Instantaneous Wave-Free Ratio (iFR) Correlates With Fractional Flow Reserve (FFR) Assessment of Coronary Artery Stenoses and Myocardial Bridges in Children

Abstract: Objectives. Instantaneous wave-free ratio (iFR) has been proven to correlate with coronary flow reserve better than fractional flow reserve (FFR) and is non-inferior to FFR in guiding coronary revascularization in ischemic heart disease. There has been no study validating the utility of iFR in children. Methods. We performed a retrospective review of clinically indicated cases in which both FFR and iFR were obtained at Texas Children’s Hospital from July, 2016 to March, 2019. FFR and iFR were obtained at baseline. Adenosine FFR (FFRa) was used for assessment of coronary artery (CA) stenoses and diastolic dobutamine FFR (dFFRd) for myocardial bridges (MBs). FFRa or dFFRd ≤0.8 and iFR ≤0.89 indicated significant flow impairment. Results. A total of 22 coronary arteries (9 CA stenoses and 13 MBs) were assessed in 20 patients with median age of 13 years (range, 4-21 years) and median weight of 60 kg (range, 19-110 kg). iFR correlated with FFRa (Spearman’s rho, 0.87; P<.01) in CA stenoses and with dFFRd (Spearman’s rho, 0.74; P<.01) in MBs and agreed with FFR in 20/22 cases (90.9%). In 1 patient with CA stenosis and 1 MB with normal FFR, iFR was positive and both patients underwent coronary revascularization. Conclusions. iFR correlated with FFR in the assessment of CA stenoses in children. iFR does not require administration of pharmacological agents; thus, it may reduce procedural time, cost, and complications, and result in more widespread adoption of invasive assessment of CA lesions in young patients.

J INVASIVE CARDIOL 2020;32(5):176-179. 

Key words: children, coronary artery stenosis, fractional flow reserve, instantaneous wave-free ratio, myocardial bridge

Instantaneous wave-free ratio (iFR) was recently developed to measure pressure-derived coronary artery flow during a period of naturally constant and low resistance due to minimal competing pressure waves in diastole.¹ These unique features eliminate the need for provocative testing with a pharmacological agent. The iFR has been proven to correlate with coronary flow reserve better than fractional flow reserve (FFR).² In addition, in two large, multicenter, randomized trials, iFR was found to be non-inferior to FFR as it relates to major adverse events at follow-up when used to guide the need for coronary revascularization in adults with ischemic heart disease.^3,4 Children with coronary artery stenoses and myocardial bridges (MBs) can present with myocardial ischemia, syncope, and even sudden cardiac death. Functional assessment of the abnormal coronary artery using cardiac catheterization has been explored by the Coronary Anomalies Program at the Texas Children’s Hospital/Baylor College of Medicine when the risk assessment of myocardial ischemia/sudden cardiac events was less definitive by non-invasive testing.⁵ To date, there has been no report of the use or validation of iFR in children with coronary artery anomalies.

Methods

We performed a retrospective review of patients in the Coronary Anomalies Program at the Texas Children’s Hospital who underwent cardiac catheterization for risk stratification of myocardial ischemia from July, 2016 to March, 2019. Consecutive clinically indicated patients with available FFR and iFR tracings were included. Institutional review board approval for this study was obtained. Patients with coronary artery stenoses included children with repaired congenital heart disease (CHD), repaired anomalous aortic origin of a coronary artery (AAOCA), and Kawasaki disease (KD). Patients with MB included children with an intramyocardial segment of an epicardial coronary artery and those with AAOCA with an intraseptal course of a coronary artery. 

Cardiac catheterizations were performed under general anesthesia and all patients were administered heparin to achieve activated clotting times >250 seconds. Invasive hemodynamics were closely monitored. Intracoronary nitroglycerin 1 µg/kg (or 100-200 µg/dose if adult size) was given prior to selective coronary artery angiography and FFR/iFR measurements for prevention of coronary artery spasm. Angiograms were obtained to delineate the anomaly and ensure no coronary artery spasm. A 4 Fr catheter was used in small children, while a 5-6 Fr guiding catheter was often used in larger patients. In order to avoid coronary artery ostial obstruction (and thus false readings), the catheters were positioned in the aorta, particularly when small coronary arteries or proximal lesions were encountered. A 0.014˝ Verrata pressure guidewire (Philips Volcano) was used to pass across the region of interest, then iFR and FFR pressure tracings were obtained using the s5/s5i Imaging System (Philips Volcano). The iFR was defined as instantaneously measured pressure ratio across a coronary lesion during a portion of diastole when microvascular resistance is low and stable; it was obtained at baseline and calculated by the s5/s5i Imaging System in all cases.^2,3 FFR was obtained with provocative testing during adenosine infusion (FFRa) in patients with coronary artery stenoses and diastolic FFR with dobutamine (dFFRd) in patients with MBs. FFRa was defined as a ratio between mean distal coronary artery and aortic pressure under condition of maximal hyperemia (using adenosine) to estimate the relative flow reduction caused by a coronary artery stenosis.² It was obtained at 3 minutes post administration of 140 µg/kg/min of adenosine. In MB patients, dobutamine was started at 10 µg/kg/min and was increased to 20-40 µg/kg/min until the desired heart rate was achieved. Atropine or glycopyrolate was used in addition to dobutamine if heart rate remained <75% of predicted heart rate for age.⁵ dFFRd was measured as an average of three pressure ratios across the stenotic lesion at end-diastole during peak pharmacologic stress with dobutamine.⁶ Before the pressure wires were removed, coronary angiograms were performed to ensure no coronary artery spasm or injury was encountered. Further intracoronary nitroglycerin was given if necessary to treat coronary artery spasm. In this study, FFRa or dFFRd ≤0.8 and iFR ≤0.89 were used to indicate significant stenoses.³ 

Statistical analysis. Analyses were conducted using STATA 14.2 software (StataCorp). Descriptive statistics were used to report numbers, proportions, and medians and ranges. Spearman’s correlation test was used to study correlation of iFR with FFRa in coronary artery stenoses and iFR with dFFRd in MBs. A P-value of <.05 was considered significant.

Results

A total of 20 children underwent 22 studies. Median age was 13.0 years (range, 3.9-21.3 years) and median weight was 60.1 kg (range, 18.5-109.5 kg). There were 9 patients with coronary artery stenoses, including 6 postsurgical CHD patients, two postsurgical patients with AAOCA, and 1 patient with KD (Table 1), and 11 patients with MB, including 2 patients with assessment before and after coronary artery revascularization (Table 2). The iFR correlated well with FFRa (Spearman’s rho, 0.87; P<.01) in coronary artery stenoses and with dFFRd (Spearman’s rho, 0.74; P<.01) in MBs (Figure 1). Using the cut-offs as mentioned above, iFR agreed with FFRa in 8/9 cases (89%) and dFFRd in 12/13 cases (92%). The iFR agreed with FFR (FFRa in coronary artery stenosis and dFFRd in MB) in all patients with FFRa/dFFRd ≤0.80. In both scenarios where there was disagreement, FFRa and dFFRd indicated non-significant coronary artery flow impairment, while iFR values were consistent with the clinical presentation of coronary insufficiency and supported surgical revision of right coronary artery stenosis after a Ross procedure (patient #4) and myotomy of a left anterior descending (LAD)-MB (patient #19). 

There were no instances of coronary artery dissection or thrombotic events. There was 1 death in a patient with Noonan syndrome and LAD-MB in the postanesthesia unit, due to extensive cerebral hemorrhage likely secondary to underlying cerebral vasculopathy and systemic hypertension exacerbated with dobutamine infusion.

Discussion

Our specialized Coronary Anomalies Program presents a unique opportunity to examine the use of FFR⁵ and iFR in children with coronary artery stenoses and MBs. Our findings demonstrated good correlation of iFR at baseline with FFR using provocative agents (and complete agreement when FFR was ≤0.80) in this unique patient population. These findings are similar to those reported by Davies et al³ and Götberg et al⁴ for adults with coronary artery disease, which validated its use in guiding important decisions regarding the need for coronary revascularization. In our experience, iFR provided helpful information in guiding important decisions regarding the need for coronary revascularization in children with coronary artery stenoses and MBs (including AAOCA with intraseptal course of a coronary artery).

Interestingly, in the 2 patients in whom both values did not agree, the iFR was abnormal and consistent with the clinical presentation of both patients, and supported the decision for coronary artery revascularization. Patient #4 was a 3-year-old boy who developed severe tricuspid regurgitation and right heart failure post operatively after a Ross-Konno procedure for recurrent valvular and subvalvular aortic stenosis. The iFR supported revision of the right coronary artery stenosis, whereas FFRa did not. Patient #19 presented with chest pain and was found to have a 28 mm MB of the mid LAD on computed tomography angiography. A dobutamine stress cardiac magnetic resonance imaging study revealed an inducible myocardial hypoperfusion with wall-motion abnormality during peak pharmacological stress and transmural and subendocardial myocardial delayed enhancement in the anteroseptal wall. The iFR again supported the decision to perform a myotomy of the MB, while dFFRd did not indicate the need for revascularization.

The use of FFR to assess the severity of coronary artery stenosis requires adenosine to stabilize and minimize the resistance of the artery.¹ Although FFR has been demonstrated to improve outcomes compared with angiographic visual assessment in guiding revascularization in ischemic heart disease, it was not widely used due to the need for adenosine infusion.² Sen et al¹ developed iFR, a drug-free pressure-derived index of stenosis severity, and proved that it was comparable with FFR. In the JUSTIFY-CFR study, iFR showed stronger correlation and better agreement with coronary flow velocity reserve when compared with FFR.² Multicenter, randomized, controlled studies in large populations found that iFR-guided coronary revascularization was non-inferior to FFR-guided procedures in terms of major cardiac events at 1 year, including death.^3,4 Moreover, the rate of adverse procedural signs and symptoms was lower and the procedural time was shorter with iFR compared with FFR.⁴ In MB, diastolic FFR with dobutamine has been proposed to quantify the effect of MB on the coronary blood flow.⁶ In fact, the principles of iFR are ideal in overcoming the shortcomings of FFR with MB (secondary to the overshoot phenomenon in systole) due to its assessment of coronary artery flow in diastole. Tarantini et al⁷ reported intracoronary assessment of MB using iFR to be more consistent with non-invasive test results and patients’ symptoms compared with FFR.

Although limited by a single-center study and small sample size, our findings from a large, pediatric, tertiary-care center have important implications. iFR does not require the administration of provocative pharmacological agents; thus, it has the potential to reduce procedural time, cost, and adverse events, and may result in a more widespread adoption of functional assessment of coronary artery stenoses and MBs in children. As the recognition of coronary artery abnormalities and their potential serious implications in children continues to increase, assessment of coronary artery stenosis severity using iFR may become a critical part of the work-up, risk stratification, and follow-up in this select group of children in the future.

Conclusion

When assessing the importance of coronary artery lesions in children, iFR provides similar diagnostic information as provocative testing with FFR. Moreover, it has the potential for more widespread use in children due to its inherent advantages. Collaboration among centers caring for this special group of children with coronary artery anomalies/stenoses and presenting with impending myocardial ischemia will allow us to further evaluate the role of iFR in the evaluation and management of these patients.

From ¹the Lillie Frank Abercrombie Section of Cardiology, Department of Pediatric Cardiology, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas; ²Le Bonheur Children’s Hospital, University of Tennessee Health Science Center, Memphis, Tennessee; ³Texas Heart Institute, 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 reports consultant fees from W.L. Gore and Associates and Edwards Lifesciences. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted November 15, 2019, final version accepted November 26, 2019.

Address for correspondence: Athar M. Qureshi, MD, The Lillie Frank Abercrombie Section of Cardiology, Department of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, 6651 Main Street, Legacy Tower, 20th Floor, Suite E. 1920, Houston, TX 77030. Email: axquresh@texaschildrens.org 

1. Sen S, Escaned J, Malik IS, et al. Development and validation of a new adenosine-independent index of stenosis severity from coronary wave–intensity analysis. J Am Coll Cardiol. 2012;59:1392-1402. 
2. Petraco R, van de Hoef TP, Nijjer S, et al. Baseline instantaneous wave-free ratio as a pressure-only estimation of underlying coronary flow reserve. Circ Cardiovasc Interv. 2014;7:492-502. 
3. Götberg M, Christiansen EH, Gudmundsdottir IJ, et al. Instantaneous wave-free ratio versus fractional flow reserve to guide PCI. N Engl J Med. 2017;376:1813-1823. 
4. Davies JE, Sen S, Dehbi H-M, et al. Use of the instantaneous wave-free ratio or fractional flow reserve in PCI. N Engl J Med. 2017;376:1824-1834. 
5. 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. 
6. Escaned J, Cortés J, Flores A, et al. Importance of diastolic fractional flow reserve and dobutamine challenge in physiologic assessment of myocardial bridging. J Am Coll Cardiol. 2003;42:226-233. 
7. Tarantini G, Barioli A, Nai Fovino L, et al. Unmasking myocardial bridge-related ischemia by intracoronary functional evaluation. Circ Cardiovasc Interv. 2018;11:e006247.