Author + information
- Received February 7, 2013
- Accepted February 8, 2013
- Published online June 1, 2013.
- Soo-Jin Kang, MD, PhD∗,
- Jung-Min Ahn, MD∗,
- Seungbong Han, PhD†,
- Jong-Young Lee, MD∗,
- Won-Jang Kim, MD∗,
- Duk-Woo Park, MD, PhD∗,
- Seung-Whan Lee, MD, PhD∗,
- Young-Hak Kim, MD, PhD∗,
- Cheol Whan Lee, MD, PhD∗,
- Seong-Wook Park, MD, PhD∗,
- Gary S. Mintz, MD‡ and
- Seung-Jung Park, MD, PhD∗∗ ()
- ∗Department of Cardiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
- †Department of Biostatistics, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
- ‡Cardiovascular Research Foundation, New York, New York
- ↵∗Reprint requests and correspondence:
Dr. Seung-Jung Park, Asan Medical Center, 388-1 Poongnap-dong, Songpa-gu, Seoul 138-736, South Korea.
Objectives This study sought to assess differences in visual-functional mismatches between men and women.
Background Sex differences in mismatch between coronary anatomy and function remain poorly understood.
Methods We assessed quantitative coronary angiography, intravascular ultrasound (IVUS), fractional flow reserve (FFR), and echocardiographic left ventricular mass in a prospective cohort of 700 patients (493 male and 207 female patients) with 700 left anterior descending coronary lesions.
Results The female patients were older than the male patients (64 ± 10 years vs. 60 ± 10 years, p < 0.001) and body surface area (BSA) (57 ± 0.13 m2 vs. 1.79 ± 0.13 m2, p < 0.001) and left ventricular mass (151 ± 37g vs. 171 ± 41 g, p < 0.001) were smaller. Although there were no sex differences in angiographic diameter stenosis, lesion length, and IVUS minimal lumen area (MLA), FFR was higher in female patients (0.83 ± 0.09 vs. 0.79 ± 0.09, p < 0.001). Female patients had a smaller reference vessel area (11.4 ± 3.3 mm2 vs. 13.1 ± 4.0 mm2), vessel area (9.0 ± 3.3 mm2 vs. 11.1 ± 4.2 mm2), and plaque burden (69.8 ± 13.7% vs. 73.8 ± 12.2%) at the MLA site compared with male patients (all p < 0.001). To predict FFR <0.80, angiography had a lower positive predictive value in female patients (44% vs. 60%, p = 0.014); this was also seen in the IVUS analysis. Unlike angiography, the IVUS-MLA had a lower concordance rate in female patients (64% vs. 71%, p = 0.046). Independent predictors of FFR were age, BSA, lesion length, angiographic diameter stenosis, and IVUS-MLA and plaque burden. When left ventricular mass was included, it also predicted FFR, replacing BSA.
Conclusions In female patients with smaller BSA, left ventricular mass, and vessel size, smaller myocardial territory may be responsible for the higher FFR value for any given stenosis compared with male patients. Considering the higher rate of visual-functional mismatch, FFR-guided decision making is especially important in female patients to avoid unnecessary procedures. (Natural History of FFR-Guided Deferred Coronary Lesions [IRIS FFR-DEFER Registry]; NCT01366404).
Fractional flow reserve (FFR) provides an objective assessment of the hemodynamic significance of individual coronary artery stenoses. With the current paradigm shift to functional angioplasty, FFR is used routinely by interventional cardiologists in making clinical decisions as to whether to treat patients and lesions (1–3). Women and men have a different prevalence of coronary disease along with different clinical presentations and outcomes (4–7). A recent secondary analysis from the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) trial demonstrated that a functionally significant stenosis (FFR <0.80) was less common in women than in men and that an FFR-guided percutaneous coronary intervention (PCI) strategy was as beneficial in women as it was in men (8). However, sex differences in the discordance between coronary anatomy and function remain unclear. Therefore, we performed an integrated analysis of quantitative coronary angiography (QCA), intravascular ultrasound (IVUS), and FFR to assess differences in anatomic or visual versus functional mismatches between men and women. We limited this analysis to single lesions in the proximal or mid left anterior descending artery (LAD) to avoid confounding factors related to lesion location and tandem lesions in the same artery.
Between November 2009 and December 2011, 1,080 consecutive patients underwent angiographic, IVUS, and invasive physiological assessment before intervention and were enrolled in a prospectively collected cohort at Asan Medical Center (Seoul, South Korea). The trial is a prospective, observational study. To avoid confounding factors related to multiple lesion locations, 700 consecutive patients with 700 LAD coronary artery lesions were finally included in the current analysis. All patients were between 35 and 85 years of age with a single proximal or mid LAD lesion of >30% angiographic diameter stenosis (DS) seen on visual estimation. Exclusion criteria included multiple stenoses (DS >30% on visual estimation) within the LAD, in-stent restenosis, any previous PCI in the LAD, Thrombolysis In Myocardial Infarction flow grade <3, angiographic thrombus-containing lesions, and cases in which the IVUS imaging catheter or FFR guidewire failed to cross the lesion. In addition, patients with acute myocardial infarction, those with scarred myocardium or a regional wall motion abnormality in the territory of the LAD, left ventricular hypertrophy, or a left main coronary artery stenosis >30% (by visual estimation) were excluded from the study. Treatment strategies were determined at the operator's discretion.
Major adverse cardiovascular events (MACE) were defined as death from cardiac causes, LAD revascularization, or myocardial infarction. Revascularization was ischemia driven if there was DS ≥50% and a documented positive functional study, ischemic changes on an electrocardiogram, or ischemic symptoms. Myocardial infarction was diagnosed by the presence of ischemic symptoms or signs plus cardiac enzyme elevation (creatine kinase-myocardial band elevation >3 times or creatine kinase elevation >2 times the upper limit of normal or troponin I >1.5 ng/ml). We obtained written informed consent from all patients, and the Ethics Committee approved this study.
In 608 patients with available echocardiographic data, left ventricular mass was derived from the formula described by Devereux and Reichek (9), and left ventricular mass index was calculated as left ventricular mass divided by body surface area (BSA).
Equalizing was performed with the guidewire sensor positioned at the guiding catheter tip. The 0.014-inch FFR pressure guidewire (Radi, St. Jude Medical, Uppsala, Sweden) was then advanced distal to the stenosis. FFR was measured at maximal hyperemia induced by an intravenous adenosine infusion administered at 140 μg/kg/min through a central vein that was increased to 200 μg/kg/min to enhance detection of hemodynamically relevant stenoses. Hyperemic pressure pull-back recordings were performed as described previously (1–3). The stenosis was considered functionally significant when the FFR was <0.80.
QCA was performed using standard techniques with automated edge-detection algorithms (CAAS-5, Pie Medical Imaging, Maastricht, the Netherlands) in the angiographic analysis center of the CardioVascular Research Foundation, Seoul, South Korea. Angiographic DS, minimal lumen diameter, lesion length, and the lumen diameters of the proximal and distal reference segments were measured.
IVUS imaging and analysis
After FFR assessment and intracoronary administration of 0.2 mg nitroglycerin, IVUS imaging was performed using a motorized transducer pullback (0.5 mm/s) and a commercial scanner (Boston Scientific, Minneapolis, Minnesota) with a rotating, 40-MHz transducer within a 3.2-F imaging sheath. Using computerized planimetry (EchoPlaque 3.0, Indec Systems, Mountain View, California), offline quantitative IVUS analysis was performed as described in a core laboratory at the Asan Medical Center (10). The proximal and distal reference segments were within 5 mm of the lesion. The proximal and distal reference external elastic membrane (EEM) and lumen areas were measured and averaged along with the minimal lumen area (MLA) and the EEM area at the MLA site that was then used to calculate the plaque burden at the MLA site as: (EEM area − lumen area) ÷ EEM area (10). The percentage of stenosis area was calculated as: (reference lumen area − MLA) ÷ reference lumen area.
All statistical analyses were performed using SPSS 10.0 (SPSS Inc., Chicago, Illinois). All values are expressed as mean ± 1 SD (continuous variables) or as numbers and percentages (categorical variables). Continuous variables were compared using an unpaired Student t test, and categorical variables were compared using the chi-square or Fisher exact test.
Receiver-operating characteristic curves were analyzed to assess the best cutoff values of the angiographic and IVUS parameters to predict FFR <0.80 with maximal accuracy and using MedCalc Software (Mariakerke, Belgium). The optimal cutoff was calculated using the Youden index. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) with their 95% confidence interval (CI) were determined. Multivariable regression analysis was performed to identify the independent determinants of FFR as a continuous variable and FFR <0.80. A p value <0.05 was considered statistically significant.
The clinical characteristics in 700 patients (493 male and 207 female patients) are summarized in Table 1. Female patients had a smaller BSA (1.57 ± 0.13 m2 vs. 1.79 ± 0.13 m2, p < 0.001) and a smaller left ventricular mass (151.1 ± 37.2 g vs. 171.1 ± 41.3 g, p < 0.001) compared with male patients. The left ventricular mass positively correlated with the BSA (r = 0.385, p < 0.001). FFR at maximal hyperemia was related to BSA (r = −0.137, p < 0.001) and left ventricular mass (r = −0.111, p = 0.006).
Although there was no difference in baseline FFR between female and male patients (0.93 ± 0.05 vs. 0.93 ± 0.06, p = 0.138), FFR at maximal hyperemia was significantly higher in female patients (0.83 ± 0.09 vs. 0.79 ± 0.09, p < 0.001), and FFR <0.80 at maximum hyperemia was less frequent in female patients than in male patients (27% vs. 43%, p < 0.001). FFR was reduced in smokers compared with nonsmokers (0.80 ± 0.10 vs. 0.81 ± 0.10, p = 0.015), whereas there was no difference in FFR between patients with or without diabetes (0.81 ± 0.08 vs. 0.80 ± 0.10, p = 0.294) or between patients with stable angina or unstable angina (0.80 ± 0.10 vs. 0.81 ± 0.09, p = 0.420).
Overall, 176 patients (25%) had 2-vessel disease, and 99 (14%) had 3-vessel disease. FFR <0.80 in the LAD was observed in 37% of patients with isolated LAD disease and in 39% of patients with multivessel disease (p = 0.577).
There was no significant difference in angiographic DS or lesion length between female and male patients, whereas reference segment lumen diameters were much smaller in female patients (Table 2). Angiographic DS (r = −0.420), MLD (r = 0.407), and lesion length (r = −0.255) correlated with FFR (all p < 0.001).
Overall, receiver-operating characteristic (ROC) curve analysis showed that an angiographic DS ≥53% best predicted FFR <0.80 with a sensitivity of 64%, a specificity of 69%, a PPV of 56%, an NPV of 76%, and an overall concordance rate of 67% (area under curve: 0.733; 95% CI: 0.70 to 0.76; p < 0.001). Using this cutoff, female patients had a significantly lower PPV (44% vs. 60%, p = 0.014), but a higher NPV (85% vs. 72%, p = 0.007). The concordance rate in females and males was 68% and 67%, respectively (p = 0.684).
Of note, separate ROC curve analyses in females and males showed identical cutoff values of a QCA DS ≥53% to predict FFR <0.80.
Using the rough criterion of a QCA DS >50%, QCA-FFR mismatch (DS >50% and FFR ≥0.80) was more frequent in female patients (30% vs. 22%, p = 0.002) (Fig. 1A). Conversely, the frequency of reverse mismatch (DS ≤50% and FFR <0.80) was significantly lower in female patients (7% vs. 12%, p = 0.002).
At the proximal and distal reference segments, the lumen and EEM areas were much smaller in females than in males (Table 3). The reference EEM area positively correlated with BSA (r = 0.283, p < 0.001) and left ventricular mass (r = 0.203, p < 0.001). At the MLA site, there was no significant difference in lumen area and percentage of stenosis area between the 2 groups. However, the EEM area and plaque burden at the MLA site were significantly smaller in female patients. The MLA (r = 0.463), plaque burden (r = −0.363), and percentage of stenosis area (r = −0.362) correlated with FFR (all p values < 0.001).
Overall, to predict FFR <0.80, IVUS-MLA ≤2.51 mm2 was the best cutoff value, with a sensitivity of 82%, specificity of 62%, PPV of 56%, NPV of 84%, and an overall concordance rate of 69% (area under curve = 0.762, 95% CI: 0.73 to 0.79, p < 0.001). The PPV was significantly lower in female patients (42% vs. 63%, p < 0.001), whereas female patients showed a higher NPV (93% vs. 81%, p = 0.009). The concordance rate was significantly lower in female patients (64% vs. 71%, p = 0.046).
As with the QCA data, separate ROC curve analyses in female and male patients showed almost identical cutoff values of an IVUS-MLA to that best predicted an FFR <0.80 (2.45 mm2 in females and 2.53 mm2 in males).
The incidence of IVUS-MLA–FFR mismatch (MLA ≤2.5 mm2 and FFR ≥0.80) was significantly higher in female patients (34% vs. 20%, p<0.001) (Fig. 1B). On the other hand, reverse mismatch (MLA >2.5 mm2 and FFR <0.80) was less frequent in female patients (3% vs. 9%, p < 0.001).
Independent determinants for FFR
In the overall population, multivariable analysis showed that the independent factors affecting FFR as a continuous variable were age, BSA, lesion length, angiographic DS, and IVUS-MLA and plaque burden (Table 4). In addition, the independent determinants for FFR <0.80 were age (odds ratio [OR]: 0.97, 95% CI: 0.949 to 0.989, p = 0.003), angiographic DS (OR: 1.04, 95% CI: 1.02 to 1.06, p < 0.001), lesion length (OR: 1.02, 95% CI: 1.006 to 1.039, p = 0.009), IVUS-MLA (OR: 0.32, 95% CI: 0.234 to 0.449, p < 0.001), plaque burden (OR: 1.03, 95% CI: 1.013 to 1.055, p = 0.010).
When the left ventricular mass was added into the analysis in the 608 patients with echocardiographic data, the independent determinants for FFR were age, left ventricular mass, lesion length, angiographic DS, IVUS-MLA, and plaque burden. However, female sex was not an independent factor affecting FFR in either analysis.
With a follow-up time of 16.7 ± 4.6 months, the 1-year MACE rate was only 1.7%. There was no cardiac death or myocardial infarction. LAD revascularization was performed in 12 patients (1.7%) (7 of 438 [1.6%] deferred lesions vs. 5 of 262 [1.9%] stented lesions, p = 0.760). There was no difference in the MACE rate between patients with FFR <0.80 versus FFR ≥0.80 (1.5% vs. 1.8%, p = 0.737) or between males and females (1.6% vs. 1.9%, p = 0.495).
The major findings of this study were the following: 1) although there was no sex difference in anatomic stenosis severity, female patients showed higher FFR values at maximum hyperemia compared with male patients with the same degree of LAD stenosis; and 2) considering that BSA, left ventricular mass, and vessel size are much smaller in women than in men, a smaller myocardial territory in the female patients may be the main reason for the more frequent visual-functional mismatch in female patients along with the higher FFR values at maximum hyperemia.
A previous observational study from the FAME I trial suggested that an FFR-guided PCI strategy in patients with multivessel disease worked equally in women and men (8). There was no interaction between sex and the benefits of FFR-guided PCI over angiography-guided PCI and their effects on the 2-year rates of MACE. Our current data consistently showed that women appear to have higher FFR values for a given stenosis severity. Using the best cutoff value of an angiographic DS ≥53%, the PPV for detecting FFR <0.80 was much lower in female patients (44% vs. 60%). Similarly, the PPV of an IVUS-MLA <2.5 mm2 was only 42% (compared with 63% in males). The data suggested that both angiographic and IVUS criteria were more likely to overestimate the true functional significance of a stenosis in female patients.
Despite a similar concordance rate using an angiographic DS ≥53% between the 2 sexes, the concordance rate of MLA ≤2.5 mm2 was significantly lower in female patients (64% vs. 71%), suggesting that the visual-functional mismatch was more remarkable for IVUS than for QCA parameters and consistent with the fact that left ventricular mass index (but not left ventricular mass per se) was likely to be similar in female and male patients.
When operator decision making is based on morphological criteria, the majority of women may undergo unnecessary PCI. Considering that female patients were at risk of higher rates of in-hospital mortality and adverse outcomes after PCI, the role of FFR measurement should be emphasized, especially in women (11,12).
We previously identified the many clinical and local factors that determined QCA-FFR discordance and the physiological effects of stenosis (13). Neither angiographic DS nor IVUS-MLA sufficiently predicted a hemodynamically significant lesion. Unlike angiography and IVUS, FFR integrated all of the individual factors including the amount of viable myocardium and the myocardial blood flow requirements.
This current observation focused on the frequency of and explanation for the visual-functional mismatches between females and males. There are several possible explanations for the observation that coronary lesions in women were less often hemodynamically significant compared with men. In this prospective cohort, there were no sex differences in lumen-based assessment of stenosis severity as represented by angiographic DS or lesion length or IVUS-MLA and the percentage of stenosis area.
Female patients had a smaller BSA and a smaller left ventricular mass compared with male patients, with the left ventricular mass correlating with the BSA. Moreover, female patients had a smaller EEM area at both the reference segments and the MLA site compared with male patients. Not only was there a significant relationship between left ventricular mass and both BSA and vessel size, left ventricular mass was also one of the independent determinants of FFR replacing BSA in the multivariable analysis. Thus, the smaller myocardial territory subtended by the relatively small female coronary artery appeared to be mainly responsible for the higher rate of mismatch and the lower rate of reverse mismatch in women.
In the current study, the female patients were older than the male patients, and patient age was also an independent determinant of FFR. For a given degree of stenosis, older patients had a higher FFR than younger patients; this might be explained by aging-related loss of functional myocytes or attenuation of the vasodilator response to adenosine (14–16).
Long-term clinical outcomes related to sex differences in visual-functional mismatch were not studied. Second, the optimal treatment strategies for the mismatched lesions were not evaluated. Third, because the study included only LAD lesions, the results could not be applied to other vessels with different, and potentially more variable, myocardial territory. The effect of left ventricular hypertrophy on FFR was not assessed in our population mostly with normal left ventricular mass index. Although all LAD lesions with DS >30% were included in the current analysis, the relatively lower rate of FFR <0.80 (27% in female patients) might have affected the results. It is possible that in a population with more severe coronary artery disease, this discordance rate might have been lower.
For a given degree of stenosis, FFR in female patients tended to be much higher than in male patients. Considering their smaller body size, smaller left ventricular mass, and smaller coronary artery size, the relatively smaller myocardial territory may be responsible for the higher FFR and the greater rate of visual-functional mismatch in female patients. Thus, FFR–guided decision making is especially important in women to avoid unnecessary PCI.
All of the authors report receiving grant support from the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065). Dr. Mintz has received grant support from Boston Scientific, Volcano, and InfraReDx; and is a consultant or speaker for Boston Scientific, Volcano, St. Jude, and InfraReDx. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- body surface area
- confidence interval
- diameter stenosis
- external elastic membrane
- fractional flow reserve
- intravascular ultrasound
- (proximal or mid) left anterior descending artery
- major adverse cardiac event(s)
- minimal lumen area
- negative predictive value
- odds ratio
- percutaneous coronary intervention
- positive predictive value
- quantitative coronary angiography
- receiver-operating characteristic
- Received February 7, 2013.
- Accepted February 8, 2013.
- American College of Cardiology Foundation
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