Malignant Interarterial Course of a Coronary Artery: Comprehensive Review with Case-Based Insights

 

Introduction

Coronary artery anomalies (CAAs) are relatively rare congenital abnormalities, yet they are clinically significant due to their potential association with myocardial ischemia, arrhythmias, and sudden cardiac death (SCD). Among the various types of CAAs, the so-called “malignant” interarterial course—in which a coronary artery passes between the aorta and the pulmonary artery—is particularly dangerous. This variant is most frequently identified in the right coronary artery (RCA) or the left coronary artery (LCA) arising from the opposite sinus of Valsalva.

Although the overall prevalence of CAAs is less than 1% in the general population, this anomaly is disproportionately represented among cases of sudden death in young athletes and military recruits. Consequently, early recognition and appropriate management are paramount.

In this article, we provide a comprehensive, expert-level review of the malignant interarterial course of coronary arteries, focusing on the pathophysiology, epidemiology, clinical manifestations, imaging features, differential diagnoses, management strategies, and prognosis. The discussion is supplemented by a real clinical case with multimodal imaging, highlighting the diagnosis and surgical correction of an anomalous RCA with an intramural course. This review is intended not only for clinicians and cardiologists but also for medical students and examination candidates preparing for board-level assessments.

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Pathophysiology

1. Anatomical Basis

• In a malignant interarterial course, the coronary artery arises from the contralateral aortic sinus and traverses between the aorta and pulmonary artery.
• The vessel often has a slit-like orifice rather than a round ostium, due to its origin tangential to the aortic wall.
• The proximal segment may follow an intramural course within the aortic tunica media, causing dynamic compression.

2. Mechanism of Ischemia

The risk of myocardial ischemia is multifactorial:

1. Slit-like Ostium: Limits blood flow, especially during increased cardiac demand.
2. Acute Angle Take-off: Increases resistance to coronary filling.
3. Intramural Compression: Aortic expansion during exertion compresses the artery further.
4. External Compression: The artery is squeezed between the aorta and pulmonary artery, particularly during exercise when both vessels dilate.

This pathophysiological cascade can lead to reduced perfusion, exertional angina, syncope, or fatal ventricular arrhythmias.

3. Sudden Cardiac Death

Numerous autopsy-based studies have confirmed that the malignant interarterial course is a leading structural cause of SCD in young, otherwise healthy individuals. The mechanism is typically ischemia-induced ventricular fibrillation, often during or immediately after strenuous activity.

4. Intramural vs. Extramural Course

• Intramural course: The coronary segment runs within the aortic wall. The dynamic compression is more severe, and this feature is strongly associated with clinical events.
• Extramural interarterial course: Less compressive, but still carries risk due to mechanical tethering.

5. Hemodynamic Studies

Advanced imaging and computational flow models have demonstrated turbulent flow and pressure drops across the proximal slit-like segment. Fractional flow reserve (FFR) and intravascular ultrasound (IVUS) studies confirm functional significance even in the absence of fixed stenosis. 

Epidemiology

1. Prevalence of Coronary Artery Anomalies

• Coronary artery anomalies (CAAs) are found in 0.2%–1.3% of the general population, depending on the imaging modality used (autopsy, angiography, or CT angiography).
• Among these, malignant variants with an interarterial course represent a small minority, but they account for a disproportionately high number of catastrophic clinical events.

2. Association with Sudden Cardiac Death (SCD)

• Autopsy studies from young athletes in the U.S. have consistently identified CAAs as one of the leading structural causes of SCD.
• Brothers et al. (2016) reported that anomalous aortic origin of a coronary artery (AAOCA) with an interarterial course contributes to 15–20% of exercise-related sudden deaths in young competitive athletes.
• In military populations, prevalence is similar, with many deaths occurring during training or exertion.

3. Demographics

• Both sexes can be affected, but there may be a slight male predominance in reported cases, possibly reflecting higher participation in competitive sports.
• Age at presentation is variable, but most symptomatic cases are diagnosed between adolescence and the fourth decade of life.
• The anomaly can remain silent into adulthood, discovered either incidentally on imaging or after a life-threatening event.

4. Global Burden

• Although considered rare, the global burden is underrecognized due to underreporting and limited widespread use of advanced cardiac imaging in screening.
• With the advent of coronary CT angiography (CCTA), detection rates have increased, shifting understanding from an autopsy-based phenomenon to a diagnosable pre-mortem entity.

Clinical Presentation

1. Symptomatic Spectrum

Patients with a malignant interarterial course of the coronary artery may present with a wide range of clinical features, from subtle to life-threatening:

• Exertional chest pain/angina: Often misattributed to musculoskeletal or anxiety-related causes in young individuals.
• Dyspnea: Due to transient ischemia and impaired cardiac output during exertion.
• Syncope or presyncope: Reflecting transient ischemia-induced arrhythmia.
• Palpitations: Due to premature beats or sustained tachyarrhythmias.
• Sudden cardiac death: In some cases, the very first manifestation.

2. Asymptomatic Cases

• A significant proportion of patients remain asymptomatic, with diagnosis made incidentally during imaging for unrelated reasons (e.g., preoperative workup, chest pain evaluation, coronary CT for calcium scoring).
• The risk of SCD persists even in asymptomatic patients, particularly those with high-risk anatomy (slit-like ostium, long intramural segment, high interarterial course).

3. Case Example (31-year-old Female)

From the provided case review:

• Chief complaint: Chest pain.
• Investigations:
• Nuclear medicine studies demonstrated inducible ischemia in the RCA territory.
• CT angiography revealed a dominant RCA arising along the medial border of the right coronary cusp with an interarterial course, and a slit-like proximal RCA, suggesting an intramural component.
• Management: Surgical unroofing was performed, resulting in a widely patent ostium without residual stenosis on postoperative imaging.
• Outcome: Symptom resolution, improved perfusion, and reduced risk of SCD.

4. Triggers for Clinical Events

• Strenuous exercise, especially high-intensity aerobic activity, is the most common trigger.
• Increased blood pressure and aortic expansion during exercise worsen the compression of the anomalous segment.
• Emotional stress or adrenergic surges may also precipitate events. 

Imaging Features

Modern imaging, especially coronary CT angiography (CCTA), is essential for identifying malignant interarterial coronary artery anomalies. In the presented case, multimodal imaging was used before and after surgical unroofing. Below, each figure is described in sequence.

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Figure 1. Chest PA View

• Findings: Normal chest X-ray appearance.
• Interpretation: No cardiomegaly, lung pathology, or vascular abnormality. This emphasizes the limitation of conventional radiography in detecting coronary anomalies.

Figure 2. Chest Lateral View

• Findings: Normal.
• Interpretation: Again, no abnormality visible, underscoring the need for advanced imaging modalities in suspected cases of congenital coronary anomalies.

Figure 3. Aortic Valve Plane, Contrast-Enhanced (Arterial Phase)

• Findings: RCA originates abnormally along the medial border of the right coronary cusp.
• Interpretation: Early evidence of anomalous origin, raising suspicion for an interarterial course.

Figure 4. Aortic Valve Plane, Contrast-Enhanced (Arterial Phase)

• Findings: Narrowing of proximal RCA with a slit-like ostium.
• Interpretation: Suggestive of an intramural course, a hallmark of malignant variants.

Figure 5. Coronal Contrast-Enhanced Arterial Phase

• Findings: The RCA follows an interarterial trajectory between the aorta and pulmonary artery.
• Interpretation: Definitive malignant course anatomy, explaining the ischemic symptoms.

Figure 6. Sagittal Contrast-Enhanced Arterial Phase

• Findings: Elongated and compressed proximal RCA segment.
• Interpretation: Further supports the intramural nature of the vessel.

Figure 7. 3D Reconstruction, Contrast-Enhanced Arterial Phase

• Findings: 3D view clearly demonstrates the anomalous RCA course relative to the aorta and pulmonary artery.
• Interpretation: Provides critical spatial understanding for surgical planning.

Figure 8. Axial Contrast-Enhanced Arterial Phase (Postoperative)

• Findings: RCA ostium after unroofing surgery.
• Interpretation: Widely patent lumen, with no residual slit-like narrowing.

Figure 9. Aortic Valve Plane, Contrast-Enhanced Arterial Phase (Postoperative)

• Findings: Smooth contour of the RCA ostium.
• Interpretation: Confirms surgical success.

Figure 10. Sagittal Contrast-Enhanced Arterial Phase (Postoperative)

• Findings: Normal-appearing RCA trajectory without compression.
• Interpretation: No evidence of residual intramural course.

Figure 11. Coronal Contrast-Enhanced Arterial Phase (Postoperative)

• Findings: RCA lumen widely patent, no stenosis or irregularity.
• Interpretation: Complete resolution of preoperative pathology.

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Summary of Imaging Findings

• Preoperative: RCA origin from right coronary cusp with interarterial + intramural course, slit-like ostium, and compression.
• Postoperative: Surgical unroofing resulted in a normal, widely patent RCA ostium, eliminating the risk of ischemia and sudden death.

📌 Imaging plays a dual role:

1. Diagnosis — identifying high-risk features (slit-like ostium, interarterial trajectory, intramural course).
2. Follow-up — confirming surgical success and ruling out restenosis.

Differential Diagnosis

When evaluating chest pain, ischemia, or anomalous findings on imaging, several entities must be distinguished from a malignant interarterial course of a coronary artery:

1. Other Coronary Artery Anomalies
• Examples: Anomalous origin of the left circumflex artery (LCX) from the right sinus, or the left anterior descending (LAD) from the right coronary cusp.
• These may be benign if they course posterior to the aorta, but malignant if they take an interarterial route.
2. Myocardial Bridging
• A segment of a coronary artery, usually the LAD, runs intramyocardially and is compressed during systole.
• Distinguished from interarterial course by the presence of systolic “milking effect” on angiography and absence of anomalous origin.
3. Coronary Artery Spasm (Prinzmetal Angina)
• Causes transient ischemia and ST-segment elevation but with normal coronary anatomy between episodes.
• Provocative testing (ergonovine, acetylcholine) may help differentiate.
4. Atherosclerotic Coronary Artery Disease (CAD)
• The most common cause of ischemic chest pain in adults.
• Distinguished by the presence of fixed stenoses, calcifications, and risk factors.
• Unlike malignant interarterial course, CAD generally develops later in life.

Treatment

Management depends on the symptomatic status, anatomical risk factors, and functional evidence of ischemia. International guidelines (ACC/AHA, ESC) provide consensus recommendations.

1. Asymptomatic Patients

• If no ischemia is detected and no high-risk features (slit-like ostium, intramural course, interarterial trajectory), conservative management with observation may be reasonable.
• Lifestyle advice: avoid high-intensity competitive sports.
• Regular follow-up with CT angiography or functional stress imaging.

2. Symptomatic Patients or Proven Ischemia

• Surgical intervention is recommended in all symptomatic patients or when objective ischemia is demonstrated.
• Main surgical approaches:

a. Unroofing Procedure

• Most widely used.
• Involves opening the intramural segment of the coronary artery within the aortic wall, converting the slit-like ostium into a wide, round opening.
• Excellent outcomes with symptom relief and normalization of flow.
• This was performed in the presented case.

b. Coronary Reimplantation

• The anomalous coronary artery is excised and reimplanted into the correct sinus.
• Technically challenging, usually reserved for specific anatomies.

c. Coronary Artery Bypass Grafting (CABG)

• Bypass graft (often LIMA to RCA or LAD) is placed to supply blood distal to the anomalous segment.
• Limitations: competitive flow from the native artery may reduce graft patency.
• Considered if unroofing is not feasible.

3. Percutaneous Coronary Intervention (PCI)

• Stenting of the slit-like ostium has been attempted in select cases.
• However, outcomes are suboptimal compared to surgery, with risks of restenosis and incomplete resolution of dynamic compression.
• Generally not first-line therapy.

4. Postoperative Management

• Antiplatelet therapy (usually aspirin) is administered after unroofing, although protocols vary.
• Return to full physical activity may be considered after 3–6 months of recovery, with repeat imaging confirming normal flow.
• Lifelong follow-up is advised due to potential late complications (rare).

Evidence from the Literature

• Yang et al. (2017): Long-term follow-up after surgical unroofing showed excellent survival and low recurrence of symptoms, with freedom from SCD >95% at 10 years.
• Brothers et al. (2016): Highlighted anomalous aortic origin as a leading cause of exertional sudden death in athletes, reinforcing the need for early surgical correction in high-risk cases.
• Cheezum et al. (2017): Showed the utility of CCTA in identifying slit-like ostium and intramural course, helping stratify surgical candidates.

✅ Key Clinical Pearls for Exam Candidates

• Symptomatic patients → always surgical (unroofing preferred).
• Asymptomatic + no ischemia → conservative observation possible.
• PCI/stenting → not standard of care.
• CABG → backup option when unroofing is not feasible. 

Prognosis

1. Natural History (Untreated)

• Patients with a malignant interarterial course, especially with an intramural segment and slit-like ostium, have a significant risk of sudden cardiac death (SCD).
• Many cases remain silent until the first catastrophic event.
• Risk is highest during adolescence and young adulthood, particularly during strenuous exertion.

2. Post-Surgical Outcomes

• Unroofing procedure: Long-term studies demonstrate excellent outcomes with normalization of coronary flow and relief of symptoms.
• Survival after unroofing is comparable to the general population, provided there are no other congenital anomalies or comorbidities.
• Late complications are rare but may include mild neointimal thickening or scarring at the ostium.

3. Quality of Life

• Most patients can resume normal physical activity postoperatively.
• Competitive athletes may be cleared for sports after full recovery and confirmation of normal coronary perfusion.
• Psychological reassurance is a significant benefit, as many young patients fear recurrent cardiac events.

4. Prognostic Factors

• Poor prognosis if untreated: symptomatic patients, demonstrable ischemia, intramural course, or slit-like ostium.
• Favorable prognosis if treated: surgical correction (especially unroofing) restores near-normal life expectancy.

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Quiz

Question 1. A 19-year-old male college athlete collapses during basketball practice. He is resuscitated successfully. Coronary CT angiography shows the right coronary artery arising from the left coronary cusp, coursing between the aorta and pulmonary artery, with a slit-like ostium. Which of the following is the most appropriate next step in management?

A. Beta-blocker therapy and restriction from competitive sports
B. Coronary artery stent placement
C. Surgical unroofing of the anomalous segment
D. Observation with annual follow-up imaging 

Question 2. Which of the following best explains the mechanism of sudden cardiac death in patients with a malignant interarterial course of a coronary artery?

A. Fixed atherosclerotic stenosis
B. Dynamic compression of the intramural coronary segment during exertion
C. Embolization from anomalous coronary origin
D. Coronary artery aneurysm rupture 

Question 3. A 31-year-old woman presents with exertional chest pain. Nuclear perfusion imaging shows ischemia in the RCA distribution. CT angiography demonstrates an intramural interarterial course of the RCA with slit-like ostium. Postoperative CT shows a widely patent ostium after unroofing. Which of the following findings is most consistent with the postoperative imaging?

A. Persistent slit-like narrowing of the RCA ostium
B. Widely patent RCA lumen without focal stenosis
C. Total occlusion of the RCA with collateral circulation
D. Myocardial bridging of the RCA

Answer & Explanation

1.    👉 Answer: C. Surgical unroofing of the anomalous segment. Explanation: Symptomatic or high-risk patients with malignant interarterial course require surgery. Stenting is not effective, and observation alone carries high risk of SCD.

2.    👉 Answer: B. Dynamic compression of the intramural coronary segment during exertion. Explanation: Exercise causes expansion of the aortic root, which compresses the intramural coronary segment, leading to ischemia and lethal arrhythmia.

3.    👉 Correct Answer: B. Widely patent RCA lumen without focal stenosis. Explanation: Unroofing surgery relieves the compression and restores a normal round ostium with unobstructed coronary blood flow. 

Key Takeaways / Clinical Pearls

• Malignant interarterial course of a coronary artery is a rare but high-risk congenital anomaly.
• The slit-like ostium and intramural course are the most dangerous features, predisposing to ischemia and sudden cardiac death.
• Exercise-induced compression between the aorta and pulmonary artery explains the lethal mechanism.
• Imaging (CCTA, 3D reconstruction) is the gold standard for diagnosis and surgical planning.
• Unroofing surgery is the treatment of choice for symptomatic or high-risk patients, with excellent long-term prognosis.
• Board exam tip: In any young patient with exertional syncope/chest pain and anomalous coronary anatomy → think surgical correction.

References

1. P. Angelini, “Coronary artery anomalies: an entity in search of an identity,” Circulation, vol. 115, no. 10, pp. 1296–1305, 2007.
2. J. A. Brothers, et al., “Anomalous aortic origin of a coronary artery: a risk factor for sudden cardiac death,” Circulation, vol. 133, no. 14, pp. 1391–1399, 2016.
3. M. K. Cheezum, et al., “Anomalous aortic origin of a coronary artery from the inappropriate sinus of Valsalva: imaging findings and clinical implications,” JACC: Cardiovascular Imaging, vol. 10, no. 4, pp. 471–481, 2017.
4. R. A. Krasuski, “Anomalous coronary arteries,” Progress in Cardiovascular Diseases, vol. 57, no. 2, pp. 196–206, 2014.
5. A. J. Taylor, K. M. Rogan, and R. Virmani, “Sudden cardiac death associated with isolated congenital coronary artery anomalies,” Journal of the American College of Cardiology, vol. 20, no. 3, pp. 640–647, 1992.
6. C. A. Warnes, et al., “ACC/AHA 2008 guidelines for the management of adults with congenital heart disease,” Journal of the American College of Cardiology, vol. 52, no. 23, pp. e143–e263, 2008.
7. Y. Yang, et al., “Surgical unroofing of intramural anomalous coronary arteries: long-term outcomes,” Annals of Thoracic Surgery, vol. 103, no. 6, pp. 1926–1932, 2017.