Original Contribution

Impaired Myocardial Perfusion on Stress CMR Correlates With Invasive FFR in Children With Coronary Anomalies

Hitesh Agrawal, MD, MBA1; J. Chris Wilkinson, MD2; Cory V. Noel, MD2; Athar M. Qureshi, MD2; Prakash M. Masand, MD2,3; Carlos M. Mery, MD, MPH4; S. Kristen Sexson-Tejtel, MD, PhD2; Silvana Molossi, MD, PhD2

Hitesh Agrawal, MD, MBA1; J. Chris Wilkinson, MD2; Cory V. Noel, MD2; Athar M. Qureshi, MD2; Prakash M. Masand, MD2,3; Carlos M. Mery, MD, MPH4; S. Kristen Sexson-Tejtel, MD, PhD2; Silvana Molossi, MD, PhD2

Abstract

Background. Invasive fractional flow reserve (FFR) is considered the gold standard to evaluate coronary artery flow. Stress cardiovascular magnetic resonance (sCMR) is an emerging non-invasive tool to evaluate myocardial perfusion in children. We sought to compare sCMR with FFR to determine impaired intracoronary flow in children with anomalous aortic origin of a coronary artery (AAOCA) and/or myocardial bridge (MB) who presented concern for myocardial ischemia. Methods. From December 2012 to May 2019, AAOCA and/or MB patients (<20 years old) were prospectively enrolled and underwent sCMR and FFR. Abnormal sCMR included perfusion/regional wall-motion abnormality in the involved coronary distribution. FFR was performed at baseline and with dobutamine/regadenoson and considered abnormal if <0.8 in the affected coronary segment. Results. Of 376 patients evaluated, a total of 19 (age range, 0.2-17 years) underwent 24 sets of sCMR and FFR studies, with 5 repeat studies following intervention. Types of anomalies included 6 isolated MB/normal CA origins, 5 single CAs, 5 left AAOCAs, and 3 right AAOCAs. Seventeen patients (89.5%) had MB/intramyocardial course — 14 involving the left anterior descending coronary artery and 3 with multivessel involvement. sCMR correlated with FFR in 19/24 sets (7 sCMR and FFR positive, 12 sCMR and FFR negative) and it did not correlate in 5/24 sets. The positive percent agreement was 77.8%, negative percent agreement was 80.0%, and overall percent agreement was 79.2%. Conclusions. Assessment of myocardial perfusion using non-invasive sCMR concurred with FFR, particularly if performed with close proximity in time, and may contribute to risk stratification and decision making in children with AAOCA and/or MB.

J INVASIVE CARDIOL 2021;33(1):E45-E51. 

Key words: anomalous coronary arteries, fractional flow reserve, stress cardiac magnetic resonance imaging


Myocardial perfusion assessment has become an integral part of risk stratification of patients with anomalous aortic origin of a coronary artery (AAOCA) and/or myocardial bridge (MB)/intramyocardial course,1 conditions that are associated with myocardial ischemia and sudden cardiac death.2 A variety of tools have been utilized in adults with coronary artery disease to assess myocardial perfusion non-invasively, including stress cardiovascular magnetic resonance (sCMR), single-photon emission computed tomography, stress echocardiogram, positron emission tomography, and stress nuclear perfusion imaging (sNPI). Invasive testing with coronary artery fractional flow reserve (FFR) is considered the gold standard,3 as it is unaffected by changes in heart rate, blood pressure, and myocardial contractility.4 It has been safely used in a select group of children with AAOCA and/or MB/intramyocardial course.5

There is inherent difficulty in performing non-invasive myocardial perfusion studies in children due to lack of patient cooperation, risks of ionizing radiation, and limited established data. Studies with sNPI have relatively high incidence of false-positive and false-negative findings,6,7 lower spatial resolution, attenuation artifacts related to the body wall and diaphragm movement, and exposure to ionizing radiation. In contrast, sCMR provides high-quality cardiac imaging with excellent spatial resolution, avoids ionizing radiation, and has compared favorably over sNPI in children with AAOCA and/or MB/intramyocardial course.6,7 In addition to myocardial perfusion imaging, sCMR also provides volumetric and functional data as well as wall-motion assessment and myocardial viability.

Depending on the mechanism of myocardial ischemia, a variety of provocative agents have been utilized. Traditionally, adenosine is used in adults with fixed coronary artery stenosis to induce hyperemia. However, the selective affinity of regadenoson to A2A receptors in the coronary circulation makes it more tolerable to the pediatric population with lower incidence of adverse events.8,9 In patients with dynamic nature of coronary artery stenosis (ie, patients with AAOCA with intramyocardial course or MB), dobutamine is preferred as a provocative agent as it increases cardiac inotropy and chronotropy and simulates physiologic exercise condition.5,10 There has been no previous study in children comparing sCMR with invasive FFR. The purpose of our study is to compare sCMR findings with invasive FFR in children with AAOCA and/or MB/intramyocardial course.

Methods

Design and study population. All patients ≤20 years of age with AAOCA and/or MB/intramyocardial course presenting to our Coronary Anomalies Program11 between December 2012 and May 2019 were prospectively enrolled, following approval by the institutional review board and signing of an informed consent, into a longitudinal database that includes clinical data, imaging studies, management strategy, and outcomes, which were compliant with the Health Insurance Portability and Accountability Act. All patients evaluated followed a standardized algorithm, established by the multidisciplinary Coronary Anomalies Program, where advanced imaging with CTA and myocardial functional studies were obtained.7,12 Cardiac catheterization with FFR measurement was performed in a select group of patients when equivocal results from non-invasive testing were present to assess the significance of long intramyocardial course of anomalous coronaries or MB, or for postoperative surveillance in patients with challenging coronary anatomy. In order to be included in this study, patients were required to have both sCMR and invasive FFR measurements. Risk status (high or low) was determined after review of the above tests and following a consensus opinion of our multidisciplinary team.

Anatomic definition. AAOCA is a congenital abnormality of the origin or course of a coronary artery that arises from the aorta. An intramyocardial coronary segment is defined as a segment that travels within the myocardium instead of a normal epicardial course. It includes intraseptal coronaries (vessels coursing behind the right ventricular outflow tract, below the level of the pulmonary valve) or more distal limited MB that may affect any of the coronary arteries.

Clinical evaluation. All patients were evaluated using a standardized algorithm created by the Coronary Anomalies Program at our institution. If the clinical evaluation and the tests showed low-risk anatomy, patients were allowed to return to full exercise. If the findings were considered high risk, surgical intervention was recommended. Surgical patients were re-evaluated at 3 months postoperatively with repeat imaging and functional studies.12 If the studies were reassuring, patients were allowed to return to full exercise. In general, exercise restriction was only recommended for patients awaiting surgical intervention, postoperatively until re-evaluation at 3 months, or those with high-risk lesions who refused surgery or who were deemed unsuitable for surgical repair given the complexity of the coronary anatomy (such as a very deep intraseptal coronary within the interventricular septum).

Stress CMR. Studies were mostly performed on awake patients without the need for sedation to allow for communication of any side effects. Patients were counseled regarding the procedure and possible side effects of the stress agent including chest pain, palpitations, and rhythm disturbance, and were monitored for 1 hour following the examination for any adverse effects. The stress agent used was either regadenoson (Lexiscan; Astellas Pharma) or dobutamine (Hospira). Dobutamine infusion was the most frequently used provocative agent (21 of 24 studies). The starting dose of dobutamine was 10 µg/kg/min and increased by 10 µg/kg/min every 4 minutes to a peak of 40 µg/kg/min. For patients who had not achieved a rise in heart rate to 75% of predicted maximum, a one-time dose of atropine at 0.01 mg/kg was given. Continuous heart rate and pulse oximetry monitoring were performed as well as blood pressure assessment before and at every 3 minutes post dobutamine dose change. Regadenoson was utilized for a small number of patients (3 of 24 studies). In these patients, regadenoson was administered at a dose of 400 µg over an infusion time of 10 seconds. Following first pass perfusion (FPP) and wall-motion analysis during peak coronary hyperemia, caffeine was administered at a dose of 50 mg for reversal. The studies were performed on either a 3 T clinical CMR scanner (Philips Medical Systems) using a 32-multichannel cardiac coil or a 1.5 T clinical CMR scanner (Philips Ingenia) using a 16-channel torso coil. Cardiac synchronization and heart rate monitoring were performed with vector electrocardiographic gating. Initial multiplanar gradient echo survey imaging was performed, followed by respiratory and vector electrocardiographic gated, black-blood T1-weighted echoplanar imaging performed in the axial plane for general anatomic overview. Depending on the age and patient cooperation, we performed breath-hold and/or free-breathing, respiratory-triggered, balanced steady-state free precession pulse sequence in the 4-chamber, ventricular long-axis, and short-axis planes. The stress-myocardial FPP acquisition was initiated after dose escalation of dobutamine or 60 seconds after administration of either 400 µg of regadenoson. FPP was performed with administration of 0.1 mmol/kg of gadolinium-based contrast agent (gadobutrol), which was injected at a rate of 3.5 mL/s. A single-shot, T1-weighted, saturation recovery gradient echo sequence with a parallel acceleration (SENSE) factor of 2, shared prepulse, repetition time/echo time/flip angle = 2.5/1.2 ms/17˚, voxel size 2-2.5 x 2-2.5 x 7 mm3 was used for FPP imaging at 3 short-axis slices (basilar, mid-ventricular, and apical levels). A saturation delay of 120 ms was used. Rest-FPP imaging was performed at a minimum of 20 minutes from the stress-FPP using the same sequence as above. Left ventricular myocardial viability was performed approximately 3-5 minutes following the administration of gadolinium, using phase-sensitive inversion-recovery sequences in short-axis and 4-chamber planes. Studies were considered abnormal in the presence of inducible or fixed perfusion defect, or regional wall-motion abnormality in the involved coronary artery distribution. The vascular territory involved was assigned using the American Heart Association 17-segment classification.13

Cardiac catheterization. Patients underwent cardiac catheterization and FFR measurement according to our institutional protocol.5,14 All procedures were performed under general anesthesia and using biplane fluoroscopy. Patients were heparinized for the duration of the procedure to achieve activated clotting time of >250 seconds. Left/right heart catheterization was performed, followed by aortic root angiogram and selective coronary angiograms. Prior to advancing FFR wires inside coronary arteries, 1 µg/kg of intracoronary nitroglycerin was administered (adult dose, 100-200 µg) to prevent coronary spasm. FFR measurement was performed at baseline, after adenosine infusion at 140 µg/kg/min for 3 minutes, and then dobutamine infusion of 20-40 µg/kg/min to achieve a heart rate of 75% of maximal heart rate. In some instances, atropine or glycopyrolate was given to augment heart rate response. An 0.014˝ Volcano FFR wire (Volcano Corporation) was used to perform FFR measurement. Diastolic and mean FFR were calculated and FFR <0.8 was considered abnormal. Diastolic FFR was used in patients with MBs as this has been found to be more accurate with regard to clinical presentation due to avoidance of an overshoot phenomenon in systole.10 Prior to advancing or pulling out FFR wire from the coronary artery, coronary angiograms were performed to assess vessel spasm/dissection and intracoronary nitroglycerin was administered. 

Statistical analysis. The data were collected and analyzed in a Microsoft Excel worksheet. Descriptive statistics were performed. The agreement between FFR and sCMR was assessed by calculating the positive, negative, and overall percent agreement.

Results

Patient demographics and clinical presentation. A total of 376 patients were evaluated during the study period and 19 patients (13 males; 68.4%) met inclusion criteria. Table 1 summarizes patient population demographics and clinical presentation. Median age at presentation was 12.6 years (range, 0.2-17 years). One-third (n = 6) presented as an incidental finding, whereas others presented with exertional (n = 11) and non-exertional symptoms (n = 2). Symptoms included chest pain (n = 10), syncope (n = 6), aborted sudden death (n = 2), and frequent premature ventricular contractions (n = 1). Significant family history included history of sudden cardiac death of father in 2 siblings, and 1 patient with history of long QT syndrome in father and sudden cardiac death of paternal grandfather during sleep. 

Clinical characteristics and study results. The types of coronary anomalies included 6 isolated MB/normal CA origins, 5 single CAs, 5 anomalous left coronary arteries (ALCAs), and 3 anomalous right coronary arteries (ARCAs). Invasive FFR was positive in 10 studies and sCMR was positive in 9 of all 24 studies performed. For sCMR, dobutamine was used in 21 of 24 examinations, and regadenoson in 3 examinations. Regadenoson was performed in cases where the pathophysiological component was believed to be a fixed obstruction rather than a dynamic component where dobutamine was traditionally selected. Table 2 summarizes the clinical details of all 19 patients. 

Abnormal sCMR findings included inducible perfusion defect in 9 studies. Coronary artery FFR was concordant with sCMR findings in the respective perfusion territory in 19 test pairs (7 pairs with abnormal/positive studies and 12 pairs with normal/negative studies). This yields positive percent agreement of 77.8%, negative percent agreement of 80.0%, and overall percent agreement of 79.2%. Figure 1 depicts a patient with ALCA from the right sinus with intraseptal course of the left main coronary artery with positive sCMR findings and positive FFR measurement. 

Five patients had repeat sCMR and FFR examinations following surgical interventions. A 13-year-old patient (Patient #6, Table 2) presented with pressure-like chest pain on exertion and troponin leak. He had an MB of the left anterior descending (LAD) coronary artery with positive sCMR and FFR, and underwent myocardial unroofing of the LAD-MB. At 3 months post operation, he had negative FFR but the inducible defect on sCMR persisted. A 5-year-old patient (Patient #10, Table 2) presented with recurrent syncope during exertion and had anomalous LAD from the right coronary artery (RCA) and extensive intramyocardial course deep within the interventricular septum with diminutive caliber, and positive FFR and sCMR. Bypass graft utilizing the left internal mammary artery to the LAD was performed and postoperative sCMR and FFR were negative. A 12-year-old patient (Patient #12, Table 2) presenting with sudden cardiac arrest and ALCA from the opposite sinus underwent unroofing and ostioplasty of both left coronary artery (LCA) and RCA ostia and was released to full activity at 3 months post operation. A normal sCMR was present at 9 months post operation. He sustained sudden cardiac arrest 17 months after surgery, at which time repeat CTA showed previously unrecognized LAD-MB given poor filling on initial CTA and compression at the LCA ostium with abnormal FFR in both the LCA and the LAD-MB. Surgery with LCA translocation and unroofing of the MB was performed and both sCMR and FFR were normal at 3 months post operation.15

A 16-year-old patient (Patient 16, Table 2) presented with pressure-like chest pain, had ALCA and an intraseptal course of LMCA and LAD with positive FFR and sCMR. He underwent reimplantation of the LCA and supra-arterial myotomy of the intraseptal segment and at 3 months postoperatively had negative FFR and sCMR.

A 14-year-old patient (Patient #18, Table 2) with ARCA and MB of the LAD with positive FFR and negative sCMR underwent translocation of the RCA and unroofing of the LAD-MB, with unchanged findings post operation (positive FFR, though improved from values prior to intervention, and negative sCMR). There was a 15-year-old patient (Patient #3, Table 2) with an MB of the LAD who underwent LAD bypass graft following positive sCMR and FFR. However, the family transferred care to another facility and has not undergone follow-up testing. 

In our study, diastolic FFR was not performed in 4 patients (3 with MB) early in our experience. In the remaining patients, mean FFR was concordant with diastolic FFR. There were no adverse events related to the sCMR or invasive FFR; specifically, there was no instance of coronary artery dissection or thrombus. Surgery was performed on 6 patients (out of which 5 had follow-up repeat testing), 1 patient is awaiting surgery, 10 patients were cleared for exercise, and 2 are restricted from exercise activities. All patients are alive at a median follow-up of 1.55 years (range, 0.5-7.1 years). 

Discussion

In this study, we demonstrate in a select group of patients with AAOCA and/or MB/intramyocardial course, that non-invasive sCMR findings concurred with results obtained with invasive FFR. To our knowledge, this is the first time these findings are reported in the literature in children, particularly with coronary anomalies. Although both modalities are intended to yield positive results relatively early in the disease process, they are based on different pathophysiologic principles and may potentially be complementary for investigating myocardial ischemia. 

The pathophysiology of myocardial ischemia in patients with AAOCA may include lateral compression, compression of the intramural/interarterial segment during exercise, and ostial stenosis.16 The mechanisms of coronary ischemia in MB remain unclear, especially given the fact that most MBs are believed to be benign. Unlike fixed obstruction in adult coronary artery disease, which persists throughout the cardiac cycle and affects a large myocardial territory, there is dynamic systolic compression of the intramyocardial segment of a coronary artery in MB and/or anomalous coronary with an extensive intramyocardial course. The systolic compression can cause delayed recovery of the luminal dimension in early diastole impairing diastolic blood flow, which can be more pronounced during exercise.10,17 This can mediate multiple effects including endothelial dysfunction, venturi effect with increasing velocity and septal steal, impaired coronary flow reserve, and plaque fissure/rupture proximal to the MB, which can be potential mechanisms of ischemia.17,18

Coronary-pressure derived FFR measures the impact of coronary stenosis in the territory supplied by the vessel and assumes minimal microvascular resistance. However, sCMR perfusion is based on the principle of altered coronary blood-flow derived coronary flow reserve. The sCMR accounts for the entire coronary microvasculature, which is neglected by FFR.19 Thus, 4 sets of scenarios can arise using these 2 modalities, namely, concordant normal or abnormal sCMR with FFR, abnormal sCMR with normal FFR, and normal sCMR with abnormal FFR.

Concordant abnormal sCMR and FFR may signify a flow-limiting disease in the intramyocardial (epicardial) segment with microvascular involvement, found in 7 sets of studies in our cohort. Abnormal sCMR with normal FFR was found in 2 sets of studies and may represent predominantly microvascular coronary artery involvement or misinterpretation of artifact as a perfusion defect. Normal sCMR with abnormal FFR was found in 3 sets of studies and may denote focal intramyocardial (epicardial), non-flow limiting coronary artery disease.20 Interestingly, a recent study found a significantly higher adverse event rate throughout 10 years of follow-up in adults with intermediate coronary artery stenosis with normal FFR and abnormal coronary flow velocity reserve.20 Given the complexity of the pathophysiology of both AAOCA and MB, it is reasonable to assume that multiple other factors could contribute to discrepant results between sCMR and FFR, such as vascular loading conditions, peak heart rate and BP attained, and overall myocardial oxygen demand. There are no current data in the literature comparing these two modalities in children and the available data come from the adult population.19,21

The sensitivity and specificity of a test can be affected by the inherent variables within a test (for example, the stress agent). Using the same provocative agent helps limit confounders across the testing modalities. However, tailoring the stress agent according to suspected mechanism of myocardial ischemia can help to elucidate the anatomic culprits. It should be noted that regadenoson was used as a stress agent for sCMR in 2 patients (3 studies) where the aim was to rule out focal coronary stenosis. The remaining patients received dobutamine infusion for sCMR, as dynamic coronary compression was suspected. Cardiac catheterization with FFR measurement was likewise performed using dobutamine and adenosine as separate conditions in this series. The degree of spatial resolution of sCMR is another variable that can affect the sensitivity and specificity; however, the spatial resolution remained constant in this study.

The cut-off values used can also affect the sensitivity and specificity of a test. A lower cut-off value of 0.75 was initially used when validating FFR in adults with coronary artery disease.22 However, nowadays, an FFR cut-off of 0.8 (as used in the present study) is universally accepted in coronary artery disease for revascularization3 and MB.23 Since we did not encounter any FFR values between 0.75 to 0.8, our results would not have been affected by a lower cut-off of 0.75. Previous studies have shown that diastolic FFR may overcome some of the shortcomings of mean FFR in the intramyocardial segment.10 First, it delineates the effect of intramyocardial segment on the diastolic coronary blood flow. Second, by limiting its measurement to diastole, it does not get affected by the falsely elevated systolic coronary pressure in the intramyocardial segment.10 In our study, diastolic FFR was not performed in 4 patients early in our experience, with 3 out of 4 patients having an MB. In the remaining patients, mean FFR was concordant with diastolic FFR.

Study limitations. Our study should be viewed in light of its limitations. The study population is from a single/large referral center; thus, the sample may be biased for race/ethnicity and higher severity of disease. The sample size was small and the operators for sCMR and cardiac catheterization were not blinded to the other clinical findings of the patients. A variety of complex coronary anomalies in children were included in this series of 19 patients, which can affect the generalizability of these results to a specific coronary anomaly. Previous studies, even in adults with multivessel coronary artery disease, have demonstrated good concordance between sCMR and FFR.19,21 The sCMR findings were examined qualitatively. Inclusion of quantitative perfusion analysis may provide additional information, may show better concordance with FFR, and may have prognostic implications.24 The sCMR testing had some variability, including the use of stress agents dobutamine/regadenoson, and 1.5 T/3 T scanners. Lastly, our definition of high risk was based on available data and the consensus opinion of our multidisciplinary team.

Conclusion

Assessment of myocardial perfusion using non-invasive sCMR concurred with invasive FFR, particularly when the studies were timed in close proximity to each other. These findings are complementary, and both modalities may contribute to risk stratification and decision making in children with complex AAOCA and/or MB/intramyocardial course. Future larger studies are warranted to assess whether invasive testing is needed at all in patients with the coronary anomalies we describe, given the diagnostic accuracy of sCMR. 


From the 1Pediatric and Congenital Cardiology Associates, The University of Texas at Austin Dell Medical School, Austin, Texas; 2Coronary Anomalies Program, The Lillie Frank Abercrombie Section of Pediatric Cardiology, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas; 3Section of Pediatric Radiology, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas; and 4Texas Center for Pediatric and Congenital Heart Disease, University of Texas Dell Medical School/Dell Children’s Medical Center, Austin, Texas. 

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Qureshi is a consultant for W.L. Gore and Edwards Lifesciences. The remaining authors report no conflicts of interest regarding the content herein.

The authors report that patient consent was provided regarding use of the images herein.

Final version accepted April 29, 2020. 

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

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