Oxygen-enhanced Magnetic Resonance Imaging (OE-MRI) of the Heart: A Feasibility Study

Coronary Artery Disease Clinical Trial

— OE-MRI  

Official title:

Oxygen-enhanced Magnetic Resonance Imaging (OE-MRI) of the Heart: A Feasibility Study

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT05163327
• Other study ID #: Cardiac-OE-MRI-01
• Status: Withdrawn
• Start date: January 2023
• Est. completion date: December 2023

Study information

• Verified date: January 2023
• Source: Manchester University NHS Foundation Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This exploratory pilot study aims to set up cardiac oxygen enhanced magnetic resonance imaging (OE-MRI). It will involve 10 healthy volunteers and 10 patients with known coronary artery disease (CAD) having a MRI scan.

If positive, this data would be used to power an appropriately sized study assessing the utility of cardiac OE-MRI in CAD and other cardiac pathologies.

Description:

Determining the presence and severity of myocardial ischaemia is a key goal in the effective management of coronary artery disease (CAD). Untreated ischaemia is an important determinant of adverse outcome, and the benefits of ischemia-driven revascularization are well recognized.1

Anatomic appearances of coronary artery disease are poorly predictive of myocardial ischemia.1 2 Therefore, concurrent assessment of the functional severity of coronary stenosis is used to guide revascularization.3 In the clinical setting, a number of imaging methods are available, including nuclear techniques, echocardiography, and cardiovascular magnetic resonance (CMR). Such modalities assess flow heterogeneity and contractile abnormalities, but these serve as surrogates of myocardial ischemia: ischemia per se is not measured. Furthermore, these functional imaging modalities rely on the use of exogenous contrast agents, which, albeit small, carry additional risks and can be contraindicated in certain populations.

Blood oxygen level dependent (BOLD) imaging exploits the inherent paramagnetic properties of haemoglobin.4 The transition from diamagnetic oxyhaemoglobin to paramagnetic deoxyhaemoglobin induces magnetic susceptibility differences, resulting in a change in magnetic resonance signal intensity and thereby generating oxygen dependent contrast. Thus BOLD imaging provides insight into myocardial tissue oxygenation. Since hypoxia is the initiator of the ischaemic cascade, assessment of regional myocardial oxygenation with BOLD imaging has been hypothesised to reflect more directly the imbalance between oxygen supply and demand and be sensitive for detecting CAD. Indeed initial evaluation of BOLD imaging for detecting CAD has produced promising results.5-7 Furthermore, BOLD has provided pathological insight into other myocardial pathologies. Myocardial perfusion (blood flow) can be dissociated from oxygenation i.e. hypoperfusion is not necessarily commensurate with tissue hypoxia. For example, myocardial oxygen demand may be down-regulated in hibernating myocardium, and may be upregulated in hypertrophic cardiomyopathy (HCM) due to the increased cost of energy metabolism. In HCM mutation carriers without left ventricular hypertrophy, Karamitsos et al demonstrated normal myocardial perfusion reserve, but abnormal myocardial oxygenation during stress, possibly explained by the fact that sarcomere gene mutations increase the energy cost of contraction before the onset of hypertrophy.8

However, BOLD imaging is associated with a number of disadvantages. First, since the BOLD signal reflects deoxyhaemoglobin which is confined to blood vessels, it doesn't truly reflect tissue oxygen status.9 Second, the BOLD signal is also dependent on vessel geometry, changes in blood flow and blood volume, which thus can confound the signal.9 Finally, the CMR techniques used to measure the BOLD signal (T2* of T2) are not quantitative since a change in T2* or T2 cannot be related to a change in the partial pressure of oxygen (PO2). Instead, semi-quantitative measurements are made using signal intensity and are assumed to reflect oxygenation.

Oxygen enhanced magnetic resonance imaging (OE-MRI) potentially overcomes these limitations. Oxygen itself has paramagnetic properties; it increases the proton longitudinal relaxation rate (R1) of water containing dissolved oxygen.10 The measured change in R1 (= 1/T1, where T1 relaxation time is an inherent magnetic property of all tissues) induced by breathing oxygen is directly proportional to the change in PO2. In OE-MRI the change in R1 on breathing elevated concentrations of oxygen is measured. The benefits of OE-MRI over BOLD are therefore that it is sensitive to tissue oxygenation, it is not dependent on changes in blood flow and volume, and it is truly quantitative, since the change in R1 is directly proportional to the change in PO2. Thus it potentially offers a quantitative measure of myocardial oxygenation. OE-MRI has been used to assess lung tissue oxygenation,11 solid tumour oxygenation12 and to assess placental oxygenation in pregnant women13 on conventional clinical MRI scanners with very encouraging results.

OE-MRI has not been applied in the heart. We hypothesise that OE-MRI will allow non-invasive, non-ionising, and quantitative assessment of myocardial tissue oxygenation, that is free from exogenous contrast agent. If this is the case, OE-MRI will offer enormous potential in terms of the diagnosis and management of CAD, and in terms of providing pathophysiological insight into cardiac disease.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: December 2023
• Est. primary completion date: December 2023
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 10 healthy volunteers and 10 patients with known significant (defined as > 70% stenosis) single or 2 vessel CAD

• Male or female > 18 years of age

• Females will be non-pregnant and non-lactating

Exclusion Criteria:

• Contraindication to MRI (including claustrophobia)

• History of any significant lung disease including asthma and COPD

• History of type II respiratory failure

• Second degree and higher atrio-ventricular conduction delay

• Patients taking Dipyridamole, or theophylline-based medication

• Significant left main stem coronary artery disease

• Recent myocardial infarction (within 2 months)

• Unstable angina

• Abnormal heart rhythm e.g. atrial fibrillation, atrial flutter, atrial or ventricular bigeminy

• Pregnancy/breast-feeding. Women of childbearing potential (not >2 years post- menopausal and/or not surgically sterilised) must have a negative blood serum pregnancy test.

Related Conditions & MeSH terms

• Coronary Artery Disease

Intervention

Procedure:
• Oxygen-enhanced Cardiac MRI
The MRI scan will include assessment of cardiac function. Myocardial magnetic properties (T1, T2, T2*) will be measured while patients are breathing room air, oxygen and during an infusion of adenosine. The scan will last for approximately 60 minutes. Prior to the scan patients will have an intravenous cannula (venflon) placed in an arm vein.

Locations

Country	Name	City	State
United Kingdom	Manchester University NHS Foundation Trust	Manchester

Sponsors (1)

Lead Sponsor	Collaborator
Manchester University NHS Foundation Trust

Country where clinical trial is conducted

United Kingdom, 

References & Publications (13)

Arnold JR, Karamitsos TD, Bhamra-Ariza P, Francis JM, Searle N, Robson MD, Howells RK, Choudhury RP, Rimoldi OE, Camici PG, Banning AP, Neubauer S, Jerosch-Herold M, Selvanayagam JB. Myocardial oxygenation in coronary artery disease: insights from blood oxygen level-dependent magnetic resonance imaging at 3 tesla. J Am Coll Cardiol. 2012 May 29;59(22):1954-64. doi: 10.1016/j.jacc.2012.01.055. — View Citation

Friedrich MG, Niendorf T, Schulz-Menger J, Gross CM, Dietz R. Blood oxygen level-dependent magnetic resonance imaging in patients with stress-induced angina. Circulation. 2003 Nov 4;108(18):2219-23. doi: 10.1161/01.CIR.0000095271.08248.EA. Epub 2003 Oct 13. — View Citation

Huen I, Morris DM, Wright C, Parker GJ, Sibley CP, Johnstone ED, Naish JH. R1 and R2 * changes in the human placenta in response to maternal oxygen challenge. Magn Reson Med. 2013 Nov;70(5):1427-33. doi: 10.1002/mrm.24581. Epub 2012 Dec 27. — View Citation

Karamitsos TD, Dass S, Suttie J, Sever E, Birks J, Holloway CJ, Robson MD, Jerosch-Herold M, Watkins H, Neubauer S. Blunted myocardial oxygenation response during vasodilator stress in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2013 Mar 19;61(11):1169-76. doi: 10.1016/j.jacc.2012.12.024. — View Citation

Karamitsos TD, Leccisotti L, Arnold JR, Recio-Mayoral A, Bhamra-Ariza P, Howells RK, Searle N, Robson MD, Rimoldi OE, Camici PG, Neubauer S, Selvanayagam JB. Relationship between regional myocardial oxygenation and perfusion in patients with coronary artery disease: insights from cardiovascular magnetic resonance and positron emission tomography. Circ Cardiovasc Imaging. 2010 Jan;3(1):32-40. doi: 10.1161/CIRCIMAGING.109.860148. Epub 2009 Nov 17. — View Citation

Kern MJ, Lerman A, Bech JW, De Bruyne B, Eeckhout E, Fearon WF, Higano ST, Lim MJ, Meuwissen M, Piek JJ, Pijls NH, Siebes M, Spaan JA; American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology. Physiological assessment of coronary artery disease in the cardiac catheterization laboratory: a scientific statement from the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology. Circulation. 2006 Sep 19;114(12):1321-41. doi: 10.1161/CIRCULATIONAHA.106.177276. Epub 2006 Aug 28. — View Citation

Kershaw LE, Naish JH, McGrath DM, Waterton JC, Parker GJ. Measurement of arterial plasma oxygenation in dynamic oxygen-enhanced MRI. Magn Reson Med. 2010 Dec;64(6):1838-42. doi: 10.1002/mrm.22571. — View Citation

O'Connor JP, Naish JH, Parker GJ, Waterton JC, Watson Y, Jayson GC, Buonaccorsi GA, Cheung S, Buckley DL, McGrath DM, West CM, Davidson SE, Roberts C, Mills SJ, Mitchell CL, Hope L, Ton NC, Jackson A. Preliminary study of oxygen-enhanced longitudinal relaxation in MRI: a potential novel biomarker of oxygenation changes in solid tumors. Int J Radiat Oncol Biol Phys. 2009 Nov 15;75(4):1209-15. doi: 10.1016/j.ijrobp.2008.12.040. Epub 2009 Mar 26. — View Citation

Padhani AR, Krohn KA, Lewis JS, Alber M. Imaging oxygenation of human tumours. Eur Radiol. 2007 Apr;17(4):861-72. doi: 10.1007/s00330-006-0431-y. Epub 2006 Oct 17. — View Citation

Pauling L, Coryell CD. The Magnetic Properties and Structure of Hemoglobin, Oxyhemoglobin and Carbonmonoxyhemoglobin. Proc Natl Acad Sci U S A. 1936 Apr;22(4):210-6. doi: 10.1073/pnas.22.4.210. No abstract available. — View Citation

Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van' t Veer M, Klauss V, Manoharan G, Engstrom T, Oldroyd KG, Ver Lee PN, MacCarthy PA, Fearon WF; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009 Jan 15;360(3):213-24. doi: 10.1056/NEJMoa0807611. — View Citation

Uren NG, Melin JA, De Bruyne B, Wijns W, Baudhuin T, Camici PG. Relation between myocardial blood flow and the severity of coronary-artery stenosis. N Engl J Med. 1994 Jun 23;330(25):1782-8. doi: 10.1056/NEJM199406233302503. — View Citation

Young IR, Clarke GJ, Bailes DR, Pennock JM, Doyle FH, Bydder GM. Enhancement of relaxation rate with paramagnetic contrast agents in NMR imaging. J Comput Tomogr. 1981 Dec;5(6):543-7. doi: 10.1016/0149-936x(81)90089-8. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To apply OE-MRI in the heart and compare it to BOLD imaging	To apply OE-MRI in the heart and compare it to BOLD imaging	24 Months