Making Sense of AAOCA: Updates on Studies of an Ill-Defined Congenital Anomaly

It’s hard to bring up the congenital anomaly known as anomalous aortic origin of a coronary artery (AAOCA) without stirring up a host of questions: Are all its forms equally dangerous? How do the various anomalies present? What are the long-term outcomes of different surgical repair techniques? Which ones need surgery?

These are some of the key questions expected to be answered with data supplied by a prospective registry of AAOCA patients ages 30 and younger created by the Congenital Heart Surgeons’ Society (CHSS) and by complementary retrospective and prospective studies of adults with the anomaly seen at Cleveland Clinic.

“Over time, the large body of data we gather will be analyzed to determine associations among clinical events, diagnostic studies and treatment choices,” says Tara Karamlou, MD, a Cleveland Clinic cardiothoracic surgeon specializing in congenital heart disease. “These previously unobtainable data will help us develop the predictive models that are so urgently needed.”

A little-understood anomaly

AAOCA with interarterial, intramural or intraconal course is a congenital heart anomaly with multiple variants. Its most important manifestation is sudden cardiac death (SCD), which occurs primarily during or just after exercise in otherwise healthy children, adolescents and young adults. Although it’s a rare deformity estimated to affect 0.1% to 1.0% of the pediatric and adult population, AAOCA is the second-leading cause of SCD in young athletes in the U.S. In adults over age 30, AAOCA is thought to be a less malignant, often incidental finding, but its prevalence and implications have yet to be determined.

The CHSS registry has been enrolling patients age 30 and younger with AAOCA since 1998. Cleveland Clinic is one of 47 participating institutions. The registry’s overarching purpose is to determine the outcome of surgical intervention relative to observation in children and young adults with AAOCA, as well as to describe the natural history of the condition over these patients’ lifetimes.

“We don’t know the denominator of patients who have this anomaly or its true prevalence,” notes Dr. Karamlou. “The information gleaned from this ongoing study will help us characterize the various anatomic variations and correlate them with risk of SCD, chest pain and major adverse cardiovascular events.”

With nearly 700 patients now enrolled, answers to critical questions are starting to surface. Dr. Karamlou and colleagues have published several papers from this registry cohort. The findings have also been used to shape evidence-based guidelines for the management of AAOCA (J Thorac Cardiovasc Surg. 2017;153:1440-1457) and for the management of adults with congenital heart disease (J Am Coll Cardiol. 2019;73:1494-1563).

Many unknowns

Five major forms of AAOCA and seven subtypes have been identified. Observational studies suggest the origin and course that AAOCA takes may impact SCD risk. “The risk may be greater for AAOCA involving the left coronary artery (AAOLCA) [shown in illustration below], but there have been reports of SCD associated with AAOCA of the right coronary artery (AAORCA) and single origin of the coronary arteries,” says Dr. Karamlou. “Furthermore, the fact that AAORCA is more prevalent than AAOLCA may increase the prevalence of SCD among this group.”

SCD is hypothesized to occur from transient mismatch of coronary blood flow and myocardial oxygen demand, which results in myocardial ischemia and/or ventricular tachyarrhythmias. Several specific mechanisms have been proposed to explain the increased risk of ischemia with exercise.

Individual mechanisms may be associated with specific varieties of AAOCA, and any one mechanism or several in combination may account for the reduction in coronary blood flow leading to SCD. “This hypothesis is consistent with the theory that some AAOCA variants are more ‘malignant’ than others,” says Dr. Karamlou.

There is no typical presentation of AAOCA. Although the initial presentation may be SCD, AAOCA is most often an incidental finding on a CT angiogram or echocardiogram taken for another reason or for symptoms related to exertion, such as chest pain. Different institutions use different protocols, and there is no consensus on how AAOCA should be diagnosed or evaluated.

Finding answers

Similarly, treatment of AAOCA is controversial and varies among clinicians. Recommendations include observation alone, exercise restriction, medication, surgical repair or a combination of these. The registry will help establish best practices based on treatment outcomes.

“We believe AAORCA are less dangerous than AAOLCA, but we have no data supporting this or whether surgery changes the disease’s natural history,” Dr. Karamlou notes. “We feel many patients do not warrant surgery, and we are trying to best identify who they may be. We suspect that unroofing the intramural segment where it makes a hairpin turn reduces the risk of SCD, but we don’t know for sure.”

AAOCA in adults

“Adult patients with AAOCA are often inaccurately thought to no longer be at risk for SCD, but this is not based on sufficient scientific data, as there is bias in the evaluation and incidence of autopsy of SCD cases in the adult population,” observes Joanna Ghobrial, MD, a cardiologist with Cleveland Clinic’s Adult Congenital Heart Disease Center.

To fill this void in data for an at-risk population, Cleveland Clinic is conducting complementary prospective and retrospective studies of AAOCA in adults.

The prospective investigation is designed to aid in risk stratification. “This study is prompted by the lack of evidence-based protocols for managing adult patients with AAOCA, especially given that most patients can be asymptomatic up until presenting with SCD and the fact that noninvasive stress tests have not correlated well with future risk of SCD,” says Dr. Ghobrial.

The study involves systematic and comprehensive preoperative evaluation with noninvasive and invasive testing to help discern which patients might be at higher risk of SCD. The noninvasive evaluation includes dobutamine PET scanning and ECG-gated CT angiography, while invasive testing includes coronary angiography with instantaneous wave-free ratio flow reserve as well as intracoronary vascular ultrasound at rest and with provocation. “This specifically protocoled evaluation will identify patients with flow compromise in their anomalous coronary artery and aid in future prediction models that identify the group of patients benefiting the most from surgical intervention,” Dr. Ghobrial explains.

Meanwhile, the retrospective study is drawing on a database of all Cleveland Clinic patients with the anomaly. An ongoing review of all cardiac catheterizations in Cleveland Clinic’s extensive Cardiovascular Disease Registry has turned up more than 4,285 patients to date with incidental or symptom-directed AAOCA.

“The retrospective Cleveland Clinic database doesn’t enroll patients who died before reaching adulthood,” Dr. Karamlou explains. “This makes it a very useful adjunct to the CHSS cohort in that it captures a slightly older population who may have more benign forms of AAOCA, may have concomitant coronary artery disease and may undergo different surgeries. The durability of alternative surgeries needs to be understood.”

Going forward

For its part, the CHSS registry will continue enrolling patients indefinitely. “The data we gather will give us the power to address unanswered questions about this rare lesion,” says Dr. Karamlou.

As a former John W. Kirklin fellow in the CHSS Data Center, Dr. Karamlou serves on the CHSS Data Center faculty with Cleveland Clinic colleague Eugene Blackstone, MD, who established the center with Dr. Kirklin in 1985. As faculty members, they help determine study design, serve as primary investigators, and are involved in reviewing data, analyzing manuscripts and presenting data at national meetings.

“This registry will be the source of critical information for providers,” Dr. Karamlou concludes. “There’s no better way to understand long-term outcomes and treatment modalities of AAOCA.