Nonatherosclerotic Coronary Artery Disease
Allen P. Burke, M.D.
Fabio R. Tavora, M.D., Ph.D.
Congenital Anomalies of Coronary Circulation
Overview
Congenital anomalies of the origin and course of coronary arteries are relatively uncommon with a reported incidence of 0.2% to 1.2%.1 They are generally divided into anomalies of origin, course, and termination (Table 155.1).
Symptoms shared by most anomalous coronary patterns include syncope and chest pain and frequently occur immediately before death or during exercise. Unfortunately, screening tests, including stress electrocardiography and echocardiography, are often negative, underscoring the need for more sensitive noninvasive imaging studies. Clinically, arteriography remains the gold standard method for evaluation of anomalous coronaries and evaluation of ischemic episodes in young patients with a suspected anomalous artery. The application of multislice computed tomography and cardiac magnetic resonance for cardiac imaging is increasing and becoming, along with other techniques, recognized methods of examination of the coronary arteries.2
TABLE 155.1 Types of Congenitally Anomalous Coronary Arteries | |||||||||||||||||||||||||||||||||||||||||||||||
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Anomalous Origin of Coronary Circulation from Pulmonary Artery
Coronaries arising in the pulmonary circulation represent a rare cause of sudden death and heart failure in infants and children and are generally fatal if not surgically corrected. Most cases are identified within the first year of life, but some patients live well into the second and even third decade without a diagnosis.3,4 Approximately 75% of patients will die before age 1 year, and the remainder dies or comes to clinical attention between 1 and 20 years of age. Symptoms occur in the majority of patients, although sudden unexpected death in the absence of prior symptoms has been reported. Anomalous origin of one coronary artery from the pulmonary trunk occurs in ˜1 in 300,000 live births and accounts for 40% of pediatric coronary anomalies.5
The most common form of this anomaly, sometimes referred to as Bland-White-Garland syndrome,6 is the anomalous left coronary artery from the pulmonary artery (ALCAPA). The origin of the left main coronary artery from the pulmonary trunk should always be considered in cases of infantile and pediatric sudden death, as well as in infantile and childhood cases of dilated cardiomyopathy or endocardial fibroelastosis. The incidence of this anomaly ranges from 1/50,000 to 1/300,000 per live births. There is female-to-male ratio in incidence of 2 to 1. In adolescents surviving with the disease, sudden death may be exertional, which is typical for adults dying suddenly with anomalous origin of the left from the aorta. As infants, the clinical course in the adolescent can mimic dilated cardiomyopathy. Pathologically, the left main coronary artery arises from the pulmonary trunk, generally the left pulmonary sinus, or rarely from the anterior pulmonary sinus (Fig. 155.1). The left main coronary artery is thin walled and appears like a vein.
The treatment of ALCAPA is surgical reimplantation of the left coronary artery onto the ascending aorta, which may be complicated by restenosis necessitating revascularization including stenting.7
 FIGURE 155.1 ▲ Anomalous origin, pulmonary trunk. The probe is inserted into the left main ostium, which arose in the anterior sinus of the pulmonary valve. |
Rare variants of coronary arteries arising from the pulmonary circulation include origin of the right coronary arising from the pulmonary trunk,8 origin of both left and right coronary arteries from the main pulmonary artery,8,9 and origin of the coronary circulation from a branch of the pulmonary artery.10
Anomalous Origin of Left Main Coronary Artery from Right Sinus of Valsalva
The two most common congenital coronary anomalies resulting in sudden death are anomalous origination of a coronary artery from the opposite sinus (ACAOS), either the left or the right.11 This anomaly is one of the most common causes of sudden death, especially exertional sudden death, in young men and women.12 The rate of left coronary artery originating from the right sinus to the right coronary artery originating from the left sinus is about 5:1.5.11
More than half of the patients with this anomaly die suddenly, and the great majority of the ones dying suddenly die during exertion.11 Most individuals who die suddenly from an anomalous left coronary artery are <30 years of age, and virtually all are younger than 40.13 The course of the left main arising at the right sinus of Valsalva is generally between the aorta and pulmonary trunk, and often, the proximal artery is of small caliber compared to the normally positioned right coronary artery (Figs. 155.2, 155.3, 155.4). The ostium is often higher than that of the right coronary and near the commissure. Fibrosis of the myocardium in the region of the artery is common, and signs of myocardial infarct can be seen in as high as 80% of the sudden death cases.
The mechanism of death is related to myocardial ischemia and can be explained by several mechanisms. The anomalous coronary usually shows an acute-angle takeoff and the ostium is slit-like, distinct from the normally round orifice of a normal coronary.13 The course of the anomalous artery in close relationship with the aortic media is also a possible explanation, since the aortic wall layers are very thin in the intramural segment and susceptible to luminal compression during systole.11
Anomalous Origin of Right Coronary Artery from the Left Sinus of Valsalva
The right coronary artery arising from the left sinus of Valsalva is less common and less lethal than the anomalous left coronary. While sudden death in the anomalous left is reported in the majority of cases, anomalous right is associated with sudden death in 20% to 45% of cases.11 In this abnormality, both ostia arise from the left sinus of Valsalva. The proximal vessel, as the anomalous left described above, courses between the aorta and the pulmonary artery (Fig. 155.5). When present, acute or chronic ischemic changes are present in the inferior left ventricle, in the distribution of the right circulation. Evidence of ischemia essentially proves that the anomaly is potentially lethal and is corroborating evidence for causation of death. As with other potential causes of sudden death, other causes of death must be excluded carefully, especially if the death is nonexertional or occurs in someone over the age of 35 years.
 FIGURE 155.2 ▲ Anomalous origin, left main from right sinus of Valsalva. Note the left main ostium just to the right of the commissure, in the same sinus as the right (right sinus of Valsalva). |
 FIGURE 155.3 ▲ Anomalous origin, right coronary from the left sinus of Valsalva. Viewed from above, note the right artery arising from the left sinus of Valsalva. The pulmonary trunk is below and to the right. There is a long course between great vessels, which may become compressed during diastole when the artery normally fills. |
 FIGURE 155.4 ▲ Anomalous origin, right coronary from the left sinus of Valsalva. There are red plastic tubes present within the ostia. The left main (LM) is normal, whereas the right coronary artery (RCA) arises from the left sinus to the left of the pulmonary trunk (PT). R, right sinus of Valsalva; L, left sinus of Valsalva; NC, noncoronary sinus. |
 FIGURE 155.5 ▲ Anomalous origin, right coronary from the left sinus of Valsalva. In the left sinus of Valsalva, there are two ostia, one compressed (arrow) (anomalous right). |
Miscellaneous Coronary Artery Anomalies that May Result in Ischemia and Sudden Death
Tunnel Left Anterior Descending Artery (Myocardial Bridge)
Tunneled coronary artery, or myocardial bridge, is defined as a segment of epicardial artery that goes intramurally beneath a muscle bridge and then becomes epicardial distal to the tunnel (Fig. 155.6). Virtually all tunnels involve the left anterior descending artery, although myocardial bridges involving the right coronary and left circumflex arteries have been reported.15
Most tunnels of the left anterior descending artery are incidental, occurring in 30% of autopsy heart specimens, and frequently occur in the presence of other cardiac findings.16 However, bridging of coronary arteries into the myocardium can precipitate myocardial ischemia and sudden death, especially in the setting of strenuous exercise, arrhythmias, acute coronary syndromes, and coronary spasm.17 Angiographically, systolic compression of the involved segment with “milking” of contrast is evidence of clinically significant disease.18 There is an association between myocardial bridges and hypertrophic cardiomyopathy, especially in children.19
The degree of coronary obstruction by the myocardial bridge depends on location, thickness, length of the muscle bridge, and degree of cardiac contractility.17 A tunneled artery of more than 3 mm in depth within the myocardium is considered a potential cause for ischemia or sudden death. Because most deaths due to coronary artery anomalies are exertional, the finding of a deep tunnel in an exercise-related death is more likely significant than in a death that occurred at rest.20
 FIGURE 155.6 ▲ Tunnel coronary artery. The left anterior descending artery is separated from the epicardial fat by a rim of cardiac muscle. |
 FIGURE 155.7 ▲ High takeoff, left coronary ostium. The ostium is normally within the sinus under (proximal to) the sinotubular junction; in this example, it is above (distal to) the sinotubular junction, which is the area along the aortic annulus. |
High-Take-Off Coronary Ostia
The coronary artery ostia are normally present within the sinus of Valsalva beneath the sinotubular junction (Fig. 155.7). High takeoffs are considered a form of ostial anomaly that may be a causative factor for sudden death. In adults, a distance of 3 to 5 mm from the sinotubular junction is considered abnormal and may occur as high as 17 mm above it.21 The diagnosis is made during life at angiography or CT angiograms.22
Ostial Stenosis and Atresia
Hearts with otherwise normal coronary artery may demonstrate stenosis of the coronary ostium attributable to a valve-like ridge with a fold in the elastic tunica media of the aorta. Ostial stenosis may be isolated, or a component of a more diffuse process, such as coronary and aortic dysplasia characteristic of supravalvar aortic stenosis. Coronary ostia may regress in utero, if there are significant coronarycameral fistulae, as is characteristic of pulmonary atresia with intact ventricular septum (Fig. 155.8). Isolated ostial stenosis can be a cause of sudden death especially in infants and children.23 Histologic
evaluation is indicated, in order to distinguish congenital ostial stenosis to that caused by vasculitis, especially Takayasu disease, or coronary atherosclerosis.
evaluation is indicated, in order to distinguish congenital ostial stenosis to that caused by vasculitis, especially Takayasu disease, or coronary atherosclerosis.
 FIGURE 155.8 ▲ Absence of coronary ostia. In this infant’s heart, there was atresia of the ostia, secondary to complex congenital heart disease (pulmonary atresia with intact ventricular septum). MV, mitral valve; LV, left ventricular outflow; PM pap, posteromedial papillary muscle. |
Incidental Coronary Artery Anomalies and Variations
Conus Origin from Right Sinus
The origin of the conus branch from the right sinus of Valsalva is a common and incidental variation that does not cause any hemodynamic compromise. Angiographic studies estimate that this variation is present in as high as 30% of the population. At autopsy, there will be two ostia in the right sinus of Valsalva; always note the normal presence of the left anterior descending in the left sinus. Furthermore, the conus ostium is small and invariably immediately adjacent to the origin of the right, well below the sinotubular junction, unlike the anomalous left main.
Anomalous Left Circumflex from Right Sinus of Valsalva
The left circumflex artery can originate from the right aortic sinus or from the very proximal right coronary artery (Fig. 155.9). This anomaly is also common and usually incidentally found at autopsy or angiographic studies. Hemodynamic compromise is rare. The anomalous vessel usually arises with an acute angle and follows a course behind the aorta toward the left atrioventricular groove. This anomaly should be suspected if no circumflex is seen taking off from the left main coronary artery.
Single Coronary Ostium
When both main coronaries arise from a single sinus of Valsalva, as described above with anomalous right and left coronaries, one possible variation is only a single ostium, giving rise to each main artery, after a course of variable length. This anomaly is usually not associated with the problematic ostial ridges and acute takeoffs of single anomalous right or left coronaries. Therefore, association of single ostium with sudden death is uncommon. Single coronary artery is more liable to atherosclerotic changes because of decreased possibility of collateralization.
 FIGURE 155.9 ▲ Anomalous origin of the left circumflex artery. A. This benign condition occurs when the left circumflex artery (CFX) arises from the right sinus near the ostium of the right coronary artery (RCA). In this case, there was a separate ostium for the conus artery, the first branch of the right coronary, also a benign condition. B. The valve is opened, demonstrating the ostia of the left circumflex (CFX), right coronary artery (RCA), and conus artery, all within the right sinus. The left main (LM) ostium is in the left sinus. LAD, left anterior descending. |
Coronary Arteritis
Kawasaki Disease
Kawasaki disease is an acute febrile syndrome, first described in 1967,24 affecting the skin, mucosa, and lymph nodes. Subsequent reports related the acute syndrome, referred to as mucocutaneous lymph node syndrome, with coronary artery aneurysms. The incidence of Kawasaki disease ranges from 20 to 100/100,000 in Japan in children <5 years and to 4 to 15/100,000 in the United States. It is the cause of 1.3% of sudden cardiovascular deaths in persons younger than 35 years.25 There is a male-to-female ratio of 1.5:1. More than 80% of cases occur between 6 months and 4 years of age. In Japan, a small proportion of cases have a positive family history, with a higher incidence in siblings overall.26
Angiographic studies have shown coronary aneurysms develop in about 5% of treated patients and 20% of untreated ones. Once established, the behavior is varied and the lesion may regress spontaneously, stay stable, progress to obstructive lesions, expand, and, in rare cases, rupture, which is the most feared complication. Infants <6 months may present a more severe form of disease and develop coronary aneurysms without any other signs and symptoms of Kawasaki disease. In adults, there are no specific gross findings and the diagnosis of Kawasaki is either assumed or established based on history (Fig. 155.10).
Pathologically, small-vessel vasculitis is believed to be the initial event in the pathogenesis in the heart and then followed by panvasculitis of the epicardial coronary arteries, aneurysms of the proximal portions, and later scarring with aneurysm of the coronary arteries. The initial phase of small-vessel vasculitis can be associated in some cases with pericarditis, myocarditis, inflammation of the atrioventricular node, and endocarditis with valvulitis. Calcification and aneurysms develop at a later stage and are detectable by imaging studies.
The histologic findings of the acutely affected artery show chronic inflammation of the media, without changes of fibrinoid necrosis as seen in polyarteritis nodosa (Fig. 155.11). The arteritis progresses through phases of healing with eventual chronic aneurysm formation, which may be recanalized and cause infarcts months and years after the initial diagnosis.27 Death is rare in the acute stage and may be caused by myocarditis, arteritis, or noncardiac causes.
 FIGURE 155.10 ▲ Kawasaki disease, adult aneurysm. There is an aneurysm of the proximal left anterior coronary artery with intimal thickening. The circumflex artery is also prominent. (Figure courtesy William Edwards, M.D.) |
Thrombosis of coronary aneurysms may lead to ischemic damage to the myocardium. Aneurysms are characterized angiographically or by intravascular ultrasound (IVUS) by the presence of calcification and their size, which is classified as small (<1.5× normal), moderate (1.5 to 4× normal), and “giant” (>4× normal or larger than 8 mm). Over 80% of small or moderate-sized aneurysms regress within 5 years, whereas giant aneurysms show a much slower rate of regression. Sudden death is a known late complication of thrombosed aneurysms in Kawasaki disease.28,29,30
 FIGURE 155.11 ▲ Kawasaki disease, acute-phase aneurysm. The patient, a 3-year-old child, died from complications of mucocutaneous lymph node syndrome and hemophagocytic lymphohistiocytosis, an uncommon association. A. At low magnification, there is ectasia of the artery with occlusive thrombus. B. The media shows chronic inflammation and thinning. There is no fibrinoid necrosis, as would be present in necrotizing arteritis such as polyarteritis nodosa. |
Histologically, the aneurysms show organized mural thrombi, medial thinning with focal destruction of the elastic laminae, frequent calcification, and variable numbers of residual chronic inflammatory cells in the adventitia. Vessels other than the coronary arteries may be involved with vasculitis and aneurysm formation. Any artery may be involved, including in approximate order of incidence, the axillary artery, common iliac artery, renal artery, subclavian artery, internal iliac artery, superior mesenteric artery, internal thoracic artery, and femoral artery. Patients with extracoronary aneurysms almost invariably have giant coronary aneurysms.
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