Abstract
Aims: Coronary calcification detected by coronary angiography is a simple risk marker for long-term clinical outcomes in stable coronary artery disease. However, the significance of angiographic coronary calcification in the culprit lesion of acute myocardial infarction (AMI) has not been fully discussed. The purpose of this retrospective study was to assess the usefulness of angiographic coronary calcification as a risk marker for long-term clinical outcomes following percutaneous coronary intervention to the culprit lesions of AMI.
Methods: We included 1209 patients with AMI and divided them into the none–mild calcification group (n=923) and the moderate–severe calcification group (n=286) according to angiographic coronary calcification in the culprit lesion of AMI. The primary endpoint was the occurrence of major adverse cardiac events (MACE), which was defined as a composite of all-cause death, nonfatal MI, readmission for heart failure, and ischemia-driven target vessel revascularization.
Results: The median follow-up duration was 542 (Q1: 182, Q3: 990) days. A total of 345 MACE were observed during the study period. The occurrence of MACE was significantly greater in the moderate–severe calcification group than in the none–mild calcification group (43.4% vs. 23.9%, p＜0.001). In the multivariate Cox hazard model, moderate–severe calcification was significantly associated with MACE (hazard ratio 1.302, 95% confidence interval 1.011–1.677, p=0.041) after controlling multiple confounding factors.
Conclusions: Angiographically moderate to severe calcification in AMI culprit lesion was associated with long-term worse clinical outcomes. Angiographic coronary calcification can be a simple risk marker in patients after AMI.
Introduction
Percutaneous coronary intervention (PCI) is widely applicable to coronary artery disease, including acute myocardial infarction (AMI)1, 2). When coronary artery lesions were divided into the culprit lesions of AMI and the non-AMI lesions, the clinical outcomes following PCI were worse in the culprit lesions of AMI than in the non-AMI lesions3, 4). However, since the clinical outcomes vary widely among the culprit lesions of AMI5), a simple risk marker would be needed to stratify long-term outcomes following PCI to the culprit lesions of AMI. Although there are several risk markers regarding the clinical outcomes of patients with AMI6, 7), simple risk markers that were derived from coronary angiography (CAG) have not been fully proposed. Coronary calcification detected by CAG is a simple marker8) and is reported as a risk marker for long-term outcomes in coronary artery lesions9, 10). However, the significance of angiographic coronary calcification in the culprit lesion of AMI has not been fully discussed. The purpose of this retrospective study was to assess the usefulness of angiographic coronary calcification as a risk marker for long-term clinical outcomes following PCI to the culprit lesions of AMI.
Methods
Study Design
This study was approved by the Institutional Review Board of Saitama Medical Center, Jichi Medical University (S21-054). All procedures were performed in accordance with the Declaration of Helsinki. We identified consecutive patients with AMI in our institution from January 2015 to December 2019. Clinical outcomes were acquired from hospital records. The inclusion criteria were (1) patients with AMI and (2) patients who underwent PCI to the culprit lesion of AMI. The exclusion criteria were (1) patients who were treated by medical therapy alone, (2) patients who underwent coronary artery bypass graft (CABG) surgery during the index admission, (3) patients who underwent PCI to the nonculprit lesion as well as the culprit lesion of AMI simultaneously, and (4) patients with unsuccessful PCI to the culprit lesion of AMI. We used the following classification regarding angiographic calcification: none–mild calcification (not visible on CAG), moderate calcification (radiopaque densities visible during heart motion), and severe calcification (densities visible without heart motion and typically affecting both sides of the vessel)8, 9). Based on the above classification, the study population was divided into the none–mild calcification group and the moderate–severe calcification group according to angiographic coronary calcification in the culprit lesion of AMI. The primary endpoint was the occurrence of major adverse cardiac events (MACE), which was defined as a composite of all-cause death, nonfatal MI, readmission for heart failure, and ischemia-driven target vessel revascularization11). The day of PCI to the culprit lesion of AMI was defined as the index day (day 1). Patients were followed up until meeting MACE or until the study end date (August 2021). Written informed consent was waived because of the retrospective study design.
PCI to the Culprit of AMI
The choice of PCI devices such as guidewire, balloon, thrombectomy device, rotational atherectomy device, and stent was left at the discretion of interventional cardiologists at our cardiology center12). Our university hospital had many operators, including senior residents. However, each PCI was strictly supervised by staff operators. Intravascular ultrasound (IVUS) or optical coherent tomography (OCT) was routinely used for almost all lesions.
Definition
AMI was defined based on the universal definition of myocardial infarction13, 14). The definition of hypertension, dyslipidemia, and diabetes mellitus was described in previous studies15, 16). We calculated the estimated glomerular filtration rate (eGFR) from the serum creatinine level, age, weight, and gender using the following formula: eGFR=194×Cr−1.094×age−0.287 for male and eGFR=194×Cr−1.094×age−0.287×0.739 for female17).
Angiographical Analysis
Quantitative coronary angiography (QCA) parameters were measured using a cardiovascular angiography analysis system (QAngio XA 7.3; Medis Medical Imaging Systems, Leiden, Netherlands). QCA parameters were measured after the acquisition of reperfusion (after ballooning or thrombectomy), if the lesion was totally occluded. The definition of lesion characteristics, including lesion length, ostial lesion, bifurcation lesion, tortuosity, and type of obstruction site, has been previously described8, 18-20). The thrombus was classified based on the TIMI thrombus grade21).
Statistical Analysis
All analyses were performed using SPSS 25/Windows (SPSS, Chicago, IL, USA). Data were expressed as mean±SD or percentage. Categorical variables were presented as numbers (percentage) and were compared using chi-square test. For continuous variables, the Shapiro–Wilk test was performed to determine whether the continuous variables were normally or nonnormally distributed. Normally distributed continuous variables were compared using the Student’s t-test. Otherwise, continuous variables were compared using the Mann–Whitney U test. Event-free survival curves were constructed using the Kaplan–Meier method, and statistical differences between the curves were assessed by the log-rank test. We performed a multivariate Cox hazard analysis to investigate the association between moderate–severe calcification and MACE after controlling confounding factors. We also performed the forced regression method. Variables that were significantly different (p＜0.05) between the none–mild calcification and moderate–severe calcification groups were considered as confounding factors. Variables with missing values were not included in the model. Moreover, similar variables were not entered into the model simultaneously to avoid multicollinearity. Hazard ratio (HR) and 95% confidence interval (CI) were calculated. A p-value of ＜0.05 was considered as statistically significant.
Results
During the study period, we had 1402 patients with AMI in our medical center. We excluded 193 patients according to the exclusion criteria. Our final study population was 1209 patients and was divided into the none–mild calcification group (n=923) and the moderate–severe calcification group (n=286). Fig.1 shows the study flowchart. Table 1 shows the comparison of patient’s clinical characteristics. The prevalence of diabetes mellitus, hemodialysis, and Killip class 3/4 was significantly higher in the moderate–severe calcification group than in the none–mild calcification group. The history of previous PCI or CABG was more frequently observed in the moderate–severe calcification group than in the none–mild calcification group. Table 2 shows the comparison of lesion and procedural characteristics. Complex features such as triple vessel disease, left main disease, or ostial lesion were more frequently observed in the moderate–severe calcification group than in the none–mild calcification group, whereas TIMI thrombus grade tended to be greater in the none–mild calcification group than in the moderate–severe calcification group.
Table 1.
Comparison of patient’s characteristics between the none-mild calcification and moderate-severe calcification groups
|
All (n = 1209)
|
None-mild calcification group (n = 923)
|
Moderate-severe calcification group (n = 286)
|
p-value
|
| Age, years |
70.3±12.5 |
69.0±12.6 |
74.4±11.1 |
＜0.001 |
| male, n (%)
|
918 (75.9) |
724 (78.4) |
194 (67.8) |
＜0.001 |
| Physical examination |
|
|
|
|
| Body mass index (kg/m2)
|
24.0±5.6 (n= 1205)
|
24.3±6.1 (n= 920)
|
23.0±3.7 (n= 285)
|
＜0.001 |
| Systolic blood pressure at admission (mmHg) |
139.2±36.3 |
140.2±34.3 |
136.0±42.1 |
0.149 |
| Diastolic blood pressure at admission (mmHg) |
80.2±22.6 (n= 1206)
|
81.8±21.9 (n= 921)
|
75.1±23.8 (n= 285)
|
＜0.001 |
| Heart rate at admission (beat per minute) |
81.6±24.0 |
80.3±23.1 |
85.9±26.3 |
＜0.001 |
| Underlying disease |
|
|
|
|
| Hypertension, n (%)
|
993 (n= 1209) (82.2)
|
746 (n= 922) (80.9)
|
247 (86.4) |
0.035 |
| Diabetes mellitus, n (%)
|
547 (n= 1203) (45.5)
|
387 (n= 918) (42.2)
|
160 (n= 285) (56.1)
|
＜0.001 |
| Dyslipidemia, n (%)
|
744 (n= 1204) (61.8)
|
566 (n= 919) (61.6)
|
178 (n= 285) (62.5)
|
0.792 |
| Hemodialysis, n (%)
|
115 (9.5) |
53 (5.7) |
62 (21.7) |
＜0.001 |
| History of previous PCI, n (%)
|
280 (23.2) |
201 (21.8) |
79 (27.6) |
0.041 |
| History of previous CABG, n (%)
|
49 (4.1) |
30 (3.3) |
19 (6.6) |
0.011 |
| History of previous MI, n (%)
|
198 (16.4) |
148 (16.0) |
50 (17.5) |
0.563 |
| Current smoker, n (%)
|
375 (n= 1180) (31.8)
|
315 (n= 898) (35.1)
|
60 (n= 282) (21.3)
|
＜0.001 |
| Medication before admission |
|
|
|
|
| Aspirin, n (%)
|
393 (n= 1198) (32.8)
|
281 (n= 913) (30.8)
|
112 (n= 285) (39.3)
|
0.007 |
| Thienopyridine, n (%)
|
229 (n= 1198) (19.1)
|
157 (n= 913) (17.2)
|
72 (n= 285) (25.3)
|
0.002 |
| Beta-blocker, n (%)
|
302 (n= 1179) (25.6)
|
217 (n= 898) (24.2)
|
85 (n= 281) (30.2)
|
0.041 |
| ACE-inhibitor, ARB, n (%)
|
468 (n= 1180) (39.7)
|
344 (n= 899) (38.3)
|
124 (n= 281) (44.1)
|
0.079 |
| Calcium channel blocker, n (%)
|
453 (n= 1178) (38.5)
|
325 (n= 897) (36.2)
|
128 (n= 281) (45.6)
|
0.005 |
| Statin, n (%)
|
440 (n= 1185) (37.1)
|
309 (n= 903) (34.2)
|
131 (n= 282) (46.5)
|
＜0.001 |
| Diuretic, n (%)
|
176 (n= 1183) (14.9)
|
127 (n= 901) (14.1)
|
49 (n= 282) (17.4)
|
0.177 |
| Hypoglycemic agents, n (%)
|
323 (n= 1188) (27.2)
|
228 (n= 907) (25.1)
|
95 (n= 281) (33.8)
|
0.004 |
| Insulin, n (%)
|
90 (n= 1190) (7.6)
|
55 (n= 907) (6.1)
|
35 (n= 283) (12.4)
|
＜0.001 |
| Laboratory data |
|
|
|
|
| Serum creatinine (mg/dl) |
1.66±2.29 |
1.37±1.81 |
2.59±3.25 |
＜0.001 |
| Estimated GFR (ml/min/1.73m2)
|
60.7±31.7 (n= 1208)
|
63.8±28.6 (n= 922)
|
50.8±38.5 |
＜0.001 |
| Hemoglobin (g/dl) |
13.1±2.17 |
13.4±2.09 |
12.3±2.22 |
＜0.001 |
| Peak creatine kinase (U/L) |
1694±2802 |
1773±2997 |
1439±2038 |
0.156 |
| Peak creatine kinase myocardial band (U/L) |
149±217 (n= 1208)
|
154±221 (n= 922)
|
134±203 |
0.392 |
| BNP on admission (pg/ml) |
443±722 (n= 1147)
|
358±648 (n= 878)
|
721±869 (n= 269)
|
＜0.001 |
| LVEF during the index admission (%) |
56.7±13.3 (n= 1106) |
57.3±13.2 (n= 856) |
54.8±13.5 (n= 250) |
0.005 |
| GRACE risk score |
161.0±51.3 |
155.7±50.0 |
178.1±51.9 |
＜0.001 |
| Killip class |
|
|
|
＜0.001 |
| 1or2 |
928 (76.8) |
735 (79.6) |
193 (67.5) |
|
| 3 |
139 (11.5) |
88 (9.5) |
51 (17.8) |
|
| 4 |
142 (11.7) |
100 (10.8) |
42 (14.7) |
|
| Cardiac arrest at prehospital or ER, n (%)
|
75 (6.2) |
53 (5.7) |
22 (7.7) |
0.232 |
| Shock vital at prehospital or ER, n (%)
|
152 (12.6) |
106 (11.5) |
46 (16.1) |
0.040 |
| STEMI (vs NSTEMI) |
696 (57.6) |
540 (58.5) |
156 (54.5) |
0.237 |
Data are expressed as the mean±SD or number (percentage). A Student’s t test was used for normally distributed continuous variables, a Mann- Whitney U test was used for abnormally distributed continuous variables, and a chi-square test was used for categorical variables.
PCI indicates percutaneous coronary intervention; CABG, coronary artery bypass grafting; MI, myocardial infarction; ACE, Angiotensin converting enzyme; ARB, Angiotensin II receptor blocker; GFR, glomerular filtration rate; BNP, brain natriuretic peptide; LVEF, left ventricular ejection fraction; GRACE, global registries of acute coronary events; ER, emergency room.
Table 2.
Comparison of lesion and procedural characteristics between the none-mild calcification and moderate-severe calcification groups
|
All (n= 1209)
|
None-mild calcification group (n=923)
|
Moderate-severe calcification group (n=286)
|
p-value
|
| Culprit lesion |
|
|
|
＜0.001 |
| Left main – left anterior descending artery, n (%)
|
601 (49.7) |
429 (46.5) |
172 (60.1) |
|
| Right coronary artery, n (%)
|
414 (34.2) |
334 (36.2) |
80 (28.0) |
|
| Left circumflex, n (%)
|
183 (15.1) |
149 (16.1) |
34 (11.9) |
|
| Graft, n (%)
|
11 (0.9) |
11 (1.2) |
0 (0) |
|
| Number of narrowed coronary arteries |
|
|
|
＜0.001 |
| 1 vessel disease, n (%)
|
523 (43.3) |
442 (47.9) |
81 (28.3) |
|
| 2 vessel disease, n (%)
|
392 (32.4) |
299 (32.4) |
93 (32.5) |
|
| 3 vessel disease, n (%)
|
294 (24.3) |
182 (19.7) |
112 (39.2) |
|
| Left main trunk lesion, n (%)
|
139 (11.5) |
82 (8.9) |
57 (19.9) |
＜0.001 |
| Left main trunk bifurcation lesion, n (%)
|
66 (5.5) |
44 (4.8) |
22 (7.7) |
0.057 |
| Ostia lesion, n (%)
|
100 (8.3) |
65 (7.0) |
35 (12.2) |
0.005 |
| Bifurcation lesion, n (%)
|
264 (21.8) |
195 (21.1) |
69 (24.1) |
0.283 |
| Initial TIMI flow grade of culprit |
|
|
|
0.008 |
| 0 |
444 (36.7) |
362 (39.2) |
82 (28.7) |
|
| 1 |
97 (8.0) |
75 (8.1) |
22 (7.7) |
|
| 2 |
198 (16.4) |
147 (15.9) |
51 (17.8) |
|
| 3 |
470 (38.9) |
339 (36.7) |
131 (45.8) |
|
| Final TIMI flow grade of culprit |
|
|
|
0.290 |
| 0 |
0 |
0 |
0 |
|
| 1 |
9 (0.7) |
5 (0.4) |
4 (1.4) |
|
| 2 |
21 (1.7) |
15 (1.6) |
6 (2.1) |
|
| 3 |
1179 (97.5) |
903 (97.8) |
276 (96.5) |
|
| TIMI Thrombus grade |
|
|
|
0.002 |
| 0 |
0 |
0 |
0 |
|
| 1 |
666 (55.1) |
481 (52.1) |
185 (64.7) |
|
| 2 |
36 (3.0) |
28 (3.0) |
8 (2.8) |
|
| 3 |
56 (4.6) |
43 (4.7) |
13 (4.5) |
|
| 4 |
29 (2.4) |
27 (2.9) |
2 (0.7) |
|
| 5 |
422 (34.9) |
344 (37.3) |
78 (27.3) |
|
| Lesion length (mm) |
15.3±9.63 |
14.7±8.86 |
17.1±11.6 |
0.066 |
| Reference diameter (mm) |
2.54±0.73 |
2.55±0.74 |
2.48±0.69 |
0.125 |
| Tortuosity |
|
|
|
0.227 |
| Mild tortuosity, n (%)
|
1057 (87.4) |
814 (88.2) |
243 (85.0) |
|
| Moderate tortuosity, n (%)
|
105 (8.7) |
73 (7.9) |
32 (11.2) |
|
| Excessive tortuosity, n (%)
|
47 (3.9) |
36 (3.9) |
11 (3.8) |
|
| Type of obstruction site |
|
|
|
0.257 |
| Blunt |
222 (18.4) |
163 (17.7) |
59 (20.6) |
|
| Tapered |
987 (81.6) |
760 (82.3) |
227 (79.4) |
|
| In-stent lesion |
102 (8.4) |
78 (8.5) |
24 (8.4) |
0.975 |
| The presence of collateral to the culprit lesion (Rentrop grade) |
|
|
|
＜0.001 |
| 0 |
919 (76.0) |
715 (77.5) |
204 (71.3) |
|
| 1 |
202 (16.7) |
144 (15.6) |
58 (20.3) |
|
| 2 |
82 (10.2) |
60 (6.5) |
22 (7.7) |
|
| 3 |
6 (0.5) |
4 (0.4) |
2 (0.7) |
|
| Approach site |
|
|
|
＜0.001 |
| Trans-radial coronary intervention, n (%)
|
762 (63.0) |
628 (68.0) |
134 (46.9) |
|
| Trans-brachial coronary intervention, n (%)
|
36 (3.0) |
21 (2.3) |
15 (5.2) |
|
| Trans-femoral coronary intervention, n (%)
|
411 (34.0) |
274 (29.7) |
137 (47.9) |
|
| PCI procedure |
|
|
|
0.068 |
| Plain old balloon angioplasty, n (%)
|
58 (4.8) |
36 (3.9) |
22 (7.7) |
|
| Aspiration only, n (%)
|
7 (0.6) |
7 (0.8) |
0 |
|
| Drug coating balloon angioplasty, n (%)
|
62 (5.1) |
48 (5.2) |
14 (4.9) |
|
| Bare metal stent, n (%)
|
24 (2.0) |
20 (2.2) |
4 (1.4) |
|
| Drug eluting stent, n (%)
|
1040 (86.0) |
800 (86.7) |
240 (83.9) |
|
| POBA and aspiration, n (%)
|
9 (0.7) |
7 (0.8) |
2 (0.7) |
|
| Other, n (%)
|
9 (0.7) |
5 (0.5) |
4 (1.4) |
|
| Size of guiding catheter (Fr) |
|
|
|
＜0.001 |
| 6 |
770 (63.7) |
654 (70.9) |
116 (40.6) |
|
| 7 |
427 (35.3) |
264 (28.6) |
163 (57.0) |
|
| 8 |
12 (1.0) |
5 (0.5) |
7 (2.4) |
|
| Use of aspiration catheter, n (%)
|
186 (15.4) |
159 (17.2) |
27 (9.4) |
＜0.001 |
| Use of rotational coronary atherectomy, n (%)
|
59 (4.9) |
1 (0.1) |
58 (20.3) |
＜0.001 |
| IVUS guide, n (%)
|
1170 (96.8) |
886 (96.0) |
284 (99.3) |
0.006 |
| OCT/OFDI guide, n (%)
|
27 (2.2) |
27 (2.9) |
0 |
0.003 |
| Temporary pacemaker, n (%)
|
76 (6.3) |
57 (6.2) |
19 (6.6) |
0.776 |
| Intra-aortic balloon pumping support, n (%)
|
113 (9.3) |
67 (7.3) |
46 (16.1) |
＜0.001 |
| V-A ECMO, n (%)
|
45 (3.7) |
28 (3.0) |
17 (5.9) |
0.023 |
| Amount of contrast media (ml) |
127.4±49.1 |
124.8±47.7 |
135.9±52.6 |
0.011 |
| Fluoroscopy time (minutes) |
24.4±13.5 |
22.1±10.4 |
31.8±18.7 |
＜0.001 |
Data are expressed as the mean±SD or number (percentage). A Student’s t test was used for normally distributed continuous variables, a Mann- Whitney U test was used for abnormally distributed continuous variables, and a chi-square test was used for categorical variables.
TIMI, Thrombolysis in myocardial infarction; IVUS, intravascular ultrasound; OCT/OFDI, optical coherence tomography/optical frequency domain imaging; V-A ECMO, veno-arterial extra-corporeal membranous oxygenation.
Fig.2 shows the Kaplan–Meier curves for MACE between the two groups. The median follow-up duration was 542 (Q1: 182 and Q3: 990) days. The occurrence of MACE was significantly greater in the moderate–severe calcification group than in the none–mild calcification group. Table 3 shows the comparison of clinical outcomes between the two groups. All clinical outcomes were more frequently observed in the moderate–severe calcification group than in the none–mild calcification group. Table 4 shows the multivariate Cox hazard analysis. The final model included the following variables that were significantly different between the none–mild calcification and moderate–severe calcification groups: age, sex, heart rate at admission, hemoglobin, hemodialysis, history of previous PCI, history of previous CABG, shock vital at prehospital or emergency room, location of the culprit lesion, presence of left main trunk lesion, ostia lesion, number of narrowed coronary arteries, initial TIMI flow grade of the culprit lesion, TIMI thrombus grade, and Rentrop grade. However, we did not include diabetes mellitus and left ventricular ejection fraction because of missing value. In the final model, the moderate–severe calcification was associated with MACE (HR 1.302, 95% CI 1.011–1.677, p=0.041) after controlling multiple confounding factors. We also performed the multivariate Cox hazard analysis for patients limited to first-time AMI (Supplemental Table 1).
Table 3.
Comparison of Clinical Outcomes between the none-mild calcification and moderate-severe calcification groups
|
All (n = 1209)
|
None-mild calcification group (n = 923)
|
Moderate-severe calcification group (n = 286)
|
p-value
|
| MACE, n (%)
|
345 (28.5) |
221 (23.9) |
124 (43.4) |
＜0.001 |
| All-cause death, n (%)
|
179 (14.8) |
101 (10.9) |
78 (27.3) |
＜0.001 |
| Cardiac death, n (%)
|
108 (8.9) |
63 (6.8) |
45 (15.7) |
＜0.001 |
| Non-fatal myocardial infarction, n (%)
|
102 (8.4) |
67 (7.3) |
35 (12.2) |
0.008 |
| Non-fatal myocardial infarction due to stent failure, n (%)
|
46 (3.8) |
29 (3.1) |
17 (5.9) |
0.030 |
| Re-admission for heart failure, n (%)
|
110 (9.1) |
74 (8.0) |
36 (12.6) |
0.019 |
| Ischemia driven target vessel revascularization, n (%)
|
91 (7.5) |
56 (6.1) |
35 (12.2) |
0.001 |
Data are expressed as number (percentage). A chi-square test was used for categorical variables. Stent failure is composed of stent thrombosis and stent restenosis.
Table 4.
Multivariate Cox hazard model to predict MACE
| Composite endpoint |
Hazard ratios |
95% confidence interval |
P value
|
| MACE |
|
|
|
| None-mild calcification |
Reference |
|
|
| Unadjusted moderate-severe calcification |
2.023 |
1.624-2.522 |
＜0.001 |
| Sex and age adjusted moderate-severe calcification |
1.834 |
1.466-2.295 |
＜0.001 |
| Adjusted moderate-severe calcification |
1.302 |
1.011-1.677 |
0.041 |
| Component endpoints |
Hazard ratios |
95% confidence interval |
P value
|
| All-cause death |
|
|
|
| None-mild calcification |
Reference |
|
|
| Unadjusted moderate-severe calcification |
2.699 |
2.008-3.627 |
＜0.001 |
| Sex and age adjusted moderate-severe calcification |
2.282 |
1.689-3.083 |
＜0.001 |
| Adjusted moderate-severe calcification |
1.629 |
1.154-2.299 |
0.006 |
| Non-fatal myocardial infarction |
|
|
|
| None-mild calcification |
Reference |
|
|
| Unadjusted moderate-severe calcification |
1.885 |
1.252-2.837 |
0.002 |
| Sex and age adjusted moderate-severe calcification |
2.005 |
1.323-3.040 |
0.001 |
| Adjusted moderate-severe calcification |
1.129 |
0.703-1.811 |
0.616 |
| Re-admission for heart failure |
|
|
|
| None-mild calcification |
Reference |
|
|
| Unadjusted moderate-severe calcification |
1.741 |
1.168-2.593 |
0.006 |
| Sex and age adjusted moderate-severe calcification |
1.452 |
0.968-2.177 |
0.071 |
| Adjusted moderate-severe calcification |
1.147 |
0.734-1.793 |
0.548 |
| Ischemia-driven target vessel revascularization |
|
|
|
| None-mild calcification |
Reference |
|
|
| Unadjusted moderate-severe calcification |
2.305 |
1.511-3.518 |
＜0.001 |
| Sex and age adjusted moderate-severe calcification |
2.441 |
1.588-3.752 |
＜0.001 |
| Adjusted moderate-severe calcification |
1.475 |
0.896-2.427 |
0.126 |
In the adjusted model, moderate-severe calcification (vs. none-mild calcification) was adjusted for Age, Sex, Heart rate at admission, Hemoglobin, Hemodialysis, History of previous PCI, History of previous CABG, Shock vital at prehospital or ER, Culprit lesion, Left main trunk lesion, Ostia lesion, Number of narrowed coronary arteries, Initial TIMI flow grade of culprit, TIMI Thrombus grade, and Rentrop grade.
Supplemental Table 1.
Multivariate Cox hazard model to predict MACE in patients limited to first-time AMI (
n = 1011)
| Composite endpoint |
Hazard ratios |
95% confidence interval |
P value
|
| MACE |
|
|
|
| None-mild calcification |
Reference |
|
|
| Unadjusted moderate-severe calcification |
2.012 |
1.558-2.598 |
＜0.001 |
| Adjusted moderate-severe calcification |
1.270 |
0.951-1.696 |
0.106 |
| Component endpoints |
Hazard ratios |
95% confidence interval |
P value
|
| All-cause death |
|
|
|
| None-mild calcification |
Reference |
|
|
| Unadjusted moderate-severe calcification |
2.717 |
1.932-3.823 |
＜0.001 |
| Adjusted moderate-severe calcification |
1.672 |
1.128-2.479 |
0.010 |
| Non-fatal myocardial infarction |
|
|
|
| None-mild calcification |
Reference |
|
|
| Unadjusted moderate-severe calcification |
1.896 |
1.143-3.147 |
0.013 |
| Adjusted moderate-severe calcification |
1.187 |
0.668-2.110 |
0.558 |
| Re-admission for heart failure |
|
|
|
| None-mild calcification |
Reference |
|
|
| Unadjusted moderate-severe calcification |
1.683 |
1.024-2.769 |
0.040 |
| Adjusted moderate-severe calcification |
1.000 |
0.581-1.720 |
1.000 |
| Ischemia-driven target vessel revascularization |
|
|
|
| None-mild calcification |
Reference |
|
|
| Unadjusted moderate-severe calcification |
2.124 |
1.222-3.691 |
0.008 |
| Adjusted moderate-severe calcification |
1.290 |
0.685-2.432 |
0.430 |
In the adjusted model, moderate-severe calcification (vs. none-mild calcification) was adjusted for Age, Sex, Heart rate at admission, Hemoglobin, Hemodialysis, History of previous PCI, History of previous CABG, Shock vital at prehospital or ER, Culprit lesion, Left main trunk lesion, Ostia lesion, Number of narrowed coronary arteries, Initial TIMI flow grade of culprit, TIMI Thrombus grade, and Rentrop grade.
Discussion
We included 1209 patients with AMI and divided them into the none–mild calcification group (n=923) and the moderate–severe calcification group (n=286) according to angiographic coronary calcification. A total of 345 MACE were observed among the study population with the median follow-up duration of 542 days. MACE was more frequently observed in the moderate–severe calcification group than in the none–mild calcification group. The multivariate Cox hazard analysis revealed that the moderate–severe calcification was significantly associated with MACE after controlling multiple confounding factors. The present study suggests that angiographic moderate–severe calcification in the culprit lesions of AMI can be a simple predictor of long-term clinical outcomes in patients with AMI undergoing PCI.
There have been some earlier reports showing that severe calcification of coronary artery was associated with poor clinical outcomes9, 10, 22). Kawashima et al.10) revealed that angiographic coronary calcification is significantly associated with 10-year all-cause mortality. They included 1800 patients without AMI with de novo triple vessel disease or left main disease who underwent either PCI or CABG10), whereas our study population was limited to patients with AMI. Huang et al.22) performed a meta-analysis including 13 studies (66,361 patients) and reported that target lesion calcification is associated with increased mortality in patients who underwent drug-eluting stents. Therefore, the role of coronary calcification as a risk factor for long-term poor outcomes was established, unless we limit the lesion as the culprit of AMI. In contrast, the plaque characteristics, including calcification, are totally different between AMI lesions and non-AMI lesions. The most dominant plaque morphology in AMI lesions was plaque rupture, followed by plaque erosion and least calcified nodule23, 24). Recently, Torii et al.25) proposed the mechanism of the occurrence of calcified nodule, in which sheet calcification would break into the necrotic core calcification at hinge point of coronary arteries, with sufficient pathological data. Moreover, Torii et al.26) reported a dedicated pathological study regarding vascular responses to coronary calcification, in which severe calcification behind drug-eluting stents delayed the vascular healing (i.e., uncovered stent struts). In our study, the occurrence of nonfatal myocardial infarction due to stent failure was significantly higher in the moderate–severe calcification group. Delayed healing might be a cause of stent failure in the moderate–severe calcification group. Zimoch et al.9) reported the significant association between coronary calcification and future acute coronary syndrome in 206 patients with AMI. However, the association between coronary calcification and all-cause mortality was not significant in their study, whereas the association between moderate–severe calcification and all-cause mortality was significant in our study. This discrepancy might be derived from the difference of sample size (206 vs. 1209 patients with AMI).
We should discuss why moderate–severe calcification was associated with long-term MACE in patients with AMI. First, severe calcification might prevent adequate stent expansion. Khalifa et al.27) compared stent expansion in AMI lesions using OCT among plaque rupture, erosion, and calcified nodule and revealed that stent expansion is the smallest in calcified nodule. Sugane et al.28) also reported that calcified nodule in patients with AMI is associated with long-term MACE. Second, severe coronary calcification might be a marker of advanced systemic atherosclerosis irrespective stent expansion because angiographically visible coronary calcification would be the advanced phase in coronary calcification progression29). Coronary artery calcification implies arteriosclerosis of systemic blood vessels, which may cause vascular events other than coronary artery30). Furthermore, since calcification of coronary arteries is easily detected by coronary computed tomography (CT), various reports regarding calcification detected by CT and clinical outcomes were published. Yamamoto et al.31) reported that all-cause mortality and cardiovascular mortality are significantly higher in patients with high CT-coronary artery calcification scores. In addition, coronary artery calcification detected by CT was associated with chronic kidney disease32), lung cancer33), and cardiovascular events after sepsis34).
The clinical implication of the present study should be noted. First, angiographic coronary calcification is a simpler marker than IVUS-coronary calcification or OCT-coronary calcification. Only cine-angiogram is necessary to detect angiographic coronary calcification. Although intravascular imaging such as IVUS or OCT is superior to angiography for the detection of coronary calcification, the usage rate of intravascular imaging was less than 10% in most countries35). Patients after AMI would have more clinical events than patients with stable coronary artery disease36). Therefore, we should follow-up patients after AMI more carefully. However, since medical resources are limited, it would be necessary to select a high-risk group for close follow-up among patients after AMI. Angiographic coronary calcification can be a simple marker to identify a high-risk group.
First, because this study was a single-center retrospective observational study, there is a risk of patient selection bias. Second, there were some variables with missing values. Some variables such as ejection fraction could not be incorporated into the multivariate analysis because of substantial missing values. Third, the detection of coronary calcification would be influenced by the setting of fluoroscopy, which varies among manufacturers. Therefore, we did not subdivide moderate–severe calcification into moderate calcification (radiopaque densities visible during heart motion) and severe calcification (densities visible without heart motion) because the visibility of calcification with or without heart motion highly depended on the setting of fluoroscopy. Fourth, since the aim of this study was to assess the relationship between coronary calcification and long-term clinical outcomes, cardiac death might be a more appropriate endpoint than all-cause death. However, there were some deaths with unknown causes (not sudden death). These deaths with unknown causes might be cardiac death, but might be noncardiac death. In other words, the number of cardiac deaths might be underestimated. Therefore, we did not adopt cardiac death as a component of MACE, but adopted all-cause death as a component of MACE.
In conclusion, angiographically moderate to severe calcification in AMI culprit lesion was associated with long-term worse clinical outcomes. Angiographic coronary calcification can be a simple risk marker in patients after AMI.
Acknowledgements
The authors acknowledge all staff in the catheter laboratory, ICU/CCU, and cardiology ward in Saitama Medical Center, Jichi Medical University, for their technical support in this study.
Conflict of Interest
Dr. Sakakura has received speaking honoraria from Abbott Vascular, Boston Scientific, Kaneka, Medtronic Cardiovascular, Terumo, OrbusNeich, Japan Lifeline, and NIPRO. He has served as a proctor for Rotablator for Boston Scientific and has served as a consultant for Abbott Vascular and Boston Scientific. Prof. Fujita served as a consultant for Mehergen Group Holdings, Inc.
References
- 1) Nakamura M, Yaku H, Ako J, Arai H, Asai T, Chikamori T, Daida H, Doi K, Fukui T, Ito T, Kadota K, Kobayashi J, Komiya T, Kozuma K, Nakagawa Y, Nakao K, Niinami H, Ohno T, Ozaki Y, Sata M, Takanashi S, Takemura H, Ueno T, Yasuda S, Yokoyama H, Fujita T, Kasai T, Kohsaka S, Kubo T, Manabe S, Matsumoto N, Miyagawa S, Mizuno T, Motomura N, Numata S, Nakajima H, Oda H, Otake H, Otsuka F, Sasaki KI, Shimada K, Shimokawa T, Shinke T, Suzuki T, Takahashi M, Tanaka N, Tsuneyoshi H, Tojo T, Une D, Wakasa S, Yamaguchi K, Akasaka T, Hirayama A, Kimura K, Kimura T, Matsui Y, Miyazaki S, Okamura Y, Ono M, Shiomi H, Tanemoto K: JCS/JSCVS 2018 Guideline on Revascularization of Stable Coronary Artery Disease. Circ J, 2022; 86: 477-588
- 2) Kimura K, Kimura T, Ishihara M, Nakagawa Y, Nakao K, Miyauchi K, Sakamoto T, Tsujita K, Hagiwara N, Miyazaki S, Ako J, Arai H, Ishii H, Origuchi H, Shimizu W, Takemura H, Tahara Y, Morino Y, Iino K, Itoh T, Iwanaga Y, Uchida K, Endo H, Kongoji K, Sakamoto K, Shiomi H, Shimohama T, Suzuki A, Takahashi J, Takeuchi I, Tanaka A, Tamura T, Nakashima T, Noguchi T, Fukamachi D, Mizuno T, Yamaguchi J, Yodogawa K, Kosuge M, Kohsaka S, Yoshino H, Yasuda S, Shimokawa H, Hirayama A, Akasaka T, Haze K, Ogawa H, Tsutsui H, Yamazaki T: JCS 2018 Guideline on Diagnosis and Treatment of Acute Coronary Syndrome. Circ J, 2019; 83: 1085-1196
- 3) Piątek Ł, Janion-Sadowska A, Piątek K, Zandecki Ł, Zabojszcz M, Siudak Z, Sadowski M: Long-term clinical outcomes in patients with unstable angina undergoing percutaneous coronary interventions in a contemporary registry data from Poland. Coron Artery Dis, 2020; 31: 215-221
- 4) Giustino G, Baber U, Stefanini GG, Aquino M, Stone GW, Sartori S, Steg PG, Wijns W, Smits PC, Jeger RV, Leon MB, Windecker S, Serruys PW, Morice MC, Camenzind E, Weisz G, Kandzari D, Dangas GD, Mastoris I, Von Birgelen C, Galatius S, Kimura T, Mikhail G, Itchhaporia D, Mehta L, Ortega R, Kim HS, Valgimigli M, Kastrati A, Chieffo A, Mehran R: Impact of Clinical Presentation (Stable Angina Pectoris vs Unstable Angina Pectoris or Non-ST-Elevation Myocardial Infarction vs ST-Elevation Myocardial Infarction) on Long-Term Outcomes in Women Undergoing Percutaneous Coronary Intervention With Drug-Eluting Stents. Am J Cardiol, 2015; 116: 845-852
- 5) Han MM, Zhao WS, Wang X, He S, Xu XR, Dang CJ, Zhang J, Liu JM, Chen ML, Xu L, Wang H: Echocardiographic Parameters Predict Short- and Long-Term Adverse Cardiovascular Events in Patients with Acute Myocardial Infarction. Int J Gen Med, 2021; 14: 2297-2303
- 6) Sonoda T, Wada H, Ogita M, Takahashi D, Nishio R, Yasuda K, Takeuchi M, Yatsu S, Shitara J, Tsuboi S, Dohi T, Suwa S, Miyauchi K, Minamino T: Clinical features and predictors of outcome in patients with acute myocardial infarction complicated by out-of-hospital cardiac arrest. BMC Cardiovasc Disord, 2022; 22: 185
- 7) Ban S, Sakakura K, Jinnouchi H, Taniguchi Y, Tsukui T, Watanabe Y, Yamamoto K, Seguchi M, Wada H, Fujita H: Association of Asymptomatic Low Ankle-Brachial Index with Long-Term Clinical Outcomes in Patients after Acute Myocardial Infarction. J Atheroscler Thromb, 2022; 29: 992-1000
- 8) Ellis SG, Vandormael MG, Cowley MJ, DiSciascio G, Deligonul U, Topol EJ, Bulle TM: Coronary morphologic and clinical determinants of procedural outcome with angioplasty for multivessel coronary disease. Implications for patient selection. Multivessel Angioplasty Prognosis Study Group. Circulation, 1990; 82: 1193-1202
- 9) Zimoch WJ, Kubler P, Kosowski M, Tomasiewicz B, Krzysztofik J, Langner A, Jankowska EA, Reczuch K: Patients with acute myocardial infarction and severe target lesion calcifications undergoing percutaneous coronary intervention have poor long-term prognosis. Kardiol Pol, 2017; 75: 859-867
- 10) Kawashima H, Serruys PW, Hara H, Ono M, Gao C, Wang R, Garg S, Sharif F, de Winter RJ, Mack MJ, Holmes DR, Morice MC, Kappetein AP, Thuijs D, Milojevic M, Noack T, Mohr FW, Davierwala PM, Onuma Y: 10-Year All-Cause Mortality Following Percutaneous or Surgical Revascularization in Patients With Heavy Calcification. JACC Cardiovasc Interv, 2022; 15: 193-204
- 11) Ishibashi S, Sakakura K, Asada S, Taniguchi Y, Jinnouchi H, Tsukui T, Watanabe Y, Yamamoto K, Seguchi M, Wada H, Fujita H: Association of collateral flow with clinical outcomes in patients with acute myocardial infarction. Heart Vessels, 2022
- 12) Yamamoto K, Sakakura K, Akashi N, Watanabe Y, Noguchi M, Taniguchi Y, Wada H, Momomura SI, Fujita H: Comparison of clinical outcomes between sufficient versus insufficient diagonal branch flow in anterior acute myocardial infarction. Heart Vessels, 2019; 34: 1096-1103
- 13) Sawano M, Yamaji K, Kohsaka S, Inohara T, Numasawa Y, Ando H, Iida O, Shinke T, Ishii H, Amano T: Contemporary use and trends in percutaneous coronary intervention in Japan: an outline of the J-PCI registry. Cardiovasc Interv Ther, 2020; 35: 218-226
- 14) Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD: Fourth Universal Definition of Myocardial Infarction (2018). J Am Coll Cardiol, 2018; 72: 2231-2264
- 15) Kubota M, Sakakura K, Yamamoto K, Taniguchi Y, Tsukui T, Seguchi M, Wada H, Momomura SI, Fujita H: Mid-term Clinical Outcomes of Immediate Protamine Use Following Elective Percutaneous Coronary Interventions. Int Heart J, 2020; 61: 865-871
- 16) Noguchi M, Sakakura K, Akashi N, Adachi Y, Watanabe Y, Taniguchi Y, Ibe T, Yamamoto K, Wada H, Momomura SI, Fujita H: The Comparison of Clinical Outcomes Between Inferior ST-Elevation Myocardial Infarction with Right Ventricular Infarction Versus Without Right Ventricular Infarction. Int Heart J, 2019; 60: 560-568
- 17) Russo A, Suri RM, Grigioni F, Roger VL, Oh JK, Mahoney DW, Schaff HV, Enriquez-Sarano M: Clinical outcome after surgical correction of mitral regurgitation due to papillary muscle rupture. Circulation, 2008; 118: 1528-1534
- 18) Asada S, Sakakura K, Taniguchi Y, Yamamoto K, Tsukui T, Seguchi M, Wada H, Momomura SI, Fujita H: Association of the long fluoroscopy time with factors in contemporary primary percutaneous coronary interventions. PLoS One, 2020; 15: e0237362
- 19) Ishibashi S, Sakakura K, Asada S, Taniguchi Y, Yamamoto K, Tsukui T, Seguchi M, Jinnouchi H, Wada H, Fujita H: Clinical Factors Associated with Long Fluoroscopy Time in Percutaneous Coronary Interventions to the Culprit Lesion of Non-ST-Segment Elevation Myocardial Infarction. Int Heart J, 2021; 62: 282-289
- 20) Mintz GS, Popma JJ, Pichard AD, Kent KM, Satler LF, Chuang YC, Ditrano CJ, Leon MB: Patterns of calcification in coronary artery disease. A statistical analysis of intravascular ultrasound and coronary angiography in 1155 lesions. Circulation, 1995; 91: 1959-1965
- 21) Tanboga IH, Topcu S, Aksakal E, Kalkan K, Sevimli S, Acikel M: Determinants of angiographic thrombus burden in patients with ST-segment elevation myocardial infarction. Clin Appl Thromb Hemost, 2014; 20: 716-722
- 22) Huang BT, Huang FY, Zuo ZL, Liu W, Huang KS, Liao YB, Wang PJ, Peng Y, Zhang C, Zhao ZG, Huang DJ, Chen M: Target lesion calcification and risk of adverse outcomes in patients with drug-eluting stents. A meta-analysis. Herz, 2015; 40: 1097-1106
- 23) Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM: Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol, 2000; 20: 1262-1275
- 24) Sakakura K, Nakano M, Otsuka F, Ladich E, Kolodgie FD, Virmani R: Pathophysiology of atherosclerosis plaque progression. Heart Lung Circ, 2013; 22: 399-411
- 25) Torii S, Sato Y, Otsuka F, Kolodgie FD, Jinnouchi H, Sakamoto A, Park J, Yahagi K, Sakakura K, Cornelissen A, Kawakami R, Mori M, Kawai K, Amoa F, Guo L, Kutyna M, Fernandez R, Romero ME, Fowler D, Finn AV, Virmani R: Eruptive Calcified Nodules as a Potential Mechanism of Acute Coronary Thrombosis and Sudden Death. J Am Coll Cardiol, 2021; 77: 1599-1611
- 26) Torii S, Jinnouchi H, Sakamoto A, Mori H, Park J, Amoa FC, Sawan M, Sato Y, Cornelissen A, Kuntz SH, Kutyna M, Paek KH, Fernandez R, Braumann R, Mont EK, Surve D, Romero ME, Kolodgie FD, Virmani R, Finn AV: Vascular responses to coronary calcification following implantation of newer-generation drug-eluting stents in humans: impact on healing. Eur Heart J, 2020; 41: 786-796
- 27) Khalifa AKM, Kubo T, Ino Y, Terada K, Emori H, Higashioka D, Katayama Y, Takahata M, Shimamura K, Shiono Y, Matsuo Y, Tanaka A, Hozumi T, Akasaka T: Optical Coherence Tomography Comparison of Percutaneous Coronary Intervention Among Plaque Rupture, Erosion, and Calcified Nodule in Acute Myocardial Infarction. Circ J, 2020; 84: 911-916
- 28) Sugane H, Kataoka Y, Otsuka F, Nakaoku Y, Nishimura K, Nakano H, Murai K, Honda S, Hosoda H, Matama H, Doi T, Nakashima T, Fujino M, Nakao K, Yoneda S, Tahara Y, Asaumi Y, Noguchi T, Kawai K, Yasuda S: Cardiac outcomes in patients with acute coronary syndrome attributable to calcified nodule. Atherosclerosis, 2021; 318: 70-75
- 29) Otsuka F, Sakakura K, Yahagi K, Joner M, Virmani R: Has our understanding of calcification in human coronary atherosclerosis progressed? Arterioscler Thromb Vasc Biol, 2014; 34: 724-736
- 30) Budoff MJ, Shaw LJ, Liu ST, Weinstein SR, Mosler TP, Tseng PH, Flores FR, Callister TQ, Raggi P, Berman DS: Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients. J Am Coll Cardiol, 2007; 49: 1860-1870
- 31) Yamamoto H, Kitagawa T, Kihara Y: Clinical implications of the coronary artery calcium score in Japanese patients. J Atheroscler Thromb, 2014; 21: 1101-1108
- 32) Chen J, Budoff MJ, Reilly MP, Yang W, Rosas SE, Rahman M, Zhang X, Roy JA, Lustigova E, Nessel L, Ford V, Raj D, Porter AC, Soliman EZ, Wright JT, Jr., Wolf M, He J: Coronary Artery Calcification and Risk of Cardiovascular Disease and Death Among Patients With Chronic Kidney Disease. JAMA Cardiol, 2017; 2: 635-643
- 33) Shipe ME, Maiga AW, Deppen SA, Edwards GC, Marmor HN, Pinkerman R, Smith GT, Lio E, Wright JL, Shah C, Nesbitt JC, Grogan EL: Preoperative coronary artery calcifications in veterans predict higher all-cause mortality in early-stage lung cancer: a cohort study. J Thorac Dis, 2021; 13: 1427-1433
- 34) Gupta VA, Sousa M, Kraitman N, Annabathula R, Vsevolozhskaya O, Leung SW, Sorrell VL: Coronary artery calcification predicts cardiovascular complications after sepsis. J Crit Care, 2018; 44: 261-266
- 35) Smilowitz NR, Mohananey D, Razzouk L, Weisz G, Slater JN: Impact and trends of intravascular imaging in diagnostic coronary angiography and percutaneous coronary intervention in inpatients in the United States. Catheter Cardiovasc Interv, 2018; 92: E410-e415
- 36) Loh JP, Pendyala LK, Kitabata H, Torguson R, Omar A, Minha S, Chen F, Satler LF, Pichard AD, Waksman R: Comparison of outcomes after percutaneous coronary intervention among different coronary subsets (stable and unstable angina pectoris and ST-segment and non-ST-segment myocardial infarction). Am J Cardiol, 2014; 113: 1794-1801
