Optimal myocardial protection strategy for coronary artery bypass grafting without cardioplegia: prospective randomised trial
http://www.100md.com
《血管的通路杂志》
Department of Cardiac Surgery, Royal Infirmary, Edinburgh, EH16 4SA, UK
Abstract
Although hypothermia and ischaemic preconditioning (IP) are independently recognised mechanisms of cardioprotection, interactions between myocardial temperature and preconditioning have not been investigated. Therefore, this study explored the possibility of inducing IP during hypothermia and quantifying its effects at two temperature regimens commonly used in clinical practice. One hundred and four patients undergoing coronary artery bypass grafting (CABG) with intermittent cross-clamping and ventricular fibrillation were randomised to four groups: N=normothermia (36.5±0.5 °C); NP=normothermia+preconditioning, H=hypothermia (31.5±0.5 °C), HP=hypothermia+preconditioning. The primary outcome measure was release of cardiac Troponin I (cTnI), measured at 6 time points from pre- to 72 h after the end of CPB. There were no hospital deaths and no significant differences in pre- and intra-operative variables (P0.05). There were significant differences in cTnI release between all groups, as follows: N: 117±12 μg/l (P0.05 vs. all groups), NP: 87±8 μg/l (P0.05 vs. groups N and HP), H: 76±6 μg/l (P0.05 vs. groups N and HP), HP: 44±6 μg/l (P0.05 vs. all groups). In conclusion, IP can be induced at both normothermia and moderate hypothermia, where it significantly reduces myocardial damage. Further studies are warranted to investigate the effects of the addition of hypothermia to pharmacological myocardial preconditioning.
Key Words: Ischaemic preconditioning; Temperature; Coronary artery bypass grafting
1. Introduction
It has been established that repeated brief periods of ischaemia followed by reperfusion have a protective effect on myocardial function and viability during and after subsequent episodes of more prolonged ischaemia. This is termed ‘ischaemic preconditioning’ (IP) and a wealth of literature has characterised this phenomenon and explored its possible mechanisms [1]. Clinical studies have shown that IP can be induced during coronary artery bypass graft surgery (CABG) performed using the technique of intermittent aortic cross clamp and induced ventricular fibrillation (ICCF) [2,3]. However, whilst one of these studies was performed at normothermia [2], another induced IP at normothermia, followed by myocardial revascularisation at hypothermia (32 °C) [3]. Molecular mechanisms of preconditioning are variable at different temperatures [1] and, to date, interactions between myocardial temperature and IP have not been investigated in the clinical setting.
Every year, despite advances in cardioplegic techniques and the popularisation of off-pump coronary surgery, approximately 20% (n17000) of all surgical procedures for myocardial revascularisation in the UK are performed on cardiopulmonary bypass (CPB) with the ICCF technique [4]. These operations are performed either at relatively normothermic (35 °C), or hypothermic (around 32 °C) systemic and myocardial temperature, on both routine and high-risk cases [5].
This study was designed to answer the following questions: (1) does IP occur in the human myocardium under hypothermic conditions (2) If so, does it confer additional benefit during non-cardioplegic hypothermic myocardial revascularisation
2. Methods
After receiving approval from the regional Ethics Committee, patients participating in this study were prospectively randomised between the use or non-use of IP and systemic normothermia (36–37 °C) or moderate hypothermia (31–32 °C). Pre-, intra- and post-operative variables that could influence the outcome measures under consideration were standardised, including induction and maintenance of anaesthesia and perfusion techniques. All operations were performed by one surgeon using the same technique (ICCF). After institution of CPB and stabilisation of haemodynamic parameters, but prior to myocardial revascularisation, patients were treated differently according to their randomisation group, as described in Fig. 1. In brief, the protocol to induce IP consisted of two periods of three minutes of ischaemia, each followed by a period of two minutes of reperfusion, as originally described by Yellon and colleagues [2]. Systemic and myocardial temperatures were controlled by means of nasopharyngeal and anterior interventricular septal probes, respectively: patients assigned to the N and NP groups were kept at normothermia throughout the duration of their operation, whereas the temperature of patients in the H and HP groups was brought to 31.5±0.5 °C after onset of CPB and maintained at that level until completion of the last distal anastomosis. This temperature management differs from those used in previous studies, where IP and the first distal anastomosis were performed at normothermia, followed by complete revascularisation at hypothermia [3,6].
Myocardial damage was assessed by measuring serum levels of cTnI, the most accurate biochemical marker available to date. Blood samples were collected at the following time points: prior to, at the end of and at 6, 24, 48 and 72 h after discontinuation of CPB. The samples were centrifuged and the separated serum frozen at –72 °C for subsequent batch analysis. cTnI levels were measured using a commercially available assay (Beckman Coulter Diagnostics Ltd, High Wycombe, UK). As for all protein immunoenzymatic assays, the reference range was based on local laboratory experience. Our laboratory has confirmed that the cut-off value for cTnI in the diagnosis of myocardial muscle cell injury is 0.1 μg/l [7].
The primary outcome measure was the extent of myocardial damage expressed by serum levels of cTnI at each time point and the area under the curve of cTnI release, calculated using the trapezoid rule. Secondary outcome measures were physiological and clinical parameters, including cardiac index, use of inotropes (defined as use of any inotropic agent at any dose after weaning from CPB), use of intra-aortic balloon pump, arrhythmias (any sustained tachy- or bradi-arrhythmia after weaning from CPB), duration of ventilation, length of stay in intensive care unit, length of stay in hospital and status at discharge. Based on previously published data from our group [7] and a pilot study of 12 patients, power calculations established that a sample size of 25 patients in each group would be sufficient to detect as significant at the 5% level a true mean difference of one standard deviation for the primary outcome measure.
The following categories of patients were excluded from the study: patients who had already undergone CABG and those requiring associated procedures necessitating the opening of a heart chamber; patients with evidence of recent (less than seven days) myocardial infarction (due to the effects on measured biochemical indices of necrosis), and/or those with elevated levels of cTnI at baseline; patients of age greater than 70 years and those taking oral sulfonylurea agents (due to their proven resistance to preconditioning).
The resultant data were analysed using commercially available statistical software (Statistica for Windows, Statsoft Inc., Tulsa, OK, USA). The data presented have been derived using standard descriptive statistics and conventional tests of significance for comparisons: Student's t, Mann–Whitney and ANOVA with Tukey's HSD post-hoc test, as appropriate. Statistical significance was set at the 5% level. Unless otherwise stated, data are presented as mean±standard error (S.E.) of the mean.
3. Results
One hundred and four patients (n=26 in each group) undergoing primary myocardial revascularisation with two or more grafts were enrolled.
There were no significant differences between groups for pre- (Table 1) and intra-operative (Table 2) variables that might have influenced the chosen endpoints. There were no hospital deaths and no significant co-morbidities. There were also no significant differences between groups for clinical secondary outcome measures (Table 2).
With regards to the extent of myocardial injury, serum levels of cTnI rose significantly (P0.05) at 6 h after the end of CPB and remained significantly elevated in all groups, when compared to baseline levels (Table 3). At 24 h after the end of CPB, peak concentrations of cTnI were detected in all groups, in keeping with the characteristic kinetics of troponin release following myocardial injury. At this prognostically important time point, there were significant differences in cTnI serum levels between groups (Table 3). Inter-group analysis also showed significant differences in the extent of myocardial cell damage, as measured by the AUC of cTnI release (Fig. 2).
4. Discussion
In patients with ischaemic heart disease undergoing myocardial revascularisation, normothermic IP and hypothermia have each been shown to have protective effects. We believe this is the first clinical study to show that (a) IP does occur even at hypothermia and (b) that their effects are additive. Two prospective randomised trials have previously demonstrated that IP is an effective strategy for myocardial protection during CABG [3,6]; however, in these studies IP and myocardial revascularisation were carried out at different temperatures during the same procedure (i.e. IP and first distal anastomosis at normothermia, followed by further anastomoses at moderate hypothermia), making it impossible to distinguish the effects of the two interventions. For the same reason, it is not appropriate to draw comparisons between our results and those mentioned above.
Hypothermia, with its attained decrease in tissue metabolism, is one of the mainstays of both cardioplegic and non-cardioplegic strategies for protecting the myocardium from the deleterious effects of ischaemia [8]. Likewise, IP at normothermia has been consistently shown to decrease the extent of ischaemic myocardial damage [1–3,6]. However, there are conflicting results regarding the effect of hypothermia on IP. It has been suggested that one of the possible mechanisms through which IP may exert its protective action is the induction of a reduction in temperature of the tissue subjected to ischaemia [9]. Also, a carefully conducted experimental study by Van der Veen and colleagues on dogs subjected to 10-min periods of aortic clamping each followed by 15 min of reperfusion, has failed to demonstrate an adjunctive beneficial effect of induced hypothermia in preserving myocardial high-energy stores [10]. In contrast, other experimental studies addressing the issue of preconditioning during hypothermia have shown that the protection offered by the reduced temperature is additive to that achieved by preconditioning [11]. In the clinical setting, the effects of hypothermia on reducing myocardial damage during cardiac surgery have been studied both in isolation [8] and in association with numerous cardioplegic techniques. However, we could find no studies in the literature that have investigated the effects of temperature on myocardial damage in the setting of non-cardioplegic techniques of myocardial protection.
Some studies, however, doubt that IP is an effective means of limiting myocite necrosis [12]. There are important elements in all these studies which must be given due consideration when interpreting their results: IP was originally demonstrated to be inducible in humans by the same protocol of short periods of ischaemia followed by reperfusion, as used in this study. Since Yellon's original description [2], almost every clinical study on IP has applied its own variations to the preconditioning protocol, and it is conceivable that these deviations may account for the different protective effects observed, or the lack thereof. Furthermore, most of the studies that doubt the existence or effectiveness of IP as a myocardial protective strategy, fail to reproduce the condition in which IP had originally been demonstrated to be effective, i.e. a relatively prolonged period of ischemia following the IP protocol [12]. Other patient-related factors have been recognised as responsible for diminishing or nullifying the effects of IP in the clinical setting, such as advanced age and intake of oral hypoglycaemic agents; to eliminate a potential cause for spurious results, such categories of patients were excluded from this study.
As a possible explanation for the additive effects of hypothermia and IP observed in this study, we propose that they may result from the activation or up-regulation of the same protective intracellular transduction pathways, as suggested by recent experimental and clinical evidence [13]. In brief, it appears that both IP and hypothermia lead to increased intramyocardial synthesis of heat shock proteins; in turn, this group of protein kinases contribute to reducing accumulation of intracellular Na+ and Ca2+ ions during ischaemia and blunt reperfusion-induced Ca2+ overload and generation of reactive oxygen species. These actions favour improved mitochondrial energy generation and suppress necrotic and apoptotic cell death. Further studies are obviously needed to test this hypothesis.
Despite using the most accurate study design for investigating different treatments in the clinical setting, this trial has some limitations: the study cohort has been selected to exclude factors that may have confounded the analysis of the chosen outcome measures, such as low ejection fraction, unstable coronary syndromes and non-insulin dependent diabetes mellitus; however, many of these factors are represented in a significant proportion of a normal patient population. Therefore, our data and conclusions must be kept in context. Furthermore, the absence of any differences in the secondary clinical outcome measures in this study underlines the need for much larger study groups or for different study populations (e.g. higher risk cases with poor ejection fraction) to address the clinical significance of these findings.
Cardiac TnI is currently regarded as the most accurate biochemical marker of myocardial damage [7]; however, recent evidence suggests that not all of the postoperative serum cTnI release represents irreversible myocardial injury [14]. According to this theory, some of the troponin leak represents protein release from non-structurally bound cytosolic pools, rather than true myocardial necrosis. Therefore, a proportion of cTnI levels rise could be due to increased cellular permeability and not associated to structural myocardial damage. To increase the accuracy in detecting myocardial damage and dysfunction, further studies investigating the effects of preconditioning may couple the use of biochemical markers and new imaging techniques showing both viability and function [15].
In summary, this study demonstrates that IP can be safely and effectively induced also at hypothermia. Furthermore, it identifies the best modality of protecting the myocardium of patients undergoing CABG without cardioplegia: in a selected population of patients undergoing elective coronary revascularisation using ICCF, the combination of IP and moderate hypothermia results in significant reduction of myocardial damage, when compared to IP at normothermia or hypothermia alone. Further studies investigating the effects of hypothermia combined with pharmacological means of inducing myocardial preconditioning are warranted.
Acknowledgements
This study has been supported by a grant from the British Heart Foundation.
References
Eisen A, Fisman EZ, Rubenfire M, Freimark D, McKechnie R, Tenenbaum A, Motro M, Adler Y. Ischemic preconditioning: nearly two decades of research. A comprehensive review. Atherosclerosis 2004; 172:201–210.
Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet 1993; 342:276–277.
Jenkins DP, Pugsley WB, Alkhulaifi AM, Kemp M, Hooper J, Yellon DM. Ischaemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass surgery. Heart 1997; 77:314–318.
Keogh BE, Kinsman R. National Adult Cardiac Surgical Database Report 2001–2003 2004;Berkshire, UK: Dendrite Clinical Systems Ltd.
Boncheck LI, Burlingame MW, Vazales BE, Lundy EF, Gassmann CJ. Applicability of noncardioplegic coronary bypass to high-risk patients. J Thorac Cardiovasc Surg 1992; 103:230–237.
Teoh LK, Grant R, Hulf JA, Pugsley WB, Yellon DM. A comparison between ischemic preconditioning, intermittent cross-clamp fibrillation and cold crystalloid cardioplegia for myocardial protection during coronary artery bypass graft surgery. Cardiovasc Surg 2002; 10:251–255.
Noble JS, Reid AM, Jordan LV, Glen AC, Davidson JA. Troponin I and myocardial injury in the ICU. Br J Anaesth 1999; 82:41–46.
Vazquez-Jimenez JF, Qing M, Hermanns B, Klosterhalfen B, Woltje M, Chakupurakal R, Schumacher K, Messmer BJ, von Bernuth G, Seghaye MC. Moderate hypothermia during cardiopulmonary bypass reduces myocardial cell damage and myocardial cell death related to cardiac surgery. J Am Coll Cardiol 2001; 38:1216–1223.
Schwartz LM, Verbinski SG, Vander Heide RS, Reimer KA. Epicardial temperature is a major predictor of myocardial infarct size. J Mol Cell Cardiol 1997; 29:1577–1583.
Van der Veen FH, van der Vusse GJ, Willemsen P, Kruger RT, van der Nagel T, Coumans WA, Reneman RS. Changes in myocardial high-energy phosphate stores and carbohydrate metabolism during intermittent aortic crossclamping in dogs on cardiopulmonary bypass at 34 °C and 25 °C. J Thorac Cardiovasc Surg 1990; 100:389–399.
Cave CA, Hearse DJ. Ischaemic preconditioning and contractile function: studies with normothermic and hypothermic global ischaemia. J Mol Cell Cardiol 1992; 24:1113–1123.
Perrault LP, Menasche P, Bel A, de Chaumaray T, Peynet J, Mondry A, Olivero P, Emanoil-Ravier R, Moalic JM. Ischemic preconditioning in cardiac surgery: a word of caution. J Thorac Cardiovasc Surg 1996; 112:1378–1386.
Qing M, Vazquez-Jimenez JF, Schumacher K, Bhardwaj RS, Klosterhalfen B, Minkenberg R, Messmer BJ, von Bernuth G, Seghaye MC. Moderate hypothermia during cardiopulmonary bypass increases intramyocardial synthesis of heat shock protein 72. J Thorac Cardiovasc Surg 2002; 124:724–731.
Bleier J, Vorderwinkler KP, Falkensammer J, Mair P, Dapunt O, Puschendorf B, Mair J. Different intracellular compartmentations of cardiac troponins and myosin heavy chains: a causal connection to their different early release after myocardial damage. Clin Chem 1998; 44:1912–1918.
Wagner A, Mahrholdt H, Holly TA, Elliott MD, Regenfus M, Parker M, Klocke FJ, Bonow RO, Kim RJ, Judd RM. Contrast-enhanced MRI and routine single photon emission computed tomography (SPECT) perfusion imaging for detection of subendocardial myocardial infarcts: an imaging study. Lancet 2003; 361:374–379.(Massimiliano Codispoti, T)
Abstract
Although hypothermia and ischaemic preconditioning (IP) are independently recognised mechanisms of cardioprotection, interactions between myocardial temperature and preconditioning have not been investigated. Therefore, this study explored the possibility of inducing IP during hypothermia and quantifying its effects at two temperature regimens commonly used in clinical practice. One hundred and four patients undergoing coronary artery bypass grafting (CABG) with intermittent cross-clamping and ventricular fibrillation were randomised to four groups: N=normothermia (36.5±0.5 °C); NP=normothermia+preconditioning, H=hypothermia (31.5±0.5 °C), HP=hypothermia+preconditioning. The primary outcome measure was release of cardiac Troponin I (cTnI), measured at 6 time points from pre- to 72 h after the end of CPB. There were no hospital deaths and no significant differences in pre- and intra-operative variables (P0.05). There were significant differences in cTnI release between all groups, as follows: N: 117±12 μg/l (P0.05 vs. all groups), NP: 87±8 μg/l (P0.05 vs. groups N and HP), H: 76±6 μg/l (P0.05 vs. groups N and HP), HP: 44±6 μg/l (P0.05 vs. all groups). In conclusion, IP can be induced at both normothermia and moderate hypothermia, where it significantly reduces myocardial damage. Further studies are warranted to investigate the effects of the addition of hypothermia to pharmacological myocardial preconditioning.
Key Words: Ischaemic preconditioning; Temperature; Coronary artery bypass grafting
1. Introduction
It has been established that repeated brief periods of ischaemia followed by reperfusion have a protective effect on myocardial function and viability during and after subsequent episodes of more prolonged ischaemia. This is termed ‘ischaemic preconditioning’ (IP) and a wealth of literature has characterised this phenomenon and explored its possible mechanisms [1]. Clinical studies have shown that IP can be induced during coronary artery bypass graft surgery (CABG) performed using the technique of intermittent aortic cross clamp and induced ventricular fibrillation (ICCF) [2,3]. However, whilst one of these studies was performed at normothermia [2], another induced IP at normothermia, followed by myocardial revascularisation at hypothermia (32 °C) [3]. Molecular mechanisms of preconditioning are variable at different temperatures [1] and, to date, interactions between myocardial temperature and IP have not been investigated in the clinical setting.
Every year, despite advances in cardioplegic techniques and the popularisation of off-pump coronary surgery, approximately 20% (n17000) of all surgical procedures for myocardial revascularisation in the UK are performed on cardiopulmonary bypass (CPB) with the ICCF technique [4]. These operations are performed either at relatively normothermic (35 °C), or hypothermic (around 32 °C) systemic and myocardial temperature, on both routine and high-risk cases [5].
This study was designed to answer the following questions: (1) does IP occur in the human myocardium under hypothermic conditions (2) If so, does it confer additional benefit during non-cardioplegic hypothermic myocardial revascularisation
2. Methods
After receiving approval from the regional Ethics Committee, patients participating in this study were prospectively randomised between the use or non-use of IP and systemic normothermia (36–37 °C) or moderate hypothermia (31–32 °C). Pre-, intra- and post-operative variables that could influence the outcome measures under consideration were standardised, including induction and maintenance of anaesthesia and perfusion techniques. All operations were performed by one surgeon using the same technique (ICCF). After institution of CPB and stabilisation of haemodynamic parameters, but prior to myocardial revascularisation, patients were treated differently according to their randomisation group, as described in Fig. 1. In brief, the protocol to induce IP consisted of two periods of three minutes of ischaemia, each followed by a period of two minutes of reperfusion, as originally described by Yellon and colleagues [2]. Systemic and myocardial temperatures were controlled by means of nasopharyngeal and anterior interventricular septal probes, respectively: patients assigned to the N and NP groups were kept at normothermia throughout the duration of their operation, whereas the temperature of patients in the H and HP groups was brought to 31.5±0.5 °C after onset of CPB and maintained at that level until completion of the last distal anastomosis. This temperature management differs from those used in previous studies, where IP and the first distal anastomosis were performed at normothermia, followed by complete revascularisation at hypothermia [3,6].
Myocardial damage was assessed by measuring serum levels of cTnI, the most accurate biochemical marker available to date. Blood samples were collected at the following time points: prior to, at the end of and at 6, 24, 48 and 72 h after discontinuation of CPB. The samples were centrifuged and the separated serum frozen at –72 °C for subsequent batch analysis. cTnI levels were measured using a commercially available assay (Beckman Coulter Diagnostics Ltd, High Wycombe, UK). As for all protein immunoenzymatic assays, the reference range was based on local laboratory experience. Our laboratory has confirmed that the cut-off value for cTnI in the diagnosis of myocardial muscle cell injury is 0.1 μg/l [7].
The primary outcome measure was the extent of myocardial damage expressed by serum levels of cTnI at each time point and the area under the curve of cTnI release, calculated using the trapezoid rule. Secondary outcome measures were physiological and clinical parameters, including cardiac index, use of inotropes (defined as use of any inotropic agent at any dose after weaning from CPB), use of intra-aortic balloon pump, arrhythmias (any sustained tachy- or bradi-arrhythmia after weaning from CPB), duration of ventilation, length of stay in intensive care unit, length of stay in hospital and status at discharge. Based on previously published data from our group [7] and a pilot study of 12 patients, power calculations established that a sample size of 25 patients in each group would be sufficient to detect as significant at the 5% level a true mean difference of one standard deviation for the primary outcome measure.
The following categories of patients were excluded from the study: patients who had already undergone CABG and those requiring associated procedures necessitating the opening of a heart chamber; patients with evidence of recent (less than seven days) myocardial infarction (due to the effects on measured biochemical indices of necrosis), and/or those with elevated levels of cTnI at baseline; patients of age greater than 70 years and those taking oral sulfonylurea agents (due to their proven resistance to preconditioning).
The resultant data were analysed using commercially available statistical software (Statistica for Windows, Statsoft Inc., Tulsa, OK, USA). The data presented have been derived using standard descriptive statistics and conventional tests of significance for comparisons: Student's t, Mann–Whitney and ANOVA with Tukey's HSD post-hoc test, as appropriate. Statistical significance was set at the 5% level. Unless otherwise stated, data are presented as mean±standard error (S.E.) of the mean.
3. Results
One hundred and four patients (n=26 in each group) undergoing primary myocardial revascularisation with two or more grafts were enrolled.
There were no significant differences between groups for pre- (Table 1) and intra-operative (Table 2) variables that might have influenced the chosen endpoints. There were no hospital deaths and no significant co-morbidities. There were also no significant differences between groups for clinical secondary outcome measures (Table 2).
With regards to the extent of myocardial injury, serum levels of cTnI rose significantly (P0.05) at 6 h after the end of CPB and remained significantly elevated in all groups, when compared to baseline levels (Table 3). At 24 h after the end of CPB, peak concentrations of cTnI were detected in all groups, in keeping with the characteristic kinetics of troponin release following myocardial injury. At this prognostically important time point, there were significant differences in cTnI serum levels between groups (Table 3). Inter-group analysis also showed significant differences in the extent of myocardial cell damage, as measured by the AUC of cTnI release (Fig. 2).
4. Discussion
In patients with ischaemic heart disease undergoing myocardial revascularisation, normothermic IP and hypothermia have each been shown to have protective effects. We believe this is the first clinical study to show that (a) IP does occur even at hypothermia and (b) that their effects are additive. Two prospective randomised trials have previously demonstrated that IP is an effective strategy for myocardial protection during CABG [3,6]; however, in these studies IP and myocardial revascularisation were carried out at different temperatures during the same procedure (i.e. IP and first distal anastomosis at normothermia, followed by further anastomoses at moderate hypothermia), making it impossible to distinguish the effects of the two interventions. For the same reason, it is not appropriate to draw comparisons between our results and those mentioned above.
Hypothermia, with its attained decrease in tissue metabolism, is one of the mainstays of both cardioplegic and non-cardioplegic strategies for protecting the myocardium from the deleterious effects of ischaemia [8]. Likewise, IP at normothermia has been consistently shown to decrease the extent of ischaemic myocardial damage [1–3,6]. However, there are conflicting results regarding the effect of hypothermia on IP. It has been suggested that one of the possible mechanisms through which IP may exert its protective action is the induction of a reduction in temperature of the tissue subjected to ischaemia [9]. Also, a carefully conducted experimental study by Van der Veen and colleagues on dogs subjected to 10-min periods of aortic clamping each followed by 15 min of reperfusion, has failed to demonstrate an adjunctive beneficial effect of induced hypothermia in preserving myocardial high-energy stores [10]. In contrast, other experimental studies addressing the issue of preconditioning during hypothermia have shown that the protection offered by the reduced temperature is additive to that achieved by preconditioning [11]. In the clinical setting, the effects of hypothermia on reducing myocardial damage during cardiac surgery have been studied both in isolation [8] and in association with numerous cardioplegic techniques. However, we could find no studies in the literature that have investigated the effects of temperature on myocardial damage in the setting of non-cardioplegic techniques of myocardial protection.
Some studies, however, doubt that IP is an effective means of limiting myocite necrosis [12]. There are important elements in all these studies which must be given due consideration when interpreting their results: IP was originally demonstrated to be inducible in humans by the same protocol of short periods of ischaemia followed by reperfusion, as used in this study. Since Yellon's original description [2], almost every clinical study on IP has applied its own variations to the preconditioning protocol, and it is conceivable that these deviations may account for the different protective effects observed, or the lack thereof. Furthermore, most of the studies that doubt the existence or effectiveness of IP as a myocardial protective strategy, fail to reproduce the condition in which IP had originally been demonstrated to be effective, i.e. a relatively prolonged period of ischemia following the IP protocol [12]. Other patient-related factors have been recognised as responsible for diminishing or nullifying the effects of IP in the clinical setting, such as advanced age and intake of oral hypoglycaemic agents; to eliminate a potential cause for spurious results, such categories of patients were excluded from this study.
As a possible explanation for the additive effects of hypothermia and IP observed in this study, we propose that they may result from the activation or up-regulation of the same protective intracellular transduction pathways, as suggested by recent experimental and clinical evidence [13]. In brief, it appears that both IP and hypothermia lead to increased intramyocardial synthesis of heat shock proteins; in turn, this group of protein kinases contribute to reducing accumulation of intracellular Na+ and Ca2+ ions during ischaemia and blunt reperfusion-induced Ca2+ overload and generation of reactive oxygen species. These actions favour improved mitochondrial energy generation and suppress necrotic and apoptotic cell death. Further studies are obviously needed to test this hypothesis.
Despite using the most accurate study design for investigating different treatments in the clinical setting, this trial has some limitations: the study cohort has been selected to exclude factors that may have confounded the analysis of the chosen outcome measures, such as low ejection fraction, unstable coronary syndromes and non-insulin dependent diabetes mellitus; however, many of these factors are represented in a significant proportion of a normal patient population. Therefore, our data and conclusions must be kept in context. Furthermore, the absence of any differences in the secondary clinical outcome measures in this study underlines the need for much larger study groups or for different study populations (e.g. higher risk cases with poor ejection fraction) to address the clinical significance of these findings.
Cardiac TnI is currently regarded as the most accurate biochemical marker of myocardial damage [7]; however, recent evidence suggests that not all of the postoperative serum cTnI release represents irreversible myocardial injury [14]. According to this theory, some of the troponin leak represents protein release from non-structurally bound cytosolic pools, rather than true myocardial necrosis. Therefore, a proportion of cTnI levels rise could be due to increased cellular permeability and not associated to structural myocardial damage. To increase the accuracy in detecting myocardial damage and dysfunction, further studies investigating the effects of preconditioning may couple the use of biochemical markers and new imaging techniques showing both viability and function [15].
In summary, this study demonstrates that IP can be safely and effectively induced also at hypothermia. Furthermore, it identifies the best modality of protecting the myocardium of patients undergoing CABG without cardioplegia: in a selected population of patients undergoing elective coronary revascularisation using ICCF, the combination of IP and moderate hypothermia results in significant reduction of myocardial damage, when compared to IP at normothermia or hypothermia alone. Further studies investigating the effects of hypothermia combined with pharmacological means of inducing myocardial preconditioning are warranted.
Acknowledgements
This study has been supported by a grant from the British Heart Foundation.
References
Eisen A, Fisman EZ, Rubenfire M, Freimark D, McKechnie R, Tenenbaum A, Motro M, Adler Y. Ischemic preconditioning: nearly two decades of research. A comprehensive review. Atherosclerosis 2004; 172:201–210.
Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet 1993; 342:276–277.
Jenkins DP, Pugsley WB, Alkhulaifi AM, Kemp M, Hooper J, Yellon DM. Ischaemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass surgery. Heart 1997; 77:314–318.
Keogh BE, Kinsman R. National Adult Cardiac Surgical Database Report 2001–2003 2004;Berkshire, UK: Dendrite Clinical Systems Ltd.
Boncheck LI, Burlingame MW, Vazales BE, Lundy EF, Gassmann CJ. Applicability of noncardioplegic coronary bypass to high-risk patients. J Thorac Cardiovasc Surg 1992; 103:230–237.
Teoh LK, Grant R, Hulf JA, Pugsley WB, Yellon DM. A comparison between ischemic preconditioning, intermittent cross-clamp fibrillation and cold crystalloid cardioplegia for myocardial protection during coronary artery bypass graft surgery. Cardiovasc Surg 2002; 10:251–255.
Noble JS, Reid AM, Jordan LV, Glen AC, Davidson JA. Troponin I and myocardial injury in the ICU. Br J Anaesth 1999; 82:41–46.
Vazquez-Jimenez JF, Qing M, Hermanns B, Klosterhalfen B, Woltje M, Chakupurakal R, Schumacher K, Messmer BJ, von Bernuth G, Seghaye MC. Moderate hypothermia during cardiopulmonary bypass reduces myocardial cell damage and myocardial cell death related to cardiac surgery. J Am Coll Cardiol 2001; 38:1216–1223.
Schwartz LM, Verbinski SG, Vander Heide RS, Reimer KA. Epicardial temperature is a major predictor of myocardial infarct size. J Mol Cell Cardiol 1997; 29:1577–1583.
Van der Veen FH, van der Vusse GJ, Willemsen P, Kruger RT, van der Nagel T, Coumans WA, Reneman RS. Changes in myocardial high-energy phosphate stores and carbohydrate metabolism during intermittent aortic crossclamping in dogs on cardiopulmonary bypass at 34 °C and 25 °C. J Thorac Cardiovasc Surg 1990; 100:389–399.
Cave CA, Hearse DJ. Ischaemic preconditioning and contractile function: studies with normothermic and hypothermic global ischaemia. J Mol Cell Cardiol 1992; 24:1113–1123.
Perrault LP, Menasche P, Bel A, de Chaumaray T, Peynet J, Mondry A, Olivero P, Emanoil-Ravier R, Moalic JM. Ischemic preconditioning in cardiac surgery: a word of caution. J Thorac Cardiovasc Surg 1996; 112:1378–1386.
Qing M, Vazquez-Jimenez JF, Schumacher K, Bhardwaj RS, Klosterhalfen B, Minkenberg R, Messmer BJ, von Bernuth G, Seghaye MC. Moderate hypothermia during cardiopulmonary bypass increases intramyocardial synthesis of heat shock protein 72. J Thorac Cardiovasc Surg 2002; 124:724–731.
Bleier J, Vorderwinkler KP, Falkensammer J, Mair P, Dapunt O, Puschendorf B, Mair J. Different intracellular compartmentations of cardiac troponins and myosin heavy chains: a causal connection to their different early release after myocardial damage. Clin Chem 1998; 44:1912–1918.
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