Clinical Outcomes and Unique Restenosis of Calcified Nodule in Heavily Calcified Coronary Artery

Abstract

Aims: Calcified nodule (CN) has been known as the advanced stage of coronary calcification. However, clinical outcomes following percutaneous coronary intervention (PCI) to CN remain unknown. This study aimed to compare clinical outcomes, including target lesion revascularization (TLR), between calcified coronary lesions with and without CN.

Methods: Two hundred forty-nine lesions undergoing intravascular ultrasound-guided PCI with rotational atherectomy (RA) were enrolled and divided into the CN group (n=100) and the non-CN group (n=149) according to the presence of CN. The cumulative incidence of clinically driven TLR (CD-TLR) and the reasons for CD-TLR were compared between the CN and non-CN groups.

Results: The incidence of CD-TLR was significantly higher in the CN group than in the non-CN group. In the landmark analysis at 1 year, the CN group showed a significantly higher incidence of CD-TLR within 1 year. However, the incidence of CD-TLR beyond 1 year was numerically lower in the CN group than in the non-CN group. In the multivariate Cox hazard model, CN was significantly associated with CD-TLR. In the CN group, in-stent CN was the major reason for CD-TLR (52%) and was observed mainly within 1 year (90%).

Conclusions: In the heavily calcified lesions requiring RA, CN was the factor associated with the higher rate of CD-TLR especially within 1 year. The timing of CD-TLR in lesions with CN may indicate that the process of CN protruding through the struts was progressed monthly.

Abbreviations: CN=calcified nodule, IVUS=intravascular ultrasound, CD-TLR=clinically-driven target lesion revascularization, PCI=percutaneous coronary intervention, RA=rotational atherectomy

Introduction

Percutaneous coronary intervention (PCI) has been widely performed in patients with atherosclerotic coronary artery disease since the 1980s^{1, 2)}. There are still unsolved issues in the field of PCI^{3, 4)}. One of those issues is unfavorable clinical outcomes in PCI to the heavily calcified lesions^5-7). Because calcified lesions would prevent delivery and expansion of coronary stents, calcified lesions that underwent PCI have a higher risk of target lesion failure^{1, 2)}. Although the usage of debulking devices such as rotational atherectomy (RA) can be helpful to improve delivery and expansion of stents in the calcified lesions, patients with heavily calcified lesions showed poor long-term clinical outcomes even if debulking devices were used^{5, 6)}. As atherosclerotic plaque progresses, the amount of calcification associated with cardiovascular events increases^8-11). Among various types of calcification, calcified nodule (CN) is thought to be a more advanced and unique form of calcification characterized by nodular calcification and the disrupted fibrous cap^{8, 12)}. CN has been widely recognized by use of intracoronary imaging devices^13-15).

There are many clinical and pathophysiological questions regarding CN. A few studies, including pathology and intracoronary imaging, showed that a hinge motion of vessels at the specific location was associated with the presence of CN^{12, 15)}. Although mechanical stress against calcification is believed to be one of the major causes of CN, the clear mechanism of CN remains unknown^{12, 15)}. Furthermore, clinical outcomes in patients with CN were not fully investigated, although there are a few intracoronary imaging studies investigating clinical outcomes in patients with CN^16-18). Especially, there are few data regarding comparison of clinical outcomes between CN and other types of severe calcification. Additionally, the reasons for target lesion revascularization (TLR) after PCI to CN have not been evaluated well. Therefore, the aim of the present study using intravascular ultrasound (IVUS) was to compare clinical outcomes following RA-PCI between severely calcified lesions with and without CN and to investigate the reasons for TLR in the lesions with CN.

Methods

Study Population

This was a single-center, retrospective observational study at Saitama Medical Center, Jichi Medical University. This study was approved by the institutional review board of Saitama Medical Center, Jichi Medical University (S21-121). Written informed consent was waived because of the retrospective study design. All clinical information was obtained from a review of hospital records. Between January 2017 and December 2020, the consecutive patients undergoing PCI to heavily calcified lesions requiring RA were reviewed. The inclusion criteria were as follows: 1) newer-generation drug-eluting stents were implanted in de novo lesions after RA, 2) available IVUS imaging before stenting with stenosis of ≥ 50% and calcification of ≥ 180°, and 3) final IVUS images after the entire PCI procedure were available. The exclusion criteria were the following: 1) available IVUS images had poor quality or 2) IVUS could not observe the entire lesion before stenting or the entire stent post-PCI. The final study lesions were divided into the CN and non-CN groups according to the presence or absence of CN by IVUS (Supplemental Fig.1).

Supplemental Fig.1. The representative IVUS images of CN and non-CN

(A) The IVUS image showing CN of approximately 270°. (B) Non-CN along with multiple reverberations.

PCI Procedure

RA was performed using standard techniques as previously described¹⁹⁾. A 0.014-inch conventional guidewire was inserted into the vessel and reached a far distal coronary segment. IVUS was attempted regardless of the degree of luminal stenosis. In the case of the pre-IVUS uncrossed lesions, a small RA burr or a small balloon was used. The 0.014-inch conventional guidewire was exchanged for a 0.009-inch RA guidewire through a micro-catheter. An RA burr was placed at a position proximal to the lesion. The rotational speed was configured with a conventional range from 140,000 to 190,000 rpm. A nicorandil-based drug cocktail was directly injected into a coronary artery via the RA catheter to prevent slow flow. The activated burr moved back and forth with a slow pecking motion. A single run was performed within 30 s, and the excessive speed down of ＞5,000 rpm was avoided as much as possible. The burr was removed after ablation. Angiography immediately following the removal of the burr assessed thrombolysis in myocardial infarction (TIMI) flow grade. Afterward, IVUS images assessed the effect of RA on the lesion. A burr was upsized depending on the necessity. After the ablation of RA, balloon dilatation was performed followed by stenting in the calcified lesions. Post-dilatation was considered as necessary. After the entire procedure, IVUS images and angiography were acquired.

Patient and Lesion Information

Definition of patient and lesion characteristics was previously described¹⁹⁾. Reference diameter and lesion length by angiography were analyzed using offline software QAgio XA7.3 (MEDIS Imaging System, Leiden, The Netherlands).

IVUS Image Acquisition and Analysis

IVUS systems were automatically pulled back at a fixed speed as follows: 1) OptiCross (Boston Scientific, Marlborough, MA, USA), 1 mm/s (30 frames/s) and 2) AltaView (Terumo, Tokyo, Japan), 3 or 9 mm/s (30 or 10 frames/s). The offline software [RadiAnt DICOM Viewer Ver. 2020.2 (Medixant, Poznan, Poland)] analyzed IVUS images.

Definition of IVUS Image

Angiography, RA fluoroscopy, and pre-IVUS images were carefully reviewed to identify regions ablated by RA. Using the first IVUS images in the IVUS-crossed lesions, the most proximal and distal frames to analyze were defined as the first and last frames with calcification of ≥ 180° and stenosis of ≥ 50% in the regions ablated by RA. Calcified lesion length was defined as the longitudinal distance from the most proximal to distal frames where IVUS frames were analyzed every 1 mm. CN was defined as convex-shaped calcification with an irregular surface^{13, 18)}. The maximum calcified angle was defined as the greatest arc of calcification in the calcified lesion. The minimal lumen area was defined as the smallest lumen area in the calcified lesion. Mean diameter was defined as the average of visually longest and shortest diameters in the lumen. In the case of IVUS uncrossed lesions before RA, the first IVUS after RA prior to stenting was used for analysis. In IVUS images after RA, the luminal surface was regarded as the modification by RA if a part of the lumen showed an artificially convex downward surface. In the frame, the ablated area was measured. Using IVUS imaging after the entire PCI procedure, proximal and distal references, and minimal stent area and percent of stent expansion were evaluated.

Definition of Clinical Outcomes

The primary study endpoints were the cumulative incidence of clinically driven TLR (CD-TLR). Definite stent thrombosis and target vessel myocardial infarction (TV-MI) were also evaluated in this study. Definitions of clinical endpoints were defined according to the Academic Research Consortium (ARC) guidelines²⁰⁾. TLR was defined as any revascularization (either repeated PCI or coronary artery bypass graft) for restenosis or thrombosis of the target lesion that included the proximal and distal edge segments. Revascularization was considered clinically driven if angiographic diameter stenosis was ≥ 50%, and if one of the following occurs: (1) positive functional ischemia study, (2) ischemic symptoms, and (3) angiographic diameter stenosis ≥ 70% without angina or positive functional study²⁰⁾. Definite stent thrombosis is considered to have occurred by angiographic confirmation based on the ARC definition²⁰⁾. TV-MI was defined as MI in the treated vessel²⁰⁾. The index day (day 0) was defined as the day when PCI was performed. The study patients were followed up until meeting death or until the study end date (October 20, 2021).

Reason for CD-TLR

The reasons for CD-TLR were assessed based on intracoronary imaging modalities, that is, IVUS or optical coherence tomography (OCT). Selectable causes included in-stent CN, edge-related disease, neointimal growth, stent underexpansion, thrombus, and an unknown cause. In-stent CN by IVUS was defined as the presence of CN inside the stent, whereas in-stent CN by OCT was defined as surface irregularity due to the disruption of the fibrous cap and protruding calcification connected to surface calcification^{13-15, 18)}. Edge-related disease by either modality was defined as TLR within 5 mm from both stent edges due to plaque progression at the stent-edge segment. Neointimal growth was defined as the excessive increase of neointima regardless of the type of plaque without thrombus and in-stent CN. Stent underexpansion was defined as remarkably narrow stent links (visually ≤ 50% of the average stent area)²¹⁾. Thrombus was defined as the mass images protruding into the lumen from the luminal surface without any selectable causes²²⁾. An unknown cause was defined as when any intracoronary imaging for in-stent culprit lesions was not acquired since coronary bypass graft was selected for revascularization or any intracoronary imaging devices could not cross lesions during the entire procedure.

Statistical Analysis

Statistical analysis was performed using JMP Pro version 16 and SPSS version 22. Data are presented as values and percentages or median (interquartile range). Categorical variables were compared between the two groups with Fisher’s exact test. Continuous variables were compared between groups using the unpaired t-test or the Mann–Whitney U test based on the data distribution. The Shapiro–Wilk test determined the data distribution. The cumulative incidence probability of CD-TLR was estimated using the Kaplan–Meier method and compared between the CN and non-CN groups using the log-rank test. To evaluate the incidence of CD-TLR within and beyond 1 year, landmark analysis at 1 year, which resets the risk set at a landmark point of 1 year, was applied to the Kaplan–Meier estimates. Of IVUS findings, the factors associated with CD-TLR were evaluated by multivariate stepwise Cox hazard model. The multivariate stepwise Cox hazard analysis with Wald Statistical criteria using the backward elimination method was performed. The continuous variables were dichotomized by clinically meaningful reference values. If there were several similar variables, we selected one variable that we considered to be more clinically relevant. Variables with a p-value of ＜0.1 in the univariate Cox models using patient, lesion characteristics, and pre- and post-IVUS findings were entered into the multivariable Cox model. If variables with a p-value of ＜0.1 in the univariate Cox models had a strong correlation with CN, the variables were entered into multivariate Cox hazard model without CN. The adjusted cumulative incidence probabilities were estimated by multivariable adjustment using the statistically significant variables in the multivariable Cox model. A two-sided p-value of ＜0.05 was considered as statistically significant.

Results

Patient and Lesion Characteristics

During this study period, 346 lesions underwent PCI with RA. Finally, of these lesions, 249 lesions with appropriate pre- and post-IVUS images were enrolled in this study (Fig.1). Those lesions were divided into two groups: 1) the CN group (100 lesions) and 2) the non-CN group (149 lesions). The patient and lesion characteristics are summarized in Table 1. The CN group showed significantly greater prevalence of diabetes mellitus, hemodialysis, RCA lesions, and any ostial lesion relative to the non-CN group.

Fig.1. Study flowchart

CN, calcified nodule; IVUS, intravascular ultrasound; OCT, optical coherence tomography; OFDI, optical frequent domain imaging; RA, rotational atherectomy.

Table 1. Comparison of Patients and Lesions Characteristics between CN and Non-CN groups

	All (n= 249)	CN group (n= 100)	Non-CN group (n= 149)	p-value
Patient characteristics
Age (years)	76 (70 - 81)	75 (70 - 81)	76 (70 - 81)	0.69
Men - n, (%)	179 (71.9)	78 (78.0)	101 (67.8)	0.09
Hypertension - n, (%)	244 (98.0)	97 (97.0)	147 (98.7)	0.39
Diabetes mellitus - n, (%)	139 (55.8)	66 (66.0)	73 (49.0)	0.009
Hyperlipidemia - n, (%)	232 (93.2)	92 (92.0)	140 (94.0)	0.61
Current smoker - n, (%) (n= 247)	43 (17.4)	13 (13.3)	30 (20.1)	0.17
Left ventricular ejection fraction (%)(n= 194)	59.8 (48.8 – 66.9)	58 (46 – 66)	62 (50 – 68)	0.18
Chronic renal failure on hemodialysis - n, (%)	65 (26.1)	39 (39.0)	26 (17.5)	0.0002
Statin treatment - n, (%)	229 (92.0)	92 (92.0)	137 (92.0)	1.00
Lesion characteristics
Culprit lesion in acute coronary syndrome - n, (%)	43 (17.3)	22 (22.0)	21 (14.1)	0.12
Chronic total occlusion - n, (%)	1 (0.4)	0 (0.0)	1 (0.7)	1.00
Target coronary artery				＜0.001
Left main- left anterior descending artery - n, (%)	184 (73.9)	58 (58.0)	126 (84.6)
Left circumflex artery - n, (%)	12 (4.8)	5 (5.0)	7 (4.7)
Right coronary artery - n, (%)	53 (21.3)	37 (37.0)	16 (10.7)
Specific target coronary artery
Any ostial lesion- n, (%)	49 (19.7)	29 (29.0)	20 (13.4)	0.003
Reference diameter (mm)	2.4 (2.1-2.8)	2.6 (2.2 - 3.0)	2.2 (2.0 - 2.6)	＜0.0001
Lesion length (mm)	23 (13-35)	23 (12 - 34)	23 (13 - 36)	0.36
Moderate to severe angulation	108 (43.4)	47 (47.0)	61 (40.9)	0.36
Severe calcification, n (%)	248 (99.6)	99 (99.0)	149 (100.0)	0.40
Final burr size				0.003
1.25-mm	43 (14.8)	15 (15.0)	23 (15.4)
1.5-mm	197 (67.9)	62 (62.0)	114 (76.5)
1.75-mm	15 (5.2)	5 (5.0)	6 (4.0)
2.0-mm	35 (12.1)	18 (18.0)	4.0 (4.0)
Mean stent diameter (mm)	2.8 (2.5-3.0)	2.8 (2.6 - 3.0)	2.6 (2.5 - 3.0)	＜0.0001
Stent lenght (mm)	38 (24-54)	32 (20 - 52)	38 (28 - 56)	0.08
Type of stent				0.08
BP-EES	174 (69.9)	62 (62.0)	112 (75.2)
BP-SES	11 (4.4)	5 (5.0)	6 (4.0)
DP-EES	37 (14.9)	17 (17.0)	20 (13.4)
DP-ZES	21 (8.4)	14 (14.0)	7 (4.7)
Hybrid stents	6 (2.4)	2 (2.0)	4 (2.7)
Final burr-to-artery ratio	0.64 (0.55-0.73)	0.59 (0.51 -	0.65 (0.58 -	0.0007
IVUS before RA/ after RA, n (%)	142 (57.0)/107 (43.0)	56 (56.0)/44 (44.0)	86 (57.7)/63 (42.3)	0.80
Follow up period, days	676 (379-1038)	780 (465-1102)	590 (278-989)	0.03

Values are presented as median (interquartile range), or n (%) for categorical variables. BP, biodegradable polymer; DP, durable polymer; EES, everolimus-eluting stent; SES, sirolimus-eluting stent; ZES, zotarolimus eluting stent; CN, calcified nodule; IVUS, intravascular ultrasound; RA, rotational atherectomy.

The CN group showed significantly greater reference diameter and mean stent diameter than the non-CN group. Final burr-to artery ratios were significantly smaller in the CN group than in the non-CN group. There was a significant difference in the final burr size between the two groups, and the 2.0-mm burr size was more frequently used in the CN group than in the non-CN group.

Complications and In-Hospital Outcomes

Complications and in-hospital outcomes are listed in Supplemental Table 1, which shows no significant differences in slow flow just after RA, final TIMI flow grade ≤ 2, periprocedural MI, burr entrapment, and in-hospital death between the two groups.

Supplemental Table 1. Comparison of Complications and Outcomes between CN and Non-CN Groups

	All (n= 249)	CN (n= 100)	Non-CN (n= 149)	p-value
Slow flow (≤ TIMI 1 just after RA– n, (%))	8 (3.2)	3 (3.0)	5 (3.4)	1.00
Final TIMI flow grade ≤ 2, (%)	4 (1.6)	0 (0.0)	4 (2.7)	0.15
Periprocedural MI – n, (%)	5 (1.6)	1 (1.0)	3 (2.0)	0.65
Burr entrapment – n, (%)	1 (0.4)	1 (1.0)	0 (0.0)	0.40
In-hospital death (irrespective of procedural complications)	1 (0.4)	0 (0.0)	1 (0.7)	1.00

Values are presented as n (%) for categorical variables. CN, calcified nodule; MI, myocardial infarction; RA, rotational atherectomy; TIMI, Thrombolysis in Myocardial Infarction.

IVUS Assessment

Data of pre- and post-IVUS are shown in Table 2. The average lumen area and mean diameter were significantly greater in the CN group than in the non-CN group. In post-IVUS findings, the CN group showed significantly greater mean reference diameter, minimal stent area, and smaller percent of stent expansion than the non-CN group (Supplemental Fig.2).

Table 2. Comparison of IVUS Findings between CN and Non-CN Groups

	All (n= 249)	CN group (n= 100)	Non-CN group (n= 149)	p-value
Pre-procedural IVUS
Mean effected area, mm2	0.43 (0.24-0.66) (n= 107)	0.41 (0.24-0.61) (n= 44)	0.45 (0.23-0.72) (n= 63)	0.48
Lesion length, mm	15 (8-25)	20 (8-28)	14 (8-23)	0.053
Maximum arc of calcification, º	360 (294-360)	360 (311-360)	360 (286-360)	0.14
Average of calcification-arc, º	242 (199-282)	247 (207-282)	232 (190-280)	0.11
Minimal lumen area, mm2	2.0 (1.6-2.6)	2.0 (1.6-2.8)	2.0 (1.6-2.5)	0.66
Mean diameter at minimal lumen, mm	1.6 (1.4-1.9)	1.7 (1.4-2.0)	1.6 (1.4-1.8)	0.14
Average of lumen area, mm2	3.5 (2.9-4.4)	4.0 (3.2-5.2)	3.3 (2.7-3.9)	＜0.0001
Mean diameter, mm	2.1 (1.9-2.4)	2.2 (2.0-2.5)	2.0 (1.8-2.2)	＜0.0001
Arc of calcification at minimal lumen area, º	268 (205-354)	275 (222-355)	261 (195-354)	0.26
Post-procedural IVUS
Mean reference diameter, (mm)	6.4 (5.2-8.1)	7.8 (5.8-9.0)	5.9 (4.9-7.2)	＜0.0001
Minimal stent area, (mm2)	4.7 (3.8-5.7)	5.0 (3.9-6.3)	4.5 (3.7-5.5)	0.005
Stent expansion, (%)	75.0 (63.4-86.1)	69.7 (57.5-83.7)	76.5 (66.1-87.4)	0.007

Values are presented as median (interquartile range), or n (%) for categorical variables. CN, calcified nodule; IVUS, intravascular ultrasound.

Supplemental Fig.2. Comparisons of minimal stent area and stent expansion between the CN and non-CN groups

CN, calcified nodule.

Factors Associated with CD-TLR

Variables (p＜0.1) in the univariate Cox hazard model to find factors associated with CD-TLR were the presence of CN, age (increase 5 years), male gender, diabetes mellitus, chronic renal failure on hemodialysis, culprit lesion in acute coronary syndrome (ACS), and lesion length by IVUS (increase 5 mm) (Supplemental Table 2). In the multivariate Cox hazard analysis, we made two models to avoid multicollinearity because the strong correlation between CN and chronic renal failure on hemodialysis was estimated. In model 1, the multivariate Cox hazard model showed that the presence of CN [hazard ratio (HR), 1.41; 95% confidence interval (CI), 1.06–1.88; p=0.02], culprit lesion in ACS (HR, 2.36; 95% CI, 1.28–4.34; p=0.006), and age (increase 5 years) (HR, 0.84; 95% CI, 0.73–0.97; p=0.01) were significantly associated with CD-TLR (Table 3). In model 2, culprit lesion in ACS (HR, 2.36; 95% CI, 1.28–4.34; p=0.006) and chronic renal failure on hemodialysis (HR, 4.25; 95% CI, 2.42–7.48; p＜0.001) were significantly associated with CD-TLR.

Supplemental Table 2. Univariate Analysis of Association between Variables and CD-TLR

	Hazard ratio (95% CI)	p-value
CN (vs. non-CN)	2.11 (1.20-3.69)	0.009
Age (increase 5)	0.26 (0.08-0.88)	0.02
Men	1.94 (0.94-4.00)	0.07
Hypertension	506128258 (0.99-NE)	0.99
Diabetes mellitus	1.94 (1.04-3.59)	0.04
Hyperlipidemia	0.61 (0.22-1.70)	0.35
Current smoker	0.79 (0.35-1.76)	0.56
Statin treatment	0.77 (0.28-2.15)	0.77
Culprit lesion in acute coronary syndrome	2.51 (1.37-4.60)	0.003
Chronic renal failure on hemodialysis	4.50 (2.57-7.89)	＜0.0001
Chronic total occlusion	3.19 (0.44-23.22)	0.25
Any ostial lesion	1.02 (0.51-2.03)	0.96
Moderate to severe angulation	0.66 (0.37-1.18)	0.16
Severe calcification	66320670 (0-NE)	0.99
Final TIMI flow grade ≤ 2	1.496e-8 (0-NE)	0.99
Final burr-to-artery ratio (increase 0.1)	1.03 (0.85-1.23)	0.75
BP-EES	0.66 (0.38-1.17)	0.16
DP-EES	1.33 (0.67-2.67)	0.41
IVUS before RA, (%)	0.84 (0.48-1.47)	0.54
IVUS findings
Lesion length (increase 5)	1.10 (0.99-1.21)	0.06
Maximum arc of calcification (increase 30)	1.06 (0.91-1.27)	0.46
Average of calcification-arc (increase 30)	1.00 (0.87-1.16)	0.97
Minimal lumen area (increase 0.2)	1.04 (0.97-1.10)	0.25
Mean diameter at minimal lumen (increase 0.2 mm)	1.12 (0.96-1.29)	0.12
Average of lumen area (＜ 3.0 mm2)	0.69 (0.35-1.35)	0.28
Arc of calcification at minimal lumen area (increase 30)	0.98 (0.89-1.09)	0.74
Post-Procedural IVUS
Mean reference diameter (increase 0.2)	1.01 (0.98-1.04)	0.37
Minimal stent area (increase 0.2)	1.00 (0.97-1.04)	0.82
Stent expansion (increase 5)	0.96 (0.89-1.05)	0.39

BP, biodegradable polymer; DP, durable polymer; EES, everolimus eluting stent; CI, confidence interval; CN, calcified nodule; IVUS, intravascular ultrasound; NE, not estimated; RA, rotational atherectomy; TIMI, Thrombolysis in Myocardial Infarction.

Table 3. Multivariate Cox Hazard Model to Find Factors Associated with CD-TLR

Model 1: CN (vs. non-CN) was included as an independent variable.
	Multivariable Model
	Hazard ratio (95% CI)	p-value
CN (vs. non-CN)	1.41 (1.06-1.88)	0.02
Culprit lesion in acute coronary syndrome	2.36 (1.28-4.34)	0.006
Age (increase 5 years)	0.84 (0.73-0.97)	0.01
Model 2: Chronic renal failure on hemodialysis was included as an independent variable.
	Multivariable Model
	Hazard ratio (95% CI)	p-value
Culprit lesion in acute coronary syndrome	2.19 (1.19-4.03)	0.01
Chronic renal failure on hemodialysis	4.25 (2.42-7.48)	＜0.001

Multivariate stepwise Cox hazard model to evaluate the association between CD-TLR and variables in Table 1 and 2. Variables that had a significant association (p＜0.10) between the 2 groups were used as independent variables. Two models were shown to avoid multicollinearity, because the strong correlation between CN (vs. non-CN) and chronic renal failure on hemodialysis was estimated. Both the model 1 and the model 2 included culprit lesion in acute coronary syndrome, lesion length by intravascular ultrasound (increase 5 mm), male, age (increase 5), and diabetes mellitus. Additionally, the model 1 included CN (vs. non-CN) as an independent variable, whereas the model 2 included chronic renal failure on hemodialysis as an independent variable. The multivariate Cox hazard analysis with Wald Statistical criteria using backward elimination methods was performed. CD-TLR, clinically-driven target lesion revascularization; CI, confidence interval; CN, calcified nodule.

Clinical Outcomes Between the CN and Non-CN Groups

Table 4 summarizes the clinical outcomes between the CN and non-CN groups in the crude population. The CN group showed significantly higher incidence of CD-TLR and TV-MI (29.0% vs. 14.1%, p=0.008 and 15.0% vs. 5.4%, p=0.02, respectively) (Fig.2A). In the landmark analysis at 1 year, the incidence of CD-TLR within 1 year was significantly higher in the CN group than in the non-CN group (p＜0.0001), whereas CD-TLR beyond 1 year showed a numerically lower incidence of CD-TLR in the CN group than in the non-CN group without reaching the significant difference (p=0.14) (Fig.2B).

Table 4. Clinical Outcomes between CN and Non-CN Groups

	Event rate (%) in the crude population			p-value
	Overall (n= 249)	CN (n= 100)	Non-CN (n= 149)
Target-vessel MI	23 (9.2)	15 (15.0)	8 (5.4)	0.02
Definite stent thrombosis	2 (0.8)	2 (2.0)	0 (0.0)	0.10
CD-TLR	50 (20.1)	29 (29.0)	21 (14.1)	0.008

P-value in the crude-population was analyzed by the log-rank method. CD-TLR, clinically-driven target lesion revascularization; CN, calcified nodule; MI, myocardial infarction.

Fig.2. Comparison of clinically driven target lesion revascularization between the CN and non-CN groups

(A) The crude population. (B) The 1-year landmark analysis in the crude population. (C) After multivariable adjustment. (D) The 1-year landmark analysis after multivariable adjustment. CN, calcified nodule.

After adjusting, the adjusted risk of the CN group for CD-TLR was significantly higher than that of the non-CN group (p=0.02) (Fig.2C). In the landmark analysis after adjusting, the CN group showed significantly higher incidence of CD-TLR within 1 year than the non-CN group (p=0.0002), whereas the adjusted risk for CD-TLR beyond 1 year was numerically higher in the non-CN group than in the CN group (p=0.11) (Fig.2D).

Reason for CD-TLR

In the CN group, in-stent CN was the most frequent reason for CD-TLR (52%), followed by edge-related disease (14%), stent underexpansion (14%), and neointimal growth (10%) (Fig.3). In contrast, in the non-CN group, neointimal growth was the main reason for CD-TLR (48%), followed by edge-related disease (33%) and in-stent CN (10%). In the CN group, of 29 events with CD-TLR, 26 CD-TLR were observed within 1 year (90%) (Fig.4). In the non-CN group, two major reasons for CD-TLR (i.e., neointimal growth and edge-related disease) were evenly distributed with respect to timing, whereas only two cases with in-stent CN were observed within 1 year.

Fig.3. Prevalence of reasons for CD-TLR in the CN and non-CN groups

CD-TLR, clinically driven target lesion revascularization; CN, calcified nodule.

Fig.4. Reasons for CD-TLR in the CN (A) and non-CN (B) groups

The graphs show the timing of events by individual reasons for CD-TLR. CD-TLR, clinically driven target lesion revascularization; CN, calcified nodule.

Discussion

Main Findings

The main findings in this study were as follows: 1) the incidence of CD-TLR was significantly higher in the CN group than in the non-CN group especially within 1 year; 2) the presence of CN was significantly associated with CD-TLR after controlling other variables in heavily calcified lesions; 3) the primary reason for CD-TLR in the CN group was in-stent CN, followed by edge-related disease, stent underexpansion, and neointimal growth, whereas the majority of the reason for CD-TLR in the non-CN group was neointima growth, followed by edge-related disease and in-stent CN; and 4) in-stent CN leading to CD-TLR in the CN group was observed mainly within 1 year, suggesting that the progression of in-stent CN was relatively early.

Characteristics of CN

The previous studies using IVUS or OCT showed that CN was associated with hemodialysis, diabetes, older age, and lesions in right coronary arteries^{14, 15)}. Additionally, reference diameter in the pre-IVUS was significantly larger in CN than in non-CN, although vessels in CN were smaller than vessels in ruptured plaque or plaque erosion^{16, 23)}. Regarding those characteristics in CN, the current study was in line with the previous studies. In the CN group of the present study, the presentation of ACS was only 22%. Although CN was recognized as the third cause of ACS, lesions with CN can present with stable angina rather than ACS depending on the degree of ischemia. Although the percent of stent expansion was significantly smaller in CN than in non-CN, minimal stent area was significantly larger in CN than in non-CN. The previous studies showed that CN lesions were frequently located in the proximal to middle right coronary arteries, which tends to have large lumen area^{12, 15)}. Such frequent location in CN might lead to larger minimal stent area in CN than in non-CN. In fact, the current study showed that the CN group had ostium lesions and larger reference lumen area more frequently than the non-CN group. However, CN lesions had smaller stent expansion compared than non-CN, probably because of the unique shape of CN (narrow angle of calcification and thick calcification)¹²⁾. The importance of stent expansion has been shown in the previous imaging studies^{24, 25)}. However, the current study could not show a clear association between CD-TLR and the percent of stent expansion, probably because of apparent dissociation between stent expansion and minimal stent area in CN and non-CN. Recently, Fujimura et al. revealed that the ratio of minimal stent area divided by vessel area at the minimal stent area site is associated with TLR and definite stent thrombosis rather than conventional stent expansion (the ratio of minimal stent area divided by the average of proximal and distal reference luminal areas)²⁵⁾. However, it is impossible to measure vessel area due to circumferentially acoustic shadow caused by severe calcification. In heavily calcified lesions where it is difficult to achieve optimal stent expansion, aggressive expansion can lead to medial dissection, which would result in restenosis and stent thrombosis^{26, 27)}. Therefore, the cut-off value of stent expansion for optimal expansion should not be applied to heavily calcified lesions, including CN.

Worse Clinical Outcomes of CN

In ACS lesions, the previous studies showed that CN had a significantly higher incidence of cardiac death, TLR, and stent thrombosis than of ruptured plaque and plaque erosion^{16, 17, 28)}. There are a few studies showing comparison between CN and other types of calcification^{16, 17)}. Morofuji et al. showed that CN is associated with worse clinical outcomes than non-CN in heavily calcified lesions¹⁶⁾. More recently, Prati et al. reported that the incidence of adverse cardiac events is significantly higher in CN than in nodular calcification without the disrupted fibrous cap¹⁷⁾. In the current study, the incidence of CD-TLR was significantly higher in CN than in non-CN. CN and hemodialysis were significantly associated with CD-TLR. Hemodialysis is a well-known predictor for worse clinical outcomes after PCI, which was in line with the results of the current study. There is a significant association between kidney function and coronary artery calcification²⁹⁾. Moreover, Lee et al. reported that hemodialysis is the independent predictor of CN¹⁵⁾. In patients with end-stage renal disease, duration of hemodialysis was significantly longer in patients with CN than in patients without CN³⁰⁾. There would be a strong correlation between CN and hemodialysis. Therefore, the present study separately showed two types of multivariate Cox hazard analysis, including CN or hemodialysis. Additionally, a significant difference between two groups was observed especially within 1 year, whereas the increasing rate of CD-TLR was numerically reversed beyond 1 year. This result suggested that CD-TLR occurs earlier and more frequently in CN than in non-CN. Additionally, considering a lower incidence of CD-TLR in CN beyond 1 year, CN without adverse events within 1 year might be more benign than non-CN in the chronic phase. In the recent study, CN in non-culprit lesions was shown to be benign, probably since most CN in non-culprit lesions was the representative of stable plaque^{8, 31)}.

Cause of Stent Failure in CN

The clear mechanism of CN remains unclear. The pathological studies and the OCT study suggested that the hinge motion in coronary arteries was associated with CN^{12, 15)}. The mechanism of in-stent CN also remains unknown. The pathological case series clearly illustrated the connection of underlying CN and in-stent CN, which cannot be shown by IVUS and OCT due to strong signal attenuation resulting from in-stent CN³²⁾. The case report suggested that CN protruding into the lumen through the stent struts is the cause of in-stent CN. Mechanical stress against the coronary arteries lasts due to the hinge motion after stent implantation³³⁾. Such stress from the outside to the inside of stent would occur especially in the heavily calcified lesions following stent implantation³⁴⁾. These stresses may induce underlying CN to project into the lumen through the stent struts. The current study showed that 52% of the causes of CD-TLR in the CN group were in-stent CN. Of 15 in-stent CN cases, 13 cases led to CD-TLR within 1 year, and the earliest CD-TLR due to in-stent CN occurred approximately 3 months following stenting. Considering the timing of CD-TLR, protrusion of CN might be progressed monthly. The process of CN formation from microcalcification requires several steps such as the formation of large calcification followed by the break of calcification into small nodules^{8, 32)}. Therefore, it is difficult to speculate that the newly isolated development of CN inside of the stent can be completed within 1 year^{8, 12, 15)}.

Clinical Implications from the New Insight

A previous study showed that CN was associated with worse clinical outcomes after stenting²⁸⁾. To avoid protrusion of CN through the stent, the amount of volume of underling CN might need to be reduced using any atherectomy devices or excimer laser as much as possible. However, our group previously showed that CN treated with RA had comparable clinical outcomes when compared to CN treated without RA¹⁸⁾, suggesting the limited efficacy of atherectomy devices for CN. There are a few reports showing the optional strategy of drug-coated balloon following debulking devices or excimer laser catheter ablation, although the effect of drugs on calcification is limited considering a functional mechanism of drug^{33, 35)}. Since there is no gold standard strategy for CN, interventional strategy for CN should be carefully considered in individual cases. Additionally, an early follow-up program should be scheduled in patients with CN especially within 1 year, since lesions with CN have a higher risk of CD-TLR within 1 year.

Study Limitation

There are several limitations in this study. First, this was a single-center, retrospective observational study. Second, the study population was small. Since the number of CD-TLR was limited, we could not include a sufficient number of variables in multivariate Cox hazard analysis to find factors associated with CD-TLR. Therefore, multi-center, prospective trials, including a large population, are warranted to confirm our results. Third, IVUS cannot detect thrombus on nodules in detail, although the pathological definition of CN includes the presence of thrombus along with fibrous disruption. Therefore, the CN group might include nodular calcification without thrombus as CN. However, the previous IVUS study showed that the current definition had a good correlation¹³⁾. Fourth, this study included lesions where IVUS was uncrossable before RA as well as those where IVUS was crossable before any procedure. However, CN after RA or ballooning generally keeps its unique characteristics. Therefore, RA or ballooning before IVUS would not affect the diagnosis of CN in initially uncrossable lesions. Finally, CN and hemodialysis were not entered into the multivariate Cox hazard model simultaneously to avoid multicollinearity. Instead, we created two multivariate Cox hazard models, including CN or hemodialysis.

Conclusions

In heavily calcified lesions requiring RA, CN had a significantly higher incidence of CD-TLR than non-CN especially within 1 year. The primary cause of CD-TLR was in-stent CN. The process of protruding CN into the lumen through the struts, which is the most likely mechanism of in-stent CN, was progressed monthly. A careful follow-up after PCI should be scheduled in lesions with CN.

Funding Statement

None.

Acknowledgement

The authors acknowledge Ryo Kokubo, M.E.; Kohei Matsuda, M.E.; and all staff in the catheter laboratory in Jichi Medical University, Saitama Medical Center for their technical support in this study.

Disclosures

Dr. Jinnouchi has received speaking honoraria from Abbott Vascular and Terumo. Dr. Sakakura has received speaking honoraria from Abbott Vascular, Boston Scientific, Medtronic Cardiovascular, Terumo, OrbusNeich, Japan Lifeline, Kaneka, and NIPRO; he has served as a proctor for Rotablator for Boston Scientific, and he has served as a consultant for Abbott Vascular and Boston Scientific. Prof. Fujita has served as a consultant for Mehergen Group Holdings, Inc.

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