Eur J Cardiothorac Surg 2009;35:48-53. doi:10.1016/j.ejcts.2008.10.004
Copyright © 2009, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
Presence of coronary collaterals is associated with a decreased incidence of cognitive decline after coronary artery bypass surgery
Jan Dielemana,*,
Anne-Mette Sauëra,
Catharina Klijnb,
Hendrik Nathoec,
Karel Moonsd,
Cornelis Kalkmana,
Jaap Kappelleb,
Diederik Van Dijka
a Division of Perioperative Care and Emergency Medicine, University Medical Center Utrecht, The Netherlands
b Department of Neurology, University Medical Center Utrecht, The Netherlands
c Department of Cardiology/Heart Lung Center Utrecht, University Medical Center Utrecht, The Netherlands
d Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands
Received 18 July 2008;
received in revised form 8 October 2008;
accepted 9 October 2008.
* Corresponding author. Address: Division of Perioperative Care and Emergency Medicine, Heidelberglaan 100, Mail stop Q04.2.313, 3584 CX Utrecht, The Netherlands. Tel.: +31 88 7555555; fax: +31 30 2541828. (Email: S.Dieleman{at}UMCUtrecht.nl).
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Abstract
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Objective: Coronary artery bypass grafting (CABG) is associated with significant cerebral morbidity, usually manifested as cognitive decline or stroke. The underlying mechanism leading to cognitive decline is still unclear. Presence of coronary collateral arteries, which may reflect an overall better cardiovascular condition, recently appeared to relate to a better cardiac outcome after CABG. In this study, we investigated the hypothesis that presence of coronary collaterals is associated with less cognitive decline after coronary artery bypass grafting. Methods: Data from 281 patients undergoing first-time coronary artery bypass grafting were used. Presence of coronary collaterals was determined on the preoperative angiogram. Cognitive function was evaluated before the operation, at 3 and 12 months and 5 years thereafter by standardised neuropsychological assessment. Cognitive decline in individuals was determined by calculating the reliable change score, a cognitive change score corrected for natural testing variability and practice effects. Results: Cognitive decline was found in 19 (8%) patients at 3 months, in 31 (12%) patients at 12 months and in 82 (34%) at 5 years follow-up. Presence of coronary collaterals was independently associated with a better cognitive outcome at both 3 months (odds ratio (OR) 0.30; 95% confidence interval (CI) 0.09–0.95; p
= 0.04) and 12 months (OR 0.42; 95% CI 0.18–0.97; p
= 0.04) after coronary artery bypass grafting. At 5 years, the OR was 0.57 (95% CI 0.31–1.05; p
= 0.07). Conclusions: In patients undergoing first-time coronary artery bypass grafting, presence of coronary collaterals is associated with a decreased risk of cognitive decline at both 3 and 12 months of follow-up. This trend persists at 5-year follow-up. Preoperative differences in the cardiac vascular condition may therefore predict cognitive outcome in patients undergoing coronary artery bypass grafting.
Key Words: Cognitive decline • Collateral circulation • Coronary artery bypass surgery
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1. Introduction
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Coronary artery bypass grafting (CABG) effectively relieves angina, but is complicated by postoperative cognitive decline. The incidence of cognitive decline varies from 3 to 50%, depending on patient characteristics, definition of decline, and timing of neuropsychological assessment [1]. Only in about 3% of CABG patients can the cognitive decline be attributed to perioperative stroke [1,2]. Although the degree of cognitive decline, as measured with extensive test batteries, does not always affect patients in functional terms, a proportion of patients experiences difficulties during postoperative rehabilitation or problems with return to employment [1].
Cerebral damage following CABG procedures has mainly been attributed to the use of cardiopulmonary bypass. To address these limitations of conventional bypass surgery (on-pump CABG), beating heart bypass surgery (off-pump CABG) has been reintroduced in clinical practice. In the Octopus trial, a small beneficial effect on cognitive outcome of off-pump CABG was demonstrated 3 months after surgery, but this effect became negligible after 12 months [3,4]. However, we recently demonstrated that patients with coronary collateral circulation who underwent off-pump CABG had a better cardiac outcome both perioperatively and at 1 year than patients without coronary collaterals [5]. This may be attributed to the nature of the off-pump technique, during which the target vessel is temporarily occluded. In the presence of coronary collateral vessels this temporary occlusion most likely results in less cardiac ischaemia and thus in a better overall cardiovascular condition.
Consequently, we hypothesised that patients with extensive coronary collateral circulation might also have an improved capacity to maintain adequate cerebral perfusion, resulting in less cognitive decline than in patients without collaterals. We therefore reanalysed the neurocognitive data from the Octopus trial [3] and studied, to our knowledge for the first time, if there is also a relationship between the presence of coronary collaterals and postoperative neurocognitive test performance.
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2. Methods
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2.1 Study population
The study population consisted of the patients enrolled in the Octopus study [3]. In this study, 281 patients were randomly assigned to on-pump or off-pump CABG. Patients were eligible if referred for first-time isolated CABG and if the off-pump procedure was technically feasible. The study was approved by the institutional review committees of the three participating centres and was performed according to institutional guidelines. All subjects gave informed consent before participation. The present analysis was based on data from all 281 patients and adjustment was made for type of surgery (i.e. on-pump or off-pump treatment) as a possible confounder in the multivariable analysis.
2.2 Coronary collaterals
The presence of coronary collaterals was defined by visual assessment of the baseline angiogram using the Rentrop criteria (0, no filling of collaterals; 1, filling of collaterals without any filling of the epicardial artery; 2, partial filling of the epicardial artery; and 3, complete filling of the epicardial artery) [6]. Collaterals were considered present in case of filling of the epicardial artery (Rentrop > 1). The angiograms were independently graded in random order by two cardiologists who were blinded to clinical and each other's data. The reproducibility of the Rentrop score has been described as high (
= 0.85, 95% CI 0.77–0.93) [6].
2.3 Cognitive outcome
Patients underwent a battery of 10 neuropsychological tests 1 day before, 3 and 12 months and 5 years after the operation. All tests were administered in the participating hospitals by trained neuropsychologists.
In accordance with the Statement of Consensus on Assessment of Neurobehavioral Outcomes after Cardiac Surgery [7], the battery included tests for motor skills, verbal memory capacity, and attention. In addition, tests were included to assess speed and capacity of working memory, visuospatial capacity, selective and sustained attention, and information processing. Each test yielded 1 or more variables, with different ranges per variable. Eleven main variables were chosen a priori to be used in the analyses. The cognitive domains that were covered, the tests, and the main variables are listed in Table 1
. Administration of the tests lasted approximately 100 min. To limit practice effects, 6 of the 10 tests were also administered 2 weeks before baseline assessment and, wherever possible, parallel forms of the tests were used in the consecutive assessments.
To determine the absence or presence of cognitive decline, each individual patient's postoperative cognitive performance was compared to his or her preoperative cognitive performance. The presence of cognitive impairment in individuals was determined by calculating a reliable change (RC) score, a standardised cognitive change score corrected for natural testing variability and practice effects [4,8,9]. To calculate an RC score, parallel cognitive test data from a non-operated control group were used. This control group has been described in detail elsewhere [4].
For each patient, scores at baseline, 3 and 12 months and 5 years postoperatively from each test were used to calculate the RC score as follows: RC = (postoperative score – baseline score) – (practice effect estimated from controls)/(standard deviation of difference scores estimated from control group). Cognitive decline was defined as a composite RC equal to or less than –1.96 or an RC equal to or less than –1.96 in two or more main variables. For analytical purposes, patients who had a stroke or had developed severe dementia were considered to have cognitive decline.
In the original report of the Octopus trial, a different definition of cognitive decline (a decrease in an individual's performance of at least 20% from baseline, in at least 20% of the main variables; the ‘standard’ definition) was used [3]. This definition was later shown to overestimate the incidence of cognitive decline [4].
2.4 Data analysis
The association between presence of collaterals and cognitive decline after 3 and 12 months and 5 years was examined by first calculating a crude odds ratio (95% confidence interval). Then the distribution of the most important confounders (i.e. age, sex, diabetes, hypertension, number of coronary artery grafts, postoperative myocardial infarction and off-pump vs on-pump treatment) across the patients with and without collaterals was quantified. We also quantified the association of these potential confounders with the outcome. Finally, we estimated the association between the presence of collaterals and the outcome, adjusted for the potential confounders using multivariable logistic regression analysis. Risks are presented as odds ratios (OR) with 95% confidence interval. All reported probability values are two-sided. Probability values <0.05 were considered statistically significant. All data were analysed using SPSS for Windows v12.0.
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3. Results
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Baseline characteristics of the patients are shown in Table 2
. Coronary collaterals were present on the angiogram in 46% of the patients. Possible confounders were equally distributed over the determinant categories, with exception of myocardial infarction (Table 2). As reported previously by Nathoe et al. [5], myocardial infarction occurred more often in the group without coronary collaterals. Three patients suffered from a perioperative stroke: two in the group with collaterals and one in the group without collaterals. The mean interval between operation and 3-month follow-up was 94 (SD 14) days, 379 (SD 57) days at 12-month follow-up, and 62 (SD 3) months at 5-year follow-up. Three months after surgery, 19 (8%) of 248 patients available for follow-up had cognitive decline. At 12 months, cognitive decline was present in 31 (12%) of 252 patients available for follow-up. Five years after surgery, 82 (34%) of 240 patients available for follow-up had cognitive decline.
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Table 2 Baseline patient characteristics and distribution of possible confounders between patients with and without collaterals.
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3.1 Relation between coronary collaterals and cognitive outcome (Tables 3 and 4)
At 3 months, cognitive decline occurred in 4 (3%) of the patients with coronary collaterals, versus 15 (12%) of the patients without collaterals (OR 0.26; 95% CI 0.09–0.82; p
= 0.02). After adjusting for age, sex, diabetes, hypertension, number of grafts, treatment type (i.e. on-pump or off-pump surgery) and myocardial infarction, the OR was 0.30 (95% CI 0.09–0.95; p
= 0.04). At 12 months, cognitive decline was present in 9 (7%) of the patients with coronary collaterals, compared to 22 (17%) of the patients without collaterals (OR 0.40; 95% CI 0.18–0.90; p
= 0.03). After adjusting for age, sex, diabetes, hypertension, number of grafts, treatment type and myocardial infarction, the association between collaterals and cognitive decline remained (OR 0.42; 95% CI 0.18–0.97; p
= 0.04). At 5 years, cognitive decline was present in 31 (27%) of the patients with coronary collaterals, compared to 51 (41%) of the patients without collaterals (OR 0.55; 95% CI 0.31–0.95; p
= 0.04). After adjusting for age, sex, diabetes, hypertension, number of grafts, treatment type and myocardial infarction, there was still a trend towards an association between collaterals and cognitive decline, although not significant (OR 0.57; 95% CI 0.31–1.05; p
= 0.07)
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3.2 Missing data
Cognitive outcome data could not be obtained in 33 (12%) patients at 3 months, in 29 (10%) patients at 12 months and in 41 (15%) patients at 5 years of follow-up. Reasons for not obtaining neuropsychological test data are summarised in Table 5
. The characteristics of the patients who were available for analysis of cognitive outcome were comparable to the patient characteristics of the entire sample, indicating that the missing data were completely random. Still, to determine whether there was some bias in our data due to selective loss to follow-up, we imputed all missing cognitive outcomes by means of multiple imputation available in S-plus for Windows v7.0. After imputation, the odds ratios for cognitive decline at 3 months (OR 0.29; 95% CI 0.10–0.86), 12 months (OR 0.42; 95% CI 0.19–0.95) and 5 years (OR 0.60; 95% CI 0.34–1.05) were comparable to the odds ratios of the complete case analysis.
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4. Discussion
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We found an association between the presence of coronary collaterals and a lower incidence of postoperative cognitive decline at 3 and 12 months and 5 years after surgery in coronary artery bypass surgery patients. This association remained significant after adjustment for the most important possible confounders at 3 and 12 months, but not at 5 years of follow-up. Nevertheless this indicates that the absence of coronary collaterals might be relevant to cognitive outcomes in both short and long term.
Previous studies on coronary collaterals have either looked at possible determinants of their presence or focused on their effect on cardiac outcomes [5,10–13]. The forming rate of coronary collaterals has been demonstrated to increase with the severity of stenotic disease of the coronary arteries [14]. Also, several mechanisms have been identified that enhance coronary collateral formation, most of which appear to have a genetic basis [15–17]. From the available evidence it seems likely that different patients will have different ‘phenotypes’ of vascular plaque formation and stability, leading to varying stimuli for collateral vessel formation. On the outcomes level, the presence of collaterals increases myocardial viability following infarction and recent studies have shown that coronary collateral circulation favours long-term cardiac outcome in patients undergoing percutaneous cardiac interventions and off-pump cardiac surgery [5,13]. However, the association between coronary collaterals and cognitive outcome has never been studied before.
Little is known of the relationship between the presence of coronary collaterals on the one hand and the ability to utilise collateral pathways in the brain on the other. In patients with significant stenosis in the carotid or vertebral arteries, alternative routes of blood flow to specific brain regions are utilised. These collateral pathways may involve the circle of Willis, leptomeningeal vessels, the ophthalmic artery and other more rare connections. Often, cardiovascular disease has affected multiple vessels and organs in patients scheduled for CABG. For example, concomitant carotid artery stenosis is present in up to 50% of these patients [18–20]. It is thus conceivable that coronary artery disease is, at least in part, related to cerebrovascular pathology and that the ability to create collaterals in the heart is associated with the same process in the brain.
Cerebral injury after cardiac surgery has been largely attributed to either insufficient brain perfusion or multiple-cause embolism during the procedure [21,22]. Consequently, a sufficiently developed intracranial collateral blood supply theoretically reduces cerebral injury by protecting watershed areas that are most susceptible to infarction, and by limiting the size of an ischaemic area following embolic vessel occlusion. In parallel with the results obtained in cardiac studies [5,13], the presence of intracranial collateral circulation in patients with severe carotid artery stenosis has been associated with a better clinical outcome: these patients have a lower risk of stroke or transient ischaemic attacks, and generally a better functional recovery following an ischaemic event [23]. It is therefore conceivable that the presence of cerebral collaterals will also positively influence neurocognitive outcome following cardiac surgery. From another perspective, it can also be argued that coronary collaterals preserve myocardial function, and consequently lead to a better cardiac output. During and after surgery, a favourable cardiac output will most likely improve end-organ perfusion, and thus cerebral blood flow. This leads to a lower risk of insufficient brain perfusion and to reduced injury from embolic events, which in turn results in a better cognitive outcome.
One step beyond, in patients with symptomatic systemic atherosclerotic disease, collateral vessel formation will probably be enhanced in both cardiac and cerebral tissue, by either recruitment of pre-existing pathways or by formation of new vessels. At least on the level of the smaller vessels, genetic predisposition in favour of formation of new vessels could play an important role here. This could be one of the mechanisms underlying the observed association between coronary collaterals and a better cognitive outcome in our study [24]. In the present study population, the only genetic polymorphisms that were assessed are variants of the apolipoprotein E (ApoE) gene locus. However, no association could be demonstrated between either cardiac collaterals or cognitive outcome and ApoE polymorphisms in this group of patients (data not shown).
In the current analysis, data were used from all patients originally included in the Octopus study (i.e. patients from both the on-pump and the off-pump treatment arms). Although for a long time cerebral injury following CABG has mainly been attributed to the use of cardiopulmonary bypass, several recent randomised studies (including our own) were unable to demonstrate a beneficial effect of off-pump CABG on cognitive outcome [3,25]. We therefore believe that using data from both on-pump and off-pump patients is justifiable, as long as treatment type (i.e. on-pump or off-pump surgery) is corrected for in a multivariable analysis.
In contrast with the original report of the Octopus study, we have now applied a more conservative definition of cognitive decline for the analysis of cognitive test scores. Using this definition, cognitive performance in operative patients is compared to cognitive performance in simultaneously tested patients in a matched non-operative control group, to take into account natural fluctuations in test performance [3]. In a recently published re-analysis of the Octopus data [4] as well as in other recent reports [9] it was shown that the previously used standard definition may overestimate the incidence of cognitive decline. Because misclassification of patients with cognitive decline decreases statistical power, we chose to use this more conservative definition of cognitive decline in the current analysis.
A limitation of this study is that the study population may not be representative for the average patient population undergoing CABG. The young age (61 years on average) [3], the patients’ eligibility for off-pump surgery and the relatively low incidence of cognitive decline during the follow-up period, disclose that the study population was at a relatively low risk for postoperative complications and cognitive deterioration. Another limitation is that, due to the relatively long testing time (100 min), subjects could have underperformed on the baseline tests, resulting in a too low estimate of the true incidence of cognitive decline. Finally, we had no information on the presence of carotid or vertebral artery stenosis in these patients. Patients with haemodynamically significant stenosis in the cerebropetal vessels may have been more at risk of cognitive deterioration after CABG.
Although the associations found in this study are strong, there is always the risk that this observation is a statistical phenomenon rather than the clinical result of an underlying mechanism by which coronary collaterals relate to a decreased risk of postoperative cognitive decline. The present study is based on a post-hoc analysis and the original Octopus study was not designed to evaluate the possible association between coronary collaterals and cognitive outcome. Therefore, these results must be interpreted with care, and must be considered primarily hypothesis generating. Future studies need to clarify possible underlying mechanisms, and should confirm whether or not this association is clinically useful in predicting the risk of cognitive deterioration after CABG.
We conclude that in patients undergoing first-time CABG surgery, presence of coronary collaterals is associated with a decreased risk of cognitive decline at both 3 and 12 months of follow-up. Moreover, a trend remained present at 5 years. Preoperative differences in the cardiac vascular condition may therefore predict cognitive outcome in patients undergoing CABG surgery.
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Footnotes
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Jan Dieleman is supported by a grant from the Netherlands Heart Association (grant number 2007B125); Catharina Klijn is supported by a clinical fellowship from The Netherlands Organization for Health Research and Development (grant number 907-00-103) and by a grant from the Netherlands Hearth Association (grant number 2003B263).
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Abstract
1. Introduction
