- Email: [email protected]
Risk of atrioventricular block during adenosine pharmacologic stress testing in heart transplant recipients
a new method for treating congenital pulmonary valve stenosis. N Engl J Med 1982;307:540 –541. 10. Beekman RH, Lioyd TR. Balloon valvuloplasty and stenting for congenital disease. In: Topol EJ, ed. Textbook of Interventional Cardiology. Philadelphia: WB Saunders; 1994;1277–1298. 11. Hoffman JIE, Buckberg GD. The myocardial supply:demand ratio: a critical review. Am J Cardiol 1978;41:327–332. 12. Klocke F. Coronary blood flow in man. Prog Cardiovasc Dis 1976;XXI: 117–122. 13. Kallikazaros I, Stratos C, Tsioufis C, Stefanadis C, Marakas S, Toutouzas P. Pulmonary balloon valvuloplasty induced acute changes in right coronary blood flow velocity pattern (abstr). J Am Coll Cardiol 1997(suppl)29:144A.
14. Chillian WM, Marcus ML. Effects of coronary and extravascular pressure on intramyocardial and epicardial blood velocity. Am J Physiol 1985;248:H170 – H178. 15. Spaan J, Breuls N, Laird J. Diastolic-systolic coronary flow differences are caused by intramyocardial pump action in the anesthetized dog. Circ Res 1981; 49:584 –589. 16. Marcus M. The Coronary Circulation in Health and Disease. RR Donnelley, 1983. 17. Murray P, Vatner S. Reduction of maximal coronary vasodilator capacity in conscious dogs with severe right ventricular hypertrophy. Circ Res 1981;48:27– 18. Doty D, Wright A, Eastham C, Marcus M. Coronary reserve in atrial septal defect. Circulation 1980;62:111–115.
Risk of Atrioventricular Block During Adenosine Pharmacologic Stress Testing in Heart Transplant Recipients Jens Toft,
MD,
Jann Mortensen,
oth dipyridamole and adenosine are used widely in pharmacologic stress testing, and their safety B profiles in patients with coronary artery disease have been established.1– 4 Adverse effects are less common with dipyridamole than with adenosine, but are more protracted and necessitate more monitoring and frequent infusions of aminophylline as well.2,3 Intravenous dipyridamole given at a dosage of 140 mg/kg/ min over 4 minutes was the standard procedure of pharmacologic stress testing in myocardial perfusion imaging in our department, but because of the more transient and milder adverse effects of adenosine, we recently changed to intravenous adenosine given by a pump (p4000 anaesthesia syringe pump, IVAC Medical Systems TM) at a dosage of 140 mg/kg/min over 6 minutes, during submaximal exercise, as recommended by Pennell et al.5 A separate intravenous catheter is used. Our experience is that the safety profile of adenosine in heart transplant recipients is markedly different from that of dipyridamole. Among nontransplant patients without a pacemaker referred to our department, the incidence of second- or thirddegree atrioventricular (AV) block, during adenosine stress, was 4% (1 of 25). In 4 of 9 heart transplant recipients, second- or third-degree AV block occurred during administration of adenosine (p ,0.01, Fisher’s test) (Table I). No patient had sustained AV block, but adenosine infusion had to be interrupted in patients 1 and 4 because of severe discomfort and chest pain. All patients had undergone pharmacologic stress tests with dipyridamole without any significant changes in the electrocardiogram during previous years. In 1 patient (no. 4), a previous dipyridamole test was accompanied by protracted headache and discomfort. From the Department of Clinical Physiology and Nuclear Medicine, Centre for Imaging, Informatics and Engineering, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. The study was supported in part by a grant from The Danish Heart Foundation. Dr. Toft’s address is: Department of Clinical Physiology and Nuclear Medicine, KF 4011, Centre for Imaging, Informatics and Engineering, Rigshospitalet, Copenhagen University Hospital, DK-2100 CPH, Copenhagen, Denmark. Manuscript received December 29, 1997; revised manuscript received and accepted April 9, 1998.
696
©1998 by Excerpta Medica, Inc. All rights reserved.
MD,
and Birger Hesse,
MD
The ability of adenosine to induce AV blockade is exploited in the treatment of paroxysmal supraventricular tachycardias, where higher doses than those used for stress testing are injected as a bolus. When adenosine is used for stress testing, usually at a dosage of 140 mg/kg/min, continuous infusion of adenosine results in second- or third-degree AV block in approximately 4% to 6% of the patients, which is in agreement with the frequency observed in our nontransplant patients.2,3 Patients taking b blockers or calcium antagonists do not have an increased risk.2 Denervation supersensitivity refers to the increased response of tissue to a neurotransmitter when its nerve supply is interrupted. After heart transplantation, the denervated sinus and AV nodes demonstrate supersensitivity to adenosine, with increased responsiveness to the negative dromotropic and chromotropic effects of adenosine.6 When the drug was injected as a bolus in lower doses (37 to 112 mg/kg) than than those traditionally used for adenosine stress, AV nodal conduction time in the denervated hearts was at least threefold longer than in hearts with intact innervation, but AV block was not reported.6 It has been proposed that the increased sensitivity only exists after a recent heart transplantation.7 Our findings in patients with 2to 8-year-old heart transplants suggest persistence of supersensitivity. The mechanism responsible for the increased sensitivity remains to be determined.8,9 Dipyridamole exerts its action by decreased cellular reuptake of endogenous adenosine10; however, the mechanisms responsible for the development of reversible defects in perfusion scintigraphy with dipyridamole stress in patients with coronary artery disease are not fully understood.11 The vasodilator potency, the ability to induce AV block, and systemic hemodynamic effects of adenosine are greater than those of dipyridamole.3,12 The incidence of AV block during a dipyridamole stress test seems to be considerably ,0.1%.1,2,4 In our department, we have performed .350 dipyridamole stress tests in 95 heart transplant recipients without occurrence of AV block. It is likely that differences in the local concentration of 0002-9149/98/$19.00 PII S0002-9149(98)00392-0
2. Cerqueira MD, Verani MS, Schwaiger M, Heo J, Iskandrian AS, and the Investigators of the Multicenter Adenoscan Trial. Safety profile of adenosine stress perfusion imaging: results from the adenoscan multicenter Years trial registry. J Am Coll Cardiol 1994;23:384 –389. 3. Johnston DL, Dailey JR, Hodge DO, Hopfenspirger Age from SPECT Degree of MR, Gibbons RJ. Hemodynamic responses and adverse Patient (yr) Sex HTX Medication* Scintigraphy AV Block effects associated with adenosine and dipyridamole pharmacologic stress testing: a comparison in 2000 1 16 F 2 0 Normal 2 patients. Mayo Clin Proc 1995;70:331–336. 2 36 M 3 Felodipine Reversible defect 2 4. Lette J, Tatum JL, Fraser S, Miller DD, Waters DD, 3 45 M 8 Nifedipine 1 furosemide Normal 3 Heller G, Stanton EB, Bom HS, Leppo J, Nattel S. 4 53 M 2 Amlodipine Normal 3 Safety of dipyridamole testing in 73,806 patients: the multicenter dipyridamole safety study. J Nucl Cardiol *All patients received immunosuppressive drugs. 1995;2:3–17. HTX 5 heart transplantation; SPECT 5 single-photon emission computed tomography. 5. Pennell DJ, Mavrogeni SI, Forbat SM, Karwatowski SP, Underwood SR. Adenosine combined with dynamic exercise for myocardial perfusion imaging. J Am Coll Cardiol 1995;25:1300 –1309. adenosine at the AV node may be responsible for the 6. Ellenbogen KA, Thames MD, DiMarco JP, Sheehan H, Lerman BB. Electroeffects of adenosine in transplanted human heart. Evidence of observed differences in inducing block. The actions of physiological supersensitivity. Circulation 1990;81:821– 828. dipyridamole may be more complex than merely caus- 7. Anderson TJ, Ryan TJ, Mudge GH, Selwyn AP, Ganz P, Yeung AC. Sinoatrial ing decreased cellular reuptake of adenosine. and atrioventricular block caused by intracoronary infusion of adenosine early Our findings suggest that adenosine stress testing, after heart transplantation. J Heart Lung Transplant 1993;12:522–524. O’Nunain S, Bertolet BD, Belardinelli L, Woodard DA, Curtis AB. Effects of with or without submaximal exercise, should be used 8. adenosine on atrial repolarization in the transplanted human heart. Am J Cardiol with caution in heart transplant recipients. Dipyridam- 1993;71:248 –251. 9. Bertolet BD, Eagle D, Conti JB, Mills RM, Belardinelli L. Bradycardia after ole can be used as an acceptable alternative. heart transplantation: reversal with theophylline. J Am Coll Cardiol 1996;28: Pharmacologic stress testing with adenosine in 396 –399. 10. Iskandrian AS. Are differences between adenosine and dipyridamole cliniheart transplant recipients implies a high risk of cally relevant. J Nucl Cardiol 1996;3:281–283. AV block. Dipyridamole is preferable as a coro- 11. McLaughlin DP, Beller GA, Linden J, Ayers CR, Ripley ML, Taylor H, Watson DD, Feldman MD. Hemodynamic and metabolic correlates of dipyrinary vasodilator. damole-induced myocardial thallium-201 perfusion abnormalities in multivessel coronary artery disease. Am J Cardiol 1994;74:1159 –1164. 12. Rossen JD, Quillen JE, Lopez JAG, Stenberg RG, Talman CL, Winniford 1. Ranhosky A, Kempthorne-Rawson J, and the Intravenous Dipyridamole ThalMD. Comparison of coronary vasodilation with intravenous dipyridamole and lium Imaging Study Group. The safety of intravenous dipyridamole thallium adenosine. J Am Coll Cardiol 1991;18:485– 491. myocardial perfusion imaging. Circulation 1990;81:1205–1209.
TABLE I Characteristics of Four Patients Developing Atrioventricular Block During Intravenous Adenosine Infusion (140 mg/kg/min)
Effect of Niacin Supplementation on Fibrinogen Levels in Patients With Peripheral Vascular Disease Claire S. Philipp,
MD,
Laura A. Cisar,
PhD,
levated fibrinogen levels and lipid abnormalities are established risk factors for peripheral vascular E disease. The predictive value of fibrinogen and lipid 1–3
levels for vascular disease suggests that therapeutic lowering of these variables may be useful in slowing or reducing the progression of atherosclerosis. Recently, hypobetalipoproteinemia has been associated with low fibrinogen levels.4 These observations suggest the possibility that lipid-lowering therapy also may result in modification of fibrinogen levels. Niacin is a highly effective agent for increasing high-density
From the Divisions of Hematology and Cardiology, Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey. This work was supported in part by grant N01-HC-25115 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland, and a grant from the Robert Wood Johnson Cardiovascular Institute, New Brunswick, New Jersey. Dr. Philipp’s address is: UMDNJ-Robert Wood Johnson Medical School, Division of Hematology, Medical Education Building, Room 378, 1 Robert Wood Johnson Place, New Brunswick, New Jersey 08903-0019. Manuscript received November 13, 1997; revised manuscript received and accepted April 7, 1998. ©1998 by Excerpta Medica, Inc. All rights reserved.
Parvin Saidi,
MD,
and John B. Kostis,
MD
lipoprotein (HDL) cholesterol and decreasing lowdensity lipoprotein (LDL) cholesterol and triglyceride levels.5,6 The aim of the present study was to evaluate the effects of niacin, antioxidants, and warfarin on hemostatic function and lipid levels in subjects with peripheral vascular disease enrolled in 1 clinical center of the Arterial Disease Multiple Intervention Trial. •••
The study population consisted of 46 subjects $30 years old with asymptomatic or symptomatic peripheral vascular disease who had an ankle brachial index ,0.85, averaged from 2 screening visits, or documented previous surgery, angioplasty, or amputation because of peripheral arterial disease.2 Medical history, including symptoms of intermittent claudication, past cardiovascular events, and smoking history, was obtained upon entry. Subjects were excluded if there was a history of unstable angina, congestive heart failure, poorly controlled diabetes, uncontrolled blood pressure, active cancer, or a history within 6 months of myocardial infarction, stroke, or vascular surgery. Subjects with liver disease or alcohol consumption 0002-9149/98/$19.00 PII S0002-9149(98)00393-2
697
14. Chillian WM, Marcus ML. Effects of coronary and extravascular pressure on intramyocardial and epicardial blood velocity. Am J Physiol 1985;248:H170 – H178. 15. Spaan J, Breuls N, Laird J. Diastolic-systolic coronary flow differences are caused by intramyocardial pump action in the anesthetized dog. Circ Res 1981; 49:584 –589. 16. Marcus M. The Coronary Circulation in Health and Disease. RR Donnelley, 1983. 17. Murray P, Vatner S. Reduction of maximal coronary vasodilator capacity in conscious dogs with severe right ventricular hypertrophy. Circ Res 1981;48:27– 18. Doty D, Wright A, Eastham C, Marcus M. Coronary reserve in atrial septal defect. Circulation 1980;62:111–115.
Risk of Atrioventricular Block During Adenosine Pharmacologic Stress Testing in Heart Transplant Recipients Jens Toft,
MD,
Jann Mortensen,
oth dipyridamole and adenosine are used widely in pharmacologic stress testing, and their safety B profiles in patients with coronary artery disease have been established.1– 4 Adverse effects are less common with dipyridamole than with adenosine, but are more protracted and necessitate more monitoring and frequent infusions of aminophylline as well.2,3 Intravenous dipyridamole given at a dosage of 140 mg/kg/ min over 4 minutes was the standard procedure of pharmacologic stress testing in myocardial perfusion imaging in our department, but because of the more transient and milder adverse effects of adenosine, we recently changed to intravenous adenosine given by a pump (p4000 anaesthesia syringe pump, IVAC Medical Systems TM) at a dosage of 140 mg/kg/min over 6 minutes, during submaximal exercise, as recommended by Pennell et al.5 A separate intravenous catheter is used. Our experience is that the safety profile of adenosine in heart transplant recipients is markedly different from that of dipyridamole. Among nontransplant patients without a pacemaker referred to our department, the incidence of second- or thirddegree atrioventricular (AV) block, during adenosine stress, was 4% (1 of 25). In 4 of 9 heart transplant recipients, second- or third-degree AV block occurred during administration of adenosine (p ,0.01, Fisher’s test) (Table I). No patient had sustained AV block, but adenosine infusion had to be interrupted in patients 1 and 4 because of severe discomfort and chest pain. All patients had undergone pharmacologic stress tests with dipyridamole without any significant changes in the electrocardiogram during previous years. In 1 patient (no. 4), a previous dipyridamole test was accompanied by protracted headache and discomfort. From the Department of Clinical Physiology and Nuclear Medicine, Centre for Imaging, Informatics and Engineering, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. The study was supported in part by a grant from The Danish Heart Foundation. Dr. Toft’s address is: Department of Clinical Physiology and Nuclear Medicine, KF 4011, Centre for Imaging, Informatics and Engineering, Rigshospitalet, Copenhagen University Hospital, DK-2100 CPH, Copenhagen, Denmark. Manuscript received December 29, 1997; revised manuscript received and accepted April 9, 1998.
696
©1998 by Excerpta Medica, Inc. All rights reserved.
MD,
and Birger Hesse,
MD
The ability of adenosine to induce AV blockade is exploited in the treatment of paroxysmal supraventricular tachycardias, where higher doses than those used for stress testing are injected as a bolus. When adenosine is used for stress testing, usually at a dosage of 140 mg/kg/min, continuous infusion of adenosine results in second- or third-degree AV block in approximately 4% to 6% of the patients, which is in agreement with the frequency observed in our nontransplant patients.2,3 Patients taking b blockers or calcium antagonists do not have an increased risk.2 Denervation supersensitivity refers to the increased response of tissue to a neurotransmitter when its nerve supply is interrupted. After heart transplantation, the denervated sinus and AV nodes demonstrate supersensitivity to adenosine, with increased responsiveness to the negative dromotropic and chromotropic effects of adenosine.6 When the drug was injected as a bolus in lower doses (37 to 112 mg/kg) than than those traditionally used for adenosine stress, AV nodal conduction time in the denervated hearts was at least threefold longer than in hearts with intact innervation, but AV block was not reported.6 It has been proposed that the increased sensitivity only exists after a recent heart transplantation.7 Our findings in patients with 2to 8-year-old heart transplants suggest persistence of supersensitivity. The mechanism responsible for the increased sensitivity remains to be determined.8,9 Dipyridamole exerts its action by decreased cellular reuptake of endogenous adenosine10; however, the mechanisms responsible for the development of reversible defects in perfusion scintigraphy with dipyridamole stress in patients with coronary artery disease are not fully understood.11 The vasodilator potency, the ability to induce AV block, and systemic hemodynamic effects of adenosine are greater than those of dipyridamole.3,12 The incidence of AV block during a dipyridamole stress test seems to be considerably ,0.1%.1,2,4 In our department, we have performed .350 dipyridamole stress tests in 95 heart transplant recipients without occurrence of AV block. It is likely that differences in the local concentration of 0002-9149/98/$19.00 PII S0002-9149(98)00392-0
2. Cerqueira MD, Verani MS, Schwaiger M, Heo J, Iskandrian AS, and the Investigators of the Multicenter Adenoscan Trial. Safety profile of adenosine stress perfusion imaging: results from the adenoscan multicenter Years trial registry. J Am Coll Cardiol 1994;23:384 –389. 3. Johnston DL, Dailey JR, Hodge DO, Hopfenspirger Age from SPECT Degree of MR, Gibbons RJ. Hemodynamic responses and adverse Patient (yr) Sex HTX Medication* Scintigraphy AV Block effects associated with adenosine and dipyridamole pharmacologic stress testing: a comparison in 2000 1 16 F 2 0 Normal 2 patients. Mayo Clin Proc 1995;70:331–336. 2 36 M 3 Felodipine Reversible defect 2 4. Lette J, Tatum JL, Fraser S, Miller DD, Waters DD, 3 45 M 8 Nifedipine 1 furosemide Normal 3 Heller G, Stanton EB, Bom HS, Leppo J, Nattel S. 4 53 M 2 Amlodipine Normal 3 Safety of dipyridamole testing in 73,806 patients: the multicenter dipyridamole safety study. J Nucl Cardiol *All patients received immunosuppressive drugs. 1995;2:3–17. HTX 5 heart transplantation; SPECT 5 single-photon emission computed tomography. 5. Pennell DJ, Mavrogeni SI, Forbat SM, Karwatowski SP, Underwood SR. Adenosine combined with dynamic exercise for myocardial perfusion imaging. J Am Coll Cardiol 1995;25:1300 –1309. adenosine at the AV node may be responsible for the 6. Ellenbogen KA, Thames MD, DiMarco JP, Sheehan H, Lerman BB. Electroeffects of adenosine in transplanted human heart. Evidence of observed differences in inducing block. The actions of physiological supersensitivity. Circulation 1990;81:821– 828. dipyridamole may be more complex than merely caus- 7. Anderson TJ, Ryan TJ, Mudge GH, Selwyn AP, Ganz P, Yeung AC. Sinoatrial ing decreased cellular reuptake of adenosine. and atrioventricular block caused by intracoronary infusion of adenosine early Our findings suggest that adenosine stress testing, after heart transplantation. J Heart Lung Transplant 1993;12:522–524. O’Nunain S, Bertolet BD, Belardinelli L, Woodard DA, Curtis AB. Effects of with or without submaximal exercise, should be used 8. adenosine on atrial repolarization in the transplanted human heart. Am J Cardiol with caution in heart transplant recipients. Dipyridam- 1993;71:248 –251. 9. Bertolet BD, Eagle D, Conti JB, Mills RM, Belardinelli L. Bradycardia after ole can be used as an acceptable alternative. heart transplantation: reversal with theophylline. J Am Coll Cardiol 1996;28: Pharmacologic stress testing with adenosine in 396 –399. 10. Iskandrian AS. Are differences between adenosine and dipyridamole cliniheart transplant recipients implies a high risk of cally relevant. J Nucl Cardiol 1996;3:281–283. AV block. Dipyridamole is preferable as a coro- 11. McLaughlin DP, Beller GA, Linden J, Ayers CR, Ripley ML, Taylor H, Watson DD, Feldman MD. Hemodynamic and metabolic correlates of dipyrinary vasodilator. damole-induced myocardial thallium-201 perfusion abnormalities in multivessel coronary artery disease. Am J Cardiol 1994;74:1159 –1164. 12. Rossen JD, Quillen JE, Lopez JAG, Stenberg RG, Talman CL, Winniford 1. Ranhosky A, Kempthorne-Rawson J, and the Intravenous Dipyridamole ThalMD. Comparison of coronary vasodilation with intravenous dipyridamole and lium Imaging Study Group. The safety of intravenous dipyridamole thallium adenosine. J Am Coll Cardiol 1991;18:485– 491. myocardial perfusion imaging. Circulation 1990;81:1205–1209.
TABLE I Characteristics of Four Patients Developing Atrioventricular Block During Intravenous Adenosine Infusion (140 mg/kg/min)
Effect of Niacin Supplementation on Fibrinogen Levels in Patients With Peripheral Vascular Disease Claire S. Philipp,
MD,
Laura A. Cisar,
PhD,
levated fibrinogen levels and lipid abnormalities are established risk factors for peripheral vascular E disease. The predictive value of fibrinogen and lipid 1–3
levels for vascular disease suggests that therapeutic lowering of these variables may be useful in slowing or reducing the progression of atherosclerosis. Recently, hypobetalipoproteinemia has been associated with low fibrinogen levels.4 These observations suggest the possibility that lipid-lowering therapy also may result in modification of fibrinogen levels. Niacin is a highly effective agent for increasing high-density
From the Divisions of Hematology and Cardiology, Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey. This work was supported in part by grant N01-HC-25115 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland, and a grant from the Robert Wood Johnson Cardiovascular Institute, New Brunswick, New Jersey. Dr. Philipp’s address is: UMDNJ-Robert Wood Johnson Medical School, Division of Hematology, Medical Education Building, Room 378, 1 Robert Wood Johnson Place, New Brunswick, New Jersey 08903-0019. Manuscript received November 13, 1997; revised manuscript received and accepted April 7, 1998. ©1998 by Excerpta Medica, Inc. All rights reserved.
Parvin Saidi,
MD,
and John B. Kostis,
MD
lipoprotein (HDL) cholesterol and decreasing lowdensity lipoprotein (LDL) cholesterol and triglyceride levels.5,6 The aim of the present study was to evaluate the effects of niacin, antioxidants, and warfarin on hemostatic function and lipid levels in subjects with peripheral vascular disease enrolled in 1 clinical center of the Arterial Disease Multiple Intervention Trial. •••
The study population consisted of 46 subjects $30 years old with asymptomatic or symptomatic peripheral vascular disease who had an ankle brachial index ,0.85, averaged from 2 screening visits, or documented previous surgery, angioplasty, or amputation because of peripheral arterial disease.2 Medical history, including symptoms of intermittent claudication, past cardiovascular events, and smoking history, was obtained upon entry. Subjects were excluded if there was a history of unstable angina, congestive heart failure, poorly controlled diabetes, uncontrolled blood pressure, active cancer, or a history within 6 months of myocardial infarction, stroke, or vascular surgery. Subjects with liver disease or alcohol consumption 0002-9149/98/$19.00 PII S0002-9149(98)00393-2
697