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

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.

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.

Eligibility Criteria:
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.