Scientific foundation

The scientists associated with Imacor AB, all work as senior researchers in the Lund cardiac MR group, at Lund University. Since 1999, a central theme for the research pursued by the research group has been the pathophysiological mechanisms associated with acute and chronic ischemic heart disease, but also myocardial function, pumping mechanics and ECG.

The research has included quantitative assessments of infarct size, myocardium at risk and, consequently, myocardial salvage as well as myocardial function and ECG changes. A close collaboration between physicians, technicians, engineers, physicists and mathematicians has enabled creation of a research platform well suited for both experimental^1-11 and clinical studies^12-20 of ischemic heart disease and cardioprotection using cardiac magnetic resonance (CMR) and myocardial perfusion SPECT (MPS).

Imacor AB has been consulted in the design and execution of several multi-centre, multi-national cardioprotection trials^9,10,16. When studying the efficacy of cardioprotective therapies in the situation of acute myocardial infarction it is important to be able to relate final infarct size to myocardium at risk. To ensure accurate and comparable quantitative assessment of infarct size and myocardium at risk using CMR it is of central importance to consider the basic mechanisms of contrast kinetics utilized in late gadolinium enhancement (LGE) CMR, but also the natural course of infarct resorption in humans.

The Lund cardiac MR group has developed and/or validated CMR methods for quantification of both infarct size using LGE^5,21,22  and myocardium at risk using T2-weighted imaging^7,23-25 and contrast-enhanced SSFP imaging^8,26. The group has shown that infarct quantification methods based on fixed standard deviation from remote is not reliable²⁷. For accurate and reproducible infarct quantification, validated and robust methods, such as the EWA-algorithm²¹ developed by the group, are needed. Such methods can be applied across different centers and different vendors which is necessary for use in clinical trials. Furthermore, contrast-enhanced SSFP imaging has been shown to be superior to T2-weighted imaging for assessment of MaR²⁸ in multicenter, multivendor trials. Therefore, CE-SSFP is recommended by Imacor AB when designing cardioprotection trials. Utilizing these quantitative techniques, the Lund CMR group was the first to directly describe infarct evolution in relation to duration of ischemia in humans²⁹. Furthermore, the group was also first to show the natural course of infarct resorption in man over the first year after acute infarction, including the early (first week) resorption of hyperenhanced myocardium¹⁶. This paper elucidates the importance of considering the initial dynamic phase of infarct involution when determining the timing of the initial LGE examination in clinical trials of cardio-protective therapies. Also, the Lund CMR group has shown the mechanisms for change of hyperenhanced myocardium early after infarction in an experimental study⁶.

Thus, the knowledge about the basic pathophysiology and contrast kinetics in combination with accurate implementation of the techniques described above can significantly affect the design of clinical cardioprotection trials. This is supported by a study by the Lund cardiac MR group showing that myocardial salvage index used as a surrogate endpoint derived from a single CMR examination will enable a significant decrease in sample size needed to reach sufficient statistical power compared to infarct size alone or biochemical markers³⁰.  

References

1.    Arheden H, Saeed M, Higgins CB, Gao DW, Bremerich J, Wyttenbach R, Dae MW, Wendland MF. Measurement of the distribution volume of gadopentetate dimeglumine at echo-planar MR imaging to quantify myocardial infarction: comparison with 99mTc-DTPA autoradiography in rats. Radiology 1999;211:698-708.

2.    Arheden H, Saeed M, Higgins CB, Gao DW, Ursell PC, Bremerich J, Wyttenbach R, Dae MW, Wendland MF. Reperfused rat myocardium subjected to various durations of ischemia: estimation of the distribution volume of contrast material with echo-planar MR imaging. Radiology 2000;215:520-8.

3.    Gotberg M, Olivecrona GK, Engblom H, Ugander M, van der Pals J, Heiberg E, Arheden H, Erlinge D. Rapid short-duration hypothermia with cold saline and endovascular cooling before reperfusion reduces microvascular obstruction and myocardial infarct size. BMC Cardiovasc Disord 2008;8:7.

4.    Hedstrom E, Arheden H, Eriksson R, Johansson L, Ahlstrom H, Bjerner T. Importance of perfusion in myocardial viability studies using delayed contrast-enhanced magnetic resonance imaging. J Magn Reson Imaging 2006;24:77-83.

5.    Heiberg E, Ugander M, Engblom H, Gotberg M, Olivecrona GK, Erlinge D, Arheden H. Automated quantification of myocardial infarction from MR images by accounting for partial volume effects: animal, phantom, and human study. Radiology 2008;246:581-8.

6.    Jablonowski R, Engblom H, Kanski M, Nordlund D, Koul S, van der Pals J, Englund E, Heiberg E, Erlinge D, Carlsson M, Arheden H. Contrast-Enhanced CMR Overestimates Early Myocardial Infarct Size: Mechanistic Insights Using ECV Measurements on Day 1 and Day 7. JACC Cardiovasc Imaging 2015;8:1379-89.

7.    Ubachs JF, Engblom H, Koul S, Kanski M, Andersson P, van der Pals J, Carlsson M, Erlinge D, Arheden H. Myocardium at risk can be determined by ex vivo T2-weighted magnetic resonance imaging even in the presence of gadolinium: comparison to myocardial perfusion single photon emission computed tomography. Eur Heart J Cardiovasc Imaging 2013;14:261-8.

8.    Nordlund D, Kanski M, Jablonowski R, Koul S, Erlinge D, Carlsson M, Engblom H, Aletras AH, Arheden H. Experimental validation of contrast-enhanced SSFP cine CMR for quantification of myocardium at risk in acute myocardial infarction. J Cardiovasc Magn Reson 2017;19:12.

9.    Nordlund D, Kopic S, Jablonowski R, Xanthis C, Bidhult S, Berg J, Kanski M, Chow K, Aletras AH, Arheden H. Verification of Pathologic ECV Estimated with Clinical T1 Mapping Methods Using an Isotope-based Reference. Radiol Cardiothorac Imaging 2025;7:e240441.

10.  Kopic S, Heiberg E, Engblom H, Carlsson M, Nordlund D, Jablonowski R, Kanski M, Xanthis C, Bidhult S, Aletras AH, Arheden H. Ex-vivo validation of nine algorithms for quantifying infarcts with late gadolinium enhancement cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2025;27:101915.

11.  Xanthis CG, Jablonowski R, Bidhult-Johansson S, Nordlund D, Haidich AB, Lala T, Arheden H, Aletras AH. Unravelling the mechanisms of CE-SSFP in imaging myocardium at risk: The effect of relaxation times on myocardial contrast. Magn Reson Imaging 2024;111:90-102.

12.  Atar D, Arheden H, Berdeaux A, Bonnet JL, Carlsson M, Clemmensen P, Cuvier V, Danchin N, Dubois-Rande JL, Engblom H, Erlinge D, Firat H, Halvorsen S, Hansen HS, Hauke W, Heiberg E, Koul S, Larsen AI, Le Corvoisier P, Nordrehaug JE, Paganelli F, Pruss RM, Rousseau H, Schaller S, Sonou G, Tuseth V, Veys J, Vicaut E, Jensen SE. Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: MITOCARE study results. Eur Heart J 2015;36:112-9.

13.  Erlinge D, Gotberg M, Lang I, Holzer M, Noc M, Clemmensen P, Jensen U, Metzler B, James S, Botker HE, Omerovic E, Engblom H, Carlsson M, Arheden H, Ostlund O, Wallentin L, Harnek J, Olivecrona GK. Rapid Endovascular Catheter Core Cooling Combined With Cold Saline as an Adjunct to Percutaneous Coronary Intervention for the Treatment of Acute Myocardial Infarction: The CHILL-MI Trial: A Randomized Controlled Study of the Use of Central Venous Catheter Core Cooling Combined With Cold Saline as an Adjunct to Percutaneous Coronary Intervention for the Treatment of Acute Myocardial Infarction. J Am Coll Cardiol 2014;63:1857-65.

14.  Gotberg M, Olivecrona GK, Koul S, Carlsson M, Engblom H, Ugander M, van der Pals J, Algotsson L, Arheden H, Erlinge D. A pilot study of rapid cooling by cold saline and endovascular cooling before reperfusion in patients with ST-elevation myocardial infarction. Circ Cardiovasc Interv 2010;3:400-7.

15.  Engblom H, Hedstrom E, Heiberg E, Wagner GS, Pahlm O, Arheden H. Size and transmural extent of first-time reperfused myocardial infarction assessed by cardiac magnetic resonance can be estimated by 12-lead electrocardiogram. Am Heart J 2005;150:920.

16.  Engblom H, Hedstrom E, Heiberg E, Wagner GS, Pahlm O, Arheden H. Rapid initial reduction of hyperenhanced myocardium after reperfused first myocardial infarction suggests recovery of the peri-infarction zone: one-year follow-up by MRI. Circ Cardiovasc Imaging 2009;2:47-55.

17.  Engblom H, Wagner GS, Setser RM, Selvester RH, Billgren T, Kasper JM, Maynard C, Pahlm O, Arheden H, White RD. Quantitative clinical assessment of chronic anterior myocardial infarction with delayed enhancement magnetic resonance imaging and QRS scoring. Am Heart J 2003;146:359-66.

18.  Nordlund D, Heiberg E, Carlsson M, Frund ET, Hoffmann P, Koul S, Atar D, Aletras AH, Erlinge D, Engblom H, Arheden H. Extent of Myocardium at Risk for Left Anterior Descending Artery, Right Coronary Artery, and Left Circumflex Artery Occlusion Depicted by Contrast-Enhanced Steady State Free Precession and T2-Weighted Short Tau Inversion Recovery Magnetic Resonance Imaging. Circ Cardiovasc Imaging 2016;9.

19.  Erlinge D, Gotberg M, Noc M, Lang I, Holzer M, Clemmensen P, Jensen U, Metzler B, James S, Botker HE, Omerovic E, Koul S, Engblom H, Carlsson M, Arheden H, Ostlund O, Wallentin L, Klos B, Harnek J, Olivecrona GK. Therapeutic hypothermia for the treatment of acute myocardial infarction-combined analysis of the RAPID MI-ICE and the CHILL-MI trials. Ther Hypothermia Temp Manag 2015;5:77-84.

20.  Hedeer F, Akil S, Oddstig J, Hindorf C, Arheden H, Carlsson M, Engblom H. Diagnostic accuracy for CZT gamma camera compared to conventional gamma camera technique with myocardial perfusion single-photon emission computed tomography: Assessment of myocardial infarction and function. J Nucl Cardiol 2023;30:1935-46.

21.  Engblom H, Tufvesson J, Jablonowski R, Carlsson M, Aletras AH, Hoffmann P, Jacquier A, Kober F, Metzler B, Erlinge D, Atar D, Arheden H, Heiberg E. A new automatic algorithm for quantification of myocardial infarction imaged by late gadolinium enhancement cardiovascular magnetic resonance: experimental validation and comparison to expert delineations in multi-center, multi-vendor patient data. J Cardiovasc Magn Reson 2016;18:27.

22.  Heiberg E, Engblom H, Engvall J, Hedstrom E, Ugander M, Arheden H. Semi-automatic quantification of myocardial infarction from delayed contrast enhanced magnetic resonance imaging. Scand Cardiovasc J 2005;39:267-75.

23.  Ubachs JF, Sorensson P, Engblom H, Carlsson M, Jovinge S, Pernow J, Arheden H. Myocardium at risk by magnetic resonance imaging: head-to-head comparison of T2-weighted imaging and contrast-enhanced steady-state free precession. Eur Heart J Cardiovasc Imaging 2012;13:1008-15.

24.  Carlsson M, Ubachs JF, Hedstrom E, Heiberg E, Jovinge S, Arheden H. Myocardium at risk after acute infarction in humans on cardiac magnetic resonance: quantitative assessment during follow-up and validation with single-photon emission computed tomography. JACC Cardiovasc Imaging 2009;2:569-76.

25.  Tufvesson J, Carlsson M, Aletras AH, Engblom H, Deux JF, Koul S, Sorensson P, Pernow J, Atar D, Erlinge D, Arheden H, Heiberg E. Automatic segmentation of myocardium at risk from contrast enhanced SSFP CMR: validation against expert readers and SPECT. BMC Med Imaging 2016;16:19.

26.  Sorensson P, Heiberg E, Saleh N, Bouvier F, Caidahl K, Tornvall P, Ryden L, Pernow J, Arheden H. Assessment of myocardium at risk with contrast enhanced steady-state free precession cine cardiovascular magnetic resonance compared to single-photon emission computed tomography. J Cardiovasc Magn Reson 2010;12:25.

27.  Heiberg E, Engblom H, Carlsson M, Erlinge D, Atar D, Aletras AH, Arheden H. Infarct quantification with cardiovascular magnetic resonance using "standard deviation from remote" is unreliable: validation in multi-centre multi-vendor data. J Cardiovasc Magn Reson 2022;24:53.

28.  Nordlund D, Klug G, Heiberg E, Koul S, Larsen TH, Hoffmann P, Metzler B, Erlinge D, Atar D, Aletras AH, Carlsson M, Engblom H, Arheden H. Multi-vendor, multicentre comparison of contrast-enhanced SSFP and T2-STIR CMR for determining myocardium at risk in ST-elevation myocardial infarction. Eur Heart J Cardiovasc Imaging 2016;17:744-53.

29.  Hedstrom E, Engblom H, Frogner F, Astrom-Olsson K, Ohlin H, Jovinge S, Arheden H. Infarct evolution in man studied in patients with first-time coronary occlusion in comparison to different species - implications for assessment of myocardial salvage. J Cardiovasc Magn Reson 2009;11:38.

30.  Engblom H, Heiberg E, Erlinge D, Jensen SE, Nordrehaug JE, Dubois-Rande JL, Halvorsen S, Hoffmann P, Koul S, Carlsson M, Atar D, Arheden H. Sample Size in Clinical Cardioprotection Trials Using Myocardial Salvage Index, Infarct Size, or Biochemical Markers as Endpoint. J Am Heart Assoc 2016;5:e002708.