Abstract
Background:
The association between cardiovascular risk factors (CVRF) and the risk of coronary events is widely acknowledged. Whether individual risk factors may be associated with distinct plaque characteristics is currently unclear. We investigated the relationship between CVRF and coronary plaque burden and phenotype.
Methods and Results:
We assessed coronary atherosclerotic plaque characteristics by optical coherence tomography in 67 patients with stable coronary artery disease undergoing coronary angiography. The plaque burden and the distinct plaque phenotypes were compared with regard to different CVRF. Overall plaque burden was significantly greater in patients with diabetes mellitus (P=0.010), prediabetes (P=0.035) and obesity (P=0.024), and correlated with the number of CVRF (R=0.358, P=0.003). Patients with diabetes had a greater extent of fibroatheroma (P=0.015), calcific fibroatheroma (P=0.031), thin-cap fibroatheroma (TCFA-P=0.011) and plaque erosion (P=0.002). Obese patients showed a greater extent of fibroatheroma (P=0.007), TCFA (P=0.015) and macrophage load (P=0.043). The number of CVRF correlated with fibroatheroma (R=0.425, P<0.001), calcific fibroatheroma (R=0.321, P=0.008), TCFA (R=0.347, P=0.004), macrophage load (R=0.314, P=0.010) and erosion (R=0.271, P=0.029). In the multivariate analysis, altered glycemic status and obesity were the only independent predictors of TCFA (P=0.026 and P=0.046, respectively), whereas altered glycemic status was the only independent predictor of plaque erosion (P=0.001).
Conclusions:
Patients with diabetes, prediabetes and obesity show more extensive coronary atherosclerosis and more vulnerable plaque phenotypes.
Atherosclerosis is a multifactorial disease that results from a complex interaction between genetic predisposition and well-recognized cardiovascular risk factors (CVRF), such as diabetes mellitus, arterial hypertension, hypercholesterolemia, smoking, obesity and age. The relationship between CVRF and the risk of experiencing a coronary event is widely acknowledged.1
Nevertheless, the mechanisms underlying the role of individual risk factors in the development and progression of atherosclerotic plaques are currently not fully understood. Pathological and imaging studies have demonstrated that the morphological composition in large part reflects the fate of an atherosclerotic plaque.2
It has been demonstrated that “stable” and “vulnerable” plaques show distinct and particular morphological features, which are differentially connected to the risk of plaque disruption and subsequent thrombus apposition, risk of vessel occlusion and acute coronary events.2
Optical coherence tomography (OCT) is a light-based intravascular imaging modality that allows for high-resolution visualization of the coronary atherosclerotic plaques.3
Currently, OCT provides the most detailed insights into plaque characteristics, allowing the measurement of lipid-pool extension and the thickness of the fibrous cap, as well as the identification of local plaque inflammation, all of which may represent key factors in determining plaque stability.4
Editorial p 1100
In the present study we evaluated a possible relationship between coronary atherosclerotic plaque phenotype assessed by OCT and the classical CVRF.
Methods
Study Population
The patients were selected from those enrolled in the Frankfurt OCT Registry, which includes both patients with stable coronary artery disease (CAD) and patients with acute coronary syndromes (ACS). Exclusion criteria were a known history of leukopenia or thrombocytopenia, severe hepatic or renal dysfunction, ongoing inflammatory or malignant disease, chronic total occlusion and the presence of coronary bypass graft. For the present study, we selected only patients with stable CAD. The registry was approved by the local ethics committee of the Goethe University of Frankfurt. Written informed consent was given by all patients.
Definition of CVRF
CVRF were defined according to the current ESC guidelines.1
Briefly, hypertension was defined as documented elevated blood pressure (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg) or as a history of hypertension with use of any antihypertensive drugs. Hypercholesterolemia was defined by the presence of low-density lipoprotein-cholesterol (LDL-C) level ≥70 mg/dL. Obesity was defined as a body mass index (BMI) >25 kg/m2. Smoking was defined as current smoking habit. Diabetes mellitus (DM) was diagnosed according to the American Diabetes Association criteria if the patient had a fasting glucose ≥126 mg/dL or a glycated hemoglobin (HbA1c) ≥6.5%,5
as well as taking hypoglycemic drugs. Prediabetes was diagnosed if patients had a fasting glucose ranging from 100 mg/dL to 125 mg/dL or an HbA1c ranging from 5.7% to 6.4%.5
OCT and Imaging Analysis
OCT was performed via a 6F guiding catheter using a femoral approach. In all patients, a frequency-domain OCT system (C7-XRTM
OCT Intravascular Imaging System, St. Jude Medical, St. Paul, MN, USA) was used and the left coronary system, including left coronary artery (LAD) and left circumflex artery (LCX) or a predominant marginal branch (M1/M2) system, was imaged. The OCT images were digitized and analyzed using the M2CV OCT console by 4 independent readers (R.D.R., D.M.L., S.M.R., C.E.T.), according to the current consensus standard.6
Briefly, a fibroatheroma was defined as an atherosclerotic plaque with an OCT-delineated necrotic core (signal-poor region with poorly delineated borders and little or no OCT backscattering), covered by a fibrous cap (signal-rich layer); a fibrotic plaque was defined as a plaque with homogeneous OCT signal and high backscattering; a calcific fibroatheroma was defined as a plaque containing calcium deposits (signal-poor regions with sharply delineated borders); a TCFA was defined as an OCT-delineated necrotic core subtending an arc >90° and covered by a fibrous cap with a thickness <65 µm; macrophage accumulation was defined as a signal-rich punctate region in the context of an atherosclerotic plaque; plaque rupture was defined by the presence of disrupted fibrous cap; plaque erosion was defined by the presence of disrupted endothelium without evidence of cap rupture, with or without attached thrombi.6
The inter- and intra-observer agreement was strong, with intraclass correlation coefficients of 0.82 and 0.91, respectively. The longitudinal and radial plaque loads of different plaque characteristics (fibrotic plaque, fibroatheroma, calcific fibroatheroma, macrophage-loaded plaque, TCFA, plaque erosion and plaque rupture) were calculated as the percent of the total scanned vessel distance, using the formula7
provided in
Supplementary File 1. The mean plaque load was calculated as the mean from LAD- and LCX-positive plaques as determined by the number of solid plaque-containing quadrants using the formula7
provided in
Supplementary File 1.
Statistical Analysis
Continuous data are presented as median (interquartile range), whereas categorical variables are presented as absolute numbers or as percentages. The Spearman correlation was used to investigate the relationship between continuous variables and different coronary plaque loads. Comparisons between groups were performed with Mann-Whitney U-test or, if 3 groups were present, the Kruskal-Wallis test for continuous variables and with Fisher’s exact test for categorical variables. All statistical calculations were performed using SPSS 22 software (SPSS Inc., Chicago, IL, USA).
Results
Patients’ Baseline Characteristics
A total of 67 patients with stable CAD undergoing coronary angiography and OCT of the left coronary system were enrolled in this study. Baseline clinical characteristics, laboratory data and medical therapy of the study population are shown in
Table 1. The mean coronary vessel distance analyzed was 96±41 mm. OCT-derived mean plaque load and distinct plaque characteristics are listed in
Table S1. Representative OCT images are shown in
Figure 1.
Table 1.
Baseline Characteristics of the Patient Population
| |
All patients (n=67) |
| Age (years) |
63 (55–71) |
| ≥65 years, n (%) |
31 (46.3) |
| Sex (F/M), n (%) |
21/46 (32.3, 68.7) |
| Postmenopausal women (yes/no) |
19/21 |
| Arterial hypertension, n (%) |
54 (80.6) |
| Diabetes mellitus, n (%) |
14 (20.9) |
| Prediabetes, n (%) |
27 (40.3) |
| Current smoker, n (%) |
23 (34.3) |
| Obesity, n (%) |
43 (64.2) |
| Cholesterol (mg/dL) |
175 (148–220) |
| LDL (mg/dL) |
91 (72–119) |
| HDL (mg/dL) |
50 (38–62) |
| Triglycerides (mg/dL) |
121 (81–159) |
| Fasting glucose (mg/dL) |
101 (89–121) |
| HbA1c (%) |
5.7 (5.4–6.1) |
| CRP (mg/dL) |
0.23 (0.08–0.5) |
| hs-troponin T (ng/mL) |
9 (5–11) |
| NT-pro-BNP |
151 (60–349) |
| WBC (×109/L) |
6.9 (5.6–8.4) |
| Serum creatinine |
0.95 (0.79–1.11) |
| Medical therapy |
| Statins, n (%) |
48 (71.6) |
| ACEI or ARB, n (%) |
52 (77.6) |
| Insulin, n (%) |
5 (7.5) |
| Antiplatelet therapy, n (%) |
48 (71.6) |
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BNP, B-type natriuretic peptide; CRP, C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; WBC, white blood cells.
Values of OCT-derived mean plaque load, as well as the specific loads of distinct plaque phenotypes according to CVRF, are shown in
Table 2. Overall plaque burden was significantly greater in patients with DM (P=0.010), prediabetes (P=0.035) and in obese patients (P=0.024). With regard to plaque phenotype, patients with DM had a significantly larger extent of fibroatheromas (P=0.015), calcific fibroatheromas (P=0.031) and TCFA (P=0.005,
Figure 2A). Moreover, the presence of DM was associated with a significantly greater extent of plaque erosion (P=0.002). When divided into subgroups according to the overall plaque burden, DM patients with lower plaque burden still showed a larger extent of plaque erosion (P=0.048) and TCFAs (P=0.051) compared with non-DM patients (Figure 3). In patients with prediabetes, there was a significantly higher extent of fibroatheromas (P=0.019) and plaque erosion (P=0.034), whereas differences in TCFAs and calcific fibroatheromas did not reach statistical significance (P=0.142 and P=0.099, respectively). A significantly greater extent of fibroatheromas (P=0.007), TCFA (P=0.015,
Figure 2B) and macrophage-loaded plaques (P=0.043), as well as a trend for greater amount of calcific fibroatheroma (P=0.066), was observed in obese patients, in comparison with normal-weight patients. The simultaneous presence of altered glycemic status (DM or prediabetes) and obesity was associated with higher extent of TCFAs in comparison with altered glycemic status and obesity alone (Figure 2C).
Table 2.
OCT-Derived Plaque Characteristics According to Cardiovascular Risk Factors
| |
Age |
Sex |
Arterial hypertension |
Diabetes |
Prediabetes |
Smoking |
Obesity |
Hypercholesterolemia |
| ≥65 y |
<65 y |
P |
M |
F |
P |
Yes |
No |
P |
Yes |
No |
P |
Yes |
No |
P |
Yes |
No |
P |
Yes |
No |
P |
Yes |
No |
P |
Plaque
burden (%) |
10
(4.9–17.3) |
15.7
(1.3–18.9) |
0.234 |
8.04
(2.2–15.9) |
9.5
(3.1–21) |
0.930 |
8.1
(4.5–15.8) |
10.3
(0.6–21.2) |
0.924 |
20.8
(7.3–51.5) |
7
(1.5–14.3) |
0.010* |
9.7
(5.1–30) |
5.3
(0.4–11.9) |
0.035* |
5.5
(0.6–15) |
9.3
(4.6–20) |
0.182 |
9.5
(5.1–21) |
5.6
(0.4–11.5) |
0.024* |
8.7
(1.7–20.7) |
8.7
(4.3–13.4) |
0.980 |
Fibrotic
plaque (%) |
18
(10–31) |
22.1
(7–28.8) |
0.841 |
23.3
(10.8–30.1) |
13.3
(7–22.2) |
0.063 |
21.3
(11–31) |
13.6
(4–27.9) |
0.156 |
15.5
(6.5–26.7) |
22.7
(10–30) |
0.316 |
19.4
(7.8–29.6) |
20.7
(10.4–29.2) |
0.776 |
16.1
(7.4–24) |
23.3
(10.7–32) |
0.119 |
18.4
(9.2–31) |
20.4
(8.8–27.8) |
0.999 |
20.3
(8.1–27) |
14.9
(10.3–39.6) |
0.709 |
Fibroatheroma
(%) |
1.6
(0–9.5) |
1.2
(0–4) |
0.657 |
1.5
(0.3–4.8) |
1.5
(0–8.9) |
0.557 |
1.5
(0.7–6.9) |
1.1
(0–6.1) |
0.548 |
6
(1.2–24.6) |
1.2
(0–2.7) |
0.015* |
1.6
(0.7–12.7) |
0.3
(0–1.9) |
0.019* |
1.5
(0–3.6) |
14.8
(0.05–9.5) |
0.580 |
1.6
(0.9–9.5) |
0.1
(0–2.6) |
0.007* |
1.4
(0–4.8) |
1.6
(1–8.9) |
0.938 |
Calcific
fibroatheroma
(%) |
2.5
(0.7–5.9) |
1.5
(0–3.4) |
0.083 |
2.2
(0.5–5.1) |
1.9
(0.2–5.2) |
0.596 |
2.2
(0.5–5.6) |
1.8
(0–10.9) |
0.873 |
4.5
(1.4–12.7) |
1.8
(0–3.7) |
0.031* |
2.9
(1–6.7) |
1.2
(0–2.9) |
0.099 |
1.5
(0–3.8) |
2.4
(0.7–5.5) |
0.127 |
2.5
(0.8–5.5) |
0.1
(0–4.2) |
0.066 |
1.8
(0.1–4.7) |
3
(0.7–5.7) |
0.495 |
| TCFA (%) |
2
(0.5–5.8) |
2.9
(0–4.1) |
0.450 |
2
(0.5–5.6) |
1.7
(0–3.7) |
0.441 |
1.8
(0.3–4.5) |
2
(0–5.9) |
0.841 |
4.8
(1.9–5.9) |
1.5
(0–3.5) |
0.011* |
2.3
(1.1–5.7) |
1
(0–2.8) |
0.142 |
1.4
(0–5.6) |
2.3
(0.6–4.4) |
0.305 |
2.3
(1.1–5.8) |
0.9
(0–2.7) |
0.015* |
1.8
(0–5.9) |
1.5
(0.2–2.3) |
0.376 |
Macrophage-
loaded plaque
(%) |
0.001
(0–0.6) |
0.001
(0–0.5) |
0.596 |
0.001
(0–0.6) |
0.001
(0–0.08) |
0.268 |
0.001
(0–0.5) |
0.001
(0–1.6) |
0.513 |
0.001
(0–3.6) |
0.001
(0–0.4) |
0.134 |
0.001
(0–1.6) |
0
(0–0.08) |
0.267 |
0.001
(0–0.6) |
0
(0–1.6) |
0.839 |
0.1
(0–1.3) |
0
(0–0.003) |
0.043* |
0
(0–0.6) |
0
(0–0.003) |
0.219 |
| Erosion (%) |
0.01
(0–1.4) |
0.01
(0–0.7) |
0.103 |
0.001
(0–1.1) |
0.001
(0–0.6) |
0.336 |
0.001
(0–1.1) |
0.005
(0–0.9) |
0.666 |
0.8
(0.1–3.1) |
0.001
(0–0.8) |
0.002* |
0.4
(0–1.3) |
0
(0–0.001) |
0.034* |
0.001
(0–0.6) |
0.005
(0–1.2) |
0.248 |
0.04
(0–1.1) |
0
(0–0.7) |
0.128 |
0.001
(0–1) |
0.7
(0–1.2) |
0.152 |
| Rupture (%) |
0.001
(0–0.01) |
0
(0–0.001) |
0.542 |
0
(0–0.001) |
0
(0–0) |
0.086 |
0
(0–0.001) |
0
(0–0.001) |
0.306 |
0
(0–0.003) |
0
(0–0.004) |
0.418 |
0
(0–0.008) |
0
(0–0.001) |
0.999 |
0
(0–0) |
0
(0–0.001) |
0.066 |
0
(0–0.006) |
0
(0–0.005) |
0.342 |
0
(0–0.005) |
0
(0–0.002) |
0.942 |
*P<0.05. OCT, optical coherence tomography; TCFA, thin-cap fibroatheroma.
No significant difference in plaque burden or plaque phenotype was observed between male and female patients. Nevertheless, it has to be underlined that just 2 of 21 female patients in our study population were premenopausal. Therefore, we cannot exclude that this may have masked potential sex-related differences in plaque characteristics. No significant differences were observed also with regard to smoking habit, higher cholesterol levels and older age. By Spearman correlation (Table 3), a significant direct correlation was observed between fasting glucose as well as HbA1c level and plaque burden (r=0.317, P=0.009 and r=0.437, P=0.001, respectively), TCFA (r=0.359, P=0.003 and r=0.422, P=0.002, respectively), calcific fibroatheromas (r=0.303, P=0.013 and r=0.294, P=0.033, respectively), macrophage-loaded plaques (r=0.340, P=0.005 and r=0.340, P=0.014, respectively) and plaque erosion (r=0.355, P=0.004 and r=0.465, P=0.001, respectively); HbA1c-levels also correlated significantly with the extent of fibroatheromas (r=0.396, P=0.003). In contrast, no significant correlation of OCT-derived plaque characteristics was found with regard to total and high-density lipoprotein-cholesterol as well as with high-sensitivity C-reactive protein (hs-CRP).
Table 3.
Correlations Between Laboratory Parameters and OCT-Derived Plaque Characteristics
| |
LDL-C |
HDL-C |
hs-CRP |
Fasting glucose |
HbA1c |
| Plaque burden |
−0.089 |
−0.058 |
0.151 |
0.317 |
0.437 |
| P value |
0.661 |
0.661 |
0.228 |
0.009* |
0.001* |
| Fibrotic plaque |
−0.137 |
−0.074 |
−0.105 |
0.171 |
0.029 |
| P value |
0.294 |
0.574 |
0.401 |
0.171 |
0.836 |
| Atheroma |
−0.020 |
−0.226 |
0.200 |
0.230 |
0.396 |
| P value |
0.876 |
0.083 |
0.107 |
0.063 |
0.003* |
| Calcific fibroatheroma |
−0.159 |
−0.078 |
0.184 |
0.303 |
0.294 |
| P value |
0.220 |
0.553 |
0.140 |
0.013* |
0.033* |
| TCFA |
−0.020 |
−0.095 |
0.045 |
0.359 |
0.422 |
| P value |
0.878 |
0.470 |
0.721 |
0.003* |
0.002* |
| Macrophage-loaded plaque |
0.037 |
−0.196 |
0.129 |
0.344 |
0.340 |
| P value |
0.781 |
0.137 |
0.307 |
0.005* |
0.014* |
| Plaque erosion |
−0.215 |
0.023 |
−0.126 |
0.355 |
0.465 |
| P value |
0.110 |
0.864 |
0.320 |
0.004* |
0.001* |
| Plaque rupture |
−0.199 |
−0.053 |
0.104 |
0.139 |
0.038 |
| P value |
0.123 |
0.686 |
0.408 |
0.267 |
0.760 |
*P<0.05. HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol. Other abbreviations as in Tables 1,2.
After having analyzed the effect of single CVRF on coronary atherosclerotic plaques characteristics, we investigated whether the simultaneous presence of more risk factors was also associated with plaque features. We calculated a risk score from 0 to 7 by adding individual CVRF8
(age ≥65 years, male sex, hypertension, hypercholesterolemia, diabetes or prediabetes, smoking habit, obesity). As shown in
Figure 4, overall plaque burden (r=0.358, P=0.003), amount of fibroatheroma (r=0.425, P<0.001), calcific fibroatheroma (r=0.321, P=0.008), TCFA (r=0.347, P=0.004), macrophage-loaded plaque (r=0.314, P=0.010) and extent of plaque erosion (r=0.271, P=0.029) significantly correlated with the number of risk factors.
Multivariate Analysis
In order to assess individual predictors of the presence of TCFA and plaque erosion, we performed a multivariate regression analysis. As shown in
Table 4, among the investigated CVRF, altered glycemic status (prediabetes or diabetes) and obesity remained the only independent determinants of TCFA in our patients (hazard ratio [HR]: 3.717, P=0.026 and HR: 3.258, P=0.046, respectively). Moreover, the presence of prediabetes or diabetes was the only independent predictor of plaque erosion (HR: 8.594, P=0.001).
Table 4.
Univariate and Multivariate Regression Analyses
| |
Univariate analysis |
Multivariate analysis |
| Exp (B) |
95% CI |
P value |
Exp (B) |
95% CI |
P value |
| Presence of TCFA |
| Age |
1.023 |
0.972–1.077 |
0.378 |
– |
– |
– |
| Sex |
0.511 |
0.168–1.551 |
0.236 |
– |
– |
– |
| Arterial hypertension |
1.786 |
0.500–6.374 |
0.372 |
– |
– |
– |
| Diabetes or prediabetes |
4.163 |
1.357–12.770 |
0.013* |
3.717 |
1.166–11.850 |
0.026* |
| Smoking |
0.625 |
0.209–1.871 |
0.625 |
– |
– |
– |
| Obesity |
3.702 |
1.219–11.246 |
0.021* |
3.258 |
1.020–10.404 |
0.0426* |
| Hypercholesterolemia |
1.045 |
0.352–3.104 |
0.937 |
– |
– |
– |
| Presence of plaque erosion |
| Age |
1.035 |
0.987–1.085 |
0.159 |
– |
– |
– |
| Sex |
0.733 |
0.255–2.103 |
0.563 |
– |
– |
– |
| Arterial hypertension |
1.280 |
0.371–4.421 |
0.696 |
– |
– |
– |
| Diabetes or prediabetes |
8.594 |
2.496–29.590 |
0.001* |
8.594 |
2.496–29.590 |
0.001* |
| Smoking |
0.584 |
0.206–1.656 |
0.312 |
– |
– |
– |
| Obesity |
2.544 |
0.878–7.374 |
0.085 |
– |
– |
– |
| Hypercholesterolemia |
0.500 |
0.178–1.405 |
0.188 |
– |
– |
– |
*P<0.05. CI, confidence interval.
Discussion
The results of our study show that, among the classical CVRF, diabetes, prediabetic status and obesity were associated with not only overall coronary atherosclerotic plaque load, but were independent predictors of distinct plaque phenotypes, including TCFA and plaque erosion. The present study is unique because for the first time it quantifies not only the extent of overall atherosclerotic coronary plaque burden, but also the extent of specific plaque phenotypes in the entire OCT-accessible left coronary system.
Diabetes and Prediabetes: Association With Overall Plaque Burden and Plaque Phenotype
DM is associated with accelerated coronary atherosclerosis and higher cardiovascular morbidity and mortality. This has been related to an accentuated proinflammatory and prothrombotic status induced by DM-associated metabolic abnormalities.9
Interestingly, a recent study enrolling both diabetic and non-diabetic patients with their first ACS showed that high glycemic variability was associated with increased plaque vulnerability in non-culprit lesions.10
However, previous studies investigating coronary plaque features in patients with DM showed contrasting results. A previous virtual histology-intravascular ultrasound11
study demonstrated a higher prevalence of TCFA in patients with DM, whereas no significant association between the presence of TCFA and DM was found in 2 recent OCT studies.12,13
Several reasons may account for these contrasting results. First, previous OCT studies analyzed plaque composition at the site of target lesions or non-target lesions with >50% stenosis within the coronary system. This approach may have missed mild atherosclerotic lesions and positively remodeled plaques. In positively remodeled plaques, even large-volume atheromas may not be apparent within the lumen, which could remain unchanged or show just a mild reduction because of outward expansion of the vessel wall.14
Second, when interpreting results the length of the imaged vessel should also be considered; whereas vulnerable plaques were previously believed to be mostly located in the proximal third of the major coronary arteries,15
recent studies suggest that a significant percentage of such plaques could also be found in the more distal segments of the coronary arteries, especially in patients with DM or prediabetes.16,17
In line with an accentuated proinflammatory status induced by DM-mediated metabolic abnormalities, we found a trend towards higher amounts of macrophage-loaded plaque in patients with DM or prediabetes, and the amount of macrophage-loaded plaque significantly correlated with both fasting glucose and HbA1c levels (Table 4). This is consistent with previous studies showing a greater extent of plaque inflammation in atherosclerotic coronary arteries in pathological specimens from diabetic patients.18
Another intriguing finding of our study is that the presence of either DM or prediabetes was significantly associated with increased plaque erosion. The amount of plaque erosion also significantly correlated with levels of fasting glucose and HbA1c. Plaque erosion is a pathological lesion characterized by absent or disrupted endothelium without evidence of plaque rupture.19
Pathological and clinical studies show that plaque erosion accounts for approximately 40% of ACS.20,21
Increased vasoconstriction,19
higher endothelial cell death and polymorphonuclear leukocyte activation22
have been related to this type of lesion. Further studies are needed to confirm and investigate the pathophysiological role of DM in plaque erosion. Interestingly, when the study population was grouped according to overall plaque burden, diabetic patients with lower plaque burden still showed a significantly higher extent of plaque erosion compared with non-diabetic patients, suggesting that DM may be associated with an eroded plaque phenotype even in patients without extensive coronary atherosclerosis.
Obesity, Overall Plaque Burden and Plaque Phenotype
In addition to its influence on the development and severity of known cardiovascular risk conditions such as DM, insulin resistance, hypertension and dyslipidemia, obesity represents per se an independent risk factor for CAD and is associated with increased incidence of acute coronary events.23
Once considered as merely lipid-storage diseases, both atherosclerosis and obesity are now recognized as chronic inflammatory processes, characterized by inflammatory cell infiltration of the arterial wall, cytokine production, and cell death.24
Until now, few studies have been performed to investigate a potential association between obesity and specific plaque characteristics. In detail, a recent intravascular ultrasound study performed in patients with stable CAD or ACS found a greater plaque burden and plaque area, as well as higher incidence of plaque rupture, in patients with higher BMI compared with patients with lower BMI.25
A non-invasive study investigating the relationship between coronary plaque characteristics by computed tomography (CT)-coronary angiography and visceral adipose tissue, observed a significant association between the latter and the amount of non-calcified plaque, as well as with CT-derived features of plaque vulnerability (low attenuation, positive remodeling).26
The present study, using high-resolution intravascular imaging, extends these previous findings, demonstrating a significant association of obesity with a thin fibrous cap and with macrophage infiltration, in addition to increased plaque burden and the amount of lipid-rich plaque. In the development and progression of atherosclerosis, macrophage infiltration of the coronary arterial wall with formation of foam cells represents a pivotal process, and macrophage-induced degradation of the fibrous cap matrix is an important contributor to plaque instability and disruption. It can be speculated that obesity could influence coronary atherosclerosis in 2 ways: first by affecting the overall plaque burden and atheroma volume and second, by determining plaque inflammation resulting in higher macrophage load and greater extent of TCFA. Indeed, we found that obese patients had significantly higher amounts of plaque burden, fibroatheroma, TCFA and macrophage infiltration. Together with DM and prediabetes, obesity was the only CVRF able to independently predict the presence of vulnerable plaques. Moreover, in patients with DM, the simultaneous presence of obesity was associated with a significantly higher extent of TCFA compared with DM alone, confirming the independent but synergetic role of these 2 conditions for coronary plaque vulnerability.
Interestingly, neither the LDL-C level nor the hs-CRP serum level as systemic markers of inflammation demonstrated any correlation with either plaque extent or specific plaque features. However, it should be noted that LDL-C levels were rather low and >70% of the patients were chronically treated with statins. Thus, the well-known plaque stabilizing effect of statin treatment may account for this observation.27
The significantly greater extent of coronary atherosclerosis, as well as the more vulnerable plaque phenotype, observed in patients with altered glycemic status and in obese patients suggests, once again, the importance of carrying out preventive pharmacological therapy with statins in these patients regardless of the need for LDL-C lowering.
Study Limitations
The present study has several limitations. First, this was a retrospective observational single-center study and the study population was small, so selection bias may have occurred. Second, we cannot rule out the effect of patients’ medical therapy on the study results. In particular, statin therapy may have influenced the observed plaque characteristics. In our population, all patients with DM were on statin therapy at the time of enrolment and obese patients were more frequently treated with statins compared with non-obese patients. As elegantly pointed out in a recent review,27
chronic statin therapy may have reshaped the morphological features of coronary atherosclerotic plaque.
Conclusions
Our study showed that patients with DM, prediabetes and obesity have more extensive coronary atherosclerosis and more vulnerable plaque phenotypes.
Funding
German Center of Cardiovascular Research (DZHK) and Excellence Cluster Cardio-Pulmonary System (ECCPS).
Supplementary Files
Supplementary File 1
Supplementary Methods
Table S1.
Optical coherence tomography-derived plaque characteristics
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-17-0054
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