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European Journal of Echocardiography Advance Access originally published online on May 30, 2008
European Journal of Echocardiography 2009 10(1):96-102; doi:10.1093/ejechocard/jen172
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

Short-term evolution (9 months) of aortic atheroma in patients with or without embolic events: a follow-up transoesophageal echocardiographic study

Stefano De Castro1,*, Emanuele Di Angelantonio2, Annalisa Celotto1, Marco Fiorelli2, Ilaria Passaseo1, Federica Papetti1, Stefano Caselli1, Andrea Marcantonio1, Ariel Cohen3 and Natesa Pandian4

1 Department of Cardiovascular, Respiratory and Morphological Sciences, University of Rome ‘La Sapienza’, Policlinico Umberto I°, Viale del Policlinico, 155, 00161 Rome, Italy
2 Department of Neurological Sciences, University of Rome ‘La Sapienza’, Rome, Italy
3 Department of Cardiology, Saint Antoine University Hospital, Université Paris VI, Paris, France
4 Tufts University, New England Medical Center, Boston, MA, USA

Received 12 December 2007; accepted after revision 7 May 2008; online publish-ahead-of-print 30 May 2008.

* Corresponding author. Tel: +39 06 4997 9050; fax: +39 06 4997 5060. E-mail address: stefano.decastro{at}uniroma1.it


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
 References
 
Aims: The influence of clinical risk factors and therapeutic options on aortic plaque changes is unknown. In this study, we have evaluated aortic atheroma (AA) evolution in patients with and without embolic events.

Methods and results: We enrolled 83 patients (mean age 67.9 ± 8.6 years). All patients were studied with transoesophageal echocardiography at baseline and 9 months after enrolment. Baseline atherosclerotic plaques were defined as uncomplicated (between 1 and 3.9 mm) and complicated aortic plaques (≥4 mm). To minimize sub-millimetre errors in plaque evolution, AA progression was defined as an increase in maximal plaque thickness ≥1 mm. Similarly, regression was defined as a decrease in maximal thickness of atheromatous plaque ≥1 mm. Aortic plaques were classified as uncomplicated in 20.5% and complicated in 79.5% of patients. Fifty-five plaques (47.8%), both complicated and uncomplicated, remained unchanged. Conversely, 16 plaques (13.9%) increased (mean plaque thickness from 3.94 ± 1.39 to 5.56 ± 1.41 mm, P < 0.001) and 44 (38.3%) decreased (mean plaque thickness from 5.25 ± 1.52 to 3.79 ± 1.53 mm, P < 0.001). Multinomial logistic regression procedure suggests that statins increase the probability of plaque thickness reduction (OR 5.92, 95% CI 1.27–27.7, P = 0.024) and decrease the probability of plaque progression (OR 0.03, 95% CI 0.01–0.28, P = 0.002).

Conclusion: This study suggests that statins may reduce the risk of AA progression.

Keywords: Echocardiography; Aortic atheroma; Plaque


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 Funding
 References
 
Severe atherosclerotic plaques in the thoracic aorta, seen on transoesophageal echocardiography (TEE), are independent risk factors for cerebral ischaemic events and peripheral emboli.1–5 Since the natural history of aortic atheroma (AA) is a dynamic process with evidence of progression and regression,6,7 it can be hypothesized that clinical risk factors and conventional therapy could affect plaque evolution. Previous studies have reported the role of lipid-lowering agents in the treatment of AA in patients with hyperlipidaemia and their effect on plaque regression.8–10 Furthermore, a retrospective observational study has shown that statins are independently and significantly associated with a risk reduction (17% in absolute and 59% in relative reduction) of embolic events (risk ratio 0.39, 95% CI 0.24–0.62; P = 0.0001). In contrast, there was no significant effect of oral anticoagulant or antiplatelet agents on the risk of embolic events.11 We hypothesized that the risk-factor-oriented medical treatment would favourably influence the evolution of the aortic plaques. Therefore, the aim of our study was to prospectively evaluate the influence of clinical risk factors and optimal medical treatment on aortic plaque evolution in patients with and without previous embolic events.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 Funding
 References
 
Between October 2002 and February 2003, all consecutive patients (n = 287) referred to our echocardiographic laboratory for TEE examinations were screened for the evaluation of AA. Of these, 98 patients who satisfied the inclusion criterion of AA ≥1 mm were selected and enrolled into the study. Indications for referral for TEE included: previous stroke or transient ischemic attack (TIA) (n = 51), evaluation of valvular diseases (n = 10), suspected atrial septal defect (n = 13), evaluation of aortic dilation and dissection (n = 9), suspected endocarditis (n = 4), suspected cardiac mass (n = 4), and evaluation of ventricular function for inadequate transthoracic window (n = 7). Fifteen (15.3%) patients refused to enter the study protocol (i.e. second TEE examination). Treatment information was recorded after the first TEE examination. Each patient was treated by his/her referring physician according to their best medical judgement, using one or more of the following treatments: antiplatelet agents (aspirin or ticlopidine), oral anticoagulant (warfarin), statins, and antihypertensive drugs. For those treated with statins was asked to the physicians, at the time of enrolment, to find a consensus on specific drug and dosage, and atorvastatin 40 mg per day was given as the first choice. No reliable pharmacological information was available on the pre-TEE treatment.

During the follow-up period, patients were contacted by telephone in order to obtain information regarding their clinical status and medical therapy. No therapeutic changes since their discharge were reported during the follow-up period. The study protocol was approved by the local ethics committee and all patients gave their informed written consent.

Cardiovascular risk factors, clinical data, and laboratory testing
Cardiovascular risk factors were evaluated for all patients on the basis of the criteria detailed below. Hypercholesterolaemia was defined in the presence of total cholesterol blood levels >220 mg/dl, and lipid-lowering therapy considered adequate for LDL cholesterol blood levels <130 mg/dl. Hypertension was defined as ‘hypertension controlled with medications or a mean systolic blood pressure >140 mm Hg or diastolic pressure >90 mmHg on 3 separate occasions’.12 A smoker was defined as a current smoker or ex-smoker at <5 years from cessation. We also recorded: history of myocardial infarction (documented by medical records with clinical, laboratory, and electrocardiographic changes); presence of diabetes mellitus; history of TIA (defined as neurological symptoms of sudden onset of vascular origin lasting <24 h); and history of stroke (defined as persistent neurological deficit of sudden onset lasting more than 24 h), diagnosed by our experienced stroke unit neurologists.

Blood samples were collected early in the morning, after an overnight fast, the day after TEE studies. Plasma concentration of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were measured by standard enzymatic methods. All other blood tests were measured by standard methods.

Transoesophageal echocardiography
Omniplane TEE (Philips Sonos 5500 system, Andover, MA, USA) with a 5–7.5 MHz transducer was performed to determine the presence and morphology of AA. The study protocol was approved by the local ethics committee and all patients gave their informed written consent. The patients fasted 5 h before TEE, lying down in the left lateral decubitus position during the procedure. Before TEE, all patients received oropharyngeal anaesthesia with lidocaine, and sedation with diazepam was performed when necessary. Patients were studied with TEE at baseline and 9 months after enrolment in the study. Detailed information from multiplane views of ascending, arch, and descending segments of the thoracic aorta were obtained. For the measurement purposes of the study, particular attention was paid to ensure the matching of images of the same patient at follow-up, using position and extension of the plaques, measuring their distance (in centimetres) from the incisors, and dividing the short-axis plane of the aorta into four perpendicular clockwise sectors. In addition, the right pulmonary artery for the ascending aorta and the left subclavian artery for the descending aorta were used for landmark orientation. To minimize sub-millimetre errors in plaque evolution, AA progression was defined as an increase in maximal plaque thickness by ≥1 mm. Similarly, regression was defined as a decrease in maximal thickness of atheromatous plaque by ≥1 mm. Finally, atherosclerotic plaques were clinically defined as uncomplicated (those with a thickness between 1 and 3.9 mm) and complicated aortic plaques (those with a thickness ≥4 mm). Plaques with mobile components or thrombus, regardless of plaque thickness, were also classified as complicated.3 A mobile or hypoechoic lesion involving surface plaque area was considered a thrombus. All examinations were recorded on videotape and reviewed by two independent senior cardiologists blinded to each other and to the time of examination. At least three measurements per plaque were performed by each observer blinded to the patient's identity and study order, and the mean values were considered for statistical analysis. Differences in the evaluation of morphological characteristics of the plaques between the two observers were resolved by consensus. Where the observers could not agree, a third one reviewed the study and gave binding judgement. Only 3 out of 83 patients were reviewed by the third observer because of discrepancies.

Statistical analysis
Continuous data are reported as the mean ± standard deviation (SD). Comparison of data was performed using the {chi}2 test or Fisher's exact test (when necessary) for discrete variables, and the unpaired or paired t-test for continuous variables. Univariable and multivariable logistic regression procedures were used to determine the independent factors associated with plaque regression. The odds ratio (OR) and the associated 95% confidence interval (CI) were calculated using robust standard errors combined with cluster analysis in order to adjust for repeated observations on individuals. The multivariable model included variables that were significant at a P < 0.2 in the univariable analysis.13 A subsidiary analysis was also performed, using a multinomial logistic regression method, in order to assess determinants of plaque evolution (progression and regression) as opposed to stable plaques, considered as the reference category. The {kappa} index assessed interobserver reliability between the two cardiologists assessing TEE evidence of AA. All analyses were performed using STATA 8.2 statistical software. In order to avoid spurious positive results due to multiple comparisons, a P-value of < 0.01 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 Funding
 References
 
Clinical characteristics
The 15 patients who refused to participate in the study protocol did not differ in terms of demographic characteristics and clinical risk factors from those who did participate. Eighty-three patients were enrolled into the study. Table 1 depicts the baseline characteristics of the study population. All hypertensive patients were treated with adequate medication including beta-blockers, calcium-antagonists, and ACE-inhibitors. Ischaemic heart disease patients were also treated with ACE-inhibitors and statins. Patients treated with statins showed, at 9 months follow-up, a significant reduction (P < 0.001) in total cholesterol (reduced by 17%), LDL cholesterol (reduced by 22%), and triglycerides (reduced by 13%), whereas no significant differences were observed in the HDL cholesterol level. No substantial modifications in lipid profile were identified in those patients not treated with statins.


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  		Table 1 Baseline characteristics and medication of study population

 
Aortic atheromas by transoesophageal examination
Baseline
Overall, 115 aortic plaques were visualized in 83 patients: 6 (5.2%) in the ascending aorta, 31 (27.0%) in the aortic arch, and 78 (67.8%) in the descending aorta. Thirty-five plaques (30.4%) were classified as uncomplicated (mean plaque thickness 3.08 ± 0.39 mm) and 80 (69.6%) as complicated (mean plaque thickness 5.24 ± 1.33 mm). Only two thrombi were found in our population. At least one complicated aortic plaque was present in 79.5% of patients. Table 2 shows patients’ characteristics (clinical and laboratory findings) according to the presence of complicated and uncomplicated aortic plaques. Patients with at least one complicated aortic plaque were slightly older and had slightly higher diastolic blood pressure values and triglyceride levels. The {kappa} indices for interobserver reliability between the two observers grading the aortic plaque were 0.75, 0.76, and 0.82 for the ascending, arch, and descending segments, respectively. The mean error for interobserver variability was 0.5 ± 0.2 mm.


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  		Table 2 Clinical characteristics and laboratory findings of study population according to complicated and uncomplicated aortic plaques at baseline

 
Nine-month follow-up
A total of 166 TEE examinations were performed during the study protocol. At 9 months, no patients had new or recurrent clinical cerebrovascular events and/or peripheral emboli. The mean plaque thickness reduction in patients treated with statins was 0.31 ± 0.77 mm. Fifty-five plaques (47.8%), both complicated (n = 22; mean plaque thickness from 4.95 ± 1.27 to 4.85 ± 1.25 mm) and uncomplicated (n = 33; mean plaque thickness from 3.15 ± 0.30 to 3.11 ± 0.25 mm), remained unchanged. Conversely, 16 plaques (13.9%) increased (mean plaque thickness from 3.94 ± 1.39 to 5.56 ± 1.41 mm, P < 0.001) and 44 (38.3%) decreased (mean plaque thickness from 5.25 ± 1.52 to 3.79 ± 1.53 mm, P < 0.001). One plaque decreased in thickness because the thrombus component disappeared and not because plaque thickness diminished. Table 3 shows univariable and multivariable models relating patients’ baseline characteristics to regression vs. stable/progression plaques. Both models identified statins as the only predictor of plaque regression. None of the clinical or molecular risk factors was significantly related to AA evolution. Subsidiary analysis was also performed by a multinomial logistic regression procedure, using stable plaques as the reference category. Our study suggests that statins increase the probability of plaque thickness reduction (OR 5.92, 95% CI 1.27–27.7, P = 0.024) and decrease the probability of plaque progression (OR 0.03, 95% CI 0.01–0.28, P = 0.002).


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  		Table 3 Uni–multivariable logistic regression analysis of aortic plaque regression according to baseline clinical and laboratory characteristics of the study population

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 Funding
 References
 
This is a clinical observational prospective study in which a second TEE was performed, following the same strict protocol described above, on each patient in order to evaluate the evolution of AA. In this study, we observed that statins were independently associated with a favourable evolution of AA in terms of decrease in plaque thickness (OR 12.53, 95% CI 2.21–70.88, P = 0.004). Previous studies, using monoplane and multiplane TEE, have reported different rates in AA progression and regression (Table 4). These studies differ from one another in several technical and clinical aspects: study population, patients risk profile, plaque grading, duration of follow-up, and treatment. Montgomery et al.6 reported an increase in moderate and severe aortic plaques in 23% and a decrease in 10% of patients over a mean period of 1 year. Compared with this study, we found plaque regression in 38.3% of cases and a lower rate of progression (13.9%) of AA. This difference could be due in part to the high percentage (73.5%) of patients in our study treated with statins compared with the aforementioned study, in which no patients were so treated. Sen et al.7 using multiplane TEE in symptomatic patients with well-defined cerebrovascular events reported a progression rate in 37% and a regression rate in 22% of patients. We found a higher regression rate with lower progression rate. However, progression in their study predominantly occurred in patients with aortic plaque <1 mm, which were not considered in our study. Furthermore, only 24% of patients were treated with lipid-lowering therapy. In another study, Pitsavos et al.8 noted a progression rate in ~19% and a regression rate in ~38%, for a group of patients with familiar hypercholesterolaemia following pravastatin therapy over 2 years. These data indicate a similar regression rate to that we found in our study, but the population examined was small and highly selected, all patients were treated with lipid-lowering therapy and were free of other risk factors; therefore, the comparison is insubstantial. More recently, another paper published by Sen et al.14 reported an AA progression rate of 28% in patients who had prevalent stroke or TIA. Among risk factors, high level of homocysteine and neutrophil count were associated with progression of atheroma, and the event-free survival distribution was significantly favourable to the non-progression group. The authors report baseline medical therapy consisting in antiplatelet agents, oral anticoagulation, and statin therapy, but the dosage and continuity or discontinuity of such a therapy is not specified and seems have not been evaluated during the follow-up period. This fact, together with Grade I plaques (<1 mm) inclusion for progression analysis, can explain the different percentage reported if compared with our results. The use of thickness as the only parameter for aortic plaque evolution ignores the effect of aortic remodelling that is associated with atherosclerosis. Hence, plaque area and plaque burden may be more useful in grading AA. However, our aim is to develop a simple and rapid technique for use in everyday clinical practice. Therefore, it may be necessary to forgo more exhaustive measurements in order to minimize time-consuming analysis and to reduce intra- and interobserver variability. It is not surprising that current data suggest a protective effect of statin therapy in patients with thoracic aortic plaques. A number of imaging studies15–18 have shown that such therapies slow the progression and promote the regression of atherosclerotic lesions. Furthermore, both experimental and clinical outcome data support the hypothesis that lipid-lowering therapies, in addition to being powerful LDL-lowering agents, also attenuate plaque inflammation, influence plaque stability, and have an antiplatelet effect.19 Importantly, recent studies using magnetic resonance imaging (MRI) have shown a significant reduction in atherosclerotic lesions in patients with documented aortic and/or carotid atherosclerosis under protracted treatment with simvastatin.20,21 Furthermore, a retrospective 12-year-period observational study, which included 519 patients with plaques ≥4 mm in thickness in the thoracic aorta, showed that statin treatment is independently and significantly associated with a reduction in the risk of embolic events (risk ratio 0.39, 95% CI 0.24–0.62). However, in contrast, there was no significant effect on the risk of events by warfarin or by antiplatelet agents.11 Our study adds further evidence to the beneficial effect of statins in the regression of atherosclerotic lesions, suggesting that lipid-lowering therapy reduces the risk of AA evolution. However, this study does have its limitations, namely: methodology, study design, and the limited sample size. As regards methodology, TEE imaging does not allow for optimal matching of lesions in serial examinations. It is true that CT scan and MRI imaging can provide a more detailed definition of the surface plaque and evaluate plaque evolution more accurately. However, the TEE approach is a widely available and accepted tool for performing this kind of analysis. As regards the study design, no objective pharmacological data were available on the pre-TEE treatment. As this was an observational study, we avoided to have a bias induced by using subjective data provided by patients themselves. Therefore, we did not include such data in our statistical analysis. As a consequence, our findings may in fact underestimate the effect of statin medication on atherosclerotic lesions. Again, the lack of randomization for statin treatment allocation did not allow a peer comparison between patients taking statins (73%) and those not taking statins (23%). The apparently limited sample size was determined to some extent by the invasive nature of the procedure. There was a certain difficulty in persuading patients to the need for a second TEE examination. This study was not performed as a randomized, placebo-controlled study and did not address pharmacological intervention (lipid lowering). Rather, it was a clinical observational study of patients with AA treated by conventional medical therapy, including lipid-lowering therapy in the majority of patients. The reason for this is that it would have been unethical to withhold statins from patients with documented ischaemic cardiovascular disease and hypercholesterolaemia.


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  		Table 4 Comparison of transoesophageal echocardiography studies on aortic atheroma evolution

 

   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
Funding
 References
 
Our study suggests that the use of statins may reduce the risk of AA progression. Indeed, it confirms a recent interventional trial documenting that statins are able to induce regression of atherosclerotic lesions in the aorta. These observations may lead to clinical modification in the management and treatment of patients with AA. The apparent lack of efficacy of warfarin and/or antiplatelet agent treatment could be due to the low frequency of thrombi present in our population and its small sample size. Therefore, if larger numbers of subjects were studied, we may find that antiplatelet agents could inhibit plaque progression. Therefore, a large, multicentre, randomized study is necessary in order to evaluate the risks and benefits of different therapeutic options in the progression/regression of AA and in the occurrence of vascular events.

Conflict of interest: none declared.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
References
 
This study was supported by a grant from the Italian Ministry of Public Health, ATEM project 2001.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
 References
 

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