Multimodality OCT, IVUS and FFR evaluation of coronary intermediate grade lesions in women vs. men

Background The pathophysiology of atherosclerotic plaque formation and its vulnerability seem to differ between genders due to contrasting risk profiles and sex hormones, however this process is still insufficiently understood. The aim of the study was to compare the differences between sexes regarding the optical coherence tomography (OCT), intravascular ultrasound (IVUS) and fractional flow reserve (FFR)-derived coronary plaque indices. Methods In this single-center multimodality imaging study patients with intermediate grade coronary stenoses identified in coronary angiogram (CAG) were evaluated using OCT, IVUS and FFR. Stenoses were considered significant when the FFR value was ≤0.8. Minimal lumen area (MLA), was analyzed by OCT in addition to plaque stratification into fibrotic, calcific, lipidic and thin-cap fibroatheroma (TCFA). IVUS was used for evaluation of lumen-, plaque- and vessel volume, as well as plaque burden. Results A total of 112 patients (88 men and 24 women) with chronic coronary syndromes (CCS), who underwent CAG were enrolled. No significant differences in baseline characteristics were present between the study groups. The mean FFR was 0.76 (0.73–0.86) in women and 0.78 ± 0.12 in men (p = 0.695). OCT evaluation showed a higher prevalence of calcific plaques among women than men p = 0.002 whereas lipid plaques were more frequent in men (p = 0.04). No significant differences regarding minimal lumen diameter and minimal lumen area were found between the sexes. In IVUS analysis women presented with significantly smaller vessel area, plaque area, plaque volume, vessel volume (11.1 ± 3.3 mm2 vs. 15.0 ± 4.6 mm2 p = 0.001, 6.04 ± 1.7 mm2 vs. 9.24 ± 2.89 mm2 p < 0.001, 59.8 ± 35.2 mm3 vs. 96.3 (52.5–159.1) mm3 p = 0.005, 106.9 ± 59.8 mm3 vs. 153.3 (103–253.4) mm3 p = 0.015 respectively). At MLA site plaque burden was significantly greater for men than women (61.50 ± 7.7% vs. 55.5 ± 8.0% p = 0.005). Survival did not differ significantly between women and men (94.6 ± 41.9 months and 103.51 ± 36.7 months respectively; p = 0.187). Conclusion The presented study did not demonstrate significant differences in FFR values between women and men, yet a higher prevalence of calcific plaques by OCT and lower plaque burden at the MLA site by IVUS was found in women vs. men.


Introduction
The pathophysiology of atherosclerotic plaque formation and its vulnerability seem to be different between genders due to contrasting risk profiles and sex hormones (1)(2)(3). However, this process is still insufficiently understood. There is still a limited amount of data on sex associated differences in plaque morphology and their influence on blood flow dynamics, underscoring the need for further research.
The primary modality for diagnosing coronary artery disease (CAD) is coronary angiogram (CAG) (4)(5)(6). However, it has several widely acknowledged limitations (4)(5)(6). It is estimated that even 50% of patients who suffered from cardiac arrest did not experience any premonitory symptoms (7). Therefore, additional techniques have been developed in order to deepen the diagnostic process and optimize treatment strategy, i.e., intravascular ultrasound (IVUS), optical coherence tomography (OCT) and fractional flow reserve (FFR).
Therefore, direct visualization of the artery wall is feasible, enabling a precise evaluation of plaque composition and its superficial layers (e.g., thin cap fibroatheroma -TCFA, plaque rapture) (19)(20)(21). Moreover, intravascular modalities are recognized to positively impact the clinical outcomes regarding CAD assessment and PCI guidance (10,22). On the other hand, FFR/iFR remain the guideline-recommended invasive modalities to identify coronary lesions requiring interventional procedures to resolve myocardial ischemia (23,24).
The aim of the study was to visualize and compare the imaging (OCT, IVUS) and functional indices of coronary lesions in women vs. men, taking into account such parameters as minimal lumen area (MLA), plaque characteristics (fibrotic, calcific, lipidic or TCFA), plaque burden and a functional index of FFR among patients undergoing CAG due to chronic coronary syndromes (CCS).

Study population
This was a single-center, prospective, observational, longitudinal, cohort study that enrolled patients with CCS (n = 112) who underwent CAG. Intermediate grade coronary stenoses were evaluated with FFR, OCT and IVUS ( Figure 1). The relevance of the stenoses was found significant if FFR ≤ 0.8. The study protocol was approved by the local Ethics Committee.
The study inclusion and exclusion criteria have been previously published (25). In brief, the inclusion criteria comprised: chronic coronary syndrome, presence of chest pain ranked 2-3 in the Canadian Cardiovascular Society classification or positive ischemia test (exercise test, single photon emission tomography -SPECT), age >18 years, intermediate grade coronary stenoses of 40%-80% evaluated visually during angiography (26), FFR and OCT examination of the same lesion.
Exclusion criteria: left main disease, ostial right coronary lesion, bypass graft lesions, hemodynamic instability, acute or chronic renal insufficiency defined as serum creatinine level >1.5 mmol/L, contraindication for adenosine administration, pregnancy.
OCT images were analyzed according to expert consensuses' definitions (27)(28)(29)(30), by the analysts blinded to patient characteristics, IVUS and FFR result. Evaluation of the reference Study flow chart. Intravascular ultrasound was performed at the discretion of the operator (in 64 patients). Baruś et al. 10.3389/fcvm.2023.1021023 Frontiers in Cardiovascular Medicine lumen area was performed in the largest lumen proximal or distal to a stenosis (within 10 mm of the stenosis). Morphometric assessment of the plaque was done at the site of MLA in at least three consecutive frames. Plaques were stratified into fibrous, calcified, lipid-rich or mixed. Fibrous plaque is characterized by high backscattering and a relatively homogenous signal, calcified plaque comprises calcium visible as a signal poor heterogeneous region with sharply delineated border (27-30) ( Figure 2). In addition, the calcium angle (the circumference of the calcium covering the lumen and presented in degrees) was assessed. Plaque was considered lipid-rich in case of inhomogeneous signal-poor region with diffused borders (28, 31). The lipid angle was computed as the arc of a low-signal region presented in degrees. Fibrous cap thickness (FCT) was defined as the distance between the arterial lumen and the inner border of the lipid or calcium pool. The FCT was assessed first at 0.2-mm intervals over the plaque and then 3 times at its thinnest part at each cross-section, and the average value was taken into the final analyses (31). TCFA was defined with minimal FCT < 65 µm.

FFR
Coronary pressure was obtained using a 0.014-inch pressure guide wire (St. Jude Medical, Minneapolis, MN, USA). Maximal hyperemia was induced by intravenous adenosine administration at 140 µg/kg/min through a large peripheral vein. The used formula for FFR calculations was mean hyperemic distal coronary pressure divided by mean aortic pressure. The stenosis was found significant in the case of a FFR ≤ 0.80 (32-34) ( Figure 3).

IVUS
In order to acquire an IVUS image, the catheter was placed in the distal fragment of the vessel and a pullback was performed at a speed of 0.5 mm/s at 40 MHz (35). IVUS image assessment was performed in 0.5 mm intervals using a dedicated software by analyst blinded to patients characteristics, FFR and OCT results. The plaque burden at MLA site was calculated using the formula: (external elastic membrane area-lumen area)/external elastic membrane area × 100%.

Statistical analysis
Statistical analyses have been performed using the SPSS version 28.0 (IBM Corp, Armonk, NY, USA). The distribution was analyzed with the Kolmogorov-Smirnov test. Normally distributed data were presented with means and standard deviation (SD), whereas the non-parametric data were presented with median and percentiles 25th and 75th (interquartile range). Categorical variables were presented by percentages within each group. Between-group comparisons were carried out with a Student t-test or Mann-Whitney U test for continuous variables and Chi-square test or Fisher's exact test, as appropriate, for categorical variables. Kaplan-Meier analysis with log-rank test was conducted to compare the MACE-free survival and death probability between the sexes. The results were considered significant for p < 0.05.

Patients characteristics
A total of 112 patients (132 lesions) that underwent CAG were included in this study. This group comprised 24 women (21.4%) and 88 men (78.6%). The prevalence of coexisting conditions was high with the two most common, hypertension and hypercholesterolemia, present in 84.0% and 66.0% of patients respectively. There were no significant differences between genders in terms of age and comorbidities in the analyzed cohort. No differences in prior medication use were recorded either ( Table 1).
There were no differences in plaque localization between men and women. Most frequently lesions were located in left anterior descending (LAD), which was the case for 20 women and 58 men. The mean FFR was 0.76 (0.73-0.86) for women and 0.78 ± 0.12 for men and did not differ significantly ( Table 2).

IVUS
In a subset of 64 patients (16 women and 48 men) parameters were assessed using IVUS ( Table 3). Women had a significantly smaller vessel area and plaque area. There were no significant differences in lumen volume, but plaque volume and vessel Frontiers in Cardiovascular Medicine volume were significantly greater in men. MLA did not differ between genders. At the MLA site, plaque burden was significantly greater for men than women. The same was true for vessel area, plaque area and average intimal thickness at MLA site.

OCT
Plaques were classified into calcified, fibrous, mixed and lipidic. The most common type overall was calcified plaque, which was observed in 49 lesions -17 in women and 32 in men. This plaque type was more common in women than men. Lipidic plaques on the other hand were more prevalent in men than women, but the type most frequently found in men was fibrous type -37 plaques accounting for 35.9% of plaques ( Table 4). Table 5. The length of the lesion did not differ significantly between men and women. Minimal lumen diameter and minimal lumen area did not show any significant differences as well. There were no significant differences in mean, minimal or maximal angle of calcium.

Follow-up
The clinical follow-up was present for 94 patients (median follow up 122 months, IQR = 107-122 months). Out of them, 25 patients died (26.6%) -7 women and 18 men, no difference in the overall mortality was found for women vs. men (31.8% vs. 25%, p = 0.526). Average survival (in months) did not differ significantly between women and men (94.6 ± 41.9 and 103.51 ± 36.7 respectively; p = 0.187). Similarly, there were no significant differences in the number of major adverse cardiac event (MACE), defined as: all-cause death, myocardial infarction, repeated revascularization, stroke and hospitalization due to heart failure (Supplementary Table S1).
There were no significant differences in the mortality rates and survival probability (Figure 4) between men and women. MACE occurrence also did not differ significantly between sexes.

Discussion
Enriching a standard CAG with intravascular imaging modalities such as OCT or IVUS allows a more thorough lesion   The values are provided as mean ± SD or median (IQR).  (37).
The results obtained using OCT show a statistically significant difference in the most common type of plaque between sexes. In our study 63% of enrolled women had a calcified plaque, whereas among men such a plaque was present in 31.1% of the cases (p = 0.002). Furthermore, lipidic plaque was more common in men (p = 0.04).
The prevalence of each plaque type in women vs. men varies between the hitherto studies. A study by Mariani et al. analyzing coronary arteries by OCT in patients with stable CAD (138 men and 42 women) showed a higher percentage of lipid rich plaques and macrophages in women (38). On the other hand, in a study by Giordana et al., women presenting with non-ST segment elevation myocardial infarction (NSTEMI) had a lower prevalence of lipid plaques (39). Similar conclusions were drawn from a study that analyzed 187 non-culprit lesions among patients with CAD, women had overall a lower lipid index and less lipid-core length (40), which is consistent with our findings. In our study the mean age for women and men is 65.17 and 64.74 years respectively. A study by Sato et al. showed, that in the case of a group of patients below the age of 70 years calcifications are present more often among women (41), what is consistent with our results. A study by Kataoka et al. evaluated differences between genders in stable CAD and acute coronary syndromes (ACS) regarding OCT indices. A total number of 320 and 115 lesions in CCS and ACS respectively, were taken into consideration. In women presenting with CAD and ACS a lower prevalence of cholesterol crystals and calcifications was observed (42). The results of the above-mentioned studies and our findings are often contrary, thus proving the need for a more thorough assessment on a larger patients sample in order to develop a more gender specific approach in CAD treatment resulting in better clinical outcomes.
Previous studies concerning gender differences in IVUS plaque morphology have reached similar conclusions. Vessel area has been repeatedly found to be smaller in women than men (43,44) Kaplan-Meier curveoverall survival (years).  (44). The same study as well as Bharadwaj et al. study found that plaque burden was greater in men in reference vessel area (44,45). The results in our study are consistent with the above. Vessel area and plaque area overall were found to be greater in men than women. At minimal lumen area vessel area, plaque area and plaque burden were also significantly greater in men than women. Moreover, this study has found the average intimal thickness at MLA to be greater in men than women, which was not reported in any previous study concerning this issue.

. A study by Kang et al. assessed vessel area and plaque burden at
The main finding of our study concerning FFR was that on average the FFR in patients undergoing CAG due to CAD does not differ significantly by gender. FFR-guided PCI is superior to classical coronary angiography. It allows to identify the hemodynamically significant lesions and therefore, to choose a more adequate treatment strategy (46)(47)(48). It was already established, that it is equally beneficial for both male and female patients with CAD, although the FFR below 0.8 has a higher positive prognostic value in men (49). Moreover, the FFR values below 0.8 are associated with a higher risk of death or MI in female patients (50).
The studies to date suggest that with the same grade of stenosis in coronary arteries, women tend to have higher values of FFR (44,51), which seems to be associated with the size of the body and hence the mass of the heart, and not as it was previously suspected with microvascular dysfunction (44,52,53). The composition of the plaque may also impact FFR value. Noncalcified and low-density plaques are associated with lower FFRs in both patients with and without hemodynamically significant narrowing of the vessel (54). A recent study showed that after adjustment for left ventricle mass and plaque characteristics, sex is not an independent factor of FFR value (53). In our population, there were no significant differences in baseline characteristics between genders, including the factors associated with the progression of CAD such as age, HT, or dyslipidemia, which is different in comparison with previously conducted studies. This would stay in line with the conclusions that gender is not an independent factor of FFR values and the higher FFR values in women (49) are due to other differences in populations' characteristics. Even though the plaque composition differed significantly in terms of calcification, the FFR remained on the same levels between sex groups which may suggest that the calcification grade did not significantly impact the outcomes.
It should be noted that our findings have limitations. We conducted a single-center and non-randomized study; thus, it is imperative that further research include more centers and randomization. Moreover, there is a high disproportion between genders as women comprise only 21.4% of the investigated group, thus future research should focus on minimizing that disparity.
Performing a vessel analysis by both OCT and IVUS requires two separate catheters. It is associated with difficulties in an accurate lesion analysis due to an imperfection of image overlapping and carries a higher risk of side effects (55,56). However, both modalities are complementary with each other, therefore combined catheters were designed, which perform an evaluation of the same area at the same time, enabling a complete vessel wall visualization and precise evaluation (19,56). Furthermore, during the last few years new diagnostic techniques have been developed in order to assess coronary blood flow disturbances and estimate FFR without using a pressure wire. Such modalities build a three-dimensional artery model based on CAG images. Recent studies proved similar sensitivity and specificity of these techniques in comparison to pressure wire-based FFR (57-61).

Conclusions
The presented study did not demonstrate significant differences in FFR values between women and men, yet a higher prevalence of calcific plaques by OCT and lower plaque burden at the MLA site by IVUS was found in women as compared to men.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Ethics statement
The studies involving human participants were reviewed and approved by Medical University of Warsaw Ethics Committee. The patients/participants provided their written informed consent to participate in this study.

Author contributions
PB and AdP contributed to the conception and design of the study, literature review, writing the initial and final version of the manuscript, data collection, analysis and/or interpretation of data. KG, AB, PD contributed to the literature review, data collection, analysis and/or interpretation of data. MGł, KS, DO contributed to the critical revision of the manuscript, analysis and/or interpretation of data. AR, ArP contributed to the data collection and the critical revision of the manuscript. MGr, JK were responsible for the supervision of the study. MT contributed to the conception and design of the study, critical revision of the manuscript, writing of the final version of the manuscript and was responsible for the supervision of the study. All authors approve the final version and agree to be accountable for all aspects of work ensuring integrity, and accuracy.