## 5 Clinical Applications
### Flow Imaging  
Phase-contrast MRI is a well-established technique to visualize and quantify blood flow, and increasingly used in the diagnosis and management of cardiovascular diseases [46]. Using a bipolar gradient, degrees of phase shift are encoded which directly correlate with the velocity of the moving protons in the bloodstream [47]. While 2D phase-contrast MRI can map blood flow in a single 2D slice, 3D phase-contrast MRI, also known as 4D flow (x-y-z-cardiac), can quantitatively evaluate haemodynamics across an entire 3D volume [48; 49]. This allows simultaneous assessment of flow in the cardiac chambers and multiple surrounding vessels [50]. Although 2D phase-contrast MRI is well-established and routinely used, 4D flow is still limited by long and variable imaging times because of the navigator technology used for respiratory motion artefact suppression. This not only leads to reduced imaging efficiency but also discards data acquired outside of end-expiration, thereby prohibiting the measurement of respiration-resolved flow dynamics. Especially in CHD patients, the respiratory effects on cardiopulmonary circulation may be of great clinical interest [51].  
In 2020, [PERSON] et al. expanded the existing FRF with bipolar gradients to enable cardiac and respiratory motion-resolved 3D flow imaging, referred to as 5D flow MRI (x-y-z-cardiac-respiratory, Figure 8) [52]. They validated its feasibility and performance in both in vitro and in vivo measurements. Although the in vitro results showed excellent agreement with conventional 4D flow-derived values, the in vivo results showed moderate agreement with conventional aortic 4D flow measurements. In 20 adult participants, 5D flow assessment demonstrated an overestimation in net flow and peak velocity up to 26% and 12%, respectively, in the ascending aorta, and an underestimation of <12% in the arch and descending aorta.  
Figure 7: Cardiac cine imaging in transversal, coronal, and sagittal views, and in left two-chamber, four-chamber, and short-axis views (using multiplanar reconstructions), acquired using the 5D free-running framework in a healthy adult subject using a 1-min and 6-min acquisition without contrast at 1.5 T. Although the significantly increased noise, lower image quality, and lower observer confidence for the 1-min acquisition are apparent, cardiac volumes and function were still comparable to reference standard 2D breath-hold cine imaging (not shown in this figure).  
Later, in 2021, [PERSON] et al. used this 5D flow FRF to explore the influence of arrhythmia on thrombogenic hemodynamic parameters in patients with atrial fibrillation (AF) [53]. Instead of using the fifth dimension for respiration, it was adapted to capture different RR interval durations in AF patients with arrhythmatic heart rates to obtain RR-resolved 5D flow data (x-y-z-cardiac-RR interval duration). The RR interval durations were, similarly to respiration, divided into four bins, while no respiratory motion correction was used. The in vitro results demonstrated successful recovery of RR-binned flow curves compared to a real-time 2D phase-contrast MRI reference standard. In vivo results showed that AF burden was significantly correlated with 5D flow-derived peak and mean velocity and stasis measurements. This work demonstrated the feasibility of using an adapted RR-resolved 5D flow FRF to capture 3D haemodynamics in patients with AF in under 10 min, thereby offering a novel imaging approach for investigating arrhythmias.