Author + information
- Kim-Lien Nguyen, MD∗ (, )
- Jiaxin Shao, PhD,
- Vahid K. Ghodrati, MS,
- Olujimi A. Ajijola, MD, PhD,
- Rohan Dharmakumar, PhD,
- J. Paul Finn, MD and
- Peng Hu, PhD
- ↵∗David Geffen School of Medicine at UCLA, VA Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, MC 111E, Los Angeles, California 90073
Researchers recently proposed using native myocardial T1 mapping with vasodilator stress testing for evaluation of ischemic heart disease (IHD) (1). A change of 1.5% in native T1 between rest and peak stress was able to detect significant epicardial coronary stenosis (1). Although this approach is promising, the modest amplitude and narrow dynamic range for native T1 reactivity (percentage of change in T1 at peak vasodilation relative to baseline) may pose challenges in daily clinical practice. We propose to increase the amplitude and dynamic range of T1 reactivity through the off-label use of ferumoxytol (Feraheme, AMAG Pharmaceuticals, Waltham, Massachusetts). Ferumoxytol is used for intravenous treatment of iron deficiency anemia, but it has superparamagnetic properties with high r1 relaxivity and a long intravascular half-life. We posited that ferumoxytol would sensitize the myocardial T1 to the vasodilator-induced dynamic differences between rest and peak stress and significantly boost the T1 reactivity. Because ferumoxytol shortens the T1, we expected the myocardial T1 to decrease during vasodilator stress because of the increased distribution space of ferumoxytol.
We studied Yorkshire swine (33 to 52 kg; n = 4 normal, n = 3 coronary stenosis [80% to 90%]) and patients with IHD (n = 5; age 38 to 71 years). For animal studies, we created partial stenosis of the mid-left anterior descending artery using a transcatheter balloon angioplasty technique (2). The animal stress cardiac magnetic resonance (CMR) protocol included the following: 1) pre-ferumoxytol cine and T1 mapping at rest and peak stress (4-min adenosine infusion [200 to 400 μg/kg/min]); 2) ferumoxytol (4 mg/kg) infusion; and 3) rest and stress ferumoxytol-enhanced (FE) T1 mapping. Five patients with positive (n = 3) or equivocal (n = 2) rubidium-82 positron emission tomography stress test results underwent regadenoson FE CMR. The FE CMR protocol included the following: 1) ferumoxytol (4 mg/kg infusion); and 2) multislice FE T1 mapping at rest and stress (regadenoson 0.4 mg intravenously). We acquired T1 maps in animal and human subjects using 5(3)3 balanced steady-state free precession (bSSFP) Modified Look-Locker Imaging (MOLLI) and used an in-house T1 fitting algorithm to account for heart rate variation. Groups were compared using paired Student’s t-tests. Values are reported as mean ± SD.
There were no ferumoxytol-related or vasodilator-related adverse events. Mean post-ferumoxytol blood pool T1 values at baseline and at peak vasodilation were similar (p = 0.5). Compared with native T1 reactivity (Figure 1A), ferumoxytol amplified the T1 reactivity by 12.8-fold in normal myocardium (native T1 reactivity: 0.8 ± 0.2%; FE T1 reactivity: −10.2 ± 5.4%; p < 0.01), 7.5-fold in remote myocardium (2.1 ± 0.8% vs. −15.7±1.7%; p < 0.01), and 18-fold in vasodilator-induced hypoperfused myocardium (0.4 ± 0.3% vs. −7.2 ± 0.7%; p < 0.01). The effect size for FE T1 reactivity was larger than native T1 reactivity (6.5 [SDpooled = 1.3] vs. 2.8 [SDpooled = 0.6]). Compared with remote myocardium of patients with IHD, the FE T1 reactivity values in hypoperfused segments were significantly blunted (−8.8 ± 1.9% vs. −3.2 ± 15.9%; p < 0.01). Figure 1B illustrates the qualitative and quantitative potential of FE T1 maps to depict hypoperfusion at rest and coronary steal physiology at peak vasodilation.
Our findings are hypothesis generating and support the early feasibility of FE CMR T1 vasodilator testing for detection of IHD. The higher amplitude and dynamic range achieved with ferumoxytol increased the effect size of FE T1 reactivity and improved its ability to differentiate between remote and hypoperfused myocardium. There are limitations, including the possibility of a blunted T1 response from capillary leakage in the setting of ischemia. The use of ferumoxytol is also not without risks and needs to be weighed against the benefits. To date, however, ferumoxytol has demonstrated a positive safety profile for off-label diagnostic use under close monitoring (3). FE CMR T1 reactivity testing has the potential to transform intramyocardial blood volume reserve quantification. Additional work is needed to systematically define its application for perfusion imaging.
Please note: This work was supported by pilot funding from the Radiological Sciences Exploratory Research Program and the Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, and by National Institutes of Health (NIH) grant R01HL127153. Dr. Nguyen has reported support from American Heart Association (AHA) grant 18TPA34170049. Dr. Ajijola has reported support from NIH grant K08HL125730. Dr. Dharmakumar has reported support from NIH grants R01HL136578 and R01HL133407. Dr. Finn has reported support from NIH grant R01HL127153; and has reported support from AHA grant 18TPA34170049. Dr. Hu has reported support from NIH grant R01HL127153; and has reported support from AHA grant 18TPA34170049. Drs. Shao and Ghodrati have reported that they have no relationships relevant to the contents of this paper to disclose.