Development of Novel Physiological CMR Methods in Health and Disease

Overview

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.

Detailed description

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

Interventions

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

Primary outcome measures

• 4D CMR Flow [Time frame: Through study completion, average 5 years]

Secondary outcome measures (2)

• Secondary 4D CMR Flow [Time frame: Through study completion, average 5 years]
• Volumetric and functional parameters [Time frame: Through study completion, average 5 years]

Eligibility 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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Other

Study locations

United Kingdom · 1 center

• Sheffield Teaching Hospitals NHS FT — Sheffield

Publications

• Obokata M, Kane GC, Reddy YN, Olson TP, Melenovsky V, Borlaug BA. Role of Diastolic Stress Testing in the Evaluation for Heart Failure With Preserved Ejection Fraction: A Simultaneous Invasive-Echocardiographic Study. Circulation. 2017 Feb 28;135(9):825-838. doi: 10.1161/CIRCULATIONAHA.116.024822. Epub 2016 Dec 30. PMID 28039229
• Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, Flachskampf FA, Gillebert TC, Klein AL, Lancellotti P, Marino P, Oh JK, Popescu BA, Waggoner AD. Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr PMID 27037982
• Sharifov OF, Schiros CG, Aban I, Denney TS, Gupta H. Diagnostic Accuracy of Tissue Doppler Index E/e' for Evaluating Left Ventricular Filling Pressure and Diastolic Dysfunction/Heart Failure With Preserved Ejection Fraction: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 2016 Jan 25;5(1):e002530. doi: 10.1161/JAHA.115.002530. PMID 26811160
• Franke A. The stress echo dilemma: time counts, but image quality too. Eur Heart J. 2006 Jul;27(14):1646-7. doi: 10.1093/eurheartj/ehl091. Epub 2006 Jun 16. No abstract available. PMID 16782718
• Westenberg JJ, Roes SD, Ajmone Marsan N, Binnendijk NM, Doornbos J, Bax JJ, Reiber JH, de Roos A, van der Geest RJ. Mitral valve and tricuspid valve blood flow: accurate quantification with 3D velocity-encoded MR imaging with retrospective valve tracking. Radiology. 2008 Dec;249(3):792-800. doi: 10.1148/radiol.2492080146. Epub 2008 Oct 10. PMID 18849503
• Crandon S, Elbaz MSM, Westenberg JJM, van der Geest RJ, Plein S, Garg P. Clinical applications of intra-cardiac four-dimensional flow cardiovascular magnetic resonance: A systematic review. Int J Cardiol. 2017 Dec 15;249:486-493. doi: 10.1016/j.ijcard.2017.07.023. Epub 2017 Sep 28. PMID 28964555
• Pedrizzetti G, La Canna G, Alfieri O, Tonti G. The vortex--an early predictor of cardiovascular outcome? Nat Rev Cardiol. 2014 Sep;11(9):545-53. doi: 10.1038/nrcardio.2014.75. Epub 2014 Jun 3. PMID 24889521
• Carlsson M, Toger J, Kanski M, Bloch KM, Stahlberg F, Heiberg E, Arheden H. Quantification and visualization of cardiovascular 4D velocity mapping accelerated with parallel imaging or k-t BLAST: head to head comparison and validation at 1.5 T and 3 T. J Cardiovasc Magn Reson. 2011 Oct 4;13(1):55. doi: 10.1186/1532-429X-13-55. PMID 21970399

Identifiers

NCT: NCT03854071 · STH20184

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗