Aim To raise awareness of congenital coronary artery anomalies (CCAAs) as an important cause of sudden cardiac death (SCD) in athletes, we describe a cohort of the malignant subset. Defining the key anatomical features for the cardiologist and pathologist to be aware of and detailing a systematic approach to examining the coronary arteries at autopsy.
Methods Retrospective non-case-controlled analysis of 2304 cases of SCD referred by pathologists between 1994 and January 2012.
Results 31 (1.3%) of the 2304 cases of SCD had CCAAs; 24 men (77%) and 7 women (23%), mean age 28 years (range 16 months–63 years). In 15 cases (48%), SCD occurred during or immediately after physical exertion. Cardiac symptoms were documented to have occurred in only seven patients (23%) prior to SCD. The anomaly had been identified by the referring pathologist in only 11 of the 31 cases (35%).
Conclusions CCAAs are a rare and mostly benign entity, but a subset has the potential to be fatal without any forewarning. In a significant proportion of cases identified in this large cohort, the victim was under exertion at the time of death, highlighting the relevance of this anomaly to the sports and exercise medicine community.
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Congenital coronary artery anomalies (CCAAs) are rare and the majority are benign with no haemodynamic or prognostic implications. Twenty per cent are considered to be ‘malignant’ lesions and have the potential for life-threatening complications, including myocardial infarction, arrhythmia, congestive heart failure and sudden cardiac death (SCD) early in life or during adulthood.1
In young, competitive athletes, coronary artery anomalies have been cited as the second most frequent cause of SCD, accounting for 12% of deaths, second only to hypertrophic cardiomyopathy, which totalled one-third of cases.2 They have also been reported to cause 1.2% of non-sports-related deaths.3
CCAAs are rarely identified before postmortem examination, often because of insufficient clinical suspicion and the finding that basic preparticipation screening, such as routine and exercise ECGs, is not sensitive in detecting the anomaly.4 Therefore, it is the pathologist who first makes the diagnosis.
This paper describes a large cohort of the malignant subset of coronary anomalies with the aim of increasing awareness of this condition within the sports and exercise medicine community. We also detail an approach pathologists can utilise in order to accurately examine the coronary artery system in order to identify the anomaly and make a more accurate diagnosis of SCD in athletes.
The Cardiac Risk in the Young (CRY) Centre for Cardiac Pathology at Royal Brompton Hospital acts as a specialist tertiary cardiac pathology centre for SCD in the UK. We have established a database of 2304 hearts between 1994 and January 2012. Histological sections from the coronary arteries, myocardium, a single myocardial transverse section of the ventricles, or whole hearts are referred by coroners and pathologists throughout the UK.
Pathological analysis of all specimens using defined protocols was performed by the senior author (MNS) with the consent of the coroner and family of the deceased.5 The heart tissue was analysed macroscopically and microscopically to identify anomalies of the coronary arteries and any resultant acute or chronic ischaemic damage.
Histological criteria for ischaemic damage in the heart included acute changes with contraction band necrosis, hypercontracted myocytes and myocyte necrosis with surrounding acute neutrophilic inflammation. Chronic changes included granulation tissue and replacement fibrosis in the myocardium.6–8 Myocardial fibrosis was highlighted after staining with H&E as well as an elastic Van Gieson stain. Other causes of fibrosis, such as coronary artery atheroma, coronary thrombosis/emboli and cardiomyopathies, including hypertrophic cardiomyopathy, dilated cardiomyopathy and arrhythmogenic right ventricular dysplasia were excluded with reference to specific criteria.5
We also defined the premortem clinical findings for each case. Patient's age, sex, circumstances of death, antecedent cardiac symptoms, medical history and a family history of cardiac disease (when available) were obtained from the referring pathologist’s case report. All patients included in this study underwent a toxicology screen as part of the coroner's mandate since all deaths were sudden and unexpected.
Examination of coronary vessels
To expose the aortic valve architecture and reveal the ostia of the coronary arteries, an incision is made across the aorta above the cusps of the aortic valve. The origin of each artery within their respective sinus is identified. While the majority arise within the sinus, there is great variation in the exact location.9 A probe 2 mm in diameter is inserted into each coronary orifice. When viewed from the frontal plane, the right coronary artery (RCA) normally arises at a nearly 90° angle to the aortic sinus, whereas the left coronary artery (LCA) commonly descends at a 45° angle.10 The first ventricular branch from RCA is the infundibular branch, which often arises from a separate orifice in the right hand facing sinus. The LCA branches after a variable distance between the pulmonary trunk and the left atrial appendage into the circumflex and left anterior descending (LAD) coronary artery, but a third branch, the intermediate branch, is occasionally found.
Detailed dissection identifying the distribution of each vessel is then performed. Transverse cuts, each 5 mm apart throughout the length of both vessels, is required. To locate RCA deep within the fat of the right atrioventricular (AV) groove can be difficult especially in obese participants; this requires deep transverse cuts, tracing the vessel from its origin to the posterior descending vessel. RCA is usually dominant, supplying the posterior descending coronary artery.
To visualise the proximal LCA deep within fat, wedged between the aorta, pulmonary artery and left atrial appendage, can be difficult. Therefore, the distal LAD is examined first in the anterior interventricular groove close to the apex and the vessel can be traced back to the division into the circumflex, the main stem and finally back to the left coronary sinus.
The course of the circumflex artery is variable and runs deep in the fat of the left AV groove beneath the left atrial appendage. In some, the course is short, supplying the obtuse margin of the left ventricle; in others, it supplies a larger territory, giving branches to the left atrium and ventricle as it courses around the left AV groove. These are known as obtuse marginal branches and can be one to five in number.
The CRY Sudden Cardiac Death Database totals 2304 cases between 1994 and January 2012. CCAAs were associated with 31 deaths, giving an incidence of 1.3%. Twenty-four of the affected individuals (77%) were men and seven were women (23%), with the age range varying from as young as 16 months to 63 years (mean 28 years). Ten of the patients (32%) in this study were in the >35 year age group.
The coronary artery anomaly had been identified by the referring pathologist in only 11 of the 31 cases (35%) prior to the detailed histological examination in our department.
In 15 cases (48%), SCD occurred during or immediately after physical exertion, 12 of which were sport related (football/rugby/cross-country) and 3 occurred after a stressful event (postfight/attack). Of these 15 cases, only 5 experienced cardiac symptoms (chest pain, syncope or breathlessness) prior to their death. Four experienced a syncopal attack on previous exertion and one experienced chest pain and breathlessness.
In 12 cases, SCD occurred at rest. One patient died following a general anaesthetic after a dental procedure. In another case, the patient died after cardiac surgery in which an unidentified anomalous RCA was inadvertently compromised after resuspension of the aortic valve following an emergency repair of an acute type A aortic dissection.
Clinical data were obtained from the referring pathologist/coroner and were available for 27 of the 31 patients. Cardiac symptoms were documented in only seven patients (23%) prior to their death. In five patients, the symptoms were related to previous exertion and in two patients, they were present at rest. In the remaining 20 patients, there were no cardiac symptoms documented to have occurred from the reports available. Also, there was no documentation of the anomaly having been identified antemortem. The toxicology screens in all patients were negative.
Cases of CCAAs were classified into three groups: (1) anomalous coronary origin (2) coronary artery ostial stenosis/atresia and (3) myocardial bridging.
An anomalous coronary artery origin was found in 21 cases, equating to 0.9% of all-cause SCDs. There were 7 cases of anomalous origin of LCA from the right coronary sinus (figure 1), 10 cases of RCA arising from the left coronary sinus, 2 cases of anomalous LCA arising from the pulmonary artery (ALCAPA; figure 2) and in the remaining 2 cases, there was high take-off of RCA from the aorta. Acute and/or chronic ischaemic damage in the regional myocardium (figure 3) was present in 14 of the 21 cases: 6 of the 7 cases of LCA, 6 of the 10 cases of RCA and in both cases of ALCAPA.
In the cases where the origin was from the opposite coronary sinus—all had an interarterial course between the aorta and the pulmonary artery (figure 4); in eight cases, the affected artery was found to have an aortic intramural course (traversing within the aortic wall), and in seven the anomalous artery had an elliptical opening.
In the two cases of ALCAPA, the SCD victims were both women, aged 22 and 43 years. There was acute and/or chronic infarction in the left ventricular wall in both the cases. The 22 years old was asymptomatic up until her death. The 43 year old died unexpectedly while swimming with no prior symptoms.
There were two cases of coronary artery high take-off, both affecting the RCA. In one case, the origin of the artery was 15 mm above the sinutubular junction and had an acute angle take-off. The other arose 6 mm above the sinutubular junction, had an intramural course of 1 mm and traversed between the great vessels for a distance of 5 mm. Both were men, aged 44 and 18 years, respectively. The heart was otherwise found to be normal macroscopically and microscopically.
Coronary artery ostial stenosis/atresia was seen in three cases: two children and an adolescent. One patient had RCA ostial stenosis with narrowing of the vessel; in the second case, the LCA ostium was narrowed by a shelf lesion, while the third case had no LCA ostium with a small elliptical indentation with hypoplasia of the LAD coronary and circumflex arteries. In all cases, acute and/or chronic ischaemic damage was identified in the myocardium supplied by the abnormal vessel.
The third group consisted of seven cases of myocardial bridging of the proximal LAD (figure 5). The bridge varied from 15 to 30 mm in length and 2–9 mm in depth. On histological analysis, there was ischaemic damage evident in the territory supplied by the bridged artery in six cases. In the remaining case, the heart appeared normal. Hypertrophic cardiomyopathy was excluded in all cases. The majority of patients were men. Three patients were under exertion at the time of SCD.
A summary of the clinical and histopathological findings for the entire cohort is displayed in table 1. The numbers were too small to perform meaningful statistical analyses.
Sudden death from cardiovascular disease is the leading cause of death in young athletes during exercise and represents 75% of all fatalities during sport.11 We define SCD as the unexpected natural death from a cardiac cause within a short time period, generally ≤1 h from the onset of symptoms, in a person without any prior condition that would appear fatal.12 A number of high profile studies in the USA have reported the rate of SCD from coronary artery anomalies in athletes as being between 9.5% and 33%13 ,14
The incidence of CCAAs has been reported as being between 0.2% and 5.6% of the general population.15 ,16 Statistics appear to vary depending on the method (angiography vs autopsy), the diagnostic criteria and the population studied. The incidence of CCAAs in this study was 1.3%, which is within the range of previously reported statistics.
The majority of CCAAs are found incidentally with little clinical significance. A small number are potentially fatal. The high-risk anatomical features to be aware of include
Anomalous origin of the coronary artery from the pulmonary trunk.
Anomalous origin of a coronary artery from the opposite sinus (ACAOS) of Valsalva with an intramural and/or interarterial course, its defining pathophysiological feature being the proximal section of the ectopic artery having an intramural course, which leads to variable degrees of functional obstruction.17
Coronary artery ostial stenosis/atresia.
Patients with an anomalous artery with an interarterial course have a high risk of SCD because of certain anatomical factors that may narrow the origin or proximal aspect of the vessel and limit flow. These include an acute angle of origin of the artery, an abnormal slit-like orifice, stretch of the intramural segment, vasospasm and compression of the anomalous artery between a distended aorta and pulmonary trunk (eg, with exercise).18 Symptomatic patients have a longer aortic intramural course than asymptomatic patients, as assessed by preoperative imaging and intraoperative measurements.19
Pathologists may overlook the above listed high-risk anomalies as evident by the fact that only 35% of the referring pathologists identified CCAAs of the SCD victim. We speculate that this is because pathologists are not routinely examining the coronary ostia in sufficient detail, which may be the reason why they are being overlooked. There is no evidence that pathologists in Europe or the USA are better at detecting coronary artery anomalies than those in the UK.
Clinically, individuals with CCAAs are often asymptomatic and SCD is the first presentation,20 which is supported by only 23% of the SCD victims in this study having documented cardiac symptoms prior to their death. Thus, it is the pathologists who first make the diagnosis. Most cases are spontaneous with no familial history and the family can usually be reassured that other members are unlikely to be affected.21
The diagnosis is rarely possible with a questionnaire, routine or exercise ECG which have been suggested for screening, especially in athletes. In the 25-year Italian preparticipation screening experience, there was a 90% reduction in the incidence of exercise-related SCD, but the number of deaths from this anomaly remained unchanged because these investigations are often normal in these cases.4 If there is any suspicion of a cardiac abnormality in an athlete, exercise testing and echocardiography are the initial diagnostic steps. Transthoracic echocardiography can show the origin of the right and left coronary arteries in 95% of cases.22 Advanced imaging modalities, such as cardiac MRI and multidetector CT, are increasingly used in the evaluation of the athlete's heart.23 Cardiac MRI is preferred below 35 years of age as it requires no radiation or intravenous contrast agent. If confirmation is needed, multidetector CT angiography can visualise the coronary tree.
Medical management of ACAOS with β-blockers has been superseded by a myriad of surgical options, including coronary artery bypass grafting, reimplantation of the anomalous vessel into its appropriate sinus or pulmonary artery translocation to reduce the risk of compression of the anomalous vessel as it traverses between the aorta and the pulmonary artery.24 ,25 Recently, unroofing the anomalous vessel along its intramural segment has become the preferred management option.26
There is controversy over which anomalies require surgical intervention and which are more appropriately left alone with the risk of surgery outweighing the risk of SCD.27 We are in support of certain anatomical factors rendering the individual at a higher risk of SCD, as we have detailed above. The decision to intervene should take into account the presence of these high-risk features and any symptoms present at the time of diagnosis. There is a general consensus among those who have published on this topic that more information is needed to aid in the clinical decision-making process.28
It is not only a threat to the young athlete where the majority of existing research is focused2 ,29 but also older adults who are also at risk of SCD from CCAAs. Our study highlights the significance of CCAAs in the >35-year age group, with 10 (32%) individuals falling into this age bracket.
In 23 of the total 31 cases, histological examination revealed acute/chronic ischaemic changes within the regional myocardium, supporting the association between the coronary anomaly and SCD. In the eight cases where a detailed macroscopic and microscopic examination revealed a morphologically normal myocardium, uncertainty arises with respect to the cause of death. A primary arrhythmic event cannot be excluded in these cases. Postmortem genetic testing (molecular autopsy) to exclude the ion channelopathies is not routinely available in the UK. Also, the presence of a mutation does not necessarily mean it is pathogenetic or a cause of SCD.30 Baum et al31 unveiled an important finding that only 20% of the survivors from out-of-hospital cardiac arrests had a new transmural infarction, with a significant number showing no infarction or necrosis in the postresuscitation period. We therefore advise that CCAAs should not be excluded as the cause of death if no ischaemic damage is present.
Anomalous origin of coronary artery
In this subset, we have included RCA and LCA arising from the opposite sinus and then traversing across the heart to resume a normal course, origin of the coronary artery from the pulmonary trunk and high take-off.
ACAOS is well established as a cause of SCD.2 ,29 Frequently quoted autopsy reports have suggested a 57% mortality for an anomalous LCA originating from the right coronary sinus and a 25% mortality rate for RCA originating from the left coronary sinus.32
ALCAPA has been reported in 1 in 300 000 live-births and is well known to be fatal in infancy if left untreated. Yau et al33 performed an extensive literature search of the adult cases of ALCAPA to find a total of 151 cases: 66% presented with symptoms of angina, dyspnoea, palpitations or fatigue; 17% presented with ventricular arrhythmia, syncope or sudden death; and 14% were asymptomatic. Early presentation of this anomaly usually induces extended myocardial necrosis and severe heart failure. Late presentation is characterised by the abundant development of intercoronary collaterals resulting in mild and rare symptoms and can cause SCD.34
High take-off of the coronary artery has been associated with SCD.35 In our study, there was no myocardial ischaemic damage, and therefore causation of SCD is controversial. High coronary ostia have been reported in up to 6% of adult hearts.36 The orifices of the coronary arteries are normally located at or below the sinutubular junction. Frescura et al36 suggested that people with a high take-off were prone to ischaemia because the coronary artery may have a vertical intramural aortic course and a slit-like lumen.
Anomalies of intrinsic coronary artery anatomy
Coronary artery ostial stenosis is another rare cause of SCD. Topaz et al37 described 12 of 21 545 patients (0.06%) who underwent coronary angiography as having an isolated LCA ostial stenosis. Most cases have been described in infants and children similar to our cases.38 It is often associated with a non-atherosclerotic membrane projecting from the wall of the aorta into the coronary ostium, resulting in a valve-like ridge.39 This anomaly is considered to be significant if the surface area of the ridge exceeds 50% of the coronary ostial luminal area.40 Coronary artery atresia is among the rarest of cardiac anomalies causing SCD.41
The significance of myocardial bridging is controversial in its relation to SCD. Many do not even consider it as a classic coronary anomaly as it has been reported to occur in >1% of the population, both in angiographic (0.5–2.5%) and autopsy (5.4–85.7%) studies.42 Some have reported that myocardial bridging is an incidental finding with no long-term clinical sequelae.43 Kramer et al44 reported the 5-year survival of 81 participants with isolated bridging to be 97.5%, with neither of the two deaths being related to the myocardial bridge. However, bridging has also been reported in association with myocardial ischaemia, arrhythmias, left ventricular dysfunction and SCD.42 This anomaly is clinically and pathologically significant when it has a long (20–30 mm) and deep (2–3 mm) intramyocardial course.45
The CRY centre acts as a specialised tertiary referral centre for SCD with pathologists referring cases when the findings are ambiguous or no clear cause of death can be identified. Hence, the reported incidence of CCAA is skewed to include a larger proportion of the rarer cardiac anomalies. In cases where there was no identified acute/chronic myocardial ischaemia at autopsy, we are less certain in attributing the coronary anomaly as a cause of SCD, and a primary arrhythmic event cannot be excluded.
CCAAs are a rare and mostly benign entity but have the potential to be fatal without any forewarning. In over half of the cases identified in this large cohort, the victim was under exertion at the time of death, highlighting the relevance of this anomaly in sports and exercise medicine. Basic preparticipation screening tests including routine or exercise ECG do not identify the anomaly. If any clinical suspicion transthoracic echocardiography will identify coronary artery abnormalities in the vast majority of cases. If identified during life, the decision to intervene should take into account the presence of high-risk anatomical features and any symptoms present at the time of diagnosis. CCAAs should be excluded as a cause of death in all athletes and this is reliant on the pathologist completing a detailed examination of the coronary artery system identifying coronary artery ostia and their course.
What are the new findings?
Incidence of malignant subset of congenital coronary artery anomalies (CCAAs) in the UK population.
Pathologists are not routinely diagnosing CCAAs as a cause of sudden cardiac death (SCD) in athletes in the UK.
Highlighting CCAA as a cause of death in the older adult population (>35 years).
Describing in detail rare coronary artery pathology.
Detailing an approach to examining the coronary artery system at autopsy.
How might it impact on clinical practice in the near future?
Draw attention to this anomaly as a cause of SCD in athletes leading to improved detection rates and a more accurate diagnosis of cause of SCD postmortem.
Impact on the training of general/cardiac pathologists in order to improve examination of the coronary artery system in SCD victims.
Contributors SFH designed, led and carried out a write-up of the entire project under the supervision of MNS.
Funding Financial support was provided by the charity Cardiac Risk in the Young (CRY). Registered Charity No. 1050845, CRY, Unit 7, Epsom Downs Metro Centre, Waterfield Tadworth Surrey KT20 5LR (http://www.c-r-y.org.uk).
Competing interests None.
Ethics approval This study has been approved by the Ethics Committee of Royal Brompton Hospital, reference number 01–112. This study complies with the requirements of the Human Tissue Act 2004.
Provenance and peer review Not commissioned; externally peer reviewed.
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