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Combined Femoral and Carotid Plaque Burden Identifies Obstructive Coronary Artery Disease in Women
Combined Femoral and Carotid Plaque Burden Identifies Obstructive Coronary Artery Disease in Women Kayla N. Colledanchise, MSc, Laura E. Mantella, MSc, Milena Bullen, BSc, Marie-France Hetu, MSc, PhD, Joseph G. Abunassar, MD, MSc, FRCPC, and Amer M. Johri, MD, MSc, FRCPC, FASE, Kingston, Ontario, Canada
Background: It remains difficult to assess cardiovascular risk in symptomatic women. The development of femoral plaque precedes adverse cardiovascular events. However, associations of femoral plaque burden with coronary artery disease (CAD) severity and extent are unknown. The aim of this study was to determine sex-specific plaque quantification markers by vascular ultrasound for identifying significant, obstructive CAD. Methods: In this cross-sectional study, 500 participants (34% women) underwent carotid and femoral ultrasound following coronary angiography. Maximal plaque height and total plaque area were quantified. Logistic regression was used to determine associations of plaque burden with significant, obstructive CAD ($50% stenosis), when adjusted for age and cardiac risk factors. CAD prediction was evaluated using receiver operating characteristic areas under the curve (AUCs). Results: Two hundred thirty-one men (70%) and 78 women (46%) had significant CAD. A combined assessment of femoral bifurcation and carotid maximal plaque height was the most accurate identifier of CAD in men (AUC = 0.773, cutoff $ 2.7 mm, 87% sensitivity, 53% specificity) but a poorer indicator of CAD in women (AUC = 0.659, P < .01). In contrast, the strongest identification of CAD in women was achieved by a combined analysis of common femoral and carotid total plaque area (AUC = 0.764, cutoff $ 42.0 mm2, 86% sensitivity, 53% specificity). At this value, more than half of women with false-positive stress test results were correctly identified as having no significant CAD. Conclusion: Combined femoral and carotid plaque burden assessments effectively ruled out significant disease in both sexes. Vascular ultrasound may have particular value for cardiovascular risk stratification in women, in whom traditional screening tools are less effective. (J Am Soc Echocardiogr 2019;-:---.) Keywords: Coronary artery disease, Sex differences, Vascular ultrasound, Plaque quantification, Peripheral arterial disease
From the Department of Biomedical and Molecular Sciences (K.N.C., L.E.M., A.M.J.); and the Department of Medicine (M.B., M.-F.H., J.G.A., A.M.J.), Queen’s University, Kingston, Ontario, Canada. This work was supported by Queen’s University; a Canada Foundation for Innovation and Ontario Research Fund (CFI 29051); a Ministry of Research,Innovation and Science Early Research Award (ER15-11-029); the Southeastern Ontario Academic Medical Organization (Clinician Scientist Development Program); the Heart and Stroke Foundation of Canada (Clinician Scientist I 7500) to Dr. Johri; and a Natural Sciences and Engineering Research Council of Canada scholarship and Canadian Institutes of Health Research Travel Award (155048) to Colledanchise. Conflicts of Interest: None. Reprint requests: Amer M. Johri, MD, MSc, FRCPC, FASE, Queen’s University, Department of Medicine, Division of Cardiology, Cardiovascular Imaging Network at Queen’s, 76 Stuart Street, FAPC3, Kingston, ON K7L 2V7, Canada (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2019 by the American Society of Echocardiography. https://doi.org/10.1016/j.echo.2019.07.024
Globally, cardiovascular disease remains the most prominent cause of death in both men and women. In 2015, 85% of these deaths were due to ischemic heart disease (IHD) and stroke.1 While such mortality rates have decreased substantially in men over the last three decades, this rate has not been matched in women,2 an alarming trend reflecting the underestimation of cardiovascular risk that leads to underdiagnoses and treatment of IHD.3 It is accepted that sex differences exist in the pathophysiology of IHD. In men, the common manifestation is anatomically obstructive coronary artery disease (CAD). In women, the burden of obstructive CAD is lower, particularly in those who are premenopausal,4 and myocardial ischemia is frequently associated with nonstenotic and diffuse atherosclerosis, plaque erosion, and coronary microvascular dysfunction.5,6 There is historical underrepresentation of women in clinical trials.7 As such, current IHD management algorithms have been derived from studies with mostly male subjects.3 Thus, although unique, sex-specific IHD pathophysiologies exist, diagnostic and therapeutic tools that focus on ‘‘critical stenosis’’ assessment are still used in both sexes. Consequently, current risk stratification tools fail to distinguish between stenotic and other ischemia-causing pathologies and thus are not adequate in ruling out obstructive CAD in women. For 1
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example, in a study of 397,954 patients undergoing elective AUC = Area under the curve angiography in the American College of Cardiology National CAD = Coronary artery Cardiovascular Data Registry, disease 73% of female patients had no CV = Coefficient of variation obstructive CAD.8 Several noninvasive imaging ICC = Intraclass correlation tools have shown value in the coefficient detection of obstructive CAD, IHD = Ischemic heart disease such as vascular ultrasound, MPH = Maximal plaque computed tomographic coroheight nary angiography, and stress testing.9-11 The unique OR = Odds ratio advantages of ultrasound, TPA = Total plaque area including low cost and the absence of radiation, lend favorability to its use as a routine screening tool. However, the majority of vascular ultrasound studies have involved male cohorts; conversely, few data are available on the use of vascular ultrasound as a cardiovascular screening tool in women. Most recently, the Progression of Early Subclinical Atherosclerosis study suggested that evaluation of carotid and femoral atherosclerosis may improve early atherosclerotic disease detection in both men and women.12 The aim of the present study was to evaluate vascular ultrasound as a sex-specific imaging marker for the identification of obstructive CAD in symptomatic men and women. Abbreviations
METHODS Participant Recruitment For this prospective study, participants referred for coronary angiography were recruited from the Cardiac Catheterization Laboratory at the Kingston Health Sciences Centre in Kingston, Ontario, Canada, between January 2017 and February 2018. Participants were eligible for the study if they met the following criteria: men and women aged $18 years, referred for clinically indicated coronary angiography, and willing to give written informed consent. Exclusion criteria were presentation of an acute coronary syndrome, clinical contraindications to angiography or ultrasound, and previous femoral or carotid artery surgery. Demographic and baseline characteristics, including cardiovascular risk factors, use of medications, and stress test results, were collected from participant medical charts and interviews. Cardiovascular risk factors were defined as follows: diabetes mellitus, fasting plasma glucose $126 mg/dL or treatment with insulin or antihyperglycemic medication; hypertension, systolic or diastolic blood pressure $140 mm Hg or 90 mm Hg or use of antihyperlipidemic medication; hyperlipidemia, total cholesterol $240 mg/dL, low-density lipoprotein cholesterol $160 mg/dL, or use of lipid-lowering drugs or use of antilipidemic medication; and current family history of cardiovascular disease, an immediate relative diagnosed with cardiovascular disease. Investigators conducting and analyzing the ultrasound imaging were blinded to the results of angiography to limit potential biases. Ethics This study was approved by the Queen’s University Health Sciences and Affiliated Teaching Hospitals research ethics board. All participants provided written informed consent before entry into the study.
Figure 1 Segments of the femoral artery visualized by ultrasound. Imaging at the proximal femoral artery (A) included the distal 3 cm of the common femoral artery, the femoral bifurcation, and the proximal 3 cm of both the superficial and profunda femoral arteries. Imaging at the adductor’s canal (B) included the distal 15 cm of the superficial femoral artery. The segment measurements shown are approximate.
Coronary Angiography Interpretation Coronary angiography was carried out by one of four experienced interventional cardiologists using the standard Judkins imaging protocol. Angiographic results were scored using a previously reported system as follows: 0 = no or minimal disease (0%–19% narrowing in any segment), 1 = mild disease (20%–49% narrowing in any segment), 2 = moderate disease (luminal narrowing of at least one segment of 50%–69%), and 3 = severe ($70% narrowing within any segment of the main branches of the coronary artery or $50% in the left main coronary artery).11 Segments with previous percutaneous coronary intervention and stenting or coronary artery bypass grafting were deemed to have severe disease (score of 3). Significant obstructive CAD was defined as a luminal diameter reduction of $50% (score of 2 or 3). CAD extent was defined by $50% stenosis in 0, 1 (single-vessel), 2 (double-vessel), or 3 (triple-vessel) coronary segments. Given its prognostic significance, $50% stenosis in the left main coronary artery was defined as triple-vessel disease.13
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HIGHLIGHTS In both sexes, femoral plaque is more indicative of coronary disease than carotid. In women, the combined femoral and carotid plaque area has the highest sensitivity. Over half of false-positive stress test cases are resolved by ultrasound assessment. Plaque assessment provides an independent benefit over traditional risk factors. Ultrasound Analysis and Interpretation Ultrasound examinations were conducted using a Vivid E9 Cardiovascular Ultrasound System equipped with a 9L transducer (GE Healthcare, Mississauga, Ontario, Canada). Ultrasound scans were performed by an experienced imaging technician within 24 hours of coronary angiography. An axial sweep and longitudinal still images were acquired from at least three different angles per segment at the distal common femoral artery, the femoral bifurcation, and the proximal superficial and profunda femoral arteries. Subsequent images were acquired at the distal region of superficial femoral artery, within the adductor’s canal (Figure 1). In the carotid artery, images were obtained at the distal 3 cm of the common carotid artery, the carotid bifurcation, and the proximal 1 cm of the internal and external carotid arteries. Acquired images were analyzed offline using GE Healthcare EchoPAC software, as previously described.14 Plaque was defined using the criteria as a focal structure that protruded into the arterial lumen by $0.5 mm or by 50% of the surrounding intima-media thickness or that was $1.5 mm in thickness from the mediaadventitia border to the intima-lumen border.15 Briefly, plaque height was measured manually by caliper in the axial or longitudinal view at right angle to the vessel wall. The maximal plaque height (MPH) between the right or left sides of each vessel was used in the analysis.16 To determine plaque area, the plaque perimeter was traced in the longitudinal view and calculated automatically. The total plaque area (TPA) was determined from a summation of all plaques in both sides of each vessel.
Statistical Analyses Statistical analyses were conducted using JMP version 12 software (SAS Institute, Cary, North Carolina). Two-group comparisons were conducted using the Wilcoxon-Mann-Whitney test for continuous variables and the Fisher exact test for categorical variables. Logistic regression was used to determine independent odds ratios (ORs) of femoral and carotid plaque burden, scaled by interquartile ranges, for significant obstructive CAD ($50% stenosis), when adjusted for age, body mass index, estimated glomerular filtration rate, and traditional cardiac risk factors, including the presence of diabetes, hypertension, hyperlipidemia, and current smoking. Stepwise forward regression analysis, including demographic data in step 1, cardiac comorbidities in step 2, referral indications in step 3, and plaque burden ultrasound assessments in step 4, was also performed. Spearman’s rank correlation coefficient was used to assess correlations of carotid and femoral plaque measures with the burden and extent of coronary disease. Receiver operating characteristic curves were created using DeLong’s methods to determine the most accurate ultrasound
Figure 2 Flowchart of the study population. The flow of participants during the study recruitment and data collection processes. methods for predicting CAD, indicated by the area under the curve (AUC). Net reclassification improvement (NRI) was also determined for plaque burden assessments. The intraclass correlation coefficient (ICC) and coefficient of variation (CV) were used to evaluate interobserver reproducibility from a subset of 60 participants (30 women and 30 men, 120 arteries), measured independently by two imaging technicians. To determine intraobserver reproducibility, an imaging technician repeated analysis of a subset of 60 participants (30 women and 30 men) twice, 60 days apart. P values < .05 were considered to indicate statistical significance.
RESULTS Study Population Characteristics The final study population was composed of 500 participants, 34% of whom were women (Figure 2). The majority of both women and men had hypertension (66% and 74%, respectively) and hyperlipidemia (56% and 73%, respectively). Men with significant obstructive CAD ($50% coronary stenosis) were older, had lower estimated glomerular filtration rates, and more often had diabetes and hyperlipidemia, with histories of myocardial infarction than those without significant CAD. Women with significant CAD were more likely to have diabetes, hypertension, and hyperlipidemia, to be current smokers, and to have histories of myocardial infarction (P < .05). The most common presenting symptom in men and women was chest pain (61% and 56%, respectively). However, in both sexes, there were no differences in the rates of chest pain presentation between participants with significant CAD and those without disease.
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Table 1 Baseline characteristics of the study population according to sex and the presence of significant, obstructive CAD Women
Variable
All (N = 170)
With CAD (n = 78)
Men
Without CAD (n = 92)
P*
All (N = 330)
With CAD (n = 231)
Without CAD (n = 99)
P*
All P value†
Cardiovascular risk factors Age, y
66 6 11
66 6 11
66 6 11
.86
64 6 10
65 6 9
60 6 11
<.01
.03
BMI, kg/m2
33 6 27
32 6 7
34 6 36
.11
30 6 6
30 6 6
30 6 6
.82
.44
eGFR, mL/min/1.73 m2
77 6 19
77 6 19
78 6 19
.73
79 6 19
78 6 19
83 6 18
.03
.28
Cardiovascular risk factors Diabetes Hypertension
43 (25)
28 (36)
15 (16)
<.01
110 (33)
91 (39)
19 (19)
<.01
.07
113 (66)
61 (78)
52 (57)
<.01
242 (74)
177 (77)
65 (66)
.06
.12 <.01
Hyperlipidemia
95 (56)
53 (68)
42 (46)
<.01
239 (73)
185 (80)
54 (55)
<.01
Current smoking
24 (14)
17 (22)
7 (8)
.01
73 (22)
53 (23)
20 (20)
.66
.04
125 (76)
64 (86)
61 (68)
.01
204 (63)
151 (67)
53 (55)
.04
<.01
7 (8)
<.01
7 (7)
<.01
.03
Family history of CVD History of MI
43 (25)
36 (46)
115 (35)
108 (47)
History of intervention
27 (16)
27 (35)
68 (21)
68 (29)
.23
26 (15)
26 (33)
66 (20)
66 (29)
.22
1 (0)
1 (1)
7 (2)
7 (3)
.28
PCI CABG Referral indications Arrhythmia
17 (10)
5 (6)
12 (13)
.20
31 (9)
16 (7)
15 (15)
.02
.87
Dyspnea
73 (43)
32 (41)
41 (45)
.76
105 (32)
71 (31)
34 (34)
.52
.02
103 (61)
47 (60)
56 (61)
$.999
185 (56)
135 (58)
50 (51)
.19
.34
Positive stress test results
67 (39)
23 (29)
44 (48)
.02
125 (38)
85 (37)
40 (44)
.54
.77
Positive ECG results
30 (18)
11 (14)
19 (21)
.80
47 (20)
31 (13)
16 (16)
.84
.36
Positive echocardiographic results
16 (9)
4 (5)
12 (13)
.38
26 (8)
12 (5)
14 (14)
.02
.59
Positive nuclear imaging results
20 (12)
8 (9)
12 (13)
.58
51 (15)
41 (18)
10 (10)
.02
.16
39 (23)
30 (38)
9 (10)
<.01
82 (25)
75 (32)
7 (7)
<.01
.66
8 (5)
3 (4)
5 (5)
.73
19 (6)
13 (6)
6 (6)
$.999
.68
17 (10)
4 (5)
13 (14)
.07
45 (14)
27 (12)
18 (18)
.16
.32
Chest pain
MI Valve disease Decreased LV function
BMI, Body mass index; CABG, coronary artery bypass graft; CVD, cardiovascular disease; ECG, electrocardiographic; eGFR, estimated glomerular filtration rate; LV, left ventricular; MI, myocardial infarction; PCI, percutaneous coronary intervention. Data are expressed as mean 6 SD or as number (percentage). Note multiple stress tests in certain participants. *P value of the differences between participants with CAD ($50% stenosis) and without. † P value of differences between men and women.
Notably, a higher proportion of participants without CAD were referred for angiography because of positive stress test results than were participants with CAD (n = 84; P < .01). Fifty-two percent of such participants were women. The baseline characteristics are summarized in Table 1. Sex Differences in Plaque Burden and Arterial Distribution Plaque burden per arterial segment and the presence or absence of significant, obstructive CAD are presented in Table 2. Women and men with significant CAD had increased plaque burden in all observed carotid and femoral segments, including the carotid bulb, and proximal superficial, profunda, bifurcation, common femoral, and adductor’s canal segments, compared with those without significant CAD (P < .05). Men had greater plaque burden than women in all segments (P < .01). When divided into age groups ($60 years) and comparing sex differences in participants with CAD (Figure 3), older men had greater plaque burden (MPH and TPA) in the common femoral, femoral bifurcation, and carotid bulb segments only (P < .05). When comparing younger men and women with CAD,
men had greater plaque burden (MPH and TPA) in the common femoral segment only (P < .05). We assessed whether the total number of plaques per vascular segment was predictive of CAD. In the overall population, the AUCs for femoral, carotid, and combined segments were 0.740, 0.676, and 0.759, respectively, for predicting significant CAD. In women, the AUCs for total plaque number in femoral, carotid, and combined segments were 0.683, 0.716, and 0.725, respectively. In men, the AUCs for femoral, carotid, and combined segments were 0.751, 0.679, and 0.756, respectively. Associations of Proximal Femoral, Adductor, and Carotid Plaque Burden with CAD Logistic regression indicated that in women, diabetes (OR, 2.3; 95% CI, 1.0–5.3; P = .04) and current smoking (OR, 5.1; 95% CI, 1.8– 16.5; P < .01) were independent contributors of significant CAD ($50 stenosis). In men, independent risk factors for significant CAD were increased age (OR, 1.1 per year; 95% CI, 1.0–1.1; P < .01), presence of hyperlipidemia (OR, 2.8; 95% CI, 1.6–5.0;
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Table 2 Plaque burden distribution according to sex and the presence of significant, obstructive CAD Women Arterial segment
Men
All (N = 170)
With CAD (n = 78)
Without CAD (n = 92)
P*
All (N = 330)
With CAD (n = 231)
Without CAD (n = 99)
P*
All P value†
MPH, mm 3.0 6 1.7
3.6 6 1.5
2.5 6 1.7
<.01
3.9 6 1.9
4.3 6 1.6
2.8 6 2.1
<.01
<.01
Profunda
0.5 6 0.9
0.7 6 0.9
0.4 6 0.8
.02
0.9 6 1.1
1.0 6 1.1
0.6 6 1.0
<.01
<.01
Superficial
1.2 6 1.3
1.4 6 1.3
1.0 6 1.3
.04
1.6 6 1.5
1.9 6 1.4
1.1 6 1.4
<.01
<.01
Bifurcation
2.2 6 1.7
2.6 6 1.7
1.8 6 1.7
<.01
2.7 6 1.9
3.2 6 1.8
1.5 6 1.8
<.01
<.01
Common
2.6 6 1.8
3.2 6 1.8
2.1 6 1.7
<.01
3.5 6 2.0
4.0 6 1.8
2.5 6 2.2
<.01
<.01
1.5 6 1.1
1.7 6 1.1
1.3 6 1.0
.06
2.3 6 1.3
2.5 6 1.4
1.9 6 1.3
<.01
<.01
2.47 6 1.55
3.0 6 1.4
2.1 6 1.6
<.01
3.0 6 1.4
3.3 6 1.3
2.3 6 1.4
<.001
<.01
89.9 6 90.5
125.8 6 101.4
59.4 6 66.8
<.01
4.1 6 9.0
5.2 6 9.8
3.1 6 8.1
Superficial
15.0 6 28.3
23.0 6 35.0
Bifurcation
29.6 6 32.9
Common
Proximal femoral
Adductor Carotid TPA, mm2
155.7 6 136.3
183.3 6 131.7
91.1 6 125.1
<.01
<.01
.02
10.0 6 17.7
11.8 6 19.1
5.6 6 12.9
<.01
<.01
8.2 6 18.6
<.01
26.9 6 44.8
31.5 6 46.9
16.2 6 37.6
<.01
<.01
40.7 6 37.6
20.1 6 24.7
<.01
41.4 6 40.4
50.5 6 40.2
20.3 6 32.7
<.01
<.01
41.3 6 42.4
56.9 6 46.8
28.0 6 33.5
<.01
77.4 6 68.0
89.8 6 63.9
48.9 6 69.3
<.01
<.01
Adductor
35.6 6 59.1
49.2 6 76.6
23.9 6 34.5
.04
88.4 6 121.5
103.2 6 132.9
53.4 6 79.0
<.01
<.01
Carotid
35.2 6 33.1
50.4 6 36.6
22.3 6 23.2
<.01
58.9 6 48.5
68.0 6 49.9
37.5 6 37.5
<.01
<.01
Proximal femoral Profunda
Data are expressed as mean 6 SD. *P value of the differences between participants with CAD ($50% stenosis) and without. † P value of the differences between men and women.
P < .01), and diabetes (OR, 2.2; 95% CI, 1.2–4.1; P = .01). Table 3 shows the adjusted ORs of significant CAD for interquartile range increases in plaque burden at the carotid artery and the proximal and adductor canal regions of the femoral artery. Notably, in both women and men, increased plaque burden at the proximal femoral artery was the strongest indicator of significant CAD. In women, increased TPA had a stronger association with CAD than increased MPH, such that each 64.0 mm2 increase corresponded to 3.6 times greater odds of significant CAD.
rior descending coronary artery and carotid TPA (OR, 2.2; 95% CI, 1.4–3.5; P < .01). In men, the strongest association was between the right coronary artery and carotid TPA (OR, 1.8; 95% CI, 1.3– 2.6; P < .01). We further assessed femoral plaque burden associations with each coronary artery. In women, the strongest association was between the circumflex coronary artery and common femoral MPH (OR, 3.5; 95% CI, 1.7–8.1; P < .01). In men, the strongest association was between the right coronary artery and femoral bifurcation MPH (OR, 2.4; 95% CI, 1.6–3.8; P < .01).
Associations of Plaque Burden at Individual Vascular Segments with CAD All femoral and carotid plaque burden segment measures were significantly correlated with increased angiographic scores, from 0 to 3, and increased extent of diseased coronary vessels, from no disease to triple-vessel disease. In comparing proximal femoral segments (adjusting for cardiac risk factors), in women, increased plaque burden at the common femoral artery segment yielded the most powerful association with significant CAD (TPA: OR, 3.4; 95% CI, 1.9–6.6; P < .01), increased angiographic score (r = 0.37, P < .01), and CAD extent (r = 0.35, P < .01). In contrast, in men, increased plaque burden at the femoral bifurcation segment was most indicative of significant CAD (MPH: OR, 4.1; 95% CI, 2.5–7.0; P < .01; Figure 4), as well as increased angiographic score and CAD extent (r = 0.39, P < .01, for both measurements). Associations of Carotid and Femoral Plaque Burden with Coronary Artery Segments We assessed carotid plaque burden associations with each coronary artery. In women, the strongest association was between the left ante-
Predictive Values of Combined Plaque Burden Assessments for CAD Associations with CAD were improved when combining femoral and carotid bulb plaque burden (Figure 5). In women, adding carotid bulb TPA information (AUC = 0.740; 95% CI, 0.665– 0.815) increased the AUC of common femoral TPA from 0.691 (95% CI, 0.610–0.772) to 0.764 (95% CI, 0.691–0.837; P < .01). A cutoff value of 42.0 mm2 for this combined assessment yielded sensitivity of 86% and specificity of 53% for ruling out significant obstructive CAD. At this value, 49 of 92 women without significant CAD were correctly identified. Twenty-three such women (47%) were referred for angiography because of positive stress test results. Assessing the NRI17-19 in relation to the stress test results (positive indicating high risk, negative indicating lower risk) for angiography referrals showed a 53% NRI for CAD reclassification. Similarly, in men, the AUC increased from 0.718 (95% CI, 0.656–0.781) when considering carotid MPH alone to 0.773 (95% CI, 0.688– 0.816) when adding femoral bifurcation MPH information
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Figure 3 Distribution of plaque burden in carotid and femoral arteries by age, presence of significant CAD, and sex. In participants with CAD, men >60 years had greater plaque burden than women in the common femoral, femoral bifurcation, and carotid bulb segments (P < .05). Error bars were constructed using 1 standard error of the mean.
Table 3 ORs of significant, obstructive CAD with plaque burden in the proximal femoral, adductor canal, and carotid arteries Women Arterial segment
Median (IQR)
Men
OR (95% CI)
P
Median (IQR)
OR (95% CI)
P
<.01
MPH, mm Proximal femoral
3.1 (2.1–4.1)
2.6 (1.6–4.7)
<.01
4.2 (2.7–5.1)
2.5 (1.7–3.9)
Adductor
1.6 (0.3–2.1)
2.4 (1.1–5.1)
.02
2.2 (1.6–3.0)
1.2 (0.9–1.8)
.27
Carotid
3.0 (2.2–3.9)
2.0 (1.2–3.5)
<.01
3.0 (2.2–3.9)
2.2 (1.5–3.3)
<.01 <.01
TPA, mm2 Proximal femoral
64.0 (14.6–134.5)
3.6 (2.0–7.1)
<.01
125.6 (43.5–233.0)
2.8 (1.7–5.0)
Adductor
12.0 (0.5–44.4)
1.7 (1.2–2.7)
<.01
43.0 (11.0–111.0)
1.2 (0.9–1.8)
.21
Carotid
27.7 (10.7–50.5)
3.2 (1.9–5.7)
<.01
48.1 (25.1–83.2)
2.1 (1.4–3.3)
<.01
IQR, Interquartile range. Logistic regression showing unit ORs of arterial territories for the identification of significant CAD ($50% stenosis) by sex, after adjusting for age, body mass index, estimated glomerular filtration rate, and cardiac risk factors.
(AUC = 0.749; 95% CI, 0.694–0.810) into the model (P < .01). A cutoff value of 2.7 mm for this combined assessment yielded sensitivity of 87% and specificity of 53% for ruling out CAD (Table 4). This vascular assessment would have produced a 37% NRI for CAD reclassification. Notably, use of this men-specific
assessment yielded a decreased AUC of 0.659 (95% CI, 0.577– 0.740) in women (P < .01; Figure 6). Such sex-specific ultrasound assessments showed independent value over participant demographic, comorbidity, and referral indication information in CAD identification (Table 5).
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Figure 4 Odds of significant CAD with increased ([) plaque burden in each proximal femoral segment by sex. The images show the odds of significant CAD (95% CI) with increased ([) TPA in women and MPH in men per each proximal femoral segment. Statin Therapy in Relation to CAD Because statins are known to affect plaque burden, we assessed differences in statin use in relation to CAD. No significant differences were found in plaque burden for any carotid or femoral segments in participants with significant CAD who were taking statins versus those who were not. In participants with no significant CAD, those taking statins had higher common femoral MPH (2.61 6 2.00 vs 2.07 6 1.90 mm, P = .04), femoral bifurcation MPH (1.93 6 1.86 vs 1.37 6 1.56 mm, P = .04), carotid MPH (1.92 6 1.50 vs 2.47 6 1.44 mm, P = .008), and carotid TPA (34.8 6 32.8 vs 26.4 6 31.4 mm2, P = .02).
Test Reproducibility Intraobserver agreement for combined carotid and femoral plaque burden quantification was deemed excellent. In women, ICCs of MPH and TPA were 0.925 (95% CI, 0.847–0.964) and 0.985 (95% CI, 0.968–0.993), while differences in CVs were 3.21% and 3.74%, respectively. In men, ICCs of MPH and TPA were 0.941 (95% CI, 0.880–0.971) and 0.983 (95% CI, 0.965–0.992), while differences in CVs were 0.75% and 0.78%, respectively. Interobserver agreement was good: ICCs of MPH and TPA in women were 0.772 (95% CI, 0.575–0.885) and 0.870 (95% CI, 0.745–0.936), while differences in CVs were 6.32% and 14.26%, respectively. In men, ICCs of MPH and TPA were 0.883 (95% CI, 0.768–0.942) and 0.953 (95% CI, 0.903–0.977), while differences in CVs were 0.58% and 9.65%.
DISCUSSION The present study demonstrates the utility of a noninvasive, risk-free, and cost-effective means to reveal significant, obstructive CAD in both women and men. Such a tool is becoming increasingly essential given prevalence rates of cardiovascular risk factors, such as diabetes, which are projected to increase dramatically over the next two decades.20 It is known that patients with peripheral artery disease are at increased risk for cardiovascular events.21 Accordingly, the 2013 American College of Cardiology/American Heart Association cardiovascular risk guideline recommends an ankle-brachial index measurement to inform treatment decision making.22 However, even with a normal resting ankle-brachial index, occlusive disease may be present in the lower extremities.23 Correspondingly, studies have sought to use peripheral artery plaque detection by ultrasound in risk assessment.24,25 To our knowledge, this study is the first to explore femoral plaque quantification in the identification of angiographic CAD. Few studies have acknowledged sex differences when exploring vascular ultrasound in cardiovascular screening. In the Atherosclerosis Risk in Communities study, accounting for carotid plaque presence in addition to intima-media thickness led to greater improvement of risk prediction in women than in men.26 More recently, in the Progression of Early Subclinical Atherosclerosis study, carotid and femoral plaque burden correlated strongly with cardiovascular risk factors in both men and women and reflected estimated cardiovascular risk better than plaque detection.12 To our knowledge,
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study using magnetic resonance imaging found that in men, tortuosity of the superficial femoral artery was greater and mean wall shear stress lower than in women, contributing to increased focal atherosclerosis, consistent with our findings.27 Additionally, although the mean age of the women in our study was 66 6 11 years, beyond the average age of menopause, endogenous estrogen–afforded protection earlier in life may have led to a delay in disease development.28
Figure 5 Odds of significant CAD with combined plaque burden assessments by sex. Forest plots show the ORs of significant CAD in women (A) and men (B) for interquartile range increases (median [25%-75%]) in combined proximal femoral and carotid MPH and TPA assessments, adjusted for age and traditional cardiac risk factors. this is the first study to reveal sex-specific vascular ultrasound markers of atherosclerotic disease in CAD identification. Sex Differences in the Pattern of Atherosclerotic Disease This work unveiled unique sex differences in the arterial distribution pattern of atherosclerotic disease. Our results were consistent with those of previous studies, which showed increased carotid and femoral plaque burden in men compared with women.12,27 Additionally, men had greater plaque burden within all proximal femoral territories. Sex differences in atherosclerotic burden may be partially attributable toward anatomic differences in vasculature. A
Femoral Plaque Has a Stronger Association with CAD than Carotid Plaque Associations of carotid plaque with cardiac risk factors, CAD, and cardiovascular outcomes are well established.16,20,29 More recently, studies have revealed the utility of a femoral plaque assessment in patient risk stratification. In a study of middle-aged men, femoral plaque presence had a stronger correlation with traditional cardiovascular risk factors and positive coronary calcium score than did carotid plaque.30 In 2009, Griffin et al.31 demonstrated increased odds of cardiovascular disease with increased number of femoral bifurcation plaques.31 In an autopsy study of 1,074 individuals by Sawabe et al.,32 it was shown that disease advanced more rapidly at the femoral arteries than at the carotid arteries. Similarly, several studies have demonstrated that the femoral arteries are more frequently affected by atherosclerosis than the carotid arteries in both women and men.33-35 Perhaps there are similar patterns of low shear stress and disturbed blood flow at the coronary and femoral arteries, leading to the relatively early onset of disease in the bifurcating and curving regions of these beds. However, few studies have accounted for sex differences when exploring vascular ultrasound screening tools. We have confirmed the stronger association of femoral over carotid atherosclerosis with coronary disease in both sexes; additionally, we have identified unique femoral segments for optimal CAD identification in either sex. Similar segment-specific patterns emerged in the association between femoral plaque burden and CAD extent. Although this was a cross-sectional analysis, there is increased risk for mortality and major adverse cardiovascular events with increased CAD extent from single- to triple-vessel disease.13 Segment-specific patterns may be attributable toward sex differences in vascular anatomy. In data collected from the European Carotid Surgery Trial, women had larger internal carotid diameters relative to common and external carotid diameters than did men, which may have contributed to external carotid arterial disease.36 It is possible that in women, anatomic effects at the common femoral artery preclude the development of disease, while in men, this occurs at the femoral bifurcation. Further studies are needed to elucidate the role of vascular anatomy in the sex-specific pattern of femoral artery disease progression. Plaque Area rather than Height is Associated with CAD in Women In addition to spatial differences, we noted sex differences in optimal atherosclerosis quantification methods. Although the CIs were wide, in women, plaque area consistently yielded the strongest association with CAD. Such a pattern suggests that plaque area may better reflect the true burden of atherosclerotic disease in women. Akin to this notion, previous studies have noted benefits of plaque quantification versus the simple detection of plaque presence in risk stratification.12 Contemporarily, three-dimensional ultrasound has emerged as a technique allowing the visualization of atherosclerosis in all planes
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Table 4 Contingency table of combined ultrasound assessments to identify significant, obstructive CAD by sex Sex
Assessment
Women Stress test
Men
n
Threshold value
79 (+) ( )
AUC
With CAD
Without CAD
PPV, % NPV, % Sensitivity,% Specificity, % LR+
LR
TP 23 FN 7
FP TN
44 4
34
36
77
8
0.84 2.80
NRI,%
Carotid
170 $16.5 mm2 <16.5 mm2
0.740 TP 60 FN 18
FP TN
45 47
57
72
77
51
1.57 0.45
37
FemoralCom
170 $11.5 mm2 <11.5 mm2
0.691 TP 64 FN 14
FP TN
48 44
57
76
82
48
1.57 0.38
45
FemoralCom + carotid 170 $42.0 mm2 <42.0 mm2
0.764 TP 67 FN 11
FP TN
43 49
61
82
86
53
1.84 0.26
53
TP 85 FN 40
FP TN
5 8
94
17
68
62
1.77 0.52
Stress test
138 (+) ( )
Carotid
330 $2.1 mm <2.1 mm
0.718 TP 202 FP FN 29 TN
57 42
78
59
87
42
1.52 0.30
22
FemoralBif
330 $1.9 mm <1.9 mm
0.752 TP 192 FP FN 39 TN
42 57
82
59
83
58
1.96 0.29
31
FemoralBif + carotid
330 $2.8 mm <2.8 mm
0.773 TP 202 FP FN 29 TN
47 52
81
64
87
55
1.84 0.24
37
Bif, Bifurcation; Com, common; FN, false negative; FP, false positive; LR+, positive likelihood ratio; LR , negative likelihood ratio; NPV, negative predictive value; NRI, net reclassification improvement; PPV, positive predictive value; TN, true negative; TP, true positive. (Values) indicate participants with positive stress test results.
Figure 6 A men-specific vascular ultrasound assessment has reduced accuracy for CAD detection in women. ROC curve analyses demonstrate the abilities of combined femoral bifurcation and carotid MPH (A) and TPA (B), as well as combined common femoral and carotid MPH (C) and TPA (D) ultrasound assessments, to identify significant CAD in either sex. A men-specific vascular ultrasound assessment has reduced accuracy for CAD detection in women (A).
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Table 5 Independent identifiers of significant, obstructive CAD by sex
Sex
Variables added in step
Women Step 1: demographics
Men
c2
Hosmer and Lemeshow Cox and goodnessSnell R2 of-fit P value
3.14
0.018
.868
Step 2: comorbidities
27.10
0.151
.816
Step 3: referral indications
41.91
0.223
.560
Step 4: TPA carotid
61.11
0.308
.924
TPA femoralCom
55.88
0.286
.245
TPA femoralCom + carotid
68.43
0.338
.859
Step 1: demographics
19.98
0.059
.709
Step 2: comorbidities
43.61
0.126
.586
Step 3: referral indications
90.79
0.244
.272
Step 4: MPH carotid
109.68
0.286
.231
MPH femoralBif
120.85
0.311
.974
MPH femoralBif + carotid
135.26
0.340
.447
BMI, Body mass index; eGFR, estimated glomerular filtration rate; MI, myocardial infarction. Stepwise forward logistic regression for the identification of significant CAD ($50% stenosis) by sex, adding participant demographics (age, BMI) in step 1, cardiac comorbidities (hypertension, hyperlipidemia, diabetes, smoking status, eGFR) in step 2, referral indications (arrhythmia, dyspnea, chest pain, positive stress test results, MI) in step 3, and ultrasound assessments in step 4. For the c2 test, P < .001 for all iterations. For the Hosmer and Lemeshow goodness-of-fit test, significant values indicate poor fit.
and, correspondingly, shows improved discriminatory capability for disease.11 Future studies that assess the utility of three-dimensional ultrasound at the common femoral artery may have value in the development of a female-specific risk stratification tool. Combined Common Femoral and Carotid Plaque Burden Best Identifies CAD In women, a combined assessment of TPA at the common femoral and carotid arteries yielded the most accurate identification of significant CAD. Previous studies have demonstrated the increased value of a combined plaque burden analysis over that of a single arterial bed.24,37 Atherosclerosis typically manifests first in the aorta, followed by the coronary, peripheral, and carotid arteries. However, as this progression is not identical among all individuals, an aggregate arterial assessment may most safely capture the disease burden.37 Importantly, most women who were referred for angiography because of positive stress test results did not have significant CAD. In both sexes, more than half of participants with falsepositive stress test results were correctly identified as having no CAD by ultrasound, and few participants with CAD were missed. In summary, the most notable findings of our study are as follows: (1) changes in femoral plaque burden are more indicative of diseased coronaries than carotid plaque burden in both sexes, and moreover, the femoral segments showing the greatest impact on risk stratification are sex specific, wherein women display the strongest association with coronary atherosclerosis at the common femoral artery, whereas
in men, this occurs at the femoral bifurcation; (2) plaque area may be a stronger indicator of coronary disease than plaque height in women; (3) a combined femoral and carotid plaque burden assessment demonstrates improved disease detection over an assessment of either arterial bed alone in both sexes; and (4) vascular ultrasound may show particular value in women, in whom traditional risk assessments are less effective. Cumulatively, our findings highlight potential value of vascular ultrasound as a cardiovascular screening tool. Study Limitations Because the study population was composed of symptomatic participants referred for angiography, it remains unknown whether these methods can be used in assessing asymptomatic risk. Because this was a cross-sectional study, we also do not yet know associations of plaque burden with future cardiovascular risk. Later analyses on outcomes will provide more information on using vascular ultrasound to assess risk in women and men. Test performance was assessed on the basis of threshold cutoff values established from receiver operating characteristic curves within the same population; because these represent ideal cut points, the sensitivity and specificity of these tests should be reassessed in another population to confirm reproducibility. Furthermore, because two-dimensional ultrasound captures images in only two planes, this may have led to overestimations or underestimations of femoral or carotid disease or affected associations with coronary disease. Correspondingly, CIs obtained from analysis of the relatively small group of women (n = 170) are wide. Variability of this plaque measurement may have artificially improved the association of plaque area with CAD in women, contributing to the sex difference observed in optimal atherosclerosis quantification methods. Further evidence of associations of vascular ultrasound with angiography is needed in a larger cohort study. Coronary quantitative techniques such as intravascular ultrasound would provide a better assessment of coronary plaque or vascular lumen and is of interest for future studies to further define association with peripheral vascular beds. Last, because our study population was primarily Caucasian (96%), these results will require validation in other cohorts. CONCLUSION The present study demonstrates an inexpensive, risk-free method to identify obstructive CAD, feasible for routine use as a cardiovascular screening tool. A combined assessment of common femoral and carotid plaque area yielded sensitivity of 86% for ruling out obstructive CAD in women and ruled out more than half of participants with false-positive stress test results. Further investigation will help elucidate the clinical value of vascular ultrasound incorporated into cardiovascular management algorithms. ACKNOWLEDGMENTS We thank the staff of the Kingston General Hospital Cardiac Catheterization and Vascular Doppler Laboratories for their kind help in this study. We also thank Wilma M. Hopman and Gopi Krishnan Rajbahadur for assistance with statistical analysis and Julia E. Herr and Paul A. D. Colosimo for assistance with figure creation. REFERENCES 1. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific
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19. Pencina MJ, D’Agostino RB Sr., D’Agostino RB Jr., Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 2008;27:157-72. 20. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014;103:137-49. 21. Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992;326:381-6. 22. Goff DC Jr., Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB, Gibbons R, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129:S49-73. 23. Flanigan DP, Ballard JL, Robinson D, Galliano M, Blecker G, Harward TR. Duplex ultrasound of the superficial femoral artery is a better screening tool than ankle-brachial index to identify at risk patients with lower extremity atherosclerosis. J Vasc Surg 2008;47:789-92. 24. Kafetzakis A, Kochiadakis G, Laliotis A, Peteinarakis I, Touloupakis E, Igoumenidis N, et al. Association of subclinical wall changes of carotid, femoral, and popliteal arteries with obstructive coronary artery disease in patients undergoing coronary angiography. Chest 2005;128:2538-43. 25. Yerly P, Marques-Vidal P, Owlya R, Eeckhout E, Kappenberger L, Darioli R, et al. The atherosclerosis burden score (ABS): a convenient ultrasound-based score of peripheral atherosclerosis for coronary artery disease prediction. J Cardiovasc Transl Res 2015;8:138-47. 26. Nambi V, Chambless L, Folsom AR, He M, Hu Y, Mosley T, et al. Carotid intima-media thickness and presence or absence of plaque improves prediction of coronary heart disease risk: the ARIC (Atherosclerosis Risk in Communities) study. J Am Coll Cardiol 2010;55:1600-7. 27. Wood NB, Zhao SZ, Zambanini A, Jackson M, Gedroyc W, Thom SA, et al. Curvature and tortuosity of the superficial femoral artery: a possible risk factor for peripheral arterial disease. J Appl Physiol (1985) 2006;101:1412-8. 28. Yang XP, Reckelhoff JF. Estrogen, hormonal replacement therapy and cardiovascular disease. Curr Opin Nephrol Hypertens 2011;20:133-8. 29. Spence JD. Ultrasound measurement of carotid plaque as a surrogate outcome for coronary artery disease. Am J Cardiol 2002;89:10B-5B. 30. Laclaustra M, Casasnovas JA, Fernandez-Ortiz A, Fuster V, Leon-Latre M, Jimenez-Borreguero LJ, et al. Femoral and carotid subclinical atherosclerosis association with risk factors and coronary calcium: the AWHS study. J Am Coll Cardiol 2016;67:1263-74. 31. Griffin M, Nicolaides A, Tyllis T, Georgiou N, Martin RM, Bond D, et al. Carotid and femoral arterial wall changes and the prevalence of clinical cardiovascular disease. Vasc Med 2009;14:227-32. 32. Sawabe M, Arai T, Kasahara I, Hamamatsu A, Esaki Y, Nakahara K, et al. Sustained progression and loss of the gender-related difference in atherosclerosis in the very old: a pathological study of 1074 consecutive autopsy cases. Atherosclerosis 2006;186:374-9. 33. Fernandez-Friera L, Penalvo JL, Fernandez-Ortiz A, Ibanez B, LopezMelgar B, Laclaustra M, et al. Prevalence, vascular distribution, and multiterritorial extent of subclinical atherosclerosis in a middle-aged cohort: the PESA (Progression of Early Subclinical Atherosclerosis) study. Circulation 2015;131:2104-13. 34. Kroger K, Kucharczik A, Hirche H, Rudofsky G. Atherosclerotic lesions are more frequent in femoral arteries than in carotid arteries independent of increasing number of risk factors. Angiology 1999;50:649-54. 35. Li LX, Wu X, Lu JX, Tu YF, Yu LB, Li MF, et al. Comparison of carotid and lower limb atherosclerotic lesions in both previously known and newly diagnosed type 2 diabetes mellitus. J Diabetes Investig 2014;5:734-42. 36. Schulz UG, Rothwell PM. Sex differences in carotid bifurcation anatomy and the distribution of atherosclerotic plaque. Stroke 2001;32:1525-31. 37. Otsuka F, Fuster V, Narula J, Virmani R. Omnipresent atherosclerotic disease: time to depart from analysis of individual vascular beds. Mt Sinai J Med 2012;79:641-53.
Background: It remains difficult to assess cardiovascular risk in symptomatic women. The development of femoral plaque precedes adverse cardiovascular events. However, associations of femoral plaque burden with coronary artery disease (CAD) severity and extent are unknown. The aim of this study was to determine sex-specific plaque quantification markers by vascular ultrasound for identifying significant, obstructive CAD. Methods: In this cross-sectional study, 500 participants (34% women) underwent carotid and femoral ultrasound following coronary angiography. Maximal plaque height and total plaque area were quantified. Logistic regression was used to determine associations of plaque burden with significant, obstructive CAD ($50% stenosis), when adjusted for age and cardiac risk factors. CAD prediction was evaluated using receiver operating characteristic areas under the curve (AUCs). Results: Two hundred thirty-one men (70%) and 78 women (46%) had significant CAD. A combined assessment of femoral bifurcation and carotid maximal plaque height was the most accurate identifier of CAD in men (AUC = 0.773, cutoff $ 2.7 mm, 87% sensitivity, 53% specificity) but a poorer indicator of CAD in women (AUC = 0.659, P < .01). In contrast, the strongest identification of CAD in women was achieved by a combined analysis of common femoral and carotid total plaque area (AUC = 0.764, cutoff $ 42.0 mm2, 86% sensitivity, 53% specificity). At this value, more than half of women with false-positive stress test results were correctly identified as having no significant CAD. Conclusion: Combined femoral and carotid plaque burden assessments effectively ruled out significant disease in both sexes. Vascular ultrasound may have particular value for cardiovascular risk stratification in women, in whom traditional screening tools are less effective. (J Am Soc Echocardiogr 2019;-:---.) Keywords: Coronary artery disease, Sex differences, Vascular ultrasound, Plaque quantification, Peripheral arterial disease
From the Department of Biomedical and Molecular Sciences (K.N.C., L.E.M., A.M.J.); and the Department of Medicine (M.B., M.-F.H., J.G.A., A.M.J.), Queen’s University, Kingston, Ontario, Canada. This work was supported by Queen’s University; a Canada Foundation for Innovation and Ontario Research Fund (CFI 29051); a Ministry of Research,Innovation and Science Early Research Award (ER15-11-029); the Southeastern Ontario Academic Medical Organization (Clinician Scientist Development Program); the Heart and Stroke Foundation of Canada (Clinician Scientist I 7500) to Dr. Johri; and a Natural Sciences and Engineering Research Council of Canada scholarship and Canadian Institutes of Health Research Travel Award (155048) to Colledanchise. Conflicts of Interest: None. Reprint requests: Amer M. Johri, MD, MSc, FRCPC, FASE, Queen’s University, Department of Medicine, Division of Cardiology, Cardiovascular Imaging Network at Queen’s, 76 Stuart Street, FAPC3, Kingston, ON K7L 2V7, Canada (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2019 by the American Society of Echocardiography. https://doi.org/10.1016/j.echo.2019.07.024
Globally, cardiovascular disease remains the most prominent cause of death in both men and women. In 2015, 85% of these deaths were due to ischemic heart disease (IHD) and stroke.1 While such mortality rates have decreased substantially in men over the last three decades, this rate has not been matched in women,2 an alarming trend reflecting the underestimation of cardiovascular risk that leads to underdiagnoses and treatment of IHD.3 It is accepted that sex differences exist in the pathophysiology of IHD. In men, the common manifestation is anatomically obstructive coronary artery disease (CAD). In women, the burden of obstructive CAD is lower, particularly in those who are premenopausal,4 and myocardial ischemia is frequently associated with nonstenotic and diffuse atherosclerosis, plaque erosion, and coronary microvascular dysfunction.5,6 There is historical underrepresentation of women in clinical trials.7 As such, current IHD management algorithms have been derived from studies with mostly male subjects.3 Thus, although unique, sex-specific IHD pathophysiologies exist, diagnostic and therapeutic tools that focus on ‘‘critical stenosis’’ assessment are still used in both sexes. Consequently, current risk stratification tools fail to distinguish between stenotic and other ischemia-causing pathologies and thus are not adequate in ruling out obstructive CAD in women. For 1
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example, in a study of 397,954 patients undergoing elective AUC = Area under the curve angiography in the American College of Cardiology National CAD = Coronary artery Cardiovascular Data Registry, disease 73% of female patients had no CV = Coefficient of variation obstructive CAD.8 Several noninvasive imaging ICC = Intraclass correlation tools have shown value in the coefficient detection of obstructive CAD, IHD = Ischemic heart disease such as vascular ultrasound, MPH = Maximal plaque computed tomographic coroheight nary angiography, and stress testing.9-11 The unique OR = Odds ratio advantages of ultrasound, TPA = Total plaque area including low cost and the absence of radiation, lend favorability to its use as a routine screening tool. However, the majority of vascular ultrasound studies have involved male cohorts; conversely, few data are available on the use of vascular ultrasound as a cardiovascular screening tool in women. Most recently, the Progression of Early Subclinical Atherosclerosis study suggested that evaluation of carotid and femoral atherosclerosis may improve early atherosclerotic disease detection in both men and women.12 The aim of the present study was to evaluate vascular ultrasound as a sex-specific imaging marker for the identification of obstructive CAD in symptomatic men and women. Abbreviations
METHODS Participant Recruitment For this prospective study, participants referred for coronary angiography were recruited from the Cardiac Catheterization Laboratory at the Kingston Health Sciences Centre in Kingston, Ontario, Canada, between January 2017 and February 2018. Participants were eligible for the study if they met the following criteria: men and women aged $18 years, referred for clinically indicated coronary angiography, and willing to give written informed consent. Exclusion criteria were presentation of an acute coronary syndrome, clinical contraindications to angiography or ultrasound, and previous femoral or carotid artery surgery. Demographic and baseline characteristics, including cardiovascular risk factors, use of medications, and stress test results, were collected from participant medical charts and interviews. Cardiovascular risk factors were defined as follows: diabetes mellitus, fasting plasma glucose $126 mg/dL or treatment with insulin or antihyperglycemic medication; hypertension, systolic or diastolic blood pressure $140 mm Hg or 90 mm Hg or use of antihyperlipidemic medication; hyperlipidemia, total cholesterol $240 mg/dL, low-density lipoprotein cholesterol $160 mg/dL, or use of lipid-lowering drugs or use of antilipidemic medication; and current family history of cardiovascular disease, an immediate relative diagnosed with cardiovascular disease. Investigators conducting and analyzing the ultrasound imaging were blinded to the results of angiography to limit potential biases. Ethics This study was approved by the Queen’s University Health Sciences and Affiliated Teaching Hospitals research ethics board. All participants provided written informed consent before entry into the study.
Figure 1 Segments of the femoral artery visualized by ultrasound. Imaging at the proximal femoral artery (A) included the distal 3 cm of the common femoral artery, the femoral bifurcation, and the proximal 3 cm of both the superficial and profunda femoral arteries. Imaging at the adductor’s canal (B) included the distal 15 cm of the superficial femoral artery. The segment measurements shown are approximate.
Coronary Angiography Interpretation Coronary angiography was carried out by one of four experienced interventional cardiologists using the standard Judkins imaging protocol. Angiographic results were scored using a previously reported system as follows: 0 = no or minimal disease (0%–19% narrowing in any segment), 1 = mild disease (20%–49% narrowing in any segment), 2 = moderate disease (luminal narrowing of at least one segment of 50%–69%), and 3 = severe ($70% narrowing within any segment of the main branches of the coronary artery or $50% in the left main coronary artery).11 Segments with previous percutaneous coronary intervention and stenting or coronary artery bypass grafting were deemed to have severe disease (score of 3). Significant obstructive CAD was defined as a luminal diameter reduction of $50% (score of 2 or 3). CAD extent was defined by $50% stenosis in 0, 1 (single-vessel), 2 (double-vessel), or 3 (triple-vessel) coronary segments. Given its prognostic significance, $50% stenosis in the left main coronary artery was defined as triple-vessel disease.13
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HIGHLIGHTS In both sexes, femoral plaque is more indicative of coronary disease than carotid. In women, the combined femoral and carotid plaque area has the highest sensitivity. Over half of false-positive stress test cases are resolved by ultrasound assessment. Plaque assessment provides an independent benefit over traditional risk factors. Ultrasound Analysis and Interpretation Ultrasound examinations were conducted using a Vivid E9 Cardiovascular Ultrasound System equipped with a 9L transducer (GE Healthcare, Mississauga, Ontario, Canada). Ultrasound scans were performed by an experienced imaging technician within 24 hours of coronary angiography. An axial sweep and longitudinal still images were acquired from at least three different angles per segment at the distal common femoral artery, the femoral bifurcation, and the proximal superficial and profunda femoral arteries. Subsequent images were acquired at the distal region of superficial femoral artery, within the adductor’s canal (Figure 1). In the carotid artery, images were obtained at the distal 3 cm of the common carotid artery, the carotid bifurcation, and the proximal 1 cm of the internal and external carotid arteries. Acquired images were analyzed offline using GE Healthcare EchoPAC software, as previously described.14 Plaque was defined using the criteria as a focal structure that protruded into the arterial lumen by $0.5 mm or by 50% of the surrounding intima-media thickness or that was $1.5 mm in thickness from the mediaadventitia border to the intima-lumen border.15 Briefly, plaque height was measured manually by caliper in the axial or longitudinal view at right angle to the vessel wall. The maximal plaque height (MPH) between the right or left sides of each vessel was used in the analysis.16 To determine plaque area, the plaque perimeter was traced in the longitudinal view and calculated automatically. The total plaque area (TPA) was determined from a summation of all plaques in both sides of each vessel.
Statistical Analyses Statistical analyses were conducted using JMP version 12 software (SAS Institute, Cary, North Carolina). Two-group comparisons were conducted using the Wilcoxon-Mann-Whitney test for continuous variables and the Fisher exact test for categorical variables. Logistic regression was used to determine independent odds ratios (ORs) of femoral and carotid plaque burden, scaled by interquartile ranges, for significant obstructive CAD ($50% stenosis), when adjusted for age, body mass index, estimated glomerular filtration rate, and traditional cardiac risk factors, including the presence of diabetes, hypertension, hyperlipidemia, and current smoking. Stepwise forward regression analysis, including demographic data in step 1, cardiac comorbidities in step 2, referral indications in step 3, and plaque burden ultrasound assessments in step 4, was also performed. Spearman’s rank correlation coefficient was used to assess correlations of carotid and femoral plaque measures with the burden and extent of coronary disease. Receiver operating characteristic curves were created using DeLong’s methods to determine the most accurate ultrasound
Figure 2 Flowchart of the study population. The flow of participants during the study recruitment and data collection processes. methods for predicting CAD, indicated by the area under the curve (AUC). Net reclassification improvement (NRI) was also determined for plaque burden assessments. The intraclass correlation coefficient (ICC) and coefficient of variation (CV) were used to evaluate interobserver reproducibility from a subset of 60 participants (30 women and 30 men, 120 arteries), measured independently by two imaging technicians. To determine intraobserver reproducibility, an imaging technician repeated analysis of a subset of 60 participants (30 women and 30 men) twice, 60 days apart. P values < .05 were considered to indicate statistical significance.
RESULTS Study Population Characteristics The final study population was composed of 500 participants, 34% of whom were women (Figure 2). The majority of both women and men had hypertension (66% and 74%, respectively) and hyperlipidemia (56% and 73%, respectively). Men with significant obstructive CAD ($50% coronary stenosis) were older, had lower estimated glomerular filtration rates, and more often had diabetes and hyperlipidemia, with histories of myocardial infarction than those without significant CAD. Women with significant CAD were more likely to have diabetes, hypertension, and hyperlipidemia, to be current smokers, and to have histories of myocardial infarction (P < .05). The most common presenting symptom in men and women was chest pain (61% and 56%, respectively). However, in both sexes, there were no differences in the rates of chest pain presentation between participants with significant CAD and those without disease.
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Journal of the American Society of Echocardiography - 2019
Table 1 Baseline characteristics of the study population according to sex and the presence of significant, obstructive CAD Women
Variable
All (N = 170)
With CAD (n = 78)
Men
Without CAD (n = 92)
P*
All (N = 330)
With CAD (n = 231)
Without CAD (n = 99)
P*
All P value†
Cardiovascular risk factors Age, y
66 6 11
66 6 11
66 6 11
.86
64 6 10
65 6 9
60 6 11
<.01
.03
BMI, kg/m2
33 6 27
32 6 7
34 6 36
.11
30 6 6
30 6 6
30 6 6
.82
.44
eGFR, mL/min/1.73 m2
77 6 19
77 6 19
78 6 19
.73
79 6 19
78 6 19
83 6 18
.03
.28
Cardiovascular risk factors Diabetes Hypertension
43 (25)
28 (36)
15 (16)
<.01
110 (33)
91 (39)
19 (19)
<.01
.07
113 (66)
61 (78)
52 (57)
<.01
242 (74)
177 (77)
65 (66)
.06
.12 <.01
Hyperlipidemia
95 (56)
53 (68)
42 (46)
<.01
239 (73)
185 (80)
54 (55)
<.01
Current smoking
24 (14)
17 (22)
7 (8)
.01
73 (22)
53 (23)
20 (20)
.66
.04
125 (76)
64 (86)
61 (68)
.01
204 (63)
151 (67)
53 (55)
.04
<.01
7 (8)
<.01
7 (7)
<.01
.03
Family history of CVD History of MI
43 (25)
36 (46)
115 (35)
108 (47)
History of intervention
27 (16)
27 (35)
68 (21)
68 (29)
.23
26 (15)
26 (33)
66 (20)
66 (29)
.22
1 (0)
1 (1)
7 (2)
7 (3)
.28
PCI CABG Referral indications Arrhythmia
17 (10)
5 (6)
12 (13)
.20
31 (9)
16 (7)
15 (15)
.02
.87
Dyspnea
73 (43)
32 (41)
41 (45)
.76
105 (32)
71 (31)
34 (34)
.52
.02
103 (61)
47 (60)
56 (61)
$.999
185 (56)
135 (58)
50 (51)
.19
.34
Positive stress test results
67 (39)
23 (29)
44 (48)
.02
125 (38)
85 (37)
40 (44)
.54
.77
Positive ECG results
30 (18)
11 (14)
19 (21)
.80
47 (20)
31 (13)
16 (16)
.84
.36
Positive echocardiographic results
16 (9)
4 (5)
12 (13)
.38
26 (8)
12 (5)
14 (14)
.02
.59
Positive nuclear imaging results
20 (12)
8 (9)
12 (13)
.58
51 (15)
41 (18)
10 (10)
.02
.16
39 (23)
30 (38)
9 (10)
<.01
82 (25)
75 (32)
7 (7)
<.01
.66
8 (5)
3 (4)
5 (5)
.73
19 (6)
13 (6)
6 (6)
$.999
.68
17 (10)
4 (5)
13 (14)
.07
45 (14)
27 (12)
18 (18)
.16
.32
Chest pain
MI Valve disease Decreased LV function
BMI, Body mass index; CABG, coronary artery bypass graft; CVD, cardiovascular disease; ECG, electrocardiographic; eGFR, estimated glomerular filtration rate; LV, left ventricular; MI, myocardial infarction; PCI, percutaneous coronary intervention. Data are expressed as mean 6 SD or as number (percentage). Note multiple stress tests in certain participants. *P value of the differences between participants with CAD ($50% stenosis) and without. † P value of differences between men and women.
Notably, a higher proportion of participants without CAD were referred for angiography because of positive stress test results than were participants with CAD (n = 84; P < .01). Fifty-two percent of such participants were women. The baseline characteristics are summarized in Table 1. Sex Differences in Plaque Burden and Arterial Distribution Plaque burden per arterial segment and the presence or absence of significant, obstructive CAD are presented in Table 2. Women and men with significant CAD had increased plaque burden in all observed carotid and femoral segments, including the carotid bulb, and proximal superficial, profunda, bifurcation, common femoral, and adductor’s canal segments, compared with those without significant CAD (P < .05). Men had greater plaque burden than women in all segments (P < .01). When divided into age groups ($60 years) and comparing sex differences in participants with CAD (Figure 3), older men had greater plaque burden (MPH and TPA) in the common femoral, femoral bifurcation, and carotid bulb segments only (P < .05). When comparing younger men and women with CAD,
men had greater plaque burden (MPH and TPA) in the common femoral segment only (P < .05). We assessed whether the total number of plaques per vascular segment was predictive of CAD. In the overall population, the AUCs for femoral, carotid, and combined segments were 0.740, 0.676, and 0.759, respectively, for predicting significant CAD. In women, the AUCs for total plaque number in femoral, carotid, and combined segments were 0.683, 0.716, and 0.725, respectively. In men, the AUCs for femoral, carotid, and combined segments were 0.751, 0.679, and 0.756, respectively. Associations of Proximal Femoral, Adductor, and Carotid Plaque Burden with CAD Logistic regression indicated that in women, diabetes (OR, 2.3; 95% CI, 1.0–5.3; P = .04) and current smoking (OR, 5.1; 95% CI, 1.8– 16.5; P < .01) were independent contributors of significant CAD ($50 stenosis). In men, independent risk factors for significant CAD were increased age (OR, 1.1 per year; 95% CI, 1.0–1.1; P < .01), presence of hyperlipidemia (OR, 2.8; 95% CI, 1.6–5.0;
Colledanchise et al 5
Journal of the American Society of Echocardiography Volume - Number -
Table 2 Plaque burden distribution according to sex and the presence of significant, obstructive CAD Women Arterial segment
Men
All (N = 170)
With CAD (n = 78)
Without CAD (n = 92)
P*
All (N = 330)
With CAD (n = 231)
Without CAD (n = 99)
P*
All P value†
MPH, mm 3.0 6 1.7
3.6 6 1.5
2.5 6 1.7
<.01
3.9 6 1.9
4.3 6 1.6
2.8 6 2.1
<.01
<.01
Profunda
0.5 6 0.9
0.7 6 0.9
0.4 6 0.8
.02
0.9 6 1.1
1.0 6 1.1
0.6 6 1.0
<.01
<.01
Superficial
1.2 6 1.3
1.4 6 1.3
1.0 6 1.3
.04
1.6 6 1.5
1.9 6 1.4
1.1 6 1.4
<.01
<.01
Bifurcation
2.2 6 1.7
2.6 6 1.7
1.8 6 1.7
<.01
2.7 6 1.9
3.2 6 1.8
1.5 6 1.8
<.01
<.01
Common
2.6 6 1.8
3.2 6 1.8
2.1 6 1.7
<.01
3.5 6 2.0
4.0 6 1.8
2.5 6 2.2
<.01
<.01
1.5 6 1.1
1.7 6 1.1
1.3 6 1.0
.06
2.3 6 1.3
2.5 6 1.4
1.9 6 1.3
<.01
<.01
2.47 6 1.55
3.0 6 1.4
2.1 6 1.6
<.01
3.0 6 1.4
3.3 6 1.3
2.3 6 1.4
<.001
<.01
89.9 6 90.5
125.8 6 101.4
59.4 6 66.8
<.01
4.1 6 9.0
5.2 6 9.8
3.1 6 8.1
Superficial
15.0 6 28.3
23.0 6 35.0
Bifurcation
29.6 6 32.9
Common
Proximal femoral
Adductor Carotid TPA, mm2
155.7 6 136.3
183.3 6 131.7
91.1 6 125.1
<.01
<.01
.02
10.0 6 17.7
11.8 6 19.1
5.6 6 12.9
<.01
<.01
8.2 6 18.6
<.01
26.9 6 44.8
31.5 6 46.9
16.2 6 37.6
<.01
<.01
40.7 6 37.6
20.1 6 24.7
<.01
41.4 6 40.4
50.5 6 40.2
20.3 6 32.7
<.01
<.01
41.3 6 42.4
56.9 6 46.8
28.0 6 33.5
<.01
77.4 6 68.0
89.8 6 63.9
48.9 6 69.3
<.01
<.01
Adductor
35.6 6 59.1
49.2 6 76.6
23.9 6 34.5
.04
88.4 6 121.5
103.2 6 132.9
53.4 6 79.0
<.01
<.01
Carotid
35.2 6 33.1
50.4 6 36.6
22.3 6 23.2
<.01
58.9 6 48.5
68.0 6 49.9
37.5 6 37.5
<.01
<.01
Proximal femoral Profunda
Data are expressed as mean 6 SD. *P value of the differences between participants with CAD ($50% stenosis) and without. † P value of the differences between men and women.
P < .01), and diabetes (OR, 2.2; 95% CI, 1.2–4.1; P = .01). Table 3 shows the adjusted ORs of significant CAD for interquartile range increases in plaque burden at the carotid artery and the proximal and adductor canal regions of the femoral artery. Notably, in both women and men, increased plaque burden at the proximal femoral artery was the strongest indicator of significant CAD. In women, increased TPA had a stronger association with CAD than increased MPH, such that each 64.0 mm2 increase corresponded to 3.6 times greater odds of significant CAD.
rior descending coronary artery and carotid TPA (OR, 2.2; 95% CI, 1.4–3.5; P < .01). In men, the strongest association was between the right coronary artery and carotid TPA (OR, 1.8; 95% CI, 1.3– 2.6; P < .01). We further assessed femoral plaque burden associations with each coronary artery. In women, the strongest association was between the circumflex coronary artery and common femoral MPH (OR, 3.5; 95% CI, 1.7–8.1; P < .01). In men, the strongest association was between the right coronary artery and femoral bifurcation MPH (OR, 2.4; 95% CI, 1.6–3.8; P < .01).
Associations of Plaque Burden at Individual Vascular Segments with CAD All femoral and carotid plaque burden segment measures were significantly correlated with increased angiographic scores, from 0 to 3, and increased extent of diseased coronary vessels, from no disease to triple-vessel disease. In comparing proximal femoral segments (adjusting for cardiac risk factors), in women, increased plaque burden at the common femoral artery segment yielded the most powerful association with significant CAD (TPA: OR, 3.4; 95% CI, 1.9–6.6; P < .01), increased angiographic score (r = 0.37, P < .01), and CAD extent (r = 0.35, P < .01). In contrast, in men, increased plaque burden at the femoral bifurcation segment was most indicative of significant CAD (MPH: OR, 4.1; 95% CI, 2.5–7.0; P < .01; Figure 4), as well as increased angiographic score and CAD extent (r = 0.39, P < .01, for both measurements). Associations of Carotid and Femoral Plaque Burden with Coronary Artery Segments We assessed carotid plaque burden associations with each coronary artery. In women, the strongest association was between the left ante-
Predictive Values of Combined Plaque Burden Assessments for CAD Associations with CAD were improved when combining femoral and carotid bulb plaque burden (Figure 5). In women, adding carotid bulb TPA information (AUC = 0.740; 95% CI, 0.665– 0.815) increased the AUC of common femoral TPA from 0.691 (95% CI, 0.610–0.772) to 0.764 (95% CI, 0.691–0.837; P < .01). A cutoff value of 42.0 mm2 for this combined assessment yielded sensitivity of 86% and specificity of 53% for ruling out significant obstructive CAD. At this value, 49 of 92 women without significant CAD were correctly identified. Twenty-three such women (47%) were referred for angiography because of positive stress test results. Assessing the NRI17-19 in relation to the stress test results (positive indicating high risk, negative indicating lower risk) for angiography referrals showed a 53% NRI for CAD reclassification. Similarly, in men, the AUC increased from 0.718 (95% CI, 0.656–0.781) when considering carotid MPH alone to 0.773 (95% CI, 0.688– 0.816) when adding femoral bifurcation MPH information
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Journal of the American Society of Echocardiography - 2019
Figure 3 Distribution of plaque burden in carotid and femoral arteries by age, presence of significant CAD, and sex. In participants with CAD, men >60 years had greater plaque burden than women in the common femoral, femoral bifurcation, and carotid bulb segments (P < .05). Error bars were constructed using 1 standard error of the mean.
Table 3 ORs of significant, obstructive CAD with plaque burden in the proximal femoral, adductor canal, and carotid arteries Women Arterial segment
Median (IQR)
Men
OR (95% CI)
P
Median (IQR)
OR (95% CI)
P
<.01
MPH, mm Proximal femoral
3.1 (2.1–4.1)
2.6 (1.6–4.7)
<.01
4.2 (2.7–5.1)
2.5 (1.7–3.9)
Adductor
1.6 (0.3–2.1)
2.4 (1.1–5.1)
.02
2.2 (1.6–3.0)
1.2 (0.9–1.8)
.27
Carotid
3.0 (2.2–3.9)
2.0 (1.2–3.5)
<.01
3.0 (2.2–3.9)
2.2 (1.5–3.3)
<.01 <.01
TPA, mm2 Proximal femoral
64.0 (14.6–134.5)
3.6 (2.0–7.1)
<.01
125.6 (43.5–233.0)
2.8 (1.7–5.0)
Adductor
12.0 (0.5–44.4)
1.7 (1.2–2.7)
<.01
43.0 (11.0–111.0)
1.2 (0.9–1.8)
.21
Carotid
27.7 (10.7–50.5)
3.2 (1.9–5.7)
<.01
48.1 (25.1–83.2)
2.1 (1.4–3.3)
<.01
IQR, Interquartile range. Logistic regression showing unit ORs of arterial territories for the identification of significant CAD ($50% stenosis) by sex, after adjusting for age, body mass index, estimated glomerular filtration rate, and cardiac risk factors.
(AUC = 0.749; 95% CI, 0.694–0.810) into the model (P < .01). A cutoff value of 2.7 mm for this combined assessment yielded sensitivity of 87% and specificity of 53% for ruling out CAD (Table 4). This vascular assessment would have produced a 37% NRI for CAD reclassification. Notably, use of this men-specific
assessment yielded a decreased AUC of 0.659 (95% CI, 0.577– 0.740) in women (P < .01; Figure 6). Such sex-specific ultrasound assessments showed independent value over participant demographic, comorbidity, and referral indication information in CAD identification (Table 5).
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Journal of the American Society of Echocardiography Volume - Number -
Figure 4 Odds of significant CAD with increased ([) plaque burden in each proximal femoral segment by sex. The images show the odds of significant CAD (95% CI) with increased ([) TPA in women and MPH in men per each proximal femoral segment. Statin Therapy in Relation to CAD Because statins are known to affect plaque burden, we assessed differences in statin use in relation to CAD. No significant differences were found in plaque burden for any carotid or femoral segments in participants with significant CAD who were taking statins versus those who were not. In participants with no significant CAD, those taking statins had higher common femoral MPH (2.61 6 2.00 vs 2.07 6 1.90 mm, P = .04), femoral bifurcation MPH (1.93 6 1.86 vs 1.37 6 1.56 mm, P = .04), carotid MPH (1.92 6 1.50 vs 2.47 6 1.44 mm, P = .008), and carotid TPA (34.8 6 32.8 vs 26.4 6 31.4 mm2, P = .02).
Test Reproducibility Intraobserver agreement for combined carotid and femoral plaque burden quantification was deemed excellent. In women, ICCs of MPH and TPA were 0.925 (95% CI, 0.847–0.964) and 0.985 (95% CI, 0.968–0.993), while differences in CVs were 3.21% and 3.74%, respectively. In men, ICCs of MPH and TPA were 0.941 (95% CI, 0.880–0.971) and 0.983 (95% CI, 0.965–0.992), while differences in CVs were 0.75% and 0.78%, respectively. Interobserver agreement was good: ICCs of MPH and TPA in women were 0.772 (95% CI, 0.575–0.885) and 0.870 (95% CI, 0.745–0.936), while differences in CVs were 6.32% and 14.26%, respectively. In men, ICCs of MPH and TPA were 0.883 (95% CI, 0.768–0.942) and 0.953 (95% CI, 0.903–0.977), while differences in CVs were 0.58% and 9.65%.
DISCUSSION The present study demonstrates the utility of a noninvasive, risk-free, and cost-effective means to reveal significant, obstructive CAD in both women and men. Such a tool is becoming increasingly essential given prevalence rates of cardiovascular risk factors, such as diabetes, which are projected to increase dramatically over the next two decades.20 It is known that patients with peripheral artery disease are at increased risk for cardiovascular events.21 Accordingly, the 2013 American College of Cardiology/American Heart Association cardiovascular risk guideline recommends an ankle-brachial index measurement to inform treatment decision making.22 However, even with a normal resting ankle-brachial index, occlusive disease may be present in the lower extremities.23 Correspondingly, studies have sought to use peripheral artery plaque detection by ultrasound in risk assessment.24,25 To our knowledge, this study is the first to explore femoral plaque quantification in the identification of angiographic CAD. Few studies have acknowledged sex differences when exploring vascular ultrasound in cardiovascular screening. In the Atherosclerosis Risk in Communities study, accounting for carotid plaque presence in addition to intima-media thickness led to greater improvement of risk prediction in women than in men.26 More recently, in the Progression of Early Subclinical Atherosclerosis study, carotid and femoral plaque burden correlated strongly with cardiovascular risk factors in both men and women and reflected estimated cardiovascular risk better than plaque detection.12 To our knowledge,
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study using magnetic resonance imaging found that in men, tortuosity of the superficial femoral artery was greater and mean wall shear stress lower than in women, contributing to increased focal atherosclerosis, consistent with our findings.27 Additionally, although the mean age of the women in our study was 66 6 11 years, beyond the average age of menopause, endogenous estrogen–afforded protection earlier in life may have led to a delay in disease development.28
Figure 5 Odds of significant CAD with combined plaque burden assessments by sex. Forest plots show the ORs of significant CAD in women (A) and men (B) for interquartile range increases (median [25%-75%]) in combined proximal femoral and carotid MPH and TPA assessments, adjusted for age and traditional cardiac risk factors. this is the first study to reveal sex-specific vascular ultrasound markers of atherosclerotic disease in CAD identification. Sex Differences in the Pattern of Atherosclerotic Disease This work unveiled unique sex differences in the arterial distribution pattern of atherosclerotic disease. Our results were consistent with those of previous studies, which showed increased carotid and femoral plaque burden in men compared with women.12,27 Additionally, men had greater plaque burden within all proximal femoral territories. Sex differences in atherosclerotic burden may be partially attributable toward anatomic differences in vasculature. A
Femoral Plaque Has a Stronger Association with CAD than Carotid Plaque Associations of carotid plaque with cardiac risk factors, CAD, and cardiovascular outcomes are well established.16,20,29 More recently, studies have revealed the utility of a femoral plaque assessment in patient risk stratification. In a study of middle-aged men, femoral plaque presence had a stronger correlation with traditional cardiovascular risk factors and positive coronary calcium score than did carotid plaque.30 In 2009, Griffin et al.31 demonstrated increased odds of cardiovascular disease with increased number of femoral bifurcation plaques.31 In an autopsy study of 1,074 individuals by Sawabe et al.,32 it was shown that disease advanced more rapidly at the femoral arteries than at the carotid arteries. Similarly, several studies have demonstrated that the femoral arteries are more frequently affected by atherosclerosis than the carotid arteries in both women and men.33-35 Perhaps there are similar patterns of low shear stress and disturbed blood flow at the coronary and femoral arteries, leading to the relatively early onset of disease in the bifurcating and curving regions of these beds. However, few studies have accounted for sex differences when exploring vascular ultrasound screening tools. We have confirmed the stronger association of femoral over carotid atherosclerosis with coronary disease in both sexes; additionally, we have identified unique femoral segments for optimal CAD identification in either sex. Similar segment-specific patterns emerged in the association between femoral plaque burden and CAD extent. Although this was a cross-sectional analysis, there is increased risk for mortality and major adverse cardiovascular events with increased CAD extent from single- to triple-vessel disease.13 Segment-specific patterns may be attributable toward sex differences in vascular anatomy. In data collected from the European Carotid Surgery Trial, women had larger internal carotid diameters relative to common and external carotid diameters than did men, which may have contributed to external carotid arterial disease.36 It is possible that in women, anatomic effects at the common femoral artery preclude the development of disease, while in men, this occurs at the femoral bifurcation. Further studies are needed to elucidate the role of vascular anatomy in the sex-specific pattern of femoral artery disease progression. Plaque Area rather than Height is Associated with CAD in Women In addition to spatial differences, we noted sex differences in optimal atherosclerosis quantification methods. Although the CIs were wide, in women, plaque area consistently yielded the strongest association with CAD. Such a pattern suggests that plaque area may better reflect the true burden of atherosclerotic disease in women. Akin to this notion, previous studies have noted benefits of plaque quantification versus the simple detection of plaque presence in risk stratification.12 Contemporarily, three-dimensional ultrasound has emerged as a technique allowing the visualization of atherosclerosis in all planes
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Table 4 Contingency table of combined ultrasound assessments to identify significant, obstructive CAD by sex Sex
Assessment
Women Stress test
Men
n
Threshold value
79 (+) ( )
AUC
With CAD
Without CAD
PPV, % NPV, % Sensitivity,% Specificity, % LR+
LR
TP 23 FN 7
FP TN
44 4
34
36
77
8
0.84 2.80
NRI,%
Carotid
170 $16.5 mm2 <16.5 mm2
0.740 TP 60 FN 18
FP TN
45 47
57
72
77
51
1.57 0.45
37
FemoralCom
170 $11.5 mm2 <11.5 mm2
0.691 TP 64 FN 14
FP TN
48 44
57
76
82
48
1.57 0.38
45
FemoralCom + carotid 170 $42.0 mm2 <42.0 mm2
0.764 TP 67 FN 11
FP TN
43 49
61
82
86
53
1.84 0.26
53
TP 85 FN 40
FP TN
5 8
94
17
68
62
1.77 0.52
Stress test
138 (+) ( )
Carotid
330 $2.1 mm <2.1 mm
0.718 TP 202 FP FN 29 TN
57 42
78
59
87
42
1.52 0.30
22
FemoralBif
330 $1.9 mm <1.9 mm
0.752 TP 192 FP FN 39 TN
42 57
82
59
83
58
1.96 0.29
31
FemoralBif + carotid
330 $2.8 mm <2.8 mm
0.773 TP 202 FP FN 29 TN
47 52
81
64
87
55
1.84 0.24
37
Bif, Bifurcation; Com, common; FN, false negative; FP, false positive; LR+, positive likelihood ratio; LR , negative likelihood ratio; NPV, negative predictive value; NRI, net reclassification improvement; PPV, positive predictive value; TN, true negative; TP, true positive. (Values) indicate participants with positive stress test results.
Figure 6 A men-specific vascular ultrasound assessment has reduced accuracy for CAD detection in women. ROC curve analyses demonstrate the abilities of combined femoral bifurcation and carotid MPH (A) and TPA (B), as well as combined common femoral and carotid MPH (C) and TPA (D) ultrasound assessments, to identify significant CAD in either sex. A men-specific vascular ultrasound assessment has reduced accuracy for CAD detection in women (A).
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Table 5 Independent identifiers of significant, obstructive CAD by sex
Sex
Variables added in step
Women Step 1: demographics
Men
c2
Hosmer and Lemeshow Cox and goodnessSnell R2 of-fit P value
3.14
0.018
.868
Step 2: comorbidities
27.10
0.151
.816
Step 3: referral indications
41.91
0.223
.560
Step 4: TPA carotid
61.11
0.308
.924
TPA femoralCom
55.88
0.286
.245
TPA femoralCom + carotid
68.43
0.338
.859
Step 1: demographics
19.98
0.059
.709
Step 2: comorbidities
43.61
0.126
.586
Step 3: referral indications
90.79
0.244
.272
Step 4: MPH carotid
109.68
0.286
.231
MPH femoralBif
120.85
0.311
.974
MPH femoralBif + carotid
135.26
0.340
.447
BMI, Body mass index; eGFR, estimated glomerular filtration rate; MI, myocardial infarction. Stepwise forward logistic regression for the identification of significant CAD ($50% stenosis) by sex, adding participant demographics (age, BMI) in step 1, cardiac comorbidities (hypertension, hyperlipidemia, diabetes, smoking status, eGFR) in step 2, referral indications (arrhythmia, dyspnea, chest pain, positive stress test results, MI) in step 3, and ultrasound assessments in step 4. For the c2 test, P < .001 for all iterations. For the Hosmer and Lemeshow goodness-of-fit test, significant values indicate poor fit.
and, correspondingly, shows improved discriminatory capability for disease.11 Future studies that assess the utility of three-dimensional ultrasound at the common femoral artery may have value in the development of a female-specific risk stratification tool. Combined Common Femoral and Carotid Plaque Burden Best Identifies CAD In women, a combined assessment of TPA at the common femoral and carotid arteries yielded the most accurate identification of significant CAD. Previous studies have demonstrated the increased value of a combined plaque burden analysis over that of a single arterial bed.24,37 Atherosclerosis typically manifests first in the aorta, followed by the coronary, peripheral, and carotid arteries. However, as this progression is not identical among all individuals, an aggregate arterial assessment may most safely capture the disease burden.37 Importantly, most women who were referred for angiography because of positive stress test results did not have significant CAD. In both sexes, more than half of participants with falsepositive stress test results were correctly identified as having no CAD by ultrasound, and few participants with CAD were missed. In summary, the most notable findings of our study are as follows: (1) changes in femoral plaque burden are more indicative of diseased coronaries than carotid plaque burden in both sexes, and moreover, the femoral segments showing the greatest impact on risk stratification are sex specific, wherein women display the strongest association with coronary atherosclerosis at the common femoral artery, whereas
in men, this occurs at the femoral bifurcation; (2) plaque area may be a stronger indicator of coronary disease than plaque height in women; (3) a combined femoral and carotid plaque burden assessment demonstrates improved disease detection over an assessment of either arterial bed alone in both sexes; and (4) vascular ultrasound may show particular value in women, in whom traditional risk assessments are less effective. Cumulatively, our findings highlight potential value of vascular ultrasound as a cardiovascular screening tool. Study Limitations Because the study population was composed of symptomatic participants referred for angiography, it remains unknown whether these methods can be used in assessing asymptomatic risk. Because this was a cross-sectional study, we also do not yet know associations of plaque burden with future cardiovascular risk. Later analyses on outcomes will provide more information on using vascular ultrasound to assess risk in women and men. Test performance was assessed on the basis of threshold cutoff values established from receiver operating characteristic curves within the same population; because these represent ideal cut points, the sensitivity and specificity of these tests should be reassessed in another population to confirm reproducibility. Furthermore, because two-dimensional ultrasound captures images in only two planes, this may have led to overestimations or underestimations of femoral or carotid disease or affected associations with coronary disease. Correspondingly, CIs obtained from analysis of the relatively small group of women (n = 170) are wide. Variability of this plaque measurement may have artificially improved the association of plaque area with CAD in women, contributing to the sex difference observed in optimal atherosclerosis quantification methods. Further evidence of associations of vascular ultrasound with angiography is needed in a larger cohort study. Coronary quantitative techniques such as intravascular ultrasound would provide a better assessment of coronary plaque or vascular lumen and is of interest for future studies to further define association with peripheral vascular beds. Last, because our study population was primarily Caucasian (96%), these results will require validation in other cohorts. CONCLUSION The present study demonstrates an inexpensive, risk-free method to identify obstructive CAD, feasible for routine use as a cardiovascular screening tool. A combined assessment of common femoral and carotid plaque area yielded sensitivity of 86% for ruling out obstructive CAD in women and ruled out more than half of participants with false-positive stress test results. Further investigation will help elucidate the clinical value of vascular ultrasound incorporated into cardiovascular management algorithms. ACKNOWLEDGMENTS We thank the staff of the Kingston General Hospital Cardiac Catheterization and Vascular Doppler Laboratories for their kind help in this study. We also thank Wilma M. Hopman and Gopi Krishnan Rajbahadur for assistance with statistical analysis and Julia E. Herr and Paul A. D. Colosimo for assistance with figure creation. REFERENCES 1. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific
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