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Ann Thorac Surg 2004;78:492-497
© 2004 The Society of Thoracic Surgeons

Original article: cardiovascular

Bradykinin preconditioning in coronary artery bypass grafting

Minxin Wei, MD, PhDa,c, Xin Wang, MDa, Pekka Kuukasjärvi, MD, PhDa, Jari Laurikka, MD, PhDa, Timo Rinne, MD, PhDb, Eva-Liisa Honkonen, MD, PhDb, Matti Tarkka, MD, PhDa*

a Division of Cardiothoracic Surgery, Tampere University Hospital, Tampere, Finland
b Department of Anesthesia and Intensive Care, Tampere University Hospital, Tampere, Finland
c Division of Cardiac Surgery, Tianjin Chest Hospital, Tianjin, People's Republic of China

Accepted for publication November 25, 2003.

* Address reprint requests to Dr Tarkka, Division of Cardiothoracic Surgery, Tampere University Hospital, PO Box 2000, Fin-33521 Tampere, Finland
e-mail: matti.tarkka{at}pshp.fi


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Experimental studies have shown that activation of bradykinin B2 receptor is one of the most important triggers of ischemic preconditioning. However, the effect of exogenous administration of bradykinin in cardiac surgery is not yet known. The present prospective randomized study was designed to investigate the effect of bradykinin pretreatment in patients undergoing elective coronary artery bypass surgery.

METHODS: Forty-one patients with multiple-vessel coronary artery disease and stable angina, admitted for the first time for elective coronary artery bypass surgery, were randomized into control or bradykinin (BK) groups. Patients in the BK group received bradykinin infusion for 7 minutes (total dose 25 µg) before the initiation of cardiopulmonary bypass. Perioperative cardiac specific troponin I (cTnI) and creatine kinase cardiac isoenzyme (CKMB) release and hemodynamics were recorded.

RESULTS: Bradykinin infusion caused acute decrease of blood pressure in most of the cases and the mean minimum mean blood pressure during bradykinin infusion was 72.7% of the original mean blood pressure (MBP) level (74.7 ± 7.9 vs 54.4 ± 12.1 mm Hg, p < 0.01). There were no differences in baseline levels of cTnI and CKMB between the groups. The postoperative cTnI levels were lower than 10 ng/mL in most patients in both groups (18 in the BK group and 15 in the control group). There was no difference in cTnI between the groups. However, patients who received bradykinin released significantly less CKMB than did the controls postoperatively (6 hours, BK, 22.1 ± 9.5 vs control, 23.6 ± 12.7 U/L; 12 hours, BK, 19.4 ± 12.4 vs control, 28.7 ± 23.8 U/L; 24 hours, BK, 21.5 ± 14.7 vs control, 35.5 ± 28.9 U/L; 48 hours, BK, 14.4 ± 7.5 vs control, 23.5 ± 13.6 U/L; analysis of variance [ANOVA] for repeated measurement, p = 0.036). Maximum CKMB was also lower in the BK group (22.4 ± 14.4 vs 37.7 ± 27.5 U/L, p = 0.044). There was no significant difference between the groups in any of the hemodynamic variables.

CONCLUSIONS: Exogenous bradykinin infusion showed weak cardioprotective effect in the low-risk patients undergoing coronary artery bypass surgery but the dose used in the study caused acute decrease of systemic blood pressure.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Preconditioning has been used as an optional strategy for protecting the heart against ischemia-reperfusion injury. Preconditioning reduces catabolite accumulation and slows ischemic metabolism, limits infarct size, reduces the risk of ischemia-reperfusion arrhythmias, and improves recovery of ventricular function [1–3]. This cardioprotective effect has been observed in different species, including rats, rabbits, dogs, and humans. It has become clear that several endogenously liberated autocrine-paracrine mediators of myocyte, endothelial, and neural origin are generated during the brief preconditioning period. They contribute critically to initiating a signal transduction cascade that rapidly results in the acquisition of tolerance to further ischemia. They include adenosine [4], catecholamines [5], opioid peptides [6], reactive oxygen species [7], and bradykinin [8]. All of them can put the heart into a preconditioned state when given exogenously.

It was demonstrated that cardiac interstitial bradykinin production increases during myocardial ischemia [9]. Vascular endothelial cells are the primary source of bradykinin in the heart. Degradation of bradykinin is very fast after its release. Enzymes that degrade bradykinin are referred to as ‘kininases’. The most important of these metalloproteases are the angiotension converting enzyme (ACE), neutral endopeptidases, kininase I, carboxypeptidase M, and aminopeptidase p [8].

Angiotensin-converting enzyme inhibitors such as ramiprilat could protect hearts against the deleterious consequences of ischemia and reperfusion [10–12]. It was suggested that angiotensin-converting enzyme inhibitors acted by inhibiting the breakdown of bradykinin, since HOE 140 (icatibant), a bradykinin B2 receptor antagonist, reversed the protective effect [13]. Study in cats found that transmural gradients of bradykinin are produced during ischemia and ischemic preconditioning enhanced bradykinin release in the myocardial interstitial fluid during subsequent ischemia [9]. This endogenously generated bradykinin was proved to mediate the cardioprotective events associated with ischemic preconditioning, as icatibant abolished the protective effect of ischemic preconditioning [14–16]. Further experimental studies confirmed the cardioprotective effect of exogenously administered bradykinin. Intracoronary infusion of bradykinin, at a dose not inducing coronary vasodilatation, was reported to suppress ischemia-induced arrhythmias in dogs [17]. Numerous studies in different animal models confirmed that exogenously administered bradykinin could mimic the effect of ischemic preconditioning to reduce myocardial infarct size [15, 18– 20]. However, the effect of exogenous administration of bradykinin in cardiac surgery is not yet known. The present prospective randomized study was designed to investigate the effect of bradykinin pretreatment in patients undergoing elective coronary artery bypass grafting (CABG).


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Patient selection
The local ethics committee approved the investigation and informed written consent was obtained from all patients entering the study. Forty-one patients with multiple-vessel coronary artery disease and stable angina, admitted for the first time for elective coronary artery bypass surgery, were invited to take part. They were randomized into control or bradykinin (BK) groups between September 2002 and January 2003. Patients with unstable angina, poor left ventricular function (ejection fraction < 30%), valve disease, and those on corticosteroid medication were deemed not eligible. No significant differences were noted between the groups in age, body surface area, and disease classification. The demographic data on the 41 patients completing the study are presented in Table 1.


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  		Table 1. Demographic Data

 
Cardiopulmonary bypass (CPB) and CABG
Anesthesia was induced with propofol (0.5 to 1.0 mg/kg), sufentanil (0.8 to 1.0 µg/kg), and rocuronium. A radial artery line and a pulmonary artery catheter were inserted for homodynamic monitoring. Propofol infusion was continued with a rate of 50 to 80 mg · kg–1 · min–1 and sufentanil with 0.03 to 0.05 µg · kg–1 · min–1. Additional midazolam boluses were given as necessary. Halogenated anesthetic gases were not used due to possible influence on the adenosine triphosphate-sensitive potassium (KATP) channels. Occasional hypertension was controlled with nitroglycerin or labetalol.

A standard CABG operation was undertaken with one internal thoracic artery (ITA) and from one to four peripheral vein grafts taken in each case from the lower extremities. The patients were perfused at a temperature of 32°C with nonpulsative flow from a membrane oxygenator (Dideco, Mirandola, Italy). The circuit was primed with 2,000 mL of Ringer acetate. Cold-blood antegrade-retrograde cardioplegia (6°C to 8°C) was delivered through a BCD-Plus device (Dideco, Mirandola, Italy), which mixed blood with asanguineous solution in a ratio of 4 to 1. The potassium concentration of the induction cardioplegia was 21 mmol/L. After each distal anastomosis, additional cardioplegic solution was delivered for one minute through the vein graft and coronary sinus catheter. Warm-blood retrograde cardioplegia was given at the end of the cross clamping. After weaning from CPB, pharmacological therapy with inotropic agents, and(or) vasodilators was used to maintain a cardiac index greater than 2.0 L · min–1 · m–1.

Bradykinin administration
Routine preoperative medication for anesthesia was the same in both groups. The BK group (n = 21) received an infusion of bradykinin (Clinalfa, Switzerland) before initiation of CPB (after complete cannulation of appropriate vessels and before administration of cardioplegic solution) through a Swan-Ganz catheter to the superior vena cava using a computer controlled pump infusion system. The initial infusion rate was with a 1 µg/min increment to the full dose of 4 µg/min at the second minute, where the infusion lasted for 6 minutes. Three minutes after the completion of bradykinin infusion CPB was started, the aorta was clamped, and cardioplegia was given. Cardiopulmonary bypass was initiated at once in patients with immediate hypotension (systolic artery pressure < 70 mm Hg) resulting from bradykinin infusion, but the drug infusion continued and, three minutes after the infusion, the heart was arrested and cardioplegia was given.

Sample collection and hemodynamic measurements
Blood samples for cardiac specific troponin I (cTnI) and creatine kinase cardiac isoenzyme (CKMB) measurements were collected from the radial artery before induction of anesthesia (baseline) at 6, 12, 24, and 48 hours after reperfusion to the myocardium. All samples were collected and cooled in 4°C immediately, then centrifuged. Serum samples were measured with a Chiron ACS180 analyzer (ACS: 180; Chiron/Diagnostics, Emeryville, CA), using a direct chemiluminescence method.

Hemodynamic monitoring comprised measurements of heart rate (HR), mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), pulmonary capillary wedge pressure (PCWP), and cardiac output. Derived cardiovascular variables, cardiac index (CI), systemic vascular resistance index (SVRI), and pulmonary vascular resistance index (PVRI) were calculated from standard formulas. All measurements were based on the thermodilution technique. Hemodynamic measurements and calculations were collected at five time points: (1) baseline value, after anesthesia induction, (2) 30 minutes, (3) 6 hours, (4) 12 hours, and (5) 24 hours after completion of CPB.

Statistical analysis
Statistical analysis was performed using SPSS (SPSS for Windows, Version 10.1; Chicago, IL) software package. The Student's p test or Mann-Whitney U test was used to distinguish demographic differences between the groups. Continuous variables were studied with analysis of variance for repeated measures. Logarithmic transformation was used as the variables were not normally distributed. The preoperative values were taken as covariates, and changes with respect to preoperative values were assessed. Statistical significance was attributed to p values lower than 0.05. All results were expressed as mean ± standard deviation (SD).


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Twenty-one patients were pretreated with bradykinin; the other 20 served as controls. Three patients in the study group could not tolerate the bradykinin infusion as a profound hypotension occurred at the first minute, and in these patients the protocol was finished in CPB. Two of the other patients who received bradykinin developed profound hypotension during infusion at the third and fourth minute, respectively, and CPB had to be started to finish the full infusion. Bradykinin infusion caused acute decrease of blood pressure in most of the cases and the average lowest MAP during bradykinin infusion was 72.8% of the original MAP level (74.7 ± 7.9 vs 54.4 ± 12.1 mm Hg). Heart rate increased only slightly, and no significant change was recorded during the infusion (Fig 1). There was no major postoperative complication in any of the 41 patients who completed the study. Essential data on operation and postoperative recovery are summarized in Table 1.



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  		Fig 1. Heart rate and MBP change during bradykinin infusion. Significant decrease of MBP and HR were seen during the infusion. *p < 0.05 as compared to the baseline blood pressure; • = HR; {circ} = MBP. (HR = heart rate; MPB = mean blood pressure.)

 
Troponin I and CK-MB
No significant difference was found in preoperative cTnI (BK, 0.21 ± 0.02 vs control, 0.24 ± 0.1 ng/mL) and CKMB (BK, 5.6 ± 4.9 vs control, 5.8 ± 5.6 U/L) levels between groups. In most of the cases, postoperative cTnI levels were lower than 10 ng/mL in both groups (18 in the BK group and 15 in the control group). The levels were no different between the groups (6 hours, BK, 5.1 ± 3.7 vs control, 4.4 ± 3.2 ng/mL; 12 hours, BK, 6.1 ± 4.7 vs control, 7.3 ± 9.0 ng/mL; 24 hours, BK, 5.5 ± 5.7 vs control, 8.1 ± 10.2 ng/mL; 48 hours, BK, 3.1 ± 4.6 vs control, 5.0 ± 6.7 ng/ml; analysis of variance (ANOVA) for repeated measurement, p = 0.81). However, in the BK patients the release of CK-MB was significantly less than in the controls postoperatively (6 hours, BK, 21.8 ± 8.9 vs control, 23.6 ± 12.7 U/L; 12 hours, BK, 19.5 ± 11.5 vs control, 28.7 ± 23.8 U/L; 24 hours, BK, 22.2 ± 14.7 vs control, 35.5 ± 28.9 U/L; 48 hours, BK, 15.3 ± 7.5 vs control, 23.5 ± 13.6 U/L; ANOVA for repeated measurement, p = 0.036, Fig 2). An angiotensin-converting enzyme (ACE) inhibitor medication, used before the operation (as a covariate), had no effect on the results (p = 0.28). Maximum CK-MB was also lower in the BK group (23.2 ± 14.3 vs 37.7 ± 27.5 U/L, Mann-Whitney U test, p = 0.044).



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  		Fig 2. Perioperative levels of CKMB in bradykinin patients and controls. The BK group release significantly lowers CKMB as compared to the controls (analysis of variance for repeated measurements, p = 0.036). • = BK; {circ} = control. (BK = bradykinin group; CKMB = creatine kinase cardiac isoenzyme.)

 
Hemodynamic
Mean systemic arterial pressure decreased and HR increased after the operation. The changes in HR, MAP, CVP, MPAP, and PCWP were similar in both groups (Table 2). The CI decreased 30 minutes after CPB in the controls; in the BK group it increased. However, there was no significant difference between the groups in any of the hemodynamic variables (Table 2) and there was no difference on inotrope use between the groups.


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  		Table 2. Hemodynamic Data

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Bradykinin receptor activation has been proposed to be involved in ischemic preconditioning. The present study found that exogenous bradykinin infusion elicits cardioprotective effects in elective low risk CABG patients.

The only study that has examined the cardioprotective of bradykinin in vivo in human showed that intracoronary bradykinin infusion appears to be as effective as ischemic preconditioning in PTCA patients [21]. Another study tested the role of bradykinin in ischemic preconditioning in human right atrial trabeculae [22]. The present investigation confirms the results by demonstrating that bradykinin preconditions the intact human heart in vivo with a longer ischemic duration as compared to that in PTCA patients. We previously reported that adenosine pretreatment is cardioprotective in CABG patients [23] in a similar clinical setting. The present finding by using bradykinin, a different agonist, elicits cardioprotective effects similar to that of adenosine, and this supports the idea that ischemic preconditioning involves multiple membrane receptors in CABG patients.

It has been shown in animal studies that bradykinin pretreatment significantly improved postischemic cardiac performance and coronary flow. The molecular mechanism of the action may be similar to those activated by ischemic preconditioning. Endogenous bradykinin protects myocytes against hypoxia-reoxygenation injury by inducing NO production and increasing cyclic guanosine monophosphate (GMP) synthesis which contributes to cardioprotection through energy preservation [24]. It was also reported that exogenous bradykinin improves recovery of ventricular and coronary vascular function via nitric oxide-dependent mechanisms, such as N-{omega}-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, abolished bradykinin-induced protection in rabbit hearts [19]. The protective action of bradykinin may also mediate by protein kinase C [15], protein tyrosine kinase [20], and the activation of the adenosine triphosphate (ATP) sensitive potassium channel [25].

It was reported that angiotensin-converting enzyme (ACE) inhibitors exert cardioprotective effects by inhibiting the breakdown of bradykinin [11]. Morris and associates [22] examined the effects of the ACE inhibitors captopril and lisinopril in combination with a subthreshold preconditioning stimulus in human atrial trabeculae. They found that the protection afforded by the combination of subthreshold ischemia and ACE inhibitors was abolished by the bradykinin B2 receptor antagonist HOE 140, suggesting that ACE inhibitors augment ischemic preconditioning by B2 receptor activation. In the present study, some of the patients used ACE inhibitors before the operation (Table 1). However, statistic analysis showed that an ACE inhibitor used before the operation, taken as a covariate in the analysis, had no effect on the results. It was difficult to issue whether an ACE inhibitor enhanced the cardioprotective effect with the small number of patients who used ACE inhibitors in the present small series. Further study will be of interest to investigate whether the use of ACE inhibitors can either enhance the effect of bradykinin preconditioning or lower the necessary dosage of exogenous bradykinin infusion.

We have found no available bradykinin infusion protocols in the literature of cardiac surgery. The systemic effect of bradykinin infusion is potentive and acute. The present protocol refers to that used in Leesar and colleagues [21] PTCA study. In their study, it was shown that intracoronary administration of 25 µg bradykinin in 10 minutes appears to be as effective as ischemic preconditioning in patients undergoing PTCA. The BK infusion is well tolerated by the patient and bradykinin has no effect on heart rate and blood pressure. Our pilot study showed that the maximum bradykinin infusion rate from the superior vena cava is 4 µg/min. Faster infusion rate will lead to profound systemic hypotension (systolic blood pressure [SBP] < 70 mm Hg) in most of the CABG patients. The present study used bradykinin in 21 patients and it was safe in most of the cases without CPB, though there were three patients who could not tolerate the infusion, even at the starting stage with an infusion rate of 1 µg/min only, and had to finish the full protocol with the help of CPB. It seems wise to recommend using the present protocol after the initiation of CPB in patients with unstable hemodynamic status before the pump is on. Further study is warranted to modify the bradykinin protocol to achieve its cardioprotective effect in cardiac surgery. Regional use of the drug might limit the effect on the target organ and therefore avoid the systemic hemodynamic side effect.

Ischemia-reperfusion results in myocardial contractile dysfunction, necrosis, and vascular injury. A lower CKMB release in the BK group indicated less myocardial injury after CABG. We could not find a significant cTnI difference between the groups and this may be caused by the fact that the study was performed in only a limited number of low-risk patients and the postoperative cTnI levels, in general, were less than 10 ng/mL in most of the cases. Recent studies have shown that ischemic preconditioning is a graded phenomenon [1]. A "threshold level" of PKC stimulation must be reached in order to trigger the preconditioning response. It was proposed that brief ischemia was associated with the release of several ligands potentially capable of evoking the response, and that the effects of adenosine and bradykinin in activating PKC were additive. Depending on the intensity of the ischemic stimulus, these ligands may or may not be released in sufficient quantity to achieve the threshold stimulation necessary to trigger ischemic preconditioning [15]. In this case, the use of adenosine or bradykinin separately may not be easy to mimic the complete effect of ischemic preconditioning. Pharmacologic preconditioning with multiple triggers may be closer to the multifactorial nature of the preconditioning response, and get more powerful effects.

In the present study, a high percentage of patients received inotropic support (mainly noradrenaline to control blood pressure), and there was no significant difference in the postoperative change of cardiac index between the groups. The inotropic support may mask the hemodynamic data. Typical for that, stunned myocardium is able to contract when exposed to inotropic stimuli [26]. Although there was no statistical significance in the difference between the groups, this effect could more or less bias the results. Myocardial stunning after CABG, in patients with a high degree of comorbidity, represents a higher risk of postoperative organ dysfunction. In this respect, patients with high operative risk might receive more benefit from the cardioprotective action of bradykinin preconditioning during cardiac surgery. The effects of bradykinin in patients with high operative risk need further investigation.

In summary, exogenous bradykinin infusion immediately before the initiation of CPB may limit myocardial injury after CABG in low-risk patients. It may be a new strategy for improving myocardial protection during heart surgery, but the protocol used here failed to show a beneficial effect on postoperative hemodynamic variables, and caused acute decrease of the systemic blood pressure.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
The present study was supported by grants from the Medical Research Fund of Pirkkanmaa Hospital District, the Finnish Cardiac Research Foundation, the Pirkkanmaa Culture Foundation, and the Tampereen Tuberculosis Foundation.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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