Abstract
Background
Distinct sex-related differences exist in coronary artery plaque burden and distribution. We aimed to explore sex differences in quantitative plaque burden by coronary CT angiography (CCTA) in relation to ischemia by invasive fractional flow reserve (FFR).
Methods
This post-hoc analysis of the PACIFIC trial included 581 vessels in 203 patients (mean age 58.1 ± 8.7 years, 63.5% male) who underwent CCTA and per-vessel invasive FFR. Quantitative assessment of total, calcified, non-calcified, and low-density non-calcified plaque burden were performed using semiautomated software. Significant ischemia was defined as invasive FFR ≤0.8.
Results
The per-vessel frequency of ischemia was higher in men than women (33.5% vs. 7.5%, p<0.001). Women had a smaller burden of all plaque subtypes (all p<0.01). There was no sex difference on total, calcified, or non-calcified plaque burdens in vessels with ischemia; only low-density non-calcified plaque burden was significantly lower in women (beta: −0.183, p=0.035). The burdens of all plaque subtypes were independently associated with ischemia in both men and women (For total plaque burden (5% increase): Men, OR: 1.15, 95%CI: 1.06-1.24,p=0.001; Women, OR: 1.96,95%CI: 1.11-3.46,p=0.02). No significant interaction existed between sex and total plaque burden for predicting ischemia (interaction p=0.108). The addition of quantitative plaque burdens to stenosis severity and adverse plaque characteristics improved the discrimination of ischemia in both men and women.
Conclusions
In symptomatic patients with suspected CAD, women have a lower CCTA-derived burden of all plaque subtypes compared to men. Quantitative plaque burden provides independent and incremental predictive value for ischemia, irrespective of sex.
Keywords: quantitative plaque analysis, fractional flow reserve, sex difference, computed tomography
TOC summary
We aimed to explore sex differences in quantitative plaque burden by coronary CT angiography in relation to ischemia by invasive fractional flow reserve (FFR). Compared to men, women had lower stenosis severity, fewer adverse plaque characteristics, lower quantitatively plaque burden and fewer abnormal FFR. In multivariable linear regression analysis, there was no sex difference on total, calcified, or non-calcified plaque burdens in vessels with ischemia; only low-density non-calcified plaque burden was significantly lower in women (beta: −0.183, p=0.035). The addition of quantitative plaque burden to stenosis severity and adverse plaque characteristics improved the discrimination of ischemia irrespective of sex.
1. Introduction
Invasive fractional flow reserve (FFR), used to evaluate the functional significance of coronary artery stenosis 1, is considered the gold standard for detection of lesion-specific ischemia. Prior studies have reported sex-related differences in FFR 2, 3, with angiographic lesions of similar stenosis severity being less likely to cause ischemia in women than in men 4–6.
Coronary CT angiography (CCTA) enables the assessment of the atherosclerotic burden in the entire coronary tree, which has prognostic importance in patients with stable coronary artery disease (CAD) 7–9. Further, the quantitative burden of total plaque and its various subtypes have been shown to improve the identification of lesion-specific ischemia 10–13.
Prior studies have reported distinct sex-related differences in CCTA-derived quantitative plaque characteristics 14–17. While women generally exhibit fewer adverse plaque characteristics (APCs) and lower quantitative plaque burdens, the relative risk of adverse cardiovascular outcomes according to CCTA plaque characteristics is higher in women than in men17, 18. Despite this, the sex-specific associations of coronary plaque burden and FFR-defined ischemia have not been explored. In the current study, we aimed to evaluate the impact of sex on CCTA-derived quantitative plaque burden and invasive FFR.
2. Methods
2.1. Study population
The present study was conducted as a post hoc substudy from PACIFIC (Prospective Comparison of Cardiac PET/CT, SPECT/CT Perfusion Imaging and CT Coronary Angiography With Invasive Coronary Angiography; NCT01521468) trial 19. A total of 208 consecutive patients with suspected stable CAD prospectively underwent CCTA and invasive FFR within a 2-week interval. The trial was approved by the institutional ethics committee and all participants provided written informed consent. Among 208 patients, we excluded five patients with suboptimal image quality for the quantitative plaque analysis. Hence, the current study included 203 patients.
2.2. CCTA acquisition
All patients underwent CCTA using a 256-slice CT scanner (Philips Brilliance iCT, Philips Healthcare, Best, the Netherlands). CCTA acquisition parameters were as follows: collimation 128 × 0.625 mm, gantry rotation 270ms, tube current 200-360 mA (according to body mass index), and tube voltage 120 kV. Prior to scanning, sublingual nitroglycerine was administered to all patients and metoprolol as required, aiming for a heart rate less than 65 beats/min. An intravenous bolus of 100ml of iodinated contrast was injected at 5.7 ml/s. The scan was triggered using an automatic bolus-tracking technique with a region of interest placed in the descending thoracic aorta. Prospective electrocardiogram gating was performed at 75% of the R-R interval.
2.3. CCTA: Qualitative analysis
CCTA analysis was performed by an independent core laboratories (St. Paul’s Hospital, Vancouver, British Columbia, Canada, and the Dalio Institute of Cardiovascular Imaing, New York-Presbyterian Hospital, New York) for the assessment of diameter stenosis severity blinded to invasive physiological results. The coronary tree was evaluated according to a 17-segment coronary artery model. All coronary segments ≥2 mm in diameter were visually graded, and classified as no CAD (0% stenosis), minimal CAD (1-24% stenosis), mild CAD (25-49% stenosis), moderate CAD (50-69% stenosis), and severe CAD (70-100% stenosis).
Coronary lesions were qualitatively assessed for the presence of four APCs by an experienced reader (RSD) blinded to clinical and FFR data. The positive remodeling was defined as remodeling index >1.120. Low attenuation plaque was defined as a plaque containing any voxel <30 HU 20. Spotty calcification was defined by a calcified plaque comprising <90° of the vessel circumference and <3 mm in length 20. The napkin ring sign was defined by a plaque with a central area of low CT attenuation surrounded by a rim-like area of higher CT attenuation 21. High risk plaque was defined as presence of two or more APCs.22
2.4. CCTA: Quantitative analysis
Standardized plaque quantification was performed using semiautomated software (Autoplaque v2.5, Cedars-Sinai Medical Center)7, 23 by expert readers (DH, AL, PM, GFT, AK, ET, EK) blinded to clinical and FFR data. The proximal and distal limits of individual coronary lesions were defined by the expert reader. Contouring of the vessel wall and lumen was automatic, with manual adjustment as required by expert reader. The absolute volumes (mm3) of total plaque, calcified plaque, non-calcified plaque, and low-density non-calcified plaque were semi-automatically quantified using adaptive scan-specific thresholds, as previously described.7, 23 The respective plaque burdens (%) were calculated as: plaque volume / analyzed vessel volume × 100.
2.5. Invasive coronary angiography and fractional flow reserve measurements
Invasive coronary angiography was performed according to standard catheterization procedures 24. To induce maximal coronary hyperemia, adenosine was infused by either intravenous or intracoronary adenosine at a dose of 140 μg·kg-1·min-1 or 150 μg, respectively. FFR was calculated as the ratio of the mean distal intracoronary pressure, measured by the pressure wire and the mean arterial pressure measured by the coronary catheter.1 All major coronary arteries were routinely interrogated by FFR, regardless of stenosis severity, except for occluded or subtotal lesions of more than 90%. A coronary lesion was considered hemodynamically significant in case of FFR≤0.80, or stenosis severity >90% obtained with quantitative coronary angiography in case of missing FFR. A stenosis with an FFR >0.80 or a stenosis severity <30% (obtained with quantitative coronary angiography) in the absence of FFR measurements was considered not to be functionally relevant. 2 In per-patient analysis, the lowest FFR among the left anterior descending (LAD), left circumflex (LCX), and right coronary (RCA) arteries was used.
2.6. Statistical Analysis
Continuous variables are represented as mean ± SD and categorical variables as numbers (percentages). The differences between groups were analyzed using Student’s t-test or Mann-Whitney U test for continuous variables and Chi-square test for categorical variables. FFR values were categorized as <0.7, 0.7-0.79, 0.8-0.89, and 0.9-1. Abnormal FFR was defined as FFR≤0.8. The relationship between sex and plaque burden was assessed using multivariable linear regression analysis after adjustment for coronary artery territory distribution (e.g. LAD, LCX or RCA), stenosis severity and APC, with reporting of beta coefficients (β) and standard errors (SE). The statistical significance of the beta coefficients (β) of the female sex was assessed using the likelihood ratio test.25 Multivariable logistic regression analyses reporting odds ratios (OR) with 95 % confidence intervals (95 % CI) were performed to estimate the likelihood of having abnormal FFR in men and women seperately after adjustement for stenosis severity, APCs, and coronary artery distribution. Backward stepwise logistic regression was performed to examine the potential relationship of clinical and imaging parameters with abnormal FFR. In order to account for within-patient correlation, clustered sandwich estimator models were employed. Global chi square analysis was used to assess the incremental value of CCTA-derived quantitative plaque burden for predicting ischemia using three nested models: 1) visual diameter stenosis categories (0%, 1-24%, 25-49%, 50-69%, and 70-100%); 2) model 1 + APCs (positive remodeling, low attenuation plaque, spotty calcification, napkin ring sign); 3) model 2 + quantitative plaque burden (total, calcified, non-calcified and low-density non-calcifieid plaque burden). In addition, we performed a sub-analysis to explore the additive value of APCs over and above the plaque burden (visual stenosis vs. visual stenosis + plaque burden vs. visual stenosis + plaque burden + APCs).
Statistical analyses were performed using STATA (version 17; StataCorp, College Station, TX, USA).
3. Results
3.1. Baseline characteristics
The mean age of the study population was 58.1±8.7, and 73 (36%) were women. Differences in baseline clinical and CT characteristics between men and women are shown in Table 1. Age and the frequency of conventional risk factors did not differ between men and women. Women presented with more atypical or non-specific angina, and men presented with more typical angina. 61% and 28.1% of the total population had moderate and severe stenosis, respectively. The proportion of patients with moderate and severe stenosis were higher in men. The frequency of APCs, including PR, LAP, and SC were lower in women than in men. Likewise, women had smaller all types of plaque volume and burden compared to men (all p<0.01).
Table 1.
Baseline characteristics of study population
| Overall | Women (n=73) | Men (n=130) | p-value | |
|---|---|---|---|---|
| Age | 58.1±8.7 | 59.5±9.3 | 57.4±8.4 | 0.098 |
| Body mass index | 26.9±3.6 | 26.7±3.8 | 27.0±3.5 | 0.688 |
| Diabetes | 31 (15.3) | 11 (15.1) | 20 (15.4) | 0.952 |
| Hypertension | 93 (45.8) | 40 (54.8) | 53 (40.8) | 0.054 |
| Dyslipidemia | 79 (38.9) | 29 (39.7) | 50 (38.5) | 0.859 |
| Current smoking | 38 (18.7) | 10 (13.7) | 28 (21.5) | 0.169 |
| Angina Status | 0.007 | |||
| Typical | 70 (34.5) | 15 (20.6) | 55 (42.3) | |
| Atypical | 76 (37.4) | 33 (45.2) | 43 (33.1) | |
| Nonspecific | 57 (28.1) | 25 (34.3) | 32 (24.6) | |
| Medication use | ||||
| Aspirin | 176 (86.7) | 58 (79.5) | 118 (90.8) | 0.023 |
| Statin | 156 (76.9) | 55 (75.3) | 101 (77.7) | 0.703 |
| Beta blocker | 130 (64.0) | 41 (56.2) | 89 (68.5) | 0.080 |
| Calcium channel blocker | 60 (29.6) | 22 (30.1) | 38 (29.2) | 0.892 |
| RAAS inhibitor | 73 (36.0) | 30 (41.1) | 43 (33.1) | 0.253 |
| Nitrates | 21 (10.4) | 10 (13.7) | 11 (8.5) | 0.247 |
| CACS | 176 (19–488) | 44 (0–249) | 314.5 (69–607) | <0.001 |
| 0 | 36 (17.7) | 21 (28.9) | 15 (11.5) | <0.001 |
| 1–99 | 48 (23.7) | 22 (30.1) | 26 (20.0) | |
| 100–399 | 55 (27.1) | 19 (26.0) | 36 (27.7) | |
| >=400 | 64 (31.5) | 11 (15.1) | 53 (40.8) | |
| CT stenosis | 0.005 | |||
| No stenosis | 20 (9.9) | 10 (13.7) | 10 (7.7) | |
| 1–24% | 30 (14.8) | 16 (21.9) | 14 (10.8) | |
| 24–49% | 29 (14.3) | 14 (19.2) | 15 (11.5) | |
| 50–69% | 67 (33.0) | 22 (30.1) | 45 (34.6) | |
| ≥70% | 57 (28.1) | 11 (15.1) | 46 (35.4) | |
| APCs | ||||
| PR | 46 (23) | 7 (9.9) | 39 (30.2) | 0.001 |
| LAP | 58 (29) | 10 (14.1) | 48 (37.2) | 0.001 |
| SC | 28 (14) | 4 (5.6) | 24 (18.6) | 0.011 |
| NRS | 19 (9.5) | 3 (4.2) | 16 (12.4) | 0.059 |
| HRP (≥2 APCs) | 45 (22.5) | 6 (8.5) | 39 (30.2) | <0.001 |
| Quantitative plaque characteristics | ||||
| Total plaque volume, mm3 | 454.3 (133.6–982.3) | 215.1 (41.7–439.6) | 713.7 (233.2–1162.4) | <0.001 |
| Calcified plaque | 62.1 (5.2–135.5) | 13.9 (0–79.8) | 91.8 (13.6–171.8) | <0.001 |
| Non-calcified plaque | 372.4 (117.3–811.6) | 163.8 (36.8–352.8) | 568.1 (196.8–1003.3) | <0.001 |
| Low-density plaque | 48.9 (14.2–128.7) | 22.8 (4.4–48.5) | 84.4 (30.4–171.4) | <0.001 |
| Total plaque burden, % | 49.3 (40.5–55.1) | 43.3 (29.8–51.4) | 51.0 (45.8–57.4) | <0.001 |
| Calcified plaque | 5.2 (1.4–9.9) | 3.7 (0–7.6) | 6.1 (2.2–11.4) | 0.006 |
| Non-calcified plaque | 41.0 (31.9–47.4) | 34.9 (23.2–43.9) | 43.1 (33.8–48.6) | <0.001 |
| Low-density plaque | 5.7 (3.3–8.4) | 4.0 (1.8–6.4) | 6.7 (3.9–8.9) | <0.001 |
Values are mean standard deviation, median (interquartile ranges) or number (percentage)
Abbreviations: RAAS, renin-angiotensin-aldosterone system; CACS, coronary artery calcium score; PR, positive remodeling; LAP, low attenuation plaque; SC, spotty calcification; NRS, napkin ring sign; HRP, high risk plaque; APC, Adverse plaque characteristics
3.2. Per-patient and per-vessel FFR values
Per-patient and per-vessel FFR results are shown in Table 2. Of the total 203 patients, 85 patients had an FFR ≤0.8 (41.9%). The mean FFR value was 0.87±0.13 in women and 0.75±0.19 in men. The frequency of ischemia was lower in women compared to men (16.4% vs. 56.2%). In per-vessel analysis, FFR values were significantly higher in women compared to men (0.93±0.1 vs. 0.86±0.16, p<0.001). This finding was consistent across all epicardial coronary arteries. Figure 1 shows the frequency of abnormal FFR according to stenosis severity. For vessels with minimal, mild, and moderate stenosis, women had lower frequency of abnormal FFR compared to men. The frequency of abnormal FFR did not differ significantly between men and women in vessels with severe stenosis.
Table 2.
Per-patient and per-vessel FFR results
| A. Per patient | ||||
|---|---|---|---|---|
| Total (n=203) | Women (n=73) | Men (n=130) | p-value | |
| FFR | 0.79±0.18 | 0.87±0.13 | 0.75±0.19 | <0.001 |
| Frequency of abnormal FFR in ≥1 vessels | 85 (41.9) | 12 (16.4) | 73 (56.2) | <0.001 |
| LAD | 72 (37.5) | 10 (14.1) | 62 (51.2) | <0.001 |
| LCX | 30 (15.8) | 3 (4.3) | 27 (22.5) | 0.001 |
| RCA | 34 (17.8) | 3 (4.2) | 31 (25.8) | <0.001 |
| B. Per vessel | ||||
| Total (n=581) | Women (n=214) | Men (n=367) | p-value | |
| FFR | 0.89±0.14 | 0.93±0.10 | 0.86±0.16 | <0.001 |
| Frequency of abnormal FFR | 139 (23.9) | 16 (7.5) | 123 (33.5) | <0.001 |
| LAD | 0.81±0.17 | 0.87±013 | 0.77±0.17 | <0.001 |
| LCX | 0.93±0.11 | 0.96±0.06 | 0.91±0.13 | 0.003 |
| RCA | 0.92±0.12 | 0.95±0.08 | 0.90±0.13 | 0.004 |
Values are mean standard deviation or number (percentage)
Abbreviations: FFR, fractional flow reserve; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery
Figure 1.
Per-vessel frequency of abnormal FFR according to degree of stenosis
Abbreviations: FFR, fractional flow reserve
3.3. Quantitative plaque burden and ischemia
The distribution of plaque volume according to subtypes is shown in Figure 2. While lower FFR values were associated with higher plaque volumes in both women and men, women had lower plaque volumes than men across all FFR categories, even in vessels without significant ischemia (FFR>0.8). Overall, per-vessel burdens of total plaque and all plaque subtypes were also lower in women compared to men (Table 3A). Even after adjustment for coronary artery territory, stenosis severity, and APCs, female sex was significantly associated with lower plaque burden of all subtypes (all p<0.01).
Figure 2.
Distribution of plaque volumes in relation to FFR by sex
Abbreviations: FFR, fractional flow reserve; CP, calcified plaque; NCP, non-calcified plaque; LD-NCP, low density non-calcified plaque
All p<0.01 for trend in men and women
Table 3.
Plaque burden and impact of female sex
| A. Total vessel | ||||||
|---|---|---|---|---|---|---|
| Univariable comparison | Female Sex in Multivariable linear regression* | |||||
| Women (n=214) | Men (n=367) | p-value | Coefficient | SE | p-value | |
| Plaque burden (%) | ||||||
| Total plaque | 33.8 (0–46.6) | 47.5 (15.8–55.7) | <0.001 | −0.149 | 0.053 | <0.001 |
| Calcified plaque | 0 (0–5.9) | 3.7 (0–10.8) | <0.001 | −0.115 | 0.056 | 0.004 |
| Non-calcified plaque | 26.4 (0–38.8) | 38.1 (10.4–46.7) | <0.001 | −0.131 | 0.053 | <0.001 |
| Low-density plaque | 1.7 (0–4.6) | 4.9 (0.8–8.4) | <0.001 | −0.145 | 0.044 | <0.001 |
| B. Vessel with positive FFR (per-vessel) | ||||||
| Univariable comparison | Female Sex in Multivariable linear regression* | |||||
| Women (n=16) | Men (n=123) | p-value | Coefficient | SE | p-value | |
| Plaque burden (%) | ||||||
| Total plaque | 47.1 (42.9–55.2) | 55.3 (48.3–60.0) | 0.023 | −0.084 | 0.083 | 0.330 |
| Calcified plaque | 10.2 (2.1–17.0) | 8.5 (3.8–14.4) | 0.992 | −0.035 | 0.129 | 0.680 |
| Non-calcified plaque | 32.9 (27.7–44.7) | 43.3 (36.3–53.3) | 0.042 | −0.061 | 0.120 | 0.481 |
| Low-density plaque | 4.0 (2.3–5.7) | 8.2 (5.4–11.8) | <0.001 | −0.183 | 0.136 | 0.035 |
Values are mean standard deviation or number (percentage)
Abbreviations: FFR, fractional flow reserve; SE, standard error
Adjustment for coronary artery distribution, stenosis severity and adverse plaque characteristics
In vessels with abnormal FFR, women had lower burdens of total, non-calcified, and low-density non-calcified plaque compared to men (Table 3B, p<0.05). Calcified plaque burden did not differ significantly between men and women (p=0.992). In multivariate analysis with adjustment for stenosis severity, APCs, and coronary artery territory, there was no effect of female sex on the total, calcified, and non-calcified plaque burden. Only low-density non-calcified plaque burden was significantly lower in women (beta: − 0.183, p=0.035). Regarding APCs, overall, 51% of vessels with abnormal FFR had any APCs (71/139 vessels). Women had a lower prevalenceof APCs compared to men in vessels with abnormal FFR (37.5% vs. 52.9%).
In multivariable logistic regression analysis, higher total plaque burden and burdens of all plaque subtypes were associated with abnormal FFR in both men and women (Figure 3, all p <0.05). No significant sex interaction existed between the burdens of all plaque subtypes and abnormal FFR. Table 4 and Supplemental Table 1 show the univariable and multivariable logistic regression analysis to predict abnormal FFR. In multivariable analysis, age, female sex, stenosis severity, number of APCs, and calcified, low-density non0calcified plaque burden were independent predictors of abnormal FFR in both overall vessels and vessels with non-obstructive CAD (Table 4).
Figure 3.
A. A case example of 68-year-old woman with moderate stenosis (50-69%) and diffuse coronary atherosclerosis in the left anterior descending artery. The fractional flow reserve (FFR) value was 0.76, indicating significant ischemia. Red and yellow overlay depict noncalcified and calcified plaque, respectively. B. In multivariable logistic regression analysis, all types of plaque burden were independently associated with FFR defined ischemia in both women and men. No significant interaction existed between sex and all types of plaque burden for predicting ischemia. *Model adjusted for stenosis severity, adverse plaque characteristics, and coronary artery distribution. Odds ratios for per 5% plaque burden increase.
Tables 4.
Logistic regression for the relationship between clinical and vessel characteristics and fractional flow reserve. in overall (A) and non-obstructive vessels (B).
| A. Overall vessels (n=581) | |||
|---|---|---|---|
| OR | 95% CI | p-value | |
| Age | 0.95 | 0.92–0.99 | 0.012 |
| Female | 0.38 | 0.20–0.74 | 0.005 |
| Hypertension | 1.15 | 1.08–1.23 | <0.001 |
| Visual stenosis | 2.26 | 1.72–2.97 | <0.001 |
| Number of adverse plaque characteristics | 1.91 | 1.32–2.76 | 0.001 |
| Calcified plaque burden | 1.07 | 1.04–1.11 | <0.001 |
| Low-density plaque burden | 1.15 | 1.08–1.23 | <0.001 |
| B. Non-obstructive vessels (<50%, n=391) | |||
| Age | 0.93 | 0.88–0.98 | 0.013 |
| Female | 0.07 | 0.02–0.31 | <0.001 |
| Hypertension | 2.48 | 0.95–6.47 | 0.064 |
| Number of adverse plaque characteristics | 3.46 | 1.80–6.63 | <0.001 |
| Calcified plaque burden | 1.12 | 1.05–1.19 | <0.001 |
| Low-density plaque burden | 1.16 | 1.02–1.34 | 0.029 |
In global chi-square analysis, the addition of quantitative plaque burden improved discriminatory value for the identification of abnormal FFR when added to model with diameter stenosis and APCs in both women (χ2 = 74.75 vs. 58.1, p=0.002, Figure 4A) and men (169.53 vs. 133.87, p<0.001, Figure 4B). In a sub-analysis, quantitative plaque burden provided additive value over diameter stenosis (χ2 values: 64.2 vs. 48.5 in women; 145.7 vs. 103.2 in men, both p<0.05). Adding APCs to the model with diameter stenosis and plaque burden further improved model performance for identifying abnormal FFR (both p<0.05).
Figure 4.
Additive value of quantitative plaque burden for identifying ischemia in women (A) and men (B) Abbreviations: DSC, diameter stenosis category; APCs, adverse plaque characteristics
4. Discussion
In the current study, we explored the sex differences in CCTA-derived quantitative coronary plaque burden and its association with invasive FFR. We confirmed that women displayed lower stenosis severity, fewer APCs, and lower volumes and burdens of all plaque subtypes compared to men. However, in vessels with abnormal FFR, there was no significant sex interaction in total, calcified, or non-calcified plaque burden. Only low-density non-calcified plaque burden was significantly lower in women in the multivariable analysis. The quantitative assessment of plaque burden by CCTA improved discriminatory performance for ischemia identification in both men and women.
Previous studies have shown that quantitative plaque assessment improved the identification of significant ischemia 10, 11, 13. Nakazato et al. identified that quantitative plaque volume by CCTA was higher in lesions with significant ischemia than lesions without ischemia in patients with intermediate stenosis (30-69%).10 In a study from NXT (coronary blood flow using coronary CT angiography: NeXt sTeps) trial, Gaur et al. reported that low-density non-calcified plaque burden was an independent predictor of lesion-specific ischemia and improved discriminatory power in identifying ischemia-causing lesions 11. Our findings are consistent with these previous reports that higher CCTA-derived quantitative plaque burden was associated with abnormal FFR in men and women.
Sex differences have previously been described in coronary artery plaque burden and distribution. In the 63,215 patients in the CAC consortium, women had less extensive calcified plaque as measured number of lesions and vessels.17 In a study including propensity-matched 525 men and 525 women who underwent CCTA, men had a greater plaque burden than women while women had a larger proportion of mixed and non-calcified plaque components.15 A subanalysis of the SCOT-HEART (Scottish Computed Tomography of the HEART) trial reported that CCTA-derived quantitative plaque burden was significantly lower in women than men.16 Despite these well-known interactions between sex and coronary plaque burden, the potential sex difference of coronary plaque burden in relation to physiologic outcome assessed by FFR has not been previously explored. As expected, the overall plaque burden was significantly lower in women compared to men in the current study. However, in multivariable analysis, vessels with abnormal FFR demonstrated similar total plaque burden and burdens of plaque subtypes between women and men except for low-density non-calcified plaque burden. Low-density non-calcified plaque is a marker of necrotic core 26, 27, which has been shown to be associated with endothelial dysfunction.11, 28 The current results may indicate that the role of the necrotic core in endothelial dysfunction and FFR is more significant in men than in women. On the other hand, there is growing evidence that menopause and estrogen play an important role in the development and progression of atherosclerotic disease in women. Early menopause or lower estrogen level at post-menopause were closely associated with higher atherosclerotic burden, endothelial dysfunction, and coronary microvascular dysfunction29–31. Further studies are needed to explore the differences in the relationship between morphological atherosclerotic plaque characteristics and hormonal/endothelial function on ischemia according to sex.
Prior studies reported that significant sex differences existed between stenosis severity and invasive FFR.4–6 That is, women have been shown to be less likely to have ischemia than men, even having a similar degree of stenosis. We also observed a significantly lower frequency of abnormal ischemia in women among vessels with mild to moderate stenosis. One of the potential explanations for the finding is the sex differences in the coronary volume and myocardial mass (V/M) ratio. A reduced coronary lumen volume to left ventricle mass ratio has been suggested to contribute to impaired coronary blood flow.32 A recent study from the ADVANCE registry revealed that women had a higher V/M ratio which was independently associated with a higher FFR independent of stenosis severity.33 The sex differences in stenosis severity, V/M ratio, and FFR may influence the differences in treatment strategy and prognosis between men and women.4, 34, 35
Since women have less extensive and obstructive and more diffuse CAD compared with men 36, 37, quantitative assessment of plaque burden may be a potential predictive marker of ischemia in addition to stenosis severity. In our analysis, quantitative plaque burden was as strong a predictor of ischemia in women as in men. Further, the addition of quantitative plaque burdens improved discriminatory value for the prediction of ischemia in both women and men. The current study findings show no existing sex interaction in the predictive value of coronary plaque burdens for FFR-defined ischemia; thus, coronary plaque quantification is helpful for the identification of ischemia-causing lesions irrespective of sex.
4.1. Limitations
This study has several limitations. The generalizability of the present findings might be limited by the relatively small sample size from a single center. Furthermore, the frequency of abnormal FFR in women was low (11.5%, 16/214). Further studies are required to confirm the association between plaque burden and FFR according to sex. The cross-sectional nature of this study limits our inference of the potential sex-related differences in the relationship between plaque burden and FFR towards adverse cardiovascular outcomes. Recent evidence indicated that microvascular dysfunction is one of the major causes of ischemic CAD and is highly prevalent in women.38, 39 In the present study, we used FFR as a physiological outcome, assessing only macrovascular flow-limiting lesions.40 The potential sex differences in the relationship between macrovascular plaque burden and microvascular dysfunction warrants further investigation.
5. Conclusion
In this post hoc analysis of a prospective trial including symptomatic patients with suspected CAD, women have a lower CCTA derived burden of all plaque subtypes and fewer abnormal FFR compared to men. Irrespective of sex, CCTA derived quantitative plaque burden provides independent and incremental predictive value for ischemia.
Supplementary Material
Acknowledgments
Funding:
This study was supported in part by grants from the National Heart, Lung, and Blood Institute, 1R01HL148787-01A1 and 1R01HL151266. The work is also by a grant from the Miriam and Sheldon G. Adelson Medical Research Foundation.
Abbreviations
- FFR
fractional flow reserve
- CCTA
Coronary CT angiography
- CAD
coronary artery disease
- APCs
adverse plaque characteristics
- LAD
left anterior descending artery
- LCX
left circumflex artery
- RCA
right coronary artery
- V/M ratio
coronary volume and myocardial mass ratio
Footnotes
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Disclosure: Outside of the current work, S.C., P.S., and D.D. received software royalties from Cedars-Sinai Medical Center. D.B, P.S., and D.D. hold a patent (US8885905B2 in USA and WO patent WO2011069120A1, Method and System for Plaque Characterization).
Outside of the current work, S.C., P.S., and D.D. received software royalties from Cedars-Sinai Medical Center. D.B, P.S., and D.D. hold a patent (US8885905B2 in USA and WO patent WO2011069120A1, Method and System for Plaque Characterization).
All other authors report no conflicts of interest.
References
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