Clinical profile of congenital coronary artery anomalies with origin from the wrong aortic sinus leading to sudden death in young competitive athletes

Selection of subjects

Cases of sudden death in competitive athletes resulting from coronary artery anomalies with wrong aortic sinus origin were retrospectively assembled based on the review of two large registries in the U.S. and Italy. First, since 1990, the Minneapolis Heart Institute Foundation has developed a U.S.-based registry of sudden cardiovascular deaths in young competitive athletes (6), consecutively identified (largely from news media accounts) and tracked in a systematic fashion.

Second, since 1979, a clinicopathologic target project on sudden death in the young has been carried out in the Veneto region of northeastern Italy (including the cities of Venice, Padova, Treviso, Verona and Vicenza), which has a population of over four million (10). All hearts from cases of sudden death in young people (including athletes) in this geographic region are systematically assessed at the University of Padova.

Inclusion criteria

For inclusion into the study group, each patient fulfilled the following criteria (6,10): 1) a diagnosis at autopsy of congenital coronary anomaly of wrong aortic sinus origin—with an absence of other cardiac and noncardiac causes of death—based either on direct examination of the heart or analysis of a complete and detailed autopsy report; 2) a competitive athlete at the time of death—one who participated in an organized team or individual sport that required systematic training and regular competition against others and that placed a high premium on athletic excellence and achievement (18); 3) an age of ≤35 years at time of death; and 4) no evidence of drug or alcohol abuse upon the postmortem toxicologic examination of blood and urine.

Clinical information

Clinical data reported here were derived differently from the U.S. and Italian registries. Among U.S. athletes, medical evaluation and testing were stimulated by symptoms suggestive of cardiac disease and were not part of systematic preparticipation screening programs.

Italian athletes were clinically evaluated as part of the longstanding and systematic national preparticipation screening program for competitive athletes (10). Standard 12-lead electrocardiograms (ECGs) and limited exercise testing (step test) are routinely obtained as part of this program. Other cardiovascular testing, including maximal exercise stress ECG, may be obtained if judged to be clinically indicated. Myocardial perfusion imaging was not part of the evaluation of any patients in this study.

Statistical analysis

Continuous variables are expressed as mean ± SD. Chi-square or Fisher exact test were used to assess the significance of differences between subgroups. Two-tailed p values <0.05 were regarded as statistically significant.

Study patients

Twenty-seven competitive athletes comprised this study group by virtue of sudden cardiac death from a congenital coronary anomaly characterized by wrong aortic sinus origin (and course between the aorta and pulmonary trunk). These coronary anomalies included origin of the left main coronary artery (LMCA) from the right aortic sinus (n = 23) and origin of the right coronary artery (RCA) from the left sinus (n = 4).

Demographics

Of the 27 athletes, 22 were men and 5 were women; ages ranged from 9 to 32 years (mean 16 ± 5). Racial distribution was 16 whites (60%), 9 African Americans (33%) and 2 Asians (7%). Most athletes were competing either in junior high school (12; 44%) or high school (11; 41%); the remainder were professional (n = 3) or collegiate (n = 1) athletes. The athletes had participated in a variety of sports: basketball (n = 8), soccer (n = 7), football (n = 3), track-sprinting (n = 2), distance running (n = 2), as well as ice hockey, rugby, softball, cross-country and swimming (one each).

Each athlete died during (n = 25) or after (n = 2) intense exertion on the athletic field; 16 died during training, and 11 during organized competition. In 12 athletes (44%) the physical effort immediately before death was not only strenuous but also continuous and prolonged (>30 min). Nineteen of the 27 sudden deaths (70%) were clustered between 3 pm and 9 pm, corresponding to the peak time for participation in most competitive sports; only eight deaths (29%) occurred during the remaining 18 h of the day.

Clinical data

Of the 27 athletes, 15 had no clinical manifestations or testing performed (Table 1, Fig. 1); however, clinical information was available for the remaining 12 patients (Table 2). These two groups did not substantially differ with respect to demographic parameters (Table 1).

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Figure 1

Flow-chart showing clinical data available and findings in the present study group of athletes who died of wrong aortic sinus coronary artery anomalies.

Clinical testing

Standard 12-lead ECGs were performed at rest in nine athletes, 6 to 18 months (mean 11 ± 3) before their sudden deaths. Electrocardiogram patterns, including voltages, intervals and T wave morphology, were within normal limits for each (Fig. 2A). Two of these athletes, however, had isolated (one and two) premature ventricular complexes.

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Figure 2

A 15-year-old male Italian soccer player with a history of exertional syncope one year before death who died suddenly while running during the second half of a game. (A) A 12-lead ECG performed 10 months before death, as part of routine preparticipation screening, is within normal limits. (B) View of the aortic root; RCA arises normally from the right aortic sinus (arrow), and the LMCA arises anomalously from the right sinus with an acute angle take-off producing a slit-like lumen (arrowhead).

A maximal stress test ECG was available for six athletes (treadmill for three athletes from U.S. and bicycle for three from Italy), performed 6 to 18 months (mean 10 ± 4) before sudden death, and each was judged to be within normal limits. All athletes reached Stage V on the standard Bruce protocol with appropriate blood pressure and heart rate response during exercise and recovery. ST segment and T wave changes, arrhythmias and cardiac symptoms were absent. Also, a limited exercise test (step-test) was available in the six Italian athletes, and none showed abnormalities.

A two-dimensional echocardiogram was performed in two athletes and was normal with regard to left ventricular thickness and cavity dimension as well as segmental and global wall motion. These echocardiograms had not been interpreted prospectively with regard to coronary artery origin from the aorta.

When clinical and demographic variables were compared for athletes with an anomalous LMCA or an anomalous RCA, a statistically significant difference between the two subgroups was evident with respect to the prior occurrence of the major symptoms of syncope and chest pain (p = 0.04), which occurred exclusively in patients with an anomalous LMCA.

Background and prevalence

Sudden death in young competitive athletes is often caused by previously unsuspected congenital cardiovascular disease (1–10). The prevalence of athletic field deaths has been estimated to be 0.5:100,000 per year in high-school-age athletes in the U.S. (19) and 1.6:100,000 per year in competitive athletes in Italy (10). In most U.S. autopsy-based series, hypertrophic cardiomyopathy is the most common cause of young athletic field deaths (1,2,5–9). By contrast, in Italy hypertrophic cardiomyopathy is an uncommon cause of such deaths, probably largely because of effective preparticipation screening and disqualification from sports; as a consequence, arrhythmogenic right ventricular cardiomyopathy has become the most common cause of these catastrophes in Italy (3,4,10). Nevertheless, in each of these populations, a variety of congenital coronary artery anomalies have been reported as frequent causes for athletic field sudden death (up to about 20%) (3–5,8–10).

Among the congenital coronary malformations, coronary artery origin from the wrong aortic sinus (coursing between aorta and pulmonary trunk) appears to be the most common in young trained athletes dying suddenly. Indeed, we have previously reported that these malformations are associated with sudden death more commonly in competitive athletes than in non-athletes (10).

However, these anomalies are rarely suspected or identified during life and are usually first recognized at autopsy, largely because there is insufficient clinical suspicion as well as the difficulties implicit in routine examination or clinical testing for these malformations (10,20,21). Consequently, such coronary anomalies are not recognized during routine preparticipation screening (10,22,23). Therefore, we thought it would be important to develop a clinical profile and assess the utility of noninvasive testing in young competitive athletes who had died suddenly with anomalous coronary artery origin from the wrong aortic sinus. Previously published descriptions are largely represented by anecdotal case reports. Thus, we believe this study is unique because it represents the first consecutive series of young athletic field deaths due to these coronary malformations in which it is possible to systematically assemble clinical data collected during life.

Premonitory symptoms

Premonitory symptoms occurred not uncommonly during life among our study patients (in about one third). Syncope or chest pain occurred in seven athletes within 24 months of sudden death. In our athlete series, these major symptoms were limited to anomalous LMCA origin, while anomalous origin of the RCA proved to be clinically silent. Other authors have, however, reported a few patients with anomalous RCA who experienced either angina or syncope before death (24,25). Therefore, although sudden death is frequently the first manifestation in patients with wrong sinus coronary artery origin, premonitory symptoms occur in a substantial proportion of these individuals (20). In both types of wrong sinus coronary artery anomalies described here, the vast majority of clinical events were related to exertion. These observations emphasize the pressing need to raise the index of clinical suspicion in an effort to identify during life any wrong aortic sinus coronary artery origin in young, physically active individuals (10).

Efficacy of ECG testing

In the present retrospective study of trained athletes, we showed that neither routine 12-lead ECG nor exercise stress tests were particularly informative for the diagnosis of congenital coronary anomalies. In particular, each of the nine ECGs recorded under resting conditions were within normal limits. These findings in our series of patients are consistent with that of several case reports in which an ECG was recorded (unassociated with symptoms) (21). In addition, exercise ECGs were available in six of our athletes, and each was within normal limits. In a review of the literature, we found 18 young patients (≤35 years) with wrong aortic sinus coronary artery anomaly and reported exercise stress test findings (Table 3), of whom only three were competitive athletes (11,14,26–38). A positive stress test ECG was present in only four of the 18 patients (22%), including two who were symptomatic (but none of the athletes). Thus, a negative even maximal-effort stress ECG does not exclude a potentially lethal coronary anomaly.

Pathophysiology of myocardial ischemia and sudden death

The clinical data available in this series suggest that myocardial ischemia in young athletes with wrong aortic sinus coronary artery anomalies probably occurs in infrequent bursts, which may be cumulative with time. This view is supported by our data showing normal ECG patterns associated with pathologic evidence of acute myocardial ischemic damage and/or chronic ischemic injury with replacement-type fibrosis (in each of the six hearts available for morphologic reassessment). Thus, repetitive ischemic episodes may result in patchy myocardial necrosis and fibrosis, which could predispose to lethal ventricular tachyarrhythmias by creating an electrically unstable myocardial substrate. Considering the fact that these trained athletes had performed intense physical exercise many times before their fatal event (average age 16 years), it is most likely that critical impairment of coronary flow to the myocardium occurs only sporadically. Several potential mechanisms have been advanced to explain myocardial ischemia and sudden death in patients with wrong sinus coronary anomalies (11,12,16): the acute angle take-off and kinking of the coronary artery as it arises from the aorta; flap-like closure of the abnormal slit-like coronary orifice; compression of the anomalous coronary artery between the aorta and pulmonary trunk during exercise; and spasm of the anomalous coronary artery, possibly as a result of endothelial injury (39,40). Moreover, in three of the hearts we documented that, as previously described by others (11,39), the proximal portion of the anomalous coronary artery was essentially intramural (i.e., within the aortic tunica media), which could further aggravate the coronary obstruction, particularly with expansion of the aorta during exercise.

Strategies for clinical identification

On the basis of our findings, preparticipation screening, whether confined to standard history and physical examination or including 12-lead or exercise ECG (as is the practice in Italy), is limited in its power to identify coronary artery anomalies in young competitive athletes (10,22). Indeed, these lesions usually can be suspected only by prior symptoms such as syncope and angina, particularly if they occur during or immediately after exertion. Our observation that all 12-lead and exercise ECGs were within normal limits would seem to suggest that these tests are unlikely to provide clinical evidence of myocardial ischemia resulting from anomalous coronary artery origin, and they are therefore unreliable for clinical recognition of these coronary anomalies at preparticipation screening of competitive athletes (10).

A strategy for clinical identification of wrong sinus coronary artery anomalies in young athletes could be summarized as follows. If the index of suspicion is sufficiently high because of the presence of potential clinical markers such as exertional syncope or chest pain (even in the setting of both a normal 12-lead ECG and maximal exercise test), the anatomy of these malformations can be suspected or defined noninvasively by transthoracic or transesophageal echocardiography. Pelliccia et al. (41) demonstrated that echocardiographic imaging of left and right coronary arteries is feasible and reliable in a substantial proportion of young athletes (about 95%). Therefore, the failure to demonstrate that both the proximal left and right coronary arteries actually originate from their usual coronary sinuses in a young person with impaired consciousness or angina suggests the necessity of further anatomic definition with coronary arteriography (42) or possibly with magnetic resonance imaging (38,43,44) or computed tomography (45). An assessment of the diagnostic reliability of echocardiography in this regard for our patients was beyond the scope of the present paper. Two of our athletes had two-dimensional echocardiograms performed, but neither examination focused on the anatomy of coronary artery origin and course, as described by Pelliccia et al. (41).

Surgical management

Timely clinical identification of wrong sinus coronary artery anomalies in young trained athletes is crucial for two reasons. First, these coronary anomalies should result in exclusion from participation in intense competitive sports to reduce the risk of a cardiac event or sudden death (10,18). Second, and more importantly, wrong sinus coronary artery anomalies are surgically correctable (46). Indeed, operation is probably mandatory in any young person, particularly if symptomatic—with or without evidence of myocardial ischemia. Coronary artery bypass grafting remains the standard procedure for restoring normal distal coronary flow with good long-term results (46). An alternative surgical approach involves reimplantation of the anomalous vessel in the proper coronary sinus, but the results are still preliminary (25). Recently, a new operative technique has been employed in the setting of a proximal aortic intramural course (such as described here), in which the ostium of the anomalous coronary artery is modified at the aorta by excising (“unroofing”) the common wall located between the aorta and the anomalous coronary artery (36,37,47).