Development of Novel Physiological CMR Methods in Health and Disease

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	Yes
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	20 Years - 80 Years
Gender	All

More Inclusion & Exclusion Criteria

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)

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT03854071
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	N/A
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Sheffield Teaching Hospitals NHS Foundation Trust
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	N/A
Principal Investigator Affiliation	N/A
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	United Kingdom
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Heart Failure, Pulmonary Hypertension, Myocardial Infarction, Coronary Artery Disease

Additional Details

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): 1. Survey. 2. Baseline cine imaging for functional imaging (rest) 3. Tissue characterisation with native T1-mapping (rest) 4. 4D flow CMR (rest) 5. Record blood pressure, heart rate and oxygen saturation. 6. Start of physiological stress (increase pre-load or pharmacological stressors) 7. 4D flow CMR (stress, at low-moderate intensity exercise aiming for heart rate up to 110bpm only) 8. Functional cines (stress, at low-moderate intensity exercise aiming for heart rate up to 110bpm only) 9. Record blood pressure, heart rate and oxygen saturation. 10. First pass perfusion imaging (only if adenosine/regadenoson used for myocardial hyperaemia) 11. Record blood pressure, heart rate and oxygen saturation. 12. Gadolinium contrast injection. 13. Early/Late gadolinium enhancement imaging in short-axis. 14. 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): 1. 4D flow CMR (rest) 2. Record blood pressure, heart rate and oxygen saturation. 3. Start of physiological stress (increase pre-load or pharmacological stressors) 4. 4D flow CMR (stress, at low-moderate intensity exercise aiming for heart rate up to 110bpm only) 5. Functional cines (stress, at low-moderate intensity exercise aiming for heart rate up to 110bpm only) 6. Record blood pressure, heart rate and oxygen saturation. 7. First pass perfusion imaging (only if adenosine/regadenoson used for myocardial hyperaemia) 8. Record blood pressure, heart rate and oxygen saturation

Arms & Interventions

Arms

Other: Group 1

Heart failure patients with preserved ejection fraction

Other: Group 2

Heart failure patients with reserved ejection fraction

Other: Group 3

Patients with pulmonary hypertension

Other: Group 4

Patients with acute myocardial infarction

Other: Group 5

Patients with suspected but not treated coronary artery disease

Other: Group 6

Healthy Volunteers

Interventions

Other: - intravenous fluid challenge

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

Contact a Trial Team

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