Gender-related differences in

carotid plaque features: focus on

instability and inflammation

Giuseppe Biondi Zoccai, MDUniversity of Modena and Reggio Emilia, Modena, Italy

On behalf of Giuseppe Sangiorgi, Sara Roversi, Francesca Servadei, Doriana Liotti, Luigi Giusto Spagnoli, Alessandro Mauriello, Maria Grazia Modena

BACKGROUND

• Severe carotid stenosis is a frequent cause of atherothrombotic stroke in both men and women.

• Several sex-related comparisons are available on coronary plaque features, suggesting that males have higher thrombotic burden and females a more severe inflammatory substrate.

• However, there are few data appraising gender-specific features of atherosclerotic carotid plaques.

GOAL

• We aimed to systematically compare the pathology of carotid plaques in males versus females, with a specific emphasis on features of thrombosis and inflammation.

METHODS

• Carotid plaque specimens were collected from patients undergoing surgical thromboendoarterectomy (TEA) for asymptomatic (>80% diameter) or symptomatic (>50% diameter) carotid stenosis.

• Standard pathologic analyses were performed, as well as sophisticated measurements for plaque hemorrhage, inflammation and foam cells.

RESULTS

• A total of 457 patients were included (132 women, 325 men).

• Baseline analyses showed a greater prevalence of hypercholesterolemia and hypertension in women, and higher prevalence of current smoking, despite a raised Framingham Heart score in men (all p<0.05).

• Women had a lower prevalence of thrombotic plaques, and smaller percentage area of necrotic core and hemorrhage extension (all p<0.05).

RESULTS

• Plaque inflammation analysis showed a lower concentration of inflammatory and foam cells in the plaque cap of females (both p<0.05).

• Even at multivariable analysis adjusting for smoking status, hypercholesterolemia, hypertension, Framingham Heart Score, plaque classification, percentage area of necrotic lipid core, hemorrhage extension, women had a significantly lower concentration of foam cells and/or lymphocytes in the cap (p=0.032).

BASELINE FEATURESFemales (N=132) Males (N=325) P value

Age (Years) 69.9±7.2 69.6±7.0 0.768Smoking historyCurrentFormerEver

32 (24.2%)71 (53.8%)29 (22.0%)

96 (29.5%)117 (36.0%)112 (34.5%)

0.002

Hypercholesterolemia 89 (67.4%) 183 (56.3%) 0.028Hypertension 61 (67.0%) 121 (53.1%) 0.023Total number of risk factors 2.9±1.4 2.7±1.5 0.228Framingham Heart Score 17.3±7.4 27.3±11.3 <0.001Statin therapy 42 (35.6%) 87 (29.6%) 0.277Symptomatic statusAsymptomaticTransient ischemic attackStroke

71 (53.8%)27 (20.5%)34 (25.8%)

149 (45.8%)92 (28.3%)84 (25.8%)

0.178

Serum fibrinogen (mg/dL) 365.1±140.6 335.3±93.0 0.420

PLAQUE PATHOLOGYFemales (N=132) Males (N=325) P value

Plaque locationCommon carotidBifurcationInternal carotid

12 (28.6%)22 (52.4%)8 (19.0%)

28 (21.7%)75 (58.1%)24 (18.6%)

0.687

Area stenosis (%) 46.8±16.7 50.6±17.1 0.387Plaque classificationWith luminal thrombusWith organized thrombusUlcerationErosionNon-thrombotic thin-cap fibro-atheromaWith calcified nodulesHealedStable fibro-calcific

11 (8.3%)7 (5.3%)

19 (14.4%)0

22 (16.7%)7 (5.3%)

15 (11.4%)51 (38.6%)

25 (7.7%)37 (11.4%)67 (20.6%)

1 (0.3%)50 (15.4%)

7 (2.2%)52 (16.0%)86 (26.5%)

0.034

PLAQUE PATHOLOGYFemales (N=132) Males (N=325) P value

Thrombotic plaque 44 (40.0%) 137 (49.8%) 0.013Any vulnerable plaque 32 (24.2%) 93 (28.6%) 0.342Multiple vulnerable plaques 4 (3.0%) 20 (6.2%) 0.195Minimum cap thickness (μm) 143.2±117.8 131.7±94.1 0.612Percentage area of necrotic lipid core

49.2±18.7 56.2±17.7 0.010

Calcium-lumen distance (μm) 866.7±721.5 1458.5±1461.6 0.144Calcified area>5% of plaque area1-5% of plaque areano calcifications

41 (64.1%)11 (17.2%)12 (18.8%)

85 (51.5%)40 (24.2%)40 (24.2%)

0.227

Hemorrhagic area>10% of plaque1-10% of plaque no hemorrhage

26 (63.2%)15 (24.6%)20 (32.8%)

98 (63.2%)23 (14.8%)34 (21.9%)

0.022

PLAQUE INFLAMMATION

Females (N=132)

Males (N=325)

P value

Plaque inflammation (HPF; 40x magnification)

20.2±13.8 25.0±14.1 0.017

CD68+CD3 positive cells in the plaque/mm2 29.3±20.0 36.3±20.4 0.017Foam cells in the cap/mm2 19.3±16.0 27.1±22.7 0.009T lymphocytes in the cap/mm2 8.5±9.9 7.4±6.1 0.541Foam cells or lymphocytes in the cap/mm2 26.0±20.2 34.1±25.8 0.028

MULTIVARIABLE ANALYSIS*R2 Regression coefficient

(95% CI)P

valuePlaque inflammation (HPF; 40x magnification)

2.4% 2.5 (-5.6; 10.5) 0.537

CD68+CD3 positive cells in the plaque/mm2

2.4% 3.6 (-1.6; 10.9) 0.537

Foam cells in the cap/mm2 2.3% 15.6 (1.5; 29.8) 0.032T lymphocytes in the cap/mm2 0.4% 3.3 (-3.7; 10.2) 0.343Foam cells or lymphocytes in the cap/mm2

2.8% 18.9 (4.6; 32.3) 0.012

*exploring the association between gender and plaque inflammation features AND adjusting for all variables associated at bivariate analyses with gender with p<0.10:

smoking status, hypercholesterolemia, hypertension, Framingham Heart Score, plaque classification, thrombotic plaque, percentage area of necrotic lipid core, hemorrhage extension, R2 was computed using as gender as the only independent variable; female

gender was coded as 2, and male gender as 1

CONCLUSIONS

• Carotid plaques are significantly different in women and men.

• In contrast to findings observed in coronary vessels, females have a lower degree of inflammation and thrombosis, and more frequently stable plaques.

• Further studies are warranted to demonstrate whether such gender-related differences in carotid pathology may have implications for the clinical management and revascularization of patients with carotid artery disease.

Thank you for your attention

For any correspondence: gbiondizoccai@gmail.com

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