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Emerging importance of alpha-adrenergic coronary vasoconstriction in acute coronary syndromes and its genetic background
Journal of the American College of Cardiology © 2003 by the American College of Cardiology Foundation Published by Elsevier Science Inc.
EDITORIAL COMMENT
Emerging Importance of AlphaAdrenergic Coronary Vasoconstriction in Acute Coronary Syndromes and its Genetic Background* Gerd Heusch, MD, FESC, FACC, FAHA, FISHR Essen, Germany As compared to the beta-adrenoceptor–mediated effects of sympathetic activation, alpha-adrenoceptor–mediated effects on coronary blood flow have long received little attention. This was largely due to the fact that, in animal experiments under physiologic circumstances, there is very little alpha-adrenergic coronary vasomotor tone at rest, and the increase in coronary blood flow during sympathetic activation is only somewhat blunted. More recent experimental studies, however, clearly demonstrated that, when the coronary circulation is compromised by hypercholesterolemia (1), endothelial dysfunction (2), exhaustion of autoregulation (3), or severe coronary stenoses (4,5), alphaadrenergic vasoconstriction is unrestrained and powerful enough to reduce coronary blood flow and induce myocardial ischemia (6). Both, alpha1- and alpha2-adrenoceptors mediate such coronary vasoconstriction, with alpha2adrenoceptors more predominant in the microcirculation (3,7). See page 190 Over the last decade, various studies using quantitative coronary angiography, Doppler flow probes, and positron emission tomography have demonstrated the importance of alpha-adrenergic coronary vasoconstriction in humans (8). As in animal experiments, studies in humans under physiologic conditions show there is no limitation of resting coronary blood flow by alpha-adrenergic coronary vasoconstriction, but there is a limitation of coronary reserve (9). However, again as in the animal experiments, alphaadrenergic coronary vasoconstriction is enhanced in patients with endothelial dysfunction and atherosclerosis (10 –12). In patients with established coronary artery disease (CAD), both selective alpha1- and alpha2-adrenoceptor activation induce augmented coronary vasoconstriction, and alpha2adrenergic vasoconstriction is then powerful enough to induce net lactate production and electrocardiographic signs *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the University Clinic, Essen, Germany.
Vol. 41, No. 2, 2003 ISSN 0735-1097/03/$30.00 S0735-1097(02)02703-1
of ischemia (11). Notably, reflex alpha-adrenergic coronary vasoconstriction is also elicited during coronary interventions (13,14), and this contributes to postinterventional contractile dysfunction (15,16). Very recently, a genetic determination of alphaadrenergic coronary vasoconstriction has emerged (17). A polymorphism in the gene encoding for the G3 subunit of pertussis-sensitive G proteins, which is associated with alternative splicing and enhanced signal transduction (18), induces a pronounced supersensitivity to alpha2-adrenergic coronary vasoconstriction in the 825T-allele carriers, which adds to the augmentation of alpha-adrenergic coronary vasoconstriction in the presence of atherosclerosis per se (19). It is against this background that the current study by Snapir et al. (20) in this issue of the Journal provides additional evidence for the importance of alpha2-adrenergic coronary vasoconstriction and its genetic determination. A deletion/insertion polymorphism in the alpha 2B adrenoceptor (21) has previously been shown by these investigators to be a novel genetic risk factor for CAD, insofar as individuals with the deletion/deletion genotype had an increased risk of acute myocardial infarction in a population-based prospective study (22). The study by Snapir et al. (20) extends the prior study and points to the importance of alpha2-adrenergic coronary vasoconstriction in the causal pathogenesis of myocardial infarction and also sudden cardiac death in a well-characterized, unselected cohort of Caucasian men who had suffered out-of-hospital death. Of note, the classical risk factors for CAD in the deletion/deletion genotype were no different from those in the insertion/deletion and insertion/insertion genotype. In addition, no difference was observed in the extent of coronary atherosclerosis at autopsy. Finally, there was no evidence for coronary thrombosis at autopsy, further supporting the importance of enhanced alpha2-adrenergic coronary vasoconstriction as the underlying mechanism of acute myocardial infarction and sudden cardiac death. The major limitation of the present study (20), as with all other association studies, is its purely descriptive nature and the lack of definition of a functional phenotype (17). Of note, such functional phenotype was defined for the G3 subunit polymorphism (19), and this clearly needs to be done for the alpha2B-polymorphism in the future, too. It is also tempting to speculate about a potentially additive genetic risk conferred by a combination of the 825Tallele of the G3 subunit and the deletion/deletion genotype of the alpha2B-adrenoceptor in further enhancing alpha2-adrenoceptor–mediated signal transduction, resulting coronary microvascular constriction and ultimately inducing acute myocardial infarction and sudden cardiac death. Future studies will most certainly resolve this question.
196
Heusch Editorial Comment
Reprint requests and correspondence: Prof. Dr. Med. Dr. h.c. Gerd Heusch, Direktor des Instituts fu¨ r Pathophysiologie, Zentrum fu¨ r Innere Medizin, Universita¨ tsklinikum Essen, Hufelandstr. 55, 45122 Essen, Germany. E-mail: [email protected].
REFERENCES 1. Rosendorff C, Hoffman JIE, Verrier ED, Rouleau J, Boerboom LE. Cholesterol potentiates the coronary artery response to norepinephrine in anesthetized and conscious dogs. Circ Res 1981;48:320 –9. 2. Jones CJH, DeFily DV, Patterson JL, Chilian WM. Endotheliumdependent relaxation competes with ␣1- and ␣2-adrenergic constriction in the canine epicardial coronary microcirculation. Circulation 1993;87:1264 –76. 3. Chilian WM. Functional distribution of ␣1- and ␣2-adrenergic receptors in the coronary microcirculation. Circulation 1991;84:2108 –22. 4. Heusch G, Deussen A. The effects of cardiac sympathetic nerve stimulation on the perfusion of stenotic coronary arteries in the dog. Circ Res 1983;53:8 –15. 5. Seitelberger R, Guth BD, Heusch G, Lee JD, Katayama K, Ross J Jr. Intracoronary alpha2-adrenergic receptor blockade attenuates ischemia in conscious dogs during exercise. Circ Res 1988;62:436 –42. 6. Heusch G. ␣-Adrenergic mechanisms in myocardial ischemia. Circulation 1990;81:1–13. 7. Heusch G, Deussen A, Schipke J, Tha¨ mer V. ␣1- and ␣2Adrenoceptor–mediated vasoconstriction of large and small canine coronary arteries in vivo. J Cardiovasc Pharmacol 1984;6:961–8. 8. Heusch G, Baumgart D, Camici P, et al. ␣-Adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation 2000;101:689 –94. 9. Lorenzoni R, Rosen SD, Camici PG. Effect of ␣1-adrenoceptor blockade on resting and hyperemic myocardial blood flow in normal humans. Am J Physiol 1996;40:H1302–6. 10. Zeiher AM, Drexler H, Wollschla¨ ger H, Just H. Endothelial dysfunction of the coronary microvasculature is associated with impaired coronary blood flow regulation in patients with early atherosclerosis. Circulation 1991;84:1–10.
JACC Vol. 41, No. 2, 2003 January 15, 2003:195–6 11. Baumgart D, Haude M, Gorge G, et al. Augmented alpha-adrenergic constriction of atherosclerotic human coronary arteries. Circulation 1999;99:2090 –7. 12. Julius BK, Vassalli G, Mandinov L, Hess OM. ␣-Adrenoceptor blockade prevents exercise-induced vasoconstriction of stenotic coronary arteries. J Am Coll Cardiol 1999;33:1499 –505. 13. Gregorini L, Fajadet J, Robert G, Cassagneau B, Bernis M, Marco J. Coronary vasoconstriction after percutaneous transluminal coronary angioplasty is attenuated by antiadrenergic agents. Circulation 1994; 90:895–907. 14. Indolfi C, Piscione F, Rapacciuolo A, et al. Coronary artery vasoconstriction after successful single angioplasty of the left anterior descending artery. Am Heart J 1994;128:858 –64. 15. Gregorini L, Marco J, Palombo C, et al. Postischemic left ventricular dysfunction is abolished by alpha-adrenergic blocking agents. J Am Coll Cardiol 1998;31:992–1001. 16. Gregorini L, Marco J, Koza`kova` M, et al. Alpha-adrenergic blockade improves recovery of myocardial perfusion and function after coronary stenting in patients with acute myocardial infarction. Circulation 1999;99:482–90. 17. Heusch G, Erbel R, Siffert W. Genetic determinants of coronary vasomotor tone in humans. Am J Physiol Heart Circ Physiol 2001; 281:H1465–8. 18. Siffert W, Rosskopf D, Siffert G, et al. Association of human G-protein 3 subunit variant with hypertension. Nat Genet 1998;18: 45–8. 19. Baumgart D, Naber C, Haude M, et al. G-protein 3 subunit 825T-allele and enhanced coronary vasoconstriction upon ␣2adrenoceptor activation. Circ Res 1999;85:965–9. 20. Snapir A, Mikkelsson J, Perola M, Penttila¨ A, Scheinin M, Karhunen PJ. Variation in the alpha2B-adrenoceptor gene as a risk factor for prehospital fatal myocardial infarction and sudden cardiac death. J Am Coll Cardiol 2003;41:190 – 4. 21. Small KM, Liggett SB. Identification and functional characterization of alpha(2)-adrenoceptor polymorphisms. Trends Pharmacol Sci 2001; 22:471–7. 22. Snapir A, Heinonen P, Tuomainen T-P, et al. An insertion/deletion polymorphism in the ␣2B-adrenergic receptor gene is a novel genetic risk factor for acute coronary events. J Am Coll Cardiol 2001;37:1516 – 22.
EDITORIAL COMMENT
Emerging Importance of AlphaAdrenergic Coronary Vasoconstriction in Acute Coronary Syndromes and its Genetic Background* Gerd Heusch, MD, FESC, FACC, FAHA, FISHR Essen, Germany As compared to the beta-adrenoceptor–mediated effects of sympathetic activation, alpha-adrenoceptor–mediated effects on coronary blood flow have long received little attention. This was largely due to the fact that, in animal experiments under physiologic circumstances, there is very little alpha-adrenergic coronary vasomotor tone at rest, and the increase in coronary blood flow during sympathetic activation is only somewhat blunted. More recent experimental studies, however, clearly demonstrated that, when the coronary circulation is compromised by hypercholesterolemia (1), endothelial dysfunction (2), exhaustion of autoregulation (3), or severe coronary stenoses (4,5), alphaadrenergic vasoconstriction is unrestrained and powerful enough to reduce coronary blood flow and induce myocardial ischemia (6). Both, alpha1- and alpha2-adrenoceptors mediate such coronary vasoconstriction, with alpha2adrenoceptors more predominant in the microcirculation (3,7). See page 190 Over the last decade, various studies using quantitative coronary angiography, Doppler flow probes, and positron emission tomography have demonstrated the importance of alpha-adrenergic coronary vasoconstriction in humans (8). As in animal experiments, studies in humans under physiologic conditions show there is no limitation of resting coronary blood flow by alpha-adrenergic coronary vasoconstriction, but there is a limitation of coronary reserve (9). However, again as in the animal experiments, alphaadrenergic coronary vasoconstriction is enhanced in patients with endothelial dysfunction and atherosclerosis (10 –12). In patients with established coronary artery disease (CAD), both selective alpha1- and alpha2-adrenoceptor activation induce augmented coronary vasoconstriction, and alpha2adrenergic vasoconstriction is then powerful enough to induce net lactate production and electrocardiographic signs *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the University Clinic, Essen, Germany.
Vol. 41, No. 2, 2003 ISSN 0735-1097/03/$30.00 S0735-1097(02)02703-1
of ischemia (11). Notably, reflex alpha-adrenergic coronary vasoconstriction is also elicited during coronary interventions (13,14), and this contributes to postinterventional contractile dysfunction (15,16). Very recently, a genetic determination of alphaadrenergic coronary vasoconstriction has emerged (17). A polymorphism in the gene encoding for the G3 subunit of pertussis-sensitive G proteins, which is associated with alternative splicing and enhanced signal transduction (18), induces a pronounced supersensitivity to alpha2-adrenergic coronary vasoconstriction in the 825T-allele carriers, which adds to the augmentation of alpha-adrenergic coronary vasoconstriction in the presence of atherosclerosis per se (19). It is against this background that the current study by Snapir et al. (20) in this issue of the Journal provides additional evidence for the importance of alpha2-adrenergic coronary vasoconstriction and its genetic determination. A deletion/insertion polymorphism in the alpha 2B adrenoceptor (21) has previously been shown by these investigators to be a novel genetic risk factor for CAD, insofar as individuals with the deletion/deletion genotype had an increased risk of acute myocardial infarction in a population-based prospective study (22). The study by Snapir et al. (20) extends the prior study and points to the importance of alpha2-adrenergic coronary vasoconstriction in the causal pathogenesis of myocardial infarction and also sudden cardiac death in a well-characterized, unselected cohort of Caucasian men who had suffered out-of-hospital death. Of note, the classical risk factors for CAD in the deletion/deletion genotype were no different from those in the insertion/deletion and insertion/insertion genotype. In addition, no difference was observed in the extent of coronary atherosclerosis at autopsy. Finally, there was no evidence for coronary thrombosis at autopsy, further supporting the importance of enhanced alpha2-adrenergic coronary vasoconstriction as the underlying mechanism of acute myocardial infarction and sudden cardiac death. The major limitation of the present study (20), as with all other association studies, is its purely descriptive nature and the lack of definition of a functional phenotype (17). Of note, such functional phenotype was defined for the G3 subunit polymorphism (19), and this clearly needs to be done for the alpha2B-polymorphism in the future, too. It is also tempting to speculate about a potentially additive genetic risk conferred by a combination of the 825Tallele of the G3 subunit and the deletion/deletion genotype of the alpha2B-adrenoceptor in further enhancing alpha2-adrenoceptor–mediated signal transduction, resulting coronary microvascular constriction and ultimately inducing acute myocardial infarction and sudden cardiac death. Future studies will most certainly resolve this question.
196
Heusch Editorial Comment
Reprint requests and correspondence: Prof. Dr. Med. Dr. h.c. Gerd Heusch, Direktor des Instituts fu¨ r Pathophysiologie, Zentrum fu¨ r Innere Medizin, Universita¨ tsklinikum Essen, Hufelandstr. 55, 45122 Essen, Germany. E-mail: [email protected].
REFERENCES 1. Rosendorff C, Hoffman JIE, Verrier ED, Rouleau J, Boerboom LE. Cholesterol potentiates the coronary artery response to norepinephrine in anesthetized and conscious dogs. Circ Res 1981;48:320 –9. 2. Jones CJH, DeFily DV, Patterson JL, Chilian WM. Endotheliumdependent relaxation competes with ␣1- and ␣2-adrenergic constriction in the canine epicardial coronary microcirculation. Circulation 1993;87:1264 –76. 3. Chilian WM. Functional distribution of ␣1- and ␣2-adrenergic receptors in the coronary microcirculation. Circulation 1991;84:2108 –22. 4. Heusch G, Deussen A. The effects of cardiac sympathetic nerve stimulation on the perfusion of stenotic coronary arteries in the dog. Circ Res 1983;53:8 –15. 5. Seitelberger R, Guth BD, Heusch G, Lee JD, Katayama K, Ross J Jr. Intracoronary alpha2-adrenergic receptor blockade attenuates ischemia in conscious dogs during exercise. Circ Res 1988;62:436 –42. 6. Heusch G. ␣-Adrenergic mechanisms in myocardial ischemia. Circulation 1990;81:1–13. 7. Heusch G, Deussen A, Schipke J, Tha¨ mer V. ␣1- and ␣2Adrenoceptor–mediated vasoconstriction of large and small canine coronary arteries in vivo. J Cardiovasc Pharmacol 1984;6:961–8. 8. Heusch G, Baumgart D, Camici P, et al. ␣-Adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation 2000;101:689 –94. 9. Lorenzoni R, Rosen SD, Camici PG. Effect of ␣1-adrenoceptor blockade on resting and hyperemic myocardial blood flow in normal humans. Am J Physiol 1996;40:H1302–6. 10. Zeiher AM, Drexler H, Wollschla¨ ger H, Just H. Endothelial dysfunction of the coronary microvasculature is associated with impaired coronary blood flow regulation in patients with early atherosclerosis. Circulation 1991;84:1–10.
JACC Vol. 41, No. 2, 2003 January 15, 2003:195–6 11. Baumgart D, Haude M, Gorge G, et al. Augmented alpha-adrenergic constriction of atherosclerotic human coronary arteries. Circulation 1999;99:2090 –7. 12. Julius BK, Vassalli G, Mandinov L, Hess OM. ␣-Adrenoceptor blockade prevents exercise-induced vasoconstriction of stenotic coronary arteries. J Am Coll Cardiol 1999;33:1499 –505. 13. Gregorini L, Fajadet J, Robert G, Cassagneau B, Bernis M, Marco J. Coronary vasoconstriction after percutaneous transluminal coronary angioplasty is attenuated by antiadrenergic agents. Circulation 1994; 90:895–907. 14. Indolfi C, Piscione F, Rapacciuolo A, et al. Coronary artery vasoconstriction after successful single angioplasty of the left anterior descending artery. Am Heart J 1994;128:858 –64. 15. Gregorini L, Marco J, Palombo C, et al. Postischemic left ventricular dysfunction is abolished by alpha-adrenergic blocking agents. J Am Coll Cardiol 1998;31:992–1001. 16. Gregorini L, Marco J, Koza`kova` M, et al. Alpha-adrenergic blockade improves recovery of myocardial perfusion and function after coronary stenting in patients with acute myocardial infarction. Circulation 1999;99:482–90. 17. Heusch G, Erbel R, Siffert W. Genetic determinants of coronary vasomotor tone in humans. Am J Physiol Heart Circ Physiol 2001; 281:H1465–8. 18. Siffert W, Rosskopf D, Siffert G, et al. Association of human G-protein 3 subunit variant with hypertension. Nat Genet 1998;18: 45–8. 19. Baumgart D, Naber C, Haude M, et al. G-protein 3 subunit 825T-allele and enhanced coronary vasoconstriction upon ␣2adrenoceptor activation. Circ Res 1999;85:965–9. 20. Snapir A, Mikkelsson J, Perola M, Penttila¨ A, Scheinin M, Karhunen PJ. Variation in the alpha2B-adrenoceptor gene as a risk factor for prehospital fatal myocardial infarction and sudden cardiac death. J Am Coll Cardiol 2003;41:190 – 4. 21. Small KM, Liggett SB. Identification and functional characterization of alpha(2)-adrenoceptor polymorphisms. Trends Pharmacol Sci 2001; 22:471–7. 22. Snapir A, Heinonen P, Tuomainen T-P, et al. An insertion/deletion polymorphism in the ␣2B-adrenergic receptor gene is a novel genetic risk factor for acute coronary events. J Am Coll Cardiol 2001;37:1516 – 22.