The first multicentre study on coronary anomalies in the Netherlands: MuSCAT

Coronary anomalies are rare and often an incidental finding in patients without concomitant congenital heart defects. Conflicting reports and lack of evidence-substantiated guidelines lead to challenging treatment decisions, especially for anomalous coronary arteries originating from the opposite sinus of Valsalva or from the opposite coronary artery (ACAOS). For an anomalous coronary artery from the pulmonary artery or coronary arteriovenous fistula (CAVF) there is a more established consensus on treatment, but results of and recommendations on long-term follow-up are scarce[1, 2]. American and European guidelines both state that there is limited evidence regarding treatment choices, and the majority of their treatment advice is based on level C evidence [1, 3]. This underlines the gap in our knowledge concerning these defects and the need for more evidence.

The prevalence of ACAOS is reported to be between 0.1 and 1% in the general population [4]. Multiple variations exist, which are divided into potentially benign and malignant variants (Fig. 1). Each variation demands a different approach in medical practice [4, 5]. The most important potentially malignant variation is an interarterial course, which can be a significant risk factor for sudden cardiac death (SCD) in physically active patients [6‐8]. Several high-risk anatomical features potentially contribute to the risk of ischaemia and SCD: a (long) intramural course (where the coronary artery shares its tunica media with the aorta), a slit-like ostium, proximal narrowing, an elliptical vessel shape, acute angle take-off and dominance of the ACAOS [4, 5, 9, 10]. The precise mechanism causing ischaemia in interarterial ACAOS is not known. The reported risk of SCD is higher for an interarterial left coronary artery (LCA) than for the more prevalent interarterial right coronary artery (RCA) [4‐6, 9, 10].

Evidence to guide treatment choices is currently scarce. Guidelines are primarily based on expert consensus and the findings of a limited number of studies [1, 3]. A class I indication for surgery exists only for ACAOS cases with an interarterial course and clear ischaemia-related complaints or proven ischaemia in the vessel’s supply area. However, age can be a complicating factor in this seemingly straightforward advice. In patients > 35 years, causes other than the ACAOS are seen to provoke complaints and ischaemia, such as obstructive or microvascular coronary artery disease or pulmonary disease, so for these patients treatment choices are not univocal [5, 11, 12]. Older patients also seem less prone to cardiac events caused by an interarterial ACAOS, for which reasons have not yet been elucidated [5]. For interarterial ACAOS without evidence of ischaemia, the American Heart Association (AHA)/American College of Cardiology (ACC) and the European Society of Cardiology (ESC) both provide a class IIa or lower level of evidence for surgical intervention. The AHA/ACC and ESC differ in their opinions on one point: the asymptomatic right interarterial ACAOS without myocardial ischaemia and without high-risk anatomy. The ESC specifically does not recommend (class III indication) surgery in these patients [3], but the AHA/ACC is not unequivocal with regard to surgical treatment versus continued observation (class IIb) [1]. Important when deciding on surgery are the expected benefits from surgery versus the peri-operative risks and risk of SCD of the uncorrected ACAOS. The methods most often applied for surgical correction are unroofing (preferred procedure in patients with a long intramural course), ostioplasty, and re-implantation of the coronary artery. Recent studies show that surgery is a safe option [4, 13, 14].

The beneficial effects of lifestyle restrictions and medical therapy (usually beta blockers) for a malignant ACAOS remain unclear and may contribute to anxiety regarding which level of exercise is considered safe [1, 4, 9]. For benign anatomical variants the consensus is that no interventions, exercise restrictions or medication are indicated [4].

In summary, the decision regarding how aggressive the approach to treat an ACAOS should be largely depends on the degree of malignant anatomical and physiological characteristics of the artery, i.e. the likelihood that the ACAOS causes ischaemia and/or a concomitant increased risk of SCD (Fig. 1). In clinical practice the criteria to decide whether an ACAOS is a benign or malignant variant are not uniform, and a ‘gold standard approach’ is lacking. Coronary computed tomography (CT) angiography is the best method to define the coronary anatomy and aids in the evaluation of anatomical high-risk features [1, 5], but physiological consequences cannot be adequately assessed with this technique. The most frequently used examinations to evaluate physiological aspects are: coronary angiography (CAG) with intracoronary measurements [15], stress echocardiography, exercise stress testing, perfusion magnetic resonance imaging with adenosine and nuclear perfusion imaging. These tests are endorsed by the 2018 AHA/ACC and 2020 ESC guidelines for the management of adults with congenital heart disease (class I indication) [1, 3], but it is unclear which examination(s) provide(s) the physician with the most useful information regarding the treatment decision. As a result, current clinical practice is very heterogeneous.

It is recommended that an aberrant left coronary artery from the pulmonary artery (ALCAPA) and an aberrant right coronary artery from the pulmonary artery (ARCAPA) are corrected because of the risk of myocardial ischaemia, SCD and effects on cardiac function [1, 3]. The infant type without adequate collateral filling mostly presents with myocardial infarction or congestive heart failure in the first few years of life. Patients with the adult type have a well-developed collateral system and may present in adult life for the first time with myocardial ischaemia-like complaints, left ventricular dysfunction or SCD [16]. The 2008 ACC/AHA guidelines for the management of adults with congenital heart disease recommend clinical follow-up every 3–5 years after repair [2]. The revised 2018 ACC/AHA and 2020 ESC guidelines do not give recommendations on the follow-up of this patient group [1, 3].

A CAVF is a communication between a coronary artery and another cardiovascular structure. Regardless of symptoms, large and haemodynamically significant fistulas are corrected, preferentially percutaneously, when they result in cardiac dysfunction. Small or haemodynamically insignificant fistulas are corrected if there are complications; otherwise conservative treatment is an accepted option [2, 3]. The 2008 ACC/AHA guidelines advise that patients visit the outpatient clinic every 3–5 years for evaluation of the haemodynamic sequelae of CAVFs [2]. The 2018 ACC/AHA and 2020 ESC guidelines do not provide recommendations on follow-up [1, 3]. Data on long-term outcomes are scarce, especially in asymptomatic patients with mostly uncorrected CAVFs [1, 2, 17].

Participating centres of the Multicentre Study on Coronary Anomalies in The Netherlands (MuSCAT) are the Leiden University Medical Centre, University Medical Centre Utrecht, Amsterdam University Medical Centre, Erasmus University Medical Centre, Radboud University Medical Centre and the Medisch Spectrum Twente. The study was approved by the Medical-Ethical Committee Leiden-The Hague-Delft in May 2020.

The study population will consist of consecutive patients with the diagnosis of an ACAOS, ALCAPA, ARCAPA or CAVF. Patient inclusion started in 2020 and will continue for at least 3 years with a minimum of 2 years of follow-up. Patients with a history of (haemodynamically significant) congenital heart defects other than the coronary anomaly and ACAOS patients with proven coronary atherosclerotic disease with significant stenosis will be excluded. After treatment of the stenosis, patients with an ACAOS are reconsidered for inclusion. Due to the rarity of the anomalies under investigation the aim is to include as many patients as possible within the study period, but a sample size target was not set.

Primary outcomes are (cardiac) death, myocardial ischaemia attributable to the anomalous vessel, re-intervention after surgical correction of ACAOS and intervention in initially conservatively treated patients. Secondary outcomes are quality of life based on the SF-36 questionnaire, thoracic complaints (typical, atypical, non-anginal) and heart failure requiring medical treatment.

Other outcomes evaluated are the influence of the work-up examinations on treatment choice, the degree of correlation between tests, and differences in treatment decision made by the referral hospital and the MuSCAT working group.

MuSCAT is the first nationally designed study in patients with ACAOS undergoing a dedicated diagnostic protocol and comparing different diagnostic techniques to evaluate their value in decision making, and also includes a registry of ALCAPA, ARCAPA and CAVF cases. The aim of the study is to provide evidence for protocolling the diagnostic work-up, treatment strategy and follow-up that can be used in daily clinical practice.