Age- and Gender-Related Differences in Coronary Lesion Plaque Composition on Optical Coherence Tomography

Abstract

Background: The pathophysiology and chronological course of atherosclerosis seems to be different between men and women due to biological differences, and age and gender differences in plaque composition of coronary lesions remain to be elucidated.

Methods and Results: A total of 860 consecutive patients with a median age of 69 years (IQR, 60–78 years) who underwent optical coherence tomography (OCT) of culprit lesions was included. The composition of culprit plaque on OCT was compared between female (n=171) and male (n=689) subjects in younger (<70 years old) and elderly (≥70 years old) patients. In elderly patients, the prevalence of thin-cap fibroatheroma (TCFA) was significantly higher in women than in men (30.6 vs. 15.2%, P<0.001). In younger patients, the prevalence of large calcification was significantly higher in women than in men (60.0 vs. 32.8%, P<0.001). The prevalence of other vulnerable plaque characteristics (i.e., macrophages, microchannels, and spotty calcification), was similar between women and men. Elderly women had a significantly higher prevalence of TCFA (OR, 2.13; 95% CI: 1.33–3.44, P=0.002) than other patients.

Conclusions: Women had a higher prevalence of TCFA and of large calcification than men in patients ≥70 and <70 years old, respectively. This may facilitate the understanding of gender differences in the pathogenesis of coronary atherosclerosis, and the tailoring of therapy and of prevention according to age and gender.

The pathophysiology of coronary atherosclerosis seems to be different between women and men due to inherent biological and social differences. Although pathological and clinical studies have investigated the gender differences in the composition of coronary plaque, specific characteristics in women and men remain undetermined due to conflicting results in previous studies. Because hormone changes including a reduction in estrogen secretion around menopause occur in women, consideration of chronological aspects may contribute to clarifying the gender difference in the morphology of coronary plaques. In fact, a recent study using grayscale and radiofrequency intravascular ultrasound (IVUS) demonstrated fewer coronary fibroatheromas in women than in men in patients <65 years old, despite there being no gender differences in patients ≥65 years old. Thus, in the present study, we examined gender differences in the composition of coronary plaque, according to age.

Methods

Subjects

This was an observational study conducted at a single center with Japanese patients. A total of 1,021 culprit lesions in 1,021 patients who underwent optical coherence tomography (OCT) and percutaneous coronary intervention (PCI) between February 2013 and March 2019 at Kitasato University Hospital (Sagamihara, Japan) were identified. Of these, a total of 860 patients with 860 de novo lesions (171 female and 689 male) were enrolled in the present study after excluding cases of restenosis (n=132) and poor OCT of culprit lesions (n=29; Supplementary Figure 1). Because the median age in this cohort was 69 years (IQR, 60–78 years), “younger” and “elderly” were defined as <70 years old and ≥70 years old, respectively. All patients provided written informed consent for the procedure, and this study was conducted in compliance with the Declaration of Helsinki and approved by the institutional ethics committee.

Definition

Culprit lesions were defined as lesion treated by PCI. If multiple lesions were treated in 1 PCI session, the lesion with more severe ischemia on scintigraphy or physiologically was retrospectively defined as the culprit lesion and included in the analysis. In patients with stable angina or asymptomatic myocardial ischemia, the presence of ischemia was determined on scintigraphy, physiology (e.g., fractional flow reserve), or the combination of typical angina and angiographic severe stenosis. All cases were categorized as either of acute coronary syndrome (ACS) or stable coronary disease. ACS consisted of ST-segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), and unstable angina pectoris. Major adverse cardiac events (MACE) were defined as a composite of cardiac death; and acute myocardial infarction was defined as STEMI and NSTEMI based on the American College of Cardiology/American Heart Association guidelines,¹ and ischemia-driven revascularization. More than 1 event recorded in the same patient at the same time point was considered 1 composite cardiac event in statistical analysis. Further definitions are described in the Supplementary Methods.

OCT

OCT of culprit vessels was acquired before stent implantation after 100–200 µg i.c. nitroglycerin using frequency-domain OCT (ILUMIEN OCT Intravascular Imaging Systems; Abbott, Santa Clara, CA, USA). If antegrade coronary flow was insufficient to enable OCT, thrombectomy and/or gentle pre-dilatation using a small balloon was performed at the operator’s discretion.² All images were analyzed using offline proprietary software at the cardiovascular laboratory in Kitasato University School of Medicine. The images were qualitatively and quantitatively analyzed at 0.2-mm intervals. Plaque composition was evaluated using previously validated criteria (Supplementary Methods, Supplementary Figure 2).^3,4 Thin-cap fibroatheroma (TCFA) was defined as lipid-rich plaque with fibrous cap thickness <65 µm. Calcification was identified as low backscatter areas with a sharp border. Large calcification was defined as calcification with arc ≥180° on cross-sectional image.⁵ Spotty calcification was defined as calcification with arc <90°.⁶ Lesion length was defined as the length of a segment to be stented, which was measured on the longitudinal reconstructed view. Analysis was conducted by 2 independent investigators blinded to patient clinical information. When there was discordance between the investigators, a consensus reading was obtained from a third independent investigator. The interobserver reproducibility of the TCFA and large calcification identification were good (intraclass correlation coefficients, 0.898 and 1.000, respectively).

Statistical Analysis

Continuous variables were compared using the Student’s t-test or Mann-Whitney U-test for comparisons between independent groups, according to the data distribution. Categorical variables are reported as n (%) and were compared using Fisher’s exact test or the chi-squared test, according to the data distribution. Normally distributed data are reported as mean±SD. Composite cardiac event-free data during the median 405 days of follow-up are presented as Kaplan-Meier estimates. Logistic regression models with multiple predictor variables of clinical characteristics were used to determine independent predictors for TCFA. Statistical significance was defined as P<0.05. Statistical analyses were performed using JMP version 9.0 (SAS Institute, Cary, NC, USA).

Results

Clinical Characteristics

Comparison of clinical characteristics according to sex and to age is given in Table 1, Supplementary Table 1. The prevalence of current smokers was significantly lower in women than in men in both younger patients (10.3 vs. 24.9%, P=0.014) and elderly patients (3.6 vs. 13.1%, P=0.006). In women compared with men, the prevalence of a family history of ischemic heart disease (33.3 vs. 21.9%, P=0.020) and chronic kidney disease (CKD; 51.7 vs. 34.8%, P=0.013) was significantly higher in women than in men in the younger patients. High-density lipoprotein cholesterol (HDL-C) was significantly higher in women than in men in both younger patients (57.9±21.8 vs. 48.9±14.3 mg/dL, P<0.001) and in elderly patients (58.7±15.6 vs. 52.4±14.0 mg/dL, P<0.001).

Table 1. Clinical Characteristics

Variables	Younger (<70 years)			Elderly (≥70 years)			Younger vs. Elderly
	Women (n=60)	Men (n=346)	P-value	Women (n=111)	Men (n=343)	P-value	Women P-value	Men P-value
Age (years)	65 (62–67)	62 (54–66)	0.004	76 (74–80)	76 (73–80)	0.300	<0.001	<0.001
BMI (kg/m2)	23.4±5.3	25.0±3.7	<0.001	23.3±4.1	23.4±3.2	0.737	0.537	<0.001
Clinical presentation			0.626			0.279	0.369	0.610
Stable	49 (81.7)	273 (78.9)		84 (75.7)	276 (80.5)
ACS	11 (18.3)	73 (21.1)		27 (24.3)	67 (19.5)
Echo LVEF (%)	54.8±12.8	56.4±11.7	0.442	58.2±11.9	56.4±11.9	0.105	0.081	0.936
Multivessel disease	37 (61.7)	224 (64.7)	0.647	66 (59.5)	222 (63.4)	0.317	0.778	0.996
Culprit vessel			0.766			0.758	0.550	0.886
RCA	18 (30.0)	88 (25.4)		30 (27.0)	94 (27.4)
LAD	33 (55.0)	197 (56.9)		66 (59.5)	195 (56.9)
LCX	8 (13.3)	58 (16.8)		15 (13.5)	51 (14.9)
LMT	1 (1.7)	3 (0.9)		0 (0.0)	3 (0.9)
Risk factors
Hypertension	46 (76.7)	249 (72.2)	0.470	89 (80.2)	278 (81.3)	0.796	0.591	0.005
Dyslipidemia	37 (61.7)	252 (73.0)	0.072	81 (73.0)	221 (64.6)	0.105	0.127	0.017
Diabetes mellitus	27 (45.0)	134 (38.8)	0.368	38 (34.2)	135 (39.5)	0.324	0.166	0.865
Current smoker	6 (10.3)	85 (24.9)	0.014	4 (3.6)	44 (13.1)	0.006	0.081	<0.001
Family history of IHD	20 (33.3)	72 (21.9)	0.020	29 (28.2)	62 (19.3)	0.055	0.288	0.407
CKD (eGFR <60 mL/min/1.73 m2)	31 (51.7)	120 (34.8)	0.013	50 (45.1)	165 (48.3)	0.557	0.408	<0.001
Hemodialysis	9 (15.0)	43 (12.5)	0.588	6 (5.4)	26 (7.6)	0.433	0.034	0.034
Medication
ARB/ACEI	43 (72.9)	249 (72.2)	0.911	75 (67.6)	243 (71.3)	0.459	0.474	0.791
β-blocker	24 (40.7)	148 (42.9)	0.750	42 (37.8)	149 (43.7)	0.278	0.718	0.833
CCB	19 (32.2)	87 (25.2)	0.260	33 (29.7)	100 (29.3)	0.935	0.739	0.227
Statin	46 (78.0)	282 (81.7)	0.493	87 (78.4)	270 (79.2)	0.857	0.951	0.398
Insulin	5 (8.5)	27 (7.8)	0.865	9 (8.1)	22 (6.5)	0.554	0.934	0.491
Aspirin	46 (78.0)	272 (78.8)	0.880	76 (68.5)	273 (80.1)	0.012	0.190	0.693
Thienopyridine	36 (61.0)	237 (68.7)	0.244	67 (60.4)	228 (66.9)	0.211	0.934	0.607
Laboratory data
HbA1c (%)	6.46±1.04	6.50±1.24	0.638	6.43±1.08	6.43±0.98	0.930	0.999	0.543
LDL-C (mg/dL)	100.9±33.1	101.2±35.9	0.761	98.7±34.1	94.1±32.2	0.160	0.743	0.023
HDL-C (mg/dL)	57.9±21.8	48.9±14.3	<0.001	58.7±15.6	52.4±14.0	<0.001	0.391	<0.001
TG (mg/dL)	130 (90–183)	147 (96–197)	0.122	114 (78–176)	120 (87–166)	0.802	0.455	<0.001
eGFR (mL/min/1.73 m2)	52.5±26.0	60.1±24.9	0.007	53.3±20.1	55.7±20.2	0.158	0.916	<0.001
Treatment type
Drug-eluting stent	58 (96.7)	342 (98.8)	0.197	109 (98.2)	338 (98.5)	0.798	0.527	0.727
ROTA	2 (3.3)	1 (0.3)	0.041	7 (6.3)	15 (4.4)	0.423	0.390	<0.001

Data given as n (%), mean±SD or median (IQR). ACEI, angiotensin converting enzyme inhibitor; ACS, acute coronary syndrome; ARB, angiotensin II receptor blocker; BMI, body mass index; CCB, calcium channel blocker; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HbA1c, glycosylated hemoglobin; HDL-C, high-density lipoprotein cholesterol; IHD, ischemic heart disease; LAD, left anterior descending artery; LCX, left circumflex artery; LDL-C, low-density lipoprotein cholesterol; LMT, left main trunk artery; LVEF, left ventricular ejection fraction; RCA, right coronary artery; ROTA, rotational atherectomy; TG, triglyceride.

Lesion Characteristics on OCT

Results of OCT analysis of culprit plaque are listed in Table 2, Supplementary Table 2. In younger patients, the prevalence of large calcification was significantly higher in women than in men (60.0 vs. 32.8%, P<0.001). In elderly patients, the prevalence of TCFA was significantly higher in women than in men (30.6 vs. 15.2%, P<0.001). The prevalence rates of other vulnerable plaque characteristics including macrophages, microchannels, and spotty calcification were similar in women and men. The distribution of TCFA and large calcification according to age is shown in Figure 1. Although the number of TCFA was smaller in women than in men in all age subgroups, the prevalence of TCFA was significantly higher in women than in men in the 70–84-years age group. In contrast, the prevalence of large calcification was significantly higher in women than in men in the <50-years and 55–59-years subgroups, although the number of large calcifications was smaller in women than in men in all age subgroups.

Table 2. OCT Culprit Lesions Characteristics

Variables	Younger (<70 years)			Elderly (≥70 years)			Younger vs. Elderly
	Women (n=60)	Men (n=346)	P-value	Women (n=111)	Men (n=343)	P-value	Women P-value	Men P-value
Qualitative analysis
Lipid-rich plaque	18 (30.0)	145 (41.9)	0.082	45 (40.5)	116 (33.9)	0.205	0.173	0.031
TCFA	11 (18.3)	77 (22.3)	0.496	34 (30.6)	52 (15.2)	<0.001	0.081	0.017
Macrophage	27 (45.0)	126 (36.4)	0.205	31 (27.9)	111 (32.4)	0.381	0.024	0.263
Microchannel	17 (28.3)	95 (27.5)	0.889	26 (23.4)	75 (21.9)	0.743	0.480	0.093
Any calcification	52 (86.7)	263 (76.0)	0.068	95 (85.6)	295 (86.0)	0.912	0.846	<0.001
Large calcification	36 (60.0)	113 (32.8)	<0.001	51 (46.0)	165 (48.1)	0.692	0.079	<0.001
Large calcification with TCFA	1 (1.7)	7 (2.0)	0.855	6 (5.4)	12 (3.5)	0.371	0.239	0.237
Spotty calcification	48 (80.0)	259 (74.9)	0.392	89 (80.2)	285 (83.1)	0.484	0.978	0.008
Thrombus	7 (11.7)	42 (12.2)	0.899	16 (14.6)	28 (8.2)	0.053	0.600	0.084
Cholesterol crystals	16 (26.7)	73 (21.4)	0.360	30 (27.0)	78 (22.7)	0.357	0.960	0.660
Quantitative analysis
Reference vessel area (mm2)	6.9±2.9	7.7±3.3	0.087	6.8±2.3	7.2±3.0	0.625	0.649	0.055
Reference vessel diameter (mm)	2.9±0.6	3.0±0.6	0.052	2.9±0.5	3.0±0.6	0.726	0.572	0.039
Minimum lumen area (mm2)	1.6±0.8	1.5±0.9	0.082	1.4±0.6	1.5±0.9	0.714	0.168	0.817
Minimum lumen diameter (mm)	1.4±0.3	1.3±0.3	0.073	1.3±0.3	1.3±0.3	0.731	0.160	0.904
Percent area stenosis (%)	72.1±10.3	75.9±10.4	0.006	73.9±11.0	73.8±13.0	0.564	0.201	0.119
Diameter stenosis (%)	46.5±11.6	52.1±10.6	<0.001	49.5±12.1	50.0±12.2	0.642	0.080	0.068
Lesion length (mm)	34.0±15.8	30.3±14.2	0.094	30.3±13.7	31.6±13.7	0.329	0.121	0.135
Lipid-rich plaque
Thinnest FCT (μm)	78.3±45.0	93.1±67.5	0.714	71.5±36.4	87.7±45.9	0.043	0.479	0.635
Maximum lipid arc (°)	249±67	265±75	0.417	291±69	274±81	0.305	0.045	0.245
Large calcification
Maximum arc (°)	241 (193–315)	261 (213–360)	0.168	298 (211–360)	283 (218–360)	0.663	0.074	0.439
Max thickness (mm)	0.81±0.28	0.77±0.27	0.311	0.86±0.25	0.86±0.27	0.784	0.471	0.003
Minimum depth (μm)	49.7±45.1	69.8±58.8	0.070	50.2±30.2	66.7±52.3	0.064	0.570	0.968

Data given as n (%), mean±SD or median (IQR). FCT, fibrous cap thickness; OCT, optical coherence tomography; TCFA, thin-cap fibroatheroma.

Figure 1.

Incidence and proportion of (A,B) thin-cap fibroatheroma (TCFA) and (C,D) large calcification according to age and gender. *P<0.05, ^†P<0.01 vs. Men.

Elderly Patients With TCFA and Younger Patients With Large Calcification: Clinical Characteristics

Comparison of clinical characteristics according to sex in elderly patients with TCFA is given in Table 3. HDL-C was significantly higher in women than in men (57.6±16.4 vs. 48.3±11.7 mg/dL, P<0.001). Low-density lipoprotein cholesterol had a tendency to be higher in women than in men (114.3±39.4 vs. 103.7±33.6 mg/dL, P=0.158). And although the differences were not statistically significant, the prevalence rates of hypertension, diabetes, current smokers, and statin intake were lower in women than in men. Comparison of clinical characteristics according to sex in younger patients with large calcification is given in Table 4. The prevalence of a family history of ischemic heart disease (43.8 vs. 24.1%, P=0.031) was significantly higher in women than in men.

Table 3. Clinical Characteristics of Elderly Patients With TCFA: Gender Difference

Variables	Women (n=34)	Men (n=52)	P-value
Age (years)	76 (73–80)	76 (73–81)	0.909
BMI (kg/m2)	23.7±3.6	24.1±2.9	0.548
Stable/ACS	21 (61.8)/13 (38.2)	36 (69.2)/16 (30.8)	0.474
Multivessel disease	17 (50.0)	32 (61.5)	0.291
Hypertension	23 (67.7)	42 (82.4)	0.117
Dyslipidemia	21 (61.8)	27 (52.9)	0.422
Diabetes mellitus	8 (23.5)	19 (37.3)	0.183
Current smoker	2 (6.1)	11 (22.0)	0.051
Family history of IHD	10 (31.3)	9 (19.2)	0.217
CKD (eGFR <60 mL/min/1.73 m2)	15 (44.1)	21 (41.2)	0.788
Hemodialysis	2 (5.9)	4 (7.8)	0.730
Statin intake	22 (64.7)	40 (78.4)	0.163
HbA1c (%)	6.38±0.78	6.40±1.02	0.495
LDL-C (mg/dL)	114.3±39.4	103.7±33.6	0.158
HDL-C (mg/dL)	57.6±16.4	48.3±11.7	0.001
eGFR (mL/min/1.73 m2)	53.6±19.6	56.6±20.0	0.600

Data given as n (%), mean±SD or median (IQR). Abbreviations as in Tables 1,2.

Table 4. Clinical Characteristics of Younger Patients With Large Calcification: Gender Difference

Variables	Women (n=36)	Men (n=113)	P-value
Age (years)	64 (59–67)	64 (60–67)	0.694
BMI (kg/m2)	23.7±5.5	24.0±3.5	0.317
Stable/ACS	28 (77.8)/8 (22.2)	95 (84.1)/18 (15.9)	0.386
Multivessel	20 (55.6)	79 (69.9)	0.112
Hypertension	25 (69.4)	85 (75.2)	0.492
Dyslipidemia	21 (58.3)	78 (69.0)	0.237
Diabetes mellitus	19 (52.8)	54 (47.8)	0.602
Current smoker	5 (14.7)	23 (20.5)	0.450
Family history of IHD	14 (43.8)	26 (24.1)	0.031
CKD (eGFR <60 mL/min/1.73 m2)	18 (50.0)	45 (39.8)	0.282
Hemodialysis	8 (22.2)	24 (21.2)	0.900
Insulin	4 (11.4)	9 (8.0)	0.527
HbA1c (%)	6.70±1.15	6.60±1.17	0.659
LDL-C (mg/dL)	97.0±35.4	97.0±34.2	0.941
HDL-C (mg/dL)	55.7±25.6	50.5±14.7	0.288
eGFR (mL/min/1.73 m2)	49.8±27.5	53.9±29.0	0.456

Data given as n (%), mean±SD or median (IQR). Abbreviations as in Table 1.

Clinical Factors for TCFA

Univariate and multivariate analyses were conducted to identify independent factors for the presence of TCFA (Supplementary Table 3). In addition to ACS (OR, 2.606; 95% CI: 1.684–4.033, P<0.001), body mass index (kg/m²; OR, 1.069; 95% CI: 1.020–1.120, P=0.006), and current smoking status (OR, 2.059; 95% CI: 1.312–3.230, P=0.002), being elderly and female also had an independent association with the presence of TCFA (OR, 2.134; 95% CI: 1.326–3.435, P=0.002). Univariate and multivariate analysis of independent predictors of large calcification is given in Supplementary Table 4.

Clinical Course According to Age and Gender

The incidence of clinical events at a median of 405 days is shown in Figure 2, Supplementary Figure 3, Supplementary Table 5. Although the incidence of MACE was significantly lower in women than in men in younger patients (5.0 vs. 17.8%, log-rank P=0.032), the incidence was similar between the genders (11.4 vs. 14.2%, log-rank P=0.509) in elderly patients.

Figure 2.

Clinical course according to age and gender in (A) younger patients (<70 years) and (B) elderly patients (≥70 years). MACE, major adverse cardiac events.

Discussion

The main findings of this study were as follows: (1) a higher prevalence of TCFA was observed in women than in men in patients ≥70 years old; (2) a higher prevalence of large calcification was observed in women than in men in patients <70 years old; and (3) in contrast to the <70-years age group, in which the incidence of MACE was lower in women than in men, in patients ≥70 years this difference was not seen. Although specific characteristics of the composition of coronary plaques in women and men remained undetermined due to conflicting results in previous studies, the present study has confirmed age- and gender-specific characteristics of plaque composition in coronary lesions. These findings may help to improve the understanding of gender differences in the pathogenesis of coronary atherosclerosis and the tailoring of therapy and prevention according to age and gender.

Elderly Women and Plaque Vulnerability

Several studies have previously demonstrated no significant gender differences in coronary plaque morphology and composition.^7–9 Bharadwaj et al investigated gender differences in the morphology of coronary plaques in patients with stable angina using OCT and IVUS.¹⁰ They reported no significant differences in plaque burden, fibrous cap thickness, or prevalence of vulnerable components, including macrophages and microvessels. Sun et al investigated gender differences in culprit plaque characteristics in patients with STEMI using OCT.¹¹ They reported no gender differences in lipid quantity or fibrous cap thickness, in addition to the similar prevalence of plaque rupture and erosion. Meanwhile, the present study identified gender differences in the characteristics of coronary plaque composition, taking age into account. In patients ≥70 years old, the prevalence of TCFA was significantly higher in women than in men in the present study. This might be partly explained by the delayed progress of atherosclerosis due to the protective effect of estrogen in premenopausal women.^12,13 In fact, Burke et al demonstrated a higher prevalence of ruptured plaque in women >50 years old than in younger women in a pathology study.¹⁴ They suggested the anti-inflammatory effect of estrogen on the stabilization of coronary plaque in younger women. Qian et al also demonstrated the increasing prevalence of necrotic cores in women aged older than the mid-50 s in a study using virtual histology (VH)-IVUS.¹⁵ They demonstrated a higher prevalence of necrotic core in women than in men >58 years old, although the prevalence was similar between the genders in patients <58 years old.¹⁵ In addition to decreased estrogen secretion, an imbalance in cholesterol metabolism including enhanced absorption might contribute to the destabilization of coronary plaques in elderly women. In a study using VH-IVUS and OCT, Nasu et al demonstrated a significant correlation between thinner fibrous caps and a greater ratio of campesterol to lathosterol, suggesting the enhanced absorption and decreased synthesis of cholesterol.¹⁶

Younger Women and Severe Calcification

The number of previous studies focusing on gender differences in the prevalence or severity of coronary calcification using IVUS or OCT is small. Hara et al reported larger calcification in the left anterior descending artery in women with a median age of 67.8 years than in men on IVUS.¹⁷ A higher prevalence of coronary calcification in women than in men in younger patients (<65 years old) was also reported by Wang et al.¹⁸ In the present study, similar to previous studies, the prevalence of large calcification was significantly higher in younger women (median age, 65 years) than in younger men. This is paradoxical given the theory of delayed progression of atherosclerosis in women. Although the precise mechanism of the higher prevalence of large calcification in younger women in the present study is unclear and might be multifactorial, the higher prevalence of a family history of ischemic heart disease in younger women than in men might partly contribute to this. In other words, the inherent risk might have accelerated the process of coronary atherosclerosis in these patients. A strong association between coronary calcification and a family history of ischemic heart disease has been shown in previous studies.^19,20 Nasir et al demonstrated that the OR of the presence of coronary artery calcification observed using electron beam tomography in individuals with a family history of premature coronary disease was 2.5 compared with those without family history.¹⁹ Although the prevalence of CKD was significantly higher in women than men in younger patients, the prevalence was similar in women and men in younger patients with large calcification. Thus, the gender-specific contribution of the presence of CKD to the development of large calcification might be limited.

Clinical Implications

Understanding age and gender differences in culprit plaque composition may lead to more appropriate pharmacological and interventional therapies for both genders.²¹ In addition to historical reports,^22,23 a recent report found that women eligible for statin therapy were less likely than men to be treated with any statins or guideline-recommended statin intensities.²⁴ The authors reported that this was partly because of women being offered statins at a lower rate by their health-care providers. In the present study, however, the prevalence of TCFA was higher in women than in men in elderly patients. This suggests the importance of intensive lipid-lowering therapy for women. In addition, a lower incidence of recurrent events in women than in men was no longer observed in elderly patients, in contrast to younger patients in the present study. Taken together, sufficient intensity and duration of lipid-lowering therapy, including statins, should be provided for women as that provided for men. Additional prescription of ezetimibe might also be effective to stabilize coronary plaque in women,²⁵ because the imbalance of cholesterol metabolism including enhanced cholesterol absorption has been shown to play an important role in the progression of atherosclerosis by increasing age in women.²⁶ In contrast to the treatment and prevention of so-called “vulnerable plaques” including TCFA, the therapeutic strategy for coronary calcification may be more complex and challenging. In the present study, the prevalence of large calcification was higher in women than in men in younger patients. Although the higher prevalence of a family history of ischemic heart disease was identified as a characteristic in younger women, no modifiable risk factor was identified in the present study. Thus, there may be no specific therapeutic option but the strict management of conventional risk factors in postmenopausal women with a family history of ischemic heart disease. For the interventional treatment of culprit lesions with large calcification, detailed assessment of the distribution and severity of calcification using intracoronary imaging modalities including OCT may provide safer procedures and better clinical outcomes.^27,28 Appropriate use of debulking device and subsequent wider stent area is also required in lesions with large calcification,²⁹ although the use of rotational atherectomy was infrequent due to the relatively milder stenosis in younger women than in elderly women in the present study. In addition to conventional therapies and strict management of conventional risk factors, lifestyle modification may be more important in women than in men regarding the risk reduction of atherosclerotic change in plaque component and subsequent disease onset. The incidence of cardiovascular events in women has been shown to be more susceptible to habitual behaviors including longer television time and shorter sleeping time than that in men.^30,31 In particular, longer sedentary time was demonstrated to be associated with a higher prevalence of coronary calcification and a higher incidence of cardiovascular disease.^32,33 Thus, the understanding of the patient’s social and lifestyle habits, in addition to risk stratification based on conventional risk factors, may help in the development of comprehensive tailored therapies and prevention according to age and gender. In the present study, in the 4 subgroups, the incidence of MACE was numerically highest in the younger men, which might be caused by the tendency toward a higher prevalence of risk factors including dyslipidemia and smoking, worse lipid profiles, and a higher prevalence of vulnerable characteristics in the culprit plaque³⁴ in the younger men than others. In contrast to inherited or biological factors, these factors are considered as modifiable. Thus, more strict application of guideline-recommended conventional therapy may further improve the clinical course in younger men.³⁵

Study Limitations

Several limitations need to be mentioned. First, the present study involved only patients treated with PCI. The impact of age and gender on plaque composition in patients who have undergone bypass grafting or received pharmacological therapy remains undetermined. Second, the use of OCT during PCI was determined at the physician’s discretion. This may have caused selection bias. Third, a low percentage of patients with ACS were enrolled in the present study, which may have caused selection bias. Further studies with a larger number of patients with ACS may yield different results. Fourth, thrombectomy and/or gentle pre-dilatation was performed if antegrade coronary flow was insufficient to enable OCT in the present study. Thus, the interpretation of quantitative findings in culprit lesions needs caution. Fifth, non-culprit plaques were not analyzed on OCT because this was a retrospective study of OCT obtained at the time of PCI for culprit lesions. Sixth, the duration of clinical follow-up was limited. Longer follow-up may yield different results. Finally, this was a pure OCT study without analyses using other imaging modalities including IVUS.

Disclosures

The authors declare no conflicts of interest.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-19-0859

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