Cardiol Res

Cardiology Research, ISSN 1923-2829 print, 1923-2837 online, Open Access

Article copyright, the authors; Journal compilation copyright, Cardiol Res and Elmer Press Inc

Journal website https://www.cardiologyres.org

Original Article

Volume 15, Number 3, June 2024, pages 144-152

Remnant Cholesterol and Carotid Intraplaque Neovascularization Assessed by Contrast-Enhanced Ultrasonography in Patients With Ischemic Stroke

Figure 1. Patient selection and study design. CEUS: contrast-enhanced ultrasonography; IPN: intraplaque neovascularization.

Figure 2. Semiquantitative analysis of neovascularization. IPN grading 0: no visible microbubbles in the plaque; IPN gradingg1: moderate microbubbles confined to the shoulder and/or adventitial side of the plaque; IPN grading 2: extensive microbubbles throughout the plaque. (a-c) Common carotid artery plaques in which the blue dotted line marks the plaque. (d-f) Contrast-enhanced ultrasonography images of the carotid artery. (d) IPN grading 0. (e) IPN grading 1. (f) IPN grading 2 (white arrow marking the continuous microbubble in the plaque (defined as IPN)). CCA: common carotid artery; IPN: intraplaque neovascularization.

Figure 3. Correlation coefficient of IPN between the two observers. The IPN analyses of 20 random plaques performed by the two researchers were compared using the Bland-Altman ± intraclass correlation coefficient. IPN: intraplaque neovascularization.

**Table 1.** Clinical Characteristics According to Carotid IPN < 2 and IPN = 2 of Stroke Onset Side
	IPN < 2 (n = 43)	IPN = 2 (n = 67)	P
BP: blood pressure; TG: triglyceride; TC: total cholesterol; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; CCB: calcium channel blockers; aIPN: average intraplaque neovascularization; IPN: intraplaque neovascularization.
Clinical
Age	69 (63 - 74)	70 (64 - 76)	0.478
Sex (men), n (%)	36 (83.7)	62 (92.5)	0.21
Hypertension, n (%)	24 (55.8)	42 (62.7)	0.551
Diabetes mellitus, n (%)	12 (27.9)	23 (34.3)	0.534
Smoking history, n (%)	22 (51.2)	38 (56.7)	0.695
Systolic BP (mm Hg)	132.93 ± 15.19	135.24 ± 16.04	0.454
Diastolic BP (mm Hg)	75 (71 - 80)	75 (71 - 80)	0.929
Lipids (mmol/L)
TG (mmol/L)	0.96 ± 0.24	1.45 ± 0.69	< 0.001
TC (mmol/L)	3.47 ± 0.94	3.71 ± 0.94	0.172
LDL-C (mmol/L)	1.86 ± 0.65	2.06 ± 0.83	0.195
HDL-C (mmol/L)	1.17 ± 0.30	1.08 ± 0.24	0.093
Non-HDL-C (mmol/L)	2.31 ± 0.64	2.63 ± 0.85	0.037
Remnant cholesterol (mmol/L)	0.44 ± 0.07	0.57 ± 0.23)	< 0.001
Glucose (mmol/L)	5.02 (4.37 - 5.70)	5.49 (4.55 - 7.29)	0.049
Hemoglobin A1c	5.9 (5.5 - 6.6)	6.3 (5.6 - 8.1)	0.240
Medication use
Aspirin, n (%)	38 (88.4)	65 (97.0)	0.108
Beta-blocker, n (%)	6 (14.0)	8 (11.9)	0.776
CCB, n (%)	15 (34.9)	36 (53.7)	0.077
Statin, n (%)	38 (88.4)	64 (95.5)	0.258
Oral hypoglycemic agent, n (%)	7 (16.3)	11 (16.4)	0.725
Insulin, n (%)	6 (14.0)	8 (11.9)	0.477
Stroke subtyping (by ASCO criteria)			0.373
A1 S0 C0 O0, n (%)	0 (0)	3 (4.5)	-
A1 S3 C0 O0, n (%)	19 (44.2)	34 (50.7)	-
A2 S1 C0 O0, n (%)	2 (4.7)	1 (1.5)	-
A2 S2 C0 O0, n (%)	1 (2.3)	0 (0)	-
A2 S3 C0 O0, n (%)	1 (2.3)	1 (1.5)	-
A3 S1 C0 O0, n (%)	10 (23.3)	19 (28.4)	-
A3 S2 C0 O0, n (%)	7 (16.3)	8 (11.9)	-
A3 S3 C0 O0, n (%)	3 (7.0)	1 (1.5)	-
Bilateral carotid
Bilateral carotid plaque, n (%)	30 (69.8)	53 (79.1)	0.364
aIPN	1 (1 - 1.5)	2 (1.5 - 2.0)	< 0.001
Stroke onset side
Lesion side			0.558
Right side, n (%)	20 (46.5)	36 (53.7)	-
Left side, n (%)	23 (53.5)	31 (46.3)	-
Degree of carotid stenosis			0.302
< 50%, n (%)	9 (20.9)	8 (11.9)	-
50-69%, n (%)	3 (7.0)	9 (13.4)	-
70-99%, n (%)	31 (72.1)	50 (74.6)	-
Plaque thickness (mm)	4.3 (3.3 - 4.8)	4.4 (3.6 - 4.8)	0.745
Plaque echogenicity			0.837
I	10 (23.3)	19 (28.4)	-
II	19 (44.2)	28 (41.8)	-
III	14 (32.6)	20 (29.9)	-

Table 1. Clinical Characteristics According to Carotid IPN < 2 and IPN = 2 of Stroke Onset Side

IPN < 2 (n = 43)

IPN = 2 (n = 67)

BP: blood pressure; TG: triglyceride; TC: total cholesterol; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; CCB: calcium channel blockers; aIPN: average intraplaque neovascularization; IPN: intraplaque neovascularization.

Clinical

Age

69 (63 - 74)

70 (64 - 76)

0.478

Sex (men), n (%)

36 (83.7)

62 (92.5)

0.21

Hypertension, n (%)

24 (55.8)

42 (62.7)

0.551

Diabetes mellitus, n (%)

12 (27.9)

23 (34.3)

0.534

Smoking history, n (%)

22 (51.2)

38 (56.7)

0.695

Systolic BP (mm Hg)

132.93 ± 15.19

135.24 ± 16.04

0.454

Diastolic BP (mm Hg)

75 (71 - 80)

0.929

Lipids (mmol/L)

TG (mmol/L)

0.96 ± 0.24

1.45 ± 0.69

< 0.001

TC (mmol/L)

3.47 ± 0.94

3.71 ± 0.94

0.172

LDL-C (mmol/L)

1.86 ± 0.65

2.06 ± 0.83

0.195

HDL-C (mmol/L)

1.17 ± 0.30

1.08 ± 0.24

0.093

Non-HDL-C (mmol/L)

2.31 ± 0.64

2.63 ± 0.85

0.037

Remnant cholesterol (mmol/L)

0.44 ± 0.07

0.57 ± 0.23)

< 0.001

Glucose (mmol/L)

5.02 (4.37 - 5.70)

5.49 (4.55 - 7.29)

0.049

Hemoglobin A1c

5.9 (5.5 - 6.6)

6.3 (5.6 - 8.1)

0.240

Medication use

Aspirin, n (%)

38 (88.4)

65 (97.0)

0.108

Beta-blocker, n (%)

6 (14.0)

8 (11.9)

0.776

CCB, n (%)

15 (34.9)

36 (53.7)

0.077

Statin, n (%)

38 (88.4)

64 (95.5)

0.258

Oral hypoglycemic agent, n (%)

7 (16.3)

11 (16.4)

0.725

Insulin, n (%)

6 (14.0)

8 (11.9)

0.477

Stroke subtyping (by ASCO criteria)

0.373

A1 S0 C0 O0, n (%)

0 (0)

3 (4.5)

A1 S3 C0 O0, n (%)

19 (44.2)

34 (50.7)

A2 S1 C0 O0, n (%)

2 (4.7)

1 (1.5)

A2 S2 C0 O0, n (%)

1 (2.3)

0 (0)

A2 S3 C0 O0, n (%)

1 (2.3)

1 (1.5)

A3 S1 C0 O0, n (%)

10 (23.3)

19 (28.4)

A3 S2 C0 O0, n (%)

7 (16.3)

8 (11.9)

A3 S3 C0 O0, n (%)

3 (7.0)

1 (1.5)

Bilateral carotid

Bilateral carotid plaque, n (%)

30 (69.8)

53 (79.1)

0.364

aIPN

1 (1 - 1.5)

2 (1.5 - 2.0)

< 0.001

Stroke onset side

Lesion side

0.558

Right side, n (%)

20 (46.5)

36 (53.7)

Left side, n (%)

23 (53.5)

31 (46.3)

Degree of carotid stenosis

0.302

< 50%, n (%)

9 (20.9)

8 (11.9)

50-69%, n (%)

3 (7.0)

9 (13.4)

70-99%, n (%)

31 (72.1)

50 (74.6)

Plaque thickness (mm)

4.3 (3.3 - 4.8)

4.4 (3.6 - 4.8)

0.745

Plaque echogenicity

0.837

10 (23.3)

19 (28.4)

19 (44.2)

28 (41.8)

III

14 (32.6)

20 (29.9)

**Table 2.** Univariable and Multivariable Analysis for IPN = 2 of Stroke Onset Side in the Study Population (N = 110)
	Exp(B)	95% CI	P
^aModel 1: remnant cholesterol + age + sex. ^bModel 2: remnant cholesterol + age + sex + smoking history + hypertension + diabetes mellitus + glucose. IPN: intraplaque neovascularization; BP: blood pressure; TG: triglyceride; TC: total cholesterol; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol.
Univariable analysis
Age	1.016	0.972 - 1.063	0.474
Sex (man), n (%)	0.415	0.123 - 1.403	0.157
Hypertension, n (%)	1.330	0.610 - 2.899	0.473
Diabetes mellitus, n (%)	1.350	0.585 - 3.114	0.481
Smoking history, n (%)	1.251	0.580 - 2.698	0.568
Systolic BP (mm Hg)	1.010	0.985 - 1.036	0.451
Diastolic BP (mm Hg)	0.998	0.948 - 1.050	0.928
TG (mmol/L)	3.746	1.814 - 7.736	< 0.001
TC (mmol/L)	1.377	0.869 - 2.181	0.173
LDL-C (mmol/L)	1.423	0.834 - 2.429	0.196
HDL-C (mmol/L)	0.285	0.064 - 1.264	0.099
Non-HDL-C (mmol/L)	1.781	1.022 - 3.101	0.042
Remnant cholesterol (mmol/L)	10.178	3.775 - 27.440	< 0.001
Glucose (mmol/L)	1.356	1.052 - 1.748	0.019
Multivariable analysis
Model 1^a	11.091	3.980 - 30.908	< 0.001
Model 2^b	12.221	4.043 - 36.940	< 0.001

Table 2. Univariable and Multivariable Analysis for IPN = 2 of Stroke Onset Side in the Study Population (N = 110)

Exp(B)

95% CI

^aModel 1: remnant cholesterol + age + sex. ^bModel 2: remnant cholesterol + age + sex + smoking history + hypertension + diabetes mellitus + glucose. IPN: intraplaque neovascularization; BP: blood pressure; TG: triglyceride; TC: total cholesterol; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol.

Univariable analysis

Age

1.016

0.972 - 1.063

0.474

Sex (man), n (%)

0.415

0.123 - 1.403

0.157

Hypertension, n (%)

1.330

0.610 - 2.899

0.473

Diabetes mellitus, n (%)

1.350

0.585 - 3.114

0.481

Smoking history, n (%)

1.251

0.580 - 2.698

0.568

Systolic BP (mm Hg)

1.010

0.985 - 1.036

0.451

Diastolic BP (mm Hg)

0.998

0.948 - 1.050

0.928

TG (mmol/L)

3.746

1.814 - 7.736

< 0.001

TC (mmol/L)

1.377

0.869 - 2.181

0.173

LDL-C (mmol/L)

1.423

0.834 - 2.429

0.196

HDL-C (mmol/L)

0.285

0.064 - 1.264

0.099

Non-HDL-C (mmol/L)

1.781

1.022 - 3.101

0.042

Remnant cholesterol (mmol/L)

10.178

3.775 - 27.440

< 0.001

Glucose (mmol/L)

1.356

1.052 - 1.748

0.019

Multivariable analysis

Model 1^a

11.091

3.980 - 30.908

< 0.001

Model 2^b

12.221

4.043 - 36.940

< 0.001

**Table 3.** Univariable and Multivariable Analysis for IPN = 2 of Stroke Onset Side in the Subset of Patients With Optimal LDL-C levels (N = 51)
	Exp(B)	95% CI	P
^aModel 1: remnant cholesterol + age + sex. ^bModel 2: remnant cholesterol + age + sex + smoking history + hypertension + diabetes mellitus + glucose. IPN: intraplaque neovascularization; BP: blood pressure; TG: triglyceride; TC: total cholesterol; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol.
Univariable analysis
Age	1.003	0.945 - 1.064	0.927
Sex(men), n (%)	0.429	0.065 - 2.822	0.378
Hypertension, n (%)	3.667	1.122 - 11.980	0.031
Diabetes mellitus, n (%)	0.857	0.259 - 2.837	0.801
Smoking history, n (%)	1.438	0.469 - 4.410	0.525
Systolic BP (mm Hg)	1.015	0.979 - 1.052	0.424
Diastolic BP (mm Hg)	1.019	0.945 - 1.099	0.620
TG (mmol/L)	7.551	2.205 - 25.864	0.001
TC (mmol/L)	0.901	0.288 - 2.817	0.858
LDL-C (mmol/L)	0.854	0.109 - 6.710	0.881
HDL-C (mmol/L)	0.114	0.011 - 1.169	0.067
Non-HDL-C (mmol/L)	3.426	0.616 - 19.059	0.160
Remnant cholesterol (mmol/L)	15.683	3.072 - 80.053	0.001
Glucose (mmol/L)	1.465	0.945 - 2.272	0.088
Multivariable analysis
Model 1^a	17.565	3.172 - 97.269	0.001
Model 2^b	27.728	2.714 - 283.253	0.005

Table 3. Univariable and Multivariable Analysis for IPN = 2 of Stroke Onset Side in the Subset of Patients With Optimal LDL-C levels (N = 51)

Exp(B)

95% CI

Univariable analysis

Age

1.003

0.945 - 1.064

0.927

Sex(men), n (%)

0.429

0.065 - 2.822

0.378

Hypertension, n (%)

3.667

1.122 - 11.980

0.031

Diabetes mellitus, n (%)

0.857

0.259 - 2.837

0.801

Smoking history, n (%)

1.438

0.469 - 4.410

0.525

Systolic BP (mm Hg)

1.015

0.979 - 1.052

0.424

Diastolic BP (mm Hg)

1.019

0.945 - 1.099

0.620

TG (mmol/L)

7.551

2.205 - 25.864

0.001

TC (mmol/L)

0.901

0.288 - 2.817

0.858

LDL-C (mmol/L)

0.854

0.109 - 6.710

0.881

HDL-C (mmol/L)

0.114

0.011 - 1.169

0.067

Non-HDL-C (mmol/L)

3.426

0.616 - 19.059

0.160

Remnant cholesterol (mmol/L)

15.683

3.072 - 80.053

0.001

Glucose (mmol/L)

1.465

0.945 - 2.272

0.088

Multivariable analysis

Model 1^a

17.565

3.172 - 97.269

0.001

Model 2^b

27.728

2.714 - 283.253

0.005