- Email: [email protected]
Revascularization of severe hibernating myocardium in the beating heart: early hemodynamic and metabolic features
Revascularization of Severe Hibernating Myocardium in the Beating Heart: Early Hemodynamic and Metabolic Features Evasio Pasini, MD, Gianna Ferrari, MD, George Cremona, MD, PhD, and Mario Ferrari, MD “S. Maugeri” Foundation IRCCS, Medical Centre of Gussago, Gussago, Cardiovascular Surgery Department, S. Rocco Hospital, Ome, and Unit of Respiratory Medicine, S. Raffaele University Scientific Institute, Milan, Italy
Background. We investigated the effects of coronary artery bypass grafting (CABG) without cardiopulmonary bypass (CPB) in selected patients with severe hibernating myocardium. Methods. Twelve patients (EF ⴝ 25% ⴞ 0.7%) with reversible ventricular dysfunction (from 2.0 ⴞ 0.06 to 1.6 ⴞ 0.05 left ventricular score index by echodobutamine, p < 0.01) in the territory of the left anterior descending artery (LAD) have been studied. Revascularization was achieved by anastomosing the left internal mammary artery to the LAD. The ischemic time of LAD was 9.0 ⴞ 0.4 minutes. Results. Left ventricular function increased 6 hours and
48 hours after revascularization (left ventricular stroke work index from 32 ⴞ 1.8 to 42 ⴞ 1.5 and 40 ⴞ 0.6 gxm/m2, respectively: p ⴝ 0.0001). During the surgical procedure, the heart did not release lactate or creatine phosphokinase. There were no perioperative deaths or severe complications. Conclusions. Early hemodynamic and metabolic features of CABG without CPB in patients with hibernating myocardium suggest that this procedure is safe and results in a significant improvement of cardiac function without affecting myocardial metabolism. (Ann Thorac Surg 2001;71:176 –9) © 2001 by The Society of Thoracic Surgeons
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morbidity of patients as well as on cardiac metabolism during and after the surgical procedure.
ecent data indicate that hibernating myocardium is present in about 78% of patients after myocardial infarction [1, 2] and that reversible ischemic contractile dysfunction has been identified in 11% of patients referred for cardiac transplantation [3]. Although the genesis and pathophysiology of hibernating myocardium are still speculative, it is now evident that restoration of blood flow by coronary bypass can result in the recovery of myocardial function [4, 5]. In spite of the success of coronary artery bypass grafting (CABG), patients with severe myocardial depression still represent a high mortality risk group when subjected to surgical cardiac revascularization during cardiopulmonary bypass (CPB) despite protection by cardioplegic solution [6]. Recently, the technique for CABG on beating heart without CBP has been shown to reduce surgical risk in patients with myocardial dysfunction [7, 8]. However, no information on the use of this procedure on patients with depressed cardiac performance because of hibernating myocardium is yet available in the literature. The aim of the present study was to investigate the effect of CABG without CPB in the revascularization of patients with documented hibernating myocardium. The study focuses on the early hemodynamic changes and Accepted for publication May 26, 2000. Address reprint requests to Dr Pasini, S. Maugeri Foundation, Medical Centre of Gussago, Via Pinidolo, 23, 25064 Gussago (BS), Italy; e-mail: [email protected].
© 2001 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
Material and Methods Patients Eleven patients (10 male, 1 female) aged ranging from 44 to 65 (mean 53.6 ⫾ 2.2) years were studied. The patients gave their informed consent to participate in this study which was approved by the Institutional Ethics Committee. All of them were severely limited in their everyday life activities (1 New York Heart Association [NYHA] II, 10 NYHA III) and 2 of them had been referred for cardiac transplantation. Six patients had previous anterior myocardial infarction (4 Q-wave infarction, 3 no Q-wave infarction), and all of them showed significant proximal narrowing (⬎75%) of the left anterior descending artery (LAD). Four had single-vessel (LAD), 6 had two-vessel (LAD and left circumflex artery [LCA]), and 1 had threevessel disease (LAD, LCA, and right coronary artery). Five patients complained of effort-induced angina. The presence of hibernating myocardium was clearly documented in the territory of the left ventricle supplied by LAD by echodobutamine as previously described [9]. The left ventricle wall motion was determined as recommended by the American Society of Echocardiography [10]. The echocardiographic data are illustrated in Table 1. All patients exhibited severe functional impairment resulting in a marked reduction of the ejection fraction (EF ⫽ 25% ⫾ 0.7%). The presence of chronically dysfunc0003-4975/01/$20.00 PII S0003-4975(00)02128-7
Ann Thorac Surg 2001;71:176 –9
PASINI ET AL REVASCULARIZATION OF HIBERNATING MYOCARDIUM
Table 1. Identification of Hibernating Myocardium Variable LVSI %NM a
Pre-dobutamine
Post-dobutamine
2.0 ⫾ 0.06 32.3 ⫾ 2.9
1.6 ⫾ 0.05a 50.1 ⫾ 4.5a
p ⬍ 0.01 versus pre-dobutamine.
LVSI ⫽ left ventricular score index; muscle.
%NM ⫽ percentage of normal
tional but viable myocardium was clearly documented by the net decrease of left ventricular score index (from 2.0 ⫾ 0.06 to 1.6 ⫾ 0.05; p ⬍ 0.01 versus basal) and the increased percentage of normal muscle (from 32.3 ⫾ 2.9 to 50.1 ⫾ 4.5 %NM, p ⬍ 0.01 versus basal) after low-dose dobutamine infusion. Exclusion criteria were: 1) lack of documented hibernating myocardium; 2) unfavorable coronary artery anatomy; 3) myocardial infarction in the previous 6 months or documented episode of acute angina in the previous 3 weeks; 4) valvular heart disease; 5) patients requiring aneurysmectomy; and 6) diabetes or other metabolic disease. We also studied 8 subjects (7 male, 1 female; mean age 56 ⫾ 3.8) with comparable coronary anatomical conditions but with normal left ventricular function (EF ⫽ 57% ⫾ 2%) who underwent the same surgical procedure. We used these data as a control.
Surgical Procedures In all patients studied, anesthesia was induced with propofol (2.0 to 2.5 mg/Kg) and muscle relaxation was achieved with atracurium (0.08 mg/Kg). Ventilation was controlled with oxygen in air (50%). Anesthesia was maintained with continuous infusion of propofol at 4/6 mg/Kg/h. Before sternotomy, an 18-gauge cannula was placed in the radial artery for arterial sampling. A Swan-Ganz catheter was introduced through the left jugular vein for hemodynamic measurements. After median sternotomy, a coronary catheter was advanced into the coronary sinus and used for coronary sinus sampling. The operative technique has been described in detail elsewhere [7]. In brief, the left internal mammary artery (LIMA) was dissected and the LAD was exposed. Before proceeding to segmental occlusion of the LAD (with 5/0 polypropylene in a length of 2.5/3 cm), 1.5 mg/Kg of heparin was administered to the patient. The mammarycoronary anastomosis was then fashioned with 8/0 polypropylene and the occlusion of LAD removed. In all subjects studied, infusion of low doses of dopamine (1.5 g/Kg) were used. At the end of the grafting procedure, protamine was injected to reverse the effect of heparin.
Hemodynamic Measurements Heart rate, arterial pressure, right atrial pressure, pulmonary wedge pressure, and cardiac output were measured. Left ventricular stroke work index (LVSWI) was used as a measure of global left ventricular function. Hemodynamic measurements were performed in the operating theater before starting the surgical procedure (T0), at the end of the grafting procedure (T1), before closing the chest (T2), 6 hours (T3) and 48 hours (T4)
177
post-surgery. During hemodynamic measurements, no inotropes or vasodilators were used.
Metabolic Measurements Sampling for metabolic measurements was undertaken in the operating theater and included myocardial arterial-venous differences for glucose, lactate, and creatine phosphokinase (CPK). These molecules were evaluated in 2 ml of fresh arterial (radial artery) and coronary sinus (venous) blood simultaneously drawn at T0, T1, and T2. Glucose, lactate, and CPK were evaluated in the extracted plasma by commercial kits (Boehringer Mannheim, GmbH, Mannheim, Germany).
Statistical Analysis The data are presented as mean ⫾ SEM. For statistical evaluation of the results, analysis of variance for repeated measure with post-hoc multiple comparisons with Scheffe’s correction or paired Student’s t test were used when appropriate. Significance was set at level of p less than 0.05.
Results Figure 1 shows the hemodynamic data before and after the operation of patients with hibernating myocardium. As expected, LVSWI was depressed before mammarycoronary anastomosis (32 ⫾ 1.8 gxm/m2). The temporary occlusion of the LAD did not modify cardiac global function. On the contrary, myocardial revascularization resulted in a significant improvement of LVSWI, which was already appreciable after 6 hours and was still present 48 hours later (42 ⫾ 1.5 and 40 ⫾ 0.6 gxm/m2, respectively: p ⫽ 0.0001 versus T0). This improvement was not found in subjects with normal ventricular function who had not had significant modification of LVSWI (data not shown). The myocardial metabolism during CABG of patients with hibernating myocardium is illustrated in Figure 2. Before surgery, the myocardium extracts glucose and lactate as energetic substrates and, as expected, did not release CPK. During the ischemic period of the anterior wall of the left ventricle and the subsequent postischemic reperfusion, there was no release of lactate and CPK. Glucose extraction was unaffected by the procedure. These data are similar to those obtained in the control group (data not shown). Patients with hibernating myocardium had 9.0 ⫾ 0.4 minutes of ischemic time of LAD. They had intensive care unit (ICU) and total inpatient stay of 1.4 ⫾ 0.06 days and 6.2 ⫾ 0.1 days, respectively. In these patients, there were no severe arrhythymias, bleeding, or myocardial infarction in the postoperative period. Likewise, no pulmonary and neurological complications were observed after surgery. These results did not differ from those obtained in patients with normal ventricular function (data not shown).
Comment These preliminary data obtained after early hemodynamic and metabolic measurements indicate that CABG
178
PASINI ET AL REVASCULARIZATION OF HIBERNATING MYOCARDIUM
Fig 1. Global left ventricular function evaluated as left ventricular stroke work index before and after coronary artery bypass graft on beating heart of patients with hibernating myocardium. Bars and lines indicate, respectively, mean and SEM values. *Indicates p ⬍ 0.01, Scheffe’s test versus T0, T1, and T2.
without CPB improved myocardial global function, in patients with severe ventricular dysfunction due to hibernating myocardium, without affecting the metabolism of the muscle during the surgical procedure. Reversible cardiac dysfunction is common in unstable angina, and 78% of patients evaluated between 5 and 21 days after acute myocardial infarction, and treated with thrombolysis, had akinetic areas with a perfusionmetabolism mismatch suggestive of hibernating myocardium [1, 2]. This has been confirmed by Louie and colleagues who showed that about 11% of subjects referred for cardiac transplantation had reversible myocardial dysfunction [3]. It is now documented that restoration of myocardial blood flow by CABG can lead to a recovery of the contractile function of hibernating myocardium [11]. However, subjects with severe cardiac dysfunction represent a high perioperative risk group for CABG with CPB with long ICU and hospital stays (3 and 11 days, respectively) and an in-hospital mortality of 4% to 10% in spite of myocardial protection with cardioplegic solution and hypothermia [6]. In fact, although hypothermia reduces the energy requirement of myocytes, the cold temperature lowers high energy phosphate production and produces cellular membrane instability leading to a temporary impairment of mechanical performance in the immediate postoperative period (stunning) [12]. The negative effects of hypothermia have been mitigated in part with the introduction of warm blood cardioplegia, which significantly reduced mortality and morbidity after CABG [13]. However, the mechanical trauma to blood components as well as microembolic events and activation of the inflammatory response by CPB can be clinically relevant [14, 15]. These observations are reinforced by recent findings that demonstrate that inflammatory
Ann Thorac Surg 2001;71:176 –9
molecules (such as interleukin 6) released during CPB have significant negative inotropic effects [16]. Previous studies demonstrate that CABG can be performed on a beating heart without CPB. It allows grafting of the left internal thoracic artery (LITA) with LAD on a normothermic and perfused heart avoiding the potential negative effects of CPB. This surgical technique has been successfully performed in elderly patients with renal or heart failure, or with impaired pulmonary function [7]. This study reports the use of CABG on beating heart to revascularize the hibernating myocardium of patients with severely compromised myocardial contractility. These early results obtained in these severely compromised patients are very encouraging. The short temporary interruption of coronary flow, necessary for grafting the arteries, did not induce any ischemic insult to the hibernating heart, as demonstrated by the absence of myocardial release of lactate and CPK, as well as by the maintenance of glucose extraction. Metabolic studies indicate that during ischemia, glucose uptake increases while lactate is produced rather than taken up by the heart [17]. This is crucial in hibernating myocytes in an unstable metabolic equilibrium, as even a brief period of anoxia may cause severe damage. The results of this study clearly show that this procedure is well tolerated by the hibernating myocardium. These data are in agreement with other studies in nonhibernating myocardium where a brief period of coronary occlusion did not alter blood troponin I levels [18] or mitochondrial structure [19]. In addition, we documented that LVSWI was not compromised by the brief period of temporary interruption of coronary flow but actually had already significantly increased a few hours and 48 hours after revascularization without postoperative stunning indicating the recovery of contractile properties of reperfused hibernating cardiomyocytes. These results are not due to effects of anesthesia or neurohormonal perturbation because in subjects with normal myocardial function undergoing the same surgical procedure, these remarkable improvements of LVSWI were not found. These positive findings are concomitant with the early postoperative data. In fact, although CABG was performed in severely compromised patients, no deaths were observed. In addition, extubation times and intensive care unit or hospital stays were similar to that of subjects operated on beating heart but without myocardial depression indicating that this surgical procedure is safe even in these high-risk patients [20]. Although the aim of this study was not to evaluate the intrinsic mechanism of hibernation, our data provide additional information to the physiopathology of hibernating myocardium. The results show that in basal conditions, hibernating myocardium extracts glucose and lactate as energetic substrates with the same magnitude as normal myocardium, suggesting that hibernating myocytes are not completely ischemic and their oxidative processes are active [21]. However, this study has some limitations. As this was a feasibility study, it was performed in highly selected patients with hibernating myocytes in the territory of LAD. Although these results are promising, further stud-
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179
References
Fig 2. Metabolic measurements before and after coronary artery bypass graft on beating heart of patients with hibernating myocardium. Panels show differences between radial artery (A) and coronary sinus (V) concentrations of: top panel, glucose; middle panel, lactate; and bottom panel, creatine phosphokinase (CPK). Bars and lines indicate, respectively, mean and SEM values.
ies would be appropriate in order to: (1) be able to select those patients who can be operated with acceptable risks; (2) investigate the long-term patency of the graft, especially in comparison to angioplasty; and (3) the long-term survival of these subjects. The technique of beating heart coronary surgery is attractive but it has some limitations. The ideal candidates for CABG on beating heart are the patients with significant lesions of the proximal left anterior descending artery, and this procedure cannot be performed in subjects with very small, calcified, or deeply buried coronary arteries. In conclusion, early hemodynamic and metabolic data suggest that CABG without CPB in patients with hibernating myocardium is safe, has low use of resources, and results in a significant improvement of global cardiac function, even in those subjects with severe left ventricular dysfunction who otherwise would be candidates for cardiac transplantation.
1. Adams JN, Norton M, Trent RJ, Mikecz P, Walton S, Evans N. Incidence of hibernating myocardium after acute myocardial infarction treated with thrombolysis. Heart 1996;75:442– 6. 2. Galli M, Marcassa C, Bolli R. Spontaneous delayed recovery of perfusion and contraction after the first 5 weeks after anterior infarction. Evidence for the presence of hibernating myocardium in the infarcted area. Circulation 1994;90: 1386–97. 3. Louie HW, Laks H, Milgalter E. Ischemic cardiomyopathy criteria for coronary revascularisation and cardiac transplantation. Circulation 1991;84(Suppl III):III290. 4. Topol EJ, Weiss JL, Guzman PA. Immediate improvement of dysfunctional myocardial segments after coronary revascularization: detection by intraoperative transesophageal echocardiography. J Am Coll Cardiol 1984;4:1123–34. 5. Takeishi Y, Tono-oka I, Kubota I. Functional recovery of hibernating myocardium after coronary bypass surgery: does it coincide with improvement in perfusion? Am Heart J 1991;122:665–70. 6. Tu JV, Jaglal SB, Naylor CD, and Steering Committee of Provincial Adult Cardiac Care Network of Ontario. Multicenter validation of a risk index for mortality, intensive care unit stay, and overall hospital length of stay after cardiac surgery. Circulation 1995;91:677– 84. 7. Moshkovitz Y, Lusky A, Mohr R. Coronary artery bypass without cardiopulmonary bypass: analysis of short-term and mid-term outcome in 220 patients. J Thorac Cardiovasc Surg 1995;110:979 – 87. 8. Laborde F, Abdelmeguid I, Piwnica A. Aortocoronary bypass without extracorporeal circulation: why and when? Eur J Cardiothorac Surg 1989;3:152–5. 9. Afridi I, Kleimain NS, Raizner AE, Zoghbi WA. Dobutamine echocardiography in myocardial hibernation: optimal dose and accuracy in predicting recovery of ventricular function after coronary angioplasty. Circulation 1995;91:663–70. 10. Schiller NB, Shah PM, Crawford M. Recommendation for quantitation of the left ventricle by two-dimension echocardiography. J Am Soc Echocardiogr 1989;2:358– 67. 11. Wijns W, Vatner SF, Camici P. Hibernating myocardium. N Engl J Med 1998;339:173– 81. 12. Sakai T, Kuihara S. Effects of rapid cooling on mechanical and electrical responses in ventricular muscle of guinea pig. J Physiol 1985;361:361–78. 13. Vaughn CC, Opie J, Florendo F, Lowell P, Austin J. Warm blood cardioplegia. Ann Thorac Surg 1993;55:1227–32. 14. Kirklin JK, Westaby S, Blackstone EH, Kirklin JW, Chenoweth DE, Pacifico AD. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;86:845–7. 15. Butler J, Rocker GM, Westaby S. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 1993;55:552–9. 16. Finkel MS, Hoffman RA, Shen L, Oddis CV, Simmons RL, Hattler BG. Interleukin-6 as a mediator of stunned myocardium. Am J Cardiol 1993;71:1231–2. 17. Opie LH. Cardiac metabolism— emergence, decline and resurgence. Cardiovasc Res 1992;26:721–33. 18. Birdi I, Caputo M, Hutter JA, Bryan AJ, Angelini GD. Troponin I release during minimally invasive coronary artery surgery. J Thorac Cardiovasc Surg 1997;114:509–10. 19. Benetti F, Naselli G, Wood M, Geffner L. Direct myocardial revascularisation without extracorporeal circulation. Experience in 700 patients. Chest 1991;100:312– 6. 20. Buffolo E, Andrade JCS, Branco JNR, Aguiar LF, Ribeiro EF, Jatene AD. Myocardial revascularisation without extracorporeal circulation. Seven-years experience in 593 cases. Eur J Cardiothorac Surg 1990;4:504– 8. 21. Svedijeholm R, Ekroth R, Joachimsson PO, Ronquist G, Svensson S, Tyden H. Myocardial uptake of amino acid and other substrates in relation to myocardial oxygen consumption four hours after cardiac operations. J Thorac Cardiovasc Surg 1991;101:688–94.
Background. We investigated the effects of coronary artery bypass grafting (CABG) without cardiopulmonary bypass (CPB) in selected patients with severe hibernating myocardium. Methods. Twelve patients (EF ⴝ 25% ⴞ 0.7%) with reversible ventricular dysfunction (from 2.0 ⴞ 0.06 to 1.6 ⴞ 0.05 left ventricular score index by echodobutamine, p < 0.01) in the territory of the left anterior descending artery (LAD) have been studied. Revascularization was achieved by anastomosing the left internal mammary artery to the LAD. The ischemic time of LAD was 9.0 ⴞ 0.4 minutes. Results. Left ventricular function increased 6 hours and
48 hours after revascularization (left ventricular stroke work index from 32 ⴞ 1.8 to 42 ⴞ 1.5 and 40 ⴞ 0.6 gxm/m2, respectively: p ⴝ 0.0001). During the surgical procedure, the heart did not release lactate or creatine phosphokinase. There were no perioperative deaths or severe complications. Conclusions. Early hemodynamic and metabolic features of CABG without CPB in patients with hibernating myocardium suggest that this procedure is safe and results in a significant improvement of cardiac function without affecting myocardial metabolism. (Ann Thorac Surg 2001;71:176 –9) © 2001 by The Society of Thoracic Surgeons
R
morbidity of patients as well as on cardiac metabolism during and after the surgical procedure.
ecent data indicate that hibernating myocardium is present in about 78% of patients after myocardial infarction [1, 2] and that reversible ischemic contractile dysfunction has been identified in 11% of patients referred for cardiac transplantation [3]. Although the genesis and pathophysiology of hibernating myocardium are still speculative, it is now evident that restoration of blood flow by coronary bypass can result in the recovery of myocardial function [4, 5]. In spite of the success of coronary artery bypass grafting (CABG), patients with severe myocardial depression still represent a high mortality risk group when subjected to surgical cardiac revascularization during cardiopulmonary bypass (CPB) despite protection by cardioplegic solution [6]. Recently, the technique for CABG on beating heart without CBP has been shown to reduce surgical risk in patients with myocardial dysfunction [7, 8]. However, no information on the use of this procedure on patients with depressed cardiac performance because of hibernating myocardium is yet available in the literature. The aim of the present study was to investigate the effect of CABG without CPB in the revascularization of patients with documented hibernating myocardium. The study focuses on the early hemodynamic changes and Accepted for publication May 26, 2000. Address reprint requests to Dr Pasini, S. Maugeri Foundation, Medical Centre of Gussago, Via Pinidolo, 23, 25064 Gussago (BS), Italy; e-mail: [email protected].
© 2001 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
Material and Methods Patients Eleven patients (10 male, 1 female) aged ranging from 44 to 65 (mean 53.6 ⫾ 2.2) years were studied. The patients gave their informed consent to participate in this study which was approved by the Institutional Ethics Committee. All of them were severely limited in their everyday life activities (1 New York Heart Association [NYHA] II, 10 NYHA III) and 2 of them had been referred for cardiac transplantation. Six patients had previous anterior myocardial infarction (4 Q-wave infarction, 3 no Q-wave infarction), and all of them showed significant proximal narrowing (⬎75%) of the left anterior descending artery (LAD). Four had single-vessel (LAD), 6 had two-vessel (LAD and left circumflex artery [LCA]), and 1 had threevessel disease (LAD, LCA, and right coronary artery). Five patients complained of effort-induced angina. The presence of hibernating myocardium was clearly documented in the territory of the left ventricle supplied by LAD by echodobutamine as previously described [9]. The left ventricle wall motion was determined as recommended by the American Society of Echocardiography [10]. The echocardiographic data are illustrated in Table 1. All patients exhibited severe functional impairment resulting in a marked reduction of the ejection fraction (EF ⫽ 25% ⫾ 0.7%). The presence of chronically dysfunc0003-4975/01/$20.00 PII S0003-4975(00)02128-7
Ann Thorac Surg 2001;71:176 –9
PASINI ET AL REVASCULARIZATION OF HIBERNATING MYOCARDIUM
Table 1. Identification of Hibernating Myocardium Variable LVSI %NM a
Pre-dobutamine
Post-dobutamine
2.0 ⫾ 0.06 32.3 ⫾ 2.9
1.6 ⫾ 0.05a 50.1 ⫾ 4.5a
p ⬍ 0.01 versus pre-dobutamine.
LVSI ⫽ left ventricular score index; muscle.
%NM ⫽ percentage of normal
tional but viable myocardium was clearly documented by the net decrease of left ventricular score index (from 2.0 ⫾ 0.06 to 1.6 ⫾ 0.05; p ⬍ 0.01 versus basal) and the increased percentage of normal muscle (from 32.3 ⫾ 2.9 to 50.1 ⫾ 4.5 %NM, p ⬍ 0.01 versus basal) after low-dose dobutamine infusion. Exclusion criteria were: 1) lack of documented hibernating myocardium; 2) unfavorable coronary artery anatomy; 3) myocardial infarction in the previous 6 months or documented episode of acute angina in the previous 3 weeks; 4) valvular heart disease; 5) patients requiring aneurysmectomy; and 6) diabetes or other metabolic disease. We also studied 8 subjects (7 male, 1 female; mean age 56 ⫾ 3.8) with comparable coronary anatomical conditions but with normal left ventricular function (EF ⫽ 57% ⫾ 2%) who underwent the same surgical procedure. We used these data as a control.
Surgical Procedures In all patients studied, anesthesia was induced with propofol (2.0 to 2.5 mg/Kg) and muscle relaxation was achieved with atracurium (0.08 mg/Kg). Ventilation was controlled with oxygen in air (50%). Anesthesia was maintained with continuous infusion of propofol at 4/6 mg/Kg/h. Before sternotomy, an 18-gauge cannula was placed in the radial artery for arterial sampling. A Swan-Ganz catheter was introduced through the left jugular vein for hemodynamic measurements. After median sternotomy, a coronary catheter was advanced into the coronary sinus and used for coronary sinus sampling. The operative technique has been described in detail elsewhere [7]. In brief, the left internal mammary artery (LIMA) was dissected and the LAD was exposed. Before proceeding to segmental occlusion of the LAD (with 5/0 polypropylene in a length of 2.5/3 cm), 1.5 mg/Kg of heparin was administered to the patient. The mammarycoronary anastomosis was then fashioned with 8/0 polypropylene and the occlusion of LAD removed. In all subjects studied, infusion of low doses of dopamine (1.5 g/Kg) were used. At the end of the grafting procedure, protamine was injected to reverse the effect of heparin.
Hemodynamic Measurements Heart rate, arterial pressure, right atrial pressure, pulmonary wedge pressure, and cardiac output were measured. Left ventricular stroke work index (LVSWI) was used as a measure of global left ventricular function. Hemodynamic measurements were performed in the operating theater before starting the surgical procedure (T0), at the end of the grafting procedure (T1), before closing the chest (T2), 6 hours (T3) and 48 hours (T4)
177
post-surgery. During hemodynamic measurements, no inotropes or vasodilators were used.
Metabolic Measurements Sampling for metabolic measurements was undertaken in the operating theater and included myocardial arterial-venous differences for glucose, lactate, and creatine phosphokinase (CPK). These molecules were evaluated in 2 ml of fresh arterial (radial artery) and coronary sinus (venous) blood simultaneously drawn at T0, T1, and T2. Glucose, lactate, and CPK were evaluated in the extracted plasma by commercial kits (Boehringer Mannheim, GmbH, Mannheim, Germany).
Statistical Analysis The data are presented as mean ⫾ SEM. For statistical evaluation of the results, analysis of variance for repeated measure with post-hoc multiple comparisons with Scheffe’s correction or paired Student’s t test were used when appropriate. Significance was set at level of p less than 0.05.
Results Figure 1 shows the hemodynamic data before and after the operation of patients with hibernating myocardium. As expected, LVSWI was depressed before mammarycoronary anastomosis (32 ⫾ 1.8 gxm/m2). The temporary occlusion of the LAD did not modify cardiac global function. On the contrary, myocardial revascularization resulted in a significant improvement of LVSWI, which was already appreciable after 6 hours and was still present 48 hours later (42 ⫾ 1.5 and 40 ⫾ 0.6 gxm/m2, respectively: p ⫽ 0.0001 versus T0). This improvement was not found in subjects with normal ventricular function who had not had significant modification of LVSWI (data not shown). The myocardial metabolism during CABG of patients with hibernating myocardium is illustrated in Figure 2. Before surgery, the myocardium extracts glucose and lactate as energetic substrates and, as expected, did not release CPK. During the ischemic period of the anterior wall of the left ventricle and the subsequent postischemic reperfusion, there was no release of lactate and CPK. Glucose extraction was unaffected by the procedure. These data are similar to those obtained in the control group (data not shown). Patients with hibernating myocardium had 9.0 ⫾ 0.4 minutes of ischemic time of LAD. They had intensive care unit (ICU) and total inpatient stay of 1.4 ⫾ 0.06 days and 6.2 ⫾ 0.1 days, respectively. In these patients, there were no severe arrhythymias, bleeding, or myocardial infarction in the postoperative period. Likewise, no pulmonary and neurological complications were observed after surgery. These results did not differ from those obtained in patients with normal ventricular function (data not shown).
Comment These preliminary data obtained after early hemodynamic and metabolic measurements indicate that CABG
178
PASINI ET AL REVASCULARIZATION OF HIBERNATING MYOCARDIUM
Fig 1. Global left ventricular function evaluated as left ventricular stroke work index before and after coronary artery bypass graft on beating heart of patients with hibernating myocardium. Bars and lines indicate, respectively, mean and SEM values. *Indicates p ⬍ 0.01, Scheffe’s test versus T0, T1, and T2.
without CPB improved myocardial global function, in patients with severe ventricular dysfunction due to hibernating myocardium, without affecting the metabolism of the muscle during the surgical procedure. Reversible cardiac dysfunction is common in unstable angina, and 78% of patients evaluated between 5 and 21 days after acute myocardial infarction, and treated with thrombolysis, had akinetic areas with a perfusionmetabolism mismatch suggestive of hibernating myocardium [1, 2]. This has been confirmed by Louie and colleagues who showed that about 11% of subjects referred for cardiac transplantation had reversible myocardial dysfunction [3]. It is now documented that restoration of myocardial blood flow by CABG can lead to a recovery of the contractile function of hibernating myocardium [11]. However, subjects with severe cardiac dysfunction represent a high perioperative risk group for CABG with CPB with long ICU and hospital stays (3 and 11 days, respectively) and an in-hospital mortality of 4% to 10% in spite of myocardial protection with cardioplegic solution and hypothermia [6]. In fact, although hypothermia reduces the energy requirement of myocytes, the cold temperature lowers high energy phosphate production and produces cellular membrane instability leading to a temporary impairment of mechanical performance in the immediate postoperative period (stunning) [12]. The negative effects of hypothermia have been mitigated in part with the introduction of warm blood cardioplegia, which significantly reduced mortality and morbidity after CABG [13]. However, the mechanical trauma to blood components as well as microembolic events and activation of the inflammatory response by CPB can be clinically relevant [14, 15]. These observations are reinforced by recent findings that demonstrate that inflammatory
Ann Thorac Surg 2001;71:176 –9
molecules (such as interleukin 6) released during CPB have significant negative inotropic effects [16]. Previous studies demonstrate that CABG can be performed on a beating heart without CPB. It allows grafting of the left internal thoracic artery (LITA) with LAD on a normothermic and perfused heart avoiding the potential negative effects of CPB. This surgical technique has been successfully performed in elderly patients with renal or heart failure, or with impaired pulmonary function [7]. This study reports the use of CABG on beating heart to revascularize the hibernating myocardium of patients with severely compromised myocardial contractility. These early results obtained in these severely compromised patients are very encouraging. The short temporary interruption of coronary flow, necessary for grafting the arteries, did not induce any ischemic insult to the hibernating heart, as demonstrated by the absence of myocardial release of lactate and CPK, as well as by the maintenance of glucose extraction. Metabolic studies indicate that during ischemia, glucose uptake increases while lactate is produced rather than taken up by the heart [17]. This is crucial in hibernating myocytes in an unstable metabolic equilibrium, as even a brief period of anoxia may cause severe damage. The results of this study clearly show that this procedure is well tolerated by the hibernating myocardium. These data are in agreement with other studies in nonhibernating myocardium where a brief period of coronary occlusion did not alter blood troponin I levels [18] or mitochondrial structure [19]. In addition, we documented that LVSWI was not compromised by the brief period of temporary interruption of coronary flow but actually had already significantly increased a few hours and 48 hours after revascularization without postoperative stunning indicating the recovery of contractile properties of reperfused hibernating cardiomyocytes. These results are not due to effects of anesthesia or neurohormonal perturbation because in subjects with normal myocardial function undergoing the same surgical procedure, these remarkable improvements of LVSWI were not found. These positive findings are concomitant with the early postoperative data. In fact, although CABG was performed in severely compromised patients, no deaths were observed. In addition, extubation times and intensive care unit or hospital stays were similar to that of subjects operated on beating heart but without myocardial depression indicating that this surgical procedure is safe even in these high-risk patients [20]. Although the aim of this study was not to evaluate the intrinsic mechanism of hibernation, our data provide additional information to the physiopathology of hibernating myocardium. The results show that in basal conditions, hibernating myocardium extracts glucose and lactate as energetic substrates with the same magnitude as normal myocardium, suggesting that hibernating myocytes are not completely ischemic and their oxidative processes are active [21]. However, this study has some limitations. As this was a feasibility study, it was performed in highly selected patients with hibernating myocytes in the territory of LAD. Although these results are promising, further stud-
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PASINI ET AL REVASCULARIZATION OF HIBERNATING MYOCARDIUM
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References
Fig 2. Metabolic measurements before and after coronary artery bypass graft on beating heart of patients with hibernating myocardium. Panels show differences between radial artery (A) and coronary sinus (V) concentrations of: top panel, glucose; middle panel, lactate; and bottom panel, creatine phosphokinase (CPK). Bars and lines indicate, respectively, mean and SEM values.
ies would be appropriate in order to: (1) be able to select those patients who can be operated with acceptable risks; (2) investigate the long-term patency of the graft, especially in comparison to angioplasty; and (3) the long-term survival of these subjects. The technique of beating heart coronary surgery is attractive but it has some limitations. The ideal candidates for CABG on beating heart are the patients with significant lesions of the proximal left anterior descending artery, and this procedure cannot be performed in subjects with very small, calcified, or deeply buried coronary arteries. In conclusion, early hemodynamic and metabolic data suggest that CABG without CPB in patients with hibernating myocardium is safe, has low use of resources, and results in a significant improvement of global cardiac function, even in those subjects with severe left ventricular dysfunction who otherwise would be candidates for cardiac transplantation.
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