Wolf in Sheep’s Clothing — The False Sense of Security in Patients With Anomalous Aortic Origin of a Coronary Artery Undergoing Submaximal Stress Testing

Dear Editor:

We read with great interest the paper by Agrawal et al,¹ wherein the authors evaluated 19 young patients (<20 years old) with an anomalous aortic origin of a coronary artery (AAOCA) and/or myocardial bridging between 2012 and 2019 using a center-specific, elaborated diagnostic approach to determine the therapeutic management. The invasive and non-invasive assessment of the hemodynamic relevance in patients with an AAOCA is a timely research topic, as the pathophysiology of ischemia is not completely understood.² Furthermore, the patient management recommendations vary (American Heart Association/American College of Cardiology 2018, European Society of Cardiology 2020) and are mainly based on case series and observational data. Therefore, there is a need to better understand the pathophysiology of AAOCA and more data are required on how to perform adequate stress testing and how to interpret the results in these individuals.

Agrawal et al¹ stated that “the pathophysiology of myocardial ischemia in patients with AAOCA may include lateral compression, compression of the intramural/interarterial segment during exercise, and ostial stenosis.” Thus, to simulate exercise rather than vasodilation alone and to provoke the coronary compression, dobutamine plus atropine was used during the pharmacologic stress when performing cardiac magnetic resonance (CMR) imaging and cardiac catheterization (ie, fractional flow reserve [FFR]). They could show that stress CMR (ie, perfusion/regional wall-motion abnormality in the involved coronary distribution) correlated with invasive FFR (cut-off FFR, 0.80) in 79.2% of cases. This resulted in a positive percent agreement of 77.8% and a negative percent agreement of 80.0%. Hence, the authors concluded that stress CMR may contribute to risk stratification and decision making in children with AAOCA.

We congratulate the authors for conducting such an important study. We widely agree with their conclusion; however, we would like to offer our perspective on some methodological issues in the study. The pathomechanism of myocardial ischemia in patients with AAOCA is different compared with coronary artery disease. As stated in a recent review by our group, the occurrence of ischemia in AAOCA is based on the extent of a fixed component (anatomic high-risk features of slit-like ostium and proximal narrowing) and a dynamic component (acute take-off angle, intramural course with the elliptic vessel shape).³ Focusing on the dynamic component, the underlying pathophysiology of increased hemodynamic relevance during exercise is based on a systolic expansion and higher wall stress of the proximal aorta as a function of the increased dP/dT and stroke volume.³ Taking into account the law of LaPlace, which states that wall stress = (transmural pressure x radius)/(2 x wall thickness), the augmented wall stress particularly affects the intramural segment of AAOCA, where a substantial decrease in aortic wall thickness is present.³ The consecutive lateral compression is not only relevant due to the reduced cross-sectional area compared with a round vessel shape, but also due to higher resistance of an elliptical vessel shape, as shown by the underlying mechanics, ie, the law of Hagen-Poiseuille. It can be hypothesized that the dynamic components of lateral compression become less relevant in elderly individuals due to increasing thickening and stiffness of the aortic wall with decreased distensibility, whereas the fixed component moves into the forefront.³ However, in young patients such as those included in the study by Agrawal et al (mean age, 12.6 years old),¹ it is most important to assess the dynamic component. We therefore advocate performing stress tests to the maximum tolerated heart rate to avoid false-negative results, which otherwise may leave physicians and patients with a false sense of security.⁴ This is, however, to our understanding, not achieved by a target heart rate of 75% of the predicted maximal heart rate (= 220 – age) as applied in the study by Agrawal et al.¹ It is therefore possible that a target heart rate of approximately 75% assessed only the fixed component in some of these young patients. This was illustrated in a case report by Lim et al,⁵ which described a 14-year-old female patient with L-AAOCA and showed similar FFR_adenosine (which assesses only the fixed component) and FFR_dobutamine (0.87 vs 0.86) values at a heart rate of 153 bpm (74% of the maximal heart rate). It might therefore be anticipated that some of the findings by Agrawal et al (negative results in 14/24 for FFR and 15/25 for CMR) might change to positive results with adequate maximal stress testing. However, in the absence of reported FFR values and achieved maximal heart rates, these considerations remain fully speculative. Importantly, as mentioned by the authors, it is reasonable to assume that multiple other factors including volume status are involved in the occurrence of myocardial ischemia in AAOCA. Since dobutamine decreases the preload, an adequate volume load during the stress test must be ensured. According to FFR measurement in the study by Agrawal et al,¹ an adequate volume status seemed to be guaranteed with a mean systemic blood pressure of approximately 160 mm Hg.

Future studies must elucidate whether CMR with dobutamine/atropine testing is the optimal non-invasive modality in all AAOCA cases, as gating issues and interpretability of wall motion/perfusion under maximal/supramaximal heart rate might be limited. It is probable that different situations might need different invasive and non-invasive approaches/modalities (eg, according to patient age, type of anomaly, presence of anomaly with concomitant coronary artery disease). Future studies should also include other promising alternative modalities, such as modern low-radiation positron emission tomography myocardial perfusion imaging, which assesses both ischemia and scar in coronary artery anomalies as well as non-invasively quantifies hyperemic blood flow and coronary flow reserve. Likewise, whether novel computational fluid-dynamic simulated computed tomography angiography FFR can improve diagnostics and refine risk stratification needs to be assessed in clinical trials comparing it to the invasive FFR dobutamine gold-standard.

Sincerely,

Marius Reto Bigler, MD;  Christian Seiler, MD;  Lorenz Räber, MD, PhD;  Christoph Gräni, MD, PhD

From the Department of Cardiology, Inselspital, Bern University Hospital, University of Bern, Switzerland.

Address for correspondence: Christoph Gräni, MD, PhD, FACC, Department of Cardiology, University Hospital Bern, Freiburgstrasse 18, CH- 3010 Bern, Switzerland. Email: christoph.graeni@insel.ch

References

1. Agrawal H, Wilkinson JC, Noel CV, et al. Impaired myocardial perfusion on stress CMR correlates with invasive FFR in children with coronary anomalies. J Invasive Cardiol. 2021;33:E45-E51.
2. Grani C, Buechel RR, Kaufmann PA, Kwong RY. Multimodality imaging in individuals with anomalous coronary arteries. JACC Cardiovasc Imag. 2017;10:471-481.
3. Bigler MR, Ashraf A, Seiler C, et al. Hemodynamic relevance of anomalous coronary arteries originating from the opposite sinus of Valsalva — in search of the evidence. Front Cardiovasc Med. 2021;7:591326.
4. Bigler MR, Ueki Y, Otsuka T, et al. Discrepancy between SPECT and dobutamine FFR in right anomalous coronary artery undergoing unroofing. Ann Thorac Surg. 2020;110:e569.
5. Lim MJ, Forsberg MJ, Lee R, Kern MJ. Hemodynamic abnormalities across an anomalous left main coronary artery assessment: evidence for a dynamic ostial obstruction. Catheter Cardiovasc Interv. 2004;63:294-298.

Authors’ Response:

We truly appreciate the feedback from this well-known group of authors whose field of interest is similar to ours. Their work has improved our understanding of hemodynamic mechanisms underlying ischemia in patients with anomalous aortic origin of a coronary artery (AAOCA).¹

We are in complete agreement with our colleagues regarding the fact that the mechanisms of ischemia in AAOCA likely involve both a fixed and dynamic component, which has prompted our testing with both adenosine and dobutamine, when indicated. Interestingly, we have acquired additional recent data with invasive fractional flow reserve (FFR) in that positive values are seen with adenosine, and nearly but not quite positive with dobutamine, indicative of the fixed component leading to obstruction in the anomalous coronary arising from the opposite sinus of Valsalva. This has been helpful in decision making for surgical management.

We also agree that the maximum tolerated heart rate should be targeted for such stress testing, which in children may be challenging due to symptomatology in an awake, older child and difficulty achieving very high heart rates under anesthesia. We have traditionally used provocative agents to achieve at least 75% of maximal heart rate during peak exercise.^2,3 Our practice has modeled the Stanford group, which utilizes a target goal of 75%-85% of maximal heart rate for evaluation of AAOCA and/or myocardial bridges.⁴ We understand that using even higher goal heart rates for stress tests may uncover some additional borderline cases and in fact that has been our goal as well, ie, to achieve heart rates more than 75% predicted, but at least 75% predicted whenever possible. One of the challenges faced in the pediatric population is that these procedures are performed with general anesthesia and, often, very high doses of dobutamine are required to counter the effects of the general anesthetic agents. This often leads to excessive degrees of systemic hypertension and an inability to proportionally augment heart rate, thus necessitating the use of additional atropine. In our dobutamine stress cardiac magnetic resonance (DSCMR) data including 224 studies in 182 patients, 2.8% of patients had significant hypertension with blood pressure reaching 200/120 mm Hg.⁵ If not performed judiciously, this may predispose patients to major procedural complications, of which we are aware. Our group has been fortunate to have faced minimal adverse events with both cardiac catheterization with FFR measurement and DSCMR, even in a very young population of children with AAOCA.

Unquestionably, there is a lot to learn about this fascinating but challenging lesion. This is an area of unchartered territory and few institutions have pursued these forms of drug-induced provocative stress tests for risk stratification. We welcome the comments from our colleagues and believe that further ongoing studies will help to streamline and standardize the protocols for evaluation of patients with AAOCA and/or myocardial bridges. Only collaboration among centers and researchers will defeat these challenges and hopefully shed bright light into the pathophysiology of AAOCA which, ultimately, will change the lives of these patients and their families.

Sincerely,

Hitesh Agrawal, MD, MBA¹;  Athar M. Qureshi, MD²;  Silvana Molossi, MD, PhD²

From the ¹Pediatric and Congenital Cardiology Associates, The University of Texas at Austin Dell Medical School, Austin, Texas; and ²Coronary Artery Anomalies Program, The Lillie Frank Abercrombie Section of Pediatric Cardiology, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas.

Address for correspondence: Silvana Molossi, MD, PhD, Texas Children’s Hospital, Baylor College of Medicine, 6651 Main Street, MC E1920, Houston, TX 77030. Email: smolossi@bcm.edu

1. Bigler MR, Ashraf A, Seiler C, et al. Hemodynamic relevance of anomalous coronary arteries originating from the opposite sinus of Valsalva — in search of the evidence. Front Cardiovasc Med. 2020;7:591326.
2. Agrawal H, Molossi S, Alam M, et al. Anomalous coronary arteries and myocardial bridges: risk stratification in children using novel cardiac catheterization techniques. Pediatr Cardiol. 2017;38:624-630.
3. Agrawal H, Wilkinson JC, Noel CV, et al. Impaired myocardial perfusion on stress CMR correlates with invasive FFR in children with coronary anomalies. J Invasive Cardiol. 2021;33:E45-E51.
4. Maeda K, Schnittger I, Murphy DJ, et al. Surgical unroofing of hemodynamically significant myocardial bridges in a pediatric population. J Thorac Cardiovasc Surg. 2018;156:1618-1626.
5. Doan TT, Molossi S, Sachdeva S, et al. Dobutamine stress cardiac MRI is safe and feasible in pediatric patients in anomalous aortic origin of a coronary artery. Int J Cardiol. 2021 (in press).