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PhD Thesis in Medical Technology of Wibeke Nordhøy

Manganese and the Heart Intracellular MR relaxation and water exchange across the cardiac cell membrane. PhD Thesis in Medical Technology of Wibeke Nordhøy. Content. General theory Paper I-III Main conclusions. . Hydrogen/Proton: A spinning top. Randomly oriented protons. B 0. z.

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PhD Thesis in Medical Technology of Wibeke Nordhøy

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  1. Manganese and the Heart Intracellular MR relaxation and water exchange across the cardiac cell membrane PhD Thesis in Medical TechnologyofWibeke Nordhøy

  2. Content • General theory • Paper I-III • Main conclusions PhD Thesis of Wibeke Nordhøy

  3. Hydrogen/Proton: A spinning top PhD Thesis of Wibeke Nordhøy

  4. Randomly oriented protons PhD Thesis of Wibeke Nordhøy

  5. B0 z M0 M0= the netto magnetization vector Aligned with the external magnetic field Resonance Frequency: 0 =  B0 PhD Thesis of Wibeke Nordhøy

  6. Z o Mo Y Mxy(t) = M0 e-t/T2* Mz S B1 T2(T2*) X time T1 and T2relaxation Mz(t) = M0 ( 1 - 2e-t/T1 ) B time PhD Thesis of Wibeke Nordhøy

  7. MR and relaxation • Magnetic properties of protons in 1H-MRI • (H), T1 and T2 are essential factors in MRI • Paramagnetic contrast agents (CA) as Mn2+ act indirectly by decreasing T1 and T2 of water protons in near proximity • T1 –weighted imaging, where T2 is decreased PhD Thesis of Wibeke Nordhøy

  8. Contrast enhancement Shorter and shorter T1 or stronger and stronger signal in a T1 weighted image where the CA is present PhD Thesis of Wibeke Nordhøy

  9. ec : Extracellular ic : Intracellular ec-1 H O H O 2 ec 2 ic ic-1 p T ic 1ic p T ec 1ec T1 and water transport Symbols -1 = water exchange p = population fraction of water T1= longitudinal relaxation time Intracellular values ic-1pic T1ic Extracellular values ec-1pec T1ec PhD Thesis of Wibeke Nordhøy

  10. Water exchange rate PhD Thesis of Wibeke Nordhøy

  11. Fast exchange Monoexponential signal Mz(t) = M0 ( 1 - 2e-t/T1 ) PhD Thesis of Wibeke Nordhøy

  12. Mz (t) = pic ( 1 - 2e-t/T1ic ) + pec ( 1 - 2e-t/T1ec )) Slow exchange Biexponential signal PhD Thesis of Wibeke Nordhøy

  13. Intermediate exchange A more complicated model: Two-site water exchange (2SX) Ref: Springer et al. PhD Thesis of Wibeke Nordhøy

  14. Main goals of Paper I-III • To establish a model for T1 measurements in myocardium • The examine the influence of water exchange across the cardiac cell membrane • To calculate the T1 efficacy in each tissue compartment • To study the interaction beetween Mn2+ and Ca2+: uptake and retention of Mn2+-ions PhD Thesis of Wibeke Nordhøy

  15. Mn2+ LVDP, HR Mn content from freeze-dried hearts Experimental setup PhD Thesis of Wibeke Nordhøy

  16. Mn administration • Langendorff-perfused hearts • control perfusion • Mn2+ ‘wash-in’ • Mn2+ ‘wash-out’ • Single wash-in and wash-out (Paper I and II) • Repeated wash-in and wash-out with Mn-accumulation (Paper III) PhD Thesis of Wibeke Nordhøy

  17. Manganese ions as intracellular contrast agents: proton relaxation and calcium interactions in rat myocardium Paper I NMR in biomedicine 16(2): 82-95 (2003) PhD Thesis of Wibeke Nordhøy

  18. T1 relaxation in the hearts without Mn (control): which model is most suited? PhD Thesis of Wibeke Nordhøy

  19. T1 relaxation in hearts with 100 µM MnCl2 hearts: PhD Thesis of Wibeke Nordhøy

  20. R1-1 = 1/T1-1 R1-2= 1/T1-2 Strong correlation (r) between ic R1-1(R1ic) and the Mn content PhD Thesis of Wibeke Nordhøy

  21. T1 model of rat myocardium • Two-components of T1: • T1-1rapid, share ~ 60 % (ic component) • T1-2 slow, share ~ 40 % (ec component) • An assumed slow water exchange situation Fast exchange Slow exchange PhD Thesis of Wibeke Nordhøy

  22. Conclusions of Paper I • Multiexponential analyses of T1 revealed two water compartments (ic and ec) with different chemical environments in the rat myocardium • The intracellular R1 correlated highly with tissue Mn content, which increased R1 effectively • These T1 components were detectable with a 0.47 T MR spectrometer due to a slow-to-intermediate water exchange across the cardiac cell membrane PhD Thesis of Wibeke Nordhøy

  23. Intracellular manganese ions provide strong T1 relaxation in rat myocardium Paper II Magnetic Resonance in Medicine 52: 506 - 514 (2004) PhD Thesis of Wibeke Nordhøy

  24. Mn dipyridoxyl-diphosphate (MnDPDP) O O O O O- P O Mn O P O- N N O O + O + O- OH N N H H O PhD Thesis of Wibeke Nordhøy

  25. Relaxation rate constants vs. Mn content PhD Thesis of Wibeke Nordhøy

  26. 2SX water exchange analysis PhD Thesis of Wibeke Nordhøy

  27. In vitror1 of MnCl2 In vitror1 of MnDPDP High intracellular relaxivity with both MnCl2 and MnDPDP r1-1 ~ 60 (s mM)-1 PhD Thesis of Wibeke Nordhøy

  28. Conclusions of Paper II • T1relaxographyand 2SX analyses revealed two compartments representing ic- and ec- water • The ic relaxivity of MnDPDP was as high as for MnCl2 • Protein binding may explain the remarkably high intracellular relaxivity of Mn2+ ions • Increased correlation time (c) between proton- and electron spins of Mn2+-ions due to increased rotational correlation time (R) of bound protons • Rapid water exchange (M-1) within Mn2+ sites PhD Thesis of Wibeke Nordhøy

  29. Paper III Manganese-Calcium interactions with contrast media for cardiac MRI: A study of manganese chloride supplemented with calcium gluconate in isolated guinea pig hearts In Press March 2005: Investigative Radiology PhD Thesis of Wibeke Nordhøy

  30. Background and Goals • What will be the optimal formulation of Mn2+-releasing contrast media? • ‘efficacy’ versus ‘safety’? • Authors have suggested different combinations of Ca2+- and Mn2+-salts (10:1 or 8:1) Three possible Mn2+-releasing agents: • A slow-release Mn2+ chelate like MnDPDP • Add a ‘cardioprotective’ Ca2+ salt to a ‘MR effective’ Mn2+ salt • Avoid cardiodepression by controlled infusion of a rapidly dissolving Mn2+ salt like MnCl2 PhD Thesis of Wibeke Nordhøy

  31. LVDP, HR and LVDPxHR Manganese Manganese-Calcium PhD Thesis of Wibeke Nordhøy

  32. Results • Normal cell metabolism in all groups (CrP, ATP) • Manganese (660 µM): • Reduced myocardial contractility (-53 %) • Reduced heart rate (-18 %) • Large Mn metal content (93 times control) • Manganese-Calcium (660 µM): • Increased myocardial contractility (+56 %) • Large Mn metal content (41 times control) • Slow water exchange and biexponential T1 PhD Thesis of Wibeke Nordhøy

  33. Conclusions of Paper III • Alternative 1: High addition of Ca2+ to Mn2+ (10:1) increases contractility, but reduces Mn uptake • MnDPDP is more suited than alternative 1 for clinical MRI studies on the heart • Depression of the contractile force can also be avoided by using a slow infusion of MnCl2 PhD Thesis of Wibeke Nordhøy

  34. Main conclusions • A biexponential model is best suited for T1 analyses • A slow-intermediate water exchange across the cardiac cell membrane was confirmed for both rat and guinea pig hearts • Mn2+ entry dependent on Ca2+ channel activity • The contractile force was not significantly reduced for clinically relevant Mn2+ concentrations • Close correlation between tissue Mn content and relaxation parameters, especially for T1ic and high intracellular efficacy PhD Thesis of Wibeke Nordhøy

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