Prognostic Utility of Nodular Calcification Detected on Non-Contrast Computed Tomography in Severely Calcified Coronary Lesions

Abstract

Background: Nodular calcification (NC) detected via intracoronary imaging is associated with adverse cardiovascular events after percutaneous coronary intervention (PCI). However, the impact of NC detected on pre-PCI non-contrast computed tomography (CT) on clinical outcomes has not been fully investigated.

Methods and Results: We retrospectively included 267 consecutive patients with chronic coronary syndrome who underwent electrocardiography-gated non-contrast CT before PCI for severely calcified lesions. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE), a composite of all-cause death, stroke, non-fatal myocardial infarction, and target lesion revascularization (TLR). Fifty-eight patients had NC detected on non-contrast CT in target lesions. The MACCE-free survival rate was significantly lower in patients with than without NC (P<0.001). All-cause death, cardiac death, and TLR-free survival rates were significantly lower among patients with than without NC. Multivariate Cox regression analysis revealed that hemodialysis (hazard ratio [HR] 3.00; P=0.003), peripheral artery disease (HR 2.65; P=0.01), and the presence of NC (HR 5.25; P<0.001) were independently associated with MACCE. Adding NC to traditional cardiovascular risk factors, peripheral artery disease, and hemodialysis can provide discriminatory and reclassification abilities in predicting MACCE.

Conclusions: NC detected on non-contrast CT was independently associated with MACCE. Therefore, evaluating NC using preprocedural non-contrast CT may be useful in predicting future clinical outcomes after PCI.

Percutaneous coronary intervention (PCI) is a well-established revascularization therapy for patients with coronary artery disease. However, PCI for severely calcified lesions remains challenging, even in the current drug-eluting stent era.^1,2 Although various atherectomy devices have been used for severely calcified lesions, clinical outcomes, including target lesion revascularization (TLR), are unfavorable.^3,4 In particularly, nodular calcification (NC) detected using intravascular imaging modalities, including intravascular ultrasound or optical coherence tomography (OCT), has a significant negative impact on clinical outcomes.^5–7 Recent reports evaluating the clinical impact of OCT-detected NC indicated that the morphology or OCT attenuation of NC is strongly associated with long-term clinical outcomes after stent implantation.^8,9 These studies imply that NC is a key determinant of the appropriate indication for PCI in severely calcified lesions.

Non-contrast computed tomography (CT) is widely used to assess the severity of coronary artery calcification. Although coronary artery calcium scoring is a well-established tool for assessing the risk of major cardiovascular outcomes, particularly in asymptomatic individuals, and planning primary prevention interventions,^10–12 non-contrast CT can qualitatively assess coronary calcium morphology non-invasively. Previously, we reported the diagnostic feasibility of detecting NC on cross-sectional non-contrast CT images using OCT findings as a reference standard in patients with angiographically severe coronary calcification.¹³ This non-invasive approach for detecting NC can contribute to a more sophisticated prognostic assessment and risk stratification in patients who plan to undergo PCI for severely calcified lesions. However, the prognostic impact of NC detected using pre-PCI non-contrast CT has not yet been investigated.

Therefore, the aim of the present study was to assess the prognostic significance of NC detected on pre-PCI non-contrast CT in patients with severely calcified coronary lesions.

Methods

Study Population

We retrospectively included consecutive patients with chronic coronary syndrome who underwent PCI for severely calcified lesions and non-contrast electrocardiogram-gated CT within 90 days before PCI at Kobe University Hospital and Hyogo Prefectural Harima-Himeji General Medical Center between April 2016 and March 2022. Severely calcified lesions were defined as angiographic radiopacities without cardiac motion before contrast injection on diagnostic coronary angiography.¹⁴ At these 2 hospitals, electrocardiogram-gated non-contrast CT was routinely performed to evaluate the distribution and morphology of coronary calcification before PCI in patients in whom severely calcified lesions were observed on diagnostic coronary angiography. PCI was performed using standard techniques for lesion preparation with an atherectomy device, and the choice of drug-eluting stents or drug-coated balloons was at the operator’s discretion. The exclusion criteria for this study were stent implantation in the target vessels before PCI and insufficient CT image quality.

This study’s protocol complied with the Declaration of Helsinki and was approved by the Ethics Committee of Kobe University Hospital (B210011). Informed consent was obtained in an opt-out manner on the Division of Cardiovascular Medicine website at Kobe University Graduate School of Medicine.

CT Data Acquisition and Reconstruction

All CT images were obtained using a dual-source CT scanner (SOMATOM Force; Siemens Healthcare, Forchheim, Germany) or a 16-cm z-axis coverage CT scanner (Revolution Apex CT [GE HealthCare, Chicago, IL, USA] or Aquilion ONE/ViSION Edition [Canon Medical Systems, Otawara, Japan]). The details of CT imaging acquisition and reconstruction parameters are presented in the Supplementary Table.

CT Image Analysis

All CT images were analyzed using a commercially available workstation (Ziostation2 version 2.4.2.3; Ziosoft Inc., Tokyo, Japan). During CT analysis, the window level was set to 200 Hounsfield units (HU), with a width of 2,000 HU. Calcification was identified when it had a density of >130 HU in the vessel wall in 2 independent planes. Curved multiplanar reconstruction (MPR) images were generated by tracing the target vessel’s centerline in axial images. We determined the presence or absence of NC by visually evaluating every 0.1-mm cross-sectional image created from the curved MPR images in each target lesion. The presence of NC was defined as a hyperattenuating mass protruding into the vessel center (Figure 1).¹³ Calcium volume was calculated as the sum of all calcified voxels in the target vessel.¹⁵ Mean CT attenuation values were calculated from those obtained from 3 contiguous axial images, where oval regions of interest were placed in the calcium deposit in target lesions avoiding the inclusion of the vessel lumen and perivascular structure. All CT images were analyzed by 2 independent investigation (S.I., T. Toba) who were blinded to the patients’ clinical characteristics except for target lesion location.

Figure 1.

Representative case of nodular calcification detected using non-contrast computed tomography. (A) Volume-rendering image of the whole heart. Ao, ascending aorta; LCA, left coronary artery; RA, right atrium; RCA, right coronary artery; RV, right ventricle. (B) Curved multiplanar reconstruction and cross-sectional images of the RCA (a–h); yellow arrows indicate nodular calcification.

Study Endpoints

This study’s primary outcome was the occurrence of major adverse cardiac and cerebrovascular events (MACCE), defined as a composite of all-cause death, stroke, non-fatal myocardial infarction (MI), and TLR. Secondary outcomes were individual MACCE components and cardiac death. Procedural success and periprocedural complications were also evaluated. This study’s endpoints were defined according to the Academic Research Consortium guidelines or a previously published paper.^16,17 Data on clinical events were obtained from medical records or telephone interviews.

Statistical Analysis

Continuous variables are presented as the median with interquartile range (IQR) and were compared using Student’s t-test and the Mann-Whitney U test for normally and non-normally distributed data, respectively. Categorical variables are presented as frequencies with percentages and were compared using the Chi-squared or Fisher’s exact test, as appropriate. The event-free survival rate was estimated using the Kaplan-Meier method, and between-group differences were assessed using the log-rank test. In addition, the Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the MACCE-related factors. Variables with P<0.10 in the univariate Cox hazard analysis were entered into the multivariate Cox hazards model. The discriminatory ability of each model was assessed via receiver operating characteristic curve analysis with C-index, and the reclassification performance of each model was compared using the relative integrated discrimination improvement (IDI) and category-free net reclassification index (NRI). Inter- and intra-observer agreements for the presence or absence of NC were assessed using Cohen’s kappa.

All statistical analyses were performed using Microsoft R Open software version 4.3.1 (R Development Core Team, Vienna, Austria) and IBM SPSS Statistics for Windows, version 29.0 (IBM Corp., Armonk, NY, USA). Statistical significance was set at 2-sided P<0.05.

Results

Study Participants

During the study period, 307 patients underwent PCI for severely calcified lesions with prior non-contrast CT within 90 days before PCI. After excluding patients with CT images that could not be evaluated (n=16) and those who had a stent implanted in the target vessel before PCI (n=24), 267 patients were finally enrolled in the present analysis. Of these patients, 58 (21.7%) had NC in their target lesions. Consequently, the enrolled patients were categorized into 2 groups: those with (NC group; n=58) and without (non-NC group; n=209) NC in the target lesions. Inter- and intra-observer Cohen’s kappa for the presence or absence of NC was 0.73 and 0.83, respectively.

Baseline Characteristics and Procedural Outcome

Baseline patient characteristics are presented in Table 1. The median age was 75 years, and 76.8% of participants were male. No significant differences were found in the prevalence of coronary risk factors or medications upon admission between the NC and non-NC groups. However, the history of coronary artery bypass grafting was significantly higher in the NC than non-NC group (P=0.02). Figure 2 shows NC distribution. NC was most frequent in the proximal left anterior descending artery (LAD), followed by the mid-LAD.

Table 1.

Patient Characteristics

	All patients (n=267)	NC		P value
		Yes (n=58)	No (n=209)
Age (years)	75 [67–80]	74 [65–80]	75 [68–79]	0.35
Male sex	205 (76.8)	49 (84.5)	156 (74.6)	0.12
BMI (kg/m2)	23.1 [20.9–25.5]	22.3 [20.1–25.6]	23.1 [21.2–25.5]	0.19
Hypertension	206 (77.2)	42 (72.4)	164 (78.5)	0.33
Dyslipidemia	157 (58.8)	31 (53.4)	126 (60.3)	0.35
Diabetes	142 (53.2)	30 (51.7)	112 (53.6)	0.80
Smoking	43 (16.1)	12 (20.7)	31 (14.8)	0.28
Hemodialysis	44 (16.5)	13 (22.4)	31 (14.8)	0.17
Prior MI	67 (25.1)	13 (22.4)	54 (25.8)	0.60
Prior PCI	116 (43.4)	27 (46.6)	89 (42.6)	0.59
Prior CABG	18 (6.7)	8 (13.8)	10 (4.8)	0.02
Prior stroke	26 (9.7)	3 (5.2)	23 (11.0)	0.19
PAD	45 (16.9)	11 (19.0)	34 (16.3)	0.63
LVEF (%)	53.7 [44.0–63.1]	56.2 [43.7–63.3]	53.2 [40.0–63.0]	0.64
Laboratory data
eGFR (mL/min/1.73 m2)	53.1 [33.4–70.0]	54.3 [22.3–72.6]	52.1 [35.1–70.0]	0.80
LDL-C (mg/dL)	83 [65–104]	75 [59–110]	83 [67–102]	0.23
LDL-C <70 mg/dL	86 (32.2)	25 (43.1)	61 (29.2)	0.056
HDL-C (mg/dL)	44.0 [36–52]	46 [36–53]	44 [35–52]	0.25
Triglyceride (mg/dL)	113 [83–168]	107 [84–156]	118 [82–168]	0.45
HbA1c (%)	6.4 [5.7–7.0]	6.5 [5.7–7.1]	6.3 [5.8–7.0]	0.39
Medication
Aspirin	260 (97.4)	56 (96.6)	204 (97.6)	0.66
P2Y12 inhibitor	263 (98.5)	56 (96.6)	207 (99.0)	0.17
Oral anticoagulant	45 (16.9)	12 (20.7)	33 (15.8)	0.38
Statin	224 (83.9)	48 (82.8)	176 (84.2)	0.79
Ezetimibe	43 (16.1)	12 (20.7)	31 (14.8)	0.31
β-blocker	146 (54.7)	37 (63.8)	109 (52.2)	0.12
RAS inhibitor	171 (64.0)	40 (69.0)	131 (62.7)	0.38

Unless indicated otherwise, data are given as the median [interquartile range] or n (%). BMI, body mass index; CABG, coronary artery bypass graft; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NC, nodular calcification; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; RAS, renin-angiotensin system.

Figure 2.

Distribution of nodular calcification (NC). Values show the number of NCs in given regions, with percentages given in parentheses. LAD, left anterior descending artery; LCx, left circumflex artery; LMT, left main trunk; RCA, right coronary artery.

Table 2 presents details of lesions, procedural characteristics, and CT findings in the NC and non-NC groups. There were no significant differences between the 2 groups in the target vessels, the number of implanted stents, stent diameter, or the number and size of drug-coated balloons. However, the use of rotational and orbital atherectomies was significantly higher in the NC than non-NC group (P=0.007 and P=0.005, respectively). The calcium volume upon CT inspection was significantly higher in the NC than non-NC group (P=0.005).

Table 2.

Lesion, Procedural, and CT Characteristics

	All lesions (n=267)	NC		P value
		Yes (n=58)	No (n=209)
Lesion location				0.15
LMT/LAD	171 (64.0)	31 (53.4)	140 (67.0)
LCx	33 (12.4)	10 (17.2)	23 (11.0)
RCA	63 (23.6)	17 (29.3)	46 (22.0)
Ostial RCA	5 (1.9)	2 (3.4)	3 (1.4)	0.30
Bifurcation lesions	72 (27.0)	12 (20.7)	60 (28.7)	0.22
Multivessel disease	126 (47.2)	27 (46.6)	99 (47.4)	0.91
Rotational atherectomy use	111 (41.6)	33 (56.9)	78 (37.3)	0.007
Orbital atherectomy use	42 (15.7)	16 (27.6)	26 (12.4)	0.005
Debulking device use	153 (57.3)	49 (84.5)	104 (49.8)	<0.001
Drug-eluting stent use	187 (70.0)	36 (62.1)	151 (72.2)	0.13
Stent diameter (mm)	3.0 [2.75–3.5]	3.0 [2.5–3.5]	3.0 [2.75–3.5]	0.71
Stent length (mm)	28 [22–34]	26 [22–33]	28 [22–34]	0.46
DCB use	83 (31.1)	21 (36.2)	62 (29.7)	0.34
DCB diameter (mm)	3.0 [2.5–3.5]	3.0 [2.5–3.25]	3.0 [2.5–3.5]	0.15
CT findings
CT dose index (mGy)	4.48 [2.98–8.34]	5.56 [2.98–9.02]	4.46 [2.96–8.14]	0.20
Target vessel
Calcium volume (mL)	0.55 [0.28–0.98]	0.89 [0.49–1.39]	0.50 [0.26–0.84]	<0.001
CT attenuation (HU)	765 [563–1,002]	1,015 [806–1,200]	692 [499–913]	<0.001

Unless indicated otherwise, data are given as the median [interquartile range] or n (%). CT, computed tomography; DCB, drug-coated balloon; HU, Hounsfield unit; LAD, left anterior descending artery; LCx, left circumflex artery; LMT, left main trunk; NC, nodular calcification; RCA, right coronary artery.

Procedural outcomes are presented in Table 3. The procedural success rate was 97.6%, and no significant differences in procedural complications were noted between the NC and non-NC groups.

Table 3.

Procedural Outcomes

	All patients (n=267)	NC		P value
		Yes (n=58)	No (n=209)
PCI outcome
Procedural success	261 (97.6)	57 (98.3)	204 (97.6)	0.76
Periprocedural complication
Death	0	0	0	N/A
Myocardial infarction	15 (5.6)	1 (1.7)	14 (6.7)	0.20
Stent thrombosis	0	0	0	N/A
Vascular complication and bleeding	3 (1.1)	1 (1.7)	2 (1.0)	0.52
Stroke	0	0	0	N/A
Cardiac tamponade	0	0	0	N/A
Emergency surgery	0	0	0	N/A

Unless indicated otherwise, data are expressed as n (%). N/A, not applicable. Other abbreviations as in Table 1.

Kaplan-Meier Curve Analysis for Primary and Secondary Endpoints

The median follow-up period was 2.5 years. The MACCE-free survival rate was significantly lower in the NC than non-NC group (log-rank P<0.001), with estimated 2-year MACCE-free survival rates of 64.2% and 93.1%, respectively (Figure 3A). All-cause death, cardiac death, and TLR-free survival rates were also significantly lower in the NC than non-NC group (Figure 3B–D), with estimated 2-year TLR-free survival rates of 81.4% and 96.4%, respectively. However, there was no significant difference in non-fatal MI and stroke-free survival rates between the NC and non-NC groups (Figure 3E,F), with 2-year MI-free survival rates of approximately 97.3% and 98.3%, respectively.

Figure 3.

Event-free survival curves for the primary and secondary endpoints according to the presence (+) or absence (–) of nodular calcification (NC): (A) major adverse cardiac and cerebrovascular events; (B) all-cause death; (C) cardiac death; (D) target lesion revascularization; (E) non-fatal myocardial infarction; and (F) stroke.

Regarding treatment strategy, Supplementary Figures 1 and 2 show Kaplan-Meier curves comparing groups with and without a debulking device or the use of only a drug-coated balloon. MACCE, cardiac death, and TLR-free survival rates were significantly lower in the group with than without a debulking device. Moreover, clinical outcomes did not differ significantly between groups with and without the use of only a drug-coated balloon.

Independent Factors Associated With MACCE

In the univariate Cox hazards model, hemodialysis (HR 5.44; 95% CI 2.99–9.89; P<0.001), peripheral artery disease (HR 3.76; 95% CI 2.04–6.91; P<0.001), debulking device use (HR 1.96; 95% CI, 1.02–3.74), the presence of NC (HR 5.59; 95% CI 3.07–10.2; P<0.001), and calcium volume (HR 1.68; 95% CI 1.33–2.16; P<0.001) were significantly associated with MACCE (Table 4). The multivariate Cox hazards model demonstrated that hemodialysis (HR 3.00; 95% CI 1.44–6.25; P=0.003), peripheral artery disease (HR 2.65; 95% CI 1.26–5.55; P=0.01), and the presence of NC (HR 5.25; 95% CI 2.76–9.97; P<0.001) were independently associated with MACCE (Table 4).

Table 4.

Univariate and Multivariate Cox Regression Analyses of Factors Related to Major Adverse Cardiac and Cerebrovascular Events

	Univariate		Multivariate
	HR (95% CI)	P value	HR (95% CI)	P value
Age	0.99 (0.96–1.02)	0.48
Male sex	0.57 (0.25–1.28)	0.17
Hypertension	0.72 (0.37–1.42)	0.35
Dyslipidemia	0.55 (0.30–1.00)	0.05	0.64 (0.34–1.22)	0.18
LDL-C <70 mg/dL	0.83 (0.45–1.55)	0.56
Diabetes	1.60 (0.87–2.96)	0.13
Smoking	1.44 (0.71–2.93)	0.31
Hemodialysis	5.44 (2.99–9.89)	<0.001	3.00 (1.44–6.25)	0.003
PAD	3.76 (2.04–6.91)	<0.001	2.65 (1.26–5.55)	0.01
Prior PCI	0.79 (0.43–1.44)	0.44
Prior CABG	1.87 (0.66–5.27)	0.24
LVEF	0.98 (0.96–1.01)	0.13
Ostial RCA lesion	1.29 (0.18–14.8)	0.80
Debulking device use	1.96 (1.02–3.74)	0.04	0.98 (0.50–1.95)	0.96
DCB-only use	1.39 (0.74–2.63)	0.30
NC	5.59 (3.07–10.2)	<0.001	5.25 (2.76–9.97)	<0.001
Calcium volume (target vessel)	1.68 (1.33–2.16)	<0.001	1.08 (0.83–1.42)	0.57
CT attenuation (target lesion)	1.00 (0.99–1.00)	0.35

CI, confidence interval; HR, hazard ratio. Other abbreviations as in Tables 1,2.

Discriminatory Ability and Reclassification Performance of NC

We constructed 3 prediction models to determine the incremental discriminatory and reclassification performance of the CT findings. Figure 4 shows Harrell’s C-index, NRI, and relative IDI values for the 3 models. Compared with Model 1 (age, sex, dyslipidemia, diabetes, and hypertension), Model 2 (Model 1 variables plus hemodialysis and peripheral artery disease) had a significantly higher discriminatory ability (C-index, 0.66 vs. 0.74; P=0.04) and reclassification ability (NRI, 0.73; P<0.001; relative IDI, 0.12; P<0.001) in identifying patients with MACCE. Furthermore, compared with Model 2, Model 3 (Model 2 variables plus NC) showed a significantly higher discriminatory ability (C-index, 0.74 vs. 0.82; P<0.001) and reclassification ability (NRI, 0.79; P<0.001; relative IDI, 0.11; P<0.001) in identifying patients with MACCE.

Figure 4.

Discriminatory and reclassification abilities of predictive models for major adverse cardiac and cerebrovascular events. IDI, integrated discrimination improvement; NC, nodular calcification; NRI, net reclassification improvement.

Discussion

The major findings of the present study are that: (1) the prevalence of CT-detected NC in lesions with angiographically severe coronary calcification was 21.7%; (2) freedom from MACCE, all-cause death, cardiac death, and TLR rates were significantly lower in patients with than without NC; (3) upon multivariate analysis, the presence of NC, in addition to hemodialysis and peripheral artery disease, was independently and significantly associated with MACCE; and (4) the presence of NC had significantly higher discriminatory and reclassification abilities than other factors in the prediction model for MACCE. To the best of our knowledge, this study is the first to demonstrate the clinical significance of NC detected using preprocedural non-contrast CT in patients who underwent PCI for severely calcified coronary lesions.

Morphological Assessment of Coronary Artery Calcification Using CT

Previous reports have underscored the feasibility of using coronary CT in the morphological assessment of cross-sectional images of coronary calcification. Sekimoto et al. reported that classifying calcium severity based on the calcium angle, determined using enhanced coronary CT, contributed to a better prediction of the need for rotational atherectomy.¹⁸ Moreover, an expert consensus document from the Society of Cardiovascular Computed Tomography indicated that evaluating the presence and extent of coronary calcification using coronary CT angiography is important in the decision to use an atherectomy device.¹⁹

We used non-contrast CT rather than enhanced CT for the morphological assessment of coronary calcium. Previous studies reported on the clinical implications of using non-contrast CT for the morphological assessment of coronary calcium with cross-sectional images. Foldyna et al. demonstrated that, in 1,330 Framingham Heart Study participants with coronary calcification, the morphology of coronary calcification (spherical shape and pericardial-sided location), evaluated using cross-sectional non-contrast CT images, was associated with fewer cardiovascular events.²⁰ Previously, we assessed the correspondence between the maximum calcium angle and the presence of NC on non-contrast CT and OCT findings in 496 cross-sectional images from 16 LAD lesions.¹³ In that study, the Pearson correlation coefficient between CT- and OCT-derived maximum calcium angle was 0.92, and the sensitivity and specificity of non-contrast CT for identifying NC was 73.3% and 97.5%, respectively. Moreover, in the present study, inter- and intra-observer Cohen’s kappa for detecting NC was 0.73 and 0.83, respectively, demonstrating acceptable diagnostic accuracy of NC with non-contrast CT.

Non-contrast CT has several advantages over enhanced CT. First, with non-contrast CT, the morphological assessment of coronary calcium can be performed without incurring the risk of contrast-induced nephropathy. This is important because patients with severe coronary calcification tend to have more severe renal impairment than those without.²¹ Second, non-contrast CT provides a clearer cross-sectional image of coronary calcium than enhanced CT because the use of contrast medium occasionally results in an inability to differentiate between luminal contrast and coronary artery calcification when they are characterized by a similar attenuation. Finally, non-contrast CT is more accessible than enhanced CT because it is broadly used as a screening tool and prognostic indicator for coronary artery disease in almost all general hospitals.

Prevalence and Distribution of NC in Severely Calcified Lesions

The prevalence of NC varies widely among different studies, even among patients with severe coronary calcification. Morofuji et al. reported that NC was detected using intravascular ultrasound in 48.5% of patients who underwent rotational atherectomy for severely calcified lesions,⁶ whereas Okamura et al. reported that NC was detected on OCT in 59.2% of patients with end-stage renal disease who underwent PCI.²² In the present study, CT detected NC in 21.7% of patients with angiographically severe calcified lesions, which is lower than the prevalence reported previously. This discrepancy may be due to differences in the study populations. In the present study, the degree of coronary calcification was relatively low because we only included patients with angiographically severe calcified lesions. In addition, debulking devices (rotational or orbital atherectomy devices) were used in only 57.3% of patients, and only 16.5% of patients underwent hemodialysis.

Another possible explanation for the apparent discrepancy is the difference in the imaging modalities used in the different studies. Intravascular imaging modalities are known to more accurately detect NC, consequently contributing to a higher prevalence of NC than non-contrast CT due to the inherently higher spatial resolution in intravascular imaging modalities. In a previous study, we indicated that the sensitivity for detecting NC in CT analysis using OCT as a reference standard was only 73.3%,¹³ suggesting that non-contrast CT tends to underestimate the presence of NC. However, in the present study we showed that the detection of NC with non-contrast CT can non-invasively stratify patient prognoses using preprocedural individual CT data. Recently, a new-generation CT scanner (photon-counting CT) has been used in daily practice and shown to reduce blooming artifacts and beam-hardening effects with low radiation exposure, consequently providing more distinct images of calcium deposits.^23,24 Therefore, the diagnostic ability of non-contrast CT for NC could be improved using this new CT technology.

In the present study, NC was more frequently observed in the proximal and mid-LAD than in the left circumflex and right coronary artery. Another observational study reported that NC most frequently developed in the distal left main bifurcation and proximal LAD,²⁵ which is consistent with our results. Meanwhile, a pathological report demonstrated that approximately half of all calcified nodules were found in the mid-right coronary artery in 25 cases of sudden cardiac death.²⁶ These findings imply that the distribution of NC varies depending on the study population and methodology. Although the pathological study investigated all 3 coronary arteries on a cross-sectional basis, we evaluated only target lesions, 65.2% of which were in the LAD or left main trunk.

Prognostic Impact of CT-Detected NC

The results of this study indicate that patients with CT-detected NC have unfavorable outcomes, particularly in revascularization after PCI, which corresponds to the results of other clinical studies using intravascular ultrasound or OCT.^6,7,21,22 In fact, the TLR-free survival rate was significantly lower in the NC than non-NC group, and time-to-event curve analysis showed that the TLR-free survival rate in the NC group was estimated to be 81.4% at the 2-year follow-up. A previous study on 236 patients in whom NC was detected on pre-PCI OCT images reported that the cumulative incidence of TLR at the 2-year follow-up was 14.3%.⁹ Another study reported that, in patients who underwent intravascular ultrasound-guided PCI with rotational atherectomy for severely calcified coronary lesions, the cumulative incidence of clinically driven TLR at the 2-year follow-up was 20.8% in the calcified nodule group.⁶ Our findings are consistent with the results reported in these previous studies.

The freedom from all-cause death and cardiac death rates were significantly lower in the NC than non-NC group, which aligns with the findings of previous studies.^6,27 The underlying mechanisms for the worse prognostic outcome of NC are not well understood. One of the possible explanations for this is that patients with NC have more comorbidity, including severe chronic kidney disease, requiring maintenance hemodialysis, which subsequently leads to poor prognosis. Several recent studies have reported that OCT-detected eruptive calcified nodules are more significantly associated with cardiac mortality than non-eruptive nodules, which may be more strongly linked to fatal coronary events.^7,9 We speculate that a higher prevalence of eruptive NC may be observed in our study. However, CT cannot differentiate between these subtypes due to its inherent limitations in spatial resolution. We expect that spectral imaging with photon-counting CT could overcome this limitation.

Although the freedom from all-cause death, cardiac death, and TLR rates were significantly lower in the NC than non-NC group, the freedom from non-fatal MI rate was relatively high and similar between the 2 groups. Prati et al. revealed that the presence of NC was not associated with a greater number of anterior MIs at the 1-year follow-up in 1,003 consecutive patients undergoing proximal LAD segment assessment using OCT.⁷ Matsuhiro et al. revealed no significant differences in the cumulative incidence of target vessel MI between lesions with OCT-detected NC and those without NC in 114 patients on hemodialysis who underwent elective drug-eluting stent implantation.²⁸ These findings suggest that the presence of NC in the target lesions is necessarily related to acute thrombotic coronary events. In the present study, 31.1% of the study population was also treated with a drug-coated balloon. Several previous studies have reported that patients who underwent drug-coated balloon treatment for de novo coronary stenotic lesions never experienced MI over the course of a 1- or 2-year follow-up.^29,30 These results suggest that the use of a drug-coated balloon contributes to the prevention of stent thrombosis, and therefore may have lowered the incidence of MI in both groups in the present study.

Several clinical studies have revealed that the treatment strategy is strongly affected by periprocedural and clinical outcomes in PCI for severely calcified lesions.^31–33 Abdel-Wahab et al. reported that the use of rotational atherectomy before stent implantation was more feasible and effective than the balloon-only strategy, with a high rate of procedural success and a low incidence of TLR and major adverse cardiac events in 205 patients with heavily calcified de novo lesions.³³ Some reviews and consensus documents noted that choosing an optimal debulking device is required to mitigate periprocedural complication risk and improve long-term outcomes.^34–36 In the present study, the use of a debulking device was significantly associated with a higher cumulative incidence of MACCE, all-cause death, cardiac death, and TLR (Supplementary Figure 1). Meanwhile, in the multivariate Cox hazard model, the use of a debulking device was not independently associated with MACCE. Although this is speculative, these findings imply that more malignant calcified lesions, including eruptive calcified nodules, are more frequently treated with debulking devices, subsequently contributing to poor clinical outcomes in the present study. Recently, intravascular lithotripsy has become commercially available in our daily practice. Although several clinical studies have demonstrated that intravascular lithotripsy facilitates safe and effective PCI in heavily calcified lesions, including NC,^37,38 its long-term clinical outcome remains unknown. More innovative treatment technology to overcome severely calcified lesions with NC is expected in the future.

Importance of Qualitative Assessment of Coronary Artery Calcification With Non-Contrast CT

Non-contrast CT-detected NC, hemodialysis, and peripheral artery disease were all independent predictors of MACCE, whereas the absolute calcium volume of the target vessel was not. Recent guidelines emphasize the importance of coronary calcium scoring, calculated using non-contrast CT findings, in assessing the risk of atherosclerotic cardiovascular disease for initiating or prolonging preventive pharmacotherapies.^10,12 Various clinical studies have also demonstrated that patient prognoses worsen as the coronary calcium score increases.^39,40 The present study indicates that the prognostic role of quantitatively evaluating coronary calcification is limited in patients with a certain amount of coronary calcium who require coronary revascularization. Iwai et al. demonstrated that in 251 patients with moderate-to-severe coronary artery calcification who underwent OCT-guided drug-eluting stent implantation, the presence of calcified nodules was an independent predictor of major adverse coronary events, whereas the quantity of calcification was not.⁴¹ These results align with our findings. Therefore, we hypothesize that assessing non-contrast CT-detected NC could be clinically useful for guiding decisions regarding PCI deferral. Given the effectiveness of contemporary optical medical therapy, including lifestyle and risk factor modification, for preventing cardiovascular events, as highlighted in the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches,⁴² it may be advisable to avoid performing PCI in patients with chronic coronary syndrome and severe coronary calcification when NC is detected using non-contrast CT. However, further prospective and large-scale studies on the clinical utility of non-contrast CT-detected NC are required to verify our hypothesis.

Study Limitations

The present study has some limitations. First, this was a retrospective study with a small number of patients. Therefore, we cannot completely exclude the possibility of selection bias. Second, some patients (n=16) were excluded due to insufficient CT image quality. Third, the diagnostic utility of NC based on visual assessment with non-contrast CT has not been fully established. However, a previous study demonstrated that this is feasible,¹² and we found acceptable intra- and interobserver agreements for this assessment in the present study. Fourth, various types of CT scanners and scanning protocols were used in this study, which may have contributed to difference in the diagnostic accuracy of the presence of NC. However, we cannot verify this because the present study does not have a sufficient sample size. Finally, we enrolled only patients with angiographically severe calcified lesions requiring PCI, limiting the generalizability of our findings to other populations.

Conclusions

We found that NC detected on non-contrast CT was independently associated with MACCE. In addition, evaluating the presence or absence of NC using non-contrast CT could be useful in predicting clinical outcomes after PCI. However, further studies are warranted to confirm our results.

Acknowledgments

The authors are grateful to Hiromi Hashimura (Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Japan), Kazuki Ishikawa (Division of Radiology and Radiation Oncology, Kobe University Hospital, Kobe, Japan), and Tomohiro Inoue (Division of Cardiovascular Medicine, Hyogo Prefectural Harima-Himeji General Medical Center, Hyogo, Japan) for reviewing our manuscript. The authors thank their other colleagues at Kobe University Hospital and Hyogo Prefectural Harima-Himeji General Medical Center for their cooperation with this study.

Sources of Funding

This research has received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Disclosures

K. Hirata and H. Otake are members of Circulation Journal’s Editorial Team. The remaining authors have no conflicts of interest to declare.

IRB Information

The study protocol was approved by the Ethics Committee of Kobe University Hospital (B210011).

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0644

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