reduced the amount of exercise-induced ischemia in patients with chronic stable angina refractory to conventional treatment. 䊚2000 by Excerpta Medica, Inc. (Am J Cardiol 2000;85:1–7)
unique way of relieving myocardial ischemia is to enhance coronary collateral circulation. A Chronic myocardial ischemia is a stimulus for the
eral observations support a protective role for adenosine, a purine metabolite released locally, during myocardial ischemia. The present study was based on the hypothesis, supported in the literature,8 –10 that myocardial ischemia leads to the production of adenosine and the transcription of heparin-bound angiogenic factors. The protocol evaluated whether repeated intravenous administrations of adenosine and heparin in patients with stable angina could reduce exercise-induced myocardial ischemia.
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development of coronary collaterals.2 Pharmacologic interventions to stimulate angiogenesis have also been suggested. Unger et al3 demonstrated that heparin accelerated the formation of coronary collaterals induced by ischemia in dogs. Thereafter, clinical studies that combined ischemia with unfractionated4 or low molecular weight heparin5,6 suggested that repeated episodes of exercise-induced ischemia with heparin improves myocardial perfusion in patients with chronic stable angina. This may be related to an upregulation of the transcription of various angiogenic growth factors during myocardial ischemia,2 some of which, including vascular endothelial growth factor, require heparin binding for biologic activity.1,7 Sev-
From the Departments of Medicine (Cardiology), and Radiology (Nuclear Medicine), University of California, San Francisco, California. This study was supported in part by a grant from Fujisawa USA, Chicago, Illinois; and Medco Research, Research Triangle Park, North Carolina. Dr. Michaels was supported in part by the American College of Cardiology/Merck Postdoctoral Cardiology Fellowship, Whitehouse Station, New Jersey. Manuscript received April 12, 1999; revised manuscript received and accepted July 30, 1999. Address for reprints: Elias H. Botvinick, MD, UCSF Medical Center, 505 Parnassus, L-340 Box 0252, San Francisco, California 94143-0252. E-mail: [email protected]. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 January 1, 2000
METHODS This study was an open-labeled, placebo-controlled trial to assess the safety and efficacy of repeated infusions of adenosine and heparin in patients with chronic stable angina. Patients were ⱖ18 years of age with a history of angina pectoris and stress-induced myocardial ischemia on exercise thallium-201 (Tl-201) single-photon emission computed tomography (SPECT) in whom myocardial perfusion imaging had been performed within the previous 3 months and who were not candidates for coronary revascularization (coronary bypass grafting or percutaneous transluminal angioplasty). If no stress test had been performed for clinical reasons, the stress test was performed with informed consent as part of the protocol. Patients with New York Heart Association class III or IV congestive heart failure, a left ventricular ejection fraction ⬍20%, who had undergone coronary 0002-9149/00/$–see front matter PII S0002-9149(99)00596-2
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FIGURE 1. Protocol design. Open-labeled, placebocontrolled study.
revascularization or who had experienced a cardiac event (e.g., myocardial infarction or unstable angina) within the prior 3 months were excluded. Patients predisposed to hemorrhage, active wheezing, or evidence of advanced heart block were also excluded. The study was approved by the Committee on Human Research at the University of California, San Francisco. All patients gave written informed consent before participating in the study. Protocol: After the screening process, which consisted of clinical evaluation, laboratory studies (prothrombin time, tissue thromboplastin time, and platelet count), and exercise Tl-201 SPECT, patients received either the protocol infusion (adenosine and/or heparin)(n ⫽ 14) or a control saline infusion (n ⫽ 7). All patients continued their current antianginal therapy throughout the study protocol. Therapy was discontinued 12 hours before the exercise test. The infusion was administered daily for 10 days and was given in the morning to patients after an overnight fast (Figure 1). The protocol infusion consisted of heparin that was administered as an intravenous bolus of 10,000 U and intravenous adenosine that was infused 15 minutes later for 6 minutes at a rate of 140 g/kg/min for a total dose of 0.84 mg/kg. Continuous electrocardiographic monitoring was performed during and for 10 minutes after the infusion. The 12-lead electrocardiogram, blood pressure, and heart rate were recorded at baseline, at 1-minute intervals during and for 10 minutes after the infusion. Patients were observed for 3 hours following the administration of either active or placebo treatment. Exercise myocardial perfusion protocol: All patients underwent an exercise myocardial perfusion study before and within 1 week after completion of the treatment. Patients performed a symptom-limited exercise treadmill test using the standard Bruce protocol with 12-lead electrocardiographic recording every minute of exercise and with continuous monitoring of leads aVF, V1, and V5. Blood pressure was measured and recorded at rest, at the end of each exercise stage, at peak exercise, and at 5 to 10 minutes after termination. The exercise duration and symptomatic end points were noted. Exercise end points included fatigue, severe angina, severe shortness of breath, sustained arrhythmia, or exertional hypotension. Symptoms were noted and their relation to the rate-pressure or double product (heart rate ⫻ systolic blood pressure, beats 2
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FIGURE 2. Sections analyzed. The short-axis and 2 vertical longaxis segments used in the SPECT myocardial perfusion analysis.
mm Hg/min) were assessed. Changes in exercise duration and the maximum rate-pressure product were evaluated. The exercise electrocardiographic response was considered uninterpretable if the patients were taking digoxin, had a paced ventricular rhythm, or if the baseline electrocardiogram demonstrated left ventricular hypertrophy, left or right bundle block, or ST-T abnormalities at rest. At near maximal exercise, Tl-201 was injected intravenously, with dose variation based on patient weight. Thallium-201 SPECT protocol: All SPECT studies were performed with a dual head Optima camera (General Electric, Milwaukee Wisconsin), equipped with a low-energy collimator and processed on a Genie computer. A circular 180° acquisition was performed with 16 projections over 90° for each head at 40 s/projection after stress, at 4 hours, and after 24 hours when needed. Two energy windows were utilized, a 20% window centered at 68 to 80 keV and a 10% window centered at 167 keV. Images were acquired using a 64 ⫻ 64 image matrix. All studies were monitored for patient motion, field uniformity, center of rotation, and other quality assurance measures. JANUARY 1, 2000
To evaluate the extent and severity of the perfusion defects, 2 indexes Characteristic All (n ⫽ 21) Heparin/Adenosine Placebo (n ⫽ 7) p Value were used.12 The extent of myocardial hypoperfusion was calculated by Age ⫾ SD (yrs) 62.4 ⫾ 9.3 62.2 ⫾ 9.4 62.8 ⫾ 9.9 0.88 adding the scores of abnormal segMen 95% 93% 100% ⬍0.99 Weight ⫾ SD (kg) 84.9 ⫾ 20.5 80.7 ⫾ 17.6 92.9 ⫾ 24.8 0.31 ments (perfusion score ⬎1) and di(range 54–128) (range 54–114) (range 60–128) viding by the total number of segWhite 76% 79% 71% ⬍0.99 ments (20). This was done on both Diabetes (treated) 33% 36% 29% ⬍0.99 the resting and stress studies. The Hypertension 100% 100% 100% ⬍0.99 Hyperlipidemia 100% 100% 100% ⬍0.99 change in the extent of the perfusion Family history CAD 52% 50% 57% ⬍0.99 abnormalities was calculated by Smoker: Ever 52% 57% 43% 0.66 comparing the number of abnormal Current 14% 14% 14% ⬍0.99 segments before and after exercise Prior CABG 71% 64% 86% 0.61 and was expressed as a percentage. Prior PTCA 71% 64% 86% 0.61 Prior MI 71% 79% 57% 0.35 The severity of myocardial ischemia Prior CHF 14% 14% 14% ⬍0.99 was determined by calculating the Prior unstable angina 100% 100% 100% ⬍0.99 sum of the perfusion scores from all Aspirin 100% 100% 100% ⬍0.99 segments and dividing by the maxi blocker 81% 86% 71% 0.57 Calcium Blocker 71% 71% 71% ⬍0.99 mum defect score of 80 (the product Nitrate 100% 100% 100% ⬍0.99 of the total number of segments [2] Statin 91% 86% 100% 0.53 and the maximum defect score [4]). ACE inhibitor 57% 50% 71% 0.64 The change in ischemia severity was Antiarrhythmic 0% 0% 0% ⬍0.99 defined as the difference between the LVEF ⫾ SD (n ⫽ 19) 50 ⫾ 14% 50 ⫾ 11% 50 ⫾ 21% 0.86 (range 25%–78%) (range 25%–65%) (range 25%–78%) severity score at stress and at rest and 3-vessel CAD 100% 100% 100% ⬍0.99 was expressed again as a percentage. IMA Patent (n ⫽ 12) 92% 100% (n ⫽ 7) 80% (n ⫽ 5) 0.42 Scores were expressed as the nearest SVG Patent: (n ⫽ 15) whole number. All 0% 0% (n ⫽ 9) 0% (n ⫽ 6) ⬍0.99 Some 20% 44% (n ⫽ 9) 0% (n ⫽ 6) 0.10 Statistical analysis: All data are Any Patent expressed as a mean ⫾ SE or as a Graft (n ⫽ 15) 80% 89% 68% 0.52 percentage. Comparisons were made Continuous variables (age, weight, LVEF). using the paired Student’s t test when ACE ⫽ angiotensin converting enzyme; CABG ⫽ coronary bypass grafting; CAD ⫽ coronary artery assessing the differences between disease; CHF ⫽ congestive heart failure; IMA ⫽ Internal mammary artery; LVEF ⫽ left ventricular ejection pre- and post-study drug administrafraction; PTCA ⫽ percutaneous transluminal angioplasty; Statin ⫽ HMG CoA reductase inhibitor drug tion and the nonpaired Student’s t therapy; SVG ⫽ Saphenous vein graft. test was used when assessing the differences between treatment groups. The chi-square test was used to comPreprocessing was performed using a Butterworth fil- pare categorical variables. A p value of ⬍0.05 was ter of order 10 with a cutoff frequency of 40% considered statistically significant. Nyquist. A ramp filter was used to reconstruct the transaxial tomograms in 6-mm slices. Short-axis, ver- RESULTS tical, and horizontal long-axis tomograms of the left Subjects: Table I describes the baseline characterventricle were extracted from the reconstructed trans- istics of the 21 patients studied. The average age of the axial tomogram by appropriate transformation with patients was 62 years. All but 1 patient was male and interpolation and displayed according to the standard most were white. All patients had undergone a revasformat. cularization procedure. Approximately two thirds of Image interpretation: Visual interpretation of short- the patients had undergone coronary bypass graft suraxis and vertical long-axis myocardial tomograms was gery. All patients were receiving aspirin and ⬎80% performed from displays using standard software were also receiving nitrates or  blockers. The mean (Medview, Med Image, Inc, Ann Arbor, Michigan). left ventricular ejection fraction of the group was 50% The intensity of each image set was normalized to the (range 25% to 78%). highest pixel value in the myocardium. A semiquanExercise thallium-201 SPECT: All patients underwent titative analysis of these tomograms was performed by both baseline and follow-up exercise tests. Tests were dividing the short-axis and vertical long-axis views discontinued due to fatigue, shortness of breath, or into 20 segments (Figure 2).11 Each segment was disabling angina. ST-segment changes could not be given a perfusion score based on the consensus of 2 evaluated due to baseline ST-T and conduction abnorexperienced observers, who were blinded to patient malities in 8 patients. Patients who received adenosine treatment and imaging sequence. The score was as- and heparin exercised for 6.4 ⫾ 0.7 minutes at basesigned using a 5-point scoring system (0 ⫽ normal, line and for 6.6 ⫾ 0.7 minutes following active treat1 ⫽ slightly reduced; 2 ⫽ moderate reduced; 3 ⫽ ment (p ⫽ NS). Similarly, those patients who received severely reduced, and 4 ⫽ tracer uptake equal to placebo had no significant change in their exercise duration (5.1 ⫾ 0.7 vs 5.6 ⫾ 0.9 minutes, p ⫽ NS). background). TABLE I Baseline Characteristics
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There was a 9% relative improvement in the extent of the exercise-induced myocardial perfusion abnormalities in those patients who received adenosine and heparin (60.6 ⫾ 4.0 vs 54.9 ⫾ 4.1, p ⫽ 0.03). No improvement was observed in the patients treated with placebo. In fact, in this group there was a nonsignificant worsening of the perfusion score from 54.0 ⫾ 4.0 to 56.0 ⫾ 4.3. There was a 14% relative improvement in the severity of the exercise-induced myocardial perfusion abnormalities in those patients who received adenosine and heparin (41.5 ⫾ 3.2 vs 35.7 ⫾ 2.9, p ⫽ 0.01). Again, this improvement was not observed in patients treated with placebo, in whom there was a nonsignificant worsening of the perfusion score from 37.1 ⫾ 3.3 to 38.1 ⫾ 2.9. Individual examples of patient studies are shown in Figures 3 and 4. Individual patient data are presented in Figure 5. A graphic display of each patient’s change in severity of ischemia as a function of change in peak double-product is presented in Figure 6. Eight of 14 patients treated with adenosine and heparin, compared with 1 in the placebo group (p ⬍0.05), had an improvement of ⱖ10% in the severity of exercise-induced ischemia, FIGURE 3. Serial study of the adenosine treatment group. Top 2 panels, short-axis slices; middle 2 panels, the vertical long-axis slices; and lower 2 without an associated reduction in the repanels, the horizontal long-axis slices of the exercise Tl-201 SPECT perfusion lated peak double product. Although in the images acquired in a patient with severe 3-vessel coronary artery disease treated group, there was no increase in douwithout evident collaterals. In each axis, the postexercise images obtained ble product or exercise time, 3 of those before adenosine and/or heparin treatment are shown above, with the postpatients who had the greatest improvement exercise images obtained after treatment below. Before treatment, perfusion in perfusion score did indeed have a signifdefects were evident in the anterolateral, inferolateral, and apical left ventricular walls in the images acquired after exercise testing (top row). After thericant improvement in double product and apy, the perfusion defect in the anterolateral wall after stress testing was less exercise duration. In these 3 patients there extensive, despite a higher double product. Other abnormal regions were was a 36% relative improvement in perfuessentially unchanged, although small variations in the color scale make sion score (38.3 ⫾ 1.8 vs 24.6 ⫾ 3.3, p ⫽ some actually appear worse. 0.1) with an associated 1.7 minute increase in exercise duration (5.5 ⫾ 1.3 vs 7.2 ⫾ 1.4, p ⫽ 0.006). No patient in the placebo group Eight of 14 patients receiving adenosine and heparin improved their exercise duration or perfusion score to experienced angina in the baseline exercise test. Only this degree. Reproducibility of the semiquantitative score analythese 8 had angina in the follow-up exercise test. The rate-pressure product at symptom onset was 20,197 ⫾ sis: Ten myocardial perfusion studies were randomly 5,202 at baseline and 18,083 ⫾ 9,642 at follow-up (p ⫽ selected from our database for evaluation. The studies 0.68). Five of 7 patients who received placebo experi- were read independently and scored as noted above by enced angina at the baseline and follow-up exercise tests. the same 2 readers. There were 4 normal and 6 abThe remaining patient, who did not experience chest pain normal studies. There was exact agreement in the score in 266 of 290 segments, 92%, and a difference during the baseline exercise test, noted shortness of of no more than 1 grade in the remaining 24 segments. breath at the follow-up test. The rate-pressure product at the onset of symptoms was 16,537 ⫾ 3,963 at baseline DISCUSSION and 15,937 ⫾ 3,109 at follow-up (p ⫽ 0.71). The peak In the present study, the repeated administration of rate-pressure product achieved was calculated before and intravenous adenosine and heparin produced a signifafter treatment. There was no difference in the peak icant improvement in exercise-induced ischemia as rate-pressure product achieved in those patients treated assessed by Tl-201 SPECT. Although not all in the with adenosine and heparin (21,162 ⫾ 1579 vs 22,290 ⫾ treatment group responded, most appeared to respond 1,293 beats 䡠 mm Hg/min, p ⫽ NS) or placebo (21,988 ⫾ well beyond the level of variability and several to an 1,505 vs 18,691 ⫾ 1,051 beats 䡠 mm Hg/min, p ⫽ NS). impressive degree, which was not evident in the pla4
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FIGURE 4. Serial study of the placebo group. As appears in Figure 3 are short-axis, vertical long-axis, and horizontal long-axis slices of the exercise Tl-201 SPECT myocardial perfusion study in a 74-year-old men with severe coronary artery disease. In each view the postexercise images obtained before placebo are shown above, whereas those postexercise images obtained after placebo are below. A perfusion defect is evident in the apical, inferior and posterioseptal left ventricular walls. There are no changes in myocardial perfusion noted.
cebo group. This reduction in ischemia was not secondary to reduced exercise intensity as assessed by either exercise duration or peak rate-pressure product. In fact, those patients who demonstrated the most marked improvement in ischemia by Tl-201 SPECT were the patients who experienced the greatest increase in their exercise duration and double product (Figure 6). Although it remains unclear whether the percentage improvement noted would make a clinical difference, it does demonstrate the potential of the method, which, when optimized, could contribute to clinical improvement. Although we did not observe any overall increase in exercise duration or in the peak rate-pressure product achieved, this may have resulted from the small sample size of this preliminary study. Alternatively, these patients with advanced coronary artery disease may have benefited by ischemia reduction in 1 bed while still limited by ischemia in others, or they may have been more limited by other noncardiac factors than their angina. Regardless, most patients treated with adenosine and heparin had an evident improvement in their Tl-201 SPECT score compared with placebo while exercising to the same workload. The mechanism by which this reduction in ischemia oc-
curred is unknown, but may involve the development of coronary collaterals. The protective nature of coronary collateral vessels is widely appreciated. There is ample evidence that coronary collateral density increases when the cardiac myocyte is rendered ischemic. Heparinbinding growth factors, such as vascular endothelial growth factor, are believed to play a role in this process. These growth factors are present in the heart, but are quiescent under normal conditions. During ischemia these molecules may be activated and stimulate angiogenesis.13,14 Several investigators have attempted to reproduce this phenomenon in humans as a means of reducing myocardial ischemia. Fujita et al4 first demonstrated that heparin in combination with short-term exercise training improves exercise tolerance as measured by dynamic exercise testing. In that study, 10 patients with stable effort angina underwent twice daily maximal treadmill exercise for 10 days after pretreatment with 5,000 U of heparin. Exercise with heparin increased the total exercise duration from 6.3 to 9.1 minutes (p ⬍0.001) and the peak rate-pressure product from 18,900 to 25,500 beat 䡠 mm Hg/min (p ⬍0.001). Repeat coronary angiography revealed an increase in collateralization of the ischemic myocardium. These effects were not observed in the 6 patients in whom treadmill exercise was performed without heparin. These investigators confirmed these observations and demonstrated that heparin alone was insufficient to improve exercise tolerance.15 Quyyumi et al5 studied the anti-ischemic effects of combined treatment with low molecular weight heparin and exercise-induced ischemia. Twenty-three patients received either heparin or placebo in combination with an exercise protocol for 4 weeks. Eighty percent of the heparin group compared with 31% of placebo group had a significant increase in rate-pressure product at the onset of 1 mm of ST-segment depression. Furthermore, the time to ischemia increased in 100% of the heparin group compared with 62% in the placebo group. In this same population the incidence and duration of ST-segment depression during ambulatory Holter monitoring decreased by 30% and 35%, respectively, compared with 0% in controls. In another double-blind, randomized, placebo-controlled trial of 29 patients with stable exercise-induced angina, a single daily subcutaneous injection of low molecular weight heparin over 3 months resulted in a significant improvement in both the time to 1-mm ST-segment depression and the peak ST-segment depression.6 The severity of the patient’s angina pectoris was also improved by low molecular weight heparin compared with placebo. Most recently Gagliardi et al16 demonstrated that the addition of heparin to an exercise program resulted in an improvement in the rate-pressure product obtained by patients with chronic stable angina. The mechanism by which heparin and exerciseinduced ischemia improves ischemia is unknown, but could result from collateral development.1,5,6,15 Ischemia may stimulate the release or expression of some
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Study limitations: The present study is limited by a relatively small population and may have been under powered to find other important treatment effects. To have 80% power to detect a 15% increase in exercise duration or peak rate-pressure product, 42 study patients would have been needed. The patient population was difficult to find and enlist, in the presence of an aggressive, interventional environment with competing protocols. Further, baseline abnormalities on the electrocardiogram at rest in most subjects prevented an accurate assessment of the time to ST-segment depression, a variable that may have been more sensitive to the treatment effect than exercise duration or peak double-product. Also, this was not a FIGURE 5. Results of the severity of ischemia. The individual patient data for all subrandomized, controlled trial. However, jects before and after treatment with either adenosine and heparin (Ado/H) or plathere were no significant clinical difcebo. ferences between those patients who received active therapy and those who received placebo. Although no automated quantitative image analysis was used because different SPECT systems were utilized to acquire the data, it has been demonstrated that the summed stress score in medically treated patients with coronary artery disease, as applied here, provides comparable prognostic information to quantitative assessment of SPECT with polar maps.17 Finally, we did not analyze angiographic collateral vessels, thus, the mechanism of benefit remains speculative.
FIGURE 6. Defect severity versus double product. The individual patient data for all subjects before and after treatment with change in severity of ischemia plotted as a function of change in peak double-product.
angiogenic substances that in combination with heparin stimulate collateral development. Vascular endothelial growth factor messenger ribonucleic acid is up-regulated by oxygen deprivation and chronic ischemia in the rat heart13 and has been shown to stimulate collateral development in dogs14 and rabbits.7 Adenosine, which is released during myocyte hypoxia, has been reported to increase vascular endothelial growth factor expression in experimental models,10 suggesting that endogenous adenosine may trigger the development of collateral vessels that occurs following chronic myocardial ischemia. It is via this mechanism that adenosine and heparin may have improved the extent and severity of myocardial ischemia in the present study. 6
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1. Sasayama S, Fujita M. Recent insights into coronary collateral circulation. Circulation 1992;85:1197–1204. 2. Schaper W, Sharma HS, Quinkler W, Markert T, Wunsch M, Schaper J. Molecular biologic concepts of coronary anastomoses. J Am Coll Cardiol 1990; 15:513–518. 3. Unger EF, Sheffield CD, Epstein SE. Heparin promotes the formation of extracardiac to coronary anastomoses in a canine model. Am J Physiol 1991;260: H1625–1634. 4. Fujita M, Sasayama S, Asanoi H, Nakajima H, Sakai O, Ohno A. Improvement of treadmill capacity and collateral circulation as a result of exercise with heparin pretreatment in patients with effort angina. Circulation 1988; 77:1022–1029. 5. Quyyumi AA, Diodati JG, Lakatos E, Bonow RO, Epstein SE. Angiogenic effects of low molecular weight heparin in patients with stable coronary artery disease: a pilot study. J Am Coll Cardiol 1993;22:635– 641. 6. Melandri G, Semprini F, Cervi V, Candiotti N, Palazzini E, Branzi A, Magnani B. Benefit of adding low molecular weight heparin to the conventional treatment of stable angina pectoris. A double-blind, randomized, placebo-controlled trial. Circulation 1993;88:2517–2523. 7. Takeshita S, Zheng LP, Brogi E, Kearney M, Pu LQ, Bunting S, Ferrara N, Symes JF, Isner JM. Therapeutic angiogenesis. A single intra-arterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest 1994;93:662– 670. 8. Ethier MF, Chander V, Dobson JJ. Adenosine stimulates proliferation of human endothelial cells in culture. Am J Physiol 1993;H131–138. 9. Symons JD, Firoozmand E, Longhurst JC. Repeated dipyridamole administration enhances collateral-dependent flow and regional function during exercise. A role for adenosine. Circ Res 1993;73:503–513. 10. Fischer S, Sharma HS, Karliczek GF, Schaper W. Expression of vascular permeability factor/vascular endothelial growth factor in pig cerebral microvascular endothelial cells and its upregulation by adenosine. Brain Res Mol Brain Res 1995;28:141–148. 11. Berman D, Kiat H, Germano G, Van Train KF, Maddahi J, De Puey EG, Garcia EV, Friedman JD. 99m Tc-sestamibi SPECT. In: DePuey EG, Berman DS, Garcia EV (eds). Cardiac SPECT Imaging. Philadelphia: Raven Press, 1995:121– 146.
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12. Santos Ocampo CD, Herman SD, Travin MI, Garber CE, Ahlberg AW, Messinger DE, Heller G. Comparison of exercise, dipyridamole, and adenosine by use of technetium 99m sestamibi tomographic imaging. J Nucl Cardiol 1994;1:57– 64. 13. Hashimoto E, Ogita T, Nakaoka T, Matsuoka R, Takao A, Kira Y. Rapid induction of vascular endothelial growth factor expression by transient ischemia in rat heart. Am J Physiol 1994;267:H1948 –1954. 14. Banai S, Jaklitsch MT, Shou M, Lazarous DF, Scheinowitz M, Biro S, Epstein SE, Unger EF. Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs. Circulation 1994;89:2183–2189. 15. Fujita M, Yamanishi K, Hirai T, Ohno A, Miwa K, Sasayama S. Com-
parative effect of heparin treatment with and without strenuous exercise on treadmill capacity in patients with stable effort angina. Am Heart J 1991;122: 453– 457. 16. Gagliardi JA, Prado NG, Marino JC, Lederer S, Ramos AO, Bertolasi CA. Exercise training and heparin pretreatment in patients with coronary artery disease. Am Heart J 1996;132:946 –951. 17. Berman D, Kang X, Van Train KF, Lewin HW, Cohen I, Areeda J, Friedman, JD, Germano G, Shaw LJ, Hachamovitch R. Comparative prognostic value of automatic quantitative analysis versus semiquantitative visual analysis of exercise myocardial perfusion single-photon emission computed tomography. J Am Coll Cardiol 1998;32:1987–1995.
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NP,
The mechanism by which ischemia stimulates angiogenesis is unknown. Adenosine is released during myocardial ischemia and may be a mediator of this process. Experimental data suggest that heparin may enhance this effect. The purpose of this open-labeled, placebocontrolled trial was to determine whether repeated intravenous administration of adenosine and heparin could mimic physiologic angiogenesis and reduce the amount of exercise-induced myocardial ischemia in patients with coronary artery disease. Subjects with chronic stable angina refractory to conventional medical therapy and not suitable for revascularization received either adenosine (140 g/kg/min for 6 minutes) and heparin (10,000 U bolus), (n ⴝ 14), or placebo, (n ⴝ 7) daily for 10 days. All patients underwent baseline and follow-up exercise testing with thallium-201 single-photon emission computed tomography myocardial perfu-
sion imaging. A semiquantitative assessment of the extent and severity of the perfusion abnormalities was calculated by 2 blinded investigators. There was no significant change in exercise duration or in the peak heart rate systolic blood pressure product associated with adenosine and heparin compared with placebo treatment. There was, however, a 9% reduction in the extent (60.6 ⴞ 4.0 vs 54.9 ⴞ 4.1, p ⴝ 0.03) and a 14% improvement in severity (41.5 ⴞ 3.2 vs 35.7 ⴞ 2.9, p ⴝ 0.01) of the myocardial perfusion abnormalities seen in patients who received adenosine and heparin compared with placebo. Thus, in this pilot study, repeated administration of adenosine and heparin reduced the amount of exercise-induced ischemia in patients with chronic stable angina refractory to conventional treatment. 䊚2000 by Excerpta Medica, Inc. (Am J Cardiol 2000;85:1–7)
unique way of relieving myocardial ischemia is to enhance coronary collateral circulation. A Chronic myocardial ischemia is a stimulus for the
eral observations support a protective role for adenosine, a purine metabolite released locally, during myocardial ischemia. The present study was based on the hypothesis, supported in the literature,8 –10 that myocardial ischemia leads to the production of adenosine and the transcription of heparin-bound angiogenic factors. The protocol evaluated whether repeated intravenous administrations of adenosine and heparin in patients with stable angina could reduce exercise-induced myocardial ischemia.
1
development of coronary collaterals.2 Pharmacologic interventions to stimulate angiogenesis have also been suggested. Unger et al3 demonstrated that heparin accelerated the formation of coronary collaterals induced by ischemia in dogs. Thereafter, clinical studies that combined ischemia with unfractionated4 or low molecular weight heparin5,6 suggested that repeated episodes of exercise-induced ischemia with heparin improves myocardial perfusion in patients with chronic stable angina. This may be related to an upregulation of the transcription of various angiogenic growth factors during myocardial ischemia,2 some of which, including vascular endothelial growth factor, require heparin binding for biologic activity.1,7 Sev-
From the Departments of Medicine (Cardiology), and Radiology (Nuclear Medicine), University of California, San Francisco, California. This study was supported in part by a grant from Fujisawa USA, Chicago, Illinois; and Medco Research, Research Triangle Park, North Carolina. Dr. Michaels was supported in part by the American College of Cardiology/Merck Postdoctoral Cardiology Fellowship, Whitehouse Station, New Jersey. Manuscript received April 12, 1999; revised manuscript received and accepted July 30, 1999. Address for reprints: Elias H. Botvinick, MD, UCSF Medical Center, 505 Parnassus, L-340 Box 0252, San Francisco, California 94143-0252. E-mail: [email protected]. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 January 1, 2000
METHODS This study was an open-labeled, placebo-controlled trial to assess the safety and efficacy of repeated infusions of adenosine and heparin in patients with chronic stable angina. Patients were ⱖ18 years of age with a history of angina pectoris and stress-induced myocardial ischemia on exercise thallium-201 (Tl-201) single-photon emission computed tomography (SPECT) in whom myocardial perfusion imaging had been performed within the previous 3 months and who were not candidates for coronary revascularization (coronary bypass grafting or percutaneous transluminal angioplasty). If no stress test had been performed for clinical reasons, the stress test was performed with informed consent as part of the protocol. Patients with New York Heart Association class III or IV congestive heart failure, a left ventricular ejection fraction ⬍20%, who had undergone coronary 0002-9149/00/$–see front matter PII S0002-9149(99)00596-2
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FIGURE 1. Protocol design. Open-labeled, placebocontrolled study.
revascularization or who had experienced a cardiac event (e.g., myocardial infarction or unstable angina) within the prior 3 months were excluded. Patients predisposed to hemorrhage, active wheezing, or evidence of advanced heart block were also excluded. The study was approved by the Committee on Human Research at the University of California, San Francisco. All patients gave written informed consent before participating in the study. Protocol: After the screening process, which consisted of clinical evaluation, laboratory studies (prothrombin time, tissue thromboplastin time, and platelet count), and exercise Tl-201 SPECT, patients received either the protocol infusion (adenosine and/or heparin)(n ⫽ 14) or a control saline infusion (n ⫽ 7). All patients continued their current antianginal therapy throughout the study protocol. Therapy was discontinued 12 hours before the exercise test. The infusion was administered daily for 10 days and was given in the morning to patients after an overnight fast (Figure 1). The protocol infusion consisted of heparin that was administered as an intravenous bolus of 10,000 U and intravenous adenosine that was infused 15 minutes later for 6 minutes at a rate of 140 g/kg/min for a total dose of 0.84 mg/kg. Continuous electrocardiographic monitoring was performed during and for 10 minutes after the infusion. The 12-lead electrocardiogram, blood pressure, and heart rate were recorded at baseline, at 1-minute intervals during and for 10 minutes after the infusion. Patients were observed for 3 hours following the administration of either active or placebo treatment. Exercise myocardial perfusion protocol: All patients underwent an exercise myocardial perfusion study before and within 1 week after completion of the treatment. Patients performed a symptom-limited exercise treadmill test using the standard Bruce protocol with 12-lead electrocardiographic recording every minute of exercise and with continuous monitoring of leads aVF, V1, and V5. Blood pressure was measured and recorded at rest, at the end of each exercise stage, at peak exercise, and at 5 to 10 minutes after termination. The exercise duration and symptomatic end points were noted. Exercise end points included fatigue, severe angina, severe shortness of breath, sustained arrhythmia, or exertional hypotension. Symptoms were noted and their relation to the rate-pressure or double product (heart rate ⫻ systolic blood pressure, beats 2
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FIGURE 2. Sections analyzed. The short-axis and 2 vertical longaxis segments used in the SPECT myocardial perfusion analysis.
mm Hg/min) were assessed. Changes in exercise duration and the maximum rate-pressure product were evaluated. The exercise electrocardiographic response was considered uninterpretable if the patients were taking digoxin, had a paced ventricular rhythm, or if the baseline electrocardiogram demonstrated left ventricular hypertrophy, left or right bundle block, or ST-T abnormalities at rest. At near maximal exercise, Tl-201 was injected intravenously, with dose variation based on patient weight. Thallium-201 SPECT protocol: All SPECT studies were performed with a dual head Optima camera (General Electric, Milwaukee Wisconsin), equipped with a low-energy collimator and processed on a Genie computer. A circular 180° acquisition was performed with 16 projections over 90° for each head at 40 s/projection after stress, at 4 hours, and after 24 hours when needed. Two energy windows were utilized, a 20% window centered at 68 to 80 keV and a 10% window centered at 167 keV. Images were acquired using a 64 ⫻ 64 image matrix. All studies were monitored for patient motion, field uniformity, center of rotation, and other quality assurance measures. JANUARY 1, 2000
To evaluate the extent and severity of the perfusion defects, 2 indexes Characteristic All (n ⫽ 21) Heparin/Adenosine Placebo (n ⫽ 7) p Value were used.12 The extent of myocardial hypoperfusion was calculated by Age ⫾ SD (yrs) 62.4 ⫾ 9.3 62.2 ⫾ 9.4 62.8 ⫾ 9.9 0.88 adding the scores of abnormal segMen 95% 93% 100% ⬍0.99 Weight ⫾ SD (kg) 84.9 ⫾ 20.5 80.7 ⫾ 17.6 92.9 ⫾ 24.8 0.31 ments (perfusion score ⬎1) and di(range 54–128) (range 54–114) (range 60–128) viding by the total number of segWhite 76% 79% 71% ⬍0.99 ments (20). This was done on both Diabetes (treated) 33% 36% 29% ⬍0.99 the resting and stress studies. The Hypertension 100% 100% 100% ⬍0.99 Hyperlipidemia 100% 100% 100% ⬍0.99 change in the extent of the perfusion Family history CAD 52% 50% 57% ⬍0.99 abnormalities was calculated by Smoker: Ever 52% 57% 43% 0.66 comparing the number of abnormal Current 14% 14% 14% ⬍0.99 segments before and after exercise Prior CABG 71% 64% 86% 0.61 and was expressed as a percentage. Prior PTCA 71% 64% 86% 0.61 Prior MI 71% 79% 57% 0.35 The severity of myocardial ischemia Prior CHF 14% 14% 14% ⬍0.99 was determined by calculating the Prior unstable angina 100% 100% 100% ⬍0.99 sum of the perfusion scores from all Aspirin 100% 100% 100% ⬍0.99 segments and dividing by the maxi blocker 81% 86% 71% 0.57 Calcium Blocker 71% 71% 71% ⬍0.99 mum defect score of 80 (the product Nitrate 100% 100% 100% ⬍0.99 of the total number of segments [2] Statin 91% 86% 100% 0.53 and the maximum defect score [4]). ACE inhibitor 57% 50% 71% 0.64 The change in ischemia severity was Antiarrhythmic 0% 0% 0% ⬍0.99 defined as the difference between the LVEF ⫾ SD (n ⫽ 19) 50 ⫾ 14% 50 ⫾ 11% 50 ⫾ 21% 0.86 (range 25%–78%) (range 25%–65%) (range 25%–78%) severity score at stress and at rest and 3-vessel CAD 100% 100% 100% ⬍0.99 was expressed again as a percentage. IMA Patent (n ⫽ 12) 92% 100% (n ⫽ 7) 80% (n ⫽ 5) 0.42 Scores were expressed as the nearest SVG Patent: (n ⫽ 15) whole number. All 0% 0% (n ⫽ 9) 0% (n ⫽ 6) ⬍0.99 Some 20% 44% (n ⫽ 9) 0% (n ⫽ 6) 0.10 Statistical analysis: All data are Any Patent expressed as a mean ⫾ SE or as a Graft (n ⫽ 15) 80% 89% 68% 0.52 percentage. Comparisons were made Continuous variables (age, weight, LVEF). using the paired Student’s t test when ACE ⫽ angiotensin converting enzyme; CABG ⫽ coronary bypass grafting; CAD ⫽ coronary artery assessing the differences between disease; CHF ⫽ congestive heart failure; IMA ⫽ Internal mammary artery; LVEF ⫽ left ventricular ejection pre- and post-study drug administrafraction; PTCA ⫽ percutaneous transluminal angioplasty; Statin ⫽ HMG CoA reductase inhibitor drug tion and the nonpaired Student’s t therapy; SVG ⫽ Saphenous vein graft. test was used when assessing the differences between treatment groups. The chi-square test was used to comPreprocessing was performed using a Butterworth fil- pare categorical variables. A p value of ⬍0.05 was ter of order 10 with a cutoff frequency of 40% considered statistically significant. Nyquist. A ramp filter was used to reconstruct the transaxial tomograms in 6-mm slices. Short-axis, ver- RESULTS tical, and horizontal long-axis tomograms of the left Subjects: Table I describes the baseline characterventricle were extracted from the reconstructed trans- istics of the 21 patients studied. The average age of the axial tomogram by appropriate transformation with patients was 62 years. All but 1 patient was male and interpolation and displayed according to the standard most were white. All patients had undergone a revasformat. cularization procedure. Approximately two thirds of Image interpretation: Visual interpretation of short- the patients had undergone coronary bypass graft suraxis and vertical long-axis myocardial tomograms was gery. All patients were receiving aspirin and ⬎80% performed from displays using standard software were also receiving nitrates or  blockers. The mean (Medview, Med Image, Inc, Ann Arbor, Michigan). left ventricular ejection fraction of the group was 50% The intensity of each image set was normalized to the (range 25% to 78%). highest pixel value in the myocardium. A semiquanExercise thallium-201 SPECT: All patients underwent titative analysis of these tomograms was performed by both baseline and follow-up exercise tests. Tests were dividing the short-axis and vertical long-axis views discontinued due to fatigue, shortness of breath, or into 20 segments (Figure 2).11 Each segment was disabling angina. ST-segment changes could not be given a perfusion score based on the consensus of 2 evaluated due to baseline ST-T and conduction abnorexperienced observers, who were blinded to patient malities in 8 patients. Patients who received adenosine treatment and imaging sequence. The score was as- and heparin exercised for 6.4 ⫾ 0.7 minutes at basesigned using a 5-point scoring system (0 ⫽ normal, line and for 6.6 ⫾ 0.7 minutes following active treat1 ⫽ slightly reduced; 2 ⫽ moderate reduced; 3 ⫽ ment (p ⫽ NS). Similarly, those patients who received severely reduced, and 4 ⫽ tracer uptake equal to placebo had no significant change in their exercise duration (5.1 ⫾ 0.7 vs 5.6 ⫾ 0.9 minutes, p ⫽ NS). background). TABLE I Baseline Characteristics
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There was a 9% relative improvement in the extent of the exercise-induced myocardial perfusion abnormalities in those patients who received adenosine and heparin (60.6 ⫾ 4.0 vs 54.9 ⫾ 4.1, p ⫽ 0.03). No improvement was observed in the patients treated with placebo. In fact, in this group there was a nonsignificant worsening of the perfusion score from 54.0 ⫾ 4.0 to 56.0 ⫾ 4.3. There was a 14% relative improvement in the severity of the exercise-induced myocardial perfusion abnormalities in those patients who received adenosine and heparin (41.5 ⫾ 3.2 vs 35.7 ⫾ 2.9, p ⫽ 0.01). Again, this improvement was not observed in patients treated with placebo, in whom there was a nonsignificant worsening of the perfusion score from 37.1 ⫾ 3.3 to 38.1 ⫾ 2.9. Individual examples of patient studies are shown in Figures 3 and 4. Individual patient data are presented in Figure 5. A graphic display of each patient’s change in severity of ischemia as a function of change in peak double-product is presented in Figure 6. Eight of 14 patients treated with adenosine and heparin, compared with 1 in the placebo group (p ⬍0.05), had an improvement of ⱖ10% in the severity of exercise-induced ischemia, FIGURE 3. Serial study of the adenosine treatment group. Top 2 panels, short-axis slices; middle 2 panels, the vertical long-axis slices; and lower 2 without an associated reduction in the repanels, the horizontal long-axis slices of the exercise Tl-201 SPECT perfusion lated peak double product. Although in the images acquired in a patient with severe 3-vessel coronary artery disease treated group, there was no increase in douwithout evident collaterals. In each axis, the postexercise images obtained ble product or exercise time, 3 of those before adenosine and/or heparin treatment are shown above, with the postpatients who had the greatest improvement exercise images obtained after treatment below. Before treatment, perfusion in perfusion score did indeed have a signifdefects were evident in the anterolateral, inferolateral, and apical left ventricular walls in the images acquired after exercise testing (top row). After thericant improvement in double product and apy, the perfusion defect in the anterolateral wall after stress testing was less exercise duration. In these 3 patients there extensive, despite a higher double product. Other abnormal regions were was a 36% relative improvement in perfuessentially unchanged, although small variations in the color scale make sion score (38.3 ⫾ 1.8 vs 24.6 ⫾ 3.3, p ⫽ some actually appear worse. 0.1) with an associated 1.7 minute increase in exercise duration (5.5 ⫾ 1.3 vs 7.2 ⫾ 1.4, p ⫽ 0.006). No patient in the placebo group Eight of 14 patients receiving adenosine and heparin improved their exercise duration or perfusion score to experienced angina in the baseline exercise test. Only this degree. Reproducibility of the semiquantitative score analythese 8 had angina in the follow-up exercise test. The rate-pressure product at symptom onset was 20,197 ⫾ sis: Ten myocardial perfusion studies were randomly 5,202 at baseline and 18,083 ⫾ 9,642 at follow-up (p ⫽ selected from our database for evaluation. The studies 0.68). Five of 7 patients who received placebo experi- were read independently and scored as noted above by enced angina at the baseline and follow-up exercise tests. the same 2 readers. There were 4 normal and 6 abThe remaining patient, who did not experience chest pain normal studies. There was exact agreement in the score in 266 of 290 segments, 92%, and a difference during the baseline exercise test, noted shortness of of no more than 1 grade in the remaining 24 segments. breath at the follow-up test. The rate-pressure product at the onset of symptoms was 16,537 ⫾ 3,963 at baseline DISCUSSION and 15,937 ⫾ 3,109 at follow-up (p ⫽ 0.71). The peak In the present study, the repeated administration of rate-pressure product achieved was calculated before and intravenous adenosine and heparin produced a signifafter treatment. There was no difference in the peak icant improvement in exercise-induced ischemia as rate-pressure product achieved in those patients treated assessed by Tl-201 SPECT. Although not all in the with adenosine and heparin (21,162 ⫾ 1579 vs 22,290 ⫾ treatment group responded, most appeared to respond 1,293 beats 䡠 mm Hg/min, p ⫽ NS) or placebo (21,988 ⫾ well beyond the level of variability and several to an 1,505 vs 18,691 ⫾ 1,051 beats 䡠 mm Hg/min, p ⫽ NS). impressive degree, which was not evident in the pla4
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FIGURE 4. Serial study of the placebo group. As appears in Figure 3 are short-axis, vertical long-axis, and horizontal long-axis slices of the exercise Tl-201 SPECT myocardial perfusion study in a 74-year-old men with severe coronary artery disease. In each view the postexercise images obtained before placebo are shown above, whereas those postexercise images obtained after placebo are below. A perfusion defect is evident in the apical, inferior and posterioseptal left ventricular walls. There are no changes in myocardial perfusion noted.
cebo group. This reduction in ischemia was not secondary to reduced exercise intensity as assessed by either exercise duration or peak rate-pressure product. In fact, those patients who demonstrated the most marked improvement in ischemia by Tl-201 SPECT were the patients who experienced the greatest increase in their exercise duration and double product (Figure 6). Although it remains unclear whether the percentage improvement noted would make a clinical difference, it does demonstrate the potential of the method, which, when optimized, could contribute to clinical improvement. Although we did not observe any overall increase in exercise duration or in the peak rate-pressure product achieved, this may have resulted from the small sample size of this preliminary study. Alternatively, these patients with advanced coronary artery disease may have benefited by ischemia reduction in 1 bed while still limited by ischemia in others, or they may have been more limited by other noncardiac factors than their angina. Regardless, most patients treated with adenosine and heparin had an evident improvement in their Tl-201 SPECT score compared with placebo while exercising to the same workload. The mechanism by which this reduction in ischemia oc-
curred is unknown, but may involve the development of coronary collaterals. The protective nature of coronary collateral vessels is widely appreciated. There is ample evidence that coronary collateral density increases when the cardiac myocyte is rendered ischemic. Heparinbinding growth factors, such as vascular endothelial growth factor, are believed to play a role in this process. These growth factors are present in the heart, but are quiescent under normal conditions. During ischemia these molecules may be activated and stimulate angiogenesis.13,14 Several investigators have attempted to reproduce this phenomenon in humans as a means of reducing myocardial ischemia. Fujita et al4 first demonstrated that heparin in combination with short-term exercise training improves exercise tolerance as measured by dynamic exercise testing. In that study, 10 patients with stable effort angina underwent twice daily maximal treadmill exercise for 10 days after pretreatment with 5,000 U of heparin. Exercise with heparin increased the total exercise duration from 6.3 to 9.1 minutes (p ⬍0.001) and the peak rate-pressure product from 18,900 to 25,500 beat 䡠 mm Hg/min (p ⬍0.001). Repeat coronary angiography revealed an increase in collateralization of the ischemic myocardium. These effects were not observed in the 6 patients in whom treadmill exercise was performed without heparin. These investigators confirmed these observations and demonstrated that heparin alone was insufficient to improve exercise tolerance.15 Quyyumi et al5 studied the anti-ischemic effects of combined treatment with low molecular weight heparin and exercise-induced ischemia. Twenty-three patients received either heparin or placebo in combination with an exercise protocol for 4 weeks. Eighty percent of the heparin group compared with 31% of placebo group had a significant increase in rate-pressure product at the onset of 1 mm of ST-segment depression. Furthermore, the time to ischemia increased in 100% of the heparin group compared with 62% in the placebo group. In this same population the incidence and duration of ST-segment depression during ambulatory Holter monitoring decreased by 30% and 35%, respectively, compared with 0% in controls. In another double-blind, randomized, placebo-controlled trial of 29 patients with stable exercise-induced angina, a single daily subcutaneous injection of low molecular weight heparin over 3 months resulted in a significant improvement in both the time to 1-mm ST-segment depression and the peak ST-segment depression.6 The severity of the patient’s angina pectoris was also improved by low molecular weight heparin compared with placebo. Most recently Gagliardi et al16 demonstrated that the addition of heparin to an exercise program resulted in an improvement in the rate-pressure product obtained by patients with chronic stable angina. The mechanism by which heparin and exerciseinduced ischemia improves ischemia is unknown, but could result from collateral development.1,5,6,15 Ischemia may stimulate the release or expression of some
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Study limitations: The present study is limited by a relatively small population and may have been under powered to find other important treatment effects. To have 80% power to detect a 15% increase in exercise duration or peak rate-pressure product, 42 study patients would have been needed. The patient population was difficult to find and enlist, in the presence of an aggressive, interventional environment with competing protocols. Further, baseline abnormalities on the electrocardiogram at rest in most subjects prevented an accurate assessment of the time to ST-segment depression, a variable that may have been more sensitive to the treatment effect than exercise duration or peak double-product. Also, this was not a FIGURE 5. Results of the severity of ischemia. The individual patient data for all subrandomized, controlled trial. However, jects before and after treatment with either adenosine and heparin (Ado/H) or plathere were no significant clinical difcebo. ferences between those patients who received active therapy and those who received placebo. Although no automated quantitative image analysis was used because different SPECT systems were utilized to acquire the data, it has been demonstrated that the summed stress score in medically treated patients with coronary artery disease, as applied here, provides comparable prognostic information to quantitative assessment of SPECT with polar maps.17 Finally, we did not analyze angiographic collateral vessels, thus, the mechanism of benefit remains speculative.
FIGURE 6. Defect severity versus double product. The individual patient data for all subjects before and after treatment with change in severity of ischemia plotted as a function of change in peak double-product.
angiogenic substances that in combination with heparin stimulate collateral development. Vascular endothelial growth factor messenger ribonucleic acid is up-regulated by oxygen deprivation and chronic ischemia in the rat heart13 and has been shown to stimulate collateral development in dogs14 and rabbits.7 Adenosine, which is released during myocyte hypoxia, has been reported to increase vascular endothelial growth factor expression in experimental models,10 suggesting that endogenous adenosine may trigger the development of collateral vessels that occurs following chronic myocardial ischemia. It is via this mechanism that adenosine and heparin may have improved the extent and severity of myocardial ischemia in the present study. 6
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1. Sasayama S, Fujita M. Recent insights into coronary collateral circulation. Circulation 1992;85:1197–1204. 2. Schaper W, Sharma HS, Quinkler W, Markert T, Wunsch M, Schaper J. Molecular biologic concepts of coronary anastomoses. J Am Coll Cardiol 1990; 15:513–518. 3. Unger EF, Sheffield CD, Epstein SE. Heparin promotes the formation of extracardiac to coronary anastomoses in a canine model. Am J Physiol 1991;260: H1625–1634. 4. Fujita M, Sasayama S, Asanoi H, Nakajima H, Sakai O, Ohno A. Improvement of treadmill capacity and collateral circulation as a result of exercise with heparin pretreatment in patients with effort angina. Circulation 1988; 77:1022–1029. 5. Quyyumi AA, Diodati JG, Lakatos E, Bonow RO, Epstein SE. Angiogenic effects of low molecular weight heparin in patients with stable coronary artery disease: a pilot study. J Am Coll Cardiol 1993;22:635– 641. 6. Melandri G, Semprini F, Cervi V, Candiotti N, Palazzini E, Branzi A, Magnani B. Benefit of adding low molecular weight heparin to the conventional treatment of stable angina pectoris. A double-blind, randomized, placebo-controlled trial. Circulation 1993;88:2517–2523. 7. Takeshita S, Zheng LP, Brogi E, Kearney M, Pu LQ, Bunting S, Ferrara N, Symes JF, Isner JM. Therapeutic angiogenesis. A single intra-arterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest 1994;93:662– 670. 8. Ethier MF, Chander V, Dobson JJ. Adenosine stimulates proliferation of human endothelial cells in culture. Am J Physiol 1993;H131–138. 9. Symons JD, Firoozmand E, Longhurst JC. Repeated dipyridamole administration enhances collateral-dependent flow and regional function during exercise. A role for adenosine. Circ Res 1993;73:503–513. 10. Fischer S, Sharma HS, Karliczek GF, Schaper W. Expression of vascular permeability factor/vascular endothelial growth factor in pig cerebral microvascular endothelial cells and its upregulation by adenosine. Brain Res Mol Brain Res 1995;28:141–148. 11. Berman D, Kiat H, Germano G, Van Train KF, Maddahi J, De Puey EG, Garcia EV, Friedman JD. 99m Tc-sestamibi SPECT. In: DePuey EG, Berman DS, Garcia EV (eds). Cardiac SPECT Imaging. Philadelphia: Raven Press, 1995:121– 146.
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12. Santos Ocampo CD, Herman SD, Travin MI, Garber CE, Ahlberg AW, Messinger DE, Heller G. Comparison of exercise, dipyridamole, and adenosine by use of technetium 99m sestamibi tomographic imaging. J Nucl Cardiol 1994;1:57– 64. 13. Hashimoto E, Ogita T, Nakaoka T, Matsuoka R, Takao A, Kira Y. Rapid induction of vascular endothelial growth factor expression by transient ischemia in rat heart. Am J Physiol 1994;267:H1948 –1954. 14. Banai S, Jaklitsch MT, Shou M, Lazarous DF, Scheinowitz M, Biro S, Epstein SE, Unger EF. Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs. Circulation 1994;89:2183–2189. 15. Fujita M, Yamanishi K, Hirai T, Ohno A, Miwa K, Sasayama S. Com-
parative effect of heparin treatment with and without strenuous exercise on treadmill capacity in patients with stable effort angina. Am Heart J 1991;122: 453– 457. 16. Gagliardi JA, Prado NG, Marino JC, Lederer S, Ramos AO, Bertolasi CA. Exercise training and heparin pretreatment in patients with coronary artery disease. Am Heart J 1996;132:946 –951. 17. Berman D, Kang X, Van Train KF, Lewin HW, Cohen I, Areeda J, Friedman, JD, Germano G, Shaw LJ, Hachamovitch R. Comparative prognostic value of automatic quantitative analysis versus semiquantitative visual analysis of exercise myocardial perfusion single-photon emission computed tomography. J Am Coll Cardiol 1998;32:1987–1995.
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