Anomalous Coronary Artery Arising From the Opposite Sinus: Descriptive Features and Pathophysiologic Mechanisms, as <br />
Documented

Coronary anomalies continue to present an arcane puzzle to most cardiologists. We wish to focus on one particularly fascinating type of defect, in which both coronary arteries arise from the same aortic sinus, or an Anomalous Coronary Artery originates from the Opposite (than normal) Sinus (ACAOS). First reported in 1966 by Jokl and associates1 and more extensively discussed in 1974 by Cheitlin2 and Liberthson3 and their colleagues, anomalous origination of the left coronary artery (LCA) from the right aortic sinus is associated with a high risk of sudden death, usually related to strenuous exercise. In 1982, Roberts et al.4 reported that anomalous origination of the right coronary artery (RCA) from the left aortic sinus is also, though less frequently, associated with sudden, exercise-related death. In both defects, the anomalous proximal portion of the artery is known to course between the aortic root and the pulmonary artery. Several pathophysiologic mechanisms have been proposed for these anomalies: the slit-like orifice of the anomalous artery may become compressed by exercise-induced aortic dilatation4; the coexistence of an ostial ridge may lead to a valve-like mechanism during exercise5,6; acute angulation of the arterial take-off may cause or augment coronary kinking during exercise5; excessive mechanical stimulation of the anomalous vessel may cause a proximal spasm6,7; and during exercise, scissors-like strangulation may occur at the level of the aortopulmonary septum (the remnant of the embryologic aortopulmonary septum), where the anomalous artery necessarily runs7. In fact, owing to multiple reports of sudden death in patients with ACAOS, the aortopulmonary septum has been referred to as the “valley of death.” Since not every patient born with ACAOS succumbs to this anomaly, cardiologists have long struggled with the difficulty of establishing a prognosis in individual cases. Like many previous authors, we have been frustrated by the inability to foresee, on the basis of generic anatomic typing alone5, which of these anomalies are lethal and which are not; therefore, we elected to investigate them with enhanced clinical tests in order to identify new markers of severity and obtain pathophysiologic information. We report our initial experience with intravascular ultrasonography (IVUS) for evaluating coronary anomalies at baseline and during functional testing. Although IVUS imaging of the coronary arteries has been mentioned in at least one other report,8 the following case reports are the first in which IVUS was used, in a pilot study, to document the functional anatomy in patients with ACAOS. Case #1: Anomalous RCA originating from the left anterior sinus. A 70-year-old diabetic man was referred to our institution because of recent-onset congestive heart failure (marked by episodic, unheralded pulmonary edema) and both resting and effort-related angina. Twenty-five years earlier, he had undergone quadruple aortocoronary bypass grafting with saphenous vein grafts to the RCA, obtuse marginal branch, and diagonal branch, and a mammary artery graft to the left anterior descending artery. Two years before the present admission, the patient began to have atrial fibrillation, and echocardiography showed a left atrial diameter of 5.8 cm and a left ventricular ejection fraction of 45%. Because of recurrent angina during moderate exercise and at rest, jointly with two episodes of pulmonary edema, the patient was reevaluated. A nuclear perfusion study showed inferior-wall myocardial scarring and reversible periinfarction ischemia. The left ventricular ejection fraction (as evaluated by echocardiography and nuclear studies) was 35%. Heart catheterization showed that the internal mammary artery graft was patent, but the native obtuse marginal branch was occluded, as were all of the vein grafts. An anomalous, dominant RCA had a tangential take-off that made selective catheterization quite difficult. Catheterization and stable coaxial catheter placement were finally achieved only after a coronary guidewire was advanced subselectively from a 7 French (Fr), 4.0 cm Judkins left guiding catheter, followed by insertion of a 3.2 Fr, 30 MHz IVUS catheter (UltraCross™; Scimed, Maple Grove, Minnesota) (Figures 1A and 1B). IVUS clearly revealed that the take-off of the RCA was tangentially oriented and that the proximal portion of the RCA was situated within the wall of the aortic root. A semilunar valve commissure and moving leaflets were also clearly visualized (Figures 1C–E). Additionally, for about 2 cm, the proximal RCA had an ovoid cross-section, the vertical diameter being about double the transverse horizontal diameter (Figures 1C–E and Table 1). During systole, the horizontal diameter showed significant further narrowing, while the vertical diameter increased slightly, causing a reduction in the cross-sectional area (Table 1). Interestingly, the intramural segment of the RCA showed a total absence of intimal thickening throughout, but the more distal portion of the RCA had a severe, diffuse, calcific atherosclerotic build-up that caused > 75% stenosis at two sites in the midsection of the vessel. We decided to perform angioplasty at these sites. Two 3 x 16 mm stents (NIR ON™; Scimed) were successfully deployed, with optimal backup support afforded by the same guiding catheter (Figure 1B). During the 12-month follow-up period, he had no more angina or congestive heart failure, so no intervention was considered necessary for the coronary anomaly. Case #2: Anomalous LCA originating from the right anterior sinus. A 17-year-old high-school student was referred to us for cardiovascular evaluation after experiencing several episodes of syncope. He had been quite active in track and field, basketball, and other sports. For the previous 2 years, he had complained of effort-related asthmatic spells, which were reversed by 2 or 3 minutes of rest. Bronchodilators resulted in doubtful improvement. During the 4 months before the current admission, the patient had had two episodes of syncope, both of which occurred a few minutes after strenuous exercise: one episode aborted spontaneously after a few seconds of rest; the second episode required external resuscitative massage, on the basketball court, which was promptly instituted by the basketball coach and lasted for 3 minutes. In both cases, the patient gradually recovered consciousness and regained a normal blood pressure within 5–10 minutes. Intubation was not required. The loss of consciousness was preceded and followed by dyspnea, cold perspiration, and a sense of chest pressure, but these symptoms disappeared within 10 minutes after consciousness was regained. A treadmill exercise test was performed according to the Bruce protocol (17.2 mets). No ischemic symptoms or electrocardiographic changes were elicited after 15 minutes of exercise, when the blood pressure reached 176/70 mmHg (having started at 146/80 mmHg) and the heart rate peaked at 168 bpm in the absence of arrhythmias. However, approximately 3 minutes after the end of the exercise test, the patient’s blood pressure suddenly decreased to 90/40 mmHg in the absence of symptoms. Within 10 minutes after he resumed the supine position, his blood pressure had returned to 140/80 mmHg. During the ensuing 2 minutes, the electrocardiogram showed transient ST-T-segment depression in the absence of symptoms. A tilt-table test was carried out: after standing at a 70-degree angle for 2 minutes, the patient became diaphoretic, his blood pressure suddenly decreased to 56/0 mmHg in the presence of a preserved heart rate of 89 bpm, and he had a near-syncopal episode. When the test was repeated after intravenous administration of 10 mg of metoprolol, the patient had a full syncopal spell, with a blood pressure of 58/0 mmHg and a heart rate of 80 bpm. After a few minutes in the supine position, he recovered spontaneously. Initial heart catheterization revealed normal left ventricular function. The coronary arteries were interpreted as being normal except for a possible spasm in the proximal portion of the left main coronary artery. Repeat heart catheterization, performed to rule out spasm, properly identified anomalous origination of the LCA from the right anterior sinus. To better visualize the coronary anomaly, a magnetic resonance study was done, but this test could not clarify the exact relationship (intramural?) between the proximal LCA and the aortic wall. The patient was admitted to our hospital for further evaluation and possible surgical treatment. To better characterize the coronary anomaly and its prognostic implications, heart catheterization was again carried out. Selective coronary angiography of the LCA was achieved with a 7 Fr, 3.5 cm Judkins left guiding catheter. A 3.2 Fr, 30 MHz IVUS catheter (UltraCross; Scimed) was then advanced over a coronary guidewire (Figures 2A and 2B). Intracoronary imaging showed that the left coronary ostium, which was located just to the right of the anterior aortic commissure, had a tangential take-off and gave rise to a laterally compressed proximal 1-cm tract of the left coronary main trunk (Figure 2C). There were signs of further systolic narrowing, with a luminal-area phasic reduction of 22%, a transverse-width reduction of 33%, and a transverse-length increase of 10% (Figures 2D, 2E and Table 1). Pullback imaging and injection of agitated contrast medium into the ascending aorta, by way of the guiding catheter, revealed that the left main coronary artery was being transiently compressed by the inner aortic wall during systole (Table 1). Distal to the ostium, the proximal left main trunk passed through a 4 mm septum, most likely representing an intramural course of the LCA in the aortic wall: visible on each side of the septum were two moving semilunar leaflets, which reached the two opposite commissures (Figures 2D and 2E). During the cardiac cycle, the pulmonary wall, which appeared to be about 1 mm thick, moved away from the intramural coronary segment at the time (systolic) of maximal coronary narrowing. Intravenous ergonovine (up to 0.8 mg) failed to cause spasticity (as observed by IVUS), hemodynamic changes, or symptoms. Surgical treatment was recommended. Although the original plan was to enlarge the coronary ostium longitudinally, this operation was precluded by the closeness of the anterior aortic commissure. Therefore, the patient underwent coronary artery bypass surgery using the left internal mammary artery. His postoperative course was uncomplicated. Ten months after surgery, he remained totally asymptomatic while performing competitive high-school sports, including basketball. His most recent submaximal treadmill test yielded negative results. His tilt-table test continues to be positive, with slight dizziness and with bradycardia and hypotension that are milder than they were preoperatively. Case #3: Anomalous RCA originating from the left sinus. A 43-year-old man with atypical chest pain and the angiographic diagnosis of anomalous RCA originating from the left sinus underwent additional provocative testing at our hospital. Nuclear stress testing indicated a mild, reversible defect in the inferior myocardial wall. We used a pressure wire (RADI Medical Systems, AB, Uppsala, Sweden) to measure the translesional gradient both at rest, during adenosine stress, and after the cardiac output was increased with dobutamine (12 mg/minute) and a bolus of saline solution (500 mL over 30 minutes). No pressure gradient was found at rest, after dobutamine infusion, or after intracoronary adenosine administration (fractional flow reserve = 1.0). During the same procedure, changes in the cross-sectional coronary anatomy were monitored by means of IVUS at baseline and during stress testing with dobutamine (12.5 mg/kg/minute) and saline infusion (500 mL/30 minute) (Table 1). No intervention was deemed necessary, and the patient was in stable condition at 4-month follow-up examination. Case #4: Anomalous RCA originating from the left sinus. A 49-year-old woman with diabetes mellitus, hypertension, and hyperlipidemia was admitted to our hospital for treatment of angina and dyspnea. A nuclear stress test indicated a small inferior-wall scar and reversible ischemia. On angiography, the RCA originated anomalously from the left aortic sinus and had borderline-severe obstructive plaquing of the mid-to-distal segments. Via a right brachial percutaneous approach, IVUS imaging of the RCA was performed with a 3.5 cm, 6 Fr left Judkins guiding catheter. This method disclosed significant calcific, diffuse obstructive disease of the mid-to-distal RCA. The proximal segment was free of atherosclerotic disease but was intramural and tangentially oriented with respect to the aortic wall. A dobutamine drip, up to 40 mg/minute, accompanied by a saline load (500 mL in 30 minutes) and atropine infusion (1 mg, intravenously) caused the heart rate to increase to 150 bpm. Table 1 shows the changes in luminal area. Angioplasty of the mid RCA lesions, with use of two stents, resulted in an adequate angiographic appearance. No intervention was advised for the congenital RCA anomaly. At 8-month follow-up examination, the patient still had angina and dyspnea, and repeat angiography showed restenosis. Balloon angioplasty was redone, resulting in angiographic success and relief of symptoms. Discussion. We postulate that in identifying the features of ACAOS, IVUS can be an important aid for elucidating pathophysiologic mechanisms and categorizing prognostic indicators in individual patients. In this initial pilot study, our aim was to develop a detailed database and diagnostic protocols that could substantiate the use of a specific treatment modality (i.e., medical vs. surgical or stenting vs. simple observation) in a given case of ACAOS. The literature contains a single report describing ultrasonography of coronary ectopia performed by means of intraaortic imaging with a 10 MHz ultrasound probe.9 That method nicely illustrated the anatomy of the aortic root, clearly revealing the relationship between the proximal coronary anatomy and the aortic wall. Potentially, intraaortic ultrasonography could also be the best method for substantiating the mechanism of extrinsic compression of the aberrant artery at the aortic wall.10 Better than transesophageal echocardiography,8 intraaortic ultrasonography can correlate phasic changes in the aortic root (systolic expansion) with phasic changes in the cross-sectional coronary dimensions. Unlike coronary IVUS, however, this technique, in itself, cannot reveal the detailed cross-sectional coronary anatomy (Figure 3). Doorey and associates8 reported recently, but only superficially, the use of IVUS in one of 14 cases in which coronary stents were implanted to “treat” coronary anomalies (or coronary stenoses in carriers of coronary anomalies?). In that case, the authors concluded that the patient had a left main coronary artery “passing through the aortic wall” (intussusception?). Such a phenomenon would be highly unlikely (but possible, although unreported), given that the case involved a vessel that originated anomalously from the right aortic sinus and had a retroaortic course, as stated by the authors. The present series: The spectrum of clinical correlates. In the literature, anatomopathologic reports about ACAOS consistently point to its dreary prognosis, which entails a cardiac mortality of 25% (RCA arising from the left sinus) to 57% (LCA arising from the right sinus).5,11–13 Although unable to reassess the fundamental issue of cardiac mortality in an unselected clinical population with ACAOS, the present pilot series is interesting because it reflects the wide spectrum of ACAOS presentations in the clinical arena. This spectrum includes the fortuitous, confounding association of a benign form of ACAOS with unrelated, fixed coronary artery disease (Cases #1 and #4); the extreme presentation of sudden aborted death (Case #2); and the apparently serendipitous occurrence of ACAOS in a mildly symptomatic population (Case #3). Our cases show the apparently tenuous correlationship between the anatomic forms of ACAOS per se and the clinical patterns observed. In reality, two issues must be resolved in any individual case: “Is the presentation related to the anomaly?” and “Is the anomaly benign, or does it require intervention?” In dealing with ACAOS, cardiologists could remain limited to their clinical experience (“intervene only for severe presentations” such as aborted sudden death), or they could attempt to add further diagnostic parameters to the clinical ones, so as to clarify the involved pathophysiology and improve prognostication. IVUS descriptive features. In view of the literature on ACAOS,1–7 IVUS has the potential for clarifying the roles of numerous anatomo-functional features, as preliminarily summarized by the following points, which are derived from our initial experience: 1) Tangential arterial origination, slit-like ostium, or acute take-off. Careful pullback of the IVUS probe consistently shows that half of the coronary wall is missing at the ostium because of the oblique entry into the aorta (Figures 1 and 2). Although one might object that noncoaxial positioning of the IVUS catheter in the coronary artery would produce false-positive findings, this possibility is quite a remote explanation for the consistent finding. Quantification of the length of the segment featuring slit-like anatomy might be necessary in order to avoid a false positive finding related to the noncoaxial positioning of the IVUS catheter. 2) Presence or absence of an ostial ridge, as evidenced by intimal thickening at the edge of the coronary ostium (Figures 1 and 2). Such a ridge, as described by anatomists, is primarily fibrous and would have a highly refractive appearance on IVUS. Most likely, an ostial ridge will undergo thickening and calcification with advancing age. These features cannot usually be diagnosed with angiography. In our initial IVUS observations, we never recognized such a ridge, specifically one bulging into the coronary lumen. 3) Intussusception of the proximal coronary tract into the aortic wall. On IVUS, this feature typically manifests as a coronary artery that is totally encapsulated into a 3- to 4-mm-thick, homogeneous, fibrous (highly reflective) body, which is continuous with the aortic media (Figures 1 and 2). The aortic (versus the pulmonary) lumen may be identified by forcefully injecting agitated saline or contrast solution at the tip of the guiding catheter while recording the IVUS image: both the aortic and the coronary lumen will transiently show microbubbles. Agitated saline solution injected into the right side of the heart or into a systemic vein will identify the pulmonary side. As described in anatomic observations,14 no adventitia can be visualized around the intramural section of an ectopic coronary artery. 4) Flattening of the proximal cross-section of the aberrant coronary artery within the aortic wall, as shown by an ovoid cross-section (Figures 1 and 2). 5) Phasic, lateral, systolo-diastolic compression of the aberrant proximal segment of the coronary trunk. In all four of our cases, this feature was observed only at the coronary segment located within the aortic wall (Figures 1 and 2). Distal to that segment, phasic compression disappeared promptly. 6) Absence of atherosclerotic intimal build-up at the level of the proximal, aberrant coronary trunk, even in aged patients with diabetes and diffuse atherosclerotic changes, as in our first and fourth cases (Figure 1). With respect to atherosclerotic build-up, an intramural course seems to have a protective effect similar to that exerted by muscular bridges.15 Absence of intimal thickening is quite a favorable feature, because even a minor atherosclerotic build-up would have critical repercussions in a laterally compressed proximal coronary segment. Additionally, development of an ulcerated, active plaque would be promoted by the observed phasic massaging of such a coronary segment. 7) Decreased inner aortic wall thickness at the level of the intussuscepted coronary segment. Functional changes in aortic wall stress and the aortic dimensions are likely to be transferred to the coronary lumen in different degrees, depending on the aortic wall thickness and stiffness. In our four cases, the aortic wall was unusually thin (Pathophysiologic mechanisms. The above-mentioned IVUS findings, some of which are new and others which confirm previous anatomic and angiographic findings, appear to implicate some pathophysiologic mechanisms and to rule out others: 1) A mildly to moderately obstructive ostium and proximal ectopic coronary artery at baseline. By serially sectioning a stripped RCA, Liberthson16 clearly demonstrated flattening of the proximal aberrant trunk inside the aortic wall. Our dynamic IVUS images support the notion that tangential origination of a coronary artery with a proximal intramural course is associated with lateral compression of the lumen, owing to outward displacement of the inner (more than the outer) layer of the aortic wall (Figures 1D–1E and 2D–2E). This mechanism is phasically accentuated during late systole and early diastole, as suggested by Taylor et al.17 It is likely, but not yet proven, that strenuous exercise further enhances this mechanism because of a volume and pressure overload that leads to increased aortic wall stress. Young athletes can increase their cardiac output from about 5 L/minute at rest (heart rate, 70 beats/minute; stroke volume, 71 mL) to approximately 25 L/minute during exercise (heart rate, about 200 beats/minute; stroke volume, 125 mL), thereby significantly augmenting aortic wall stress while expanding the aortic dimensions.18 Individual variations in the ability to tolerate different forms of ACAOS may also be related to variable aortic wall distensibility.19 As an extreme example, Marfan-type mediocystic necrosis is accompanied by greatly increased aortic distensibility, which is measurable as a change in the aortic diameter under the influence of changes in the aortic pressure.19,20 In this regard, it may be interesting to note that, in the United States, sudden death in athletes with ACAOS occurs most frequently in basketball players,21 who often have Marfanoid features. Conversely, the expected decrease in aortic compliance observed with aging could contribute to the fact that ACAOS entails a more benign prognosis in older patients.7 Because of the ovoid cross-section of the lumen (the largest diameter being the vertical), the severity of such coronary obstruction is poorly evaluated by routine coronary angiography.22 On IVUS images, however, we observed that the intramural segment had an area reduction of 22% to 69% compared with the reference distal vessel (Table 1), and this reduction increased even further during the dobutamine stress test. The current challenge for clinicians is to develop a meaningful and predictive laboratory test that can simulate strenuous exercise by causing volume and pressure increases in the presence of tachycardia. The fact that, during maximal exercise, a patient can undergo sudden death, or at least syncope, on the basis of 69% narrowing of a large coronary artery, is not unheard of in cases of atherosclerotic coronary artery disease. Again, most of our patients with isolated ACAOS have been spontaneously symptomatic (usually with angina, dyspnea, syncope, or aborted sudden death) at a clinical stage when maximal treadmill exercise testing is consistently negative for ischemia or even clinical symptoms.23 Therefore, one must ask what other intervening mechanisms can occur to cause an occasional dramatic clinical event. 2) Spasm of the ostium and/or the proximal ectopic coronary artery. This mechanism has been postulated in the literature.6,10,24–26 We have performed provocative tests, but have not yet found conclusive evidence of its occurrence in symptomatic patients. 3) Clot formation at the ostium and/or the intramural coronary segment. Clot formation could potentially be the missing link between an apparently mild lesion and a catastrophic event. In the literature, however, clotting has been described as the cause of death in only one case involving tangential origination or acute take-off of the LCA (from the proper sinus) in the presence of an ostial ridge with an unruptured but obstructive atherosclerotic plaque.24 The patient was a 44-year-old woman without any other evidence of coronary artery disease at necropsy. In our brief series, IVUS imaging did not reveal any intraluminal thrombus formation. 4) Aortopulmonary scissors effect: The pathophysiologic relevance of pulmonary artery proximity to the aberrant artery (the potential presence of an aortopulmonary scissors effect)27 can be reconsidered in the light of IVUS findings. Our impression is that the ectopic coronary artery indeed passes through the aortopulmonary isthmus within the aortic wall and that the influence on the proximal coronary trunk is exerted entirely by the aorta. The pulmonary artery, even when adjacent to the proximal aberrant coronary segment, is not likely to cause coronary luminal collapse, because the pulmonary pressure is much lower than that of the coronary artery.25 Additionally, systolic aortic distensibility itself seems to account for phasic compression of the coronary lumen. 5) Aortic hinge effect: Intracoronary IVUS is not suitable for assessing the likelihood that coronary distortion at the level of a given form of ACAOS could ensue during exercise, because of the hinge effect exerted by the aortic wall on a coronary artery that becomes subtended between the aortic orifice and the intramyocardial arterial bed (the anchor).10 However, this proposed mechanism can be studied with intraaortic ultrasonography.9 Each of these possible pathophysiologic mechanisms may act alone, or in any combination, on aberrant coronary arteries. Surely, however, it is the size of the dependent myocardium that mainly determines the clinical manifestations. Small arteries (such as a nondominant RCA) will have a minor or nonexistent clinical expression, even when definite pathophysiologic alterations are involved. The opposite is true for larger coronary arteries, especially the left main trunk or a single coronary artery with an abnormal ostium. Conclusions. We have presented new findings, obtained by means of IVUS in patients with ACAOS, that may be important for better understanding many unusual features of functional coronary anatomy and their prognostic implications. We propose that ACAOS patients, especially when they have serious symptoms (syncopal spells, aborted sudden death, myocardial infarction, myopathy, or acute unheralded pulmonary edema), should undergo IVUS, both at baseline and during a variety of pharmacologic challenges, particularly to rule out coronary artery spasm but also to explore coronary anatomo-functional behavior under exercise-like conditions in individual cases. We are currently developing a firm protocol for institutional-review-board approval after initial pilot testing. The ultimate goal is to produce a large database of meaningful parameters that can be correlated with specific prognoses and be used to facilitate therapeutic decision-making in individual cases.

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