- Email: [email protected]
Comparison of response to serotonin of radial artery grafts and internal mammary grafts to native coronary arteries and the effect of diltiazem
Comparison of Response to Serotonin of Radial Artery Grafts and Internal Mammary Grafts to Native Coronary Arteries and the Effect of Diltiazem Giovanni Sperti, MD, Eric Manasse, MD, Amir Kol, MD, Carlo Canosa, MD, Susanna Grego, MD, Caterina Milici, MD, Rocco Schiavello, MD, Gian Federico Possati, MD, Filippo Crea, MD, and Attilio Maseri, MD se of the radial artery (RA) for coronary artery bypass grafting (CABG) initially was introduced U by Carpentier et al in 1973 but subsequently was 1
abandoned because of frequent early closure and vessel spasm.2 The introduction of calcium antagonists to prevent spasm and the unexpectedly good long-term results of some of the initial cases prompted reevaluation of this conduit by the same group. In a recent series of 104 patients (122 RA grafts) treated with calcium antagonists after revascularization, Acar et al3 found a patency rate of 93.5% in 27 patients who underwent angiographic control 9.2 months after CABG. Despite treatment with calcium antagonists, however, 6 of 50 patients (12%) who underwent an early angiogram (within 3 weeks) had RA spasm. This frequency raises the question of whether the RA is more reactive to physiologic stimuli than other arterial conduits. To test this hypothesis, we evaluated the response to serotonin of the free RA grafts, pedicled left internal mammary artery (IMA) grafts, and native coronary arteries in 22 patients who had undergone CABG. We also evaluated the effect of chronic treatment with diltiazem on the basal tone and reactivity of the RA grafts and the effect of serotonin and native vessels distal to graft anastomosis. •••
As part of a larger study on medium- and long-term results of arterial revascularization in CABG, which included a control angiogram 1 year after the operation, we studied 22 consecutive patients not taking antianginal medications (19 men and 3 women; mean age 59 years, range 45 to 73; mean follow-up 338 days, range 243 to 484). Seventeen patients had multivessel disease and 5 had 2-vessel disease. Twentytwo patients had a graft prepared with an RA, and 18 patients also had a graft with a left IMA. Nine patients were receiving chronic diltiazem treatment (8 men and 1 woman; mean age 61 years, range 46 to 68; mean follow-up 301 days, range 229 to 339). Six patients had multivessel disease and 3 had 2-vessel disease. The 2 groups did not differ significantly with respect to age, sex, mean follow-up duration, and number of diseased coronary arteries. In all patients, both the RA and the left IMA were widely patent without angiographic evidence of focal From the Institute of Cardiology and Cardiac Surgery, and the Department of Anesthesia, Catholic University, Rome, Italy. Dr. Sperti’s address is: Institute of Cardiology, Catholic University, Largo A Gemelli 8, Rome 00168, Italy. E-mail: [email protected]. Manuscript received May 6, 1998; revised manuscript received and accepted September 8, 1998.
592
©1999 by Excerpta Medica, Inc. All rights reserved.
stenosis. The study protocol was approved by the Clinical Research Ethical Committee of the Catholic University School of Medicine. Written informed consent was obtained from all patients. The RAs were pretreated after harvesting and anastomosed proximally to the aorta. Pretreatment consisted of the injection of normal saline solution supplemented with heparin, papaverine, and blood at a constant pressure of 70 mm Hg, associated with a careful opening of the fascia down to the outer lining of the adventitia. One patient had 2 grafts prepared with the same RA. All patients were administered intravenous diltiazem, begun intraoperatively and continued in the intensive care unit at a dosage of 1 mg/kg/min. Diltiazem 120 mg given orally twice daily was started as soon as oral medications were resumed after the operation. In the first 22 patients, antianginal medications including diltiazem were discontinued 48 hours before the study. In the remaining 9 patients, diltiazem was not stopped and angiography was performed 2 to 4 hours after the morning dose of diltiazem. Antiaggregant therapy was continued in all patients. In the first group of patients, serotonin was selectively infused into the left IMA and then into the RA at concentrations of 1 3 1026 M and 1 3 1025 M for 3 minutes at a rate of 3 ml/min. A 2-mg bolus of isosorbide dinitrate was injected into the radial artery after the serotonin injection. Because left IMA grafts did not show any response to serotonin after a 48-hour washout period, in the second group of 9 patients still taking diltiazem at the time of the study, the infusion of serotonin was made into the RA only. Angiograms obtained at baseline and after serotonin and isosorbide dinitrate administration were analyzed using computerized quantitative angiography (Medis, Neuen, The Netherlands).4 – 6 Populations were compared using the chi-square test. Vessel diameters were compared using 2-way analysis of variance and the Newman-Keuls test. A p value #0.05 was considered statistically significant. Results are expressed as mean 6 1 SD. In the first group of patients who were not taking diltiazem at the time of the study, 3 of 22 RA grafts were excluded from the study, because cannulation was not sufficiently selective in 1 case and because nitrates were administered during the cardiac catheterization procedure before the planned serotonin infusion owing to chest pain in the other 2 cases. Of a total of 18 left IMA grafts, 5 were excluded because cannulation was not deemed sufficiently selective for 0002-9149/99/$–see front matter PII S0002-9149(98)00920-5
FIGURE 1. RA response to serotonin (5HT) infusion during pharmacologic washout. Statistically significant vasoconstriction was observed after selective infusion at concentrations of 1 3 1026 M and 1 3 1025 M for 3 minutes at a rate of 3 ml/min. Vessel diameter returned promptly to baseline after selective injection of 2 mg of isosorbide dinitrate (ISDN). Closed circles with bars represent mean 6 SD.
FIGURE 2. Right caudal oblique projection of an RA graft anastomosed to the circumflex artery. A, baseline; B, after selective injection of serotonin 1026 M, a small diameter reduction can be appreciated; C, after selective injection of serotonin 1025 M, a diffuse highgrade vasoconstriction is observed; D, after administration of nitrates, vasoconstriction resolves immediately. BRIEF REPORTS
593
FIGURE 3. Left internal mammary artery (LIMA) response to selective infusion of serotonin (5HT). No vasoconstriction was observed at the same doses used for the RA (1026 M and 1025 M). Closed circles with bars represent mean 6 SD.
drug infusion. Serotonin infusion into the RA at concentrations of 1 3 1026 M and 13 1025 M determined a significant vasocontriction from a diameter of 2.06 6 0.48 mm (mean 6 SD) to 1.69 6 0.46 mm (15.6% diameter reduction, p ,0.03) and 1.14 6 0.79 mm (42.6% diameter reduction, p ,0.0001), respectively (Figure 1). Serotonin induced vasoconstriction in all grafts but 1. The lumen reduction was distributed over the entire length of the vessel, was short lasting, and promptly resolved after administration of nitrates. In 4 cases, a diffuse high-grade vasoconstriction developed with virtually no runoff of contrast dye (Figure 2). In contrast, left IMA grafts did not show any change in diameter compared with baseline after serotonin infusion (p 5 NS) (Figures 3 and 4). After intraluminal injection of nitrates, the diameters of the left IMA and RA grafts were not significantly different from baseline values (Figures 1 and 3). In patients who were taking diltiazem at the time of angiography, serotonin infusion at a concentration of 1 3 1026 M reduced the lumen diameter from 2.10 6 0.46 to 1.72 6 0.23 mm (mean 6 SD, 21.1% diameter reduction, p 5 0.15). The higher concentration of 1 3 1025 M induced a significant diameter reduction to 1.40 6 0.72 mm (37.5% diameter reduction, p ,0.0004). In 2 cases the vessel diameter showed the same pattern of subtotal occlusion as the 4 cases of the untreated group, in 1 case after administration of the lower serotonin dose (Figure 5). The effect of serotonin and isosorbide dinitrate was assessed in the native vessels distal to the graft anastomosis. In agreement with previous observations,7 a nonsignificant degree of lumen diameter reduction was observed after serotonin administration at 1 3 1025M, from a baseline value of 1.60 6 0.45 to 1.46 6 0.23 mm (8.7% diameter reduction, p ,0.3). However, after nitrate administration there was a significant increase of vessel diameter compared with 594 THE AMERICAN JOURNAL OF CARDIOLOGYT
VOL. 83
FIGURE 4. Left anterior oblique projection of a left internal mammary artery graft anastomosed to the left descending anterior coronary artery. A, baseline; B, after selective infusion of serotonin 1025 M, no vasocontrictive response is observed.
baseline values, to 1.91 6 0.46 mm (16.9% diameter increase, p ,0.03) (Figure 6). FEBRUARY 15, 1999
FIGURE 5. RA response to serotonin (5HT) infusion in the group of patients taking diltiazem at the time of angiography. Selective 5HT infusion at the lower dose of 1 3 1026 M induced a nonstatistically significant vasocostriction; the diameter reduction induced by the higher dose of 1 3 1025 M was statistically significant. Vessel diameter returned promptly to baseline values after selective injection of 2 mg of isosorbide dinitrate (ISDN). Closed circles with bars represent mean 6 SD.
FIGURE 6. Effect of serotonin (5HT) and isosorbide dinitrate (ISDN) on the native vessels distal to the graft anastomosis. Caliber reduction after 5HT 1 3 1025 M was not statistically significant. However, after ISDN infusion there was a significant increase of vessel diameter compared with baseline values. Closed circles with bars represent mean 6 SD.
•••
Our results show that RA grafts develop significant vasocontriction in response to serotonin. In contrast, no response to serotonin was observed in the left IMA grafts, although both the RA and the left IMA appear to be dilated in the basal state. This strikingly different constrictive response could be accounted for by differences in the wall structure. The RA is muscular, with all 3 layers, intima, media, and adventitia thicker than those of the left IMA. However, the smooth muscle layer of the left IMA is capable of causing significant changes in vessel diameter, as demonstrated by the clinical observation of severe spasm in the periprocedural period.8 Serotonin is a potent vasoconstrictor9,10 that plays an important role in the homeostasis of the cardiovascular system and in the pathogenesis of coronary heart disease.11 Its vasoconstrictive effects vary among species and different anatomic sites.12 In vitro, however, left IMA can respond to serotonin with a sensitivity
similar to that observed in the RA,13,14 although with a somewhat lower developed force. This indicates that the signal transduction pathway involving serotonin is functioning normally in the left IMA. It cannot be excluded that a higher degree of endothelial-mediated vasodilation in response to serotonin compared with the RA could account for its unresponsiveness to this hormone. However, this seems unlikely, as the degree of endothelial-mediated vasodilation in response to serotonin appears to be negligible in the isolated left IMA. A different extent of endothelial damage occurring during surgical harvesting of the 2 arteries is unlikely to be relevant, because patients were studied about 1 year after surgery, and it is likely that any endothelial denudation would have been repaired by that time. Pedicled grafts also differ from the free ones in other important aspects. In the latter, a permanent consequence of preparing a conduit for aortocoronary anastomosis is denervation. It is conceivable that denervation supersenBRIEF REPORTS
595
sitivity and the loss of neural modulatory influences could alter the response to mediators. Nitrate administration into native coronary arteries determines a vasodilation demonstrating the presence of a basal tone.7 This was confirmed in our patients after isosorbide dinitrate administration. On the other hand, both left IMA and RA grafts did not show any increase in diameter compared with baseline after selective isorbide dinitrate administration. This may imply an inability of the arterial conduits used for CABG to dilate in response to higher flow requirements compared with native coronary arteries. In our patients, oral diltiazem did not prevent serotonin-induced contraction of RA grafts. The extent of vasoconstriction at a dose of 1025 M was comparable to that observed in washout patients. A similar trend was detectable at the lower dose of 1026 M, although it was not statistically significant because of the fewer patients. Severe diffuse vasoconstriction still was observed in 2 of 9 patients, 1 at the lower dose of 1026 M. Our study has some limitations. The number of patients, particularly in the diltiazem group, is relatively small. It must be considered, however, this is an invasive study. Another confounding factor could be the relatively short period of pharmacologic washout. An incomplete washout, however, would have blunted the extent of vasoconstriction determined by the serotonin infusion, which in our experimental conditions was clearly detectable. Our study clearly demonstrates that the response to agonists and vasodilators in vivo is strikingly different among different arteries when used for coronary grafting and requires further investigations to better understand the mechanisms un-
derlying this biologic variability and to devise better targeted treatments. 1. Carpentier A, Guermonprez JL, Deloche A, Frechette C, Dubost C. The
aorto-to-coronary radial artery bypass graft: a technique avoiding pathological changes in grafts. Ann Thorac Surg 1973;16:111–121. 2. Fisk RL, Bruosk CH, Callaghan JC, Dvorkin J. Experience with the radial artery for coronary bypass. Ann Thorac Surg 1976;21:513–518. 3. Acar C, Jebara VA, Portoghese M, Beyssen B, Pagny JY, Grare P, Chachques JC, Fabiani JN, Deloche A, Guermonprez JL, Carpentier A. Revival of the radial artery for coronary bypass grafting. Ann Thorac Surg 1992;54:652– 660. 4. Reiber JHC, Serruys PW, Koojman CJ, Wijns W, Slager CJ, Shuurbiers JCH, Den Boer A, Hugenholtz PG. Assessment of short-, medium- and long-term variations in arterial dimensions from computer-assisted quantification of coronary cineangiograms. Circulation 1985;71:280 –288. 5. Reiber JHC, van der Zwet PMJ, Konig G, von land CD, van Meusen B, Gerbrands JJ, Buis B, van Voorthiiusen AE. Accuracy and precision of quantitative digital coronary arteriography; observer-, as well as short- and mediumterm variabilities. Cathet Cardiovasc Diagn 1993;28:187–198. 6. Zijlstra F, Van Ommeren J, Reiber JHC, Serruys PW. Does the quantitative assessment of coronary artery dimensions predict the physiologic significance of a coronary artery stenosis? Circulation 1987;75:1154 –1161. 7. McFadden EP, Clarke JG, Davies GJ, Kaski JC, Haider AW, Maseri A. Effect of intracoronary serotonin on coronary vessels in patients with stable angina and patients with variant angina. N Engl J Med 1991;324:648 – 654. 8. Sarabu MR, McClung JA, Fass A, Reed GE. Early postoperative spasm in left internal mammary artery bypass grafts. Ann Thorac Surg 1987;44:199 –200. 9. Luscher TF, Richard V, Tschudi M, Yang Z. Serotonin and the endothelium. Clin Physiol Biochem 1990;8(III):108 –119. 10. Connor HE, Feniuk W, Humphrey PPA. 5-Hydroxytryptamine contracts human coronary arteries predominantly via 5-HT2 receptor activation. Eur J Pharm 1989;161:91–94. 11. Houston D, Vanhoutte PM. Serotonin and the vascular system: role in health and disease and implications for therapy. Drugs 1986;31:149 –163. 12. Burrows ME, Vanhoutte PM. Pharmacology of arterioles: some aspects of variability in response to norepinephrine, histamine and 5-hydroxytryptamine. J Cardiovasc Parmacol 1981;3:1370 –1380. 13. Conti A, Monopoli A, Forlani A, Ongini E, Antona C, Biglioli P. Role of 5-HT2 receptors in serotonin-induced contraction in the human mammary artery. Eur J Pharm 1990;176:207–212. 14. Dignan RJ, Yeh T Jr, Dyke CM, Francis LK, Lutz HA, Ding M, Wechsler AS. Reactivity of gastroepiploic and internal mammary arteries. J Thorac Cardiovasc Surg 1992;103:116 –123.
Effect of Beta-Adrenergic Blocker Therapy on the Circadian Rhythm of Heart Rate Variability in Patients With Chronic Stable Angina Pectoris Andrew J. Burger,
MD,
and Masoor Kamalesh,
eart rate variability (HRV), an indirect measurement of cardiac autonomic tone, has been shown H to be reduced in patients with coronary artery disease. Decreased HRV has been associated with increased mortality in this patient population.1 In addition, the occurrences of acute myocardial infarction and cardiac ischemia exhibit circadian variation.2 Sudden cardiac death, including ischemic and nonischemic (presumably ventricular arrhythmia) etiologies, has been shown to have circadian patterns.3 These circadian From the Division of Cardiology, Beth Israel Deaconess Medical Center, West Campus, Harvard Medical School, Boston, Massachusetts. Dr. Burger’s address is: Beth Israel Deaconess Medical Center, West Campus, Noninvasive Cardiology Laboratory, Baker-3, 1 Deaconess Road, Boston, Massachusetts 02215. E-mail: aburger@ bidmc.harvard.edu. Manuscript received July 23, 1998; revised manuscript received and accepeted September 28, 1998.
596
©1999 by Excerpta Medica, Inc. All rights reserved.
MD
rhythms have been attributed to a number of earlymorning physiologic and hematologic changes, including an early-morning increase in sympathetic tone.2 Beta-adrenergic blocker therapy has been shown to improve cardiac autonomic function by increasing HRV, which translates clinically into decreased cardiac events.4 Data are limited as to the degree of improvement in autonomic function that b-blocker therapy achieves in coronary artery disease. By increasing parasympathetic activity and decreasing sympathetic tone, b-adrenergic blockers are one of the few pharmacologic interventions available that improve outcome in patients at risk of sudden death. We analyzed the amount of improvement in cardiac autonomic function in patients with chronic stable angina receiving b-blocker therapy and compared it with normal controls. 0002-9149/99/$–see front matter PII S0002-9149(98)00921-7
abandoned because of frequent early closure and vessel spasm.2 The introduction of calcium antagonists to prevent spasm and the unexpectedly good long-term results of some of the initial cases prompted reevaluation of this conduit by the same group. In a recent series of 104 patients (122 RA grafts) treated with calcium antagonists after revascularization, Acar et al3 found a patency rate of 93.5% in 27 patients who underwent angiographic control 9.2 months after CABG. Despite treatment with calcium antagonists, however, 6 of 50 patients (12%) who underwent an early angiogram (within 3 weeks) had RA spasm. This frequency raises the question of whether the RA is more reactive to physiologic stimuli than other arterial conduits. To test this hypothesis, we evaluated the response to serotonin of the free RA grafts, pedicled left internal mammary artery (IMA) grafts, and native coronary arteries in 22 patients who had undergone CABG. We also evaluated the effect of chronic treatment with diltiazem on the basal tone and reactivity of the RA grafts and the effect of serotonin and native vessels distal to graft anastomosis. •••
As part of a larger study on medium- and long-term results of arterial revascularization in CABG, which included a control angiogram 1 year after the operation, we studied 22 consecutive patients not taking antianginal medications (19 men and 3 women; mean age 59 years, range 45 to 73; mean follow-up 338 days, range 243 to 484). Seventeen patients had multivessel disease and 5 had 2-vessel disease. Twentytwo patients had a graft prepared with an RA, and 18 patients also had a graft with a left IMA. Nine patients were receiving chronic diltiazem treatment (8 men and 1 woman; mean age 61 years, range 46 to 68; mean follow-up 301 days, range 229 to 339). Six patients had multivessel disease and 3 had 2-vessel disease. The 2 groups did not differ significantly with respect to age, sex, mean follow-up duration, and number of diseased coronary arteries. In all patients, both the RA and the left IMA were widely patent without angiographic evidence of focal From the Institute of Cardiology and Cardiac Surgery, and the Department of Anesthesia, Catholic University, Rome, Italy. Dr. Sperti’s address is: Institute of Cardiology, Catholic University, Largo A Gemelli 8, Rome 00168, Italy. E-mail: [email protected]. Manuscript received May 6, 1998; revised manuscript received and accepted September 8, 1998.
592
©1999 by Excerpta Medica, Inc. All rights reserved.
stenosis. The study protocol was approved by the Clinical Research Ethical Committee of the Catholic University School of Medicine. Written informed consent was obtained from all patients. The RAs were pretreated after harvesting and anastomosed proximally to the aorta. Pretreatment consisted of the injection of normal saline solution supplemented with heparin, papaverine, and blood at a constant pressure of 70 mm Hg, associated with a careful opening of the fascia down to the outer lining of the adventitia. One patient had 2 grafts prepared with the same RA. All patients were administered intravenous diltiazem, begun intraoperatively and continued in the intensive care unit at a dosage of 1 mg/kg/min. Diltiazem 120 mg given orally twice daily was started as soon as oral medications were resumed after the operation. In the first 22 patients, antianginal medications including diltiazem were discontinued 48 hours before the study. In the remaining 9 patients, diltiazem was not stopped and angiography was performed 2 to 4 hours after the morning dose of diltiazem. Antiaggregant therapy was continued in all patients. In the first group of patients, serotonin was selectively infused into the left IMA and then into the RA at concentrations of 1 3 1026 M and 1 3 1025 M for 3 minutes at a rate of 3 ml/min. A 2-mg bolus of isosorbide dinitrate was injected into the radial artery after the serotonin injection. Because left IMA grafts did not show any response to serotonin after a 48-hour washout period, in the second group of 9 patients still taking diltiazem at the time of the study, the infusion of serotonin was made into the RA only. Angiograms obtained at baseline and after serotonin and isosorbide dinitrate administration were analyzed using computerized quantitative angiography (Medis, Neuen, The Netherlands).4 – 6 Populations were compared using the chi-square test. Vessel diameters were compared using 2-way analysis of variance and the Newman-Keuls test. A p value #0.05 was considered statistically significant. Results are expressed as mean 6 1 SD. In the first group of patients who were not taking diltiazem at the time of the study, 3 of 22 RA grafts were excluded from the study, because cannulation was not sufficiently selective in 1 case and because nitrates were administered during the cardiac catheterization procedure before the planned serotonin infusion owing to chest pain in the other 2 cases. Of a total of 18 left IMA grafts, 5 were excluded because cannulation was not deemed sufficiently selective for 0002-9149/99/$–see front matter PII S0002-9149(98)00920-5
FIGURE 1. RA response to serotonin (5HT) infusion during pharmacologic washout. Statistically significant vasoconstriction was observed after selective infusion at concentrations of 1 3 1026 M and 1 3 1025 M for 3 minutes at a rate of 3 ml/min. Vessel diameter returned promptly to baseline after selective injection of 2 mg of isosorbide dinitrate (ISDN). Closed circles with bars represent mean 6 SD.
FIGURE 2. Right caudal oblique projection of an RA graft anastomosed to the circumflex artery. A, baseline; B, after selective injection of serotonin 1026 M, a small diameter reduction can be appreciated; C, after selective injection of serotonin 1025 M, a diffuse highgrade vasoconstriction is observed; D, after administration of nitrates, vasoconstriction resolves immediately. BRIEF REPORTS
593
FIGURE 3. Left internal mammary artery (LIMA) response to selective infusion of serotonin (5HT). No vasoconstriction was observed at the same doses used for the RA (1026 M and 1025 M). Closed circles with bars represent mean 6 SD.
drug infusion. Serotonin infusion into the RA at concentrations of 1 3 1026 M and 13 1025 M determined a significant vasocontriction from a diameter of 2.06 6 0.48 mm (mean 6 SD) to 1.69 6 0.46 mm (15.6% diameter reduction, p ,0.03) and 1.14 6 0.79 mm (42.6% diameter reduction, p ,0.0001), respectively (Figure 1). Serotonin induced vasoconstriction in all grafts but 1. The lumen reduction was distributed over the entire length of the vessel, was short lasting, and promptly resolved after administration of nitrates. In 4 cases, a diffuse high-grade vasoconstriction developed with virtually no runoff of contrast dye (Figure 2). In contrast, left IMA grafts did not show any change in diameter compared with baseline after serotonin infusion (p 5 NS) (Figures 3 and 4). After intraluminal injection of nitrates, the diameters of the left IMA and RA grafts were not significantly different from baseline values (Figures 1 and 3). In patients who were taking diltiazem at the time of angiography, serotonin infusion at a concentration of 1 3 1026 M reduced the lumen diameter from 2.10 6 0.46 to 1.72 6 0.23 mm (mean 6 SD, 21.1% diameter reduction, p 5 0.15). The higher concentration of 1 3 1025 M induced a significant diameter reduction to 1.40 6 0.72 mm (37.5% diameter reduction, p ,0.0004). In 2 cases the vessel diameter showed the same pattern of subtotal occlusion as the 4 cases of the untreated group, in 1 case after administration of the lower serotonin dose (Figure 5). The effect of serotonin and isosorbide dinitrate was assessed in the native vessels distal to the graft anastomosis. In agreement with previous observations,7 a nonsignificant degree of lumen diameter reduction was observed after serotonin administration at 1 3 1025M, from a baseline value of 1.60 6 0.45 to 1.46 6 0.23 mm (8.7% diameter reduction, p ,0.3). However, after nitrate administration there was a significant increase of vessel diameter compared with 594 THE AMERICAN JOURNAL OF CARDIOLOGYT
VOL. 83
FIGURE 4. Left anterior oblique projection of a left internal mammary artery graft anastomosed to the left descending anterior coronary artery. A, baseline; B, after selective infusion of serotonin 1025 M, no vasocontrictive response is observed.
baseline values, to 1.91 6 0.46 mm (16.9% diameter increase, p ,0.03) (Figure 6). FEBRUARY 15, 1999
FIGURE 5. RA response to serotonin (5HT) infusion in the group of patients taking diltiazem at the time of angiography. Selective 5HT infusion at the lower dose of 1 3 1026 M induced a nonstatistically significant vasocostriction; the diameter reduction induced by the higher dose of 1 3 1025 M was statistically significant. Vessel diameter returned promptly to baseline values after selective injection of 2 mg of isosorbide dinitrate (ISDN). Closed circles with bars represent mean 6 SD.
FIGURE 6. Effect of serotonin (5HT) and isosorbide dinitrate (ISDN) on the native vessels distal to the graft anastomosis. Caliber reduction after 5HT 1 3 1025 M was not statistically significant. However, after ISDN infusion there was a significant increase of vessel diameter compared with baseline values. Closed circles with bars represent mean 6 SD.
•••
Our results show that RA grafts develop significant vasocontriction in response to serotonin. In contrast, no response to serotonin was observed in the left IMA grafts, although both the RA and the left IMA appear to be dilated in the basal state. This strikingly different constrictive response could be accounted for by differences in the wall structure. The RA is muscular, with all 3 layers, intima, media, and adventitia thicker than those of the left IMA. However, the smooth muscle layer of the left IMA is capable of causing significant changes in vessel diameter, as demonstrated by the clinical observation of severe spasm in the periprocedural period.8 Serotonin is a potent vasoconstrictor9,10 that plays an important role in the homeostasis of the cardiovascular system and in the pathogenesis of coronary heart disease.11 Its vasoconstrictive effects vary among species and different anatomic sites.12 In vitro, however, left IMA can respond to serotonin with a sensitivity
similar to that observed in the RA,13,14 although with a somewhat lower developed force. This indicates that the signal transduction pathway involving serotonin is functioning normally in the left IMA. It cannot be excluded that a higher degree of endothelial-mediated vasodilation in response to serotonin compared with the RA could account for its unresponsiveness to this hormone. However, this seems unlikely, as the degree of endothelial-mediated vasodilation in response to serotonin appears to be negligible in the isolated left IMA. A different extent of endothelial damage occurring during surgical harvesting of the 2 arteries is unlikely to be relevant, because patients were studied about 1 year after surgery, and it is likely that any endothelial denudation would have been repaired by that time. Pedicled grafts also differ from the free ones in other important aspects. In the latter, a permanent consequence of preparing a conduit for aortocoronary anastomosis is denervation. It is conceivable that denervation supersenBRIEF REPORTS
595
sitivity and the loss of neural modulatory influences could alter the response to mediators. Nitrate administration into native coronary arteries determines a vasodilation demonstrating the presence of a basal tone.7 This was confirmed in our patients after isosorbide dinitrate administration. On the other hand, both left IMA and RA grafts did not show any increase in diameter compared with baseline after selective isorbide dinitrate administration. This may imply an inability of the arterial conduits used for CABG to dilate in response to higher flow requirements compared with native coronary arteries. In our patients, oral diltiazem did not prevent serotonin-induced contraction of RA grafts. The extent of vasoconstriction at a dose of 1025 M was comparable to that observed in washout patients. A similar trend was detectable at the lower dose of 1026 M, although it was not statistically significant because of the fewer patients. Severe diffuse vasoconstriction still was observed in 2 of 9 patients, 1 at the lower dose of 1026 M. Our study has some limitations. The number of patients, particularly in the diltiazem group, is relatively small. It must be considered, however, this is an invasive study. Another confounding factor could be the relatively short period of pharmacologic washout. An incomplete washout, however, would have blunted the extent of vasoconstriction determined by the serotonin infusion, which in our experimental conditions was clearly detectable. Our study clearly demonstrates that the response to agonists and vasodilators in vivo is strikingly different among different arteries when used for coronary grafting and requires further investigations to better understand the mechanisms un-
derlying this biologic variability and to devise better targeted treatments. 1. Carpentier A, Guermonprez JL, Deloche A, Frechette C, Dubost C. The
aorto-to-coronary radial artery bypass graft: a technique avoiding pathological changes in grafts. Ann Thorac Surg 1973;16:111–121. 2. Fisk RL, Bruosk CH, Callaghan JC, Dvorkin J. Experience with the radial artery for coronary bypass. Ann Thorac Surg 1976;21:513–518. 3. Acar C, Jebara VA, Portoghese M, Beyssen B, Pagny JY, Grare P, Chachques JC, Fabiani JN, Deloche A, Guermonprez JL, Carpentier A. Revival of the radial artery for coronary bypass grafting. Ann Thorac Surg 1992;54:652– 660. 4. Reiber JHC, Serruys PW, Koojman CJ, Wijns W, Slager CJ, Shuurbiers JCH, Den Boer A, Hugenholtz PG. Assessment of short-, medium- and long-term variations in arterial dimensions from computer-assisted quantification of coronary cineangiograms. Circulation 1985;71:280 –288. 5. Reiber JHC, van der Zwet PMJ, Konig G, von land CD, van Meusen B, Gerbrands JJ, Buis B, van Voorthiiusen AE. Accuracy and precision of quantitative digital coronary arteriography; observer-, as well as short- and mediumterm variabilities. Cathet Cardiovasc Diagn 1993;28:187–198. 6. Zijlstra F, Van Ommeren J, Reiber JHC, Serruys PW. Does the quantitative assessment of coronary artery dimensions predict the physiologic significance of a coronary artery stenosis? Circulation 1987;75:1154 –1161. 7. McFadden EP, Clarke JG, Davies GJ, Kaski JC, Haider AW, Maseri A. Effect of intracoronary serotonin on coronary vessels in patients with stable angina and patients with variant angina. N Engl J Med 1991;324:648 – 654. 8. Sarabu MR, McClung JA, Fass A, Reed GE. Early postoperative spasm in left internal mammary artery bypass grafts. Ann Thorac Surg 1987;44:199 –200. 9. Luscher TF, Richard V, Tschudi M, Yang Z. Serotonin and the endothelium. Clin Physiol Biochem 1990;8(III):108 –119. 10. Connor HE, Feniuk W, Humphrey PPA. 5-Hydroxytryptamine contracts human coronary arteries predominantly via 5-HT2 receptor activation. Eur J Pharm 1989;161:91–94. 11. Houston D, Vanhoutte PM. Serotonin and the vascular system: role in health and disease and implications for therapy. Drugs 1986;31:149 –163. 12. Burrows ME, Vanhoutte PM. Pharmacology of arterioles: some aspects of variability in response to norepinephrine, histamine and 5-hydroxytryptamine. J Cardiovasc Parmacol 1981;3:1370 –1380. 13. Conti A, Monopoli A, Forlani A, Ongini E, Antona C, Biglioli P. Role of 5-HT2 receptors in serotonin-induced contraction in the human mammary artery. Eur J Pharm 1990;176:207–212. 14. Dignan RJ, Yeh T Jr, Dyke CM, Francis LK, Lutz HA, Ding M, Wechsler AS. Reactivity of gastroepiploic and internal mammary arteries. J Thorac Cardiovasc Surg 1992;103:116 –123.
Effect of Beta-Adrenergic Blocker Therapy on the Circadian Rhythm of Heart Rate Variability in Patients With Chronic Stable Angina Pectoris Andrew J. Burger,
MD,
and Masoor Kamalesh,
eart rate variability (HRV), an indirect measurement of cardiac autonomic tone, has been shown H to be reduced in patients with coronary artery disease. Decreased HRV has been associated with increased mortality in this patient population.1 In addition, the occurrences of acute myocardial infarction and cardiac ischemia exhibit circadian variation.2 Sudden cardiac death, including ischemic and nonischemic (presumably ventricular arrhythmia) etiologies, has been shown to have circadian patterns.3 These circadian From the Division of Cardiology, Beth Israel Deaconess Medical Center, West Campus, Harvard Medical School, Boston, Massachusetts. Dr. Burger’s address is: Beth Israel Deaconess Medical Center, West Campus, Noninvasive Cardiology Laboratory, Baker-3, 1 Deaconess Road, Boston, Massachusetts 02215. E-mail: aburger@ bidmc.harvard.edu. Manuscript received July 23, 1998; revised manuscript received and accepeted September 28, 1998.
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©1999 by Excerpta Medica, Inc. All rights reserved.
MD
rhythms have been attributed to a number of earlymorning physiologic and hematologic changes, including an early-morning increase in sympathetic tone.2 Beta-adrenergic blocker therapy has been shown to improve cardiac autonomic function by increasing HRV, which translates clinically into decreased cardiac events.4 Data are limited as to the degree of improvement in autonomic function that b-blocker therapy achieves in coronary artery disease. By increasing parasympathetic activity and decreasing sympathetic tone, b-adrenergic blockers are one of the few pharmacologic interventions available that improve outcome in patients at risk of sudden death. We analyzed the amount of improvement in cardiac autonomic function in patients with chronic stable angina receiving b-blocker therapy and compared it with normal controls. 0002-9149/99/$–see front matter PII S0002-9149(98)00921-7