The high prevalence of aortic atheromas in stroke

Transcription

1 The Topography of Aortic Atherosclerosis Enhances Its Precision as a Predictor of Stroke Jan van der Linden, MD, PhD, Per Bergman, MD, PhD, and Leonidas Hadjinikolaou, MD, FRCS Karolinska Institute, Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Sweden Background. Atherosclerosis of the thoracic aorta is an independent risk factor for stroke after cardiac surgery. No attention had so far been paid to its topography. The relationship between the topography of aortic atherosclerosis and stroke was studied in patients admitted for coronary surgery. Methods. The extent and location of atherosclerosis in the ascending aorta and arch was assessed intraoperatively with epiaortic ultrasound and transesophageal echocardiography in 611 consecutive patients. They were followed for years (mean SE), amounting to 3,358 patient-years. Results. The incidence of early postoperative (<30-day) stroke was 6.4% in patients with atherosclerosis of the ascending aorta and 1.5% in those without (p 0.004). The five-year stroke-free survival rates (>30 days after the operation) for patients without aortic disease, with less than 50%, and with greater than 50% of the ascending aorta affected, were %, %, and %, respectively (p < ). Conclusions. Atherosclerosis of the ascending aorta stands out as a predictor of late stroke. High risk is predominantly linked to atheromas in its distal part and lesser curvature. (Ann Thorac Surg 2007;83: ) 2007 by The Society of Thoracic Surgeons The high prevalence of aortic atheromas in stroke patients [1, 2], as well as the high incidence of stroke in patients with such atheromas [3 5], bears witness to the close connection between atherosclerosis of the thoracic aorta and stroke. The connection looms large in coronary surgery because aortic atheromas occur in about 25% of patients [6]. While methods are available to reduce the risk of procedure-related stroke, the risk of late stroke can only be eliminated by replacement surgery that carries increased risks itself. To increase the precision with which the risk of late stroke can be estimated the search is on for additional information about the predictive value of aortic atheromas. As part of that search, the present prospective study follows patients with coronary heart disease and focuses on the topography of the atheromas. Patients and Methods This study is based on longer term follow-up of a subset of patients from an earlier study on postoperative stroke [6]. The local Hospital Ethics Committee approved the study and informed written consent was obtained from all patients. We prospectively studied 611 consecutive patients undergoing coronary surgery. Both acute and Accepted for publication Feb 7, Address correspondence to Professor van der Linden, Karolinska Institute, Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, S , Sweden; janvan@ki.se. elective cases were enrolled. All patients had permanent residence in Sweden. Patients with asymptomatic carotid bruits or a history of stroke and (or) transient ischemic attacks who were found to suffer from significant carotid stenosis ( 50% decrease in diameter, n 25) were excluded from the study. However, patients with a history of stroke without significant carotid disease were included. After induction of anesthesia, all patients were evaluated by an experienced anesthetist with transesophageal echocardiography (TEE) with a multiplane probe (Hewlett Packard Sono 1500, Andover, MA) according to a standard protocol. Apart from the study of the heart, special attention was paid to the ascending aorta, aortic arch, and descending aorta with regard to atherosclerotic changes. After a median sternotomy, the surgeon carefully examined the ascending aorta by digital palpation and by epiaortic ultrasound. Epiaortic ultrasound was performed with an ultrasound scanner (Site-Rite II, 9.0 MHz, Dymax Corporation, Pittsburgh, PA) [6]. The TEE was not applied for visualization of plaques in the ascending aorta. All operations were performed with conventional coronary artery bypass methods, including cannulation of the ascending aorta and right atrium, mildly hypothermic cardiopulmonary bypass at a flow of 2.4 L/m 2 or greater, and myocardial protection with antegrade and (or) retrograde blood cardioplegia. Bypass conduits included one or two internal thoracic arteries and vein grafts and all proximal anastomoses were placed on the ascending aorta. Various minor procedural changes were 2007 by The Society of Thoracic Surgeons /07/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 2088 VAN DER LINDEN ET AL Ann Thorac Surg AORTIC ATHEROSCLEROSIS TOPOGRAPHY PREDICTS STROKE 2007;83: adopted on the basis of the findings of the epiaortic ultrasound. These included changes in the position of the aortic cross-clamp, the placing of the aortic and cardioplegia cannulas, and the site of the proximal anastomoses in order to avoid direct manipulation of atheromas. Clinical demographics were prospectively recorded. For the mapping of the atherosclerotic disease in the ascending aorta, transverse and longitudinal images were obtained from the level of the aortic root to the level of the proximal arch, just distal to the innominate artery. The ascending aorta was divided into three equal transverse (proximal, middle, and distal third) and four equal longitudinal segments (anterior, posterior, right, and left). Extensions of atheromas into the proximal arch, beyond the origin of the innominate artery, were classified as aortic arch disease. The presence of ascending aortic atheroma (intimal thickening 0.5 mm) and calcification were recorded for every segment. Extent of disease was defined as the number of segments concomitantly involved. The definitions and the diagnosis of postoperative stroke have earlier been described in detail [6]. Late stroke was defined as a stroke occurring greater than 30 days after coronary surgery. All 611 patients were followed up for late stroke by individual and systematic review of medical records of our hospital. After obtaining the permission from the Epidemiologic Center at the National Board of Health and Welfare and the Local Ethics Committee (Feb 2, 2003), follow-up information was retrieved from the National Swedish Database on mortality and stroke. A register of all hospital discharge diagnoses from all hospitals in Sweden was used to identify patients who were hospitalized outside Stockholm and treated for stroke (ICD-10; I63). Statistical Analysis The Kaplan-Maier with log-rank test and Cox multiple regression analysis (stepwise forward model with clinically relevant variables) were used to analyze follow-up data. Differences between groups were evaluated with one-way analysis of variance. The Student t test and 2 analysis were used when appropriate. Results were expressed as mean standard error. Odd ratios (OR) and Table 1. Demographic Data (n 611) Age (years) Gender (male) 78.2% Hypertension 54.2% Diabetes mellitus 19.6% Hypercholesteremia 43.5% Intermittent claudication 6.4% History of stroke 5.7% Reoperation 1.0% Ascending aortic atherosclerosis a 23.1% Aortic arch atherosclerosis a,b 27.3% Descending aortic atherosclerosis b 36.0% a Identified by epiaortic ultrasound. echocardiogram. b Identified by transesophageal Table 2. Epiaortic Scan Findings (n 141) Ascending aorta calcification 36.2% Extent of atherosclerotic disease in the ascending aorta 1 segment 52.5% 2 segments 25.5% 3 12 segments 21.3% Topography Distal third: Anterior 50.4% Posterior 29.8% Right 14.9% Left 11.3% Middle third: Anterior 19.1% Posterior 24.8% Right 10.6% Left 11.3% Proximal third: Anterior 14.9% Posterior 14.2% Right 7.1% Left 7.1% their 95% confidence intervals (95% CI) were calculated from number of events per patient-year. Differences were considered significant at a probability level of p less than Data were analyzed with the SPSS version 10.0 statistical program (SPSS Inc, Chicago, Illinois). Results The preoperative patient characteristics, epiaortic ultrasound, and TEE data are summarized in Table 1. Atherosclerotic disease in the ascending aorta was detected in 23% of patients. The details of the epiaortic ultrasound findings are presented in Table 2. Most often involved was the distal-anterior segment (50%). The mean follow-up time was years (range, 0 to 8 years) and covered 3,358 patient-years. We first compared patients with and without atherosclerotic disease in the ascending aorta. Patients with atherosclerosis of the ascending aorta were older ( vs , p 0.001) than those without. They also had a lower incidence of diabetes mellitus (12.8% vs 21.6%, p 0.02), and a higher incidence of atherosclerotic disease in the aortic arch (68.4% vs 15.1%, p 0.001) as well as in the descending aorta (71.2% vs 25.6%, p 0.001). However, the two groups did not differ in the incidence of stroke prior to surgery (7.1% vs 5.4%, p 0.54) or of claudication (9.9% vs 5.5%, p 0.08). There were, in the whole patient sample, 16 cases of early ( 30 days) and 34 of late postoperative ( 30 days) stroke. The mean length of time elapsing between surgery and late stroke was months. The overall incidence of early postoperative stroke was 2.6%. Comparison of patients with and without atherosclerotic dis-

3 Ann Thorac Surg VAN DER LINDEN ET AL 2007;83: AORTIC ATHEROSCLEROSIS TOPOGRAPHY PREDICTS STROKE 2089 Table 3. Multivariate Analysis on the Predictors of Late Stroke After Coronary Surgery 95.0% CI for Exp(B) Variables in the Equation B SE p Value Exp(B) Lower Upper p Value Age (years) Hypertension Diabetes mellitus ADAA Hypertension Diabetes mellitus Aortic arch atherosclerosis Hypertension Diabetes mellitus Extent of ADAA Hypertension Diabetes mellitus High-risk aortic disease Hypertension Diabetes mellitus ADAA atherosclerotic disease of ascending aorta; B partial coefficient; CI confidence intervals; Exp(B) exponential partial coefficient; High-risk aortic disease atherosclerotic disease in the distal-posterior, distal-right, distal-left, and middle-left segments of the ascending aorta; SE standard error. ease in the ascending aorta showed a highly significant difference. In these two groups the incidence of early postoperative stroke was 6.4% and 1.5%, respectively (p 0.004). By contrast, there was no difference in the incidence of early stroke between patients with and without atherosclerotic disease in the aortic arch (3.1% vs 2.6%, respectively, p 0.77). The incidence of late stroke was significantly higher in patients with atherosclerotic disease in the ascending aorta or arch than in those without. The five-year stroke-free survival rate was % (1.75%/patient-year) in patients with atherosclerotic disease in the ascending aorta and % (0.75%/patient-year) in patients without (OR 4.1, 95% CI 2.1 to 8.0, p 0.005). The corresponding figures for patients with and without atherosclerosis in the aortic arch were % (1.69%/patient-year) and 95.5 Table 4. Topographic Analysis for the Risk of Long-Term Stroke in Coronary Patients With Atherosclerotic Disease in the Ascending Aorta Topography (5-Year Stroke Free Survival) 95% CI Individual Any Other Area in Segment Ascending Aorta Odds Ratios Lower Upper p Value Distal third: Anterior Posterior Right Left Middle third: Anterior Posterior Right Left Proximal third: Anterior Posterior Right Left CI confidence interval.

4 2090 VAN DER LINDEN ET AL Ann Thorac Surg AORTIC ATHEROSCLEROSIS TOPOGRAPHY PREDICTS STROKE 2007;83: Fig 1. Risk of stroke connected with atherosclerosis in various areas of the ascending aorta. The ascending aorta was divided into 12 segments; ie, three transverse (proximal, middle, and distal third) and four longitudinal segments (anterior, posterior, right, and left). The color changes from dark red (high risk in the distal left segment) into dark blue (low risk). 1.1% (0.75%/patient-year), respectively (OR 2.45, 95% CI 1.2 to 5.0, p 0.007). Cox regression analysis provided evidence that both atherosclerosis of the ascending aorta and atherosclerosis of the arch were strong predictors for late stroke (Table 3). Using the number of segments affected by the disease as an estimate of its extent, the strong association between extensive disease in the ascending aorta and a high incidence of late stroke stood out in both univariate and multivariate analyses. The five-year stroke-free survival rates for patients without ascending aortic disease, patients with less than 50%, and patients with more than 50% of the ascending aorta affected by atherosclerosis, were %, %, and %, respectively (p ). Furthermore, the risk for stroke in the same period for patients with simultaneous disease in the ascending aorta and arch was 3.5-fold higher (p ). In cases in which atherosclerosis was limited to the ascending aorta the number of affected segments was about the same as in those in which the arch was also diseased ( vs segments, p 0.26). Moreover, there was no statistical difference in the risk for stroke in patients with atherosclerosis in the arch compared with the ascending aorta, 2.4 versus 4.1 (p 0.05). Hypertension and diabetes mellitus were also independent predictors of late stroke. Topographic analysis of the ascending aorta for the risk of long-term stroke is shown in Table 4. The table gives data on the risk of long-term stroke associated with atherosclerosis in various parts of the aorta. The middleleft and distal-left segments of the ascending aorta were associated with an approximately fivefold increase and the distal-posterior and distal-right segments with an approximately 3.5-fold increase in the five-year stroke rate. By contrast, all segments of the proximal third and all anterior segments had odds ratios less than 2. A distinct pattern appeared with the lowest values in the proximal anterior segments and the highest values distal left. In Figure 1, the same variation in risk is displayed with colors ranging from dark blue for the low risk, to dark red for the high risk zones. In our total sample of 611 patients there were 51 (8.3%), in whom at least one of the high-risk segments of the ascending aorta was affected by atherosclerosis. In this high-risk group the five-year stroke-free survival was % while the corresponding figure for all other non-high-risk patients was % (2.74% vs 0.75%/patient-year; OR 3.74, 95% CI 1.65 to 8.4, p ). Thus, Cox regression analysis revealed that the presence of atherosclerosis in at least one of these high-risk zones was the strongest independent predictor for late stroke (Table 3). Comment In the present study the cut-off point found useful for the thickness of the aortic wall (0.5 mm) was much lower than the 4.0 mm cut-off point found suitable in the pioneer French Study of Aortic Plaques in Stroke [5, 7]. Given the very different ways the two patient samples were selected, differences of this kind are not unexpected. In the French study [5, 7] the sample consisted of stroke survivors. Our sample consisted of survivors of cardiac episodes referred for coronary surgery. Neither sample can in any way be considered representative of the total population. In all these studies the patient samples are of necessity selective. This seriously limits the value of comparisons and of extrapolations. But it does not affect the main finding of the present study that atherosclerosis in some segments of the aorta carries a greater risk than in others. For, even if the finding is considered valid only for patients with coronary sclerosis who are fit for surgery, such a restriction does not detract from its clinical significance. The reason is obvious. It is only in patients so selected that the finding is of clinical interest. Our study confirms that the presence of the atherosclerosis increases the risk of late stroke. Its extent in the ascending aorta was found to be a strong predictor but the predictive value of the location of the disease was even greater. Location of the disease in the distal-left segment of the aorta (Fig 1) was found to be especially ominous and carried a fivefold higher risk for late stroke. Only slightly less dangerous was its location in the middle-left, distal-posterior, and distal-right segments. Thus, atherosclerosis in the middle and distal part of the ascending aorta, just before the origin of the innominate artery and especially on the left side, is mainly responsible for the association of the disease with late stroke. If this is correct, the group of patients at high risk for late stroke can be narrowed down to what, in our patient sample, are only 8% of coronary patients. A focal area of atherosclerosis affecting the outer edges of a vessel bifurcation (here the innominate artery), where the disease is more severe and thus might carry a greater risk of stroke, is compatible with the idea of a predisposed area. In such an area the hemodynamic shear stress, the fractional force acting on the endothelial cell surface as a result of blood flow, is weaker than in protected areas [8]. The only earlier study of the influence of atherosclerosis in the ascending aorta [9] on the later occurrence of

5 Ann Thorac Surg VAN DER LINDEN ET AL 2007;83: AORTIC ATHEROSCLEROSIS TOPOGRAPHY PREDICTS STROKE 2091 stroke used transient ischemic attack and stroke as its endpoint. The study found that atherosclerosis of the ascending aorta carried less risk than what others, using only stroke as their endpoint [3 5], had found for the arch. The present study using reliable, independently registered data on stroke as its endpoint, could not confirm this. Instead, multivariate analysis showed atherosclerosis in the ascending aorta to have an equivalent, if not better, predictive value than that in the arch. How can this discrepancy be explained? In previous studies, atherosclerosis in the arch was diagnosed with transesophageal echocardiography, TEE [3 5], while epiaortic ultrasonography was used for the ascending aorta [9]. The known lower sensitivity of TEE [10] might have led to identification of only the more severe cases; ie, cases more prone to neurologic events later on. Moreover, due to insufficient visualization of the innominate artery with TEE [4, 5], plaques located at the junction of the ascending aorta and the aortic arch may erroneously have been assigned to the arch. Topography being our main interest, we complemented TEE with epiaortic ultrasonography to identify disease in the arch. This more meticulous approach may have resulted in the identification of less serious disease in the arch, which could explain the observed differences. The present study can neither give information on the importance of atrial fibrillation, which was beyond its scope, nor on that of grading the thickness of the atheromas, which was beyond its range of interest. Its message is simple. Location of atherosclerosis in the distal part and lesser curvature of the aorta was mainly responsible for the association with late stroke. Hypertension and diabetes mellitus have been identified as independent risk factors for late stroke after coronary bypass surgery in the present and previous studies [9, 11 13]. The most likely mechanism for this is rapid progression of atherosclerosis in the aorta and the carotid arteries because aortic atherosclerosis has been found to be independently associated with hypertension [14] and the presence of both hypertension and diabetes accelerates the development of atherosclerosis more than either comorbid factor alone [15, 16]. Nevertheless, the exact mechanisms of stroke in hypertensive and diabetic patients deserve further investigation. To date there is no clear guidance as to what is the optimal surgical approach for patients needing coronary surgery and suffering from atherosclerosis of the ascending aorta. Two opposing surgical strategies have been advocated for these patients. On the one hand, a number of studies have suggested that off-pump coronary surgery is associated with significantly less perioperative stroke [17 20]. It is reasonable to assume, however, that this approach does not address the problem of late stroke. On the other hand, Rokkas and Kouchoukos [21] and Kouchoukos and colleagues [22] have suggested a radical surgical approach including the replacement of the ascending aorta. Although this method was associated with relatively higher perioperative mortality, it showed promising results regarding late stroke. In view of the findings in the present study, one may suggest that a more radical surgical approach should be reserved for a selected high-risk subgroup with disease in the specific areas shown in Figure 1. It is of surgical importance that the distal-anterior part of the ascending aorta is associated with neither early stroke [6] nor late stroke. Therefore, in case of replacement of the high-risk part of the ascending aorta, aortic cannulation can still be undertaken. Thanks are due to Em Prof Willem van der Linden for help with the preparation of the manuscript. Karolinska Institute funded the study and there was no potential conflict of interest. References 1. Amarenco P, Duyckaerts C, Tzourio C, Henin D, Bousser MG, Hauw JJ. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med 1992;326: Jones EF, Kalman JM, Calafiore P, Tonkin AM, Donnan GA. Proximal aortic atheroma. An independent risk factor for cerebral ischemia. Stroke 1995;26: Tunick PA, Rosenzweig BP, Katz ES, Freedberg RS, Perez JL, Kronzon I. High risk for vascular events in patients with protruding aortic atheromas: a prospective study. J Am Coll Cardiol 1994;23: Mitusch R, Doherty C, Wucherpfennig H, et al. Vascular events during follow-up in patients with aortic arch atherosclerosis. Stroke 1997;28: The French Study of Aortic Plaques in Stroke Group. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Engl J Med 1996;334: van der Linden J, Hadjinikolaou L, Bergman P, Lindblom D. Postoperative stroke in cardiac surgery is related to the location and extent of atherosclerotic disease in the ascending aorta. J Am Coll Cardiol 2001;38: Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994;331: Malek AM, Alper SL, Izumo S. Hemodynamic shear stress and its role in atherosclerosis. JAMA 1999;282: Davila-Roman VG, Murphy SF, Nickerson NJ, Kouchoukos NT, Schechtman KB, Barzilai B. Atherosclerosis of the ascending aorta is an independent predictor of long-term neurologic events and mortality. J Am Coll Cardiol 1999;33: Konstadt SN, Reich DL, Kahn R, Viggiani RF. Transesophageal echocardiography can be used to screen for ascending aortic atherosclerosis. 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6 2092 VAN DER LINDEN ET AL Ann Thorac Surg AORTIC ATHEROSCLEROSIS TOPOGRAPHY PREDICTS STROKE 2007;83: tension. A comparative morphometric study of their progression using an atherometric system. Zentralbl Pathol 1991;137: Goto T, Baba T, Matsuyama K, Honma K, Ura M, Koshiji T. Aortic atherosclerosis and postoperative neurological dysfunction in elderly coronary surgical patients. Ann Thorac Surg 2003;75: Leacche M, Carrier M, Bouchard D, et al. Improving neurologic outcome in off-pump surgery: the no touch technique. Heart Surg Forum 2003;6: Lev-Ran O, Ben-Gal Y, Matsa M, et al. No touch techniques for porcelain ascending aorta: comparison between cardiopulmonary bypass with femoral artery cannulation and off-pump myocardial revascularization. J Card Surg 2002;17: Bergman P, Hadjinikolaou L, Dellgren G, van der Linden J. A policy to reduce stroke in patients with extensive atherosclerosis of the ascending aorta undergoing coronary surgery. Interact Cardiovasc Thorac Surg 2004;38: Rokkas CK, Kouchoukos NT. Surgical management of the severely atherosclerotic ascending aorta during cardiac operations. Semin Thorac Cardiovasc Surg 1998;10: Kouchoukos NT, Wareing TH, Daily BB, Murphy SF. Management of the severely atherosclerotic aorta during cardiac operations. J Card Surg 1994;9: INVITED COMMENTARY The risk of stroke with cardiac surgery has been well documented particularly in the perioperative period. With the advent of transesophageal echocardiography and epiaortic imaging, a long-term association between the degree of aortic atheromatous disease and the subsequent risk of stroke has become clear; although there is still controversy regarding the quality of either modality to assess the ascending aorta and proximal arch adequately. Two dimensional epiaortic imaging of the ascending aorta seems to be superior. Less controversy exists about the superiority of these modalities in assessing the distal arch and descending aorta. There are numerous grading systems used to measure the severity of atheroma. All recognize the increasing risk associated with plaque thickness and plaque mobility. In this issue, van der Linden and colleagues [1] add to our knowledge by carefully quantifying the anatomic location and extent of atheroma and correlating that data to the long-term stroke risk in a group of coronary artery bypass grafting patients using cardiopulmonary bypass [1]. With significant atheroma ( 50% circumference) centered in the proximal lesser curve of the aorta, a third of patients experienced a stroke within 5 years. Incidence data from general population-based studies suggest lower stroke risks for similar atheromatous involvement, although with less careful anatomic delineation, implying that the need for coronary artery bypass grafting may be a longterm risk factor. So far the modification of surgical practice consists of replacement, endarterectomy, or avoidance of the aorta by off-pump coronary artery bypass or modifications, with modest results in the former two, and lack of good randomized data in the latter. The challenge remains for surgeons to find an effective surgical treatment plan for these patients and a postoperative management strategy that improves quality and duration of life. Thomas V. Bilfinger, MD, ScD Department of Surgery SUNY at Stony Brook HSC T19 Rm 80 Stony Brook, NY tbilfinger@notes.cc.sunysb.edu Reference 1. van der Linden J, Bergman P, Hadjinikolaou L. The topography of aortic atherosclerosis enhances its precision as a predictor of stroke. Ann Thorac Surg 2007;83: by The Society of Thoracic Surgeons /07/$32.00 Published by Elsevier Inc doi: /j.athoracsur