Perioperative myocardial infarction in coronary artery bypass graft (CABG) surgery has been the topic of several studies [1–12]. Despite this, many questions have remained unanswered concerning its aetiology, risk factors and clinical relevance. Two main reasons underlie the conflicting opinions in this field. The first relates to the diagnostic criteria for perioperative myocardial infarction. Basically, there are four options for assessing perioperative myocardial infarction: (a) electrocardiographic criteria (new Q-waves); (b) biochemical markers [myocardial fraction of creatine kinase (CK-MB), troponin-I and -T]; (c) echocardiographic criteria (wall motion abnormalities); and (d) technetium-99m pyrophosphate tomography. The above criteria can be used alone or in combination, but the rate of identified perioperative myocardial infarction greatly varies depending on the diagnostic technique chosen. Jain and his colleagues found a rate of 25% when the criterion was Q-wave, CK-MB, or autopsy; the incidence of perioperative myocardial infarction reduced to 4% when the criterion was Q-wave plus CK-MB or autopsy . Burns and his colleagues found a perioperative myocardial infarction rate of 21% using the technetium-99m pyrophosphate tomographic criterion; the rate fell to 3.1% on the basis of electrocardiographic criteria alone . Using a combined CK-MB and electrocardiographic criterion, Greaves and his colleagues found a perioperative myocardial infarction rate of 5% . Using a new Q-waves criterion, Spiess and his colleagues found a rate of 11.2% ; similar results were obtained by Svedjeholm and his colleagues – they found a 8.1% rate using an electrocardiographic criterion, a 1% rate when adding CK-MB, and 8.4% when troponin-T levels only were taken as a diagnostic criterion . Finally, Gensini and his colleagues used combined echocardiography and electrocardiography and found a rate of myocardial infarction of 19%, with a 100% sensitivity and specificity of troponin-I plasma values .
The second confounding factor is the direct consequence of the first, and deals with the clinical relevance of perioperative myocardial infarction. Patients with perioperative myocardial infarction, if they survive, have a worse late outcome, with higher rates of angina, new infarctions and mortality . The early consequences of myocardial infarction are less clearly established, and this seems to reflect the difficulty in using adequate diagnostic criteria. O'Connor and his colleagues, in a large series of 8641 CABG patients, found a 2.9% in-hospital mortality rate due to heart failure, with or without a diagnosis of perioperative myocardial infarction . Silber and his colleagues, in a series of 16 673 patients, identified an in-hospital rate of cardiac emergencies (including perioperative myocardial infarction) of 5.8%, leading to death in 1.6% of the patients . If the diagnostic criteria are strict, myocardial infarction-related in-hospital mortality is high, at around 2% . In case of death (fatal myocardial infarction), the two already mentioned confounding problems (clinical relevance and diagnosis) do not apply.
Fatal myocardial infarction is not only and obviously clinically relevant for the patient, but is also accompanied by a sequence of events implying human and economical efforts (re-operation, pharmacological and mechanical assistance, nursing). Moreover, in case of fatal myocardial infarction, a specific diagnosis is allowed, not only based on the classical criteria, but confirmed at autopsy or by direct observation of the infarcted myocardial region in case of re-operation.
The present study aims to determine patient- and procedure-related risk factors for fatal myocardial infarction after coronary artery bypass graft surgery.
This is a retrospective analysis of 1561 consecutive patients undergoing a coronary artery bypass graft operation in our Institution. All patients who received at least one coronary graft were been admitted to the study, including additional valve surgery or left ventricle aneurysmectomy, urgent procedures or failed percutaneous transluminal coronary angioplasty.
Intermittent antegrade cold (4°C) crystalloid cardioplegia and moderate (32°C) systemic hypothermia have been routinely used. One in situ internal mammary artery anastomosis was constructed on the left anterior descending coronary artery whenever feasible (98%). Two internal mammary artery grafts were used in 22 patients. The other obstructed vessels were grafted with a sequential aorto-coronary vein graft on the left side (marginal and diagonal vessels); the right-sided coronary vessels were revascularized with a single aorto-coronary venous graft.
Cardiopulmonary bypass (CPB) was established after heparinization with 300 IU porcine heparin and once the activated clotting time reached the target value of 450 s. The activated clotting time was measured with a celite-activating method, usually in a single determination. Anticoagulation was maintained with further heparin bolus administration (80 IU) whenever the activated clotting time fell below the target value. During cardiopulmonary bypass, the activated clotting time was checked every 20 min and was the only determinant of heparin administration. Considering our strategy of moderate hypothermia and haemodilution (priming volume 1000 mL), no compensation for hypothermia and haemodilution was applied. At the end of the cardiopulmonary bypass, heparin was antagonized with protamine sulphate at a 1:1 ratio.
The main purpose of the present study was to investigate the potential risk factors for fatal myocardial infarction after coronary surgery. To detect the patients suffering from fatal myocardial infarction the following criteria were applied:
(a) The event must have occurred during the early postoperative course (within 48 h from the end of the operation).
(b) The event must have been responsible for the death of the patient directly or after a prolonged low output state due to an infarction-dependent myocardial dysfunction.
(c) All the patients who died with a diagnosis of myocardial infarction had a significant ST-segment elevation at the electrocardiogram followed, when time allowed, by new Q-waves and an elevation of CK-MB isoenzyme greater than 130 IU L−1 (local criteria for the diagnosis of perioperative myocardial infarction). The diagnosis of myocardial infarction was always confirmed through a post-mortem examination or a direct observation of the heart and the grafts if the patient was re-operated.
The following patient-related variables were collected: (a) continuous variables: age, weight, platelet count, activated partial thromboplastin time, prothrombin activity, haematocrit, fibrinogen concentration, heparin sensitivity index. A heparin sensitivity index was calculated according to the activated clotting time after the loading dose of heparin: a heparin sensitivity index = (activated clotting time postheparin – baseline activated clotting time)/heparin loading dose (IU kg−1), according to the criterion published by Dietrich and coworkers . (b) binary (yes/no) variables: gender, ejection fraction < 0.30, diabetes, left main obstruction ≥ 50%, presence of a calcified ascending aorta, preoperative anticoagulation with subcutaneous heparin (a daily dosage ranging from 5000 to 25 000 IU fractionated in two or three doses for at least 1 week until the day of surgery) or intravenous heparin (a daily dosage of 24 000 IU in a continuous infusion for at least 2 days and until the day of surgery).
The following procedure related variables were collected: (a) continuous variables: total heparin dose, time of cardiopulmonary bypass. time of aortic cross-clamping, number of distal anastomoses; (b) binary (yes/no) variables: failed percutaneous transluminal coronary angioplasty, redo surgery, the need for an anterior left descending thromboendarterectomy; associated procedures (valve or left ventricle aneurysmectomy). Additionally, we considered the surgeon and the anaesthesiologist as discrete variables being potential risk factors.
Variables, before and during surgery, were analysed in an univariate way with a two-sided unpaired Student's t-test for continuous variables and a Pearson's χ2-test or relative risk analysis for binary variables. Linearity of the correlation for continuous variables was checked using a locally weighted scatter-plot technique. When appropriate cut-points were detectable (age and a heparin sensitivity index), continuous variables were transformed to binary variables and consequently tested. All the variables that correlated with fatal myocardial infarction with a P-value < 0.1 were considered as potential risk factors and admitted to a subsequent stepwise multivariate logistic regression analysis. As the result of this analysis is expressed as an odds ratio, it is presented with a 95% confidence interval and can be interpreted as an approximation of a relative risk. Variables being correlated with fatal myocardial infarction with a P-value < 0.05 were considered risk factors for the event. Statistical analysis was performed using a statistical software package (SPSS-PC, SPSS Inc, Chicago, IL, USA).
Fatal myocardial infarction occurred in 41 (2.6%) patients. Overall mortality was 4.2%. After the onset of myocardial infarction, death occurred within a period of time ranging from a few hours to 47 days. Twenty-five patients underwent an immediate re-operation due to the severity of the haemodynamic conditions. Five patients underwent a transluminal angioplasty. All patients received intra-aortic balloon pump assistance and inotropic support; four patients were treated with a continuous flow left ventricle assistance; 13 patients died within 24 h due to cardiac arrest; 21 patients died within the following 9 days due to a low cardiac output syndrome; seven died in the following period due to a multiple organ failure associated with low cardiac output syndrome.
Discrete variables (surgeon and anaesthesiologist) did not correlate with fatal myocardial infarction.
Factors being associated with fatal myocardial infarction in the univariate analysis (Tables 1 and 2, P < 0.1) were age (0.09), heparin sensitivity index (0.09), thromboendarterectomy of the left anterior descending coronary artery (0.002), ejection fraction < 0.3 (0.057), preoperative use of intravenous (0.051), subcutaneous (0.055) or any kind of heparin therapy (0.004), age greater than 65 years (0.06) and a heparin sensitivity index < 1.3 (0.004). The relative risk values for fatal myocardial infarction at the univariate analysis are shown in Table 3 for the above variables.
At the stepwise multivariate logistic regression analysis (Table 4), three independent risk factors for fatal myocardial infarction could be identified: preoperative use of any kind of heparin (odds ratio 2.06); heparin sensitivity index < 1.3 (odds ratio 2.0) and a thromboendarterectomy of the left anterior descending coronary artery (odds ratio 5.51).
The intraoperative heparin requirements were explored in patients receiving heparin pretreatment vs. patients who did not receive heparin pretreatment. The first group needed significantly more heparin (26 357 ± 6495 IU vs. 24 464 ± 5.342 IU, P = 0.001). The same analysis was carried out for patients with a heparin sensitivity index < 1.3 vs. patients with a heparin sensitivity index ≥ 1.3. The first group needed significantly more heparin than the second group (26 245 ± 6957 IU vs. 24 543 ± 5218 IU, P = 0.001).
This is a retrospective study, with no prespecified hypothesis and, of course, no randomization; therefore, the results of the risk analysis are less certain compared with a prospective randomized trial. The rate of patients with fatal myocardial infarction in our series (2.6%) is consistent with the data from the literature, given the definition of fatal myocardial infarction as perioperative myocardial infarction accompanied by a low cardiac output state leading to death. This definition is less inclusive than ‘mortality due to cardiac event’ which, in a recent study, had a rate of 2.9% . In our series, we had a 0.5% mortality due to cardiac events in the absence of myocardial infarction, thus reaching an overall mortality due to cardiac events of 3.1%.
We are not aware of studies searching for fatal myocardial infarction risk factors; conversely, there is a great body of literature about risk factors for perioperative myocardial infarction regardless of its consequences. Spiess and his colleagues could identify four predictors for perioperative myocardial infarction: a haematocrit value ≥ 34% upon arrival in the Intensive Care Unit, age > 70 years, a previous myocardial infarction and a history of smoking . Burns and his colleagues identified two predictors: preoperative New York Heart Association class, and smallest grafted distal vessel lumen calibre . Slogoff and Keats highlighted the importance of intraoperative events, demonstrating that perioperative myocardial ischaemia and tachycardia significantly correlated with perioperative myocardial infarction . Eritsland and his colleagues found that a small body surface area was a predictor for perioperative myocardial infarction . Greaves and his colleagues identified four independent predictors for perioperative myocardial infarction: emergency procedure, aortic cross-clamping time, recent myocardial infarction and redo surgery . In their large series, Sergeant and his colleagues identified four predictors for perioperative myocardial infarction: thromboendarterectomy of the left anterior descending coronary artery, unstable angina, incomplete revascularization and absence of arterial grafts . From these data, the confounding nature of this topic is confirmed, being only one risk factor quoted by more than one single author (recent myocardial infarction). The retrospective nature of the present work did not allow us to include in our model all the factors mentioned in other studies. In particular, haematocrit upon arrival in the Intensive Care Unit, smoking history, previous myocardial infarction, quality of the revascularization and intraoperative events were not considered in our multivariate model. In our series, we could identify three independent risk factors for fatal myocardial infarction: thromboendarterectomy of the left anterior descending coronary artery, preoperative use of heparin and a heparin sensitivity index < 1.3.
A thromboendarterectomy of the left anterior descending coronary artery carries a fivefold relative risk of mortality due to myocardial infarction, confirming the data from Sergeant and his colleagues . The main reason for this may be an enhanced likelihood of native coronary thrombosis or early internal mammary artery graft closure, or both. The preoperative anticoagulation profile and/or the heparin sensitivity of the patient seem to be associated to fatal myocardial infarction. Patients receiving preoperatively either subcutaneous or intravenous heparin have a twofold relative risk for fatal myocardial infarction. In our study, no patient received low molecular weight heparin. If considered separately, the two variables (subcutaneous/intravenous heparin) were both not statistically significant and had the same degree of correlation with fatal myocardial infarction (FMI), but intravenous heparin carries a slightly higher relative risk (2.28 vs. 1.89). Only the use of any kind of heparin, regardless of the method of administration, was identified as a statistically significant independent risk factor for fatal myocardial infarction, with a relative risk of 2.06. Preoperative heparin therapy may be responsible for heparin resistance during cardiopulmonary bypass [15–17]: the majority of authors ascribe this effect to a chronic antithrombin-III consumption [15,17,18], but other mechanisms have been claimed. Other possible mechanisms involved in heparin resistance after heparin therapy are an enhancement of factor VIII activity  and heparin-induced thrombocytopenia .
Many authors pointed out the possible thromboembolic risks in case of heparin resistance [15,17]. An inadequate response to heparin may lead to catastrophic coagulation of the extracorporal circulation circuit and also to postoperative coagulation of the peripheral vascular system . Concerning the possible relationship between heparin resistance and perioperative myocardial infarction, there are a few case reports suggesting early closure of native coronary vessels distal to the anastomoses [22,23]. Unfortunately, despite the possible correlation between preoperative heparin use, heparin resistance and perioperative myocardial infarction, the preoperative coagulation profile has not been considered as a possible risk factor in the previously published risk analyses for perioperative myocardial infarction.
In our series, this chain of events seems to be important in determining fatal myocardial infarction. As a matter of fact, the third independent predictor for fatal myocardial infarction was a heparin sensitivity index < 1.3, that included all the patients with any pattern of heparin resistance. A heparin sensitivity index cannot be considered as an absolute index: as the relationship between heparin loading dose and activated clotting time raise is not linear, the value of 1.3 can be considered as an adequate cut-off point only when the heparin loading dose is 300 IU kg−1. Protocols, including a loading dose of 375 IU kg−1, recognize lower values of a heparin sensitivity index as being suggestive for heparin resistance . In our model, a heparin sensitivity index < 1.3 is in an independent risk factor for fatal myocardial infarction, regardless of preoperative heparin administration, thus suggesting that other mechanisms may be implicated in heparin resistance. Regardless of the mechanism, patients with a reduced sensitivity to heparin (whether or not preoperatively treated with heparin) require higher doses of intraoperative heparin to reach and to maintain the target activated clotting time (ACT) value. In our series, patients with a heparin sensitivity index < 1.3 received more heparin than patients with an index ≥ 1.3; the same was true for patients pretreated with any kind of heparin.
In both these subpopulations, and moreover when both the risk factors (heparin pretreatment and heparin sensitivity index < 1.3) are present, a postoperative hypercoagulation profile is likely to occur, due to the intraoperative antithrombin-III consumption (which normally determines a decrease in antithrombin-III functional activity of about 30%  but that can be magnified by an overuse of heparin ) in patients often demonstrating reduced levels of antithrombin-III before surgery . This hypercoagulability state may increase the risk of native coronaries and/or graft thrombosis whenever the run-off below the anastomoses is suboptimal. The patients in our study have not been randomized for preoperative heparin treatment; therefore, we must be cautious in drawing the conclusion that heparin pretreatment is a risk factor for fatal myocardial infarction. There is the possibility that patients receiving the drug are sicker than the others, and then much more prone to FMI. In Table 5, we have stressed this point, comparing the perioperative profile of patients receiving intravenous or subcutaneous heparin or no heparin. Patients receiving intravenous heparin had a higher rate of left main coronary vessel obstruction; patients receiving subcutaneous heparin had a higher rate of redo surgery; both groups had a higher fibrinogen level, a lower heparin sensitivity index, a longer activated partial thromboplastin time (reflecting the effectiveness of the preoperative anticoagulant therapy) and a higher number of times with an activated clotting time < 450 s (reflecting the heparin-resistant pattern and the need for more intraoperative heparin). So, the perioperative profile of patients receiving heparin seems to be different; anyway the presence of left main coronary vessel obstruction and redo surgery were not risk factors for fatal myocardial infarction in our study. On the basis of our data we cannot conclude that the higher rate of fatal myocardial infarction observed in heparin pretreated patients was due to the preoperative underlying risk or to the treatment itself. Conversely, the evidence that preoperative heparin therapy induces a ‘procoagulant’ effect (heparin resistance and high fibrinogen concentrations) concurs in suggesting a possible role of this therapy in determining a fatal myocardial infarction. In conclusion, this study suggests that the rate of fatal myocardial infarction is higher whenever a patient receives a thromboendarterectomy of the left anterior descending coronary artery, preoperative heparin treatment, or has a reduced sensitivity to heparin.
We are indebted to Alessandra Boncilli, CCP, Simonetta Brozzi, CCP, Giorgia Vancini, CCP, Mauro Cotza, CCP and Antonio Ditta, chief of the CCP team, for their help in collecting data.
We are also indebted to Daniela Conti, MD, Muriel Ceccopieri, MD and Ermanno Mazza, MD for their invaluable clinical effort in assisting our patients.
This paper is dedicated to 41 patients in our Institution.
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