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Published in: Journal of Cardiovascular Magnetic Resonance 1/2011

Open Access 01-12-2011 | Research

Preliminary assessment of cardiac short term safety and efficacy of manganese chloride for cardiovascular magnetic resonance in humans

Authors: Juliano L Fernandes, Pippa Storey, Jose Alvaro da Silva, Gabriel S de Figueiredo, Jose M Kalaf, Otavio R Coelho

Published in: Journal of Cardiovascular Magnetic Resonance | Issue 1/2011

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Abstract

Background

Manganese based agents are intracellular and accumulate inside myocytes allowing for different imaging strategies compared to gadolinium contrasts. While previous agents release manganese very slowly in the circulation, MnCl2 allows for rapid Mn2+ uptake in myocytes, creating a memory effect that can be potentially explored. Data on animal models are very encouraging but the safety and efficacy of this approach in humans has not yet been investigated. Therefore, our objectives were to study the safety and efficacy of a rapid infusion of manganese chloride (MnCl2) for cardiovascular magnetic resonance (CMR) in humans.

Methods

Fifteen healthy volunteers underwent a CMR scan on a 1.5 T scanner. Before the infusion, cardiac function was calculated and images of a short axis mid-ventricular slice were obtained using a 2D and 3D gradient-echo inversion recovery (GRE-IR) sequence, a phase-sensitive IR sequence and a single breath-hold segmented IR prepared steady-state precession acquisition for T1 calculations. MnCl2 was infused over three minutes at a total dose of 5 μMol/kg. Immediately after the infusion, and at 15 and 30 minutes later, new images were obtained and cardiac function re-evaluated.

Results

There was a significant decrease in T1 values compared to baseline, sustained up to 30 minutes after the MnCl2 infusion (pre,839 ± 281 ms; 0 min, 684 ± 99; 15 min, 714 ± 168; 30 min, 706 ± 172, P = 0.003). The 2D and 3D GRE-IR sequence showed the greatest increase in signal-to-noise ratio compared to the other sequences (baseline 6.6 ± 4.2 and 9.7 ± 5.3; 0 min, 11.3 ± 4.1 and 15.0 ± 8.7; 15 min, 10.8 ± 4.0 and 16.9 ± 10.2; 30 min, 10.6 ± 5.2 and 16.5 ± 8.3, P < 0.001 for both). There was a slight increase in systolic pressure and heart rate after three and four minutes of the infusion with normalization of these parameters thereafter. Patients showed good tolerance to MnCl2 with no major adverse events, despite all reporting transient facial flush.

Conclusions

In the short term, MnCl2 appears safe for human use. It effectively decreases myocardium T1, maintaining this effect for a relatively long period of time and allowing for the development of new imaging strategies in CMR, especially in ischemia research.
Appendix
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Literature
1.
go back to reference Lima JA, Desai MY: Cardiovascular magnetic resonance imaging: current and emerging applications. J Am Coll Cardiol. 2004, 44: 1164-1171. 10.1016/j.jacc.2004.06.033.CrossRefPubMed Lima JA, Desai MY: Cardiovascular magnetic resonance imaging: current and emerging applications. J Am Coll Cardiol. 2004, 44: 1164-1171. 10.1016/j.jacc.2004.06.033.CrossRefPubMed
2.
go back to reference Shan K, Constantine G, Sivananthan M, Flamm SD: Role of cardiac magnetic resonance imaging in the assessment of myocardial viability. Circulation. 2004, 109: 1328-1334. 10.1161/01.CIR.0000120294.67948.E3.CrossRefPubMed Shan K, Constantine G, Sivananthan M, Flamm SD: Role of cardiac magnetic resonance imaging in the assessment of myocardial viability. Circulation. 2004, 109: 1328-1334. 10.1161/01.CIR.0000120294.67948.E3.CrossRefPubMed
3.
go back to reference Thomsen HS, Marckmann P, Logager VB: Update on nephrogenic systemic fibrosis. Magn Reson Imaging Clin N Am. 2008, 16: 551-560. 10.1016/j.mric.2008.07.011. viiCrossRefPubMed Thomsen HS, Marckmann P, Logager VB: Update on nephrogenic systemic fibrosis. Magn Reson Imaging Clin N Am. 2008, 16: 551-560. 10.1016/j.mric.2008.07.011. viiCrossRefPubMed
4.
go back to reference Schneider G, Fries P, Ahlhelm F, Kindermann I, Kramann B, Bohm M: Contrast-enhanced cardiac MR imaging. Eur Radiol. 2003, 13 (Suppl 3): N11-18. 10.1007/s00330-003-0002-4.CrossRefPubMed Schneider G, Fries P, Ahlhelm F, Kindermann I, Kramann B, Bohm M: Contrast-enhanced cardiac MR imaging. Eur Radiol. 2003, 13 (Suppl 3): N11-18. 10.1007/s00330-003-0002-4.CrossRefPubMed
5.
go back to reference Lee JH, Koretsky AP: Manganese enhanced magnetic resonance imaging. Curr Pharm Biotechnol. 2004, 5: 529-537. 10.2174/1389201043376607.CrossRefPubMed Lee JH, Koretsky AP: Manganese enhanced magnetic resonance imaging. Curr Pharm Biotechnol. 2004, 5: 529-537. 10.2174/1389201043376607.CrossRefPubMed
6.
go back to reference Koretsky AP, Silva AC: Manganese-enhanced magnetic resonance imaging (MEMRI). NMR Biomed. 2004, 17: 527-531. 10.1002/nbm.940.CrossRefPubMed Koretsky AP, Silva AC: Manganese-enhanced magnetic resonance imaging (MEMRI). NMR Biomed. 2004, 17: 527-531. 10.1002/nbm.940.CrossRefPubMed
7.
go back to reference Natanzon A, Aletras AH, Hsu LY, Arai AE: Determining canine myocardial area at risk with manganese-enhanced MR imaging. Radiology. 2005, 236: 859-866. 10.1148/radiol.2363040413.CrossRefPubMed Natanzon A, Aletras AH, Hsu LY, Arai AE: Determining canine myocardial area at risk with manganese-enhanced MR imaging. Radiology. 2005, 236: 859-866. 10.1148/radiol.2363040413.CrossRefPubMed
8.
go back to reference Saeed M, Wendland MF, Watzinger N, Akbari H, Higgins CB: MR contrast media for myocardial viability, microvascular integrity and perfusion. Eur J Radiol. 2000, 34: 179-195. 10.1016/S0720-048X(00)00198-4.CrossRefPubMed Saeed M, Wendland MF, Watzinger N, Akbari H, Higgins CB: MR contrast media for myocardial viability, microvascular integrity and perfusion. Eur J Radiol. 2000, 34: 179-195. 10.1016/S0720-048X(00)00198-4.CrossRefPubMed
9.
go back to reference Bremerich J, Saeed M, Arheden H, Higgins CB, Wendland MF: Normal and infarcted myocardium: differentiation with cellular uptake of manganese at MR imaging in a rat model. Radiology. 2000, 216: 524-530.CrossRefPubMed Bremerich J, Saeed M, Arheden H, Higgins CB, Wendland MF: Normal and infarcted myocardium: differentiation with cellular uptake of manganese at MR imaging in a rat model. Radiology. 2000, 216: 524-530.CrossRefPubMed
10.
go back to reference Federle MP, Chezmar JL, Rubin DL, Weinreb JC, Freeny PC, Semelka RC, Brown JJ, Borello JA, Lee JK, Mattrey R, et al: Safety and efficacy of mangafodipir trisodium (MnDPDP) injection for hepatic MRI in adults: results of the U.S. multicenter phase III clinical trials (safety). J Magn Reson Imaging. 2000, 12: 186-197. 10.1002/1522-2586(200007)12:1<186::AID-JMRI21>3.0.CO;2-2.CrossRefPubMed Federle MP, Chezmar JL, Rubin DL, Weinreb JC, Freeny PC, Semelka RC, Brown JJ, Borello JA, Lee JK, Mattrey R, et al: Safety and efficacy of mangafodipir trisodium (MnDPDP) injection for hepatic MRI in adults: results of the U.S. multicenter phase III clinical trials (safety). J Magn Reson Imaging. 2000, 12: 186-197. 10.1002/1522-2586(200007)12:1<186::AID-JMRI21>3.0.CO;2-2.CrossRefPubMed
11.
go back to reference Wolf GL, Baum L: Cardiovascular toxicity and tissue proton T1 response to manganese injection in the dog and rabbit. AJR Am J Roentgenol. 1983, 141: 193-197.CrossRefPubMed Wolf GL, Baum L: Cardiovascular toxicity and tissue proton T1 response to manganese injection in the dog and rabbit. AJR Am J Roentgenol. 1983, 141: 193-197.CrossRefPubMed
12.
go back to reference Federle M, Chezmar J, Rubin DL, Weinreb J, Freeny P, Schmiedl UP, Brown JJ, Borrello JA, Lee JK, Semelka RC, et al: Efficacy and safety of mangafodipir trisodium (MnDPDP) injection for hepatic MRI in adults: results of the U.S. Multicenter phase III clinical trials. Efficacy of early imaging. J Magn Reson Imaging. 2000, 12: 689-701. 10.1002/1522-2586(200011)12:5<689::AID-JMRI5>3.0.CO;2-Z.CrossRefPubMed Federle M, Chezmar J, Rubin DL, Weinreb J, Freeny P, Schmiedl UP, Brown JJ, Borrello JA, Lee JK, Semelka RC, et al: Efficacy and safety of mangafodipir trisodium (MnDPDP) injection for hepatic MRI in adults: results of the U.S. Multicenter phase III clinical trials. Efficacy of early imaging. J Magn Reson Imaging. 2000, 12: 689-701. 10.1002/1522-2586(200011)12:5<689::AID-JMRI5>3.0.CO;2-Z.CrossRefPubMed
13.
go back to reference Slutsky RA, Peterson T, Strich G, Brown JJ: Hemodynamic effects of rapid and slow infusions of manganese chloride and gadolinium-DTPA in dogs. Radiology. 1985, 154: 733-735.CrossRefPubMed Slutsky RA, Peterson T, Strich G, Brown JJ: Hemodynamic effects of rapid and slow infusions of manganese chloride and gadolinium-DTPA in dogs. Radiology. 1985, 154: 733-735.CrossRefPubMed
14.
go back to reference Maceira AM, Prasad SK, Khan M, Pennell DJ: Normalized left ventricular systolic and diastolic function by steady state free precession cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2006, 8: 417-426. 10.1080/10976640600572889.CrossRefPubMed Maceira AM, Prasad SK, Khan M, Pennell DJ: Normalized left ventricular systolic and diastolic function by steady state free precession cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2006, 8: 417-426. 10.1080/10976640600572889.CrossRefPubMed
15.
go back to reference Firbank MJ, Coulthard A, Harrison RM, Williams ED: A comparison of two methods for measuring the signal to noise ratio on MR images. Phys Med Biol. 1999, 44: N261-264. 10.1088/0031-9155/44/12/403.CrossRefPubMed Firbank MJ, Coulthard A, Harrison RM, Williams ED: A comparison of two methods for measuring the signal to noise ratio on MR images. Phys Med Biol. 1999, 44: N261-264. 10.1088/0031-9155/44/12/403.CrossRefPubMed
16.
go back to reference Schmitt P, Griswold MA, Jakob PM, Kotas M, Gulani V, Flentje M, Haase A: Inversion recovery TrueFISP: quantification of T(1), T(2), and spin density. Magn Reson Med. 2004, 51: 661-667. 10.1002/mrm.20058.CrossRefPubMed Schmitt P, Griswold MA, Jakob PM, Kotas M, Gulani V, Flentje M, Haase A: Inversion recovery TrueFISP: quantification of T(1), T(2), and spin density. Magn Reson Med. 2004, 51: 661-667. 10.1002/mrm.20058.CrossRefPubMed
17.
go back to reference Flacke S, Allen JS, Chia JM, Wible JH, Periasamy MP, Adams MD, Adzamli IK, Lorenz CH: Characterization of viable and nonviable myocardium at MR imaging: comparison of gadolinium-based extracellular and blood pool contrast materials versus manganese-based contrast materials in a rat myocardial infarction model. Radiology. 2003, 226: 731-738. 10.1148/radiol.2263020151.CrossRefPubMed Flacke S, Allen JS, Chia JM, Wible JH, Periasamy MP, Adams MD, Adzamli IK, Lorenz CH: Characterization of viable and nonviable myocardium at MR imaging: comparison of gadolinium-based extracellular and blood pool contrast materials versus manganese-based contrast materials in a rat myocardial infarction model. Radiology. 2003, 226: 731-738. 10.1148/radiol.2263020151.CrossRefPubMed
18.
go back to reference Hu TC, Christian TF, Aletras AH, Taylor JL, Koretsky AP, Arai AE: Manganese enhanced magnetic resonance imaging of normal and ischemic canine heart. Magn Reson Med. 2005, 54: 196-200. 10.1002/mrm.20516.CrossRefPubMed Hu TC, Christian TF, Aletras AH, Taylor JL, Koretsky AP, Arai AE: Manganese enhanced magnetic resonance imaging of normal and ischemic canine heart. Magn Reson Med. 2005, 54: 196-200. 10.1002/mrm.20516.CrossRefPubMed
19.
go back to reference Mahoney JP, Small WJ: Studies on manganese. 3. The biological half-life of radiomanganese in man and factors which affect this half-life. J Clin Invest. 1968, 47: 643-653.PubMedCentralCrossRefPubMed Mahoney JP, Small WJ: Studies on manganese. 3. The biological half-life of radiomanganese in man and factors which affect this half-life. J Clin Invest. 1968, 47: 643-653.PubMedCentralCrossRefPubMed
20.
go back to reference Maynard LS, Cotzias GC: The partition of manganese among organs and intracellular organelles of the rat. J Biol Chem. 1955, 214: 489-495.PubMed Maynard LS, Cotzias GC: The partition of manganese among organs and intracellular organelles of the rat. J Biol Chem. 1955, 214: 489-495.PubMed
21.
go back to reference Wendland MF, Saeed M, Bremerich J, Arheden H, Higgins CB: Thallium-like test for myocardial viability with MnDPDP-enhanced MRI. Acad Radiol. 2002, 9 (Suppl 1): S82-83. 10.1016/S1076-6332(03)80405-1.CrossRefPubMed Wendland MF, Saeed M, Bremerich J, Arheden H, Higgins CB: Thallium-like test for myocardial viability with MnDPDP-enhanced MRI. Acad Radiol. 2002, 9 (Suppl 1): S82-83. 10.1016/S1076-6332(03)80405-1.CrossRefPubMed
22.
go back to reference Brady TJ, Goldman MR, Pykett IL, Buonanno FS, Kistler JP, Newhouse JH, Burt CT, Hinshaw WS, Pohost GM: Proton nuclear magnetic resonance imaging of regionally ischemic canine hearts: effect of paramagnetic proton signal enhancement. Radiology. 1982, 144: 343-347.CrossRefPubMed Brady TJ, Goldman MR, Pykett IL, Buonanno FS, Kistler JP, Newhouse JH, Burt CT, Hinshaw WS, Pohost GM: Proton nuclear magnetic resonance imaging of regionally ischemic canine hearts: effect of paramagnetic proton signal enhancement. Radiology. 1982, 144: 343-347.CrossRefPubMed
23.
go back to reference Wendland MF, Krombach GA, Higgins CB, Novikov V, Saeed M: Contrast enhanced MRI of stunned myocardium using Mn-based MRI contrast media. Acad Radiol. 2002, 9 (Suppl 2): S341-342. 10.1016/S1076-6332(03)80224-6.CrossRefPubMed Wendland MF, Krombach GA, Higgins CB, Novikov V, Saeed M: Contrast enhanced MRI of stunned myocardium using Mn-based MRI contrast media. Acad Radiol. 2002, 9 (Suppl 2): S341-342. 10.1016/S1076-6332(03)80224-6.CrossRefPubMed
24.
go back to reference Hu TC, Pautler RG, MacGowan GA, Koretsky AP: Manganese-enhanced MRI of mouse heart during changes in inotropy. Magn Reson Med. 2001, 46: 884-890. 10.1002/mrm.1273.CrossRefPubMed Hu TC, Pautler RG, MacGowan GA, Koretsky AP: Manganese-enhanced MRI of mouse heart during changes in inotropy. Magn Reson Med. 2001, 46: 884-890. 10.1002/mrm.1273.CrossRefPubMed
25.
go back to reference Eriksson R, Johansson L, Bjerner T, Ahlstrom H: Dobutamine-induced stress affects intracellular uptake of manganese: a quantitative magnetic resonance imaging study in pigs. J Magn Reson Imaging. 2005, 21: 360-364. 10.1002/jmri.20279.CrossRefPubMed Eriksson R, Johansson L, Bjerner T, Ahlstrom H: Dobutamine-induced stress affects intracellular uptake of manganese: a quantitative magnetic resonance imaging study in pigs. J Magn Reson Imaging. 2005, 21: 360-364. 10.1002/jmri.20279.CrossRefPubMed
26.
go back to reference Storey P, Chen Q, Li W, Seoane PR, Harnish PP, Fogelson L, Harris KR, Prasad PV: Magnetic resonance imaging of myocardial infarction using a manganese-based contrast agent (EVP 1001-1): preliminary results in a dog model. J Magn Reson Imaging. 2006, 23: 228-234. 10.1002/jmri.20500.CrossRefPubMed Storey P, Chen Q, Li W, Seoane PR, Harnish PP, Fogelson L, Harris KR, Prasad PV: Magnetic resonance imaging of myocardial infarction using a manganese-based contrast agent (EVP 1001-1): preliminary results in a dog model. J Magn Reson Imaging. 2006, 23: 228-234. 10.1002/jmri.20500.CrossRefPubMed
27.
go back to reference Storey P, Danias PG, Post M, Li W, Seoane PR, Harnish PP, Edelman RR, Prasad PV: Preliminary evaluation of EVP 1001-1: a new cardiac-specific magnetic resonance contrast agent with kinetics suitable for steady-state imaging of the ischemic heart. Invest Radiol. 2003, 38: 642-652. 10.1097/01.rli.0000077057.88108.3f.CrossRefPubMed Storey P, Danias PG, Post M, Li W, Seoane PR, Harnish PP, Edelman RR, Prasad PV: Preliminary evaluation of EVP 1001-1: a new cardiac-specific magnetic resonance contrast agent with kinetics suitable for steady-state imaging of the ischemic heart. Invest Radiol. 2003, 38: 642-652. 10.1097/01.rli.0000077057.88108.3f.CrossRefPubMed
28.
go back to reference Skjold A, Amundsen BH, Wiseth R, Stoylen A, Haraldseth O, Larsson HB, Jynge P: Manganese dipyridoxyl-diphosphate (MnDPDP) as a viability marker in patients with myocardial infarction. J Magn Reson Imaging. 2007, 26: 720-727. 10.1002/jmri.21065.CrossRefPubMed Skjold A, Amundsen BH, Wiseth R, Stoylen A, Haraldseth O, Larsson HB, Jynge P: Manganese dipyridoxyl-diphosphate (MnDPDP) as a viability marker in patients with myocardial infarction. J Magn Reson Imaging. 2007, 26: 720-727. 10.1002/jmri.21065.CrossRefPubMed
29.
go back to reference Skjold A, Kristoffersen A, Vangberg TR, Haraldseth O, Jynge P, Larsson HB: An apparent unidirectional influx constant for manganese as a measure of myocardial calcium channel activity. J Magn Reson Imaging. 2006, 24: 1047-1055. 10.1002/jmri.20736.CrossRefPubMed Skjold A, Kristoffersen A, Vangberg TR, Haraldseth O, Jynge P, Larsson HB: An apparent unidirectional influx constant for manganese as a measure of myocardial calcium channel activity. J Magn Reson Imaging. 2006, 24: 1047-1055. 10.1002/jmri.20736.CrossRefPubMed
30.
go back to reference Skjold A, Vangberg TR, Kristoffersen A, Haraldseth O, Jynge P, Larsson HB: Relaxation enhancing properties of MnDPDP in human myocardium. J Magn Reson Imaging. 2004, 20: 948-952. 10.1002/jmri.20200.CrossRefPubMed Skjold A, Vangberg TR, Kristoffersen A, Haraldseth O, Jynge P, Larsson HB: Relaxation enhancing properties of MnDPDP in human myocardium. J Magn Reson Imaging. 2004, 20: 948-952. 10.1002/jmri.20200.CrossRefPubMed
31.
go back to reference Mergler D: Neurotoxic effects of low level exposure to manganese in human populations. Environ Res. 1999, 80: 99-102. 10.1006/enrs.1998.3902.CrossRefPubMed Mergler D: Neurotoxic effects of low level exposure to manganese in human populations. Environ Res. 1999, 80: 99-102. 10.1006/enrs.1998.3902.CrossRefPubMed
32.
go back to reference Stepens A, Logina I, Liguts V, Aldins P, Eksteina I, Platkajis A, Martinsone I, Terauds E, Rozentale B, Donaghy M: A Parkinsonian syndrome in methcathinone users and the role of manganese. N Engl J Med. 2008, 358: 1009-1017. 10.1056/NEJMoa072488.CrossRefPubMed Stepens A, Logina I, Liguts V, Aldins P, Eksteina I, Platkajis A, Martinsone I, Terauds E, Rozentale B, Donaghy M: A Parkinsonian syndrome in methcathinone users and the role of manganese. N Engl J Med. 2008, 358: 1009-1017. 10.1056/NEJMoa072488.CrossRefPubMed
33.
go back to reference Dickerson RN: Manganese intoxication and parenteral nutrition. Nutrition. 2001, 17: 689-693. 10.1016/S0899-9007(01)00546-9.CrossRefPubMed Dickerson RN: Manganese intoxication and parenteral nutrition. Nutrition. 2001, 17: 689-693. 10.1016/S0899-9007(01)00546-9.CrossRefPubMed
34.
go back to reference Olanow CW: Manganese-induced parkinsonism and Parkinson's disease. Ann N Y Acad Sci. 2004, 1012: 209-223. 10.1196/annals.1306.018.CrossRefPubMed Olanow CW: Manganese-induced parkinsonism and Parkinson's disease. Ann N Y Acad Sci. 2004, 1012: 209-223. 10.1196/annals.1306.018.CrossRefPubMed
35.
go back to reference Wendland MF: Applications of manganese-enhanced magnetic resonance imaging (MEMRI) to imaging of the heart. NMR Biomed. 2004, 17: 581-594. 10.1002/nbm.943.CrossRefPubMed Wendland MF: Applications of manganese-enhanced magnetic resonance imaging (MEMRI) to imaging of the heart. NMR Biomed. 2004, 17: 581-594. 10.1002/nbm.943.CrossRefPubMed
Metadata
Title
Preliminary assessment of cardiac short term safety and efficacy of manganese chloride for cardiovascular magnetic resonance in humans
Authors
Juliano L Fernandes
Pippa Storey
Jose Alvaro da Silva
Gabriel S de Figueiredo
Jose M Kalaf
Otavio R Coelho
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Journal of Cardiovascular Magnetic Resonance / Issue 1/2011
Electronic ISSN: 1532-429X
DOI
https://doi.org/10.1186/1532-429X-13-6

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