Relationship between Coronary Artery Calcium Score and Coronary Stenosis

Background The coronary artery calcium score (CACS) is commonly employed to quantify the degree of calcification in coronary atherosclerosis. Indeed, increased coronary stenosis severity is associated with a progressive increase in CACS. Objectives This study sought to explore the association between CACS and coronary stenosis of ≥50% and ≥70%. Methods We conducted a retrospective analysis of patient data collected between July 1, 2017, and March 3, 2022, at Jiangmen Central Hospital. A total of 208 patients, presenting with both symptomatic and asymptomatic manifestations and suspected coronary artery disease (CAD), were included. Statistical analyses included ROC curve assessments, subgroup analyses based on age, and comparisons of CACS values against the presence of coronary stenosis ≥50% and ≥70%. Results Ultimately, 208 patients were included, with a median age of 65.0 years and a median CACS of 115.7 (interquartile range: 13.7–369.4). A CACS threshold of ≥1300 demonstrated a specificity of 100% for coronary stenosis of ≥50%. Notably, the percentage of patients with obstructive CAD showing CACS = 0 was significantly higher in those under 65 years (15.1%) compared to patients over 65 years (3.8%) (P=0.005). The inflection point, at which the risk probability for coronary stenosis of ≥50% shifted from being a protective factor to a risk factor, was observed when CACS fell within the range of 63.3 to 66.0. Conclusion CACS demonstrates good performance for the detection of coronary artery stenosis.


Introduction
It is well established that atherosclerotic cardiovascular disease (ASCVD) exhibits a high prevalence and mortality rate globally.In China, a total of 2.4 million deaths were attributed to ASCVD alone in 2016, accounting for approximately 25 percent of all mortality cases.Coronary calcifcation is a component of atherosclerosis [1].For asymptomatic patients, if a patient presents with multiple risk factors, such age, family history, smoking, diabetes, hypertension, and abnormal lipid levels, healthcare providers may consider CCTA as a noninvasive imaging modality to assess the health of the coronary arteries [2].
Te past few years have witnessed the advent of the coronary artery calcium score (CACS) to quantify coronary calcifcation and predict the presence of coronary artery stenosis [3].Indeed, the severity of stenosis is increased with an increase in CACS [4].Te prognostic outcome can be predicted by CACS with a deterioration in prognosis corresponding to an increase in CACS [5].It has been reported that the 10-year event rates of CACS values of 0, >100, and >300 were 5.6%, 7.5%, and 13.1%, respectively.
Current guidelines for coronary artery revascularization defne signifcant stenosis as non-left main disease diameter stenosis ≥70% and left main stenosis ≥50% [6].Palumbo et al. suggested the use of CACS as a preliminary screening tool for coronary computed tomography angiography (CCTA) [7].Alshumrani employed various cutof values of CACS to assess coronary stenosis ≥50% and ≥70%, revealing that all symptomatic patients had coronary stenosis ≥50% when CACS was ≥250 [4].However, it is worth noting that this previous study did not employ coronary angiography (CAG) as a criterion for evaluating the severity of coronary stenosis.It should be acknowledged that high cutof values for CACS may lead to an overestimation of the extent of coronary stenosis [8].Te present study employed CAG for diagnosing coronary stenosis, encompassing both symptomatic and asymptomatic patients with suspected CAD.Te objectives of this study were as follows: (1) To assess the diagnostic value of CACS for coronary artery stenosis ≥50% and 70%.(2) To investigate the impact of age on CACS-based diagnosis of coronary stenosis.(3) To analyze the relationship between CACS and the risk probability of coronary stenosis ≥50% and 70% using restricted cubic spline (RCS).
1.1.Patient Data.Tis study was approved by the Ethics Committee of Jiangmen Central Hospital ([2022]56).Informed consent was not required, given that anonymous patient data was used in the study.Tis retrospective study focused on patients who underwent CCTA and subsequent CAG at Jiangmen Central Hospital between July 1, 2017, and March 3, 2022.Te study population consisted of patients presenting with either symptomatic or asymptomatic manifestations but exhibiting suspected CAD.Te observed symptoms encompassed angina, dyspnea, syncope, or palpitation.Exclusion criteria are as follows: Patients who had undergone percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery prior to CCTA or lacked CACS data were excluded from the study.Baseline clinical data were collected, including demographic characteristics, nutritional status, past medical and surgical history, laboratory tests, CACS, and CAG results.Comorbidities such as diabetes mellitus and hypertension were defned using the International Classifcation of Diseases, 10th revision diagnostic codes.All CCTA were assessed by an experienced radiologist who was blinded to the results of CAG.CAG and severity of coronary stenosis were performed and evaluated by an experienced cardiologist who was blinded to the CCTA results.

Computed Tomography. Te Siemens Somatom Dual
Source Force Computed Tomography was employed for the examinations.Te procedure began with a localization phase acquisition, which was followed by a scan to determine the coronary artery calcifcation score.To enhance imaging quality, nonionic contrast media was intravenously administered via the cubital vein prior to the CT scanning.Te scan covered the area from the tracheal bifurcation down to 2 cm below the left diaphragm, with a slice thickness of 0.625 mm.One of the advantages of Siemens Somatom Dual Source Force CT is that it circumvents the need for prescan heart rate control with beta-blockers, producing highquality images, even in patients with elevated or irregular heart rates.Te raw data from the scans are transferred to imaging workstations, allowing for postprocessing techniques such as multiplanar reconstruction, maximum density projection, and 3D volume reproduction.Te CACS was determined using Agatston's algorithm.
1.3.Coronary Angiography.Te cardiologist, who was blinded to the CCTA results, performed a right radial artery puncture using Seldinger's technique and inserted a 6Fr sheath.Heparin (3000 μ) was administered prior to conducting left and right coronary angiography with a 6Fr Heartrail angiography catheter.Subsequently, the severity of stenosis in the left main coronary artery (LM), left anterior descending artery (LAD), left circumfex artery (LCX), and right coronary artery (RCA) was evaluated.
1.4.Statistical Analysis.Te data analyses were performed using the R software.Te study population characteristics were presented as mean ± SD (standard deviation) for continuous variables, while categorical variables were expressed in percentages.Continuous variables that were not normally distributed were expressed using the median and interquartile range.Diferences in categorical variables were assessed using a Chi-square test.Te Pearson test was employed to assess the correlation between continuous variables following a normal distribution, while Spearman's correlation was utilized for examining the correlation among continuous variables with non-normal distribution characteristics.A receiver operating characteristic curves (ROC) curve analysis was performed, including calculations of specifcity, sensitivity, positive predictive value (PPV), negative predictive value (NPV), and area under the ROC curve (AUC) for CACS predicting coronary stenosis and was used to identify the best cutof point by the Youden index.A generalized additive model was used to analyze the relationship between CACS and coronary stenosis.RCS was employed to investigate the functional form of this association.Te signifcance level was set at a two-sided P value threshold of <0.05.Te diference in the area under the curve was evaluated and tested using the test method proposed by Hanley and McNeil.Te severity of coronary stenosis is evaluated using CAG as a reference standard.

Patient Characteristics.
Te present study included a total of 208 patients exhibiting male predominance (n � 138, 66.3%) who presented symptomatically or asymptomatically with suspected CAD.Te age of the entire patient cohort ranged from 33 to 89 years, with a median age of 65.0 years (interquartile range: 58-71 years).Te median time interval between CCTA and CAG was 6 days (non-normal distribution, interquartile range 3-20 days).Te median duration between CCTA and serum calcium measurements was 4 days (non-normal distribution, interquartile range 2-7 days).Te median age of patients with coronary stenosis ≥50% and ≥70% was 66.0 (60.3-70.0)and 65.0 (57.8-71.0)years, respectively, with no signifcant diference between the two groups (P � 0.87).Among the cohort of 208 patients, the median CACS was 115.7, ranging from 0 to 2243.6, and the interquartile range was 13.7-369.4(Table 1).

Association between CACS and the Risk Probability of Coronary Stenosis.
After adjusting for body mass index (BMI), hemoglobin (Hb), N-terminal pro-B-type natriuretic peptide (NTproBNP), estimated glomerular fltration rate (eGFR), high-density lipoprotein cholesterol (HDL), lowdensity lipoprotein cholesterol (LDL), triglyceride (TG), cardiac troponin-I (TnI), ejection fraction (EF), systolic blood pressure, diastolic blood pressure, heart rate, total cholesterol, calcium, history of smoking, diabetes mellitus, and hypertension, RCS was used to analyze the association between CACS and the risk probability of coronary stenosis ≥50% and 70%.After adjusting for multiple variables, the cubic spline model showed nonlinear associations between CACS and the risk probability of coronary stenosis ≥50% (P for nonlinear associations = 0.002) (Figure 2).CACS and the risk probability of coronary stenosis ≥70% exhibited a linear correlation (total P � 0.0172, P for nonlinear associations = 0.189) (Figure 3).Te infection point in the risk probability of coronary stenosis of ≥50% was observed within a CACS range of 63.3-66.0(Figure 2).Beyond this range, a substantial escalation in risk was observed, peaking at 230.8; thereafter, the risk stabilized.In subgroup analyses stratifed by age (≤65 years or >65 years), no signifcant association between CACS and the occurrence of coronary stenosis was found (coronary stenosis ≥50%, P � 0.975; coronary stenosis ≥70%, P � 0.618).

Discussion
Tis study evaluated multiple CACS cutof values for diagnosing coronary stenosis and investigated the association between CACS and the presence of coronary stenosis.CAG High CACS cutof values demonstrated high specifcity and PPV for the diagnosis of coronary stenosis ≥50% and ≥70%.In this respect, de Agustin et al. showed that the specifcity and PPV for detecting coronary stenosis ≥70% in patients presenting with chest pain and CACS ≥400 were 93.5% and 85.8%, respectively [9].Accordingly, it is recommended that patients experiencing chest pain and having CACS of ≥400 should refrain from undergoing CCTA.Consistently, our study demonstrated a high PPV of 95.7% for detecting coronary stenosis ≥50% when CACS ≥400.Besides, CACS ≥1300 yielded good specifcity and a positive predictive value of 100% for diagnosing coronary  Such patients can make an informed decision about foregoing CCTA and instead choose early percutaneous coronary revascularization based on their preferences regarding invasive procedures.Kiani et al. showed that age exerts an impact on the optimal cutof value [10,11].Durhan et al. conducted a ROC curve analysis to assess the predictive ability of CACS for coronary artery stenosis across diferent age groups, revealing that patients aged 50-59 exhibited a signifcantly higher AUC than other age groups [12].However, the above studies failed to consider whether the diferences were statistically signifcant.In the present study, the diagnostic value of CACS in coronary stenosis in the two age groups was assessed by ROC curve analysis.However, the diference in performance of CACS in predicting coronary stenosis ≥50% in patients aged ≤65 years and >65 years was not statistically signifcant.During subgroup analyses based on age, there was no signifcant association between CACS and the occurrence of coronary stenosis.
A CACS � 0 does not defnitively rule out the presence of coronary stenosis of ≥50% or ≥70%, especially in younger patients.Previous studies have shown that among patients with CACS � 0, a range of 1.5% to 8.3% displayed coronary stenosis of ≥50%, and 1.4% presented with coronary stenosis of ≥70% [13][14][15][16][17]. Feuchtner et al. found that 12.5% of young adults aged 35-49 years with CACS � 0 had coronary stenosis ≥50% [18].In our study, among patients with CACS � 0, 50.0%exhibited coronary stenosis of ≥50%, while 31.3% had coronary stenosis of ≥70%.Terefore, it can be concluded that coronary stenosis of ≥50% or ≥70% cannot be completely excluded when CACS � 0 in patients with symptomatic or asymptomatic CAD.Tere are several possible explanations for this phenomenon.First of all, CCTA categorizes plaques based on the presence or absence of calcifed components, distinguishing between calcifed, mixed calcifed, and noncalcifed plaques.However, CACS cannot visualize coronary stenosis caused by noncalcifed plaque.In patients with CACS � 0, most plaques were predominantly noncalcifed [19].Kelly et al. found noncalcifed plaque in 10 of 12 patients with a CACS of zero and coronary stenosis of ≥50% [20].Besides, it should be borne in mind that the early stages of coronary atherosclerosis do not exhibit any calcifcation.Tese results suggest that CCTA or CAG should still be considered to identify coronary stenosis of ≥50% in young patients.Interestingly, Konieczyńska et al. found that women with a CACS of zero demonstrated an NPV of 100% for the presence of coronary stenosis, suggesting that coronary stenosis can be ruled out in symptomatic female patients when their CACS is zero [11,21].However, in our study, the infuence of gender on the exclusion of coronary stenosis of ≥70% with a CACS of zero remained uncertain due to the male predominance of our study population.Additional research with a larger sample size is warranted to clarify this aspect.
Age is an infuential factor in excluding coronary stenosis ≥50% when the CACS is zero [22,23].A higher proportion of patients aged ≤65 years with both coronary stenosis ≥50% and CACS � 0 was observed compared to those aged >65 years.Te fndings of this study align with those reported by Mortensen et al., which showed that among the fve age groups of patients with coronary stenosis ≥50%, the proportions of patients with a CACS of zero were 58% for individuals under 40 years, 34% for those aged 40 to 49 years, 18% for those aged 50 to 59 years, 9% for those aged 60 to 69 years, and fnally, only 5% for individuals over the age of 70 years, consistent with Albuquerque et al.'s study [22,23].Te exclusion of coronary stenosis ≥50% using CACS � 0 should be approached with caution in young patients, as its value decreases with decreasing age.
Te infection point for the risk probability of coronary stenosis ≥50% was observed within a CACS range of 63.3-66.0.Te risk probability exhibited a signifcant increase after the infection point, reaching its peak at 230.8, and subsequently stabilized.When the CACS ranged from 66 to 230.8, there was a progressive increase in the risk probability of coronary stenosis ≥50%.Te risk probability of developing coronary stenosis ≥50% remained consistent as the CACS increased beyond 230.8.Previous studies have indicated a positive correlation between higher CACS and an increased likelihood of coronary stenosis [24][25][26].Tis study further suggested that a CACS of 63.6-66 is an   infection point for coronary stenosis ≥50%.Clinicians should be cautious of coronary stenosis when CACS exceeds this threshold.CACS <63.6 serves as a protective factor against coronary stenosis ≥50%, and further investigation is required to understand its mechanism.
Te assessment of coronary stenosis may exhibit some diferences between CAG and CCTA.Tis variation depends on factors such as the patient population, operator experience, and technological nuances [27,28].We need to carefully consider these factors for a more accurate evaluation of coronary artery health.
Limitations of the analysis include the following: (1) Tis retrospective study included patients who had indications for CAG, potentially introducing selection bias.(2) Te sample size in this study was limited.(3) Tis study did not further investigate the relationship between vascular-based CACS, the degree of stenosis, and the nature of plaques.Indeed, the total CACS does not ofer a distinct evaluation of calcifcation in individual coronary vessels and is unable to detect noncalcifed plaques.

Conclusions
Te utilization of CACS is benefcial in detecting coronary artery stenosis.High CACS cutof values exhibit high specifcity and PPV in the diagnosis of coronary stenosis ≥50% and ≥70%.Te presence of CACS � 0 does not consistently exclude the possibility of coronary stenosis ≥50% or ≥70%, especially in young patients.Te infection point for risk probability of coronary stenosis ≥50% shifts from being a protective factor to a risk factor is observed within the CACS range of 63.3 to 66.0.

Figure 2 :
Figure 2: Multivariable-adjusted cubic spline model for the association between CACS and risk probability for coronary stenosis ≥50%.

Figure 3 :
Figure 3: Multivariable-adjusted cubic spline model for the association between CACS and risk probability for coronary stenosis ≥70%.

Table 1 :
Clinical characteristics of the study population.
particularly in younger patients.Te point of transition in the risk probability of coronary stenosis of ≥50% shifted from being a protective factor to a risk factor when CACS fell within the range of 63.3 to 66.0.In subgroup analyses stratifed by age, no signifcant association between CACS and the occurrence of coronary stenosis was found.