Novel Cardiac MRI techniques for the diagnosis of coronary artery disease compared to PET imaging and Invasive Coronary Angiography.

Coronary artery disease (CAD) is the second most common cause of death in the UK and it is very important to identify patients who have CAD early so that prevention can be started before a heart attack occurs.

A wide range of tests are used to detect CAD. Coronary angiography is routinely used in the NHS, and without extra flow measurements, we do not know how important CAD is. Heart scans can be used to detect important CAD including a scan that uses radioactive dye, ultrasound or cardiac MRI (CMR) which are interpreted by simply looking at images on a computer console. This visual interpretation is generally accurate but even with well trained individuals, scan reporters can differ in their interpretation especially in cases where there is such widespread CAD that the test may be appear normal.

We can measure the heart's blood flow with heart scans and the best method to do this is with Positron Emission Tomography (PET). This is better than visual inspection in identifying heart disease, can help with predicting the risk of a heart attack and other health hazards and help doctors decide which patients to treat with heart surgery. Unfortunately PET scanning is expensive (over £2,000 per scan), not available widely and uses potential harmful ionising radiation.

CMR can be used to measure the heart's blood flow. It has a major advantage over PET because it is much cheaper (around £500), more widely available and is safer as no harmful radiation is used. In previous research studies (the largest one performed at King's College London), blood flow measurements with PET and CMR were compared and found to be similar but not to agree perfectly. This study had some important limitations, as patients were scanned using separate CMR and PET scanners, on different days and separate analysis. Therefore, there has yet to be a conclusive comparison of PET and CMR blood flow measurements.

ADVANCES IN TECHNOLOGY
- We are privileged to have a 'hybrid PET-MR scanner', only the second one in the UK, which is able to perform PET and CMR scans at the same time. This scanner allows us to perform heart blood flow measurements at exactly the same time with PET and CMR and therefore allows a true head on comparison of the tests. This will help us to determine with more certainty if CMR is as good as PET for measuring the heart's blood flow.
- We have developed a new method to measure the heart's blood flow which is very accurate in animal and flow model studies but we need to test this in humans.
- Measuring blood flow is cumbersome and time-consuming with CMR and can take several hours even for an expert. We have developed an automated software to perform this which may be used for routine clinical diagnosis at point of care in the NHS.

AIM
I aim to test if CMR can be a cheaper, more widely available and safer alternative to PET. If proven to be comparable, automated CMR tools can be readily translated to clinical practice across the UK to enhance diagnosis of CAD. I will compare blood flow measured with PET and CMR using a novel hybrid PET-MR scanner and novel CMR techniques in patients with heart disease. We will compare blood flow measurements with novel CMR with findings with coronary angiography.

METHODS
-10 healthy volunteers without heart disease will undergo a PET-MR scan to measure blood flow with PET and CMR at the same time. This will allow us to test the method in humans.
-77 patients who are scheduled for an angiogram will have a PET-MR scan of their heart . We will compare blood flow measurements with CMR, PET and presence of CAD with coronary angiography.

We hope to get a better understanding of the heart's blood flow and test if this CMR tool is as good as PET and angiography. This will be helpful to patients as CMR is safe, non-invasive and does not use radiation. This tool may help doctors treat patients better by guiding doctors on which patients needs medications, stents or heart surgery.

Routine coronary angiography alone cannot detect significant coronary artery disease (CAD) unless further invasive measurements are performed. Measurement of myocardial blood flow (MBF) with imaging tests for detection of CAD improves diagnostic accuracy, adds incremental independent prognostic value and provides utility for clinical decision-making. PET is the gold standard to measure MBF, although not widely available, expensive and uses ionising radiation. We have developed novel automated MBF techniques with CMR. Hybrid PET-MR imaging allows simultaneous PET and CMR acquisition to overcome confounders from previous studies.

AIMS
1. To validate novel CMR techniques against the non-invasive gold standard of PET for measurement of MBF.
2. To validate novel CMR techniques against the invasive gold standard coronary angiography.

HYPOTHESES
1. MBF measured with novel CMR agrees and correlates strongly with the non-invasive gold standard PET.
2. MBF measurement with novel CMR techniques is superior to conventional visual CMR analysis for the detection of CAD and in clinical decision-making.
3. Non-invasive novel CMR techniques can detect significant CAD on invasive coronary angiography with a high precision.

METHODS
1. 10 healthy volunteers will undergo a cardiac PET-MR study for method development and optimisation of the clinical protocol.
2. 77 patients with suspected CAD listed for coronary angiography will undergo a PET-MR scan. PET and CMR perfusion data will be acquired during adenosine stress and at rest. MBF with CMR will be compared against the gold standard for measurement of MBF with PET. MBF measured with novel CMR methods will be compared with invasive FFR data to detect flow-limiting CAD.

IMPACT
Validation of a robust CMR tool to measure MBF and detect significant CAD will lead to translation for routine clinical care for enhanced diagnosis, added clinical value and utility for enhanced clinical decision-making for patient benefit.

The socio-economical impact of this research is accentuated by the health burden from coronary artery disease (CAD). CAD is the UK's second most common cause of death and is responsible for 70,000 deaths annually with an economic cost exceeding £15 billion. This research aims to enhance the diagnostic accuracy of detection of CAD, to allow risk stratification, and tailor expensive revascularisation options more rationally and cost-effectively to patients in different risk strata.

CLINICIANS
A robust automated technique that can be deployed throughout the UK can improve diagnostic accuracy and provide clinicians with important incremental information regarding prognosis of their patients and guide with clinical decision making. This tool would use existing CMR facilities throughout the UK, which is far more freely available and accessible to clinicians than the current gold standard PET.

RESEACHERS
CMR myocardial blood flow may be used as an alternative endpoint in future research studies to study the effect of medications and coronary revascularisation. In turn, through a greater precision of measurement of blood flow, this may allow future powered studies to be performed with smaller sample sizes. Given the lower cost of CMR compared with PET, a CMR tool will be more cost-effective and accessible for use by wider audience of researchers, host institutions and more attractive to funders.

This study will provide insights into the mechanisms and discrepancies of different methods of blood flow quantification and the detection of CAD. This will be of importance to academic physicists, modellers and clinicians. A reduction in perfusion is the earliest step in the ishaemia cascade and therefore absolute measurement of perfusion with bioimaging may generate insights into pathophysiological of a range of disease spectrum including ischaemic heart disease.

This project will be the first to undertake simultaneous blood flow measurements with PET-MR. Hence this project will generate considerable interest into the methodology of simultaneous hybrid imaging which will be of interest worldwide to the cardiac, imaging, CMR and nuclear community. There is a timely and strategic need to develop Cardiac PET-MR research to position the UK at the forefront internationally in this modality. Development of methods and techniques on this hybrid imaging will spur the development of future cardiac PET-MR studies. This is of strategic importance to the MRC who are rolling out 6 new PET-MR systems across the UK. In turn, this will cultivate a cadre of academic researchers with expertise in niche cardiac PET-MR imaging.

This study will generate important data and spin-off projects that can be used for motion correction and coregistration of images acquired with PET-MR imaging. This is of interest to physicists involved in optimising image acquisition and are transferrable to a wide spectrum of diseases that require motion correction including vascular, oncology and neurological disease.

HEALTHCARE SERVICE
This study is likely to provide an alternative and more cost effective method to measure blood flow for CAD detection. This is important to the NHS and Government decision-makers to target the increasingly limited resources more effectively. This study has already generated interest to health economists with a subsequent cost-effectiveness study following on from the completion of this project. These will help to translate findings of this research to routine clinical care and be of interest to key decision makers at NICE for local and national implementation of this tool.

INDUSTRY
This technique has commercial potential and we anticipate finalising a commercial version of our tool by the end of the proposed fellowship. Through the development of a commercial product with a pre-existing large international market, such a tool would directly benefit the economic competitiveness of the UK.