Curr Cardiol Rep (2014) 16:481 DOI 10.1007/s11886-014-0481-8
CARDIAC PET, CT, AND MRI (SE PETERSEN, SECTION EDITOR)
4D Flow Imaging: Current Status to Future Clinical Applications Michael Markl & Susanne Schnell & Alex J. Barker
Published online: 5 April 2014 # Springer Science+Business Media New York 2014
Abstract 4D flow MRI permits a comprehensive in-vivo assessment of three-directional blood flow within 3dimensional vascular structures throughout the cardiac cycle. Given the large coverage permitted from a 4D flow acquisition, the distribution of vessel wall and flow parameters along an entire vessel of interest can thus be derived from a single measurement without being dependent on multiple predefined 2D acquisitions. In addition to qualitative 3D visualizations of complex cardiac and vascular flow patterns, quantitative flow analysis can be performed and is complemented by the ability to compute sophisticated hemodynamic parameters, such as wall shear stress or 3D pressure difference maps. These metrics can provide information previously unavailable with conventional modalities regarding the impact of cardiovascular disease or therapy on global and regional changes in hemodynamics. This review provides an introduction to the methodological aspects of 4D flow MRI to assess vascular hemodynamics and describes its potential for the assessment and understanding of altered hemodynamics in the presence of cardiovascular disease.
This article is part of the Topical Collection on Cardiac PET, CT, and MRI Electronic supplementary material The online version of this article (doi:10.1007/s11886-014-0481-8) contains supplementary material, which is available to authorized users. M. Markl (*) : S. Schnell : A. J. Barker Department of Radiology, Feinberg School of Medicine, Northwestern University, 737 N. Michigan Avenue Suite 1600, Chicago, IL 60611, USA e-mail: [email protected] M. Markl Department Biomedical Engineering, McCormick School of Engineering, Northwestern University, Chicago, IL, USA
Keywords 4D flow MRI . PC-MRI . Blood flow . Hemodynamics . 3D flow visualization . Flow quantification . Aorta . Heart . Pulmonary arteries
Introduction Phase contrast (PC) MRI exploits the intrinsic sensitivity of magnetic resonance imaging (MRI) signal to fluid flow or tissue motion [1–3]. Bipolar flow encoding gradients are applied to generate a velocity sensitive MR signal phase, which can be used to directly quantify blood flow velocities. In combination with ECG gated time-resolved (CINE) MR imaging, 2D CINE PC-MRI has become a routine diagnostic tool for the acquisition and quantification of pulsatile blood flow in the heart and large vessels. In the clinical routine, 2D CINE PC-MRI is typically accomplished using methods that resolve two spatial dimensions in individual slices and encode the component of time-resolved velocity directed perpendicularly to the 2D plane (i.e., through-plane flow). Typical clinical applications include the calculation of standardized flow parameters such as peak velocity, net flow, stroke volume, regurgitant fraction, Qp/Qs ratio, and shunt flows in congenital and acquired heart disease, and others [4–6]. A number of more advanced and promising flow MR imaging techniques have been reported, which allow a more comprehensive emulation of blood flow characteristics, e.g., & & &
Real time phase contrast MRI for the evaluation of flow changes on short time scales [7–9]. Fourier or Bayesian multi-point velocity encoding to encode flow velocities as a separate dimension and assess sub-voxel velocity distributions [10–13]. 4D flow MRI for the comprehensive analysis of complex time-resolved 3D blood flow characteristics [14–19].
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& &
Direct encoding of the acceleration component of blood flow [10, 20]. Direct/derived quantification of fluid mechanical energy loss [21–23].
In this review, the focus is set on the comprehensive evaluation of cardiovascular hemodynamics using 4D flow MRI (also termed ‘flow sensitive 4D MRI’, “time-resolved 3D velocity mapping”, or “4D velocity mapping”), which provides a non-invasive method for the qualitative and quantitative characterization of blood flow with full volumetric coverage of the heart and great vessels [19, 24, 25••, 26]. Since 4D flow MRI permits the assessment of three-directional blood flow within entire 3D vascular structures in-vivo we will discuss newly developed analysis techniques with a focus on the ability to visualize and quantify the distribution of vessel wall and flow parameters along an entire vessel of interest. It should be noted that singular measurements, dependent on multiple predefined 2D acquisitions, were previously incapable of achieving such measurements. Within this framework, we review the underlying techniques for 4D flow MRI data acquisition, basic flow analysis, the current role of 4D flow MRI for the evaluation of advanced cardiovascular hemodynamics, and its future potential for the assessment and understanding of altered hemodynamics in the presence of cardiovascular disease. The primary focus will be on 4D flow based characterization of 3D blood flow in the thoracic aorta.
Data Acquisition and Analysis 4D flow MRI (3D spatial encoding and temporally resolved data acquisition along the cardiac cycle) offers the ability to measure and visualize the temporal evolution of complex flow patterns with full volumetric coverage of the cardiovascular region of interest. The technique is based on prospectively or retrospectively ECG gated 3D PC MRI using 3-directional velocity encoding [26, 27]. For application on the thorax and abdomen such as the heart, aorta, main pulmonary arteries or the liver vasculature, respiratory control by bellows, selfgating techniques, or navigator gating of the diaphragm motions is used to minimize breathing artifacts. For the application of 4D flow MRI to the clinical setting, total scan times are optimized to meet a window of 5–15 minutes. Within these scan time constraints, the efficient implementation of imaging protocols often employs the use of time-efficient velocity encoding gradients, parallel imaging, and adaptive respiration control with increased efficiency. Typical imaging parameters for thoracic 4D flow MRI applications are summarized below: &
Thoracic aorta: spatial resolution=(2.0–2.5) mm3, temporal resolution=35–50 ms, velocity sensitivity (venc)= 150–300 cm/s, total scan time: 5–12 min.
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&
Heart: spatial resolution=(2.5–3.0) mm3, temporal resolution = 35–45 ms, velocity sensitivity (venc) = 100– 120 cm/s, total scan time: 10–15 min.
Recent developments and improvements include highly under sampled radial 4D flow techniques (PC-VIPR) [28–32], and highly accelerated 4D flow methods (kt-GRAPPA [33–36], kt-PCA [37–39], and compressed sensing [40–42]). For the 3D visualization of cardiovascular hemodynamics and flow patterns, the most commonly used techniques are 3D streamlines and time-resolved 3D pathlines [15, 43, 44]. 3D streamlines are instantaneous traces which run parallel to the direction of the measured blood flow velocity field, and are independently computed for each time frame in the cardiac cycle to represent the instantaneous velocity field isocontours. Figure 1 illustrates the use of 3D streamlines to depict systolic 3D flow patterns in the thoracic aorta of a patient with bicuspid aortic valve and aortic coarctation (for details see figure legend). Time-resolved 3D pathlines utilize the full 4D (3D and time) information and represent the path a massless particle would trace over time, and are highly dependent on the predefined seed, or ‘release’ point. Pathlines can be used to visualize the spatio-temporal dynamics of pulsatile 3D blood flow patterns and can be thought of as the path a massless red blood cell would trace in the vasculature under investigation. The supplemental Video file demonstrates the use of pathlines for the 3D visualization in the aorta and main pulmonary arteries in a patient with aortic sinus to right heart fistula flow (for details see also Fig. 2). Both streamlines and pathlines are often color coded to display the local absolute blood flow velocity (Fig. 1). The anatomic and velocity information of the 4D flow data can additionally be used to derive a 3D phase contrast angiogram (3D PCMRA), which can be combined with 3D blood flow visualization to guide anatomic orientation and analysis plane placement for flow quantification (Figs. 1 and 2).
4D flow MRI versus Standard 2D CINE PC-MRI 4D flow MRI can be employed to detect and visualize changes in global and local blood flow characteristics in targeted vascular regions. The nature of the 4D flow data (three spatial dimensions, three blood flow velocity directions, and time) points toward its ability to provide comprehensive evaluation of derived parameters with complete volumetric coverage. A summary and comparison of advantages and disadvantages of 4D flow MRI compared to standard 2D CINE PC MRI is provided in Table 1. 3D blood flow visualization (streamlines/pathlines) permit the depiction of complex flow patterns and changes in cardiovascular hemodynamic associated with cardiovascular disease. A benefit compared to traditional 2D PC-MR imaging
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Fig. 1 Acquisition of 4D velocity mapping data (a) and visualization and quantification of 3D hemodynamics (b) in the aorta. a: The 4D flow MRI raw data comprises information along all three spatial dimension, three velocity directions and time in the cardiac cycle. b: 3D streamline visualization of thoracic aortic systolic blood flow as assessed by 4D flow MRI. The patient is an asymptomatic 33-year-old man with a bicuspid aortic valve (BAV) with fusion of the right- and left-coronary leaflets and aortic coarctation at the proximal descending aorta who underwent cardiovascular MRI including 4D flow MRI as part of regular clinical follow-up. 3D flow visualization and peak velocity quantification demonstrate a posteriorly directed, high velocity flow jet in the ascending
aorta (AAo) with associated right-handed helix formation. Complex aortic geometry near the coarctation results in vortex formation proximal to the coarctation, a right-handed helix distal to the coarctation, and flow acceleration through the aortic narrowing. The case illustrates the potential of 4D flow MRI to capture the impact of localized pathologies (BAV, coarctation) on complex changes in aortic hemodynamics affecting the entire thoracic aorta. In addition, the complete volumetric coverage provides the user with the ability to identify the optimal location for retrospective quantification of clinically relevant parameters such as peak jet flow velocities distal to the BAV and within the coarctation (see also supplemental Video file for a dynamic display of 3D blood flow)
is related to the possibility for retrospective and flexible quantification and visualization of cardiovascular blood flow without being limited to 2D planes as in standard 2D PC MRI. In Fig. 1, an example for aortic 4D flow MRI is shown in a patient with bicuspid aortic valve and aortic coarctation
[45–49]. 4D flow MRI offers a single and easy method to prescribe the data acquisition (3D volume covering entire cardiovascular region of interest), instead of multiple 2D planes for flow analysis with standard 2D PC MRI. 2D planes are time consuming and difficult to position in cases with
Fig. 2 4D flow MRI in a patient with severe aortic sinus to right heart fistula flow (Qp/Qs=5.3). Flow originating at the fistula directly connects the ascending aorta (AAo) with the right ventricle and pulmonary outflow tract. The gray-shaded iso-surface represents a 3D PC MR angiogram that was derived from the 4D flow data. Retrospective flow quantification in manually positioned 2D analysis planes in the AAo and main pulmonary artery (PA) was used for the calculation of flow-time curves in both vessels and the evaluation of Qp/Qs. The flow channel redirecting the blood flow from the AAo through the right ventricle to the pulmonary trunk can be viewed dynamically in the supplemental Video. PA: pulmonary artery
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Table 1 Comparison of typical features of 4D flow MRI and standard 2D CINE PC-MRI
MR sequences, protocols & availability velocity encoding respiration control total scan time data analysis
flow visualization flow quantification other metrics of hemodynamics
4D flow MRI
Standard 2D CINE PC MRI
research sequences and ‘works in progress’ packages by vendors three-directional, full 3D velocity vector field free breathing: navigator gating, bellows, self-gating techniques 5–20 minutes (dependent on heart rate, efficiency of respiration control, type of parallel imaging) not standardized, time consuming, large variety of options (3D flow visualization, other metrics of hemodynamics) in addition to standard flow parameters
all vendors, ECG gated 2D CINE PC
3D (pathlines, streamlines) potential to identify complex flow patterns, viewed dynamically in 3D retrospective analysis at any location in 3D acquisition volume, volumetric analysis possible wall shear stress, 3D pressure difference maps, turbulent kinetic energy, energy loss, pulse wave velocity
single-direction (through-plane or in-plane) breath hold, real time imaging 8–15 seconds per 2D plane, acquisition during multiple breath-holds similar software packages for flow quantification of standard parameters (peak velocity, stroke volume, net flow, retrograde f raction, Qp/Qs, etc.) 2D, gray scale, local velocity profiles and location of stenotic flow jets pre-defined location, single-direction through plane velocity encoding pulse wave velocity, wall shear stress (limited by single-direction encoding)
Note that scan protocols are may differ between sites and vendors, e.g., protocols may include 2D CINE PC with three-directional velocity encoding in combination with long breath-holds or during free breathing with respiration control
complex vascular architecture (e.g., congenital heart disease, liver vasculature), often requiring multiple acquisitions. As a result, 4D flow MRI may help to avoid missing regions of interest for flow quantification where 2D PC MRI may not have been acquired or planes were misplaced. In this context, a recent study has confirmed that volumetric analysis based on 4D flow MRI allows for improved assessment of aortic and pulmonary peak velocities, which may be underestimated by Doppler echocardiography or 2D PC MRI being limited by 2D analysis planes and single-directional velocity encoding [50]. Moreover, a number of studies have demonstrated low observer variability, test-retest reliability and good correlation between flow parameters obtained by 4D flow MRI and 2D CINE PC MRI [47–49]. In addition, the technique can be used to derive new physiologic and pathophysiologic homonymic parameters such as wall shear stress vectors [45, 51–53, 54•, 55–57], pulse wave velocity [28, 58], 3D pressure difference maps [59–62, 63•, 64], energy loss [12, 21–23, 65], and others. These new hemodynamic measures cannot be non-invasively assessed in-vivo with 2D PC MRI or Doppler echocardiography and can provide quantitative information on the impact of altered hemodynamics associated with vascular pathologies.
Clinical Applications A growing number of patient studies have demonstrated the potential of 4D flow MRI for improved characterization of cardiovascular disease. Previously reported results include the
application of 4D flow MRI for the analysis of 3D blood flow in the heart [16, 46, 66–70], atria [71, 72] and heart valves [17, 54•, 65, 73], the thoracic [54•, 55–57, 74–79] and abdominal aorta [80], the main pulmonary vessels [30, 81–83], carotid arteries [40, 84–86], large intracranial arteries and veins [87–91], the arterial and portal venous systems of the liver [29–31, 92, 93], peripheral arteries [94], and renal arteries [61, 63•, 95]. A description of the findings from these studies is beyond the scope of this review article. The reader is referred to a number of other recently published review articles describing in detail the application of 4D flow in different cardiac and vascular regions throughout the body [19, 24, 25••, 26, 43]. Here, we will briefly describe the main findings focusing on the application in the thoracic aorta. A number of 4D flow studies have shown that small and unsuspicious morphologic alterations (e.g., mild aneurysms or moderate valve disease) can result in substantial alterations of local blood flow patterns [24, 75, 78]. These findings indicate the potentially important role of 4D flow MRI for the comprehensive analysis of the impact of a focal disease (valve abnormality, stenosis) on 3D blood flow in the entire vascular system. In addition, previous studies have provided evidence of the potential diagnostic value of new physiologic/pathophysiologic parameters (wall shear stress, turbulent kinetic energy, energy loss) for the quantification of the influence of common aortic diseases (aortic valve disease, aneurysms, coarctation, dissection) on changes in aortic hemodynamics and wall parameters [21, 53, 96]. For example, aortic aneurysms, which frequently involve the aortic root and ascending aorta, can be life threatening and
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can lead to dissection or rupture [97]. Established risk factors for an accelerated aneurysm growth rate include simple geometric markers such as initial size or localization. Also, the presence of aortic valve disease (stenosis), congenital abnormalities (bicuspid aortic valve), or connective tissue disorders can influence aneurysmal growth. However, predicting aneurysm progression is still challenging and a matter for research [98]. In this context, the assessment of aortic hemodynamics and the presence of altered flow patterns, as well as distribution and changes in wall shear stress and its association with changes in aorta size and type of aortopathy may provide further insights in how aneurysms develop and in assessing the risk of dissection. Recent studies based on 4D flow MRI provide evidence that the modified hemodynamic environments associated with aortic valve abnormalities can cause altered wall shear stress in the ascending aorta, which may trigger maladaptive vascular remodeling [54•, 55, 56]. Other investigators have demonstrated that even the type of valvular dysfunction and aortopathy differs significantly between the different phenotypes of aortic valve disease [99, 100]. Thus, the investigation of the relationship between aortic valve disease, changes in aortic hemodynamics, and phenotype of aortopathy may shed new light on the search for a mechanistic link between aortic valve abnormalities and differences in the development of aortic pathology.
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3D visualization and regional flow quantification. Future efforts thus need to focus on the development of standardized algorithms and software tools that can better integrate with clinical workflows and enable multi-center studies.
Conclusion 4D flow MRI is a promising technique for detailed qualitative and quantitative assessment of cardiovascular hemodynamics. The method allows for the evaluation of a large body of hemodynamic parameters (flow, WSS, pressure difference maps, turbulent kinetic energy, energy loss, etc.) that can be derived from the 4D flow data. Initial reports on the clinical application of these parameters are promising. It is still unclear, however, which parameters are most suitable for the evaluation of different types of cardiovascular pathologies. Longitudinal studies are thus warranted to investigate the predictive value of novel 4D flow hemodynamic parameters and their utility to complement existing clinical risk stratification and therapy management strategies. Acknowledgments Grant support has been received from NIH NHLBI grant R01HL115828 and AHA 13SDG14360004. Compliance with Ethics Guidelines
Limitations and Future Directions Current limitations of 4D flow MRI data acquisition techniques include a trade-off between spatial resolution, temporal resolution, and total scan time. Recently introduced advanced imaging acceleration techniques such as k-t under sampling, compressed sensing, or radial under sampling are promising and have helped to considerably reduce total scans times in order to allow for more flexibility regarding the selection of spatial and temporal resolution. However, in case of large anatomical coverage, such as whole heart 4D flow MRI or high spatio-temporal resolution acquisitions, scan time can still be on the order of 10–15 minutes. Thus, further technical improvements to reduce acquisition are needed. Other drawbacks are related to sensitivity of 4D flow to irregular heart rate or breathing patterns, which can result in imaging blurring or ghosting artifacts. An additional consideration for 4D flow MRI is the requirement of extensive post-acquisition data analysis, which enables the 3D visualization of complex flow patterns and quantification of hemodynamic indices. This analysis can be cumbersome and often time-consuming. Currently, 4D flow data analysis is based on a variety of commercial and home built analysis tools with limited compatibility across sites and vendors. As a result, there are no unified and standardized strategies to account for phase offset errors (eddy currents),
Conflict of Interest Michael Markl, Susanne Schnell, and Alex J. Barker declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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CARDIAC PET, CT, AND MRI (SE PETERSEN, SECTION EDITOR)
4D Flow Imaging: Current Status to Future Clinical Applications Michael Markl & Susanne Schnell & Alex J. Barker
Published online: 5 April 2014 # Springer Science+Business Media New York 2014
Abstract 4D flow MRI permits a comprehensive in-vivo assessment of three-directional blood flow within 3dimensional vascular structures throughout the cardiac cycle. Given the large coverage permitted from a 4D flow acquisition, the distribution of vessel wall and flow parameters along an entire vessel of interest can thus be derived from a single measurement without being dependent on multiple predefined 2D acquisitions. In addition to qualitative 3D visualizations of complex cardiac and vascular flow patterns, quantitative flow analysis can be performed and is complemented by the ability to compute sophisticated hemodynamic parameters, such as wall shear stress or 3D pressure difference maps. These metrics can provide information previously unavailable with conventional modalities regarding the impact of cardiovascular disease or therapy on global and regional changes in hemodynamics. This review provides an introduction to the methodological aspects of 4D flow MRI to assess vascular hemodynamics and describes its potential for the assessment and understanding of altered hemodynamics in the presence of cardiovascular disease.
This article is part of the Topical Collection on Cardiac PET, CT, and MRI Electronic supplementary material The online version of this article (doi:10.1007/s11886-014-0481-8) contains supplementary material, which is available to authorized users. M. Markl (*) : S. Schnell : A. J. Barker Department of Radiology, Feinberg School of Medicine, Northwestern University, 737 N. Michigan Avenue Suite 1600, Chicago, IL 60611, USA e-mail: [email protected] M. Markl Department Biomedical Engineering, McCormick School of Engineering, Northwestern University, Chicago, IL, USA
Keywords 4D flow MRI . PC-MRI . Blood flow . Hemodynamics . 3D flow visualization . Flow quantification . Aorta . Heart . Pulmonary arteries
Introduction Phase contrast (PC) MRI exploits the intrinsic sensitivity of magnetic resonance imaging (MRI) signal to fluid flow or tissue motion [1–3]. Bipolar flow encoding gradients are applied to generate a velocity sensitive MR signal phase, which can be used to directly quantify blood flow velocities. In combination with ECG gated time-resolved (CINE) MR imaging, 2D CINE PC-MRI has become a routine diagnostic tool for the acquisition and quantification of pulsatile blood flow in the heart and large vessels. In the clinical routine, 2D CINE PC-MRI is typically accomplished using methods that resolve two spatial dimensions in individual slices and encode the component of time-resolved velocity directed perpendicularly to the 2D plane (i.e., through-plane flow). Typical clinical applications include the calculation of standardized flow parameters such as peak velocity, net flow, stroke volume, regurgitant fraction, Qp/Qs ratio, and shunt flows in congenital and acquired heart disease, and others [4–6]. A number of more advanced and promising flow MR imaging techniques have been reported, which allow a more comprehensive emulation of blood flow characteristics, e.g., & & &
Real time phase contrast MRI for the evaluation of flow changes on short time scales [7–9]. Fourier or Bayesian multi-point velocity encoding to encode flow velocities as a separate dimension and assess sub-voxel velocity distributions [10–13]. 4D flow MRI for the comprehensive analysis of complex time-resolved 3D blood flow characteristics [14–19].
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& &
Direct encoding of the acceleration component of blood flow [10, 20]. Direct/derived quantification of fluid mechanical energy loss [21–23].
In this review, the focus is set on the comprehensive evaluation of cardiovascular hemodynamics using 4D flow MRI (also termed ‘flow sensitive 4D MRI’, “time-resolved 3D velocity mapping”, or “4D velocity mapping”), which provides a non-invasive method for the qualitative and quantitative characterization of blood flow with full volumetric coverage of the heart and great vessels [19, 24, 25••, 26]. Since 4D flow MRI permits the assessment of three-directional blood flow within entire 3D vascular structures in-vivo we will discuss newly developed analysis techniques with a focus on the ability to visualize and quantify the distribution of vessel wall and flow parameters along an entire vessel of interest. It should be noted that singular measurements, dependent on multiple predefined 2D acquisitions, were previously incapable of achieving such measurements. Within this framework, we review the underlying techniques for 4D flow MRI data acquisition, basic flow analysis, the current role of 4D flow MRI for the evaluation of advanced cardiovascular hemodynamics, and its future potential for the assessment and understanding of altered hemodynamics in the presence of cardiovascular disease. The primary focus will be on 4D flow based characterization of 3D blood flow in the thoracic aorta.
Data Acquisition and Analysis 4D flow MRI (3D spatial encoding and temporally resolved data acquisition along the cardiac cycle) offers the ability to measure and visualize the temporal evolution of complex flow patterns with full volumetric coverage of the cardiovascular region of interest. The technique is based on prospectively or retrospectively ECG gated 3D PC MRI using 3-directional velocity encoding [26, 27]. For application on the thorax and abdomen such as the heart, aorta, main pulmonary arteries or the liver vasculature, respiratory control by bellows, selfgating techniques, or navigator gating of the diaphragm motions is used to minimize breathing artifacts. For the application of 4D flow MRI to the clinical setting, total scan times are optimized to meet a window of 5–15 minutes. Within these scan time constraints, the efficient implementation of imaging protocols often employs the use of time-efficient velocity encoding gradients, parallel imaging, and adaptive respiration control with increased efficiency. Typical imaging parameters for thoracic 4D flow MRI applications are summarized below: &
Thoracic aorta: spatial resolution=(2.0–2.5) mm3, temporal resolution=35–50 ms, velocity sensitivity (venc)= 150–300 cm/s, total scan time: 5–12 min.
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&
Heart: spatial resolution=(2.5–3.0) mm3, temporal resolution = 35–45 ms, velocity sensitivity (venc) = 100– 120 cm/s, total scan time: 10–15 min.
Recent developments and improvements include highly under sampled radial 4D flow techniques (PC-VIPR) [28–32], and highly accelerated 4D flow methods (kt-GRAPPA [33–36], kt-PCA [37–39], and compressed sensing [40–42]). For the 3D visualization of cardiovascular hemodynamics and flow patterns, the most commonly used techniques are 3D streamlines and time-resolved 3D pathlines [15, 43, 44]. 3D streamlines are instantaneous traces which run parallel to the direction of the measured blood flow velocity field, and are independently computed for each time frame in the cardiac cycle to represent the instantaneous velocity field isocontours. Figure 1 illustrates the use of 3D streamlines to depict systolic 3D flow patterns in the thoracic aorta of a patient with bicuspid aortic valve and aortic coarctation (for details see figure legend). Time-resolved 3D pathlines utilize the full 4D (3D and time) information and represent the path a massless particle would trace over time, and are highly dependent on the predefined seed, or ‘release’ point. Pathlines can be used to visualize the spatio-temporal dynamics of pulsatile 3D blood flow patterns and can be thought of as the path a massless red blood cell would trace in the vasculature under investigation. The supplemental Video file demonstrates the use of pathlines for the 3D visualization in the aorta and main pulmonary arteries in a patient with aortic sinus to right heart fistula flow (for details see also Fig. 2). Both streamlines and pathlines are often color coded to display the local absolute blood flow velocity (Fig. 1). The anatomic and velocity information of the 4D flow data can additionally be used to derive a 3D phase contrast angiogram (3D PCMRA), which can be combined with 3D blood flow visualization to guide anatomic orientation and analysis plane placement for flow quantification (Figs. 1 and 2).
4D flow MRI versus Standard 2D CINE PC-MRI 4D flow MRI can be employed to detect and visualize changes in global and local blood flow characteristics in targeted vascular regions. The nature of the 4D flow data (three spatial dimensions, three blood flow velocity directions, and time) points toward its ability to provide comprehensive evaluation of derived parameters with complete volumetric coverage. A summary and comparison of advantages and disadvantages of 4D flow MRI compared to standard 2D CINE PC MRI is provided in Table 1. 3D blood flow visualization (streamlines/pathlines) permit the depiction of complex flow patterns and changes in cardiovascular hemodynamic associated with cardiovascular disease. A benefit compared to traditional 2D PC-MR imaging
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Fig. 1 Acquisition of 4D velocity mapping data (a) and visualization and quantification of 3D hemodynamics (b) in the aorta. a: The 4D flow MRI raw data comprises information along all three spatial dimension, three velocity directions and time in the cardiac cycle. b: 3D streamline visualization of thoracic aortic systolic blood flow as assessed by 4D flow MRI. The patient is an asymptomatic 33-year-old man with a bicuspid aortic valve (BAV) with fusion of the right- and left-coronary leaflets and aortic coarctation at the proximal descending aorta who underwent cardiovascular MRI including 4D flow MRI as part of regular clinical follow-up. 3D flow visualization and peak velocity quantification demonstrate a posteriorly directed, high velocity flow jet in the ascending
aorta (AAo) with associated right-handed helix formation. Complex aortic geometry near the coarctation results in vortex formation proximal to the coarctation, a right-handed helix distal to the coarctation, and flow acceleration through the aortic narrowing. The case illustrates the potential of 4D flow MRI to capture the impact of localized pathologies (BAV, coarctation) on complex changes in aortic hemodynamics affecting the entire thoracic aorta. In addition, the complete volumetric coverage provides the user with the ability to identify the optimal location for retrospective quantification of clinically relevant parameters such as peak jet flow velocities distal to the BAV and within the coarctation (see also supplemental Video file for a dynamic display of 3D blood flow)
is related to the possibility for retrospective and flexible quantification and visualization of cardiovascular blood flow without being limited to 2D planes as in standard 2D PC MRI. In Fig. 1, an example for aortic 4D flow MRI is shown in a patient with bicuspid aortic valve and aortic coarctation
[45–49]. 4D flow MRI offers a single and easy method to prescribe the data acquisition (3D volume covering entire cardiovascular region of interest), instead of multiple 2D planes for flow analysis with standard 2D PC MRI. 2D planes are time consuming and difficult to position in cases with
Fig. 2 4D flow MRI in a patient with severe aortic sinus to right heart fistula flow (Qp/Qs=5.3). Flow originating at the fistula directly connects the ascending aorta (AAo) with the right ventricle and pulmonary outflow tract. The gray-shaded iso-surface represents a 3D PC MR angiogram that was derived from the 4D flow data. Retrospective flow quantification in manually positioned 2D analysis planes in the AAo and main pulmonary artery (PA) was used for the calculation of flow-time curves in both vessels and the evaluation of Qp/Qs. The flow channel redirecting the blood flow from the AAo through the right ventricle to the pulmonary trunk can be viewed dynamically in the supplemental Video. PA: pulmonary artery
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Table 1 Comparison of typical features of 4D flow MRI and standard 2D CINE PC-MRI
MR sequences, protocols & availability velocity encoding respiration control total scan time data analysis
flow visualization flow quantification other metrics of hemodynamics
4D flow MRI
Standard 2D CINE PC MRI
research sequences and ‘works in progress’ packages by vendors three-directional, full 3D velocity vector field free breathing: navigator gating, bellows, self-gating techniques 5–20 minutes (dependent on heart rate, efficiency of respiration control, type of parallel imaging) not standardized, time consuming, large variety of options (3D flow visualization, other metrics of hemodynamics) in addition to standard flow parameters
all vendors, ECG gated 2D CINE PC
3D (pathlines, streamlines) potential to identify complex flow patterns, viewed dynamically in 3D retrospective analysis at any location in 3D acquisition volume, volumetric analysis possible wall shear stress, 3D pressure difference maps, turbulent kinetic energy, energy loss, pulse wave velocity
single-direction (through-plane or in-plane) breath hold, real time imaging 8–15 seconds per 2D plane, acquisition during multiple breath-holds similar software packages for flow quantification of standard parameters (peak velocity, stroke volume, net flow, retrograde f raction, Qp/Qs, etc.) 2D, gray scale, local velocity profiles and location of stenotic flow jets pre-defined location, single-direction through plane velocity encoding pulse wave velocity, wall shear stress (limited by single-direction encoding)
Note that scan protocols are may differ between sites and vendors, e.g., protocols may include 2D CINE PC with three-directional velocity encoding in combination with long breath-holds or during free breathing with respiration control
complex vascular architecture (e.g., congenital heart disease, liver vasculature), often requiring multiple acquisitions. As a result, 4D flow MRI may help to avoid missing regions of interest for flow quantification where 2D PC MRI may not have been acquired or planes were misplaced. In this context, a recent study has confirmed that volumetric analysis based on 4D flow MRI allows for improved assessment of aortic and pulmonary peak velocities, which may be underestimated by Doppler echocardiography or 2D PC MRI being limited by 2D analysis planes and single-directional velocity encoding [50]. Moreover, a number of studies have demonstrated low observer variability, test-retest reliability and good correlation between flow parameters obtained by 4D flow MRI and 2D CINE PC MRI [47–49]. In addition, the technique can be used to derive new physiologic and pathophysiologic homonymic parameters such as wall shear stress vectors [45, 51–53, 54•, 55–57], pulse wave velocity [28, 58], 3D pressure difference maps [59–62, 63•, 64], energy loss [12, 21–23, 65], and others. These new hemodynamic measures cannot be non-invasively assessed in-vivo with 2D PC MRI or Doppler echocardiography and can provide quantitative information on the impact of altered hemodynamics associated with vascular pathologies.
Clinical Applications A growing number of patient studies have demonstrated the potential of 4D flow MRI for improved characterization of cardiovascular disease. Previously reported results include the
application of 4D flow MRI for the analysis of 3D blood flow in the heart [16, 46, 66–70], atria [71, 72] and heart valves [17, 54•, 65, 73], the thoracic [54•, 55–57, 74–79] and abdominal aorta [80], the main pulmonary vessels [30, 81–83], carotid arteries [40, 84–86], large intracranial arteries and veins [87–91], the arterial and portal venous systems of the liver [29–31, 92, 93], peripheral arteries [94], and renal arteries [61, 63•, 95]. A description of the findings from these studies is beyond the scope of this review article. The reader is referred to a number of other recently published review articles describing in detail the application of 4D flow in different cardiac and vascular regions throughout the body [19, 24, 25••, 26, 43]. Here, we will briefly describe the main findings focusing on the application in the thoracic aorta. A number of 4D flow studies have shown that small and unsuspicious morphologic alterations (e.g., mild aneurysms or moderate valve disease) can result in substantial alterations of local blood flow patterns [24, 75, 78]. These findings indicate the potentially important role of 4D flow MRI for the comprehensive analysis of the impact of a focal disease (valve abnormality, stenosis) on 3D blood flow in the entire vascular system. In addition, previous studies have provided evidence of the potential diagnostic value of new physiologic/pathophysiologic parameters (wall shear stress, turbulent kinetic energy, energy loss) for the quantification of the influence of common aortic diseases (aortic valve disease, aneurysms, coarctation, dissection) on changes in aortic hemodynamics and wall parameters [21, 53, 96]. For example, aortic aneurysms, which frequently involve the aortic root and ascending aorta, can be life threatening and
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can lead to dissection or rupture [97]. Established risk factors for an accelerated aneurysm growth rate include simple geometric markers such as initial size or localization. Also, the presence of aortic valve disease (stenosis), congenital abnormalities (bicuspid aortic valve), or connective tissue disorders can influence aneurysmal growth. However, predicting aneurysm progression is still challenging and a matter for research [98]. In this context, the assessment of aortic hemodynamics and the presence of altered flow patterns, as well as distribution and changes in wall shear stress and its association with changes in aorta size and type of aortopathy may provide further insights in how aneurysms develop and in assessing the risk of dissection. Recent studies based on 4D flow MRI provide evidence that the modified hemodynamic environments associated with aortic valve abnormalities can cause altered wall shear stress in the ascending aorta, which may trigger maladaptive vascular remodeling [54•, 55, 56]. Other investigators have demonstrated that even the type of valvular dysfunction and aortopathy differs significantly between the different phenotypes of aortic valve disease [99, 100]. Thus, the investigation of the relationship between aortic valve disease, changes in aortic hemodynamics, and phenotype of aortopathy may shed new light on the search for a mechanistic link between aortic valve abnormalities and differences in the development of aortic pathology.
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3D visualization and regional flow quantification. Future efforts thus need to focus on the development of standardized algorithms and software tools that can better integrate with clinical workflows and enable multi-center studies.
Conclusion 4D flow MRI is a promising technique for detailed qualitative and quantitative assessment of cardiovascular hemodynamics. The method allows for the evaluation of a large body of hemodynamic parameters (flow, WSS, pressure difference maps, turbulent kinetic energy, energy loss, etc.) that can be derived from the 4D flow data. Initial reports on the clinical application of these parameters are promising. It is still unclear, however, which parameters are most suitable for the evaluation of different types of cardiovascular pathologies. Longitudinal studies are thus warranted to investigate the predictive value of novel 4D flow hemodynamic parameters and their utility to complement existing clinical risk stratification and therapy management strategies. Acknowledgments Grant support has been received from NIH NHLBI grant R01HL115828 and AHA 13SDG14360004. Compliance with Ethics Guidelines
Limitations and Future Directions Current limitations of 4D flow MRI data acquisition techniques include a trade-off between spatial resolution, temporal resolution, and total scan time. Recently introduced advanced imaging acceleration techniques such as k-t under sampling, compressed sensing, or radial under sampling are promising and have helped to considerably reduce total scans times in order to allow for more flexibility regarding the selection of spatial and temporal resolution. However, in case of large anatomical coverage, such as whole heart 4D flow MRI or high spatio-temporal resolution acquisitions, scan time can still be on the order of 10–15 minutes. Thus, further technical improvements to reduce acquisition are needed. Other drawbacks are related to sensitivity of 4D flow to irregular heart rate or breathing patterns, which can result in imaging blurring or ghosting artifacts. An additional consideration for 4D flow MRI is the requirement of extensive post-acquisition data analysis, which enables the 3D visualization of complex flow patterns and quantification of hemodynamic indices. This analysis can be cumbersome and often time-consuming. Currently, 4D flow data analysis is based on a variety of commercial and home built analysis tools with limited compatibility across sites and vendors. As a result, there are no unified and standardized strategies to account for phase offset errors (eddy currents),
Conflict of Interest Michael Markl, Susanne Schnell, and Alex J. Barker declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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