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Changes in Carotid Plaque Predict MI Risk
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Are you getting regular cardiology referral and checkup??
A repeat carotid artery ultrasound several months after the first may reveal a heart attack risk better than a single snapshot of vessel stenosis, researchers here said.
Vessels that showed increasing signs of plaque instability from one scan to the next were associated with higher risk of major adverse cardiac events over the next three years, reported Markus Reiter, M.D., of Medical University Vienna, and colleagues, in the September issue of Radiology.
The prospective ultrasound study showed a 71% higher risk for those with the greatest decrease versus largest increase on gray-scale median score over a period of six to nine months (P=0.018).
Because increased risk was independent of stenosis, the researchers said, "these findings suggest that patients with mild or moderate carotid stenoses may also benefit from repeat gray-scale median testing irrespective of their initial cardiovascular status."
They cautioned that the study was limited by the hospital referral-based nature of the cohort and by the observational design, which could not entirely rule out a potential influence of concomitant medical therapy. Also, the findings may not be generalizable because of the older, primarily white patient population with a relatively high rate of high-grade stenosis, they said.
Because increased risk was independent of stenosis, the researchers said, "these findings suggest that patients with mild or moderate carotid stenoses may also benefit from repeat gray-scale median testing irrespective of their initial cardiovascular status."
They cautioned that the study was limited by the hospital referral-based nature of the cohort and by the observational design, which could not entirely rule out a potential influence of concomitant medical therapy. Also, the findings may not be generalizable because of the older, primarily white patient population with a relatively high rate of high-grade stenosis, they said.
medpagetoday.com
Increasing Carotid Plaque Echolucency is Predictive of Cardiovascular Events in High-Risk Patients1
Radiology Aug 2008
Markus Reiter, MD, Isabella Effenberger, MD, Schila Sabeti, MD, Wolfgang Mlekusch, MD, Oliver Schlager, MD, Petra Dick, MD, Stefan Puchner, MD, Jasmin Amighi, MD, Robert A. Bucek, MD, Erich Minar, MD, and Martin Schillinger, MD
1 From the Departments of Radiology, Division of Cardiovascular and Interventional Radiology (M.R., I.E., S.P., R.A.B.), and Internal Medicine II, Division of Angiology (S.S., W.M., O.S., P.D., J.A., E.M., M.S.), Medical University Vienna, General Hospital, Wahringer Gurtel 18-20, A-1090 Vienna, Austria.
ABSTRACT
Purpose: Carotid plaque echolucency seen at ultrasonography (US) is a potential indicator of plaque instability and may help identify patients at risk for major adverse cardiovascular events (MACEs). The authors performed this study to determine whether decreasing gray-scale median (GSM) levels at repeat carotid US examinations are associated with future MACEs.
Materials and Methods: The study was approved by the institutional ethics committee and all patients provided informed consent. The authors prospectively studied 574 patients with carotid plaques of at least 30% from a group of 1268 consecutive patients who were initially asymptomatic with respect to carotid disease. GSM levels were determined with carotid US at baseline and after a median of 7.5 months (range, 6-9 months), and the mean change of the GSM was calculated. Patients were then followed up clinically for a median of 3.2 years for the occurrence of composite MACE.
Results: During the initial period, the median change in carotid GSM was 2.9 (interquartile range [IQR], -6.9 to 11.0). Of 574 study participants, 230 (40%) showed a reduction of GSM levels and 344 (60%) showed an increase. MACEs were observed in 177 (31%) of the 574 patients. Adjusted hazard ratios for the lowest quartile (GSM change less than -6.9), the second quartile (GSM change between -6.9 and 2.9), and the third quartile (GSM change between 3.0 and 11.0) were 1.71 (95% confidence interval [CI]: 1.09, 2.66), 1.36 (95% CI: 0.86, 2.16), and 1.22 (95% CI: 0.77, 1.95), respectively, compared with the highest quartile (GSM change greater than 11.0) (P = .018).
Conclusion: Increasing echolucency of carotid artery plaques within a 6- to 9-month interval is predictive of midterm clinical adverse events of atherosclerosis.
INTRODUCTION
Complications of atherosclerosis are the most common causes of morbidity and mortality in Western societies. Coincidence of the clinical sequel of coronary, cerebrovascular, and peripheral artery disease is observed in a considerable proportion of patients, and unstable atherosclerotic plaques in any vascular segment are associated with a markedly increased risk for clinical complications (1-3). Noninvasive identification of plaque types prone to complications may help improve the effectiveness of therapeutic strategies. In this context, it is well recognized that most cardiovascular and cerebrovascular events are encountered in patients with lesions with a reduction in lumen diameter of less than 70%, indicating that determination of the degree of stenosis alone is insufficient for predicting the patient's risk (4,5).
Ultrasonographic (US) measurement of carotid plaque echolucency is a potential marker of plaque instability (5-8). The subjective grading of plaque echogenicity with B-mode US has been replaced by objective computer-assisted evaluation-the so-called gray-scale median (GSM) (5-12). In several observations, low GSM levels were associated with the presence of neurologic symptoms and the development of future strokes in previously symptomatic individuals as well as with the occurrence of acute coronary syndromes (5,8-12). The effect of changes in the GSM in serial investigations, however, remains unknown as yet.
We performed this study to determine whether increasing carotid plaque echolucency measured at repeat US examinations and defined by decreasing GSM levels can help identify patients at high risk for future clinical events of atherosclerosis in the coronary, cerebrovascular, and peripheral circulation in a population initially asymptomatic for cerebrovascular disease.
DISCUSSION
We demonstrated in a large-scaled clinical study that increasing echolucency of carotid artery plaques during a short-term interval is predictive of midterm clinical adverse events of atherosclerosis in the coronary, cerebrovascular, and peripheral circulation in cardiovascular high-risk patients. These findings suggest that repeat GSM testing may help identify patients at particularly high risk for near-future events.
Previous studies have demonstrated that echolucent plaques are associated with an increased risk of cardiovascular events (5-8). However, different definitions and approaches for measuring plaque echogenicity limit the comparability of the previously published data. In addition, the previous authors determined GSM levels and the associated risk with a single measurement by using different US machines and different methods of image documentation, that is, digitalized video images or digitalized scanned image prints, which includes the risk of loosing the original image information (5-12,20). We directly transferred images in the tagged image file format between the US machine and workstation, and our results are made on the basis of the comparison between images obtained at baseline and control visits at the same institution by the same operators who used standardized parameters. This approach should accurately reflect the activity and dynamic of an individual's atherosclerotic disease during the initial follow-up interval and might enable a more accurate and objective risk assessment because the results had not been compared with GSM cut-offs of previous studies by using different equipment and image documentation. In addition, the previously published studies (6-8) especially focused on cerebrovascular disease; the only study evaluating a composite endpoint of cerebrovascular and coronary events included 246 patients and was performed by Gronholdt et al (5) by using a single determination of plaque echolucency and following up patients with telephone interviews. In accordance with our results, they failed to detect a significant correlation between a single determination of plaque echolucency and vascular events in their total study population but reported that echolucent plaques were related to an increased risk of stroke in the previously symptomatic subgroup (5). It is well known, however, that acute symptomatic events increase the risk for short-term future events, and this may have influenced the results of these studies (5,21,22).
Repeat GSM testing seems to help identify the presence of "vulnerable plaques." Plaque instability seems to occur systemically not only in the coronary arteries, leading to the recommendation that it is essential to assess total vulnerability burden of atherosclerosis in the carotid, femoral, and other arteries and not just search for a single unstable coronary plaque (5,7,23,24). It is important to note that a decrease of GSM was confirmed as a robust marker of cardiovascular risk independent of traditional risk factors or the degree of carotid stenosis at baseline. These findings suggest that patients with mild or moderate carotid stenoses may also benefit from repeat GSM testing irrespective of their initial cardiovascular status.
The pathophysiologic mechanism of the relationship between plaque echolucency and increased cardiovascular risk is not completely understood. El-Barghouty et al (10) found that the content of soft tissue (ie, lipid and hemorrhage) was associated with plaque echolucency. Conversely, a highly fibrous tissue content was associated with echo-rich plaques, and this has been confirmed by other authors (11,25). Plaques rich in lipids or with a necrotic core are thought to be most prone to rupturing and causing clinical events (24,26). This fact seems to be a potential explanation for our findings. In addition, inflammation as a trigger for endothelial dysfunction and plaque growth is an important pathophysiologic substrate in the process of generalized atherosclerosis and has also been linked to echolucent carotid plaques (13,27).
We are aware that the hospital referral-based nature of the cohort is a potential study limitation. However, given the expected low percentage of patients in the general population with cardiovascular events during a midterm follow-up, a population-based approach did not seem feasible. The indications for performing carotid US at our department were consensually defined, rather homogeneous, and reproducible. Nevertheless, the generalizability of our findings to younger individuals and ethnic/racial minorities is uncertain, especially because of the relatively high percentage of patients with high-grade stenosis included in our study. In addition, although computer-assisted classification exhibits an acceptable reproducibility, the method might be influenced by measurement errors in some cases, especially with regard to the outlining and standardization of the plaque (12,28). Finally, because of the observational nature of our study, a potential influence of concomitant medical therapy cannot completely be excluded. In particular, the effect of statins may have been underestimated because the patients received different doses not selected by a randomized study design.
In conclusion, patients with increasing plaque echolucency quantified by decreasing GSM levels of carotid plaques are at high risk for midterm adverse events of atherosclerosis affecting the coronary, peripheral, and cerebrovascular circulation, irrespective of the individual's cardiovascular risk profile and prevalent atherosclerotic comorbidities. GSM testing of the carotid arteries in 6- to 9-month intervals may help identify patients who have a particularly high cardiovascular risk.
RESULTS
GSMs
The median GSM level was 48.2 (IQR, 31.4-67.6) at baseline and 51.1 (IQR, 35.1-70.6) at 6- to 9-month follow-up, resulting in a median GSM change of 2.9 (IQR, -6.9 to 11.0). The mean GSM level decreased in 230 (40%) of 574 study participants and increased in 344 (60%). The median time between baseline and follow-up US was 7.5 months for all patients with increasing plaque echolucency and patients with decreasing plaque echolucency (P = .94). The remaining demographic data and clinical characteristics from the two patient groups are given in the Table.
Initial Study Phase
During the initial phase of the study, two MIs, 11 percutaneous coronary interventions, two coronary bypass graft procedures, eight strokes, 10 peripheral percutaneous interventions, and one peripheral vascular surgical procedure were recorded. According to the study protocol, these events were not considered to be study endpoints.
Follow-up for MACE
During a median clinical follow-up of 3.2 years (IQR, 2.6-3.6 years), 296 MACEs occurred in 177 (31%) of 574 patients, including 21 MIs, 48 percutaneous coronary interventions, 17 coronary artery bypass graft procedures, 34 strokes, 69 percutaneous transluminal angioplasties, 13 peripheral surgical procedures, five amputations owing to critical limb ischemia, and 89 deaths.
GSM Levels and Risk for MACE
Absolute GSM levels-whether obtained at baseline or follow-up-were not associated with the risk of MACE in the near future (P = .18 and P = .21, respectively). However, patients in whom mean GSM levels decreased from baseline to follow-up US exhibited a significantly increased risk for near-future MACE during the clinical follow-up period compared with patients with increasing GSM levels (P = .008, univariate analysis). Event-free survival rates at 1, 2, and 3 years were 91%, 83%, and 68%, respectively, for the lowest quartile (mean GSM change <-6.9); 90%, 85%, and 74% for the second quartile (mean GSM change between -6.9 and 2.9); 94%, 84%, and 77% for the third quartile (mean GSM change of 3.0-11.0); and 91%, 86%, and 78% for the highest quartile (mean GSM change >11.0).
We then calculated a multivariable Cox proportional hazards model, assessing the risk for MACE according to the change in GSM levels and adjusted for age, sex, history of hypertension, current smoking, low-density lipoprotein cholesterol levels, glycosylated hemoglobin A1 levels, body mass index, positive family history for cardiovascular disease, history of MI or stroke, prevalent peripheral artery disease, use of statins during the study period, and degree of carotid stenosis at baseline. Adjusted hazard ratios for the lowest quartile (mean GSM change <-6.9), second quartile (mean GSM change between -6.9 and 2.9), and third quartile (mean GSM change of 3.0-11.0) were 1.71 (95% CI: 1.09, 2.66), 1.36 (95% CI: 0.86, 2.16), and 1.22 (95% CI: 0.77, 1.95), respectively, compared with the highest quartile (mean GSM change >11.0, P = .018) (Figure).
Even when only hard cardiovascular endpoints (MI, stroke, amputation, and death) were considered alone, hazard ratios still inversely correlated with GSM change. Adjusted hazard ratios for the lowest, second, and third quartile were 1.64 (95% CI: 1.02, 3.12), 1.24 (95% CI: 0.72, 2.78), and 1.08 (95% CI: 0.50, 2.23), respectively, compared with the highest quartile (P = .046).
MATERIALS AND METHODS
Study Design
We prospectively enrolled all consecutive neurologically asymptomatic patients who underwent duplex US investigations of the extracranial carotid arteries from March 2002 until March 2003 at our institution in the Inflammation in Carotid Arteries Risk for Atherosclerosis Study (13-16). Patients underwent a baseline carotid US investigation and a second US examination after 6-9 months. After the second US examination, patients were followed up clinically for the occurrence of cardiovascular endpoints. The study was approved by the local review board and institutional ethics committee, and all patients provided informed consent.
Patient Selection
We intended to include cardiovascular high-risk patients with a high likelihood for progressive carotid disease and, therefore, chose a hospital referral-based approach. Our US laboratory serves the departments of a 2200-bed university hospital. The main indications for performing carotid US were carotid bruits; multiple cardiovascular risk factors such as smoking, diabetes mellitus, arterial hypertension, hyperlipidemia, and known atherosclerotic disease in other vessel areas (coronary or peripheral artery disease).
Inclusion and Exclusion Criteria
Patients with carotid artery plaques at the level of the bifurcation with a diameter reduction of at least 30% and who were initially asymptomatic with respect to carotid artery disease, defined by a neurologist as the absence of transient ischemic attacks, amaurosis fugax, or stroke in the patient's recent 12-month history, were eligible for our analysis. Patients were excluded if they were younger than 18 years, had symptomatic carotid artery disease necessitating revascularization therapy, had current infectious or inflammatory diseases, had recently (within 14 days) undergone surgery or endovascular interventions, had bilateral carotid occlusions, or had undergone bilateral stent implantation or bilateral carotid endarterectomy.
Of 1268 patients from the Inflammation in Carotid Arteries Risk for Atherosclerosis Study sample, 396 (31%) did not have the required dimensions of carotid plaque and were not included in the present study, 95 (8%) had to be excluded owing to missing duplex US follow-up data after the initial 6- to 9-month period (28 patients died and 67 refused to undergo repeat duplex US investigation), and 203 (16%) were lost to clinical follow-up. Thus, 574 (45%) patients were included in the final analysis.
Study Endpoint
The study endpoint was the occurrence of a first major adverse cardiovascular event (MACE), a composite of myocardial infarction (MI), percutaneous coronary intervention, coronary artery bypass grafting, stroke, peripheral percutaneous angioplasty, peripheral vascular surgery, amputation owing to critical limb ischemia, and all-cause mortality. Surgical or endovascular procedures in the carotid arteries were not included as a study endpoint, as these procedures might have been directly related to the qualifying carotid US investigation at study entry or during follow-up.
We intended to predict cardiovascular events by performing repeat carotid US investigations. Therefore, the occurrence of study endpoints was assessed in an interval starting after the second carotid US investigation. Cardiovascular events occurring between the first and second carotid US investigations were not considered as study endpoints because they could not have been predicted with the findings from the repeat US investigations.
Color-Coded Duplex US, Grading of Internal Carotid Artery Stenosis, and Plaque Evaluation
Duplex examinations at baseline and during follow-up were performed with a US machine with a 7-MHz linear-array probe (128 XP10; Acuson, Mountain View, Calif) by experienced technical assistants who were supervised by two of the authors (M.R. and M.S.). Operators were blinded with respect to the patients' clinical data, laboratory findings, and results of previous US investigations. Carotid stenosis was graded at US as described previously (17).
For the measurement of GSM levels, b mode settings were adjusted and standardized by using a maximum dynamic range (60 dB) and by setting the gain to ensure an almost noiseless vessel lumen (blood) and an echodense area of adventitia. One representative longitudinal image was obtained for each plaque. All patients were included only once. In patients with qualifying plaques on both sides, the GSM of the plaques were averaged. In case of two geographically separated plaques of one carotid artery, the more extended plaque was evaluated and followed up. All images were stored in tagged image file format and standardized, as described previously on a personal computer by using software (Adobe Photoshop, version 7.0; Adobe Systems, San Jose, Calif) to calculate the GSM values (12). In short, we adjusted the linear scale of the "curves" facility of the software to achieve gray values of the blood between 185 and 195. In such standardized images, plaques were outlined with the cursor and measurements of the GSM obtained from the histogram. To evaluate changes in plaque echolucency, the mean change of GSM levels between baseline and follow-up was calculated. In the prestudy phase, we observed an interobserver variability between five different investigators of 3.5% and an intraobserver variability of the investigator analyzing the study plaques (I.E.) of 2.5%. Intraobserver mean difference reported in the literature for the method exhibits 1.7 (95% confidence interval [CI]: -0.5, 3.8) (12).
Surveillance Protocol
After undergoing baseline US, patients were scheduled for a follow-up visit 6-9 months later for repeat clinical examination and duplex US. Thereafter, patients underwent repeat clinical examination every 6 months at the outpatient ward of our department until December 2005. A follow-up questionnaire was then sent to each patient during January 2006 to reevaluate the occurrence of MACE. Information from the follow-up questionnaire was validated by reviewing the original hospital discharge reports of corresponding readmissions owing to MACE. If the follow-up questionnaire was not returned, personal telephone contact to the patients or to the treating physicians was established. Further information was obtained by reviewing the hospital discharge reports of any other readmission during the follow-up period. The performance of percutaneous coronary interventions, percutaneous transluminal angioplasty, coronary artery bypass grafting, peripheral vascular surgery, and amputation were validated with review of the original procedure protocols. Endpoints were adjudicated by two independent observers (S.S. and W.M.), who were blinded to the patients' baseline clinical and US data.
Definitions
MI and stroke were defined according to guidelines (18,19). For stroke, cranial computed tomography or magnetic resonance imaging were used to confirm the diagnosis. Definitions of traditional cardiovascular risk factors are given elsewhere (13).
Statistical Methods
Continuous data are presented as median and interquartile range (IQR, range from the 25th to the 75th percentile) or total range. Discrete data are given as counts and percentages. We used Yates corrected 2 tests and Mann Whitney U tests for univariate analyses, as appropriate. Multivariable Cox proportional hazards models were applied to assess the relationship between increasing echolucency (quartiles of mean carotid artery GSM changes) and the occurrence of a first MACE after the second carotid US investigation. Multivariable models were adjusted for established risk factors for MACE. Results of the Cox models are presented as the hazards ratio and the 95% CI. We tested for interactions between baseline variables by using multiplicative interaction terms and log likelihood 2 tests. We assessed the overall model fit by using Cox-Snell residuals. Furthermore, we tested the proportional hazard assumption for all covariates by using Schoenfeld residuals (overall test) and the scaled Schoenfeld residuals (variable-by-variable testing). According to the tests, the proportional hazards assumption was not violated. A two-sided P value of less than .05 was considered significant. Calculations were performed with software (Stata, release 8.0, Stata, College Station, Tex; SPSS for Windows, version 12.0, SPSS, Chicago, Ill).
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