| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Ann Thorac Surg 2003;75:S745-S752
© 2003 The Society of Thoracic Surgeons
These abstracts were presented at the 3rd International Symposium on "Myocardial Protection From Surgical Ischemic–Reperfusion Injury" as a moderated poster session. They represent cutting-edge investigations into a wide range of areas related to the pathophysiology of myocardial ischemic-reperfusion injury and myocardial protection. It is the purpose of this portion of our supplement to use these superb investigations to stimulate further ideas and discussion of the topics presented here. Perhaps the novel information presented in these abstracts will provide stimulus for further research leading to innovative changes in the clinical practice of myocardial protection.
Myocardial preservation and pre-load recruitable stroke work relationships following off-pump and on-pump coronary revascularization
PV Ching, HB Bittner. Division of Cardiovascular and Thoracic Surgery, University of Minnesota, Minneapolis, MN
Background: It is shown that coronary artery bypass grafting (CABG) without cardiopulmonary bypass or CPB (off-pump or OPCABG) preserves better cerebro-cognitive, pulmonary, hepato-renal, and blood cell function compared to on-pump surgery due to an attenuated inflammatory response. The degree of ischemia/reperusion injury, myocardial protection as well as quantitative changes in myocardial contractile performance following OPCABG are not well documented.
Methods: A canine myocardial ischemic injury model (60 minutes LAD occlusion,n = 30,27 to 35 kg) was used to assess postoperative regional left ventricular function (sonomicrometry, micromanometry, preload-recruitable stroke work=PRSW) quantitatively,oxygenation, and inflammatory response(cytokines/adhesion molecules). The left internal thoracic artery (LITA) to distal LAD was anastomosed in off-pump/on-pump CABG with antegrade/retrograde cold blood cardioplegic arrest (CPB-time 58 minutes ± 2; cross clamp time 28 minutes ± 3). (ANOVA, t-test, *=p < 0.05 vs base line).
Results: LAD occlusion resulted in ischemia/infarction (CK-MB on-pump/off-pump vs base line 17.5 ± 1.4*/19.5 ± 1.8* mg/L vs 1.5 ± 0.3/2.1 ± 0.4) and a significant decrease in regional myocardial function in both groups (PRSW decrease by 50%, see Fig 1). Revascularization led to reestablishment of myocardial function to base line (on-pump/off-pump PRSW = 57 to 196 ergcm-2x103, mean 127 ± 25/81 to 98, mean 90 ± 15. There was significantly elevated postoperative cytokine/adhe sion molecule activation in the on-pump cases. On 100% inspired FIO2 oxygen tension decreased significantly more in the on-pump group (from 489 mm Hg to 180 mm Hg vs 418 mm Hg to 345 mm Hg) post bypass surgery. All anastomoses were widely patent 14 days after surgery in all animals.
|
Grant Support: Minnesota Medical Foundation, AO-168 to 00.
Adenosine and lignocaine: a new concept in cardiac arrest and preservation
GP Dobson, MW Jones. Department of Physiology and Pharmacology, James Cook University, Townsville, Queensland, Australia 4811
Background: Currently 99% of cardioplegic solutions contain high depolarising potassium which is typically present at or above 16 mmol/L. Over the past ten years, prolonged potassium arrest has been linked to ionic and metabolic imbalances, myocardial stunning, ventricular arrhythmias, ischemic injury, tissue edema, free radical production and functional loss during the reperfusion period. The major damage is thought to arise from oxidative stress and accelerated intracellular Ca2+ overload, which can lead to mitochondrial dysfunction, apoptosis and cell death. A new cardioplegia was developed employing ‘hyperpolarizing’ adenosine and ‘polarising’ lignocaine (AL) as the arresting agents in a normokalemic Krebs-Henseleit buffer (5.9 mmol/L K+) delivered under normothermic conditions.
Methods and Results: Hearts were rapidly excised from anesthetized male Sprague-Dawley rats (323 ± 6 g) and perfused in the Langendorff and working mode (preload 10 cm H2O: afterload 100 cm H2O). After 30 minutes stabilization, hearts were switched back to Langendorff mode and subjected to intermittent perfusion with either 200 uM adenosine and 0.5 mmol/L lignocaine in air-equilibrated Krebs-Henseleit (10 mmol/L glucose, pH 7.7 @ 37°C) or modified St. Thomas No 2 Hospital solution (16 mmol/L K+) delivered at a constant pressure head of 70 mm Hg and 37°C. Hearts receiving AL cardioplegia achieved mechanical arrest in less than half the time (25 ± 2 seconds, n = 23) compared to St. Thomas solution (70 ± 5 seconds n = 24). Following 30 minutes arrest (2 minutes induction and a 2 minutes pulse at 15 minutes), there were no significant functional differences between working hearts arrested with either cardioplegia. However, after 2 and 4 hours of arrest (cardioplegia pulsed every 20 minutes for 2 minutes at 37°C), only 50% (4 out of 8) and 14% (1 out of 7) of the St. Thomas’ hearts recovered aortic flow respectively. All hearts arrested with AL cardioplegia recovered 70 to 85% aortic flow after 2 hours (n = 7) and 4 hours arrest (n = 9) and coronary flows were 70 to 80% prearrest values. Heart rate, systolic and diastolic pressures, and rate-pressure product returned to 85 to 100%.
Conclusions: AL normokalemic cardioplegia provides greater myocardial and presumably endothelial protection during arrest and recovery than hyperkalemic St. Thomas’s solution in the isolated rat heart model. Future studies will investigate the efficacy of AL crystalloid and blood cardioplegia in larger animal models undergoing cardio-pulmonary bypass.
Partially supported by JCU Small grants 6215.93766.004 (GPD) and 6215.94591.2828 (GPD) and Australian Heart Foundation Grant G00B O547 (GPD).
Reperfusion with tepid blood improves heart function after myocardial ischemia/reperfusion (I/R) injury
DV Jayakar, U Williams, E Bacha, V Jeevanandam. Department of Cardiac Surgery, University of Chicago Hospitals, Chicago, Illinois
Background: Reperfusion injury contributes significantly to myocardial dysfunction following ischemia. We have examined the effect of tepid (30°C) blood reperfusion and its effect of myocardial function following ischemic injury. This is a simple and novel method to decrease I/R injury and improve allograft donor heart function following heart transplant.
Methods: 48 Male Sprague-Dawley rat hearts were perfused with modified Krebs-Henseleit buffer (KHB) on working heart model with adjustable independent preload and afterload. After stabilization, the hearts were subjected to no-flow ischemia for 15 minutes and then reperfused 5-minutes with diluted whole blood or KHB at 20°C, 30°C or 36°C. The heart function was analyzed on working heart mode for 60 minutes. Preand after-load were normalized. ABGs, and aortic and coronary flows were measured at base line and every 15 minutes after ischemia under both 8 and 12 mm Hg preload.
Results: All hearts recovered function. The table below summarizes the data. At 8 & 12 mm Hg preload, when compared to warm or cold blood reperfusion, hearts reperfused with tepid blood had the best function. Also, the tepid blood group did better than the acellular Krebs group at similar temperature.
Conclusions: This is the first time that reperfusion with tepid blood has shown to decrease myocardial I/R injury even after a severe no- flow ischemic insult. Previous reports demonstrate superiority of acelluar solutions compared to blood due to presence of leukocytes and plaelets during reperfusion. We have shown that alteration in temperature makes blood superior to Krebs solution. Since working heart function model is a true myocardial function model, it has clinical implications as reperfusion with tepid blood before release of cross-clamp during heart transplant should improve immediate postsurgical myocardial function.
| |||||||||||||||||||||||||||||||||||||||||||||
Pre-conditioning with glutamine improves heart function - novel protective mechanism against myocardial ischemia/reperfusion injury
DV Jayakar, U Williams, E Bacha, V Jeevanandam. Department of Cardiac Surgery, University of Chicago Hospital, Chicago, Illinois
Background: Ischemia/reperfusion (I/R) injury is a major cause of donor allograft dysfunction after heart transplant. Glutamine (GLN) administration to chick myocytes increases production of heat shock protein 72 (HSP 72) and attenuates I/R injury. Pretreating hearts with glutamine would be a novel method to improve heart function after I/R injury. We tested the effect of GLN preconditioning on myocardial performance using a rat working heart model.
Methods: Male rats were injected IP with either 0.52 g/kg GLN in 15% RL (n = 10, GLN group) or RL alone (n = 10, control). 18 hours later their hearts were removed and immediately connected to the perfusion apparatus. Hearts were initially perfused via the aorta (Langendorff mode) and then switched to left atrial perfusion (working heart mode). After stabilization, the hearts were subjected to no-flow ischemia for 15 minutes and then reperfused on working heart mode for 60 minutes. Preand after-load were normalized. ABGs, and aortic and coronary flows were measured at base line and every 15 minutes after ischemia under both 8 and 12 mm Hg preload.
Results: All hearts recovered some function. The table below summarizes the data. At end-diastolic pressure of 8 mm Hg, both groups had similar preischemic aortic flow, but after ischemia the GLN group demonstrated higher percentage of recovered flow. 12 mm Hg preload results were similar. ABG’s and perfusates were similar in both groups.
Conclusions: GLN can induce HSP 72, help clear lactate, and increase the antioxidant glutathione. This is the first time preconditioning whole body administration of GLN has shown to decrease myocardial I/R injury even after a severe no- flow ischemic insult. Administration of this nonessential and nontoxic amino acid to donors several hours before cross clamping would improve post transplant heart function and thus enlarge the donor pool by increasing the period of safe ischemic, and allowing use of marginal heart donors.
| ||||||||||||||||||||||||||||||
*Glutamine vs Krebs = difference statistically significant.
High-dose insulin therapy after cardiac surgery for patients with impaired left ventricular function
Bothe, T Doenst, F Beyersdorf. Department of Cardiovascular Surgery, University of Freiburg, 79106, Freiburg, Germany
Background: Metabolic therapy with high-dose glucose-insulin-potassium (GIK)-infusion improves postoperative recovery of myocardial contractile function after cardioplegic arrest. GIK may act through insulin or through a reduction in serum free fatty acids. However, the application of high doses of insulin may cause profound disturbances in glucose and potassium homeostasis. We set out to establish a high-dose insulin therapy for patients with impaired left ventricular function undergoing cardiac surgery with cardioplegic arrest.
Methods: Insulin therapy was started immediately after arrival in the ICU in 4 patients with a preoperative ejection fraction less than 40% and a creatinine level less than 2.0 mg/dL. We infused insulin for 8 hours at a constant rate of 2.5IU · kg-1 · h-1. We started glucose and potassium infusion at a rate of 0.25 g · kg-1 · h-1 and 0.5 mval · kg-1 · h-1, adjusting the rates hourly to keep blood glucose levels between 150 to 250 mg/dL and serum potassium levels between 4.5 and 5.0 mval/L. We measured serum levels of glucose, insulin, c-peptide and free fatty acids.
Results: Glucose levels were 235 ± 81 mg/dL before, 170 ± 51 mg/dL during, and 151 ± 57 mg/dL after treatment. Insulin levels were 3.91 ± 2.99 µU/ml before and increased to 11129 ± 7671 µU/ml and 24582 ± 12759 µU/ml 1 hour and 7 hours after start of insulin, respectively. After insulin infusion, we noted a long-lasting elevation in insulin levels with a rise in elimination-half-life from approx. 5 minutes to 1°,51 ± 0°,57 hours, requiring a continuation of glucose infusion. C-peptide levels did not change during the study period. Serum-free fatty acids were 0.65 ± 0.30 mmol/L before and 0.51 ± 0.28 mmol/L and 0.28 ± 0.08 mmol/L 1 hour and 3 hours after start of insulin, respectively. Insulin therapy did not disturb potassium homeostasis and there were no adverse events.
Conclusions: High-dose insulin therapy a.) does not disturb glucose or potassium hemostasis, b.) increases the elimination half life of insulin, and c.) causes a delayed reduction of free fatty acids, suggesting that a reduction of free fatty acids may not be a major mechanism of insulin action.
A protocol achieving the two-day discharge in conventional cardiac surgery
SD Herman, R Sahni, MF Aliasghapour, J Haft, D Bregman. St. Michael’s Medical Center, Newark, New Jersey
Background: A protocol has been designed to improve heart surgery outcomes by managing the inflammatory response and reperfusion injury of cardiopulmonary bypass. The goal was to decrease complications and length of stay (LOS). Recently others have attempted to achieve this by discarding the pump. However, benefits of cardiopulmonary bypass (CPB), which made surgical coronary revascularization the gold standard, have been lost. Our method retains the pump, but overcomes many deficiencies of CPB, allowing patients to recover and be discharged in 1 or 2 days.
Method: Our medication and technical based protocol addressed postoperative cardiac and cerebral function, reperfusion injuries, and the inflammatory response to CPB. It sought to reduce weight gain, arrhythmias, and pulmonary dysfunction. A unique technique of mammary artery preparation and testing maximized immediate cardiac reperfusion in CABG.
Results: 35 of 178 (20%) consecutive unselected patients managed by the protocol were discharged home in 1 or 2 days. Median LOS of the entire group was 3 days. 30/35 (85%) had CABG (3.23 grafts/pt), while 5/35 (15%) under-went valve replacement, including one reop MVR. Ages of patients discharged within 2 days were 32 to 87 years (average 64.1). EF’s ranged 20 to 70% (average 46%). Complications were minimal. 3/35 (8.5%) patients developed atrial fibrillation. All were converted to NSR by discharge using a medication protocol designed specifically to not retard recovery. No patient required hospital readmission and all returned expeditiously to full activity.
Conclusions: If specific techniques and protocols are followed, traditional CPB can achieve recoveries equal to and surpassing nonpump based techniques without sacrificing benefits of pump-supported surgery.
Right ventricular support improves systemic hemodynamics during beating heart surgery: the ABACAB trial
T Acuff, D Cheng, J Kelley, C Otero, V Kshettry. Denton Regional Medical Center, 333 Colorado Blvd. Denton, Texas 76210
Background: Theoretically the best approach for myocardial protection is to prevent ischemia altogether. Beating heart surgery transforms the global ischemia of aortic occlusion into regional ischemia of coronary occlusion or manipulation. However, both experimentally and clinically, beating heart techniques cause alterations of systemic hemodynamics that may compromise coronary artery perfusion, prevent optimal exposure and offset the theoretical benefits of avoiding global ischemia. Right ventricular support has been suggested as a means of restoring hemodynamic compromise during beating heart surgery while decompressing the RV for better exposure and enabling the surgeon to perform beating heart techniques.
Method: The hemodynamics of 147 primary multi-vessel CABG patients were prospectively recorded interoperatively at base line, three minutes into each distal anastomosis and after each anastamosis. Right ventricular support was used with each patient during each anastamosis then momentarily stopped after each anastamosis to measure the effect of RV support after each distal graft was completed. RV support was performed with right atrial to pulmonary artery bypass (Paraflow, AMed). 470 grafts were performed for an average of 3.2 grafts per patient. Average patient age was 67.3 (40 to 91) and average EF was 51.4 (11 to 81). 34% had previous MI, 29% had DM and 40% were urgent cases.
Results: No patients died. Two (1.4%) required conversion to CPB. No patient required new IABP. There appeared to be less need for pharmacological support in this group of patients. Only 20.8% of patients required more pressors than base line to main hemodynamics. 44% of patients required no pressor support at all during this study. The following table shows the effect of RV support on hemodynamics during the anastamosis on different coronary distributions.
Conclusions: RV support is an effective method of maintaining hemodynamics during Beating Heart surgery. Maintenance of systemic pressure and perfusion are significantly improved during the exposure of inferior, lateral and even anterior vessels for CABG by use of RV support. The lesser effect of RV support to improve hemodynamics with exposure of the main RCA in contradistinction to other coronary distribution lends credence to the theory of distortion of the RV outflow tract as a mechanism of impaired hemodynamics during OPCAB. RV support can safely minimize hemodynamic compromises in a large group of patients and may be the most appropriate method of restoring systemic perfusion during Beating Heart surgery. Study supported by Amed.
|
Intermittent aortic crossclamping versus HTK-cardioplegia in coronary bypass surgery: a prospective randomized trial
U Sunderdiek, B Korbmacher, P Feindt, JD Schipke, E Gams. Department of Thoracic and Cardiovascular Surgery; Heinrich-Heine University Dusseldorf, Germany
Background: Intermittend, hypothermic aortic crossclamping (IAC) with myocardial fibrillation has been established as an effective cardioprotective method in coronary artery surgery (CABG). Compared to cardioplegic arrest (CA) there exsists controversy about the more beneficial cardioprotective method in CABG-patients.
Methods: This prospective study was designed to compare the clinical outcome, ischemic serum-markers (CK-MB, troponin I), ECG-changes, hemodynamic data on 112 patients. Randomization (n = 61) was done on routine, consequetive patients. For cardioplegic arrest the Bretschneider-HTK solution was used. Data were collected before ischemic arrest, 5 and 60 minutes after reperfusion, 1 and 6 hrs. after operation, 1, 2 and 10 days postoperatively.
Results: Both groups were age-matched (IAC 68,3 yrs vs 66,1 yrs CA), no differences were found in LV-function data (i.e. EF IAC 54,2% vs CA 58,6%). The amount of bypass vessels were similar (IAC 3.4 vs CA 3.6). Total operation time was comparable IAC 214 minutes versus CA 231 minute, where as total time of ischemia was significant less in IAC 37 minutes versus CA 53 minutes.
In the IAC-group, a higher mortality was noticed (7.7% vs 3.9%; NS), incidents of cerebral stroke were seen in 2 IAC-pts, none for CA-pts. CK-MB increases more than 40 U/l and troponin I more than 50 ng/ml were seen in 17 IAC-pts and 9 in CA-pts. Ischemic ECG-changes: 22 IAC versus 16 CA. Persistant ECG-changes in 7 IAC versus 5 CA-pts.
Conclusions: Both cardioprotective methods, IAC and HTK-cardioplegia, seem to offer sufficient myocardial protection in routine CABG-procedures. Although neurologic disorders and mortality rates were slightly higher in patients with intermittent aortic crossclamping, the differences to the cardioplegia group were not significant. According to the analysis of increased ECG-changes, higher CK-MB and troponin I values which occurred especially in patients with myocardial ischemia time longer than 50 minutes we conclude that cardioplegic arrest with HTK seems to offer more beneficial effects in procedures with prolonged ischemia.
Effect of antioxidants on reducing the damaging effect of cardiopulmonary bypass and ischemia in coronary artery surgery
M Marzban, K Abbasif, NG Movahedi, B Hanafi, MH Mndegar, AA Karimi, D Javidi. Shariati Hospital, Department of Cardiovascular Surgery, Tehran, Iran
Background: Oxygen derived free radicals play a crucial role in myocardial damage during cardiopulmonary bypass (CPB) and global myocardial ischemia. In this study we evaluated the effect of allopurinol, vitamin E and vitamin C on clinical and paraclinical indices oc coronary patients undergoing CABG using CPB and cross clamp of aorta.
Method: Between Sep.2000 and Aug.2000, 96 consecutive patients underwent elective CABG operation using CPB, mild hypothermia and cold blood cardioplegia in our institution, patients were randomized to two groups: group A (N = 48) received allopurinol (1200 mg/d) vit.C (3gm/d)and vit. E(600 mg/d)orally for two days before operation, group B as control received placebo in a double blind study. In hospital mortality and morbidity, ICU and hospital stay, duration of ventilatory support postoperative hemodynamic parameters ECG abnormalities, cardiac enzymes arterial oxygen pressure and saturation alveolo-arterial o2 difference and ionotropic need are measured in two groups and compared using statistical analysis by K-2 test and P-value.
Results: Two groups were matched for risk factors, demographic, CPB and operative variables. Mean LVEF was similar (A:45.1%, B45.5%, p-val = 0.84).There was no mortality in either group. Two cases in gp. A and one case in gp. B needed intraaortic balloon pump. NO reoperation for bleeding and no major wound infection occurred in either group. ICU stay was shorter in gp. A (26.7 hours vs30.5 hours) The need for ionotropic support was less in gp A.(10.1% vs23.8%)Ischemic ECG changes and enzyme rising were more in gp B (23.9% vs25%)There was no difference in arterial o2 saturation, pressure and alveolo-arterial o2 gradient hospital stay were similar (8.6 vs 8.5 days)Evident adverse drug reaction was not recorded in any of our patients .
Conclusions: Combination pretreatment of coronary patients with allopurinol vit. E and vit.C, can reduce the damaging effect of CPB and ischemia on myocardium but have not any demonstrable effect on pulmonary function .These drugs are safe and are recommended at least for poor risk patients routinely.
Pharmacological preconditioning via intracoronary adenosine during coronary bypass surgery with intermittent aortic cross-clamping
B Korbmacher, KK Klein, U Sunderdiek, U Mohan, JD Schipke, E Gams. Department of Thoracic and Cardiovascular Surgery, University Hospital Dusseldorf, Dusseldorf, Germany
Background: Endogenous myocardial protection during CABG can be achieved with intermittent aortic cross-clamping. To test whether exogenous adenosine can additionally protect the myocardium, a clinical, prospective, randomized, double-blind study was performed.
Methods: Two groups: placebo (Pla; n = 18; age 67.2 ± 7.7 ys) and adenosine (ADO; n = 15; 62.3 ± 9.7 ys). Male pts; EF more than 50%; three-vessel disease; elective operation. During the first aortic cross-clamping, 5 mg/min adenosine infused together with sufficient blood at systemic perfusion pressure via the aortic root for 10 minutes. Pts in the Pla group received the same dose of physiologic solution. Blood samples were collected before onset of anesthesia, before the onset of ECC, 1 hour after end of surgery, on the first and second day post surgery to assess: CK-MB, LDH, GOT, GPT, troponin I, Hb, Hct and leukocytes. Following hemodynamic variables were assessed: HR, CVP, LVPmax, LVPed, dP/dtmax, and dP/dtmin.
Results: ECC time between the Pla and ADO group was comparable: 115 versus 130 minutes, as well as the total aortic clamping 37 versus 40 minutes. LVPmax before ECC (115 ± 20 vs 113 ± 19 mm Hg) and after ECC (109 ± 17 vs 117 ± 23 mm Hg) did not differ between both groups. LVPed before ECC was not different between Pla and ADO (11 ± 6 vs 10 ± 4 mm Hg) and was moderately elevated in both groups after ECC (14 ± 5 vs 19 ± 7 mm Hg). Troponin I, as very sensitive marker of myocardial damage, was comparable before ECC, had a maximum at day 1 after surgery (77 ± 59 vs 107 ± 92 ng/ml) and was already decreased at day 2 (52 ± 30 vs 51 ± 33 ng/ml).
Conclusions: According to these results, there is no significant difference between the two groups. Apparently, sufficient myocardial protection is achieved via intermittent cross-clamping and low temperature during surgery. Thus, pharmacological preconditioning using exogenous adenosine did not exert the expected, beneficial effect.
A specific bradycardic agent to treat postischemic ventricular dysfunction: a study on in vitro and in vivo rabbit hearts
JD Schipke, S Schmitz-Spanke, V Pomblum, N Amaral, E Gams. Department of Thoracic and Cardiovascular Surgery, University Hospital Dusseldorf, D-40225 Dusseldorf, Germany
Background: Heart rate (HR) is a major factor determining myocardial oxygen consumption. Thus, HR reduction would improve the energy balance in various heart diseases. In addition, specific bradycardic agents could be helpful to reduce HR during off-pump surgery and to prevent unwanted tachycardia after thoracic surgery. Since HR considerably contributes to the severity of myocardial ischemia, HR reduction may also be an effective therapy for dysfunctional myocardium. In this study, different aspects of bradycardia produced by either a sinus node inhibitor cilobradine (DK-AH 269, CL) or a Ca2+-channel antagonist verapamil (VP) were tested in in vitro and in vivo rabbit hearts.
Methods: In a first series, isolated, blood-perfused rabbit hearts were subjected to a 60 minutes, global, low-flow ischemia that was followed by a 60 minutes reperfusion. In a second series, rabbit hearts were subjected to 60 minutes occlusion of a coronary artery and 180 minutes reperfusion. In both series, experiments were performed on placebo-, cilobradine- and verapamil-treated hearts. The infarct area was assessed via TTC staining.
Results: In the isolated hearts, HR was significantly reduced by both CL and VP. Whereas stroke volume (SV) remained unchanged in the CL group (n = 10), SV decreased in the VP group (n = 10). Myocardial oxygen consumption was reduced by both CL and VP (14 vs 24%). After 60 minutes reperfusion, ventricular function was better preserved in the CL group than in the placebo and the VP group. Infarct size was significantly reduced by CL and VP. In the anesthetized rabbits, VP, at a dose to reduce HR by about 30%, impaired ventricular function so drastically that it ceased during ischemia (n = 4). At a lower dose (n = 10), VP still impaired ventricular function but prevented the ischemia-induced increase in HR. During reperfusion, ventricular function started to recover. CL (n = 7) reduced HR (-28%) and increased both length of diastole (+54%) and SV (+33%). During reperfusion, ventricular function remained deteriorated. Infarct size in the CL group was significantly smaller compared with the placebo and the VP groups.
Conclusions: Cilobradine reduces HR both in vitro and in situ and has no direct inotropic and vasoactive effects. Reduction in HR effectively reduces infarct size. The specific bradycardic agent seems to outmatch the Ca2+ antagonist in protecting the myocardium in vivo and in vitro by reducing HR.
Tetrahydrobiopterin: new target for myocardial protection?
S Verma, PWM Fedak, RD Weisel, R-K Li, DAG Mickle. Division of Cardiac Surgery, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada
Background: Pharmacological interventions may restore ischemic hearts to full functional integrity during cardioplegic arrest. Contemporary cardioprotective strategies to prevent perioperative ischemia-reperfusion (I/R) injury have focused on the L-arginine NO pathway. Tetrahydrobiopterin (BH4) is an absolute cofactor required for the enzyme nitric oxide synthase (NOS) and is thus a critical determinant of nitric oxide (NO) production. We hypothesized that diminished levels of BH4 represents a key cellular defect underlying endothelial and myocyte dysfunction following I/R. To this aim, we examined the effects of BH4 supplementation in (i) an in vivo experimental model of global I/R and (ii) an in vitro human ventricular heart cell model of simulated I/R. Measures of endothelial function, oxidant production, cell survival and cardiac function were used to assess outcome.
Methods Study 1: Wistar rats were divided into 2 groups (n = 10 per group). One group received BH4 (25 mg/kg/d, 7 days) while the other group served as the control group. Hearts were subjected to 30 minutes of ischemia followed by 30 minutes of reperfusion and LVDP, LVSP and LVEDP were determined using the modified Langendorff technique.
Study 2: In a separate study, we quantitated myocardial malondialdehyde (MDA), a marker of lipid peroxidation, in ventricular tissues from both groups of animals using butanol phase extraction and spectrophotometric analysis.
Study 3: Coronary vascular responses were determined in vascular segments of the left anterior descending coronary artery in both groups of animals before and after reperfusion. Endothelium-dependent and –independent vasodilatation to acetylcholine (Ach) and sodium nitroprusside (SNP) respectively were compared between groups.
Study 4: Using a human ventricular heart cell model of simulated I/R, we studied the effects of BH4 (20 µmol/L) on cellular injury (assessed by trypan blue uptake).
Results: Following I/R, myocardial dysfunction was evidenced by a decrease in LVDP and an increase in LVEDP (p < 0.01). Hearts from BH4 treated rats exhibited protection against I/R injury (LVDP 74 ± 4 vs control 42 ± 8 mm Hg, p < 0.01; LVEDP 12 ± 3 vs 34 ± 7, p < 0.001). Futhermore, BH4 treatment attenuated the rise in MDA following I/R (p < 0.01). Following reperfusion, coronary endothelial function to Ach was attenuated while responses to SNP remained unchanged. BH4 treated rats exhibited an improvement in Ach-mediated vasorelaxation (p < 0.01). Cellular injury, assessed by trypan blue uptake, was higher in human ventricular heart cells subjected simulated ischemia and reperfusion (p = 0.01); this effect was prevented by BH4 treatment (p < 0.001).
Conclusions: Supplemental BH4 provides a novel cardioprotective effect on LV function, endothelial/vascular reactivity, oxidative damage and cardiomyocyte injury following I/R and may represent an important cellular target for future operative myocardial protection strategies.
Endothelin blockade improves cardiac allograft recovery after prolonged storage
PWM Fedak, S Verma, RD Weisel, P Kazemian, P Boylen, CM Feindel, V Rao. Division of Cardiac Surgery, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada
Background:Improved methods of allograft preservation may allow for prolonged storage and permit remote procurement. Donor shed blood perfusion (DSBP) was demonstrated to be superior to static cold storage and allows supplementation with protective agents during preservation. The vasoactive peptide endothelin (ET-1) may produce primary graft dysfunction and ET-1 blockade with Bosentan may aid in allograft preservation.
Method: Yorkshire pigs (60 to 70 kg) were used to perform orthotopic cardiac transplants using either DSBP (n = 8) or 100 µmol/L Bosentan (BST) enhanced DSBP (n = 8). After organ procurement, donor blood was harvested and perfused antegrade for 6 hours before transplant. Pre and post transplant LV function was determined with a conductance catheter. End-systolic elastance (Es) and preload-recruitable stroke work (PRSW) were determined by pressure-volume loop analysis. Male Wistar rats were subjected to 30 minutes of global ischemia followed by 30 minutes of reperfusion in the presence and absence of Bosentan (100 µmol/L) (n = 10 per group). Endothelial function was determined using videomicroscopy.
Results: BST-augmented DSBP significantly improved functional recovery after transplantation (see Figure 2; p = 0.02). Furthermore, BST supplementation improved weaning from cardiopulmonary bypass (7/8 vs 5/8). Coronary endothelial dysfunction was limited by BST enhanced reperfusate (%Emax to Ach: 68 ± 5 vs control 42 ± 8, p = 0.003).
|
The anti-endotoxin agent, taurolidine potentially reduces reperfusion injury through its metabolite taurine
KK Doddakula, J Wang, S Sookhai, A O’Donnell, T Aherne, D Bouchier-Hayes, HP Redmond. Department of Cardiac Surgery, Academic Department of Surgery, Cork University Hospital, Cork, Ireland
Background: Cardio-pulmonary bypass results in ischemia-reperfusion induced endotoxemia. A prospective randomized trial to investigate the effect of taurolidine, an antiendotoxin agent with antioxidant and membrane stabilizing properties, on patients undergoing coronary artery bypass surgery (CABS).
Methods: 60 patients undergoing CABS were randomized into four groups. Two groups (A and B) received taurolidine intravenously at induction, with two more doses at 12 hourly intervals, groups C and D received a placebo infusion of normal saline. In groups A and C st.thomas cold crystalloid cardioplegia and in groups B and D cold blood cardioplegia was used. Pro and antiinflammatory cytokines, IL-6, IL-10 and ischemia-reperfusion induced arrhythmias were assessed perioperatively.
Results: Administration of taurolidine in crystalloid cardioplegia patients resulted in a significant reduced circulating IL-6 and increased IL-10 production when compared to crystalloid+placebo. Taurolidine treatment also significantly reduced reperfusion induced arrhythmias (p < 0.003) compared to placebo.
Conclusion: This study demonstrates that taurolidine induces a potent anti inflammatory tissue response in CABS patients that is associated with significant reduction in arrhythmias.
| ||||||||||||
Data = mean ± SD,
* statistically significant p<0.05
Beating-heart coronary artery bypass grafting in 25 patients with ejection fractions of 25% and Parsonnet scores greater than 25
HB Bittner, S Huerd, K Liao, SJ Park. University of Minnesota, Division of Cardiovascular and Thoracic Surgery, Minneapolis, MN
Background: The perioperative morbidity and mortality for coronary artery disease (CABG) surgery remains high in patients presenting with severely depressed ventricular ejection fraction (EF) and comorbidity. The objective is to assess the benefits, morbidity and mortality risks of beating-heart surgery and off-pump CABG (OPCABG) in a selected group of high-risk patients.
Methods: The more than 18-months period prospectively and consecutively gathered data of selected coronary artery disease patients were analyzed. Comorbidity and surgical risk of the patients were assessed using the modified Parsonnet morbidity/mortality score and stratification system for cardiac surgery. The age of the twenty-one patients ranged from 47 to 85 years of age (mean = 67.5 ± 11.6, 24% females) and the (EF 10%-35%, mean = 27.1 ± 8.7). The average Parsonnet surgical risk stratification score was 24.7 (±10.9). The most significant morbidity/mortality risk factors included age greater than 80 years (28%), left main disease with greater than 70% occlusion (16%), EF less than 30% and end-stage ischemic cardiomyopathy (67%), and preop IABP and emergency surgery (20%). Interventions: These patients underwent beating-heart coronary artery bypass grafting.
Results: The perioperative mortality was 0%. The 30-day mortality rate was 10%. The conversion to on-pump CABG occurred in three patients. Complete target vessel revascularization was accomplished in 19 of the 21 patients with an average of 2.2 (range 1 to 4, ±0.8) including posterolateral coronary artery branches in 80%. Postoperative cardiac troponin I was 2.8 ng/mL (±2.3) for all the patients. Two patients underwent a hybrid procedure. A follow-up evaluation (15.5 months ± 4) revealed unchanged mortality and improved angina and heart failure classification.
Conclusions: Off-pump coronary artery bypass grafting might become an important asset to already existing surgical treatment options in coronary artery revascularization for patients with very low EF. This technology provides excellent myocardial protection. OPCABG seems to be an alternative approach with acceptable morbidity and mortality.
Angiogenesis and fibrosis in diverse human cardiomyopathies
KA Hutcheson, GW Wheatley, MD White, D Bellotto, DM Meyer, ME Jessen, MA Wait, WS Ring, RS Williams, JM DiMaio. University of Texas Southwestern Medical Center at Dallas, Dallas, Texas
Background: The molecular mechanisms that define distinct human cardiomyopathies (CM) are poorly understood, often making therapeutic intervention difficult. To define two molecular differences among three types of end-stage heart failure, we measured angiogenesis and fibrosis in the left ventricle (LV) of five patients that underwent cardiac transplantation for ischemic CM (ICM), idiopathic CM (IdCM), and postpartum CM (PCM).
Methods: Explanted hearts were immediately harvested in the operating room. Transmural LV sections were excised and formalin-fixed before staining with toluidine blue. Under standard light microscopy (LM), capillaries per high power field (HPF, 40x) were counted from 24 sections per patient. Normal myocardium from a trauma patient was similarly processed as a CONTROL. Fibrosis was determined in serial sections as percent collagen per HPF by electron microscopy.
Results: The number of capillaries per HPF in ischemic CM was approximately threefold less than in the normal heart (ICM:17 ± 8 vs CONTROL:45 ± 4). Interestingly, nonischemic CMs had a twofold (idiopathic) and sixfold (postpartum) increase in capillary number as compared to CONTROL (IdCM: 83 ± 9, PCM: 289 ± 20 vs CONTROL: 45 ± 4). In addition, we observed a 10-fold increase in fibrosis in postpartum CM as compared to ischemic and CONTROL hearts.
Conclusions: These data suggest that decreased vascularity within myocardium may not be the major determinant of all etiologies of heart failure. Furthermore, failure of the postpartum heart may follow maladaptive angiogenesis and fibrosis in the myocardium. Lastly, this study stresses the importance of finding a molecular test that reliably determines functionality of blood vessels present in different types of heart disease. Such a test combined with standard clinical tests such as echo and PET scans may allow targeted clinical therapies long before cardiac transplantation. This directed treatment might preserve or improve cardiac function in sick patients thus lightening the load on the organ donor pool.
Efficacy of modified endoventricular circular patch plasty in ischemic cardiomyopathy – innovative delimitation technique using integrated myocardial management
M Nakamura, F Okamoto, E Hatta, K Nakanishi, K Sakai. Department of Cardiovascular Surgery, Teine Keijinkai Hospital, 1-12 Maeda, Teine-ku, Sapporo 006-8555, Japan
Background: Since optimal delimitation is one of the most important factors for successful endoventricular circular patch plasty (EVCPP), we have developed an innovative delimitation technique as an application of integrated myocardial management. We hypothesized that 1) this modification enables reproducible delimitation, resulting in a decrease in the in-hospital mortality rate and better clinical outcome and 2) EVCPP is suitable for ischemic cardiomyopathy (ICM) patients.
Methods: Between September 1998 and November 2001, twenty-two ICM patients with an ejection fraction (EF) of less than 30%underwent EVCPP with coronary artery bypass grafting (CABG) {group I, n = 14} or CABG only {group II, n = 8}. Indication for EVCPP was left ventricular end-systolic volume index (LVESVI) of more than 100 mL/m2 in akinesis (n = 7) or 70 mL/m2 in dyskinesis (n = 7). Most of patients (93% in group I and 88% in group II) had congestive cardiac failure, and mean NYHA classes in groups I and II were 2.9 ± 0.5 and 2.9 ± 0.7, respectively. After complete revascularization, delimitation was determined by palpation with empty beating during antegrade warm blood perfusion without declamping of the aorta. The heart was then rearrested for secure cryotherapy and suturing. All procedures were performed under single aortic clamping.
Results: There were no in-hospital deaths, and none of the patients in either group required any mechanical support. Preoperative angiographic results showed a worse EF in group I than in group II (21.2 ± 4.0 vs 26.8% ± 2.6%, p < 0.01) and more-dilated LV in group I than in group II (LVESVI: 115 ± 39 vs 72 ± 16 mL/m2, p < 0.01). In contrast, early postoperative results in group I and group II were comparable in EF (39 ± 12 vs 43% ± 9%) and LV volume (LVESVI: 55 ± 26 vs 55 ± 12 mL/m2, suggesting modified EVCPP resulted in better functional recovery in patients with worse ejection fraction and dilated LV. During follow-up (15 ± 10 months), freedom from cardiac death was 100%, and 95% of our patients were NYHA I or II.
Conclusions: Our modified technique appears to be not only useful for determination of delimitation but also a safe strategy that results in more satisfactory clinical outcome.
Specific inhibition of p38 mitogen-activated protein kinase with FR167653 attenuates myocardial ischemia-reperfusion injury in mice
A Shimamoto, CR Hampton, AJ Chong, JM Griscavage-Ennis, CL Rothnie, TH Pohlman, ED Verrier. Division of Cardiothoracic Surgery, Department of Surgery, University of Washington School of Medicine, Seattle, Washington
Background: Many studies have used SB203580 during lethal ischemia to assess the role of p38 mitogen-activated protein kinase (MAPK) in myocardial ischemia-reperfusion (MI/R) injury. However, in addition to p38 MAPK, SB203580 also inhibits thromboxane synthase, cyclooxygenases (COX), and the c-Jun N-terminal kinases (JNKs), all of which may directly affect injury following MI/R. Thus, it is difficult to discern the role of p38 MAPK in MI/R by using this nonspecific drug. Recently, FR167653 has been shown to be a selective p38 MAPK inhibitor without affecting COX or other MAPKs. In the current study, we evaluate the effects of FR167653 on MI/R injury in mice.
Methods: CD-1 mice were administered FR167653 (2 mg/kg, intraperitoneal) or vehicle (saline) 24 hours before MI/R (30 minutes ischemia followed by 2 hours reperfusion) via in situ occlusion of the left anterior descending artery. At the completion of reperfusion, the area at risk (AAR), infarct size, phosphorylation of MAPKs (p38 MAPK, extracellular sinal-regulated kinase (ERK) 1/2, stress-activated protein kinase (SAPK)/JNK) by Western immunoblotting, and p38 MAPK activity with immunoprecipitation, kinase assay, and Western immunoblotting methods, were determined.
Results: The AAR was similar between groups. Pretreatment with FR167653 significantly reduced infarct size within the AAR by 73.6% compared to vehicle pretreatment (FR167653 vs vehicle: 11.4 ± 6.76 vs 43.2% ± 3.26%)[p = 0.0069]. Phosphorylation of p38 MAPK was significantly reduced in FR167653 pretreated mice compared to vehicle (5.68 ± 1.46 vs 10.2 ± 2.77 fold)[p = 0.018], while phosphorylation of ERK1/2 and SAPK/JNK was not affected. Moreover p38 MAPK activity was significantly attenuated by FR167653 pretreatment compared to vehicle (9.74 ± 3.56 vs 6.51 ± 3.36 fold)[p = 0.047].
Conclusions: We have shown that MI/R injury significantly increases phosporylation of MAPKs that is associated with tissue injury. Specific inhibition of p38 MAPK phosphorylation and activity with FR167653, which does not affect ERK1/2 or SAPK/JNK phosphorylation, significantly attenuates tissue injury after MI/R. Taken together, these data suggest that p38 MAPK may play a central role in the molecular events that underlie MI/R injury.
Targeted deletion of inducible heat shock proteins 70-1 & 70-3 abrogates the late infarct-sparing effect of myocardial ischemic preconditioning
CR Hampton, A Shimamoto, CL Rothnie, JM Griscavage-Ennis, DJ Dix, TH Pohlman, ED Verrier. Division of Cardiothoracic Surgery, The University of Washington, Seattle, WA 98195
Background: The goal of this study was to assess the role of the inducible heat shock protein 70 seconds in the late phase of myocardial ischemic preconditioning (IP).
Methods: Mice homozygous for null Hsp70i -/- alleles (Hsp70 to 1 and Hsp70 to 3) were used for experimental groups. Wild type mice (C57Bl/6) served as controls. Mice underwent 30 minutes regional myocardial ischemia followed by three hours reperfusion (I/R). Preconditioned mice underwent three five-minute cycles of alternating ischemia and reperfusion (IPC), followed in 24 hours by I/R. Sham mice were subjected to sham operation on day one followed 24 hours later by I/R. Hearts were examined for infarct size, cytoplasmic Hsp70 expression by Western immunoblotting, and nuclear heat shock factor (HSF) activation by electrophoretic mobility shift assay (EMSA).
Results: IPC of wild type mice and Hsp70i -/- increased HSF activity in the nucleus by 
30% (162.2 ± 13.9 and 148.6 ± 5.8, respectively, arbitrary units) compared to sham preconditioned wild type mice (121.6, arbitrary units) as detected by EMSA. Wild type mice exhibited a 2.5 fold increase in Hsp70 expression 24 hours after IP compared to sham preconditioned mice (230.12 ± 16.8 vs 90.8 ± 15.6, respectively, arbitrary units). IPC of Hspi70 -/- failed to increase Hsp70 relative to wild type mice (96.4 ± 27.7 vs 90.8 ± 15.6, respectively, arbitrary units). When wild type mice underwent IPC 24 hours before I/R, infarct size was reduced by 43% compared to controls (17.4% ±2.3 vs 30.6% ±3.1) [p less than 0.006] and was not affected by sham operation (28.1% ± 4.1)[p = NS versus controls]. In contrast, IPC of Hsp70i -/- mice had no infarct sparing effect compared to controls (31.4% ±2.6 vs 30.6% ±3.1), or compared to Hsp70i -/- mice that were not preconditioned (30.4% ±3.4).
Conclusions: These results demonstrate that the late phase of protection following IPC coincides with dramatic upregulation of inducible Hsp70 seconds in the mouse myocardium. Further, targeted deletion of the inducible Hsp70 seconds (Hsp70 to 1 and Hsp70 to 3) abrogates the late infarct-sparing effects of IPC. Taken together, these data provide direct evidence that inducible Hsp70 plays a critical role in the late phase of cardioprotection following IPC. Moreover, Hsp70 may be a potential therapeutic target in clinical situations of myocardial ischemia and reperfusion.
This work supported in part by National Institutes of Health Cardiovascular Training Grant #5T32HL007828 to 05 and National Institutes of Health grant #5R01HL061762 to 03
Performing fasciotomy on radial artery conduits does not alter inhibition of constriction to alpha adrenergic therapy by phenoxybenzamine
JS Corvera, RA Guyton, JD Puskas, OA Lattouf, WA Cooper, J Vinten-Johansen. The Carlyle Fraser Heart Center, The Division of Cardiothoracic Surgery and The Cardiothoracic Research Laboratory, Emory University School of Medicine, Atlanta, Georgia
Background: Vasospasm to adrenergic agents may occur in the highly muscular radial artery (RA) when used as a coronary artery bypass conduit. The RA is frequently harvested with the surrounding muscular pedicle, which potenitally impedes exposure of the vessel to topically applied agents designed to attenuate vasoconstriction, such as papaverine or phenoxybenzamine (PBZ). We tested the hypothesis that incising the musculofascial tissue of the radial artery (RA) increases exposure of pedicled human RA grafts to antivasospastic agents, thereby potentiating their inhibitory effect on vasoconstriction induced by the widely used vasopressors norepinephrine (NE) and phenylephrine (PE).
Methods: RA conduits were harvested en bloc with the flanking veins and musculofascial tissue (without fasciotomy). Depending upon surgeon preference, musculofascial and aerolar tissue was opened sharply to expose the advential surface on one side of the RA (with fasciotomy). The conduit was flushed intraluminally followed by a 30-minute immersion in a solution of papaverine and lidocaine (pap/lido) in heparinized blood, with or without 10-3 M PBZ. RA segments were tested in organ chambers for the constrictor responses to increasing concentrations (0.5 to 15 µmol/L) of NE and PE. Endothelial function was tested via the relaxation response to increasing concentrations of acetylcholine.
Results: There was no difference in the contractile response of PBZ treated RA grafts with and without fasciotomy. Pretreatment with 10-3 M PBZ significantly blocked vasocontraction to PE to the same extent with (–4.33% ± 4.55%) or without (–9.95% ± 6.35%) fasciotomy, while papaverine/lidocaine did not significantly block contraction with (28.45% ± 6.83%) or without (22.83% ± 9.04%) fasciotomy. PBZ pretreatment comparably blocked vasocontraction to 10 µmol/L NE with (–15.36% ± 8.13%) or without (-26.86% ± 7.05%) fasciotomy when compared to papaverine/lidocaine with (35.30% ± 6.64%) or without (43.88% ± 7.22%) fasciotomy. Additionally, there was no difference between RA grafts with and without fasciotomy in the relaxation response to acetylcholine (i.e. endothelial function).
Conclusions: Fasciotomy does not significantly alter the smooth muscle or endothelial function of RA grafts. However, there is comparable blockade of the constrictor responses of the RA with or without fasciotomy to NE and PE using 10-3 M PBZ. Therefore, performing a fasciotomy on the RA graft does not further enhance the inhibitory effect of PBZ on vasoconstriction responses to the clinically used alpha adrenergic agents NE and PE.
Perfusion-assisted direct coronary artery bypass enhances intraoperative hemodynamic stability and facilitates complete revascularization
WA Cooper, JS Corvera, VH Thourani, JD Puskas, JM Craver, OM Lattouf, RA Guyton. The Division of Cardiothoracic Surgery, Emory University School of Medicine and The Carlyle Fraser Heart Center at Crawford Long Hospital, Atlanta, Georgia
Background: This case series outlines the intraoperative findings, clinical outcomes and resource utilization of our first year clinical experience with perfusion-assisted direct coronary artery bypass (PADCAB), a novel method of initiating early reperfusion of grafted coronary artery segments during off pump surgery.
Methods: From November 1999 to November 2000, 169 PADCAB operations were performed at the Emory University Hospitals. The decision to use the PADCAB was predicated on surgeon preference and lack of contraindications for off pump coronary bypass. Perfusion pressure and flow, amount of nitroglycerin, total perfusion time and volume, and time to complete each distal anastomosis were recorded at the time of operation.
Results: Perfusion pressure in PADCAB grafts was 44% higher than mean arterial pressure. Nitroglycerin, infused locally by PADCAB, was used in 67 (40%) patients to resolve ischemic episodes during heart manipulation and/or vessel occlusion. Hospital death occurred in 2.4% of patients. There were no patients who required emergent conversion to cardiopulmonary bypass. The mean number of grafts was 3.3 ± 0.8 which included successful grafting of lateral wall vessels in 83% of patients. Average time to completion of the distal anastomosis was 8.9 ± 2.0 minutes. Hospital charges were not statistically different from patients who underwent off pump coronary bypass without PADCAB during the same time period.
Conclusions: PADCAB can provide suprasystemic perfusion pressures and add vasoactive drugs to target coronary vessels. PADCAB enhances cardiodynamic and hemodynamic stability allowing easier grafting of lateral wall vessels and facilitates complete revascularization. It does not increase the time to complete the distal anastomosis nor increase hospital cost.
Early, pump-assisted graft perfusion in OPCAB ameliorates acute stunning in a short-term hibernating myocardium
J Budde, C Morris, S Muraki, Z-Q Zhao, R Guyton, J Vinten-Johansen. Crawford Long Hospital, Cardiothoracic Research Laboratory, Atlanta, Georgia
Background: Coronary artery ligation during off-pump bypass grafting (OPCAB) causes ischemic injury. In a clinically-relevant coronary stenosis model, we tested whether avoidance of ischemia with intracoronary shunt, or pump-assisted graft perfusion, during OPCAB attenuates injury.
Methods: Anesthetized canines underwent 2 hours of LAD stenosis; the LAD was then occluded for 15 minutes to construct a distal veno-coronary anastomosis. During ligation in n = 8 (OPCAB), there was no intervention during LAD ligation, while in n = 6 (Shunt) an intraluminal shunt was interposed during ligation. For 30 minutes before proximal anastomosis, the ligation was released and blood flow through the stenosis resumed in OPCAB and Shunt. In n = 7 (PADCAB), no shunt was used during occlusion, but the graft was pump-perfused during those 30 minutes to match LAD pressure to mean arterial pressure (MAP). Two hours of open-graft perfusion followed proximal anastomosis.
Results: LAD stenosis reduced area at risk (AAR) blood flow (microspheres, mL/min/g) from 0.52 ± 0.03 to 0.38 ± 0.02* and shortening (sonomicrometry) in LAD myocardium from 13.5% ± 1.2% to 5.6% ± 1.5%*. LAD ligation further impaired AAR blood flow (OPCAB: 0.07 ± 0.02*, PADCAB: 0.08 ± 0.02*) and shortening (-5.2% ± 3.4%*, -4.4% ± 0.8%*), but not in Shunt (0.14 ± 0.02*; 2.4% ± 3.3%). After ligature release, AAR blood flow through the stenosis was restored in OPCAB (0.39 ± 0.06) and Shunt (0.28 ± 0.04), but contractile dysfunction increased (-7.6% ± 2.7%* and -0.16% ± 1.2%). Conversely, PADCAB achieved LAD perfusion pressures (76 ± 10 mm Hg) equal to MAP (81 ± 7.3), compared to LAD pressures in OPCAB and Shunt (45 + 4.4* and 40 + 4.2*). Consequently, AAR blood flow (1.2 ± 0.42) and contractile shortening (0.39% ± 2.1%*) were improved in PADCAB. After 2 hours of open-graft reperfusion, shortening remained impaired in OPCAB (1.3% ± 1.6%*) and Shunt (0.81% ± 2.4%*), but was restored in PADCAB (8.5% ± 3%). LAD endothelial function (acetylcholine) was impaired in OPCAB (59% ± 10%*) and Shunt (63% ± 9%*) but was greater in PADCAB (99% ± 8%).
Conclusions: Pump-assisted graft perfusion attenuates contractile and endothelial dysfunction during OPCAB. *p less than 0.05.
Integrated myocardial management during prolonged cross-clamp times
K Nakanishi, F Okamoto, M Nakamura, E Hatta, J Matano, K Sakai. Department of Cardiovascular Surgery, Teine Keijinkai Hospital, 1-40, Maeda 1-Jo Sapporo, Japan 12-chome, Teine-ku, Sapporo 006-8555, Japan
Background: The purpose of this study was to assess the adequacy of integrated myocardial management that combined antegrade/retrograde delivery, warm/cold blood cardioplegia, intermittent/continuous perfusion, and blood/blood cardioplegia for complex cardiac and aortic procedures which required prolonged aortic cross-clamp times due to technical difficulties or unexpected incidents.
Methods: From January 2000 to December 2001, 443 consecutive patients underwent cardiovascular procedures using the aforementioned technique. We retrospectively evaluated the case of 12 patients (2.7%) who required cross-clamp times greater than 4 hours. Mean patient age was 65 ± 8 years (range, 46 to 78 years). Procedures performed included coronary artery bypass grafting (CABG) plus valve procedures (n = 4), total aortic arch replacement (n = 3), combined ascending aorta and aortic valve replacements (n = 2), CABG plus Dor’s operation (n = 2), and CABG only (n = 1). Emergency operation was performed in 4 patients (33%). Preoperative intraaortic balloon pumping was required in 1 patient (8%). Two patients (17%) had previous operations.
Results: Despite aortic cross-clamp times of 273 ± 36 minutes (range, 243 to 372 minutes), all patients except one were successfully weaned from cardiopulmonary bypass without any mechanical circulatory support. There was 1 hospital death (8%) which was caused by cerebral bleeding on the 23 rd postoperative day. All other patients survived and discharged from the hospital in good clinical condition.
Conclusions: We conclude that integrated myocardial management combined the advantages of various strategies provides optimal myocardial protection even in prolonged complicated procedures.
Activation of cardiac glutamate receptors preconditions against contractile dysfunction and myocardial infarction: role of ATP-sensitive potassium channels
AS Abd-Elfattah, JH Guo, R Marktanner, AS Wechsler. Department of Surgery, Medical College of Virginia, VCU, Richmond, VA
Background: The presence of metabotropic glutamate receptor subtypes (mGluR5) in cardiac tissue of different species including humans has been confirmed in our lab. We determined whether intracoronary infusion of glutamate (GLU) preconditions against acute myocardial stunning (STN) and infarction (MI) in dogs and whether mitochondrial KATP channels play a role in this protection.
Methods: Dogs (n = 51) instrumented to monitor LV contractility using sonomicrometry, were divided into two sets studies, 1) STN (15 minutes LAD occlusion and four hrs reperfusion, and 2) INF (90 minutes LAD occlusion and 4 hrs reperfusion). Each study contains three groups; the control, GLU (50 ml of 100 µmol/L) and 5-HD+GLU (5 mg/Kg, iv., 15 minutes before ischemia) treated groups. Coronary blood flow was measured at base line and during ischemia (ISCH) using colored microspheres. LV function (stroke work/end diastolic relationships) was obtained. The infarct size and LV and risk areas were delineated and measured. Five animals were excluded. Data were analyzed by ANOVA and presented as mean± SEM, n = 6 each group.
Results: In STN study (with no necrosis), LV function (dyn.cm20.103)was 60.39±2.5, 76.79±8.2 and 81.76±2.8, at base line, after GLU treatment and at the end of 4 hrs REP, respectively. Percent LV recovery (%base line) was 52.3±5% in the control group and 58.6±8% in 5-HD+GLU group. In acute MI study, LV function (dyn.cm2.103) was 85.14±8.73, 86.61±9.27 and 91.65±16.83, at base line, after GLU infusion and at the end of REP, respectively. LV functional recovery in the control (36.2±5%) and 5-HD+GLU (46.1±6%) groups were poor. However, GLU treatment significantly reduced the infarct size from 38.2±6% in the control group to 11.1±4% in GLU group (p < 0.05). 5-HD pretreatment abolished infarct size limitation. The areas at risk/LV area were 52.5±6, 45.2±7 and 48.9±4, respectively.
Conclusions: Intracoronary infusion of a low dose of GLU preconditions the myocardium against LV STN and INF and this protection is abolished by blocking of mito KATP channels suggesting the role of these channels in GLU-mediated cardioprotection.
Ischemic preconditioning of the infarcted hearts: role of ATP-sensitive potassium channels
AS Abd-Elfattah, AF El-Watidy, I Hegab, DR Salter, A Mohamed. Department of Surgery, Medical College of Virginia, VCU Richmond, VA
Background: Ischemic preconditioning (IPC) is well documented in healthy but not in infarcted hearts. It is not known whether infarcted hearts could be ischemically preconditioned against another acute MI.
Methods: New Zealand male rabbits (3 to 4 kg, n = 55) were randomly divided into eight groups (Gp) according to which coronary artery was occluded first, right RCA, circumflex (CFX) or left anterior descending (LAD) coronary artery. Gp-RCA, Gp-CFX, Gp-LAD (n = 6/Gp) underwent a sustained lethal coronary artery occlusion (CAO) for 30' + 2 hrs reperfusion (Rep). Gp-CFX-RCA (n = 7) had CFX occlusion first for 30'+10' Rep and then RCA occlusion 30'+2hrs Rep. Similarly, Gp-RCA-CFX (n = 6) had RCA occlusion and Rep first before the CFX. Gp-LAD-RCA (n = 6) had LAD occlusion before RCA or vise versa Gp-RCA-LAD (n = 6). GP-LAD-IPC-RCA in which the IPC (2X5' LAD + 10' R) was applied to the RCA before 30' occlusion and Rep. Differential staining with Evans Blue and TTC delineated risk areas of the right (RV) and left ventricular areas (LV) and infarct size (INF). Mito-K-ATP blocker, 5-hydroxydecanoate (5-HD, 5 mg/Kg, IV) was administered before the first MI. Results are presented as a percent of INF/RA, RA/RV and RA/LV and analyzed by ANOVA for multiple comparisons.
Results: In rabbits, the INF size in the RV was reduced from 21.1% ± 2.8% in Gp-RCA to 4.1% ± 2.3% and 9.1% ± 4% in the groups that had prior MI, Gp-CFX-RCA and Gp-LAD-RCA, p less than 0.01). The second MI of either the Gp-CFX or Gp-LAD segments reduced the INF size to 3.9% ± 1.6% and 3.6% ± 1.2% compared to Gp-CFX (20.4% ± 2.8%) and Gp-LAD (21.6% ± 3.8%) (p < 0.05). IPC of the RCA in the infarcted LAD segment further reduced infarction in the RCA (p < 0.001). 5-HD abolished the limitation of infarct size after second acute MI.
Conclusions: Hearts with prior acute infarction are preconditioned against acute MI and apparently exhausted the preconditioning reserve for further preconditioning. Pharmacologic or surgical interventions that abolish this protection may make infarcted hearts more vulnerable to injury and death.
Utility of CMA microdialysis system in measuring interstitial and plasma levels of glutamate, adenosine, glucose, lactate, pyruvate in a rabbit model of an acute MI, in vivo
AS Abd-Elfattah, M Fraykor, OL Alves, RC Bullock, DR Salter. Department of Surgery, Medical College of Virginia, VCU, Richmond, VA
Ischemia triggers glutamate release and depletion. The role of glutamate (Glu) release in myocardial injury and protection is not known. Recently, we have identified expression of Glu receptor subtypes in the hearts of human and animals and reported that activation of Glu receptor subtypes, with selective agonists, preconditions against myocardial stunning and infarction in dogs, rabbits and rats. The correlation between interstitial and plasma levels of Glu and adenosine has not been established. The present study demonstrated the utility and validity of CMA Microdialysis System, which is clinically used in head injury, in measuring interstitial levels of Glu, lactate, pyruvate and glucose. We employed this system in a rabbit model of acute MI, in vivo. We fully instrumented the heart with sonomicrometric crystals and pressure transducers to monitor hemodynamics and myocardial contractility. CMA-20 microdialysis probe (0.3 mm diameter) was introduced into the midmyocardium of rabbit heart via a home made catheter and secured in such a way that it moves with the heart without dislodging from the myocardium. The probe was connected to CMA Microdialysis miniature battery-operated pump 107 delivering 2 micro liters per minutes of dialysate and collected in CMA sealed sterile tubes. Samples were collected every 30 min from the dialysate and from the hepranized venous blood via an iv catheter into sealed tubes containing stopping solution. Samples from microdialysate and extracted plasma were kept at –80°C and later prepared for analysis using CMA-600 Automated Microdialysis Analyzer. Samples from the same dialysates and extracts were injected into HPLC to measure adenine nucleosides and purine bases and uric acid. Interstitial Glu and adenosine levels significantly increased during 30 min LAD occlusion and decreased during reperfusion. Plasma levels of g Glu and adenosine were also increased during ischemia and decreased during reperfusion. Depletion of myocardial Glu is associated with ventricular dysfunction and increased infarct size. Inhibition of glutamate release attenuated the rise in interstitial Glu during ischemia and depletion during reperfusion. Infusion of glutamate was protective. Results demonstrated the utility and validity of CMA system in correlating interstitial adenosine, amino acids
Myocardial apoptosis after surgical revascularization is attenuated by adjunct adenosine in blood cardioplegia
VH Thourani, N-P Wang, Z-Q Zhao, RA Guyton, J Vinten-Johansen. Joseph B. Whitehead Department of Surgery, Division of Cardiothoracic Surgery, Carlyle Fraser Heart Center, Cardiothoracic Research Laboratory, Emory University School of Medicine, Atlanta, Georgia
Background: Apoptosis is triggered not only by ischemia-reperfusion, but also by cytokines and other inflammatory mediators that may be released during cardiopulmonary bypass (CPB). Adenosine (ADO) in cardioplegia attenuates inflammatory responses involved in postischemic and postcardioplegic injury and necrosis. Our purpose is to test the hypothesis that ADO administered as an adjunct to blood cardioplegia or as peri-reperfusion therapy reduces apoptosis after surgical revascularization.
Methods: Dogs (n = 6/group) underwent 75 mins of LAD occlusion, were then placed on CPB for 60 mins, and followed by 2 hrs of reperfusion (Rep). Cold (4°C) antegrade CP (8:1 blood:crystalloid) was delivered q 20 mins for the first 3 infusions, and at 27°C for the terminal "hot shot" infusion using the MPS cardioplegic a delivery system (Allen, TX). Dogs were randomized to receive unsupplemented blood cardioplegia (BCP), ADO (100 µmol/L/L) in all cardioplegia infusions (ADO-CP), or ADO (100 µmol/L/L) only in the terminal infusion with iv adenosine (140 µg · kg-1 · min-1) for the first 30 mins of Rep (ADO-R). Infarct size was determined by 1% TTC staining and creatine kinase activity by spectrophotometry. In situ detection of apoptosis was determined by the TUNEL method and nucleosomal DNA fragmentation of myocytes by gel electrophoresis. Group differences were analyzed using ANOVA; significance was assigned at p less than 0.05. Mean±SEM are reported and correlation was performed by linear regression.
Results: Infarct size (AN/AAR) was reduced in ADO-CP (29% ± 2%*) and ADO-R (21% ± 2%*) groups compared to BCP (42% ± 4%). Plasma creatine kinase activity (IU/g protein) at 2 hrs of Rep was reduced in ADO-CP (31 ± 2*) and ADO-R (26 ± 1*) groups compared to BCP (48 ± 3). Percent apoptotic nuclei versus total nuclei was reduced in the nonnecrotic area at risk in ADO-CP (12% ± 2%*) and ADO-R (9% ± 1%*) groups compared to BCP group (19% ± 2%). Percent apoptosis was also reduced in the necrotic area at risk in ADO-CP (21% ± 4%*) and ADO-R (14% ± 1%*) groups compared to BCP group (37% ± 2%). There was a strong correlation (R = 0.841) between percent apoptosis in the AAR and infarct size. Attenuated apoptosis by TUNEL method was confirmed by reductions of DNA ladders.
Conclusions: Apoptosis occurs in surgically revascularized myocardium using blood cardioplegia. While ADO as an adjunct to CP provides a reduction in myocardial apoptosis and necrosis, a greater reduction is achieved when ADO is administered during the peri-reperfusion period. In high risk cardiac surgical patients, the administration of ADO as an adjunct to BCP and/or when administered during early reperfusion may be a useful cardioprotective treatment strategy.glucose, lactate and pyruvate with excellent reproducibility in cardiovascular research.
Coexistence of down-regulated vascular endothelial growth factor with myocardial blood flow defect and endothelial dysfunction during reperfusion
Z-Q Zhao, CD Morris, JM Budde, N-P Wang. Crawford Long Hospital, Cardiothoracic Research Laboratory, Atlanta, Georgia
Exogenous administration of vascular endothelial growth factor (VEGF) has been shown to protect heart from ischemia/reperfusion injury by reducing myocardial blood flow defect and preserving endothelial function. The purpose of the present study was to determine the change in the time course of endogenous VEGF expression and correlated this change with myocardial blood flow defect and endothelial dysfunction during reperfusion (R). Twenty eight dogs were subjected to 1 h LAD coronary occlusion followed by 6, 24, 48 and 72 h of R, respectively (n = 7 for each group). VEGF mRNA and protein expression was quantitatively analyzed by northern and western blot assay and the localization of VEGF was confirmed by immunohistochemical staining. Myocardial blood flow was determined by colored microspheres and endothelial function was determined by endothelium-dependent vasodilator. Northern blots of samples from ischemic myocardium showed progressively decreased levels of VEGF mRNA after 6 h of R (p < 0.05), consistent with down-regulated protein expression at these time points. Nonischemic myocardium showed diffuse immunohistochemical staining for VEGF, but the intensity of the staining was decreased after 6 h of R. Consistent with the change in time course of VEGF expression, regional myocardial blood flow at 6 h of R was further attenuated at 24 h of R (p < 0.05), but no further reduction was detected at 48 and 72 h of R. In addition, the dose-response of agonist-stimulated vascular relaxation was blunted at 6, 24 and 48 h of R versus normal vessels (p < 0.05). These data suggest that the extended reperfusion after coronary occlusion causes a down-regulation of VEGF expression. Coexistence of changes in expression of VEGF with myocardial blood flow defects and attenuation of vascular endothelial responses indicates that endogenous VEGF may participate in preservation of myocardial blood flow and endothelial function after ischemia and reperfusion.
Experimental surgical revascularization after coronary occlusion: comparison of on-pump, off-pump, and perfusion-assisted off-pump surgery
CD Morris, S Muraki, JM Budde, RN Otto, Z-Q Zhao, RA Guyton, J Vinten-Johansen. Crawford Long Hospital, Cardiothoracic Research Laboratory, Emory University Hospital, Atlanta, Georgia
Background: Reperfusion of acutely ischemic myocardium is associated with increased necrosis and neutrophil-mediated coronary endothelial dysfunction. Conventional coronary artery bypass surgery using cardiopulmonary bypass and cardioplegia attenuates such injury. In contrast, few cardioprotective techniques are available for off-pump coronary surgery (OPCAB). Perfusion-assisted direct coronary artery bypass (PADCAB), a technique that regionally perfuses myocardial segments via graft conduits, may avoid the ischemia inherent in OPCAB procedures. This study tested the hypothesis that reperfusion of acutely ischemic myocardium using cardiopulmonary bypass and cardioplegia reduces postischemic injury compared to OPCAB or PADCAB.
Methods: In anesthetized canines, the LAD was occluded for 75 minutes, and were then randomized to: 1) CPB-BCP: one hour of 4°C intermittent potassium blood cardioplegia; 2) OPCAB: release of the LAD after 75 minutes; and 3) PADCAB: pump-assisted perfusion of target myocardium for the first 30 minutes of reperfusion. In all groups, reperfusion was continued for two hours.
Results: The area at risk (AAR) was comparable between CPB-BCP, OPCAB, and PADCAB (26.3% ± 0.7%, 26.3% ± 1.8%, 25% ± 1%, respectively). At two hours reperfusion, segmental shortening (SS%) of the reperfused segment decreased from a base line of 21% ± 3% to -4% ± 0.8% in CPB-BCP, from 23% ± 4% to -2% ± 0.6% in OPCAB, and from 14% ± 3% to –3.1% ± 1.9% in PADCAB with no group differences. Infarct size (triphenyltetrazolium chloride) only tended to be greater in OPCAB (39.7% ± 5.2%) compared to CPB-BCP (25% ± 5.6%) and PADCAB (28% ± 4%, p = 0.12). Creatine kinase activity (CK) at 120 minutes of reperfusion were comparable between OPCAB (25% ± 5%), CPB-BCP (25% ± 5%), and PADCAB (18% ± 4%). Myeloperoxidase activity (units abs/min/g tissue) was significantly lower in the CPB-BCP group (17 ± 4) versus PADCAB group (87 ± 21) in the AAR. Endothelial function (vasodilator response to maximal concentrations of acetylcholine) was impaired in the ischemic-reperfused vessel compared to the normal vessel in the OPCAB (80 ± 5 vs 57% ± 4%) and PADCAB (79 ± 10 vs 101% ± 8%)groups, but not the CPB-BCP (121 ± 9 vs 97% ± 4%) group. Edema in the AAR was greater in the PADCAB (86% ± 1%) group versus the other two groups (OPCAB 83% ± 0.4%; CPB-BCP 82% ± 0.4%) in the AAR.
Conclusions: Outcomes in off-pump and perfusion-assisted techniques of surgical reperfusion of acutely ischemic myocardium are comparable to those using cardiopulmonary bypass and blood cardioplegia.
|
Perioperative glucocorticoids preserved myocardial function after cardiopulmonary bypass and deep hypothermic circulatory arrest in neonates
JY Duffy, DP Nelson, SM Schwartz, CJ Wagner, JM Pearl. Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229
Background: Glucocorticoid (GC) administration during cardiopulmonary bypass (CPB) is beneficial to pediatric patients undergoing repair of congenital heart defects. The intraoperative addition of glucocorticoids to the CPB prime has become routine therapy, but the optimal timing of GC administration and underlying mechanisms have not been fully examined. The objectives were to determine whether preoperative GC administration could further improve cardiac function and decrease myocardial injury after surgery by altering the balance of pro- and antiinflammatory cytokines.
Methods: Piglets (4 to 6 kg) were cooled with CPB to 18°C with 2 hours of deep hypothermic circulatory arrest, then were rewarmed and maintained for 2 hours. Methylprednisolone was administered only in the CPB prime (60 mg/kg, intraoperative GC) or both in the prime (30 mg/kg) and 6 hours before CPB (30 mg/kg, preand intraoperative GC). The control group received no GC treatment. Plasma cytokine levels were measured by ELISA and tissue levels by immunoblot analyses.
Results: LV systolic function (+dP/dt) in controls decreased to 69% ± 8% and 62% ± 9% of base line at 90 and 120 minutes of recovery, respectively (p < 0.05). The mean LV +dP/dt of animals receiving only intraoperative GC was 97% ± 9% and 96% ± 6% while LV +dP/dt in animals administered GC both preand intraoperatively was 99% ± 7% and 95% ± 10% of base line at 90 and 120 minutes after CPB. Plasma levels of the proinflammatory cytokine, interleukin (IL)-6, increased after CPB in all groups but was not affected by GC administration. Plasma levels of the antiinflammatory cytokine, IL-10, were higher 60 minutes after CPB with GC than in controls (174 ± 45 pg/mL in controls vs 212 ± 79 pg/mL with intraoperative GC and 338 ± 62 pg/mL with preand intraoperative GC). There was no change in myocardial IL-6 protein levels with GC treatment. However, the ratio of IL-10 to GAPDH protein levels in LV collected 2 hours after CPB increased with GC treatment from 0.8 ± 0.02 in controls to 0.96 ± 0.08 after intraoperative GC therapy and to 0.95 ± 0.04 after preand intraoperative GC (p < 0.05 vs controls).
Conclusions: Improved cardiac recovery after CPB and deep hypothermic circulatory arrest with GC treatment correlated with elevated plasma and myocardial antiinflammatory cytokine levels. No additional improvement in cardiac recovery, beyond that seen with one dose of GC, was detected with two-dose therapy. This project was supported by a grant to JMP from The Children’s Heart Foundation.
Cardiac preconditioning with calcium provides superior cardioprotection versus ischemia, pacing or isoproterenol
J Budde, L Mulligan, J Corvera, A Chandramouly, J Vinten-Johansen. Crawford Long Hospital, Cardiothoracic Research Laboratory, Atlanta, Georgia
Background: Ischemic preconditioning (IPC) augments recovery in ischemic/reperfused (IR) rat hearts in the isolated perfused heart model. We tested whether equivalent or superior cardioprotection could be induced in IR with alternate techniques of PC.
Methods: IPC was induced in group I by three episodes of three minutes without flow, separated by five minutes each. For demand PC (DPC, group II), hearts were overdrive-paced at 500 bpm for three three-minute episodes, separated by five minutes each, before ischemia. In group III, IsoPC, isoproterenol was administered at 3x10-8 M before ischemia; and in group IV, CaPC, calcium chloride (3 mmol/L) was given before ischemia. Normothermic global ischemia and reperfusion each lasted 30 minutes. Two additional control groups included ischemia and reperfusion without PC (no PC), and a time-matched control group without PC or ischemia (time control, TC).
Results: LV function after IR with no PC was depressed (LVDP 28.9 ± 6.14 mm Hg and dP/dt 570 ± 210), and was not restored with DPC (LVDP 45.4 ± 7.7 and dP/dt 800 ± 163). Incomplete recovery was observed in IsoPC (LVDP 61.6 ± 5.81 mm Hg*, dP/dt 1360 ± 429) and IPC (LVDP 66.3 ± 3.43 mm Hg* dP/dt 1400 ± 160). CaPC hearts achieved greater recovery of LV function at reperfusion (LVDP 73.6 ± 12.5 mm Hg* and dP/dt 2500 ± 550*) versus the IPC group.
Conclusion: Pharmacological PC with calcium provides equal or superior protection against global IR injury compared to IPC, with only partial protection with isoproterenol PC, and no protection from demand-induced PC. (*p < 0.05).
Footnotes
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
