The left side of Figure 2A shows the distribution of triple-vessel or LM disease among AAC grades 0, 1, 2, and 3; the rate of triple-vessel or LM disease positively correlated with higher AAC grade. The proportions of AAC grades ≥2 among 1-, 2-, and 3-vessel or LM diseases were 9.2%, 21.4%, and 46.3%, respectively (P < .001; Fig. 2A, right side).
Multivariate regression analysis was performed to determine which variables were independently related to the AAC extent. Statistically significant correlates of AAC extent were age (coefficient β = 0.102, P < .001), female (coefficient β = 0.484, P = .012), hypertension (coefficient β = 0.414, P = .009), diabetes (coefficient β = 0.360, P = .012), CKD (coefficient β = 0.681, P = .040), PAD (coefficient β = 2.590, P < .001), LVEF (coefficient β = 0.023, P = .039), 2-vessel disease (compared to 1-vessel disease, coefficient β = 0.975, P < .001), 3-vessel or LM disease (compared to 1-vessel disease, coefficient β = 1.984, P < .001), proximal left anterior descending stenosis (coefficient β = 1.074, P < .001), and chronic total occlusions (coefficient β = 0.738, P < .001).
During the follow-up period, MACE occurred in 168 (18.4%) patients, including 22 (2.4%) deaths, 17 (1.9%) deaths from CV causes, 5 (0.5%) deaths from non-CV causes, 11 (1.2%) nonfatal strokes, 28 (3.1%) events of nonfatal MI, and 148 (16.2%) cases of unplanned repeat revascularization.
The clinical outcomes among patients with AAC grades 0, 1, 2, and 3 are shown in Table 3. Compared with those without, patients with MACE had higher rates of diabetes (n = 90, 53.6% vs n = 290, 39.0%; P = .001), PAD (n = 38, 22.6% vs n = 49, 6.6%; P < .001), previous MI (n = 43, 25.6% vs n = 139, 18.7%; P = .043) and past PCI (n = 44, 26.2% vs n = 138, 18.5%; P = .025). Patients with MACE had higher pulse pressure (56±15 vs 54±14; P = .037), increased levels of fasting plasma glucose (6.14 [5.34–8.07] vs 5.63 [5.10–6.85]; P < .001), and higher glycosylated hemoglobin A1c (6.4 [5.7–7.4] vs 5.9 [5.5–6.8]; P < .001). Moreover, patients with MACE had a higher incidence of 4-vessel or LM disease (n = 120, 71.4% vs n = 394, 53.0%; P < .001), more restenotic lesions (n = 31, 18.5% vs n = 76, 10.2%; P = .003), and a lower incidence of 2-vessel (n = 34, 20.2% vs n = 222, 29.8%; P = .012) and 1-vessel (n = 14, 8.3% vs n = 128, 17.2%; P = .004) diseases. LVEF was significantly lower in patients with MACE (63 [58–68] vs 65 [60–68]%; P = .028). Use of medications was not different between patients with and without MACE at discharge, except for aspirin (n = 162, 96.4% vs n = 740, 99.5%; P = .003) and cilostazol (n = 5, 3.0% vs n = 5, 0.7%; P = .029).
The rates of MACE among AAC grades 0, 1, 2, and 3 were 9.3%, 16.9%, 24.7%, and 42.4%, respectively (P < .001; Fig. 2B, left side). Patients with MACE had a higher proportion of AAC grades ≥2 than those without MACE (n = 86, 51.2% vs n = 220, 29.6%; P < .001; Fig. 2B, right side). Kaplan-Meier analyses revealed significantly higher incidences of primary and key secondary end points in patients with higher AAC grades (log-rank test, all P < .001; Fig. 3). Similarly, the incidence of death (log-rank test, P < .001), CV death (log-rank test, P = .003), nonfatal stroke (log-rank test, P = .001), nonfatal MI (log-rank test, P = .001), or unplanned repeat revascularization (log-rank test, P < .001) was significantly higher in patients with AAC grade 3 than in those with AAC grades 0, 1, or 2.
The results of Cox-proportional hazards regression analyses are shown in Table 4, which includes the AAC extent, diabetes, CKD, previous MI, past PCI, PAD, pulse pressure, serum levels of triglyceride, LVEF, and CAD severity. Multivariate Cox-proportional hazards regression analyses revealed that, in comparison to AAC grade 0, the HRs for AAC grades 1, 2, and 3 in predicting MACE were 1.63 (95% CI 0.99–2.67; P = .056), 2.15 (95% CI 1.27–3.62; P = .004), and 2.88 (95% CI 1.41–5.86; P = .004), respectively.
Based on the Cox-proportional hazards regression analyses, we calculated the C-index for the predictive value of MACE. The C-index of the variables, including PAD and serum levels of triglyceride, was 0.644 (95% CI 0.600–0.687) versus 0.677 (95% CI 0.635–0.719) when AAC grades were included; the continuous net reclassification improvement was 16.5% (8.7%–23.4%; P < .001).
This study revealed 3 important aspects. First, increasing AAC grade is associated with increased risk of MACE among ACS patients undergoing PCI, as determined via log-rank test. Second, multivariate Cox-proportional hazards regression analyses indicated that AAC extent is an independent predictor of MACE in patients with ACS that undergo PCI. Third, predictive modeling is significantly improved after adding AAC extent to the model, as well as including the other independent predictive values. These findings suggest that ACS patients who undergo PCI and have higher AAC grades should receive closer follow-up and more intensive medical therapy.
AAC is associated with CV morbidity and mortality in the general population and several patient cohorts.[3,9,11–15] Iribarren et al evaluated risk factors for AAC and long-term (median follow-up, 28 years) association between AAC and CV diseases in a large population-based cohort study. Among the 116,309 participants, AAC was present in 2.3% of all participants and was independently associated with older age, current smoking, hypertension, and elevated serum cholesterol level. The crude rates (per 1000 person-years) of coronary heart disease (CHD) and ischemic stroke were higher in AAC patients than in those without AAC. After adjustment for several traditional risk factors, AAC was associated with a 1.27-fold increased risk of CHD in men (95% CI, 1.11–1.45), a 1.22-fold increased risk of CHD in women (95% CI 1.07–1.38), and a 1.46-fold increased risk of ischemic stroke in women (95% CI 1.28–1.67). However, the study merely evaluated whether AAC was present or absent using chest x-rays without considering the extent of calcification.
Iijima et al evaluated the validity by which AAC extent can predict new CV events that comprise CHD (angina pectoris, MI), cerebrovascular disease (transient ischemic attack, ischemic stroke, cerebral hemorrhage), PAD, heart failure, and CV death in a retrospective cohort study. AAC was graded according to the same algorithm used in this study. Among 239 asymptomatic outpatients without history of CV events, follow-up recording of CV events was completed with 209 patients. At baseline, the AAC grade was positively related to age, pulse pressure, diabetes, and renal dysfunction. A total of 57 CV events occurred during a mean follow-up period of 69 ± 45 months. Patients with higher AAC grade (grades 2 and 3) had a higher incidence of CV events than those with grade 0 or 1 (P < .01). After adjustment for several traditional risk factors, AAC that was detected by chest x-ray was a strong independent predictor of CV events (HR, 2.49; P = .01).
A recent meta-analysis was conducted to assess the association between the presence and extent of AAC and CV or all-cause mortality risk in maintenance dialysis patients. A total of 8 observational studies with 3256 dialysis patients were identified, with follow-up duration ranging from 1.8 to 10 years. Compared with patients without AAC, the presence of AAC was associated with greater risk of CV mortality (HR 2.30; 95% CI 1.78–2.97) and all-cause mortality (HR 1.44; 95% CI 1.19–1.75). Subgroup analyses indicated that the pooled HR of AAC grades ≥2 for all-cause mortality was 1.45 (95% CI 1.08–1.96) and CV mortality was 2.31 (95% CI 1.57–3.40).
Recently, the prognostic value of AAC extent for future CV outcomes in patients with stable angina was studied in a large, respective cohort study. Among 2018 patients, 620 had a significant CAD that required coronary revascularization, whereas 191 developed adverse CV events comprising death from all causes, MI, repeated coronary revascularizations, or stroke over a mean follow-up period of 3.8 ± 0.7 years (range 0.7–5.1 years). There were higher rates of significant CAD (Grade 0 vs Grade 1/2 vs Grade 3: 25.9% vs 42.4% vs 54.5%, P < .001) and adverse CV events (Grade 0 vs Grade 1/2 vs Grade 3: 8.4% vs 11.1% vs 19.3%, P < .001) with increasing AAC grade.
To date, few clinical studies have focused on the prognostic role of AAC extent in patients with ACS that undergo PCI. Yang et al revealed a significant association between AAC extent and outcomes in patients with ACS. Among 225 patients, 190 underwent coronary revascularization at baseline and patients with AAC had a similar revascularization rate to those without AAC (83% vs 87%, P = .46), whereas patients with AAC had significantly higher 30-day mortality (17.3% vs 7.1%, log-rank P = .02). During a mean follow-up period of 165 ± 140 days (maximum 492 days), patients with AAC had significantly increased CV deaths (27.6% vs 11.2%, log-rank P = .002), all-cause mortality (28.3% vs 11.2%, log-rank P = .001), and a composite end point of major adverse CV events that comprised nonfatal MI, nonfatal stroke, and CV death (39.4% vs 24.6%, log-rank P = .01). However, the study had several major limitations. First, the study was based on a retrospective observational ACS registry. Second, patient characterizations and procedures (ie, revascularization strategy, end point event definition, and follow-up method) were poorly defined. Third, the study had a relatively small sample size and a short follow-up period. Finally, the authors did not consider ACC extent when multivariate Cox-proportional hazards regression analyses were performed to identify AAC as an independent prognostic factor.
There are several advantages and differences within this study as compared to the report by Yang et al. This report is based on a prospective study that had a larger sample size and a longer follow-up period. Moreover, this study described patient baseline characteristics in more detail and better-defined end point events and follow-up methods. In addition, this study used AAC grades as the basis for grouping, demonstrating a potent predictive value of using high AAC grades to precisely forecast subsequent adverse CV events. Analyzing HRs for each AAC grade, AAC grade 1 had a borderline significance (P = .056) for predicting MACE compared to grade 0, suggesting that even trivial calcium deposition in aortic arch implies increased CV risk for ACS patients undergoing PCI.
Aortic calcification is closely associated with increased aortic stiffness,[23–25] often resulting in early wave reflection of the aortic pulse wave. Consequently, the early pulse wave reflection increases systolic blood pressure but decreases diastolic blood pressure. These hemodynamic changes cause increased left ventricular afterload and myocardial wall stress, as well as impair coronary perfusion. Furthermore, several studies have indicated that increased aortic stiffness is an independent predictor of adverse CV events in patients with acute MI.[26,27] Aortic calcification is significantly associated with vascular endothelial dysfunction, which generally triggers platelet adhesion and aggregation, in addition to fibrin formation, which all play critical roles in systemic hypercoagulability. Adverse CV events, such as MI or ischemic stroke, have been demonstrated to be commonly characterized at the pathophysiological level by vascular endothelial dysfunction. Moreover, vascular endothelial dysfunction is a vital component of both coronary plaque vulnerability and other CV complications, such as vascular remodeling. Aortic calcification is also associated with decreased coronary flow reserve as measured by 82Rb positron emission tomography/computed tomography, which is positively correlated with CV morbidity and mortality. Notably, a previous study revealed that AAC observed by chest x-ray or fluoroscopy is significantly associated with greater necrotic core-containing plaques—as detected by virtual histology and intravascular ultrasound—which is an independent predictor of adverse CV events. The aforementioned sequential associations suggest a potential prognostic relevance for AAC in ACS patients.
Older age, female sex, hypertension, diabetes, CKD, PAD, LVEF, and CAD severity are all important risk factors for future CV events in ACS patients. In this study, we found that AAC extent was significantly correlated with these risk factors, which also partially explains the association between AAC extent and adverse CV outcomes. We demonstrated that increasing AAC grade was independently associated with higher rates of MACE, even after adjusting for diabetes, CKD, previous MI, past PCI, PAD, pulse pressure, serum levels of triglyceride, LVEF, and CAD severity, while adding AAC extent to a risk model that is comprised of other independent MACE predictors significantly improved the early risk stratification of ACS patients treated with PCI. These findings are of significant clinical relevance, as assessing AAC extent might contribute to improved early risk stratification for ACS patients undergoing PCI, which could enhance prognostic evaluations and guidance of secondary prevention treatment. Patients who develop MACE are older and exhibit higher incidences of coronary triple-vessel or LM disease, highlighting the prognostic role for these conditions.
There are several limitations in the present study. First, as in any observational study, this study cannot exclude influences that were due to unmeasured and undetected confounding variables such as calcification-related biomarkers, SYNTAX Score, periprocedural anticoagulants use, and drug eluting stent types. However, we used as many well-known risk factors as possible for CV outcomes as confounders. Second, at each follow-up, we recorded the medications the patients were taking. Medication adjustment according to patients’ conditions was frequent, especially year after PCI. As we know, the change of medications was also associated with MACE. However, we did not include medication adherence in the analysis. Third, chest x-ray-based methods to assess AAC are only semiquantitative and the precise amount of calcium deposition in the aortic arch could be underestimated. Fourth, positional changes on chest x-rays could potentially alter the appearance of AAC and influence the measured value of AAC thickness. Fifth, follow-up data were obtained via telephone, but the authenticity of adverse events was often verified by obtaining corresponding medical records from patients or their family members. Finally, the patients enrolled in this study were in relatively stable condition. Patients who were unstable on admission and those who developed severe heart failure (LVEF <30% or Killip class >2) were not included. Therefore, the results of this study cannot be generalized to other ACS patient cohorts, particularly those that include patients with unstable hemodynamic conditions. Moreover, all patients in this study had been treated with PCI and, therefore, our results may not be applicable to patients undergoing coronary artery bypass grafting or were treated conservatively.
In this well-designed prospective study, the extent of AAC as detected by chest x-ray was demonstrated to be an independent predictor of MACE in ACS patients undergoing PCI at a mean follow-up of 917 days. Further research is required to evaluate whether specific treatment strategies based on AAC extent are useful for optimal risk reduction in relevant patient populations.
The authors thank LetPub (www.letpub.com) for linguistic assistance during the revision of this manuscript.
Conceptualization: Zhijian Wang, Yujie Zhou.
Data curation: Lixia Yang, Zhijian Wang, Yujie Zhou.
Formal analysis: Xiaoteng Ma, Lisha Dong, Zhen Zhou, Jing Tian, Zhijian Wang, Yujie Zhou.
Funding acquisition: Yujie Zhou.
Investigation: Xiaoteng Ma, Lisha Dong, Qiaoyu Shao, Zhen Zhou, Jing Tian, Yue Ma, Jie Yang, Sai Lv, Yujing Cheng, Hua Shen.
Methodology: Xiaoteng Ma, Lixia Yang, Zhijian Wang, Yujie Zhou.
Project administration: Yujie Zhou.
Resources: Yujie Zhou.
Software: Xiaoteng Ma, Lisha Dong, Qiaoyu Shao, Lixia Yang, Zhijian Wang.
Supervision: Zhijian Wang, Yujie Zhou.
Validation: Hua Shen, Lixia Yang, Zhijian Wang, Yujie Zhou.
Visualization: Zhijian Wang, Yujie Zhou.
Writing – original draft: Xiaoteng Ma, Lisha Dong.
Writing – review & editing: Zhijian Wang, Yujie Zhou.
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Keywords:Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.
acute coronary syndrome; aortic arch calcification; chest x-ray; clinical outcomes; percutaneous coronary intervention