Ann Thorac Surg 2002;74:695-699
© 2002 The Society of Thoracic Surgeons
Original article: cardiovascular
Acute effects of 17ß-estradiol on left internal mammary graft after coronary artery bypass grafting
Gianluca Polvani, MD*a,
Maria Rosa Marino, MDb,
Maurizio Roberto, MDa,
Luca Dainese, MDa,
Alessandro Parolari, MDa,
Giulio Pompilio, MDa,
Silvia Di Matteo, MDa,
Andrea Fumero, MDa,
Aldo Cannata, MDa,
Fabio Barili, MDa,
Paolo Biglioli, MDa
a Department of Cardiac Surgery, University of Milan, Centro Cardiologico Monzino, Milan, Italy
b Department of Cardiac Anesthesia, University of Milan, Centro Cardiologico Monzino, Milan, Italy
Accepted for publication April 30, 2002.
* Address reprint requests to Dr Polvani, Department of Cardiac Surgery, University of Milan, Centro Cardiologico Monzino IRCCS, Via Parea 4, 20138 Milan, Italy
e-mail: luca.polvani{at}cardiologicomonzino.it
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Abstract
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Background. Vasospasm of arterial conduits used for coronary surgical procedures is an important cause of postoperative graft failure. Mounting experimental evidence suggests that estrogen reverses acetylcholine-induced vasospasm of the coronary arteries in animals and humans. Estrogen also affects endothelium-derived constrictor factors. We therefore investigated the in vivo vasomotor responses to transdermal 17ß-estradiol of the left internal mammary artery (LIMA) grafted on the anterior descending coronary artery.
Methods. We studied 20 women, mean age of 62 ± 7.2 years (range, 48 to 73 years), who had undergone cardiopulmonary bypass for coronary artery bypass grafting. They received transdermal 17ß-estradiol on the fifth day after operation. The diameter, cross-sectional area, and blood flow of the LIMA graft were measured by transthoracic color Doppler echography before (basal values) and after the transdermal administration of 50 µg of 17ß-estradiol (control).
Results. LIMA graft vasodilation after the administration of 17ß-estradiol was observed. A significant increase in diameter (2.06 ± 0.4 mm versus 2.37 ± 0.28 mm; p = 0.035) and cross-sectional area (3.45 ± 1. 2 mm2 versus 4.24 ± 1 mm2; p = 0.039) was registered. The LIMA graft mean flow increased by 49% (44.76 ± 27.19 mL/min versus 56.62 ± 27.69 mL/min), but this increase was not statistically significant (p = 0.06).
Conclusions. The acute postoperative transdermal administration of 17ß-estradiol induced a significant increase of LIMA graft diameter and cross-sectional area in postmenopausal women who underwent coronary artery bypass grafting. The LIMA graft vasodilation was also associated with an improvement in LIMA blood flow.
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Introduction
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Interest about use of arterial grafts in coronary artery bypass grafting (CABG) has increased significantly in recent years. Left internal mammary artery (LIMA) is the first-choice arterial graft [1].
The most important advantage of arterial grafts compared with vein grafts is the superior long-term patency and lower mortality rate [1–3]. Several factors may account for superior long-term patency of arterial grafts. First, arteries are less susceptible to vasoactive substances than veins. Second, the venous wall is supplied only by the vasa vasorum, whereas the arterial wall may be supplied also through the lumen. Third, the endothelium of arteries may release larger quantities of endothelium-derived relaxing factor. Finally, the structure of the vein is physiologically subject to lower pressures than is that of arteries. Therefore, after CABG, venous grafts have to adapt to aortic pressure, whereas arterial grafts do not. These differences may account for the difference in long-term patency rate.
A potential drawback of arterial grafting is perioperative graft spasm [1, 4]. Clinically, although spasm may develop in all arterial grafts, the gastroepiploic artery and the radial artery seem to be more susceptible to spasm than the LIMA [1]. Vessel spasm may be induced by physical (eg, direct mechanical stimulation during the operation) and pharmacologic stimulation (eg, vasoconstrictor substances released by the damaged endothelium) [1]. However, the exact mechanism of vessel spasm is still not clearly understood. It seems mainly related to compromise of normal endothelial function. Endothelial injury during surgical harvesting of the graft may elicit spasm. An adequate antispastic protocol during graft preparation could be helpful in prevention of perioperative vessel spasm. Various drugs have been studied to prevent vasospasm, such as calcium-channel blockers [5], papaverine [6], and nitrates [7].
Recent clinical and experimental studies investigated the effects of estrogen on vessels. A direct effect of estrogens on the vascular wall has been recently observed, as demonstrated by the identification of specific estrogen receptors on endothelial and vascular smooth muscle cells [8]. So far, several studies have investigated the effect of hormone replacement therapy on peripheral arteries and coronaries in postmenopausal women [9] and men [10], and a few studies have investigated the effect of 17ß-estradiol administration on coronary flow [11]. We are not aware, however, of any reports about the effects of 17ß-estradiol on bypass grafts. This study aims to evaluate the effects of the acute transdermal administration of 17ß-estradiol on the LIMA anastomosed to the left anterior descending (LAD) coronary artery after CABG.
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Material and methods
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Patient population
Patients were considered eligible for inclusion in this study only if all following criteria applied: (1) time from menopause was longer than 10 years; (2) agreement was obtained to have elective CABG using LIMA graft; and (3) visualization of the LIMA graft by postoperative transthoracic color Doppler echography (TTCD) was technically feasible.
The final study population consisted of 20 female patients (mean age, 66.57 ± 7.25 years) undergoing elective CABG operation. All the patients were in Canadian Cardiovascular Society class I of angina and were affected by one or more cardiovascular risk factors (Table 1).
The population of patients was homogeneous with respect to age and factors that might affect endothelial function, such as lipid profile, blood pressure, and coronary arteriosclerosis. The patients were all postmenopausal (mean age of menopause, 47.5 ± 7.5 years; mean time from menopause, 14 ± 8.4 years). Fifteen women (75%) had had hysterectomy, whereas the remaining 5 (25%) women were in physiologic menopause. Only 3 patients (15%) were receiving or had ever received hormone replacement therapy, and contraceptive drugs had been taken by 2 patients (10%) in the past. Symptomatic coronary artery disease was diagnosed at a mean age of 57.4 ± 4.3 years. In the preoperative period, ß-blockers were taken by 12 patients (60%), nitrates by 8 (40%), and calcium-channel blockers by 5 (25%). All medication was stopped 5 days before operation. Left ventricular dysfunction was not present in any case. In all cases, angiography proved severe coronary artery disease and indicated that elective CABG was appropriate. Fifteen patients (75%) were affected by three-vessel disease, and the remaining 5 patients (25%) by two-vessel disease. In 9 patients (45%), the LAD was occluded; moreover, in 4 patients (20%), the LAD showed a stenosis ranging between 90% and 99%, and in 7 patients (35%) between 70% and 90%. All patients had cardiopulmonary bypass. Cardiac standstill was obtained by means of cold blood cardioplegia. The blood flow from divided distal LIMA was judged satisfactory in all cases. An average of 2.7 ± 0.6 (range, 2 to 4) bypass grafts per patient was performed. No patients required perioperative inotropic support because of low cardiac output. No cases of perioperative myocardial infarction were recorded. On the fifth day after operation, a patch of estradiol was applied to the patients on the gluteus medius muscle. We chose the most commonly used clinical dose of transdermal estradiol, a patch of 10 cm2 containing 4.0 mg of 17ß-estradiol with a delivery rate of 50 µg/d (Estraderm 50, Ciba-Geigy).
Informed consent
Written informed consent was obtained from every patient by the senior investigator in accordance with institutional guidelines. The protocol had the approval of the Ethics Committee of Milan University School of Medicine.
Study design: Doppler studies
A preoperative selective angiography of the left subclavian artery and LIMA was evaluated in all patients to determine its patency. Left subclavian artery and LIMA stenosis were not found. On the fifth postoperative day and after a 24-hour period of antianginal therapy washout, TTCD of the LIMA grafted to the LAD was recorded. The TTCD was performed before (baseline) and 2 hours after the application of transdermal 17ß-estradiol to evaluate diameter, area, and blood flow of the LIMA graft. During the Doppler study, all patients were in sinus rhythm. The TTCD was performed using a 7-MHz color Doppler probe (Acuson 128 XP10 Art, Acuson Inc., Mountain View, CA), and two-dimensional images and pulsed Doppler signals were obtained. The scanner head was positioned in the first intercostal space. The Doppler waveform of LIMA grafted to anterior descending coronary artery was biphasic with an early systolic peak followed by a lower and longer diastolic wave [12]. Doppler spectrum curves were quantified for determination of the maximum systolic velocity, the end-diastolic velocity, and the time average mean flow velocity (TAMX; Table 2).
On B-mode imaging, the diameter and the cross-sectional area of the LIMA were measured. Blood flow was derived from the following formula:
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Typical flow patterns in the LIMA graft before and after application of transdermal 17ß-estradiol are demonstrated in Figure 1.
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Fig 1. Postoperative echocardiographic Doppler imaging of left internal mammary artery (LIMA) graft before (A) and after (B) transdermal 17ß-estradiol administration. The Doppler waveform of the left internal mammary artery grafted to the anterior descending coronary artery was biphasic with an early systolic peak followed by a lower and longer diastolic wave. After transdermal administration of 17ß-estradiol, the left internal mammary artery grafted wave increased, showing an increase in left internal mammary artery graft flow.
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We chose this technique instead of coronary artery catheterization to avoid other postoperative invasive procedures. Comparable results between the two techniques have been already reported in the literature [13].
Plasma estradiol assay
Venous blood was sampled before and 2 hours after the patch application of 17ß-estradiol for plasma estradiol assay. Blood samples were centrifuged immediately and plasma frozen at -20°C. All samples were assayed in one batch by radioimmunoassay. Intraassay coefficient of variation was 9.4%, and detection limit was 3 pmol.
Statistical analysis
The TTCD was repeated three times, either in basal conditions or after estradiol administration to reduce the biased error caused by the operator. The same operator always did the examinations. These measurements were averaged so that a single mean value was obtained for each patient. Serial changes in LIMA diameter, area, and blood flow were compared by means of Student’s t test for paired data. A two-tailed probability level of less than 0.05 was considered to be significant. All results are expressed as mean ± standard deviation.
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Results
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Plasma estradiol assay
Blood estrogen levels were measured in all patients before and 2 hours after the administration of 17ß-estradiol. A significant increase in the estradiol plasma level was found (7 ± 2.2 pg/mL versus 33 ± 4.1 pg/mL; p < 0.05).
Doppler measurements
Transdermal 17ß-estradiol had a significant effect on the diameter and cross-sectional area of the LIMA graft. After the acute administration of 17ß-estradiol, the LIMA graft diameter increased by 15% (2.06 ± 0.4 mm versus 2.37 ± 0.28 mm; p = 0.035; Fig 2),
and the cross-sectional area increased by 30% (3.45 ± 1. 2 mm2 versus 4.24 ± 1 mm2; p = 0.039; Fig 3).
The LIMA graft mean flow increased by 49% (44.76 ± 27.19 mL/min versus 56.62 ± 27.69 mL/min; Fig 4),
but this increase was not statistically significant (p = 0.06). Figure 1 shows the TTCD evaluation of the LIMA graft before and after acute administration of 17ß-estradiol.
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Fig 2. Histogram showing effects of transdermal 17ß-estradiol on left internal mammary artery (LIMA) graft diameter. It increased by 15% (2.06 ± 0.4 mm versus 2.37 ± 0.28 mm; p = 0.035).
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Fig 3. Histogram showing effects of transdermal 17ß-estradiol on left internal mammary artery (LIMA) graft cross-sectional area. It increased by 30% (3.45 ± 1. 2 mm2 versus 4.24 ± 1 mm2; p = 0.039).
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Fig 4. Histogram showing effects of transdermal 17ß-estradiol on left internal mammary artery (LIMA) graft mean flow. It increased by 49% (44.76 ± 27.19 mL/min versus 56.62 ± 27.69 mL/min; p = 0.06).
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Comment
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Our results showed that in postmenopausal female patients who had undergone CABG, a statistically significant dilatation of the LIMA graft anastomosed to the LAD resulted within 2 hours from transdermal administration of 17ß-estradiol. To the best of our knowledge, the present work is the first report about the acute effects of transdermal estrogen on the LIMA.
A number of drugs, including calcium-channel blockers (eg, diltiazem, nifedipine) [5], papaverine [6], and nitrates [7], have been studied for prevention of arterial graft spasm. Although these drugs are widely used in clinical practice, spasm still occurs in at least 5% to 10% of arterial grafts [7]. Recent studies investigating the possibility of overcoming arterial vasospasm identified Rho-kinase inhibitors [14], endothelin-1 receptor blockade [15], and gene therapy [7] as future likely potential targets.
Estrogen may also play an important role in the treatment of arterial graft vasospasm. 17ß-Estradiol has been shown to induce relaxation of precontracted coronary artery rings and to decrease inward calcium current and reduce intracellular free calcium in isolated cardiac myocytes [16]. Ethinyl estradiol reverses acetylcholine-induced vasoconstriction in monkeys and humans [11], and 17ß-estradiol improves exercise-induced myocardial ischemia in female patients [17]. The recognized presence of estrogen receptors on endothelial and vascular smooth muscle cells, as targets for estrogen action, implies that there are numerous effects of estrogen on the vascular wall.
Estrogen has short-term and long-term effects on vessels. A short-term vasodilation is elicited by means of both endothelium-dependent and endothelium-independent pathways. The vasodilatory effect seems mainly mediated by the increased production of nitric oxide by the endothelium [18]. Long-term effects of estrogen involve gene expression of vasodilatory enzymes. Long-term administration of estrogen is associated with increased vascular expression of the genes for vasodilatory enzymes such as prostacyclin synthase and nitric oxide synthase [19]. Moreover, an intracoronary 17ß-estradiol administration decreased the coronary endothelin-1 levels determining a net increased ratio of nitric oxide to endothelin-1 in plasma, thus promoting vasodilation [20].
Experimental evidence also suggests that adventitial activation plays a role in the vascular injury response, contributing to neointima formation in response to vascular injury. Estrogen seems to inhibit the vascular response to the injury, attenuating both adventitial activation and the potential translocation of adventitial fibroblasts into medial and neointimal compartments [21]. Also, estrogen is reported to accelerate endothelial cell growth after vascular injury, perhaps through an increased expression of vascular endothelial growth factor [22].
All these findings led us to attempt to verify the plausible hypothesis of the role of estrogen in the treatment and prevention of arterial graft vasospasm. In this study, the vasomotor responses of the LIMA graft to 17ß-estradiol resulted in a significant increase in diameter and cross-sectional area. The increase in LIMA blood flow was not significant. A possible explanation of this lack of significance can be related to the fact that LIMA graft flows into coronary circulation in confluence with native coronary artery flow. Recent studies indicate that LIMA flow is influenced by the grade of stenosis of the native coronary artery. The LIMA graft flow with moderate coronary stenosis is lower than with severe coronary stenosis [23]. One possible reason for this competition is that the LIMA is a branch of the subclavian artery in which mean diastolic pressure is lower than that in the aortic root from which the coronary arteries originate. Other possible reasons may include stenosis of left subclavian artery and LIMA, a direct vasodilatory effect of estrogen on the native coronary artery, the steal of blood flow from the LIMA through a large proximal branch (eg, the first intercostal artery), the weakness of contractility in the area affected by myocardial infarction, and flow competition with additional saphenous vein graft anastomosed on the LAD or diagonal branches. To reduce the effect of these confounding factors, in this study the LIMA was harvested for its full length, dividing between metal clips any collateral branch; patients underwent preoperative angiography to exclude stenosis of left subclavian artery or LIMA; complementary vein grafting of the LAD was not performed; and diagonal branches were vein grafted only if occluded at the origin.
Limitations of the study
This study is a nonrandomized trial, and it lacks of a control group. Moreover, echocardiography color Doppler is an operator-dependent technique. To decrease the operator-related bias, all the measurements were made by the same physician, repeated three times, and the mean value was considered. Furthermore, we evaluated the effects of transdermal administration of 17ß-estradiol without considering sublingual or intravenous administration, and we did not consider chronic effects of estrogens.
Conclusions
Results of the present study clearly show that acute estrogen supplementation induces significant vasodilation of the LIMA graft. This response likely reflects a direct effect of estrogen on the vascular wall. This important finding supports the hypothesis of the beneficial effect of estrogen in the treatment of arterial vasospasm, thus improving perioperative coronary perfusion. Echocardiographic color Doppler is a validated noninvasive test to visualize LIMA graft and detect significant changes in its hemodynamic pattern. The Doppler analysis was conducted 2 hours after the administration of estradiol. This is the time required to observe an increase in plasma estrogen levels [24]. The shorter the time for therapeutic effect, the better the estrogen efficacy against vasospasm that can usually occur in the early postoperative period (in only a few minutes or hours after operation). Our findings strongly support that estrogen could play an important role in the treatment of perioperative arterial graft spasm. It could assure relief of spasm and improved coronary perfusion without interfering with cardiac function. Studies comparing antispastic properties of estrogens with conventional vasodilators should be conducted.
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References
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- He G.W. Arterial grafts for coronary surgery: vasospasm and patency rate. J Thorac Cardiovasc Surg 2001;121:431-433.[Free Full Text]
- Boylan M.J., Lytle B.W., Loop F.D., et al. Surgical treatment of isolated left anterior descending coronary stenosis. Comparison of left internal mammary artery and venous autograft at 18 to 20 years of follow up. J Thorac Cardiovasc Surg 1994;107:657-662.[Abstract/Free Full Text]
- Loop F.D., Lytle B.W., Cosgrove D.M., et al. Influence of the internal-mammary artery graft on 10 years survival and other cardiac events. N Engl J Med 1986;314:1-6.[Abstract]
- Sarabu M.R., McLung J.A., Fass A., et al. Early postoperative vasospasm in left internal mammary artery bypass grafts. Ann Thorac Surg 1987;44:199-200.[Abstract]
- He G.W., Yang C.G. Comparative study on calcium channel antagonists in the human radial artery: clinical implications. J Thorac Cardiovasc Surg 2000;119:94-100.[Abstract/Free Full Text]
- Salmenpera M., Levy J.H. The in vitro effects of phosphodiesterase inhibitors on the human internal mammary artery. Anesth Analg 1996;82:954-957.[Abstract]
- Cable D.G., Caccitolo J.A., Pearson P.J., et al. New approaches to prevention and treatment of radial artery graft vasospasm. Circulation 1998;98(Suppl):II-15-II-22.
- Venkov C.D., Rankin A.B., Vaughan D.E. Identification of authentic estrogen receptor in cultured endothelial cells. Circulation 1996;94:727-733.[Abstract/Free Full Text]
- Penotti M., Nencioni T., Gabrielli L., et al. Blood flow variations in internal carotid and middle cerebral arteries induced by postmenopausal hormone therapy. Am J Obstet Gynecol 1993;169:1226-1232.[Medline]
- Reis S.E., Bhoopalam V., Zell K.A., et al. Conjugated estrogens acutely abolish abnormal cold-induced coronary vasoconstriction in male cardiac allografts. Circulation 1998;97:23-25.[Abstract/Free Full Text]
- Reis S.E., Gloth S.T., Blumenthal R.S., et al. Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. Circulation 1994;89:52-60.[Abstract/Free Full Text]
- Takemura H., Kawasuji M., Sakakibara N., et al. Internal thoracic artery graft function during exercise assessed by transthoracic Doppler echography. Ann Thorac Surg 1996;61:914-919.[Abstract/Free Full Text]
- Lethen H., Ekinci O., Tries H.P., et al. Echocardiographic measurements of coronary flow reserves in the left anterior descending artery allows detection of significant stenosis. Dtsch Med Wochenschr 2000;125:551-556.[Medline]
- Batchelor T.J.P., Sadaba R., Beech D.J., et al. Rho-kinase inhibitors prevent agonist-induced vasospasm in human internal mammary artery. Br J Pharmacol 2001;132:302-308.[Medline]
- Verma S., Lovren F., Dumont A.S., et al. Endothelin receptor blockade improves endothelial function in human internal mammary arteries. Cardiovasc Res 2001;49:146-151.[Abstract/Free Full Text]
- Jiang C., Poole-Wilson P.A., Sarrel P.M., et al. Effect of 17ß-oestradiol on contraction, Ca2+ current, and intracellular free Ca2+ in guinea-pig isolated cardiac myocytes. Br J Pharmacol 1992;106:739-745.[Medline]
- Rosano G.M.C., Sarrel P.M., Poole-Wilson P.A., et al. Beneficial effect of oestrogen on exercise-induced myocardial ischaemia in women with coronary artery disease. Lancet 1993;342:133-136.[Medline]
- Guetta V., Quyyumi A.A., Prasad A., et al. The role of nitric oxide in coronary vascular effects of estrogen in postmenopausal women. Circulation 1997;96:2795-2801.[Abstract/Free Full Text]
- Weiner C.P., Lizasoain I., Baylis S.A., et al. Induction of calcium-dependent nitric oxide synthases by the sex hormones. Proc Natl Acad Sci USA 1994;91:5212-5216.[Abstract/Free Full Text]
- Webb C.M., Ghatei M.A., McNeill J.C., et al. 17ß-Estradiol decreases endotelin-1 levels in the coronary circulation of postmenopausal women with coronary artery disease. Circulation 2000;102:1617-1622.[Abstract/Free Full Text]
- Oparil S., Chen S.J., Chen Y.F., et al. Estrogen attenuates the adventitial contribution to neointima formation in injured rat carotid arteries. Cardiovasc Res 1999;44:608-614.[Abstract/Free Full Text]
- White C.R., Shelton J., Oparil S., et al. Estrogen restores endothelial cell function in an experimental model of vascular injury. Circulation 1997;96:1624-1630.[Abstract/Free Full Text]
- Nasu M., Akasaka T., Okazaki T., et al. Postoperative characteristics of left internal thoracic artery grafts. Ann Thorac Surg 1995;59:154-162.[Abstract/Free Full Text]
- Setnikat I., Rovati L.C., Vens-Cuppell B., et al. Bioavailability of estradiol from two transdermal patches. Arzneimittelforschung 1996;46:307-310.[Medline]
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Abstract
Introduction
