Coronary artery anomalies: contemporary approaches to risk stratification and management

Abstract

The widespread adoption of coronary computed tomography angiography (CCTA) has led to a growing detection of coronary artery anomalies in contemporary clinical practice, often as incidental findings during the evaluation of suspected or known coronary artery disease. Among these, anomalous aortic origin of a coronary artery (AAOCA) represents the most clinically debated entity, historically associated with myocardial ischaemia and sudden cardiac death, yet increasingly identified in asymptomatic or minimally symptomatic adults. Accumulating evidence indicates that most AAOCA diagnosed in adulthood are not associated with functionally relevant ischaemia and frequently follow a benign clinical course, highlighting the limitations of anatomy-based risk stratification alone. In this context, CCTA plays a pivotal role by accurately defining coronary origin and course, characterizing proximal vessel morphology, and assessing concomitant atherosclerotic disease, which often represents the predominant determinant of symptoms and prognosis in adult patients. Recent studies have demonstrated that quantitative CCTA-derived parameters can reliably exclude hemodynamically significant AAOCA and reduce unnecessary downstream testing. In selected cases, invasive functional assessment and intracoronary imaging provide incremental value by clarifying the presence and mechanisms of ischaemia but should be reserved for carefully selected patients. This review summarizes current evidence on coronary artery anomalies with a specific focus on AAOCA and proposes a pragmatic, stepwise approach integrating anatomical and functional assessment to guide clinical decision-making in daily practice.

Introduction

The progressive expansion of cardiovascular imaging in contemporary cardiology has profoundly reshaped clinical practice. Non-invasive anatomical imaging, particularly coronary computed tomography angiography (CCTA), is now widely used not only for the evaluation of chest pain syndromes but also as a first-line tool in the diagnostic work-up of suspected or known coronary artery disease (CAD).¹ Large, randomized trials have demonstrated that an imaging-driven strategy improves risk stratification, optimizes preventive medical therapy, and translates into better long-term outcomes without increasing unnecessary invasive procedures.² Within this paradigm shift, however, an inevitable consequence has been the growing detection of cardiovascular conditions that were previously considered rare, clinically silent, or largely anecdotal.

Among these, coronary artery anomalies (CAAs) represent one of the most challenging entities for the practicing cardiologist. Once predominantly identified in autopsy series or in young athletes with sudden cardiac death (SCD), CAAs are now increasingly diagnosed incidentally during CCTA performed for unrelated indications, often in middle-aged or elderly individuals.³ This epidemiological transition has exposed a substantial gap between anatomical detection and evidence-based clinical management, generating uncertainty regarding prognosis, need for further testing, and indications for intervention.⁴

The clinical dilemma is particularly evident for anomalous aortic origin of a coronary artery (AAOCA), a subset of CAAs historically associated with myocardial ischaemia, malignant ventricular arrhythmias, and SCD. While early reports suggested a dramatic risk profile, more recent data indicate that the majority of AAOCA detected in adulthood follow a benign course, especially in the absence of ischaemia or high-risk anatomical features.⁵ As a result, contemporary practice faces a dual and opposing risk: overtreatment driven by superficial anatomy evaluation, and under-recognition of truly high-risk patients.⁶ In addition to imaging tests, European⁷ and US guidelines⁸ have highlighted the importance of functional assessment, particularly using tools that are able to reduce false-negative results. Against this background, the focus of modern management is shifting from mere anatomical description of incidental cases to an integrated, multimodality approach aimed at identifying functional relevance, dynamic mechanisms of ischaemia, and patient-specific risk. In this review, we provide a contemporary overview of coronary artery anomalies with a specific focus on AAOCA, discussing the pivotal role of CCTA in initial evaluation and risk stratification, critically appraising the strengths and limitations of invasive functional and imaging tools, and reviewing emerging evidence supporting pragmatic approaches to guide clinical decision-making in daily practice.

Coronary artery anomalies: clinical relevance and the central role of AAOCA

Coronary artery anomalies encompass a heterogeneous group of congenital conditions characterized by an abnormal origin, course, or termination of one or more epicardial coronary arteries.⁹ Their reported prevalence varies widely depending on the diagnostic modality, ranging from approximately 0.5–1% in invasive coronary angiography series to over 5% in large CCTA cohorts.^4,6 This variability reflects not only differences in spatial resolution but also the inclusion of variants with uncertain or negligible clinical significance.

From a clinical standpoint, the majority of CAAs are benign incidental findings with no measurable impact on myocardial perfusion or prognosis. These include separate ostia of the left anterior descending and circumflex arteries, high take-off of a coronary artery, or retroaortic course of the circumflex artery. Conversely, a small but clinically relevant subset of anomalies has been consistently associated with adverse events, particularly in young individuals exposed to intense physical exertion. Consistently, coronary anomalies are estimated to be the second cause of sudden cardiac death (SCD) in young athletes in the United States.¹⁰ Furthermore, impairment in coronary blood supply may increase other cardiac conditions. Flow limitation in coronary vessels supplying blood to the atrium has been associated with atrial ischaemia, which can serve as an electro-anatomical substrate for the development of arrhythmias.^11,12 As such, recognizing impairment in blood supply (e.g. malignant origin of right coronary artery) may identify patients at higher risk of developing arrhythmias.¹³

AAOCA, defined as the origin of a coronary artery from the opposite sinus of Valsalva, represents the most debated and clinically consequential subgroup. The anomaly may involve the right coronary artery arising from the left sinus (R-AAOCA) or the left main or left anterior descending artery arising from the right sinus (L-AAOCA). The clinical relevance of AAOCA is not determined by the anomalous origin per se, but rather by the subsequent proximal course and morphological characteristics of the vessel.

Several anatomical features have historically been labelled as ‘high risk,’ including an interarterial course between the aorta and pulmonary artery, an intramural segment within the aortic wall, a slit-like orifice, acute take-off angle, and proximal luminal narrowing with an elliptical shape. Among these, the intramural course has emerged as the dominant pathophysiological substrate, giving rise to dynamic luminal compression during periods of increased aortic wall stress.¹⁴ Importantly, contemporary observational data suggest that the absolute risk associated with AAOCA detected in adulthood is substantially lower than previously assumed. Event-free survival into middle age likely reflects a selection of less malignant phenotypes or adaptive remodelling over time, with atherosclerotic disease progressively becoming the dominant determinant of outcome. These observations underscore the need for careful patient selection and refined risk stratification beyond anatomical labels.

The role of CCTA: cornerstone of diagnosis and anatomical risk stratification

CCTA has become the reference standard for non-invasive evaluation of patients with atherosclerotic coronary artery disease. Its high spatial resolution and three-dimensional reconstruction capability allow for accurate risk stratification and guidance of treatment, with the possibility of detect response to anti-atherosclerotic pharmacological treatment.^15,16 Furthermore, its ability to depict the relationship between coronary arteries and surrounding structures made it uniquely suited for the assessment of AAOCA.¹⁴ In contemporary practice of patients with coronary anomalies, CCTA serves three fundamental purposes. First, it allows accurate identification of the coronary origin and proximal course, reliably distinguishing benign variants from potentially malignant configurations. Second, it enables detailed characterization of anatomical features that may contribute to ischaemia, including ostial morphology, intramural length, minimal luminal area, and vessel eccentricity. Third, it provides comprehensive assessment of concomitant atherosclerotic disease, a critical element in adult patients where CAD often coexists and may confound symptom attribution.

However, reliance on anatomy alone has important limitations. Several studies have demonstrated a poor correlation between traditional ‘high-risk’ anatomical features and objective evidence of ischaemia. In particular, the mere presence of an interarterial course has been shown to overestimate risk when not accompanied by functionally relevant luminal compromise. This has led to increasing concern that current definitions may misclassify a substantial proportion of patients, exposing them to unnecessary anxiety, repeated testing, or even unwarranted intervention.

Recent advances have sought to refine the anatomical assessment by identifying quantitative CCTA-derived parameters associated with haemodynamic significance. Minimal lumen area, maximal lumen narrowing relative to a distal reference, and dynamic changes in vessel geometry have emerged as more robust markers than qualitative descriptors alone. Recently, the NARCO trial¹⁷ (Noninvasive Anatomical Assessment for Ruling Out Haemodynamically Relevant Coronary Artery Anomalies) represented a landmark step in this direction by systematically comparing CCTA-derived anatomical metrics against invasive fractional flow reserve (FFR) measured during pharmacologic stress (dobutamine). Among 50 patients prospectively enrolled, CCTA-derived anatomic features minimum lumen are (MLA) and MLN, are associated with hemodynamic significance assessed via FFRDobutamine. CCTA-derived MLA (using a cut-off of 5.6 mm²; 100% negative predictive value) and maximal lumen narrowing (MLN) predicted haemodynamic significance (P < 0.001 for both), showing excellent negative predictive value, whereas take-off angle, elliptic ratio and intramural length showed no significant association. Of note, the majority (75%) of patients with R-AAOCA and interarterial/intramural course did not demonstrate haemodynamically significant ischaemia. These findings supported a paradigm in which CCTA is not merely a diagnostic tool but an effective gatekeeper able to defer most patients from further unnecessary invasive downstream testing and unneeded revascularization. More recent multimodality studies have further reinforced this concept, suggesting that a stepwise approach—a starting with CCTA for anatomical exclusion of high-risk physiology and reserving functional imaging or invasive testing for selected cases—may optimize diagnostic efficiency while minimizing patient burden.¹⁸

Invasive testing: functional assessment and intracoronary imaging

Despite advances in non-invasive imaging, invasive assessment retains a pivotal role in patients with coronary artery disease. Invasive coronary angiography provides high temporal resolution and allows direct interrogation of coronary physiology, and anatomy when combined with pressure-based measurements and intracoronary imaging. The increasing use of intracoronary imaging has dramatically changed the understanding of coronary artery disease in recent era, from detecting mechanisms of acute coronary instability to identify patients at high-risk of developing myocardial infarction and guiding coronary interventions.^1,19,20 Invasive FFR measured during pharmacologic stress with dobutamine has emerged as the reference standard for functional assessment in AAOCA.^1,21 Unlike adenosine-induced hyperaemia, dobutamine better reproduces the physiological conditions associated with exercise-related ischaemia, including increased heart rate, blood pressure, and myocardial contractility. When combined with volume loading and atropine, this approach can unmask dynamic luminal compromise not apparent at rest.

However, invasive functional testing is technically demanding, requires specific expertise, and carries inherent procedural risks. Moreover, the interpretation of FFR values in the context of dynamic compression and non-atherosclerotic disease is not straightforward, and standardized cut-offs have not been prospectively validated. These limitations underscore the importance of careful patient selection and integration with anatomical findings. Intracoronary imaging has provided unique insights into the mechanisms of ischaemia in AAOCA. Intravascular ultrasound (IVUS) allows visualization of the vessel wall and accurate quantification of luminal area throughout the cardiac cycle, revealing phasic compression of intramural segments and ostial deformation. IVUS studies have demonstrated that the severity of dynamic narrowing may be substantially underestimated by angiography alone, particularly under resting conditions. Optical coherence tomography (OCT), while offering superior spatial resolution, has a more limited role due to reduced tissue penetration and challenges in imaging proximal segments adjacent to the aortic wall. Nevertheless, in selected cases, OCT may complement IVUS by providing detailed assessment of luminal surface and ostial morphology.

Recently, Stark et al. investigated the diagnostic accuracy of FFRAdenosine and IVUS-based minimal lumen area (IVUS-MLA) against the reference standard of FFRDobutamine for identifying haemodynamically relevant R-AAOCA.²² Among 73 patients with R-AAOCA and interarterial/intramural course, FFRAdenosine ≤0.80 predicted FFRDobutamine ≤0.80 with 100% specificity and positive predictive value (PPV), 29% sensitivity and 82% negative predictive value (NPV) (AUC 0.81). IVUS-MLA ≤5.5 mm² predicted haemodynamic relevance with 100% sensitivity and NPV, 68% specificity, and 49% PPV (AUC 0.88). According to the study findings, FFR Adenosine could reliably rule-in, while IVUS-MLA could effectively rule-out relevant R-AAOCA, potentially reducing the need for FFRDobutamine testing.

Collectively, invasive imaging and physiology can inform therapeutic decision-making, particularly when considering surgical or percutaneous coronary intervention. Importantly, the absence of inducible ischaemia on comprehensive invasive assessment supports conservative management, even in the presence of anatomically ‘high-risk’ features.

Conclusions

The contemporary management of coronary artery anomalies, particularly AAOCA, remains clinically challenging in the era of widespread non-invasive imaging. The increasing detection of AAOCA in adults has highlighted the limitations of historical risk concepts largely derived from young athletic populations and has underscored the need for a more balanced interpretation of anatomical findings in everyday practice. Available evidence suggests that most AAOCA identified in adulthood are not associated with functionally relevant myocardial ischaemia and often follow a benign clinical course. Accordingly, anatomical features traditionally considered high risk, such as an interarterial or intramural course, should not be interpreted in isolation. Coronary computed tomography angiography plays a central role in this setting, not only by accurately defining coronary origin and course, but also by enabling a comprehensive assessment of proximal vessel morphology and concomitant atherosclerotic disease, which frequently represents the dominant determinant of symptoms and prognosis in adult patients. In selected cases, when clinical presentation, CCTA findings, or non-invasive testing raise persistent concern, invasive functional assessment and intracoronary imaging may provide incremental value by clarifying the presence and mechanisms of ischaemia. However, these investigations should be reserved for carefully selected patients and interpreted within the broader clinical context. The absence of inducible ischaemia on comprehensive evaluation supports a conservative management strategy, even in the presence of anatomically complex AAOCA. In daily clinical practice, the key question in patients with AAOCA is therefore not simply the identification of an anomalous coronary anatomy, but whether that anatomy is associated with myocardial ischaemia. A stepwise approach integrating CCTA, selective functional testing, and invasive assessment when appropriate represents a pragmatic strategy to guide management and avoid both unnecessary interventions and missed high-risk cases.

Funding

None.

Data availability

Not applicable.

Disclaimer

This paper was originally published in the Italian language as ‘Anomalie delle Arterie Coronarie: Approcci Contemporanei alla Stratificazione del Rischio e alla Gestione’, in the Volume degli Atti del Congresso “Conoscere e Cuare il Cuore 2026”, published by Centro per la Lotta contro l'Infarto for distribution at the CCC Conference. This paper was translated by Dr. Mario Albertucci, representative of the CLI Foundation, and republished with permission.