Table 1. Key principles, clinical translation, advantages, pitfalls and validation studies for 4D-flow, DTI and PET-MR.

	4D-flow	Diffusion Tensor Imaging	PET-MR
Key principles	►Acquires three-directional, three-dimensional, phase-contrast data over time (the fourth dimension) ►Allows assessment of intracardiac flow in three dimensions	►Measures the direction and magnitude of the diffusion of water molecules ►In the myocardium, water diffusion occurs preferentially along the long axis of cardiomyocytes ►Used to characterise myocardial microstructure	►PET and MRI hardware in the same gantry allows for simultaneous PET-MR acquisition ►Wide potential given exploration for novel PET tracers for cardiac application and emerging MRI methods
Clinical applications	►Insight into complex intracardiac flow in several disease states ►Quantification of valvular flow—both forward and backward (regurgitant) flows, for example, mitral regurgitation ►Accurate assessment systemic to pulmonary blood flow ►Visualisation and identification of shunt in congenital heart disease ►Identification and assessment of peak velocity through aortic valve in three-dimension for confirming pressure gradient in aortic stenosis ►Emerging role in left ventricular diastolic assessment	►Myocardial infarction: depiction of oedema and scar tissue, changes to the helical cardiomyocyte arrangement and myocardial sheetlet orientations ►Hypertrophic cardiomyopathy: detect early microstructural changes and detection of fibre disarray which can identify patients at greater risk of arrhythmias and sudden cardiac death ►Dilated cardiomyopathy: assessment of myocardial sheetlet mobility between diastole and systole, which is significantly reduced in patients with DCM ►Congenital heart disease: DTI can help elucidate how microstructural abnormalities in impacts on clinical outcomes	►Evaluation of cardiac masses using PET and MRI ►Assessment of cardiac sarcoidosis, although requires strict dietary preparation. May help to improve diagnosis and allow for risk stratification ►Emerging role of coronary imaging with CMRA and PET imaging of high-risk plaque
Advantages	►Offline multiplanar assessment of vascular, valvular and intracardiac flow ►Allows to quantify transvalvular flow for all four valves for the same averaged cardiac cycle—this improves precision for Qp:Qs assessment ►Valve tracking allows to improve valvular flow assessment ►Fast acceleration techniques have made it possible to acquire 4D-flow in 6–10 min	►Non-invasive method of examining in vivo myocardial microstructure ►Non-contrast sequence ►Can be acquired free-breathing ►Relatively quick acquisition time	►Simultaneous acquisition allows precise coregistration of images and cross-validation of findings ►PET allows absolute quantification of biological processes which can be combined with multiparametric data derived from MRI on anatomy, morphology and tissue characterisation ►Can use MRI data to motion correct PET data ►Potential to reduce ionising radiation dose
Pitfalls	►Lower temporal resolution when compared with standard two-dimensional phase-contrast imaging ►Cumbersome quality checks and corrections are necessary for postprocessing	►Susceptibility to artefacts from bulk motion during the cardiac cycle as well as myocardial strain during diffusion encoding, which significantly impacts on signal-to-noise ratio ►Newer sequences require more powerful gradient hardware	►Expensive and requires access to cyclotron or generator for PET tracers ►Ionising radiation to patients ►Challenges with attenuation correction
Validation studies	►Garg P, Westenberg JJM, van den Boogaard PJ, Swoboda PP, Aziz R, Foley JRJ, Fent GJ, Tyl FGJ, Coratella L, ElBaz MSM, van der Geest RJ, Higgins DM, Greenwood JP, Plein S. Comparison of fast acquisition strategies in whole-heart four-dimensional flow cardiac MR: two-center, 1.5 Tesla, phantom and in vivo validation study. J Magn Reson Imaging. 2018 Jan;47(1):272-281. ►Zhang JM, Tan RS, Zhang S, Geest RV, Garg P, Leong BR, Bryant J, Tangcharoen T, Zhao X, Tan JL, Westenberg JJ, Zhong L. Comparison of image acquisition techniques in four-dimensional flow cardiovascular mr on 3 tesla in volunteers and tetralogy of fallot Patients. Conf Proc IEEE Eng Med Biol Soc. 2018 Jul;2018:1115-1118. ►Archer GT, Elhawaz A, Barker N, Fidock B, Rothman A, van der Geest RJ, Hose R, Briffa N, Hall IR, Grech E, Bissell M, Al-Mohammad A, Treibel TA, Swift AJ, Wild JM, Garg P. Validation of four-dimensional flow cardiovascular magnetic resonance for aortic stenosis assessment. Sci Rep. 2020 Jun 29;10(1):10 569. ►Kamphuis VP, Roest AAW, Ajmone Marsan N, et al. Automated cardiac valve tracking for flow quantification with four-dimensional flow MRI. Radiology. 2019 Jan;290(1):70-78.	►Abdullah OM, Drakos SG, Diakos NA, Wever-Pinzon O, Kfoury AG, Stehlik J, Selzman CH, Reid BB, Brunisholz K, Ratan Verma D, Myrick C, Sachse FB, Li DY, Hsu EW. Characterisation Of diffuse fibrosis in the failing human Heart Via Diffusion tensor imaging And quantitative histological validation nih public access. NMR Biomed. 2014;3100(1):1378-86. ►Kung GL, Nguyen TC, Itoh A, Skare S, Ingels NB, Miller DC, etal. The presence of two local myocardial sheet populations confirmed by diffusion tensor MRI and histological validation. J Magn Reson Imaging. 2011 ►Teh I, Mcclymont D, Zdora M-C, Whittington HJ, Davidoiu V, Lee J, Lygate CA, Rau C, Zanette I, Schneider JE. Validation of diffusion tensor MRI measurements of cardiac microstructure with structure tensor synchrotron radiation imaging.	►Nensa F, Tezgah E, Poeppel TD, Jensen CJ, Schelhorn J, Kohler J, Heusch P, Bruder O, Schlosser T, Nassenstein K: Integrated 18F-FDG PET/MR imaging in the assessment of cardiac masses: a pilot study. J Nucl Med 2015, 56(2):255-260. ►Dweck MR, Abgral R, Trivieri MG, Robson PM, Karakatsanis N, Mani V, Palmisano A, Miller MA, Lala A, Chang HL et al: Hybrid MRI and positron emission tomography with fluorodeoxyglucose to diagnose active cardiac sarcoidosis. JACC Cardiovasc Imaging 2018, 11(1):94-107.

4D, four-dimensional; DII, diffusion tensor imaging; PEI-MR, positron emission tomography-magnetic resonance.