Summary
Coronary artery anomalies are observed in approximately 2% of the population and have a high variability. Clinically they may be asymptomatic or there are anomalies that may lead to infarction or sudden death. Especially coronary artery anomalies such as origin from the pulmonary artery and interarterial course of coronary arteries of abnormal origin may cause sudden death. Multislice computed tomography, and coronary angiography can detect coronary artery anomalies with high sensitivity.
Introduction
The prevalence of coronary artery anomalies is rare in the population. In angiographic studies, the incidence ranges from 0.6% to 5.64% [1, 2], and, clinically, most patients are asymptomatic. Although the prognosis of coronary artery anomalies is generally good, some patients suffer from angina, dyspnea, syncope, ischemic heart disease, heart failure, ventricular arrhythmias, cerebrovascular accident, and even sudden death [3–6]. The latter is often associated with young individuals engaged in sporting activity [7].
Coronary anomalies (CAs) are mostly detected incidentally during autopsy, conventional coronary angiography (CCA) or through coronary computed tomography angiography (CCTA). While CCA is the gold standard technique for imaging coronary arteries, it is an invasive method, and imaging some complex CAs via CCA can be challenging. In such cases, CCTA is a more suitable method, especially in course anomalies [8].
Aim
This study evaluated follow-up data from a single tertiary care center to determine the prevalence of CAs and their effect on major cardiovascular events.
Material and methods
Between January 2015 and January 2023, 3095 consecutive patients who had undergone CCTA (age 18–90 years) were retrospectively enrolled. CCTA cases were excluded if they involved coronary artery disease (CAD), assessment of coronary artery grafts or stents, or evaluation of congenital heart disease. Exclusion criteria were: a history of allergies to iodinated contrast material, impaired renal function defined with an estimated glomerular filtration rate of < 45 ml/min/1.73 m2, diagnosed acute coronary syndrome, having been previously diagnosed with coronary artery anomalies, or pregnancy. As 78 patients were excluded from the study due to the inability to interpret images, the study included 3017 patients. The study is summarized in Figure 1.
The classification method was used according to Angelini’s descriptions [9]. Myocardial bridges (MB) were excluded from the category of coronary anomalies because of the lack of clarity regarding their definition: some authors considered MB to be a normal variant, whereas others considered it to be an anomaly [10–12]. Some types of CAs were represented in the central illustration of the study (Figure 2).
Figure 2
Central illustration of the study. The following schematic representation depicts the principal categories of anomalous coronary arteries. A – Anomalous origin from the opposite aortic sinus, B – coronary aneurysms, C – congenital atresia of LMCA, and D – anomalous origin from the pulmonary artery
AV – aortic valve, LAD – left anterior descending artery, LCC – left coronary cusp, LMCA – left main coronary artery, NCC – non-coronary cusp, PV – pulmonary valve, RCA – right coronary artery, RCC – right coronary cusp.
After CA had been determined, the patients were divided into two groups. Group 1 consisted of patients without CAs, while Group 2 consisted of patients with CAs. All patients were followed up, and follow-up symptom status was collected through a review of electronic medical records. Moreover, the results of cardiac testing were recorded via electronic medical records. Elective coronary intervention, acute coronary syndromes (ACS), and cerebrovascular events (CVE) were defined as major cardiovascular events (MACE).
Patients with significant coronary artery disease detected after CCTA underwent elective coronary angiography. According to the 2018 ESC/EACTS Guidelines on myocardial revascularization, the need for elective percutaneous coronary artery intervention was decided [13]. In patients who underwent elective coronary angiography due to clinical need during the follow-up period, elective percutaneous coronary artery intervention was performed, and was also defined as MACE. The mortality and MACE were recorded via the national medication report. Diagnosis of ACS was made according to the diagnostic criteria of the ESC for the management of ACS guidelines, published in 2023 [14]. CVE was defined as obstruction within a blood vessel supplying blood to the brain with imaging evidence, by either magnetic resonance imaging (MRI), or computed tomography (CT) scans, and a new neurologic deficit which lasted for at least 24 h [15].
Scan protocol and image acquisition
CCTA studies were performed using a 320-row CT scanner (Aquilion ONE, Toshiba Medical Systems, Otawara, Japan) with a gantry rotation time of 350 ms and a minimum temporal resolution of 175 ms. Metoprolol was administered orally (50–100 mg depending on heart rate) 1 h before CCTA acquisition to patients with a heart rate of > 65 beats per minute (bpm), unless contraindicated. The scanning technique was performed according to the patient’s heart rate.
Tube voltage and tube current depended on the body mass index (BMI) of the patients. Tube voltage was 100 kV (BMI < 23 kg/m2), 120 kV (BMI 23–34 kg/m2) or 135 kV (BMI > 35 kg/m2) and tube current was 320–580 mA. A total of 60–80 ml of non-ionic contrast agent (Iohexol, Omnipaque 350 mgI/ml, GE Healthcare Milwaukee, WI) was injected into the antecubital vein. A triphasic injection protocol of contrast agent was used. The initial step was for 50–70 ml of contrast agent to be injected at an injection rate of 5–6 ml/s, followed by 20 ml of 50% contrast/saline with the same injection rate. Subsequently, a saline chaser of 25 ml was injected at a flow rate of 3 ml/s. The scanning delay was determined with a bolus tracking technique by placing the region of interest (ROI) into the ascending aorta and setting the trigger threshold to 180 Hounsfield units (HU). All images were acquired during an inspiratory breath-hold of approximately 5 s. The raw data set was reconstructed at 75% of the R-R interval, with a slice thickness of 0.5 mm, and an interval of 0.25 mm, by using an iterative reconstruction algorithm. For processing and evaluation, images were transferred to a remote workstation with dedicated CCTA analysis software (Vitrea version 6.4, Vital Images, USA).
CCTA image analysis was performed by two radiologists in consensus, experienced in the assessment of CCTA. Data sets considered to be of poor image quality were excluded from this study.
Coronary arteries were assessed for atherosclerotic disease, anomalous origins, courses, and terminations. For the evaluation of coronary artery anomalies, all CCTA images were first reviewed in axial projection, then with different post-processing tools such as multiplanar reconstruction, curved multiplanar reconstruction, thin-slab maximum-intensity projection and volume rendered technique. Segments were classified according to the American Heart Association scheme [16].
Statistical analysis
The statistical analysis of data was conducted using IBM SPSS Statistics 22.0 for Windows, (IBM Corp, Armonk, NY, USA). Normality of data distribution was assessed using the Kolmogorov-Smirnov test. Data with a normal distribution were expressed as the mean ± standard deviation, while those with a non-normal distribution were expressed as the median (25–75% percentile). The Mann-Whitney U test and Student’s t-test were used to compare continuous variables. Categorical variables were shown as numbers and percentage values and were analyzed with the χ2 test. A survival plot of the effect of CAs on mortality and MACE in Group 2 was made by Kaplan-Meier analysis. A p-value of < 0.05 was considered statistically significant.
Results
This study consisted of 3017 patients, and 60 (2%) cases had CA among these patients (Group 2), with Group 1 consisting of 2957 patients. The median follow-up time was 56 months (28–76 months). The maximum follow-up time was 98 months and the minimum follow-up time was 2 months. Clinical and demographic parameters are summarized in Table I. The groups were similar in terms of history of chronic diseases such as cerebrovascular accident, congestive heart failure, coronary artery disease, diabetes mellitus, dyslipidemia, and, hypertension (respectively p = 0.68, 0.58, 0.96, 0.38, 0.89, and 0.98). Demographic characteristics such as gender, age, and smoking status were similar in both groups. (respectively p = 0.47, 0.58, and 0.38). The groups were compared in terms of clinical presentation, with syncope and palpitations found to be more common in Group 2 (p = 0.008 and 0.004 respectively). There were similar results in the groups for chest pain and dyspnea symptoms (respectively p = 0.36 and 0.92).
Table I
Demographic and clinical parameters of both groups
Additionally, the groups were compared for mortality and MACE, and no difference was found between the groups (respectively p = 0.527 and 0.098). CVE and elective percutaneous procedures were more frequent in Group 2, but this frequency did not contribute to a significant difference between the groups in terms of MACE. Figures 3 A and B present the Kaplan-Meier analysis of MACE and mortality, respectively (log-rank = 0.516 and 0.206). Censored patients in the Kaplan-Meier analysis are those with unclear follow-up time.
Figure 3
A – Kaplan-Meier survival curve for mortality in both groups (log-rank p = 0.516), B – Kaplan Meier survival curve for major cardiovascular event-free survival rate in both groups (log-rank p = 0.206)
Origin anomalies were the most common abnormality, the coronary artery originating from the opposite coronary sinus. Right coronary artery (RCA) arising from the left coronary sinus (LCS) was the most common anomaly (21.7%). In second place was left main coronary artery (LMCA) (20%) atresia. These patients had no LMCA, a separate ostium of the left anterior descending coronary artery (LAD), and the left circumflex artery (LCX) from the LCS. The LMCA originated from the right sinus of Valsalva (RSV) in 1 (1.7%) case. In 4 patients, the left circumflex artery (LCX) arose from the RSV (6.7%) and the RCA (4 patients, 6.7%). Two (3.3%) patients had a single coronary artery, and 9 (15%) high-takeoff coronary arteries were determined. Sixteen (26.6%) patients had course anomalies, with coronary artery aneurysm being detected in 9 (15%) patients, and coronary artery fistulas in 3 (5%) patients. The results are summarized in Table II. Four patients were also found to have more than one anomaly.
Table II
Prevalence of coronary anomalies
Figure 4 illustrates the tomographic images of a 46-year-old male patient who was subjected to an investigation for chest pain. It can be observed that the LMCA has its origin in the right coronary sinus.
Figure 4
Left main coronary artery arising from the right sinus of Valsalva with an interarterial course in a 46-year-old man. Axial (A) and volume rendering (B–D) CCTA images show left main coronary artery arising from the right sinus of Valsalva, coursing between aorta and pulmonary artery, dividing to left anterior descending and left circumflex arteries
Ao – aorta, LAD – left anterior descending artery, LCX – left circumflex artery, LMCA – left main coronary artery, PA – pulmonary artery, RCA – right coronary artery, RSV – right sinus of Valsalva.
Discussion
The prevalence of coronary artery anomalies in our series was 2%, and this finding is supported by previous studies [1, 2]. According to this study, results of MACE and mortality were similar in both groups. To the best of our knowledge, this is the first study to investigate the prevalence of coronary anomalies, determined via CCTA, and their effect on MACE and mortality in the literature of our country.
Conventional coronary angiography is the gold standard technique to diagnose and treat coronary artery disease. However, to understand some CAs, clinicians need additional diagnostic techniques. CCTA, a non-invasive test, can provide accurate information, especially course anomaly, termination of fistula, and relation of anomalous vessels to cardiac chambers and major arteries [17, 18].
The main cause of CAs remains unknown, and there is also no consistent definition in terms of gender and genetic transmission. There are 4 subgroups according to the Angelini classification [9]: origin, course, number, and termination anomalies of the coronary arteries. Origin anomalies, which are generally the most frequent, and anomalous origins of coronary arteries where the artery crosses over to the opposite sinus, show four course patterns: (1) an anterior course anterior to the pulmonary trunk or the right ventricular outflow tract, (2) an interarterial course between the pulmonary artery and the aorta, (3) a septal course through the interventricular septum, and (4) a retroaortic course posteriorly between the aortic root and the left atrium. The interarterial course between the pulmonary artery and the aorta is clinically significant because the compression of the coronary ostium may induce sudden death, myocardial ischemia, and congestive heart failure [10]. In the current study, the most common CAs were origin and course anomalies. Among origin anomalies, the most common was the RCA arising from the LSV (12, 20%). While 12 (92.3%) of 13 patients had an interarterial course, one of these cases was operated on and only one had a retroaortic course. The second most frequent anomaly determined in the study was atresia of the LMCA (12, 20%), and consisted of more than one ostium in the LSV. In the literature, the ranking of this anomaly is variable, and the prevalence of these CAs is 0.5–8% [19].
A single coronary artery is very rare in CAs, and is classified into 20 categories according to the location of this anomaly [20]. In this study, only 2 (3.3%) cases had a single coronary artery, both of which arose from the RSV and coursed to the anterior and right atrioventricular groove. In one study, it was suggested that the presence of a single coronary artery with an inter-arterial course may increase the risk of MACEs [21].
High takeoff of the coronary artery refers to it arising more than 0.5 cm above the sinotubular junction, rather than from the aortic sinus. This is a hemodynamically benign coronary anomaly and usually considered a normal variant, but it may cause technical difficulties [10]. In our study, the prevalence of high takeoff was 8.8%.
Coronary artery fistulas (CAf) are abnormal communications between a coronary artery and another structure such as a heart chamber, arteries, veins or the coronary sinus. The clinical situation varies according to the size of the CAf. Small CAf diagnoses incidentally occur during CA or CCTA, whereas large CAf causes steal syndrome and can lead to ischemia. CAfs are observed in 0.05–0.25% of patients undergoing conventional angiography. In this study, the prevalence of CAfs was 0.1% [22].
Myocardial ischemia is regarded as the principal underlying cause of life-threatening complications in patients with CAs. While some CAs (e.g., pulmonary origin of coronary arteries, coronary atresia) are invariably linked with severe impairment of myocardial perfusion, the relationship between other anomalies (e.g., anomalous aortic origin of coronaries) and myocardial ischemia is much more nuanced, with the clinical significance of these anomalies sometimes being more difficult to prove. Although provocative tests are recommended in cases where the etiology remains uncertain, the mechanisms linking some CAs to myocardial ischemia remain debatable. Furthermore, even in instances of myocardial ischemia, it remains unclear whether this is associated with an increased risk of life-threatening events [21]. The findings of our study lend support to this argument. The paucity of studies making such an assessment renders this finding particularly valuable.
In the current study, the MACE rate was not higher than in Group 2. Elective percutaneous intervention and cerebrovascular accident were more common in Group 2. However, these results did not affect the total. In a study by Musiani et al., it was found that congenital atresia of the left main coronary artery was associated with congestive heart failure or malignant arrhythmias during infancy in most cases [23]. Additionally, in a meta-analysis including 5486 subjects with MB, it was found that MB was associated with a higher risk of myocardial infarction. However, the same results were not observed in other MACE [24]. Conversely, a report pooling 21 studies showed that, although MACE and myocardial ischemia were more common in patients with myocardial bridging, no significant differences emerged when myocardial infarction and cardiovascular death were considered endpoints [25].
The latest 2018 American College of Cardiology/American Heart Association guidelines for the management of adults with congenital heart disease recommend that all patients exhibiting symptoms or evidence of ischemia during diagnostic testing should undergo repair (Class I). However, for patients with left anomalous aortic origin of a coronary artery (AAOCA), or those who do not meet this criteria, surgical intervention is now only a Class IIa recommendation, which decreases to IIb in right AAOCA, unless patients present with ventricular arrhythmias [26]. The recommendations of the 2020 adult congenital heart disease guideline of the European Society of Cardiology are similar [27]. In both guidelines, all recommendations are based on the demonstration of ischemia and individualization of treatment. However, the surgery is the first-line treatment choice according to guidelines. In the study of Mainwaring et al. including 115 subjects, 97% exhibited no symptoms during the follow-up period, and no deaths were documented, either perioperatively or postoperatively [28]. Moreover, a systematic review of surgically corrected left coronary artery originating from the right aortic sinus (n = 325) revealed a low mortality rate (0.9%), and only 2.2% of patients exhibited symptoms at the last follow-up [29]. Nevertheless, there is no evidence that surgery reduces SCD in these patients. The lack of controlled studies and long-term follow-up data means that the true risk-to-benefit ratio of surgery is currently unknown. Furthermore, although anatomic clues historically associated with SCD should not be overlooked, it is imperative to demonstrate a causal link between CAs and myocardial ischemia before surgery is indicated. Indeed, in a study including 24 patients with such CAs, subclinical signs of inducible ischemia persisted even after surgical correction, which highlights the necessity for caution against unwarranted surgical intervention.
There are two separate studies in the literature in which patients with CAs were medically followed up. A study consisting of 56 adults, who were managed conservatively with exercise restriction or medical therapy (namely β-blockers, calcium channel blockers, nitrates, and antiarrhythmic drugs), observed no cases of sudden cardiac death at a mean follow-up of 5.6 years [30]. In contrast to the findings of this study, Opolski et al. reported that 19 out of 70 (27%) patients who underwent medical management reported exacerbation of chest pain, or a reduction in exercise tolerance, at a mean follow-up period of 1.3 years [31]. This was particularly prevalent in individuals with an interarterial course. In our study, only 1 patient was operated on and the other patients were followed up.
The study did have some limitations. The first was that it was single-centered and retrospective. Therefore, some important clinical characteristics of the patients included in this study were not documented due to its retrospective nature. Moreover, the national death notification system is not connected with the hospital medical record system. Therefore, patients whose medication reports had not been renewed after the last day of medication reports were accepted as having died. Patients who had not been prescribed via the national medical system in the previous year were accepted as being dead. In addition, minor CAs, such as coronary artery ectasia and MB artery, were excluded.
