Development of Novel Physiological CMR Methods in Health and Disease

Physiological cardiovascular stress test plays a crucial role in the assessment of patients with suspected heart disease. There are several methods of cardiac physiological stress tests and each of them offer varied insight into cardiac physiological adaptation: passive leg raise, intra-venous fluid challenge, pharmacological stressors and physical exercise stress test. Echocardiography, which is the mainstay for the non-invasive rest/stress assessment of the left ventricular (LV) haemodynamics has several limitations. Novel methods of CMR imaging allow to map intra-cardiac flow in three-dimension using novel flow acquisitions. These novel flow acquisitions are called four-dimensional flow CMR, where the fourth dimension is time. Additionally, traditional cine CMR imaging for functional assessment can now be done without breath-holds using advanced acceleration methods, allowing them to be used during exercise. A comprehensive understanding of functional-flow coupling at rest, during increased pre-load (fluid challenge) to the heart or during exercise, is lacking in the literature. There is an important need to validate these novel CMR methods for developing mechanistic insight into physiological cardiac adaptation to increased pre-load or to exercise in health and how it alters in heart disease.

For this study, the investigators will perform comprehensive physiological CMR in healthy volunteers and patients with suspected or known heart disease (coronary artery disease and heart failure). A sub-set of patients will have follow-up scans after they receive treatment to investigate the therapeutic target role of these physiological CMR metrics. Patients who have given informed consent for this research will receive one physiological stress test depending on the clinical context. There will be 5 clinical subgroups to which patients will be recruited to: Group 1. Heart failure with preserved ejection fraction (HFpEF), Group 2. Heart failure with reserved ejection fraction (HFrEF), Group 3. Pulmonary hypertension (PH), Group 4. Acute myocardial infarction (AMI) and Group 5. Suspected but not treated coronary artery disease (sCAD). Patients will be selected in each group by the clinical specialist/research team as per the published guidelines and local protocols - Group 1 and 2 (19), Group 3 (20), Group 4 (21) and Group 5 (22). First 4 groups of patients will receive pre-load increasing stress test (either passive leg raise or equivalent 500mls intravenous fluid challenge depending on the tolerability). This will be done to investigate if increase in pre-load will help unravel subtle dysfunction which is not apparent at euvolemic state. AMI patients may also receive ischaemia testing stress CMR depending on the main clinically question needed to answer. Patients with sCAD will receive clinically relevant pharmacological stress test (dobutamine, adenosine or regadenoson, inhaled nitric oxide) to diagnose ischaemia. Healthy volunteers who have given informed consent will receive matched physiological stress test so that head-on comparison can be made with the relevant patient cohort. The CMR scan protocol will involve minimal breath-holds and will be patient-friendly. This is achieved by using accelerated, advanced cine and late gadolinium enhancement (LGE)-imaging techniques which require fewer breath-holds and shorter scan. All CMR stress studies will be supervised by an Advanced Life Support (ALS) certified doctor. The CMR protocol for healthy volunteers will include the following components (45 minutes): Survey Baseline cine imaging for functional imaging (rest) Tissue characterisation with native T1-mapping (rest) 4D flow CMR (rest) Record blood pressure, heart rate and oxygen saturation Start of physiological stress (increase pre-load or pharmacological stressors) 4D flow CMR (stress, at low-moderate intensity exercise aiming for heart rate up to 110bpm only) Functional cines (stress, at low-moderate intensity exercise aiming for heart rate up to 110bpm only) Record blood pressure, heart rate and oxygen saturation First pass perfusion imaging (only if adenosine/regadenoson used for myocardial hyperaemia) Record blood pressure, heart rate and oxygen saturation Gadolinium contrast injection Early/Late gadolinium enhancement imaging in short-axis Post contrast T1-mapping End of study For patient's receiving clinical CMR scans, the 'bolt-on' stress CMR protocol will include the following components (20-25minutes): 4D flow CMR (rest) Record blood pressure, heart rate and oxygen saturation Start of physiological stress (increase pre-load or pharmacological stressors) 4D flow CMR (stress, at low-moderate intensity exercise aiming for heart rate up to 110bpm only) Functional cines (stress, at low-moderate intensity exercise aiming for heart rate up to 110bpm only) Record blood pressure, heart rate and oxygen saturation First pass perfusion imaging (only if adenosine/regadenoson used for myocardial hyperaemia) Record blood pressure, heart rate and oxygen saturation

Patients will be selected in each group by the clinical specialist/research team as per the published guidelines and local protocols - Group 1, Group 2, Group 3, Group 4 and Group 5.

Patients will undergo a receive a pre-load increasing stress test with intravenous fluids depending on tolerability

The primary outcome measures will include 4D flow CMR derived mitral inflow diastolic parameter: E/A ratio. This parameter will be quantified once both at rest and during physiological stress.

Other 4D flow CMR derived outcome metrics will include mitral, tricuspid and pulmonary valve flow quantification - net forward flow (mls), E-velocity (cm/sec), E-velocity deceleration time (msec, both for mitral and tricuspid), A-velocity (cm/sec) and valvular regurgitation (mls).

2) Right and left heart volumetric and functional parameters: end-diastolic and end-systolic volumes; ejection fraction

Inclusion Criteria: Healthy Volunteers age 20 to 80, recruited from Sheffield Teaching Hospitals staff members Patients age 20 to 80 with suspected or known heart disease (group 1 to 5) Capable of giving written informed consent Exclusion Criteria: Inability to perform the study protocol secondary to severe heart failure requiring IV therapy Patients recruited in the suspected CAD and acute myocardial infarction arms of the study and in need for detection of ischaemia should not have any past medical history of MI, ACS or cardiomyopathy Patients with significant valvular heart disease will be excluded from any patient group Patient with in atrial fibrillation will be excluded Contraindication to MRI (as per standard MRI screening questionnaire issued to patients prior to clinical MRI procedures)

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