Assessment of stunned and viable myocardium using manganese-enhanced MRI

Nick B Spath, Trisha Singh, Giorgos Papanastasiou, Andrew Baker, Rob J Janiczek, Gerry P McCann, Marc R Dweck, Lucy Kershaw, David E Newby, Scott Semple, Nick B Spath, Trisha Singh, Giorgos Papanastasiou, Andrew Baker, Rob J Janiczek, Gerry P McCann, Marc R Dweck, Lucy Kershaw, David E Newby, Scott Semple

Abstract

Objective: In a proof-of-concept study, to quantify myocardial viability in patients with acute myocardial infarction using manganese-enhanced MRI (MEMRI), a measure of intracellular calcium handling.

Methods: Healthy volunteers (n=20) and patients with ST-elevation myocardial infarction (n=20) underwent late gadolinium enhancement (LGE) using gadobutrol and MEMRI using manganese dipyridoxyl diphosphate. Patients were scanned ≤7 days after reperfusion and rescanned after 3 months. Differential manganese uptake was described using a two-compartment model.

Results: After manganese administration, healthy control and remote non-infarcted myocardium showed a sustained 25% reduction in T1 values (mean reductions, 288±34 and 281±12 ms). Infarcted myocardium demonstrated less T1 shortening than healthy control or remote myocardium (1157±74 vs 859±36 and 835±28 ms; both p<0.0001) with intermediate T1 values (1007±31 ms) in peri-infarct regions. Compared with LGE, MEMRI was more sensitive in detecting dysfunctional myocardium (dysfunctional fraction 40.5±11.9 vs 34.9%±13.9%; p=0.02) and tracked more closely with abnormal wall motion (r2=0.72 vs 0.55; p<0.0001). Kinetic modelling showed reduced myocardial manganese influx between remote, peri-infarct and infarct regions, enabling absolute discrimination of infarcted myocardium. After 3 months, manganese uptake increased in peri-infarct regions (16.5±3.5 vs 22.8±3.5 mL/100 g/min, p<0.0001), but not the remote (23.3±2.8 vs 23.0±3.2 mL/100 g/min, p=0.8) or infarcted (11.5±3.7 vs 14.0±1.2 mL/100 g/min, p>0.1) myocardium.

Conclusions: Through visualisation of intracellular calcium handling, MEMRI accurately differentiates infarcted, stunned and viable myocardium, and correlates with myocardial dysfunction better than LGE. MEMRI holds major promise in directly assessing myocardial viability, function and calcium handling across a range of cardiac diseases.

Trial registration numbers: NCT03607669; EudraCT number 2016-003782-25.

Keywords: heart failure; magnetic resonance imaging; myocardial infarction.

Conflict of interest statement

Competing interests: SIS has a consultancy agreement with GSK. DEN and SIS hold unrestricted educational grants from Siemens Healthineers.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Manganese-enhanced MRI in healthy volunteers. Representative T1 colour maps (A) and T1 over time (B, n=20) following manganese dipyridoxyl diphosphate (MnDPDP). Dashed line represents mean end of infusion, SD of the mean.
Figure 2
Figure 2
Manganese-enhanced MRI (MEMRI) in patients with myocardial infarction. Representative late gadolinium enhancement (LGE), native and MEMRI T1 mapping (A) and T1 profiles of myocardial regions of interest over time following manganese dipyridoxyl diphosphate (MnDPDP) (C) in a patient with extensive anterior myocardial infarction, compared with healthy control myocardium (n=20). Comparative representative LGE, native and MEMRI T1 mapping (B) and T1 profiles of myocardial regions of interest over time following MnDPDP (D) in a patient with subendocardial myocardial infarction, compared with healthy control myocardium (n=20). Dashed line represents end of infusion, error bars are SD of the mean.
Figure 3
Figure 3
Manganese-enhanced MRI (MEMRI) in myocardial regions of interest. MEMRI T1 values in patients with myocardial infarction (A) and influx constant (Ki), (B) in patients with myocardial infarction; infarct core, peri-infarct and remote myocardial regions of interest, compared with healthy control myocardium. ANOVA, analysis of variance.
Figure 4
Figure 4
Wall motion, late gadolinium enhancement (LGE) and manganese-enhanced MRI (MEMRI) T1 mapping colour maps at the core infarct slice in five patients, represented as 100-chord plots (anterior right ventricle insertion as reference point). Values demonstrate stronger correlation between MEMRI T1 than LGE with reduced wall motion in every patient.
Figure 5
Figure 5
Differential manganese uptake over time. Kinetic modelling of manganese uptake (Ki, influx constant) in patients with myocardial infarction; infarct core, peri-infarct and remote myocardial regions of interest, at acute (n=20) and 3-month (n=14) imaging time points.
Figure 6
Figure 6
Differential manganese uptake after myocardial infarction. Representative late gadolinium enhancement (LGE) and manganese-enhanced MRI (MEMRI) T1 mapping images (A) and Patlak plots (B) in a patient with myocardial infarction, demonstrating differential Ki (influx constant) between myocardial regions of interest over time. Grouped comparison T1 profiles for all patients and healthy control subjects (C). Dashed line represents end of infusion, error bars are SD of the mean. MnDPDP, manganese dipyridoxyl diphosphate.

References

    1. Townsend N, Wilson L, Bhatnagar P, et al. . Cardiovascular disease in Europe: epidemiological update 2016. Eur Heart J 2016;37:3232–45. 10.1093/eurheartj/ehw334
    1. Jernberg T, Hasvold P, Henriksson M, et al. . Cardiovascular risk in post-myocardial infarction patients: nationwide real world data demonstrate the importance of a long-term perspective. Eur Heart J 2015;36:1163–70. 10.1093/eurheartj/ehu505
    1. Lesyuk W, Kriza C, Kolominsky-Rabas P. Cost-of-illness studies in heart failure: a systematic review 2004-2016. BMC Cardiovasc Disord 2018;18:74. 10.1186/s12872-018-0815-3
    1. Allman KC, Shaw LJ, Hachamovitch R, et al. . Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol 2002;39:1151–8. 10.1016/S0735-1097(02)01726-6
    1. Anavekar NS, Chareonthaitawee P, Narula J, et al. . Revascularization in Patients With Severe Left Ventricular Dysfunction: Is the Assessment of Viability Still Viable? J Am Coll Cardiol 2016;67:2874–87. 10.1016/j.jacc.2016.03.571
    1. Moon JC. What is late gadolinium enhancement in hypertrophic cardiomyopathy? Rev Española Cardiol 2007;60:1–4.
    1. Kim RJ, Wu E, Rafael A, et al. . The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med 2000;343:1445–53. 10.1056/NEJM200011163432003
    1. Khan JN, Nazir SA, Singh A, et al. . Relationship of myocardial strain and markers of myocardial injury to predict segmental recovery after acute ST-segment-elevation myocardial infarction. Circ Cardiovasc Imaging 2016;9:e003457. 10.1161/CIRCIMAGING.115.003457
    1. Kidambi A, Mather AN, Swoboda P, et al. . Relationship between myocardial edema and regional myocardial function after reperfused acute myocardial infarction: an Mr imaging study. Radiology 2013;267:701–8. 10.1148/radiol.12121516
    1. Beanlands RSB, Nichol G, Huszti E, et al. . F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2). J Am Coll Cardiol 2007;50:2002–12. 10.1016/j.jacc.2007.09.006
    1. Dilsizian V, Bacharach SL, Beanlands RS, et al. . ASNC imaging guidelines/SNMMI procedure standard for positron emission tomography (PET) nuclear cardiology procedures. J Nucl Cardiol 2016;23:1187–226. 10.1007/s12350-016-0522-3
    1. , Windecker S, Kolh P, et al. , Authors/Task Force members . 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541–619. 10.1093/eurheartj/ehu278
    1. Spath NB, Thompson G, Baker AH, et al. . Manganese-enhanced MRI of the myocardium. Heart 2019;105:1695–700. 10.1136/heartjnl-2019-315227
    1. Wen L-Y, Yang Z-G, Li Z-L, et al. . Accurate identification of myocardial viability after myocardial infarction with novel manganese chelate-based MR imaging. NMR Biomed 2019;32:e4158. 10.1002/nbm.4158
    1. Massaad CA, Pautler RG. Manganese-enhanced magnetic resonance imaging (MEMRI). Methods Mol Biol 2011;711:145–74. 10.1007/978-1-61737-992-5_7
    1. Skjold A, Amundsen BH, Wiseth R, et al. . MnDPDP) as a viability marker in patients with myocardial infarction. J Magn Reson Imaging 2007;26:720–7.
    1. Spath N, Tavares A, Gray GA, et al. . Manganese-enhanced T1 mapping to quantify myocardial viability: validation with 18F-fluorodeoxyglucose positron emission tomography. Sci Rep 2020;10:32029765. 10.1038/s41598-020-58716-x
    1. Thygesen K, Alpert JS, Jaffe AS, et al. . Third universal definition of myocardial infarction. Eur Heart J 2012;33:2551–67. 10.1093/eurheartj/ehs184
    1. Piechnik SK, Ferreira VM, Dall'Armellina E, et al. . Shortened modified look-locker inversion recovery (ShMOLLI) for clinical myocardial T1-mapping at 1.5 and 3 T within a 9 heartbeat breathhold. J Cardiovasc Magn Reson 2010;12:69. 10.1186/1532-429X-12-69
    1. Spath NB, Singh T, Papanastasiou G, et al. . Manganese-enhanced magnetic resonance imaging in dilated cardiomyopathy and hypertrophic cardiomyopathy. Eur Heart J Cardiovasc Imaging 2020;00:1–10. 10.1093/ehjci/jeaa273
    1. Skjold A, Kristoffersen A, Vangberg TR, et al. . An apparent unidirectional influx constant for manganese as a measure of myocardial calcium channel activity. J Magn Reson Imaging 2006;24:1047–55. 10.1002/jmri.20736
    1. Sutcliffe RP, Lewis D, Kane PA, et al. . Manganese-enhanced MRI predicts the histological grade of hepatocellular carcinoma in potential surgical candidates. Clin Radiol 2011;66:237–43. 10.1016/j.crad.2010.08.007
    1. Wang C, Gordon PB, Hustvedt SO, et al. . MR imaging properties and pharmacokinetics of MnDPDP in healthy volunteers. Acta Radiol 1997;38:665–76. 10.1080/02841859709172399
    1. Du C, MacGowan GA, Farkas DL, et al. . Calibration of the calcium dissociation constant of Rhod2 in the perfused mouse heart using manganese quenching. Cell Calcium 2001;29:217–27. 10.1054/ceca.2000.0186
    1. Skjold A, Vangberg TR, Kristoffersen A, et al. . Relaxation enhancing properties of MnDPDP in human myocardium. J Magn Reson Imaging 2004;20:948–52. 10.1002/jmri.20200
    1. Food and Drug Administration . Mangafodipir Trisodium
    1. European Medicines Agency . Teslascan (mangafodipir)
    1. Ibanez B, Aletras AH, Arai AE, et al. . Cardiac MRI Endpoints in Myocardial Infarction Experimental and Clinical Trials: JACC Scientific Expert Panel. J Am Coll Cardiol 2019;74:238–56. 10.1016/j.jacc.2019.05.024

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