carotid intima-media thickness measurement as a … · carotid intima-media thickness measurement...

Cardiovascular

Original article

Carotid intima-media thickness measurement as a risk predictor of transient ischemic attackStella Maris Batallés, María Natalia Heredia, Luciana Della Rosa, Mauricio Capomasi, Roberto Villavicencio, Stella Maris Pezzotto*

ResumenObjetivos. Determinar si el riesgo de accidente isqué-mico transitorio (AIT) es mayor en pacientes con valo-res anormales de espesor miointimal carotídeo (EMIC). Materiales y Métodos. Evaluación de 168 pacientescon y sin AIT estudiados con ecografías de vasos decuello, midiendo EMIC. Diseño de casos y controlesapareados por distintas variables. Análisis estadístico:variables continuas (media ± DS), comparadasmediante prueba “t de Student” para muestras relacio-nadas. Variables categóricas (porcentajes) comparadasmediante pruebas de McNemar. Para evaluar EMICcomo predictor de AIT, se ajustaron dos modelos deregresión logística condicional, considerando EMICcomo variable continua y como variable binaria EMICnormal (≤1 mm) vs. patológico (>1 mm). Se construyóuna curva ROC para evaluar la capacidad discrimina-tiva de EMIC, calculando la sensibilidad y especifici-dad para diferentes puntos de corte.Resultados. Valor de EMIC: casos 1,03 ± 0,31 mm (IC95%: 0,97–1,10); controles 0,77 ± 0,27mm (IC 95%: 0,71–0,83); p<0,001. El riesgo de AIT fue casi 9 veces mayoren pacientes con EMIC patológico (OR=8,8; p<0,001).Con un 95% de confianza pudo afirmarse que por cada0,05 mm de incremento en el EMIC, el riesgo de AITaumentó entre 16 y 44%. Área bajo la curva ROC: 0,75(IC 95%: 0,67-0,82).Conclusiones. Los valores anormales de EMIC estánsignificativamente asociados a una mayor probabili-dad de presentar AIT. En nuestra experiencia, el estu-dio de las paredes carotídeas con ecografía permitiríapredecir enfermedad pre-clínica cerebrovascular.Palabras clave. Accidente isquémico transitorio.Ecografía. Espesor miointimal carotídeo.

AbstractCarotid Intima - Media Thickness measurement as arisk predictor of transient ischemic attack Objectives. To determine if the risk of transient ischemicattack (TIA) is higher in patients with abnormal values ofcarotid intima-media thickness (CIMT).Materials and Methods. We evaluated 168 patients withand without TIA by ultrasound of the neck vessels, measur-ing CIMT. Case and controls were matched according to dif-ferent variables. Statistical analysis: continuous variables(mean ± SD) were compared using the Student’s t test forrelated samples. Categorical variables (percentages) werecompared using the McNemar tests. In order to assess CIMTas a predictor of TIA, two models of conditional logisticregression were adjusted, considering CIMT both as a con-tinuous variable and as a binary variable: normal CIMT (<1mm) vs. pathologic (>1 mm). A ROC curve was performedto determine the discriminative capacity of CIMT, estimatingthe sensitivity and specificity for different cutoff values.Results. CIMT value: cases 1.03±0.31 mm (95% CI: 0.97-1.10); controls 0.77±0.27 mm (95% CI: 0.71-0.83);p<0.001. The risk of TIA was about 9 fold higher in patientswith abnormal CIMT (OR=8.8; p<0.001). With 95 % con-fidence interval we were able to affirm that for each 0.05 mmincrease in CIMT, the risk of TIA increased between 16 and44%. Area under ROC curve: 0.75 (95% CI: 0.67-0.82).Conclusions. Abnormal values of CIMT are significantlyassociated with a higher probability of suffering a TIA.According to our experience, the carotid wall US examinationwould allow to predict cerebrovascular preclinical disease.Key words. Carotid intima-media thickness. Transientischemic attack. Ultrasound.

INTRODUCTIÓN

Atherosclerosis is a chronic, diffuse and systemicdisease that causes focal complications in differentvascular beds and disorders that may lead to cerebro-vascular, peripheral and coronary artery disease. Thehypothesis that the interface and interaction betweenthe vascular wall and the circulation is the primarysite of the mechanism underlying cardiovascularevents is based on the fact that all stages of atheroscle-rosis may be at distant and at multiple locations

simultaneously (1, 2).According to Furchgott and Zawadzki (3), for many

years the endothelium has been considered as an inertlayer of cells lining the inner surface of blood vessels.However, current evidence has shown that it is astructure that senses and responds to a large numberof internal and external stimuli, through membranereceptor complexes and signal-transduction mecha-nisms, leading to the synthesis and release of vasoac-tive, thromboregulatory and growth factor substan-ces. It is known to play an essential role in vascular

Instituto Cardiovascular de Rosario- Oroño 450 – 2000, Rosario, Argentina.* Carrera del Investigador. Consejo de Investigaciones. UniversidadNacional de Rosario.Correspondencia: Dra. Stella M. Batallés – [email protected]

Recibido: noviembre 2010; aceptado: junio 2011Received: november 2010; accepted: june 2011©SAR-FAARDIT

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Carotid intima-media thicness measurement as a risk

tone regulation, thrombogenicity, muscle cell prolife-ration and platelet adhesion and aggregation (4). Forthis reason, the endothelial dysfunction is one of theinitial steps in the development of atherosclerosis andit is directly associated with an increase in cardiac,cerebrovascular and peripheral artery disease (5). Riskfactors such as hypertension, diabetes, smoking,dyslipidemia, sedentary lifestyle, among others, con-tribute to endothelial dysfunction, favouring the rele-ase of vasoconstrictors, pro-aggregant substances,pro-inflammatory factors, atherosclerosis due toincreased oxidation of LDL, procoagulant factors andantiplatelet factors (6).

The transient ischemic attack (TIA) –-defined as abrief episode of neurological dysfunction caused byfocal brain or retinal ischemia, with clinical symptomstypically lasting less than one hour, and without evi-dence of acute infarction (7)— occurs in 200,000 to500,000 patients per year in the United States (8). Aftera TIA, the recurrence risk is 8% in the first month, 5%yearly and there is also a 5% annual risk for acutemyocardial infarction. The risk of stroke after a TIAranges from 24% to 29% in 5 years, 4% to 8% in thefirst month and 12% to 13% in the first year (9).

Carotid intima-media thickness measurement byhigh-definition ultrasound is a useful tool for theearly diagnosis of subclinical atherosclerosis, cerebralvascular disease and coronary artery disease (10). Thismarker provides a safe, noninvasive and reproduciblemethod for assessing the extent and progression of thedisease and response to treatment (10, 11-13).

The aim of our study was to determine if the riskof TIA is higher in patients with abnormal values ofcarotid intima-media thickness (CIMT) using high-resolution carotid ultrasound.

MATERIALS AND METHODS

We present an epidemiological matched case-con-trol study. All patients with a clinical diagnosis of TIAas per the definition provided by Albers et al (7), whohad been hospitalized at our institution fromFebruary 2009 to May 2010 (n = 84) were included inthe analysis. In addition, we selected eighty-fourpatients without TIA who were hospitalized duringthe same period, and who were matched to case sub-jects according to the following variables: age (± 5years), gender, hypertension (HTN), type I and type IIdiabetes (DBT), dyslipidemia and smoking.

All cases and controls were subjected to carotidultrasound with intima-media thickness measurement.Scans were performed with a Philips HD11® scannerwith automated software for measurement of CIMT.With the patients in the dorsal decubitus position andin the same position as in a standard carotid ultra-sound, twelve CIMT measurements were obtained:• Anterior (near) and posterior (far) walls of the

main segments of extracranial carotid arteries, onthe right and left sides, followed by calculation ofthe mean value for each segment on both sides:

- The CIMT on the common carotid artery was mea-sured 1 cm below the carotid bifurcation.

- The CIMT at the bifurcation was measured fromthe origin of the bifurcation to the flow divider(carotid bulb).

- The internal carotid artery CIMT was measuredfrom the flow divider, at the proximal 1 cm of thecarotid.Measurements were performed from the intima-

lumen interface to the adventitia-media interphase,over a 1-cm segment, with an automated system.

For confounding variables considered, HTN wasdefined at systolic pressure values ≥ 130 mmHg, dias-tolic pressure values ≥ 85 mmHg and dyslipidemia asplasma triglycerides ≥ 1.7 mmol/l or HDL cholesterol< 1 mmol/l in males and <1.29 mmol/l in females. Fordiabetes, one of the following three criteria had to bemet (and where confirmed on more than one occa-

Página 2 RAR - Volumen 75 - Número 3 - 2011

Fig. 1: CIMT below 1 mm, measured on the right common carotidartery. (B mode, longitudinal view).

Fig. 2: Automated measurement of CIMT on the common carotidartery. Ten-millimeter wide ROI shows thickening of the intima-mediainterphase, which is 1.18 mm.

Stella Maris Batallés et al.

sion): 1. Blood glucose (at any time) ≥ 200 mg / dL,associated with classic symptoms (polyuria, polydip-sia and weight loss); 2. Blood glucose ≥ 126 mg/dl ontwo or more testing occasions; 3. Abnormal responseto glucose overloads with two-hour post-overloadglucose ≥ 200 mg /dl.

Statistical Analysis

Continuous variables were expressed as mean ±standard deviation and compared between the groupsof analysis using the Student’s t test for paired sam-ples and Wilcoxon signed-rank test. Categorical varia-bles were expressed as absolute and relative frequen-cies. The McNemar test was used to compare if theprobability of pathologic CIMT is the same for casesand controls. Tests with p values < 0.05 were conside-red as significant.

In order to assess CIMT as a predictor of TIA, twomodels of conditional logistic regression were adjus-ted: one of them considering CIMT as a continuousvariable and the other as a binary variable (normalCIMT <1mm or abnormal CIMT >1 mm) (Figs. 1, 2).The odds ratio (OR) and their 95% confidence inter-vals were calculated. Using the coefficients obtainedby logistic regression, the odds of disease were esti-mated for each individual. Proposing different cut-offpoints for such disease and considering individualswith odds above such cut-off values as individualswith the disease, the status assigned by the model wascompared to the real status, estimating the sensitivityand specificity for each cut-off value, and the ROC(Receiver Operating Characteristic) plot was perfor-med. The sensitivity and specificity for each cut-offvalue of the odds estimated by the logistic model wascalculated by standard formulas.

Finally, an important aspect to evaluate the validityof the logistic regression model is its discriminativecapacity (the extent to which the logistic model diffe-rentiates individuals in whom the event occurs fromthose in whom it does not occur). The area under theROC curve is used as a discriminative measure, whichcan be considered as a predictive value measure.

All statistical analyses were performed with thestatistical software STATA version 8.

RESULTS

Table 1 shows case-control matching results accor-ding to the potential confounding variables analyzed.

Table 2 shows the frequency distribution of nor-mal vs. abnormal CIMT in case and control subjects.In 29 matched pairs (case-control), CIMT was normalboth in case and control subjects; in 16 matched pairs,it was abnormal both in case and control subjects; in35 matched pairs CIMT was abnormal in case andnormal in control subjects; and in 4 matched pairsCIMT was normal in case and abnormal in controlsubjects. The proportion of matched pairs in whichCIMT was abnormal in case and normal in control(41.7%) subjects was significantly higher (McNemarTest: p < 0.001) than the proportion of matched pairsin which CIMT was normal in case and abnormal incontrol (4.8%) subjetcs. This result indicates that theodd of abnormal CIMT is significantly higher in casesthan in controls.

Table 3 shows mean CIMT values in cases andcontrols, with their respective 95% confidence inter-vals (95% CI). The mean CIMT value for cases wassignificantly higher than that for controls (t test forpaired samples: p<0.001). Graph 1 (box plot) showsthe different distribution of CIMT values in cases and


Graph 1: Box plot showing median, 25th and 75th percentiles, andminimum and maximum values of CIMT for case and control subjects.

Graph 2: ROC plot: CIMT’s capacity to predict TIA.


controls (Wilcoxon signed-rank test: p<0.01).The application of the conditional logistic regres-

sion model showed that CIMT is significantly associa-ted with the risk of TIA (OR = 8.8; p < 0.01 - 95% CI:3.11 – 4.62), as the risk is about 9 fold higher inpatients with abnormal CIMT (>1mm).

In addition, for each 0.05 mm increase in CIMT,there was a 29% increase in the risk of TIA (OR = 1.29;95% CI = 1.16 – 1.44; p<0.001). With 95% confidenceinterval we can affirm that for each 0.05 mm increasein CIMT, the risk of TIA increases between 16 and44%. Based on this result and with the aim of asses-sing the usefulness of CIMT as predictor of TIA occu-rrence, the area under the curve was calculated(Graph 1, ROC plot), and it was 0.746 (95% CI: 0.671-0.821) with a good discriminative capacity (p<0.001).For CIMT values above 0.75 mm, the specificity was63% and the sensibility was 75%, while for valuesabove 1.05 mm, the specificity was 76% and the sensi-tivity was 61%.

DISCUSSION

As shown by a great number of studies and reviews(14-23), intima-media thickening of carotid and peripheralarteries is a powerful predictor and indicator of subcli-nical cardiovascular and cerebrovascular disease.

Endothelial dysfunction starts when morphologi-cally and functionally intact endothelium is exposed

to a variety of potentially damaging risk factors. If therisk factor persists, the vessel wall is damaged and theatheromatous plaques develop generating vulnerableplaques with a risk of rupture and occurrence of car-diovascular or cerebrovascular events (10, 11, 24).

Carotid ultrasound, with CIMT measurement,makes it possible to infer in a simple and non-invasi-ve manner the state of the patient's vascular system,and to assume the diffuse presentation of atheroscle-rotic disease (25, 26).

B-mode ultrasound has become the imagingmethod of choice for the assessment of CIMT and theatheromatous plaque, when present. This method notonly allows us to measure the intima-media interphase,but also to characterize the plaque by permitting visua-lization of plaque echogenicity, which is influenced byits composition: heterogeneous hypoechoic plaque isassociated with the presence of lipids, whereas homo-geneous hyperechoic plaque is mostly fibrous. This dif-ferentiation may help predict plaque behaviour (27),since softer, more echolucent plaques (poorly reflectingultrasound waves) are the most prone to rupture andcause embolic events. In our study, the independentvariable of interest was the CIMT value obtained andno assessment of atheromatous plaques was performedbecause, if present, they were an exclusion criterion forour analysis. We considered that their mere presenceeliminated any opportunity for an early detection ofearly endothelial changes.

In epidemiological and observational studies,


Variable Cases (n = 84) Matched controls (n = 84) p

Age, Mean ± Standard Deviation 66.1 ± 10.5 66.2 ± 9.9 0.636

Male gender: % (n) 46.4 (39) 46.4 (39) 1.000

Hypertension: % (n) 51.2 (43) 51.2 (43) 1.000

Type I diabetes: % (n) 4.8 (4) 4.8 (4) 1.000

Type II diabetes: % (n) 13.1 (11) 13.1 (11) 1.000

Abnormal lipids: % (n) 66.8 (56) 66.8 (56) 1.000

Smoker: % (n) 46.4 (39) 46.4 (39) 1.000

Table 1: Characteristics of cases and controls matched by the confounding variables considered.

CIMT (case/control matched pair) N %

Normal/Normal 29 34.5

Normal/Abnormal 4 4.8

Abnormal/Normal 35 41.7

Abnormal/Abnormal 16 19.0

Mc Nemar Test: p < 0.001

Table 2: Normal and abnormal CIMT values in the 84case-control matched pairs.

Group Mean ± Standard Deviation (mm) 95% CI

Cases 1.03 ± 0.31 0.97 – 1.10

Controls 0.77 ± 0.27 0.71 – 0.83

Total 0.90 ± 0.32 0.85 – 0.95

t test for paired samples: p < 0.001

95% CI: 95% Confidence Interval

Table 3: Mean CIMT values (mm) with their 95% CI.

Stella Maris Batallés et al.

CIMT thickening and the occurrence of TIA have beenpositively associated with classical cerebrovascularand cardiovascular risk factors such as age, gender,HTN, dyslipidemia, smoking and DBT. There is alsoan association between CIMT and the summation ofrisk factors, as observed in Framingham risk score (5, 28-

32). In our analysis, these variables, which have shownto be associated with CIMT thickening, were conside-red to match cases to controls, as shown in Table 1.Thus, we prevented these factors from behaving asconfounding variables when studying the associationbetween abnormal CIMT and risk of TIA.

The association of risk factors (HTN, DBT, dyslipi-demia, etc) with TIA or CIMT thickening was notexplored.

A controversial aspect in the evaluation of CIMT isthe variety of protocols used for CIMT measurement,since it makes results interpretation and comparisondifficult (5). The various protocols reported include thecommon carotid artery, carotid bulb or bifurcation andthe internal carotid artery. Some authors prefer to mea-sure the diffuse increase in intima-media thicknessexcluding areas with atheromatous plaques and othersprefer to incorporate plaque thickness as part of theintima-media complex. Some authors measure theposterior wall of the common carotid artery only or ofthe three carotid segments, or the anterior and poste-rior walls of the three segments, and then calculate anaverage value (5, 33). Some studies (the earliest) reportCIMT measurement only in the right carotid artery (34,36). As most authors, in our study we measured theCIMT in both carotid arteries, in the anterior and pos-terior walls of the three segments (12 measurements).

Normal intima-media thickness (IMT) valuesdepend on gender and age. The cut-off point to definea normal IMT value is usually arbitrary and is gene-rally set above the 75th percentile of the studied popu-lation (5).

The range of normal CIMT values in adults, bothfor measurements at the common carotid artery orcombined measurements in all carotid artery seg-ments, ranges from 0.4 to 1 mm with an annual pro-gression of 0.01 to 0.02 mm (5, 37). In agreement withSalonen et al (38), we consider abnormal a CIMT valueabove 1 mm thick. However, Bots et al (39), reported ahigher risk of cerebrovascular events in adults withintima-media thickness values in the common carotidartery above 0.82 mm.

In consistency with our hypothesis and using theconditional logistic regression model, we observedthat the risk of TIA is about nine-fold higher inpatients with CIMT >1 mm (p<0.001 – 95% CI: 3.11 –24.62). If we considered the CIMT cut-off point of 0.82mm reported by Bots et al (39) in our series of patients,the risk of TIA would be even higher.

In our experience, for each 0.05 mm increase inCIMT, there was a 29% increase in the risk of TIA (OR= 1.29; 95% CI = 1.16 – 1.44; p<0.001); therefore, wecan affirm with 95% confidence interval that for each

0.05 mm increase in CIMT, the risk of TIA increasesbetween 16 and 44%.

It should be noted that although the confidenceinterval obtained when estimating the risk of TIA bycomparing patients with abnormal CIMT values vs.patients with normal CIMT values was wide, and thatthis could be due to the scarce number of patientsincluded in the analysis, the result obtained was sta-tistically significant.

The ROC curve obtained showed, for each poten-tial cut-off value for CIMT, the true positive rate onthe ordinate (Sensitivity) and the false positive rate onthe abscissa (1- Specificity). Furthermore, it indicatedthat CIMT measurement is a test that allows distin-guishing normal from abnormal CIMT cases. The areaunder the curve showed 75% diagnostic accuracy ofCIMT to predict TIA (considering 100% as the maxi-mum diagnostic accuracy).

CONCLUSIONS

CIMT measurement is a tool with a very gooddiagnostic accuracy to detect TIA.

Abnormal CIMT values are highly associated witha higher risk of TIA. For each 0.05 mm increase inCIMT, the risk of TIA increases between 16 and 44%.

In our experience, high-resolution ultrasoundassessment of the carotid artery would allow to pre-dict cerebrovascular preclinical disease.

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