| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Ann Thorac Surg 1995;60:1021-1027
© 1995 The Society of Thoracic Surgeons
Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine and Carlyle Fraser Heart Center, Cardiothoracic Research Laboratory, Crawford Long Hospital, Atlanta, Georgia
 |
Abstract |
|---|
 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Methods. Oxygenated cold crystalloid cardioplegia and cold blood cardioplegia groups, (n = 11 each) had hypothermic cardiopulmonary bypass (28°C), topical cooling, antegrade arrest, and intermittent antegrade delivery. A warm blood cardioplegia group (n = 11) had normothermic cardiopulmonary bypass (37°C), antegrade arrest, and continuous antegrade delivery. All groups underwent cardioplegic arrest for 1 hour followed by 1 hour of reperfusion. Dogs that did not have instrumentation were used as controls (n = 10). Coronary microvessels (100 to 200 µm in internal diameter) were examined in a pressurized, no-flow state with video microscopic imaging and electronic dimension analysis.
Results. Ischemic arrest with cold crystalloid cardioplegia significantly (p < 0.05) impaired endothelium-dependent relaxations in both ventricles to acetylcholine (left ventricle, 69% ± 4%, and right ventricle, 73% ± 5%, versus control left ventricle, 100% ± 0.3%, and control right ventricle, 100% ± 0.3%) and the calcium ionophore (left ventricle, 70% ± 6%, and right ventricle, 68% ± 3%, versus control left ventricle, 98% ± 1%, and control right ventricle, 98% ± 1%). In the cold blood cardioplegia group, endothelium-dependent relaxations to acetylcholine (left ventricle, 96% ± 1%, and right ventricle, 87% ± 4%) and the calcium ionophore (left ventricle, 88% ± 3%, and right ventricle, 78% ± 7%) were preserved. In the warm blood cardioplegia group, endothelium-dependent responses to acetylcholine (92% ± 3%) and the calcium ionophore (96% ± 1%) were preserved in the left ventricle, but the right ventricle showed reduced (p < 0.05) reactivity to the endothelium-dependent acetylcholine (77% ± 8%) and the calcium ionophore (69% ± 8%). Endothelium-independent relaxation to sodium nitroprusside was similar to controls in all groups for both ventricles, thus indicating normal smooth muscle responsiveness.
Conclusions. Cardioplegic arrest with cold blood cardioplegia preserved the endothelium-dependent response in the right and left ventricles, whereas cold crystalloid cardioplegia impairs this response. Warm blood cardioplegia preserved the endothelium-dependent response in the left ventricle, but this response was reduced in the right ventricle. This suggests that blood cardioplegia and hypothermia may be important in protection of microvascular endothelium and that the right ventricle may be more vulnerable to damage than the left ventricle.
|
Introduction |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
The coronary microvasculature plays a central role in the regulation of myocardial perfusion. Cardiac dysfunction after cardiopulmonary bypass (CPB) and ischemic arrest with crystalloid cardioplegia may be related to reduced myocardial perfusion secondary to impaired endothelium-dependent microvascular reactivity [1, 2]. Sellke and co-workers [3] found preserved endothelium-dependent relaxation in the microvasculature after the addition of either blood or albumin to a crystalloid cardioplegic solution.
There is a subset of patients in whom the popular cold ischemic cardioplegic techniques may not offer adequate myocardial protection. These are patients with severely compromised ventricular function or an evolving myo-cardial injury. Continuous warm blood cardioplegia (WB) has been proposed as an alternative to the cold ischemic techniques [4]. In studies performed at this institution [5], left ventricular functional recovery was superior in animals protected with WB compared with oxygenated cold crystalloid (CC) and cold blood cardioplegia (CB) in a canine model of acute global myocardial ischemia. Studies in this laboratory [6] also showed the superiority of WB compared with CC and CB in a canine model of an acute evolving regional infarct.
Not enough is known about the effect of WB on microvascular relaxation, and about the response of microvessels from the right ventricle in comparison to the left ventricular microvessels after CPB, cardioplegic arrest, and reperfusion. This study examined microvessels from branches of both the right coronary artery and the left circumflex artery to determine the effect of continuous WB on preservation of microvascular reactivity compared with two cold ischemic cardioplegic techniques.
|
Material and Methods |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
In the control group (n = 10), a sternotomy was performed. The heart was rapidly excised and immediately placed in cold (1° to 4°C) Krebs/HEPES buffered solution of the following composition (mmol/L): NaCl, 99.0; KCl, 4.7; CaCl, 2.5; MgSO4, 1.2; NaHCO3, 25.0; KH2PO4, 1.0; NaHEPES, 20.0; and glucose, 11.1. Responses of microvessels from these hearts served as nonischemic controls for the three cardioplegia groups.
After induction of anesthesia, intubation, and preparation, arterial blood gases were measured and adjusted by ventilatory rate, tidal volume, and inspired oxygen fraction to maintain oxygenation greater than 100 mm Hg, pH between 7.35 and 7.45, and carbon dioxide tension between 30 and 45 mm Hg. A median sternotomy was used for exposure. A limited laparotomy for ligation of the splenic vessels was performed to prevent sequestration of blood during CPB. Both phrenic nerves were divided, the thymus was removed, and the azygos vein was ligated. All animals were given an intravenous bolus (4 mg/kg) of heparin sodium. The left subclavian artery was cannulated for inflow from the CPB circuit with cannulation of the inferior vena cava for venous return to the pump.
Cardiopulmonary bypass was instituted using a membrane oxygenator (Cobe) and standard roller pump. Blood flow was kept between 2.0 and 3.0 L/min (2.6 to 4.2 L•min-1•m-2) to maintain mean perfusion pressure between 50 and 80 mm Hg. An ascending aortic cardioplegia delivery cannula was placed and secured. All animals underwent cardioplegic arrest by cross-clamping of the ascending aorta and initiation of one of three cardioplegic myocardial protection methods (Table 1
). Cardioplegia hematocrit averaged 27% ± 2% in the blood groups. Animals receiving either of the hypothermic techniques were systemically cooled on CPB to 28°C. The WB group was maintained at a systemic temperature of 37°C. Hearts were vented through the left ventricular apex.
|
After 60 minutes of cardioplegic arrest, animals that had been systemically cooled were rewarmed to 37°C 5 minutes prior to aortic cross-clamp removal. The aortic cross-clamp was removed, and the heart was reperfused for 60 minutes. The heart was kept decompressed with the ventricular vent until a stable rhythm was obtained. The mean reperfusion pressure was maintained between 50 and 80 mm Hg. In the case of ventricular fibrillation, 10 mg of lidocaine hydrochloride was infused intravenously and the heart was defibrillated with 15 J after the myocardial temperature rose to greater than 30°C. Animals were separated from CPB and decannulated. Those that were unable to finish the reperfusion period were excluded from the study. After 60 minutes of reperfusion, the hearts were rapidly excised and placed in cold Krebs/HEPES buffered solution.
All animals received humane care in compliance with the ``Principles of Laboratory Animal Care'' formulated by the National Society for Medical Research and the ``Guide for the Care and Use of Laboratory Animals'' prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication no. 85-23, revised 1985).
Coronary Microvessel Studies
Microarterial vessels (100 to 200 µm in internal diameter) were dissected from the right and left ventricles of the hearts from the three experimental groups using a 10x to 60x dissecting microscope. The vessels were placed in an isolated double-chambered Plexiglas organ chamber, cannulated with dual glass micropipettes (tip measuring 40 to 80 µm in diameter), and secured with 10-0 nylon monofilament suture. Krebs/HEPES buffered solution warmed to 37°C was continuously circulated through both organ chambers and both reservoirs. Total volume of each organ chamber and reservoir was 100 mL. The microvessels were pressurized to 20 mm Hg in a no-flow state. With an inverted microscope connected to a video camera, the vessel image was projected onto a black-and-white television monitor. A Halpern video dimension analyzer was used to measure internal lumen diameter. The vessels were allowed to bathe in the organ chamber for 30 to 120 minutes before an intervention.
Study Protocol
After equilibration, the microvessels were constricted with endothelin I (0.1 to 10 nmol/L) by 30% to 40% of the baseline diameter. Acetylcholine chloride (1 x 10-10 to 3 x 10-5 mol/L), calcium ionophore (1 x 10-10 to 3 x 10-5 mmol/L), or sodium nitroprusside (1 x 10-10 to 3 x 10-5 mol/L) was applied extraluminally. The order of administration was random, except for calcium ionophore, which was always administered last. The microvessels were washed and allowed to equilibrate for 10 to 15 minutes between interventions. One intervention to four interventions were performed on each vessel, and right and left ventricular vessels were examined from each heart. The endothelin I, acetylcholine chloride, calcium ionophore A23187, and nitroprusside were obtained from Sigma Chemical Co, St. Louis, MO.
Data Analysis
Microvascular relaxations are expressed as the percent relaxation of the endothelin I--induced constriction of the vessel diameter [
]. Values are expressed as the mean ± the standard error of the mean. Statistical analyses were carried out with the aid of a statistician (R. S. Clark, PhD, Emory University). Responses of the microvessels to all drugs at all drug concentrations were compared by two-way analysis of variance with repeated measures. Whenever significance was observed, Tukey's test for multiple comparisons was used to determine significance between the cardioplegia groups. Bonferroni's test for multiple comparisons was used to determine significance within the cardioplegia groups' right and left ventricular microvessels. Significance was assumed when the p value was less than 0.05.
|
Results |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Vessel Characteristics
Microvessel internal diameter ranged between 100 and 200 µm in both right and left ventricles. Average internal diameter of the left ventricle was 143 ± 6 µm, 151 ± 7 µm, 157 ± 5 µm, and 169 ± 10 µm in the control, CC, CB, and WB groups, respectively. The right ventricle had an average internal diameter of 161 ± 10 µm, 167 ± 8 µm, 168 ± 11 µm, and 171 ± 8 µm in the control, CC, CB, and WB groups, respectively. The percent constriction after administration of endothelin I in the left ventricular microvessels was 36% ± 1%, 36% ± 1%, 35% ± 1%, and 36% ± 0.8% in the control, CC, CB, and WB groups, respectively. The percent constriction after administration of endothelin I in the right ventricular microvessels was 36% ± 1%, 33% ± 1%, 37% ± 1%, and 36% ± 2% in the control, CC, CB, and WB groups, respectively.
Endothelium-Independent Response
Relaxations to the endothelium-independent vasodilator nitroprusside were similar in the microvasculature from the right and left ventricles of the control group and the three different cardioplegia groups, thereby indicating normal smooth muscle responsiveness (Table 2).
|
). The endothelium-dependent response to the nonreceptor-mediated vasodilator calcium ionophore was likewise impaired significantly (p < 0.05) in the CC (68% ± 3%) and WB (69% ± 8%) groups compared with the control group (98% ± 1%). This response was preserved in the CB group (78% ± 7%) compared with the control group (98% ± 1%) (Fig 2).
|
|
). The endothelium-dependent response to the nonreceptor-mediated vasodilator calcium ionophore was impaired (p < 0.05) in the CC group (70% ± 6%) compared with the control group (98% ± 1%). The microvessel response was preserved in the CB (88% ± 3%) and WB (96% ± 1%) groups compared with the control value (98% ± 1%) (Fig 4).
|
|
). Microvascular responses to the nonreceptor-mediated endothelium-dependent vasodilator calcium ionophore were similar in microvessels from the right and left ventricles in the control, CC, and CB groups. This response was impaired (p < 0.05) in the right ventricle (69% ± 8%) of the WB group compared with the response of the left ventricle (96% ± 1%) (Fig 6).
|
|
|
Comment |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Another advantage to this study is the use of a receptor-mediator agonist (acetylcholine), a nonreceptor-mediator agonist (calcium ionophore), and a receptor-independent agonist (nitroprusside) to determine if there are any alterations in the pathway to stimulation of endothelium-derived relaxing factor. Indomethacin was not used in this study. In previous studies, Dr Sellke examined indomethacin to determine the role of prostaglandin in the stimulation of endothelium-derived relaxing factor. He concluded that the role of prostaglandin was not significant in stimulating production of this factor after ischemia and reperfusion.
As noted previously, Sellke and associates [3] have shown that adding blood to cardioplegia preserves microvascular reactivity, but a WB group was not studied. Ko and colleagues [11] studied the effects of WB and CB on endothelial relaxation in larger vessels and found that WB provided no added benefit over CB to endothelial relaxation. Our study extends these findings to the microvasculature. This is important because the coronary microcirculation is much more likely to develop endothelial dysfunction after ischemia and reperfusion than larger vessels [12].
Previous studies on cardioplegia and microvascular reactivity examined left ventricular microvessels exclusively. In the present study, right and left ventricular microvessels were examined to determine endothelium-dependent relaxation after cardioplegic arrest and reperfusion. We found that CC impaired endothelium-dependent vasodilation of the coronary microvasculature in both the right and left ventricles. Cold blood cardioplegia preserved the endothelium-dependent vasodilation in the coronary microvessels of both ventricles. Unlike CB, WB failed to improve endothelium-dependent vasodilation in the right ventricle relative to both the control hearts and the left ventricle of the WB hearts.
Prevention of intraoperative myocardial damage with cardioplegic solution depends on completeness of delivery. The difference in right and left ventricular microvascular reactivity during WB may be due to the heterogeneous delivery of cardioplegic solutions. Previous studies [13] have shown significant variability in the delivery of cardioplegia to different regions of the left ventricular region. Dorsey and colleagues [14] observed a 41% decrease in distensibility in regions of the myocardium that had inadequate delivery of cardioplegia. In those regions that had adequate cardioplegia delivery, there was a 97% return of systolic function.
One might suspect that there exists regional variability in cardioplegia delivery in the right ventricle. Inadequate myocardial protection of the right ventricle resulting from ineffective cardioplegia delivery may result in impairment of the endothelium-dependent response of the microvasculature seen in the WB group. It should be noted that WB was delivered in an antegrade manner in this study. Antegrade delivery of cardioplegia is distributed through open coronary arteries but may not be adequately delivered in patients with obstructed coronary vessels. Cardioplegia can be delivered retrograde through the coronary venous system and can be distributed to regions of the myocardium that are not adequately protected with antegrade delivery because of coronary disease. All cardioplegia had antegrade delivery in this study because the animals had no obstructed coronary vessels.
Infusion pressure of cardioplegia is a major determinant of the completeness of cardioplegia delivery. In this study, blood cardioplegia was infused at a rate of 75 mL/min, which is analogous to a rate of 150 mL/min in humans. Aldea and associates [13] have shown that a low coronary perfusion pressure increases the heterogeneity of cardioplegia delivery to the myocardium. Even at normal coronary perfusion pressure, regional flow in the diastolically arrested heart is heterogeneous, and this flow can be relatively low in certain regions of the myocardium.
The basis for this flow heterogeneity may be metabolic [15]. Flynn and colleagues [16] noted that regional variation in myocardial oxygen demand results in metabolic regulation of flow appropriate to meet those demands. Metabolic differences between the right ventricle and left ventricle have been demonstrated by Crystal and associates [17]. In essence, the right ventricular region has a smaller work load, a lower oxygen uptake and extraction, and a lower blood flow. In contrast, the left ventricle, because of its increased oxygen extraction, is dependent on an increased blood flow to maintain myocardial oxygen uptake [17]. With these findings in mind, Flynn and co-workers [16] concluded that the greater variability in flow at low coronary perfusion pressure may be due to the fact that a portion of the ventricular regions fall below the pressure range necessary for effective autoregulation, while other regions maintain such regulation.
One might suspect that in the present study, perfusion pressure of WB in the right ventricular region was below the perfusion pressure required for effective autoregulation. As a result, there was a greater variability in cardioplegia delivery to the right ventricular region, and thus, inadequate myocardial protection of the right ventricle. This lack of protection in the right ventricular region was detected by the impairment of endothelium-dependent relaxation in the WB group.
Hypothermic infusion of blood cardioplegia appears to be a factor determining adequate protection of right ventricular microvascular reactivity. Studies have shown that there is uneven myocardial cooling during cardioplegic arrest, resulting in the right ventricular region having a higher temperature than the left ventricular region [18]. Investigators [19, 20] have demonstrated that this higher temperature in the right ventricle may detrimentally affect right ventricular function after cardioplegic arrest. Couple the uneven distribution of cardioplegia with a warmer temperature in the right ventricle, and the impaired endothelium-dependent response of the right ventricular microvessels might be anticipated in the WB group.
Inadequate myocardial protection can be a major determinant of morbidity and death after cardiac operations [21]. Advantages of blood cardioplegia over crystalloid cardioplegia are many [6, 22–] and can provide enough protection to the myocardium if the cardioplegic solution is adequately delivered. Proper protection of the microvasculature will ensure good blood flow to the myocardium. Failure to protect the coronary microvasculature may lead to derangements in coronary flow and possibly alterations in ventricular function. Low coronary perfusion pressure seen in clinical cardiac operations may be the cause of right ventricular failure after an apparently successful operation. This may be important especially in those clinical situations in which coronary disease exists or in the presence of hypertrophied myocardium.
This study demonstrates impairment of right ventricular endothelium-dependent microvascular relaxation relative to the left ventricular response with continuous WB. We suggest that in addition to the use of blood cardioplegia, close attention to cardioplegia distribution and hypothermia may be useful in the preservation of endothelium-dependent microvascular relaxation.
|
Acknowledgments |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
|
Footnotes |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Address reprint requests to Dr Guyton, Carlyle Fraser Heart Center, Crawford Long Hospital of Emory University, 550 Peachtree St NE, Suite 4356, Atlanta, GA 30365-2225.
|
References |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Related Article
This article has been cited by other articles:
|
|
 |
|
  J. Steuer, T. Bjerner, O. Duvernoy, L. Jideus, L. Johansson, H. Ahlstrom, E. Stahle, and B. Lindahl Visualisation and quantification of peri-operative myocardial infarction after coronary artery bypass surgery with contrast-enhanced magnetic resonance imaging Eur. Heart J., August 1, 2004; 25(15): 1293 - 1299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Flynn, D. Winters, P. Breen, G. O'Sullivan, G. Shorten, D. O'Connell, A. O'Donnell, and T. Aherne Dopexamine increases internal mammary artery blood flow following coronary artery bypass grafting Eur. J. Cardiothorac. Surg., October 1, 2003; 24(4): 547 - 551. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Alamanni, A. Parolari, R. Visigalli, O. Bussolati, P. Rubini, R. Sala, L. Bonati, G. C. Gazzola, P. Biglioli, and V. Dall'Asta Endothelial cell injury induced by preservation solutions: a confocal microscopy study Ann. Thorac. Surg., May 1, 2002; 73(5): 1606 - 1614. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-K. Wu, M. R. Tarkka, E. Pehkonen, L. Kaukinen, E. L. Honkonen, and S. Kaukinen Beneficial effects of ischemic preconditioning on right ventricular function after coronary artery bypass grafting Ann. Thorac. Surg., November 1, 2000; 70(5): 1551 - 1557. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. G. Duarte, S. T. Shearer, M. J. MacDonald, J. P. Gott, W. M. Brown III, J. Vinten-Johansen, and R. A. Guyton Myocardial Distribution of Antegrade Cold Crystalloid and Tepid Blood Cardioplegia Ann. Thorac. Surg., June 1, 1998; 65(6): 1610 - 1616. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kawasuji, S. Tomita, T. Yasuda, N. Sakakibara, H. Takemura, and Y. Watanabe Myocardial Oxygenation During Terminal Warm Blood Cardioplegia Ann. Thorac. Surg., May 1, 1998; 65(5): 1260 - 1264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Parolari, R. Sala, C. Antona, O. Bussolati, F. Alamanni, P. Mezzadri, V. Dall'Asta, G. C. Gazzola, and P. Biglioli Hypertonicity Induces Injury to Cultured Human Endothelium: Attenuation by Glutamine Ann. Thorac. Surg., December 1, 1997; 64(6): 1770 - 1775. [Abstract] [Full Text]
|
|
|
|
|
|
D. Curro, G. Bombardieri, C. Barilaro, P. Di Francesco, C. Varano, G. Possati, and C. Pragliola Time Dependence of Endothelium-Mediated Vasodilation by Intermittent Antegrade Warm Blood Cardioplegia Ann. Thorac. Surg., November 1, 1997; 64(5): 1354 - 1359. [Abstract] [Full Text]
|
|
|
|
|
|
M. Tofukuji, A. Stamler, J. Li, M. D. Hariawala, A. Franklin, and F. W. Sellke Comparative Effects of Continuous Warm Blood and Intermittent Cold Blood Cardioplegia on Coronary Reactivity Ann. Thorac. Surg., November 1, 1997; 64(5): 1360 - 1367. [Abstract] [Full Text]
|
|
|
|
|
|
G. F. O. Tyers and R. A. Guyton Microvascular Reactivity After Cardioplegia Ann. Thorac. Surg., February 1, 1997; 63(2): 598 - 599. [Full Text]
|
|
|
|
|
|
C. O. Murphy, Pan-Chih, J. P. Gott, and R. A. Guyton Coronary Microvascular Reactivity After Ischemic Cold Storage and Reperfusion Ann. Thorac. Surg., January 1, 1997; 63(1): 20 - 27. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. R. Handy Jr., B. H. Dorman, M. J. Cavallo, R. B. Hinton, R. C. Roy, F. A. Crawford, and F. G. Spinale DIRECT EFFECTS OF OXYGENATED CRYSTALLOID OR BLOOD CARDIOPLEGIA ON ISOLATED MYOCYTE CONTRACTILE FUNCTION J. Thorac. Cardiovasc. Surg., October 1, 1996; 112(4): 1064 - 1072. [Abstract] [Full Text]
|
|
|
|
|
|
H. Gohra, H. Tsuboi, G. Sasaki, Y. Minami, K. Hamano, T. Katoh, Y. Fujimura, and K. Esato Effect of Cardioplegic Arrest and Reperfusion on Coronary Reserve and Autoregulation Ann. Thorac. Surg., September 1, 1996; 62(3): 744 - 749. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
