**10. Screening and risk identification**

Screening of ANOCOR in young populations and risk identification of known ANOCOR are both, two great challenges in order to impact on the incidence of life-threatening cardiac events.

#### **10.1 Screening**

In view of the fairly rare nature of ANOCOR it would be inappropriate to screen an unselected population. Moreover, the economic impact of screening in large populations should always be taken in consideration. Major obstacle of large-scale screening is the substantial number of young athletes eligible for evaluation (Maron et al. 2005). The subgroup of young athletes is certainly an interesting population in which to develop screening strategies. In a review of 387 sudden death in young athletes <35 years of age (Maron, 2003), the third most frequent cause is congenital anomalies of coronary arteries (13.7%) after hypertrophic cardiomyopathy (26.4%) and commotio cordis (19.9%). Among athletes suffering from an ANOCOR-related sudden death, a considerable number of anomalies were clinically silent. Although an intense exertion remains sometimes difficult to quantify, it would be reasonable to select among the young athletes those who will be exposed to competitive and high-intensity sports. However, time and content of such screening remain debatable. In the absence of specific European guidelines, the Study Group on Sports Cardiology of the Working Group on Cardiac Rehabilitation and Exercise Physiology of the European Society of Cardiology proposed recently, through a consensus statement, a screening project of young competitive athletes for prevention of sudden death (Corrado et al. 2005). The latter, based mainly on the large Italian experience, includes medical history, physical examination and 12-lead ECG. The screening should start at the beginning of competitive activity, which usually corresponds to an age of 12-14 years. This strategy seems useful in diagnosing an early hypertrophic cardiomyopathy. Otherwise, a resting ECG is unable to identify young people with ANOCOR except some anomalous connections in pulmonary artery (Cohen & Berger, 2010). Exercise stress test, with a known low sensibility in symptomatic high risk ANOCOR, is clearly inadequate for screening of an asymptomatic population. Among non-invasive imaging tools, ETT has the potential to identify some ANOCOR. Nevertheless, capacity for ETT should be dramatically increased and cardiologist should be trained to visualize coronary ostia. Meanwhile, better information among young athletes of frightening cardiac symptoms, i.e. chest pain or syncope in exertion, appears probably as a useful preventive measure to reduce the calamitous impact on the well-know sport benefits of each exercise-related sudden death. In addition, the visualization (or at least a meticulous search for) of origins of coronary arteries should be a routine part of any echocardiographic procedure in young population referred for functional assessments. Recently, the first series of familial ANOCOR was published with identification of 5 families in which a child or a young person <30-year old was diagnosed with preaortic ANOCOR generally symptomatic and another family member was identified with a preaortic ANOCOR through echocardiographic screening (Brothers et al., 2008). A systematic TTE screening for children and young people in families with a history of a major cardiac ANOCOR-related event (sudden death or aborted sudden death) may be discussed.

### **10.2 Risk identification**

212 Congenital Heart Disease – Selected Aspects

210,700 adult patients underwent selective coronary angiography (Krasuski et al., 2011). The mean age (58 ± 14 years) was relatively high in the ANOCOR cohort. As presenting symptoms, chest pain and dyspnea were common (66% and 58% of patients, respectively), as well as a myocardial infarction (24% of patients). However, the prevalence of significant CAD was of 68% in this population. Clinical presentations similar to CAD-related presentations are

The clinical presentation of anomalous connections with the pulmonary artery is different in children and adult populations. The mortality rate is high in infancy. In anomalous connection of the LCA with the pulmonary artery, an intermediate survival is possible with a major enlargement of the RCA and multiple intercoronary collaterals. In patients who survive into childhood, left ventricular enlargement and/or dysfunction, mitral valve incompetence, heart failure, myocardial infarction, or ventricular arrhythmias are reported, usually before 35 years age. Dyspnea and/or angina on exertion are the most frequent presenting symptoms (Kottayil et al., 2011). However, sudden death due to malignant ventricular arrhythmias may be the first cardiac event (Frapier et al., 1999). Fortuitous discovery is rare in asymptomatic patients with a continuous murmur due to

Screening of ANOCOR in young populations and risk identification of known ANOCOR are both, two great challenges in order to impact on the incidence of life-threatening cardiac

In view of the fairly rare nature of ANOCOR it would be inappropriate to screen an unselected population. Moreover, the economic impact of screening in large populations should always be taken in consideration. Major obstacle of large-scale screening is the substantial number of young athletes eligible for evaluation (Maron et al. 2005). The subgroup of young athletes is certainly an interesting population in which to develop screening strategies. In a review of 387 sudden death in young athletes <35 years of age (Maron, 2003), the third most frequent cause is congenital anomalies of coronary arteries (13.7%) after hypertrophic cardiomyopathy (26.4%) and commotio cordis (19.9%). Among athletes suffering from an ANOCOR-related sudden death, a considerable number of anomalies were clinically silent. Although an intense exertion remains sometimes difficult to quantify, it would be reasonable to select among the young athletes those who will be exposed to competitive and high-intensity sports. However, time and content of such screening remain debatable. In the absence of specific European guidelines, the Study Group on Sports Cardiology of the Working Group on Cardiac Rehabilitation and Exercise Physiology of the European Society of Cardiology proposed recently, through a consensus statement, a screening project of young competitive athletes for prevention of sudden death (Corrado et al. 2005). The latter, based mainly on the large Italian experience, includes medical history, physical examination and 12-lead ECG. The screening should start at the beginning of competitive activity, which usually corresponds to an age of 12-14 years. This strategy seems useful in diagnosing an early hypertrophic cardiomyopathy. Otherwise, a

possible in ≥ 50-year old patients free of significant CAD (Angelini et al., 2006).

**9.3 Anomalous connection with the pulmonary artery** 

interventricular collateral flow.

events.

**10.1 Screening** 

**10. Screening and risk identification** 

It is insufficient to note an abnormal origin of a coronary artery. A complete diagnosis with the orifice and the course of the ANOCOR will allow an accurate prognostic stratification. Risk identification is a major stage after a diagnosis of ANOCOR, because important therapeutic decisions and restrictive recommendations on lifestyle may follow from the final classification of the coronary abnormality. Usually, ANOCOR are identified at low-risk or high-risk with a strong evaluation criterion (sudden death). Nevertheless, one have to keep in mind that low-risk does not signify no risk. This classification is based first on postmortem examinations, because many of the patients with high-risk ANOCOR were previously diagnosed at autopsy. Now, with a better knowledge of these abnormalities and the development of imaging tools allowing an early diagnosis, it is mandatory that cardiologists and radiologists be familiar with the spectrum of congenital coronary abnormalities and their potential clinical relevance. However, the angiographers may be faced with difficult decisions for example a symptomatic patient with a low-risk ANOCOR or an asymptomatic patient with a high-risk ANOCOR. So far, no solid data are available on the natural history of ANOCOR with abnormal origin from the aorta. Several characteristics and parameters allow evaluation of sudden-death risk in most ANOCOR. However, in some cases, the classification may be difficult, and without enough information, it seems preferable to avoid too strict therapeutic rules. Indeed, it is always intriguing and not clear that among patients with the same high-risk ANOCOR, some will suffer from early sudden death, while others will die later in life of unrelated cause .

### **10.2.1 Type of coronary abnormality**

Despite its rare frequency, the natural history of anomalous connections with the pulmonary artery is better known, and the latter are classified as high-risk. The risk of sudden death is related to malignant arrhythmias or acute myocardial infarction. Progressive left ventricular dilatation and dysfunction secondary to chronic myocardial ischemia is the trigger for rhythmic disturbances occurring usually before 35 years of age. The main subgroup of high-

Proximal Anomalous Connections of Coronary Arteries in Adults 215

Age at the time of anomaly discovery is an important parameter in risk identification. In anomalous connections with the pulmonary artery, the risk of major adverse cardiac events exists probably during the entire life, even if this risk is more pronounced in early childhood. In contrast, for anomalous origins from the aorta, most sudden deaths occur between 10 and 35 years of age. Clinicopathologic presentations of 142 cardiac deaths in patients with congenital coronary anomalies were reviewed (Taylor et al., 1992). Sudden death occurred in 78 patients (32%). Younger patients (≤ 30-year old) died suddenly more frequently in comparison with older patients, 62% versus 12%, p=0.001, respectively, despite a lower frequency of CAD, 1% versus 40%, p = 0.00001, respectively. In a series of 690 sudden deaths occurred between 14 and 40 years of age, prevalence of ANOCOR identified as sole cause of death was of 8% between 14 and 20 years of age, of 4% between 21 and 30 years of age, and of 0.5% between 31 an 40 years of age (Virmani et al., 2001). Risk of sudden death in the absence of CAD seems very low after the age of 50 years, including so-called interarterial high-risk ANOCOR. However, some ANOCOR with intramural segment may be symptomatic late requiring interventional and/or surgical treatment (Angelini et al., 2006).

Obviously, the presence of CAD will interfere with the management of ANOCOR. A significant ostial or juxtaostial narrowing due to an intramural segment should not be confused with a fixed atherosclerotic stenosis. Sites of significant atherosclerotic lesions should be clearly distinguished, especially between ectopic segment and normal path. Association of CAD with ectopic segment of ANOCOR with a single ostium or with proximal path of a single coronary increases the risk. A higher prevalence of CAD has been suggested in CX coronary arteries but the location of atherosclerotic lesions is not always defined accurately in studies. However, most of them seem concordant with a higher incidence of atherosclerotic lesions in CX coronary arteries (Click et al., 1989, Wilkins et al. 1988). Table 9 summarizes the main

characteristics of low-risk and high-risk ANOCOR in young and adult populations.

 Low-risk High-risk Anomalous connection with the pulmonary artery - + Preaortic course with intramural segment - + Other courses with intramural segment - + Other courses without intramural segment + - Valve-like ostial stenosis - + Other anomalous connections + - History of aborted sudden death - + History of chest pain related to exertion - + History of syncope related to exertion - + History of severe ventricular arrhythmias - + Induced-myocardial ischemia - + Any anomaly above age of 50 years\* + - Ectopic segment with significant atherosclerotic lesion - +

Table 9. Main characteristics of low-risk and high-risk proximal anomalous connections of

**10.2.3 Age** 

**10.2.4 Associated coronary artery disease** 

\* Except anomalous connections with the pulmonary artery.

the coronary arteries.

risk ANOCOR includes abnormalities with a preaortic course associated with an intramural segment, especially anomalous connections of LCA and RCA from the opposite sinus. If initially, the LCA with preaortic course has been recognized as the most frequent sudden death-related ANOCOR, it is clear that the RCA arising from the opposite sinus may also be a cause of sudden death (Frescura et al, 1998, Kragel & Roberts, 1988, Taylor et al., 1992). As previously discussed, almost without exception, the RCA originating from the left sinus has a preaortic course and thus a high-risk profile. The smaller myocardial territory at risk in right versus left ANOCOR is hypothesized to explain the lower incidence of sudden death in right ANOCOR despite it being more frequent than left ANOCOR. Universally, anomalous connection of the CX coronary artery, with an almost exclusive retroaortic course, is classified as low-risk ANOCOR. The subgroup of ectopic LMCA or LAD coronary artery represents certainly the greatest challenge for angiographers to accurately identify the ectopic course. As mentioned above, ANOCOR with preaortic course and ANOCOR with retroinfundibular course were previously often confused. The latter are recognized as lowrisk in contrast to the ANOCOR with preaortic course. In the young population, a misdiagnosis may lead to dramatic consequences. Currently, the widely used tomographic tools allow an easy and flexible image interpretation, which should limit the risk of mistake. Other courses of LMCA or LAD coronary artery, i.e. preinfundibular and retroaortic courses are classified as low-risk. Surprisingly, anomalous origins in the opposite sinus and anomalous origins in the contralateral artery are rarely distinguished. As aforementioned, frequency of an intramural segment may be different between an abnormal connection near the orifice of the contralateral artery and an abnormal connection in the contralateral artery.

#### **10.2.2 Symptoms and induced-myocardial ischemia**

The numerous ANOCOR-related sudden deaths reported in the literature suggest that they are in most cases unpredictable. However, a more accurate analysis of the data shows that in more than half of patients suffering from sudden death, premonitory symptoms were identified after the fatal event, especially chest pain and syncope on exertion. These deaths are always to be deplored but some characteristics of the exposed population can explain an absence of diagnosis. On the one hand, young athletes may hide or underestimate symptoms, and they do not systematically interfere with usual intensive and repetitive efforts. On the other hand, medical teams can misinterpret some clinical presentations in a young and healthy population with a low prevalence of CAD, as unimportant. In addition, exercise stress tests are usually reassuring. Difficulties in inducing myocardial ischemia with the usual tools are well-described, even in symptomatic high-risk ANOCOR. In as series of 27 sudden deaths in young athletes, due to ANOCOR, all maximal exercise stress tests (6/6) were judged within normal limits (Basso et al. 2000). In addition, intermittent ischemia was described in rare cases (Brothers et al., 2010). The experience of fractional flow reserve (FFR) assessment with a pressure-wire during coronary catheterization remains limited. Angelini and coworkers speculated that functional tests suggested usually in patients with CAD are probably not appropriate for risk evaluation in patients with ANOCOR, and proposed pharmacologic tests simulating extreme exercise efforts (Angelini et al. 2003). In order to increase dramatically cardiac output and stroke left ventricular volume, concomitant administration of saline, atropine and dobutamine may lead to a significant systolic expansion of aorta. IVUS can identify the impact of this on the degree of lateral compression in the intramural segment, with sometimes a visualization of >50% area stenosis.

#### **10.2.3 Age**

214 Congenital Heart Disease – Selected Aspects

risk ANOCOR includes abnormalities with a preaortic course associated with an intramural segment, especially anomalous connections of LCA and RCA from the opposite sinus. If initially, the LCA with preaortic course has been recognized as the most frequent sudden death-related ANOCOR, it is clear that the RCA arising from the opposite sinus may also be a cause of sudden death (Frescura et al, 1998, Kragel & Roberts, 1988, Taylor et al., 1992). As previously discussed, almost without exception, the RCA originating from the left sinus has a preaortic course and thus a high-risk profile. The smaller myocardial territory at risk in right versus left ANOCOR is hypothesized to explain the lower incidence of sudden death in right ANOCOR despite it being more frequent than left ANOCOR. Universally, anomalous connection of the CX coronary artery, with an almost exclusive retroaortic course, is classified as low-risk ANOCOR. The subgroup of ectopic LMCA or LAD coronary artery represents certainly the greatest challenge for angiographers to accurately identify the ectopic course. As mentioned above, ANOCOR with preaortic course and ANOCOR with retroinfundibular course were previously often confused. The latter are recognized as lowrisk in contrast to the ANOCOR with preaortic course. In the young population, a misdiagnosis may lead to dramatic consequences. Currently, the widely used tomographic tools allow an easy and flexible image interpretation, which should limit the risk of mistake. Other courses of LMCA or LAD coronary artery, i.e. preinfundibular and retroaortic courses are classified as low-risk. Surprisingly, anomalous origins in the opposite sinus and anomalous origins in the contralateral artery are rarely distinguished. As aforementioned, frequency of an intramural segment may be different between an abnormal connection near the orifice of the contralateral artery and an abnormal connection in the contralateral artery.

The numerous ANOCOR-related sudden deaths reported in the literature suggest that they are in most cases unpredictable. However, a more accurate analysis of the data shows that in more than half of patients suffering from sudden death, premonitory symptoms were identified after the fatal event, especially chest pain and syncope on exertion. These deaths are always to be deplored but some characteristics of the exposed population can explain an absence of diagnosis. On the one hand, young athletes may hide or underestimate symptoms, and they do not systematically interfere with usual intensive and repetitive efforts. On the other hand, medical teams can misinterpret some clinical presentations in a young and healthy population with a low prevalence of CAD, as unimportant. In addition, exercise stress tests are usually reassuring. Difficulties in inducing myocardial ischemia with the usual tools are well-described, even in symptomatic high-risk ANOCOR. In as series of 27 sudden deaths in young athletes, due to ANOCOR, all maximal exercise stress tests (6/6) were judged within normal limits (Basso et al. 2000). In addition, intermittent ischemia was described in rare cases (Brothers et al., 2010). The experience of fractional flow reserve (FFR) assessment with a pressure-wire during coronary catheterization remains limited. Angelini and coworkers speculated that functional tests suggested usually in patients with CAD are probably not appropriate for risk evaluation in patients with ANOCOR, and proposed pharmacologic tests simulating extreme exercise efforts (Angelini et al. 2003). In order to increase dramatically cardiac output and stroke left ventricular volume, concomitant administration of saline, atropine and dobutamine may lead to a significant systolic expansion of aorta. IVUS can identify the impact of this on the degree of lateral compression

in the intramural segment, with sometimes a visualization of >50% area stenosis.

**10.2.2 Symptoms and induced-myocardial ischemia** 

Age at the time of anomaly discovery is an important parameter in risk identification. In anomalous connections with the pulmonary artery, the risk of major adverse cardiac events exists probably during the entire life, even if this risk is more pronounced in early childhood. In contrast, for anomalous origins from the aorta, most sudden deaths occur between 10 and 35 years of age. Clinicopathologic presentations of 142 cardiac deaths in patients with congenital coronary anomalies were reviewed (Taylor et al., 1992). Sudden death occurred in 78 patients (32%). Younger patients (≤ 30-year old) died suddenly more frequently in comparison with older patients, 62% versus 12%, p=0.001, respectively, despite a lower frequency of CAD, 1% versus 40%, p = 0.00001, respectively. In a series of 690 sudden deaths occurred between 14 and 40 years of age, prevalence of ANOCOR identified as sole cause of death was of 8% between 14 and 20 years of age, of 4% between 21 and 30 years of age, and of 0.5% between 31 an 40 years of age (Virmani et al., 2001). Risk of sudden death in the absence of CAD seems very low after the age of 50 years, including so-called interarterial high-risk ANOCOR. However, some ANOCOR with intramural segment may be symptomatic late requiring interventional and/or surgical treatment (Angelini et al., 2006).

#### **10.2.4 Associated coronary artery disease**

Obviously, the presence of CAD will interfere with the management of ANOCOR. A significant ostial or juxtaostial narrowing due to an intramural segment should not be confused with a fixed atherosclerotic stenosis. Sites of significant atherosclerotic lesions should be clearly distinguished, especially between ectopic segment and normal path. Association of CAD with ectopic segment of ANOCOR with a single ostium or with proximal path of a single coronary increases the risk. A higher prevalence of CAD has been suggested in CX coronary arteries but the location of atherosclerotic lesions is not always defined accurately in studies. However, most of them seem concordant with a higher incidence of atherosclerotic lesions in CX coronary arteries (Click et al., 1989, Wilkins et al. 1988). Table 9 summarizes the main characteristics of low-risk and high-risk ANOCOR in young and adult populations.


\* Except anomalous connections with the pulmonary artery.

Table 9. Main characteristics of low-risk and high-risk proximal anomalous connections of the coronary arteries.

Proximal Anomalous Connections of Coronary Arteries in Adults 217

gold standard anatomical technique. A slit-like orifice may have a large area, but can collapse with a valve-like manner, during an abrupt increase in pressure and/or volume in the aorta. Vessel hypoplasia is another potential cause of decrease in blood supply under extreme conditions. CT imaging and IVUS are useful to demonstrate a non atherosclerotic reduction of the lumen vessel in the initial ectopic path (figure 22). Another abnormality contributing to myocardial ischemia is the intramural segment of the ectopic vessel. Histology and ultrasonography demonstrated the non circular shape of intramural segment thoroughly. The oblong area of the latter may be more exposed to the dynamic changes of the aortic wall.

Fig. 22. Multiplanar reconstruction of computed tomography showing an hypoplasia of the initial path (arrow) of a right coronary artery arising from the left sinus. AO: aorta, RV: right

If numerous anatomical risk factors were identified, the relative contribution of each factor is not clear. In a study, no significant differences were found in length of intramural segment, coronary ostial size, or angle of coronary take-off between right or left ANOCOR arising from the opposite sinus, with (n=12) and without (n=18) sudden death (Taylor et al., 1997). Age ≥ 30 years was the only factor with a lower incidence of sudden death. Apart from the fact that intensive exercises are preferably performed during the young age, the dramatic reduction of sudden death risk after the age of 30 years remains surprising. The progressive hardening of the aortic wall has been suggested as a pathophysiological mechanism, with less dynamic changes of the aortic media during exertion. Otherwise, clotting and spasm have often been suspected but rarely proven as further mechanisms leading to acute coronary events. Furthermore, large sequelae of transmural myocardial infarction are rare in necropsy cases. Nevertheless, chronic myocardial ischemic damage may occur and lead to fatal arrhythmias. Histologic examination of heart specimens of young athletes suffering from sudden death may show patchy replacement-type fibrosis (Basso et al., 2000) or scattered foci of contraction band necrosis (Corrado et al., 1992). CX coronary artery arising from the opposite sinus or the RAC is a well-known abnormality deemed benign. Nevertheless, suspicion exists about an earlier atherosclerotic formation in

ventricle.
