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Ann Thorac Surg 2000;69:696-702
© 2000 The Society of Thoracic Surgeons
a Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center of Crawford Long Hospital, and Emory University School of Medicine, Atlanta, Georgia, USA
Address reprint requests to Dr Vinten-Johansen, Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center of Crawford Long Hospital, 550 Peachtree St NE, Atlanta, GA 30365
e-mail: jvinten{at}emory.edu
Presented at the Forty-Fifth Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 12–14, 1998.
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Abstract |
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Methods. Anesthetized pigs on cardiopulmonary bypass were: (1) cooled to 18°C, and had their circulation arrested (60 minutes) and reperfused at 37°C for 90 minutes (DHCA, n = 8); or (2) time-matched normothermic controls on bypass (CPB, n = 6). Endothelial function in cerebral, pulmonary, and renal vessels was assessed by vasorelaxation responses to endothelial-specific bradykinin (BK) or acetylcholine (ACh), and smooth muscle-specific nitroprusside.
Results. In vivo transcranial vasorelaxation responses to ACh were similar between the two groups. In small-caliber cerebral arteries, endothelial relaxation (BK) was impaired in CPB vs DHCA (maximal 55% ± 2% [p < 0.05] vs 100% ± 6%). Pulmonary artery ACh responses were comparable between CPB (110% ± 10%) and DHCA (83% ± 6%), but responses in pulmonary vein were impaired in DHCA (109% ± 3%, p < 0.05) relative to CPB (137% ± 6%). In renal arteries, endothelial (ACh) responses were impaired in DHCA (71% ± 13%) relative to CPB (129% ± 14%). Apoptosis (DNA laddering) occurred primarily in duodenal tissue, with a greater frequency in DHCA (56%, p < 0.05) compared with normothermic CPB (17%) and nonbypass controls (0%).
Conclusions. DHCA is associated with endothelial dysfunction in cerebral microvessels but not in the in vivo transcranial vasculature; in addition, endothelial dysfunction was noted in large-caliber renal arteries and pulmonary veins. DHCA is also associated with duodenal apoptosis. Vascular endothelial dysfunction and apoptosis may be involved in the pathophysiology of multisystem organ failure after DHCA.
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Introduction |
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[TNF]) and initiating the complement cascade, thereby activating vascular endothelial cells and neutrophils [3]. Activated neutrophils cause vascular injury by stimulating the generation of oxygen free radicals and the release of proteolytic enzymes [4, 5]. A manifestation of endothelial cell injury is impaired vasorelaxation of micro- and macrovessels secondary to impaired basal and agonist-stimulated release of autacoids such as nitric oxide [5]. In addition, neutrophil-mediated injury to vascular endothelium has been associated with damage and dysfunction to the underlying parenchymal tissue. Accordingly, impaired release of endothelium-derived nitric oxide has been associated with myocardial infarction, cerebrovascular hypoperfusion, and abnormal metabolism, and pulmonary hypertension and abnormal permeability. In addition to vascular endothelial dysfunction, inflammatory mediators involved in ischemia and reperfusion trigger apoptosis (genetically programmed cell death) as an alternative pathway to cellular and organ dysfunction and cell death [6]. Deep hypothermic circulatory arrest (DHCA), often employed during the repair of complex congenital anomalies as well as dissections and aneurysms of the great vessels, combines two inflammatory stimuli: CPB and whole-body systemic ischemia/reperfusion (circulatory arrest and resuscitation). DHCA has been associated with delayed clinical recovery of cerebral blood flow and abnormal metabolism [7], and a higher incidence of postoperative neurologic deficits [1]. Impairment of vascular function and organ function has also been reported for other organ systems as well. Thus, because total circulatory arrest exposes all organ systems and related vasculature to ischemia-reperfusion, the pathophysiologic alterations leading to vascular endothelial dysfunction, organ dysfunction, and apoptosis may occur on a multisystem level (ie, multiorgan dysfunction syndrome).
In the present study, we hypothesized that profound hypothermic circulatory arrest during extracorporeal circulation impairs vascular endothelial function of cerebral macro- and microvessels and pulmonary and renal macrovessels, and triggers apoptosis in selected organ systems.
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Material and methods |
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Pigs (17 to 25 kg) were premedicated with intramuscular ketamine (30 mg/kg), xylazine (20 mg/kg), and diazepam (0.2 mg/kg), and anesthetized with sodium thiopental 20 mg/kg intravenously. Subsequent dosing of 1 to 2 mg/kg of sodium thiopental was given as needed to maintain deep anesthesia. Mechanical ventilation was instituted via tracheostomy. The right femoral artery was cannulated to measure mean arterial pressure (MAP) using a fluid-filled catheter. The right femoral vein was cannulated for administration of intravenous fluids and supplemental anesthesia.
A median sternotomy with a right cervical extension was performed in each animal. The right internal carotid artery (ICA) and internal jugular vein (IJV) were carefully isolated. The artery and vein were each instrumented with a 4F Millar Microtip catheter (Millar Instruments, Houston, TX) in its proximal portion for measurement of the internal carotid artery pressure (ICP) and jugular venous pressure (JVP), respectively. A 23-gauge intraarterial infusion catheter was placed distal to the carotid artery pressure transducer for direct infusion (infusion pump; Harvard Apparatus, South Natick, MA) of incremental doses of the vasoactive drugs acetylcholine (0.05 to 0.5 mg/kg/min; Sigma Chemical, St. Louis, MO) and sodium nitroprusside (0.05 to 0.5 µg/kg/min; Elkins-Sinn, Cherry Hill, NC). A 2.5-mm-diameter 20-KHz ultrasonic flow probe (Triton Technology, San Diego, CA) was placed around the ICA distal to the infusion catheter for measurement of internal carotid artery flow velocity (ICF) in centimeters per second. After systemic heparinization (300 U/kg), each animal was placed on CPB via cannulation of the right atrium using a two-staged venous catheter and cannulation of the ascending aorta. The CPB circuitry incorporated a Sarns infant membrane oxygenator and reservoir (Sarns, Ann Arbor, MI) and Bentley cardiotomy reservoir (Anaso, Puerto Rico). Pump flow was adjusted to maintain a MAP of 60 mm Hg. Arterial blood pH was maintained at 7.35 to 7.45 by regulating oxygen flow and sodium bicarbonate as necessary for acidemia. An alpha-stat pH management strategy was followed during hypothermia. Animals were not weaned from extracorporeal circulation in either group. This avoided preexperimental vs postexperimental variations in systemic MAP during measurements of ICF at steady state and in response to vasodilator agonists.
Protocol
In vivo studies
After surgical preparation, the animals were randomly assigned to one of two groups: normothermic cardiopulmonary bypass (CPB, n = 6) or deep hypothermic circulatory arrest (DHCA, n = 8). In each group, baseline hemodynamic measurements were obtained. Baseline cerebrovascular vascular responses were then obtained by infusing incremental concentrations of acetylcholine and sodium nitroprusside while systemic MAP was held constant at 80 mm Hg until the maximal vasodilator response was achieved. In the CPB group, normothermic (37°C) bypass was maintained for 3 hours, after which steady-state postexperimental hemodynamic and cerebrovascular responses were again recorded. In the DHCA group, systemic temperature was cooled to 18°C and CPB was discontinued for 60 minutes of total circulatory arrest. The average time to achieve 18°C body temperature with a 10°C blood-heat exchanger temperature gradient was 20 minutes. After 1 hour of circulatory arrest, extracorporeal flow was reinstituted, the animals were rewarmed to 37°C, and postexperimental steady-state measurements and ICA flow velocity responses to acetylcholine and nitroprusside were again recorded. All data were recorded on computer using an analog-to-digital converter (Data Translation, Waltham, MA) sampling at 150 Hz for slow wave data (MAP, carotid flow velocities, etc). During steady state, hemodynamic and blood flow velocity data were recorded over a 6-second period and mean values calculated using the Spectrum cardiovascular data analysis program (Wake Forest University, Winston-Salem, NC). All measurements during steady-state and intracarotid vasodilator infusions were taken at a MAP of 80 mm Hg. At least 10 minutes was allowed between different drug infusions.
At the completion of the experiment, a frontal craniotomy and midline laparotomy were performed. The brain was removed for harvesting of microvessels and wet-dry ratios as an indicator of cerebral parenchymal edema. Additionally, the heart, lungs, kidneys, stomach, small intestine, and skeletal muscle were harvested for isolation of macrovessels (brain, kidney, and pulmonary) and histological analysis of apoptosis (brain, lung, heart, skeletal muscle, small intestine, and stomach).
In vitro protocols
Microvessel studies
The cerebrum was immediately harvested and placed in a Krebs-Henseleit (K-H) buffer solution. Microvessels, 110 to 254 µm in diameter, were dissected from the middle cerebral artery region of the left hemisphere (opposite the side of in vivo drug infusion). After 40 minutes of equilibration, the vessels were preconstricted with the thromboxane A2 mimetic U46619 (Upjohn Pharmaceutical, Kalamazoo, MI) to 30% to 40% of the baseline diameter. The vessels were then exposed to the receptor-dependent endothelium-dependent vasodilator bradykinin, to the receptor-independent endothelium-dependent vasodilator calcium ionophore A23187, and to the receptor-independent smooth muscle dilator sodium nitroprusside (NTP), each separated by serial washings and restabilization. The average vessel internal diameter along the entire length of the vessel was measured at each drug concentration using Image Pro Plus for Windows image analysis software (Media Cybernetics, Silver Spring, MD). Relaxation to each concentration of vasoactive agent was expressed as a percentage of the preconstricted lumenal diameter.
Macrovessel studies
After the experiment, the left lung and left kidney were excised and placed in cold preoxygenated K-H buffer having the following composition (in mmol/L): 118 NaCl, 4.7 KCl, 1.2 KH2PO4, 1.2 MgSO4, 2.5 CaCl2, 12.5 NaHCO3, and 10 glucose. Segments of the second pulmonary artery branch and the second branch of the pulmonary vein extending into the upper lobe of the lung and segments of the second branch of the renal artery were carefully removed. In addition, similar vessels were also excised from time-matched sham pigs exposed to anesthesia and median sternotomy (no CPB). Isolated vessels were cleaned of adipose and connective tissue, cut into rings approximately 4 to 5 mm in length, and placed into Radnoti organ chambers (Radnoti Glass, Monrovia, CA) containing oxygenated (95% O2-5% CO2) K-H solution at 37°C. Vasorelaxation responses to incremental concentrations of the endothelium-dependent receptor-dependent vasodilator acetylcholine (ACh, 10-9 to 10-6 M), the endothelium-dependent receptor-independent vasodilator calcium ionophore A23187 (10-9 to 10-6 M), and the endothelium-independent vasodilator sodium nitroprusside (SNP, 10-7 to 5 x 10-3 M) were recorded as described previously [8]. Drug concentration is expressed as final concentrations in the organ chamber, and relaxation is expressed as a percentage of the preconstricted tension.
DNA isolation and gel electrophoresis for detection of apoptosis
Tissue samples were rapidly frozen upon excision and kept in a -70°C freezer until analyzed. Freshly frozen tissue samples (20 to 30 mg) were prepared for electrophoresis as described previously [9]. DNA (10 µg) was loaded onto 1.5% agarose gels containing 0.5 µg/mL ethidium bromide. Electrophoresis was carried out at 80 V for 1 to 2 hours. DNA ladders, an indicator of tissue apoptotic nucleosomal DNA fragmentation, were visualized under ultraviolet light and the gels photographically recorded.
Data analysis
In vivo hemodynamic and ICA blood flow velocity data were analyzed for group, time, and group-time interactions using analysis of variance for repeated measures (ANOVA). In vitro macrovessel and microvessel vascular reactivity data were analyzed for group differences at each concentration of drug using either ANOVA for three-group comparison (CPB, DHCA, and sham) or Student’s t test for two-group comparison (CPB and DHCA), respectively. A p value less than 0.05 was considered statistically significant. Data are expressed as mean ± standard error of the mean.
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Results |
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Steady-state
In the CPB group, steady-state ICF velocity after 3 hours of normothermic bypass was comparable with that at baseline (19.4 ± 3 vs 19.3 ± 3 cm/s). There were no significant differences between baseline and postresuscitation steady-state ICF velocity in the DHCA group (14.4 ± 2 vs 17.8 ± 2 cm/s).
Vasodilator responses in the CPB group
In the CPB group, preexperimental ICF velocity responses to incremental doses of ACh increased in a step-wise fashion from 29.5 ± 7.4 cm/s at 0.05 mg/kg/min ACh to a peak of 48.9 ± 7.9 cm/s at 0.3 mg/kg/min ACh, with no further flow augmentation thereafter. Similar vasodilator responses were observed after 3 hours of bypass, with no significant differences between pre- and postexperimental time points at each dose. ICF increased from 26.6 ± 5.0 cm/s at 0.05 mg/kg/min ACh to 43.5 ± 8.1 cm/s at 0.3 mg/kg/min ACh. There were no significant differences between pre- and postexperimental ICF velocity responses at each incremental dose of the smooth muscle vasodilator sodium nitroprusside (data not shown).
Vasodilator responses in the DHCA group
In the DHCA group, pre- and postexperimental endothelium-dependent vasodilator responses to incremental infusions of ACh reached a maximum of 0.3 mg/kg/min (pre 40.9 ± 7.4, post 43.7 ± 8.3 cm/s). There were no significant differences between precirculatory and postcirculatory arrest responses to each dose of ACh. In addition, there were no significant differences in the incrementally increasing pre- vs postexperimental ICF velocity responses to graded doses of sodium nitroprusside (data not shown). Therefore, neither CPB nor DHCA groups demonstrated significant transcranial endothelial dysfunction after their respective interventions.
In vitro studies
Cerebral microvessels
Middle cerebral arteries isolated from animals after DHCA demonstrated complete endothelial-dependent relaxation responses to bradykinin at a concentration of 5 x 10-7 (Fig 1). In the CPB group, however, complete vasorelaxation was not achieved at this same concentration of bradykinin. There was a general shift to the right in the concentration-response curve in the CPB group relative to that in the DHCA group. In contrast, there was no significant group difference in the vasorelaxation responses to the endothelium-dependent receptor-independent agonist A23187, and to the smooth muscle vasodilator sodium nitroprusside (Fig 1). Therefore, in contrast to in vivo cerebrovascular responses, an impairment in endothelium-dependent responses was found in the cerebral microvessels in the normothermic CPB group.
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Pulmonary and renal macrovessels
Endothelium-dependent receptor-mediated relaxation responses to ACh in pulmonary artery rings were generally comparable between CPB and DHCA groups, which were in turn comparable with responses in normal sham control hearts. Relaxation responses were similar at all concentrations of ACh, with peak relaxations of 83.0% ± 6.4% in DHCA, 109.6% ± 10.8% in CPB, and 103.5% ± 10.6% in shams at 10-6 M ACh. Responses to the receptor-independent endothelium-dependent stimulator A23187 showed no significant group differences, and EC50 for A23187 were comparable among groups (DHCA -7.09 ± 0.09, CPB -7.23 ± 0.02, sham -7.49 ± 0.26). Relaxation responses to the smooth muscle dilator sodium nitroprusside were comparable among groups.
In contrast to pulmonary artery rings, vascular responses in pulmonary veins showed a significant shift to the right in the concentration-response curve to ACh (Fig 2A). Starting at 5 x 10-7 M ACh, relaxation responses were significantly lower for DHCA than for sham controls and CPB groups, respectively. Accordingly, maximal relaxation was significantly less in DHCA than in sham controls or CPB groups, and the EC50 was significantly greater in the DHCA group (-7.24 ± 0.09 M) compared with normal controls (-7.62 ± 0.14 M) and CPB (-7.45 ± 0.06 M, p = 0.04), suggesting a relative impairment in both maximal relaxation response and receptor sensitivity to ACh. Similarly, receptor-independent endothelium dilator responses to A23187 showed a significant right shift between normal controls and DHCA (EC50 -7.95 ± 0.02 M vs EC50 -7.19 ± 0.12 M, respectively), and significantly lower responses between 1 x 10-8 and 5 x 10-6 M A23187 (Fig 2B). Maximal relaxation responses to the highest concentration of A23187 were not significantly different among the three groups (p = 0.07). Smooth muscle responses to sodium nitroprusside were comparable among the three groups at all concentrations (data not shown).
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Comment |
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In the present study, responses of carotid blood flow to acetylcholine and nitroprusside were used as a measure of in vivo vascular reactivity occurring largely in the brain. However, contributions made by other vascular beds (facial muscles, skin, etc) will also influence responses in carotid artery flow. We found that neither normothermic CPB nor DHCA altered carotid flow responses to endothelial-dependent (ACh) or direct smooth muscle (nitroprusside) vasodilators under constant pressure conditions. However, in contrast to the in vivo data, impaired endothelial reactivity was observed in microvessels from the area of the middle cerebral artery in the CPB group. The presence of impaired endothelial function in microvessels without similar dysfunction observed in the transcranial (carotid) responses (reflecting integrated responses in multiple vascular beds) may be related to: (1) absence of endothelial injury in extracerebral and extracranial tissue within the perfusion territory supplied by the internal carotid artery; (2) the presence of vascular shunts, which would mask any changes in vascular resistance; (3) decreased sensitivity and increased variability in the in vivo responses; or (4) biologic differences between larger conduit vessels and cerebral microvessels. A difference between small-caliber and larger conduit vessels in the brain may mask microvascular dysfunction when vasodilation responses are measured in an integrated or mixed vascular bed with both large and small vessels. It is possible that the presence of microvascular dysfunction in the CPB group may be related to longer pump time in that group compared with the DHCA group, because the release of cytokines, complement, and other inflammatory mediators is correlated with the duration of CPB.
Impaired endothelial-dependent responses in microvessels after normothermic or moderately hypothermic CPB in a porcine model have been previously reported by Sellke and associates [10] and Stamler and associates [11]. In these studies, normothermia was associated with impaired cholinergic- and ß-adrenergic-mediated relaxation in cerebral microvessels, whereas second messenger systems remained intact. In the study by Stamler and associates [11], moderate hypothermia to 25°C attenuated impaired microvessel reactivity compared with normothermic CPB, in general agreement with our observations in the DHCA group. In contrast, Wagerle and associates [12] demonstrated endothelial-dependent dysfunction of cerebral microvessels during hypothermia (18°C) CPB using a closed cranial window preparation in which pial arteriolar diameter was measured by video microscopy. An important difference between the present study and that of Wagerle and associates [12] is that measurements of microvascular reactivity by Wagerle and associates were performed at 18°C during CPB, whereas our measurements in the DHCA group were obtained at 37°C after hypothermic circulatory arrest. The normal stimulus-release relationship between acetylcholine and nitric oxide or other endothelium-dependent vasodilator factor may be blunted when measured at cold temperatures, as it is for autoregulatory mechanisms, possibly accounting for the decreased vasodilator responses to agonist stimulators of nitric oxide synthase observed by Wagerle and associates [12]. In addition, cerebral ischemia was not imposed by Wagerle and associates [12] as it was in our study, in which ischemia, reperfusion, or most likely both contributed to the observed endothelial dysfunction.
The pulmonary vasculature is vulnerable to injury caused by CPB. Loss of endothelial-dependent relaxation of pulmonary resistance vessels after normothermic CPB has previously been reported by Shafique and associates [13], demonstrating that bypass per se with pulmonary vascular stasis is associated with endothelial injury. Pulmonary endothelial dysfunction was also reported after DHCA by Kirshbom and associates [14]. Although agonist-stimulated receptor-mediated dilator responses were blunted after DHCA in the study by Kirshbom and colleagues [14], tonic (basal) nitric oxide release was observed, possibly suggesting that the endothelial defect was limited to agonist-stimulated nitric oxide synthase activity. We have extended these observations in the present study by showing differential effects on endothelial-dependent vasodilator responses in pulmonary arteries vs veins. The pulmonary venous vasculature differs from its arterial counterpart by having a lower endothelial cell population per unit surface area of the vessel, and less production of nitric oxide after a given stimulus, accompanied by less stimulation of cGMP [15]. The selective endothelial dysfunction in pulmonary veins may be related to these anatomic and functional differences in the pulmonary venous endothelium.
Apoptosis, or genetically programmed cell death, has recently undergone renewed interest as an alternative mechanism of cellular injury. Apoptosis can be induced by stressors including oxidants, nutritional deprivation, cytokines, complement components [16], and ischemia-reperfusion [6]. Apoptosis contributes to overall cell injury and organ dysfunction. Although apoptosis has been demonstrated in endothelium in vitro [17], its association with endothelial cell dysfunction is not clearly demonstrated. Apoptosis was observed in duodenal tissue in the normothermic CPB group, induced possibly by the actions of cytokines and complement released during extracorporeal circulation. Cytokines are a known trigger of apoptosis in numerous cell types. Apoptosis was not observed in brain, lung, kidney, or duodenum from normal control animals not exposed to CPB (data not shown). However, the greater extent of apoptosis observed in duodenal tissue and heart in the DHCA group compared with the normothermic bypass group suggests an additive effect of systemic circulatory arrest and hypothermia in the setting of extracorporeal circulation. Ischemia-reperfusion is a potent stimulator of apoptosis [6], which may superimpose on the moderate stimulation observed with CPB. Although apoptosis has been demonstrated specifically in endothelial cells [17, 18], it is not clear from our study whether apoptosis contributed to vascular dysfunction. The absence of apoptosis in brain tissue in which there was microvascular dysfunction would argue against a causative link between the two observations. However, apoptosis may contribute to end-organ dysfunction in numerous conditions such as heart failure and ischemia-reperfusion, and may contribute to multisystem organ dysfunction after extracorporeal circulation and hypothermic circulatory arrest.
Conclusions
The principal findings of this study are that receptor-mediated cerebral microvascular reactivity after normothermic CPB was impaired, which was not observed with DHCA. In contrast to cerebral microvessels, endothelial dysfunction was noted in large caliber pulmonary veins and renal arteries after DHCA. This endothelial dysfunction may be associated with the adult respiratory distress syndrome and renal failure after DHCA. In addition, the endothelial dysfunction in cerebral microvessels may be a contributing factor to neuropsychologic complications of CPB in addition to the suspected culprits of particulate or air embolization, and formation of aneurysmal dilatations in cerebral microvessels.
The endothelium may be more vulnerable to damage mediated by inflammatory responses to CPB and systemic ischemia-reperfusion in patients with underlying diseases such as diabetes, hypercholesterolemia, and preexisting pulmonary or cerebrovascular disease. Therefore, clinical strategies to attenuate endothelial dysfunction require further investigation to elucidate mechanisms of cellular and multiorgan dysfunction.
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